ࡱ>  bjbj "jj!{ltttttttxxx84D"144JJJJJJ0000000$@2 `40tJJJJJ0-ttJJ0---J.tJtJ0-J0--0e0tt0J( -1hxxT }0000"104,440-,ttttAbstracts for Citations For citations entered from PubMed that contained abstracts. 1. Institute of Medicine, Gulf War Veterans: Treating Symptoms and Syndromes. Committee on Identifying Effective Treatments for Gulf War Veterans' Health Problems. Editors Bernard M. Rosof and Lyla M. Hernandez. 2001, Washington, D.C.: National Academy Press. 152. 2. Moher, D., et al. Does the inclusion of grey literature influence the estimates of intervention effectiveness reported in meta-analyses? [abstract]. in Research Seminar Series, UCLA Division of General Internal Medicine/Health Services Research and the Clinical Scholars Program. June 2000. 2000. Los Angeles. Background: Including only a subset of all available evidence in a meta-analysis may introduce biases and threaten its validity. This is particularly likely if the subset of included studies differ from those not included, as may be the case for published and grey literature. We set out to examine whether exclusion of grey literature, compared to its inclusion in meta-analysis, provides different estimates of the effectiveness of interventions evaluated in randomized trials. Methods: From a random sample of 135 meta-analyses, we identified and retrieved 33 publications that included both grey and published primary studies. The 33 publications contributed 41 separate meta-analyses from several disease areas. General characteristics of the meta-analyses and associated studies and outcome data at the trial level were collected. We explored the effects of the inclusion of grey literature on the quantitative results using logistic regression analyses. Findings: Thirty-three percent of the meta-analyses were found to include some form ofgrey literature. The grey literature, when included, accounts for between 4.5% and 75% of the studies in a meta-analysis. On average, the published literature, compared to the grey literature, yielded significantly larger estimates of the intervention effect by 12% [ROR = 1.12; 95%CI: 1.01, 1.23]. Excluding abstracts (i.e. only including unpublished studies, conference proceedings, graduate theses, book chapters, company reports and applications) from the analysis further compounded the exaggeration [ROR = 1.38, 95%CI: 1.15, 1.64]. The exclusion of grey literature from a meta-analysis may increase the likelihood of a biased result. Interpretations: This study provides evidence that the exclusion of grey literature from meta-analyses can lead to exaggerated estimates of intervention effectiveness. In general, meta-analysts should attempt to identify, retrieve and include all literature, grey and published, that meets pre-defined inclusion criteria. 3. Collins, J.F., et al., The antibiotic treatment trial of Gulf War Veterans' Illnesses: issues, design, screening, and baseline characteristics. Control Clin Trials, 2002. 23(3): p. 333-53. Many veterans who were deployed to the Persian Gulf during the 1990-1991 Gulf War developed multiple unexplained symptoms such as pain, fatigue, and neurocognitive problems. This constellation of symptoms has been termed Gulf War Veterans' Illnesses (GWVI). Although there is no proven explanation for the cause of GWVI, one fairly widespread explanation is systemic Mycoplasma fermentans infection. The Antibiotic Treatment Trial of GWVI is a randomized placebo-controlled trial to determine whether a 1-year course of doxycycline treatment in deployed Gulf War veterans with GWVI and testing as Mycoplasma species positive will improve their overall functional status as measured by the Physical Component Summary of the SF-36V questionnaire. The study of a multisymptom illness such as GWVI is complicated by the nonspecific nature of the illness, the unknown etiology, and the lack of a widely accepted outcome measure. The presumption of mycoplasma infection raises concerns regarding the methodology for determination of mycoplasma infection, the choice of treatment, and the duration of treatment. However, such a presumption allows the formulation of a clear testable hypothesis that can be tested with treatments with known rates of adverse events and known activity against Mycoplasma species. This paper describes the major issues faced by the investigators during planning, the study design, the patient screening results, and the baseline characteristics of the study patients. There were 2712 patients screened for study entry at 26 Department of Veterans Affairs and two Department of Defense medical centers. Of these, 491 met all study entry criteria and were randomized to either 1 year of doxycycline (200 mg/day) or 1 year of placebo. All patients were seen monthly during treatment and at 6 months after the end of treatment. Study patients had a mean age of 41 years and were mostly male (86%), white (64%), married (68%), and employed full-time (71%). 4. Hilborne, L. and B. Golomb, A Review of the Scientific Literature as it Pertains to Gulf War Illnesses, Vol 1: Infectious Diseases, . 1998, RAND: Washington, DC. 5. Hyman, E.S., Urinary sediment examination and Gulf War Syndrome. Am J Med Sci, 1998. 316(6): p. 411-3. 6. Nicolson, G.L. and N.L. Nicolson, Diagnosis and treatment of mycoplasma infections, . 1995. 7. Nicolson, G.L. and N.L. Nicolson, The isolation, purification, and analysis of specific gene-containing nucleoproteins and nucleoprotein complexes. Methods Mol Genetics, 1994. 5: p. 281-298. 8. Rea, W.J., et al., Reduction of chemical sensitivity by means of heat depuration, physical therapy and nutritional supplementation in a controlled environment. J Nutritional Medicine, 1996. 6. 9. Kilburn, K.H., R.H. Warsaw, and M.G. Shields, Neurobehavioral dysfunction in firemen exposed to polycholorinated biphenyls (PCBs): possible improvement after detoxification. Arch Environ Health, 1989. 44(6): p. 345-50. Fourteen firemen exposed to polychlorinated biphenyls (PCBs) and their byproducts generated in a transformer fire and explosion had neurophysiological and neuropsychological tests 6 mo after the fire. They were re-studied 6 wk later after undergoing 2-3 wk of an experimental detoxification program consisting of medically supervised diet, exercise, and sauna. A case-control comparison with firemen matched from the same department, but who did not participate in controlling the transformer fire, had shown significant impairment of memory for stories, visual images, and digits backwards. Cognitive function was impaired for block design, identifying embedded figures, and design association and recognition using Culture Fair. Making of trails and choice reaction time, which measured cognitive function and perceptual motor speed, were also impaired. These signs of protracted neurobehavioral impairment were attributed to PCBs and heat-produced byproducts. No relationship, however, was found between the firemen's serum or fat levels of PCBs as Arochlor 1248 and their type or degree of neurobehavioral impairment. Retesting following the detoxification program showed significantly improved scores on: three memory tests, block design, trails B, and embedded figures. Thus, there was significant reversibility of impairment after the detoxification interval. However self-appraisal scores for depression, anger, and fatigue--which were initially elevated--and for vigor--which was reduced--did not change across this interval. 10. Folkers, K. and J.L. Nilsson, [Coenzyme Q regarded as a vitamin]. Nord Med, 1970. 83(16): p. 489-93. 11. Bargossi, A.M., et al., Exogenous CoQ10 preserves plasma ubiquinone levels in patients treated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Int J Clin Lab Res, 1994. 24(3): p. 171-6. Ubiquinone is a carrier of the mitochondrial respiratory chain which regulates oxidative phosphorylation: it also acts as a membrane stabilizer preventing lipid peroxidation. In man the quinone ring originates from tyrosine, while the formation of the polyisoprenoid lateral chain starts from acetyl CoA and proceeds through mevalonate and isopentenylpyrophosphate; this biosynthetic pathway is the same as the cholesterol one. We therefore performed this study to evaluate whether statins (hypocholesterolemic drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase) modify blood levels of ubiquinone. Thirty unrelated outpatients with primary hypercholesterolemia (IIa phenotype) were treated with 20 mg of simvastatin for a 3-month period (group S) or with 20 mg of simvastatin plus 100 mg CoQ10 (group US). The following parameters were evaluated at time 0, and at 45 and 90 days: total plasma cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, Apo A1, Apo B and CoQ10 in plasma and in platelets. In the S group, there was a marked decrease in total cholesterol low-density lipoprotein-cholesterol and in plasma CoQ10 levels from 1.08 mg/dl to 0.80 mg/dl. In contrast, in the US group we observed a significant increase of plasma CoQ10 (from 1.20 to 1.48 mg/dl) while the hypocholesterolemic effect was similar to that observed in the S group. Platelet CoQ10 also decreased in the S group (from 104 to 90 ng/mg) and increased in the US group (from 95 to 145 ng/mg).(ABSTRACT TRUNCATED AT 250 WORDS). 12. England, J.D., et al., Mitochondrial myopathy developing on treatment with the HMG CoA reductase inhibitors--simvastatin and pravastatin [letter]. Australian and New Zealand Journal of Medicine, 1995. 25(4): p. 374-5. 13. Barbiroli, B., et al., Coenzyme Q10 improves mitochondrial respiration in patients with mitochondrial cytopathies. An in vivo study on brain and skeletal muscle by phosphorous magnetic resonance spectroscopy. Cellular and Molecular Biology, 1997. 43(5): p. 741-9. 14. Chen, R.S., C.C. Huang, and N.S. Chu, Coenzyme Q10 treatment in mitochondrial encephalomyopathies. Short-term double-blind, crossover study. European Neurology, 1997. 37(4): p. 212-8. 15. Folkers, K. and R. Simonsen, Two successful double-blind trials with coenzyme Q10 (vitamin Q10) on muscular dystrophies and neurogenic atrophies. Biochimica et Biophysica Acta, 1995. 1271(1): p. 281-6. 16. Kuz'menko, I.V., et al., [Efficiency of ubiquinone and p-oxybenzoic acid in prevention of E-hypovitaminosis-induced development of muscular dystrophy]. Ukr Biokhim Zh, 1981. 53(5): p. 73-9. It is shown that E-hypovitaminosis-induced muscular dystrophy in rabbits is accompanied by a sharp decrease in the body mass, an increase in the urine creatine-index, a decrease in the vitamin E and ubiquinone contents in the liver and skeletal muscle tissues. In the myocardium mitochondria a decrease in the vitamin E content and an increase in the ubiquinone content are observed. The activity of NADH-cytochrome c-, NADH-ubiquinone- and succinate-ubiquinone-reductase also varies in mitochondria of the studied tissues. In myocardium organellas a direct dependence is found between the content of ubiquinone, NADH- and succinate-ubiquinone-reductase activity and an inverse one-between its content and the activity of the NADH-cytochrome c-reductase system. It is established that p-oxybenzoic acid as well as vitamin E prevents development of muscular dystrophy and causes changes analogous in direction in the activity of the ubiquinone-dependent enzymic systems of mitochondria. Ubiquinone-9 is less efficient in preventing the development of muscular dystrophy. 17. Shimomura, Y., et al., Protective effect of coenzyme Q10 on exercise-induced muscular injury. Biochem Biophys Res Commun, 1991. 176(1): p. 349-55. The effect of coenzyme Q10 administration on exercise-induced muscular injury was examined in rats. Coenzyme Q10-treated and control rats were exercised by 90 min of downhill treadmill running. A part of the animals in both groups were killed immediately after exercise and the others were 40 h postexercise. After the exercise bout, serum creatine kinase and lactate dehydrogenase activities were elevated in the control rats, but not in the coenzyme Q10-treated rats. These enzyme activities in the latter increased to the similar level of the former 40 h postexercise. The muscle coenzyme Q10 content increased by the coenzyme Q10 treatment. These results suggest that the coenzyme Q10 treatment protected skeletal muscles against injury caused during exercise, but not against damage related with inflammatory processes after exercise. 18. Kamikawa, T., et al., Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiol, 1985. 56(4): p. 247-51. The effects of coenzyme Q10(CoQ10) on exercise performance were studied in 12 patients, average age 56 years, with stable angina pectoris. The study involved a double-blind, placebo-controlled, randomized, crossover protocol, using multistage treadmill exercise tests. CoQ10(150 mg/day in 3 daily doses) was administered orally for 4 weeks, tended to reduce anginal frequency from 5.3 +/- 4.9 to 2.5 +/- 3.3 attacks for 2 weeks and nitroglycerin consumption from 2.6 +/- 2.8 to 1.3 +/- 1.7 tablets for 2 weeks compared with patients receiving the placebo, but the reduction was not statistically significant. Exercise time increased from 345 +/- 102 seconds with placebo to 406 +/- 114 seconds during CoQ10 treatment (p less than 0.05). The time until 1 mm of ST-segment depression occurred increased from 196 +/- 76 seconds with placebo to 284 +/- 104 seconds during CoQ10 treatment (p less than 0.01). During the exercise test, ST-segment depression, heart rate and pressure-rate product at the same and at the maximal workload showed no significant difference between patients after placebo and CoQ10 administration. The average CoQ10 plasma concentration increased from 0.95 +/- 0.48 microgram/ml to 2.20 +/- 0.98 microgram/ml after CoQ10 treatment. This increase was significantly related to the increase in exercise duration (r = 0.68, p less than 0.001). Only 1 patient had a loss of appetite, but continued therapy. This study suggests that CoQ10 is a safe and promising treatment for angina pectoris. 19. Alleva, R., et al., Coenzyme Q blocks biochemical but not receptor-mediated apoptosis by increasing mitochondrial antioxidant protection. FEBS Lett, 2001. 503(1): p. 46-50. Generation of free radicals is often associated with the induction and progression of apoptosis. Therefore, antioxidants can prove anti-apoptotic, and can help to elucidate specific apoptotic pathways. Here we studied whether coenzyme Q, present in membranes in reduced (ubiquinol) or oxidised (ubiquinone) forms, can affect apoptosis induced by various stimuli. Exposure of Jurkat cells to alpha-tocopheryl succinate (alpha-TOS), hydrogen peroxide, anti-Fas IgM or TRAIL led to induction of apoptosis. Cell death due to the chemical agents was suppressed in cells enriched with the reduced form of coenzyme Q. However, coenzyme Q did not block cell death induced by the immunological agents. Ubiquinol-10 inhibited reactive oxygen species (ROS) generation in cells exposed to alpha-TOS, and a mitochondrially targeted coenzyme Q analogue also blocked apoptosis triggered by alpha-TOS or hydrogen peroxide. Therefore, it is plausible that ubiquinol-10 protects cells from chemically-induced apoptosis by acting as an antioxidant in mitochondria. Our results also indicate that generation of free radicals may not be a critical step in induction of apoptosis by immunological agents. 20. Di Giovanni, S., et al., Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurology, 2001. 57(3): p. 515-8. Two brothers with myopathic coenzyme Q10 (CoQ10) deficiency responded dramatically to CoQ10 supplementation. Muscle biopsies before therapy showed ragged-red fibers, lipid storage, and complex I + III and II + III deficiency. Approximately 30% of myofibers had multiple features of apoptosis. After 8 months of treatment, excessive lipid storage resolved, CoQ10 level normalized, mitochondrial enzymes increased, and proportion of fibers with TUNEL-positive nuclei decreased to 10%. The authors conclude that muscle CoQ10 deficiency can be corrected by supplementation of CoQ10, which appears to stimulate mitochondrial proliferation and to prevent apoptosis. 21. Fernandez-Ayala, D.J., et al., Coenzyme Q protects cells against serum withdrawal-induced apoptosis by inhibition of ceramide release and caspase-3 activation. Antioxid Redox Signal, 2000. 2(2): p. 263-75. Coenzyme Q10 (CoQ10) is a component of the antioxidant machinery that protects cell membranes from oxidative damage and decreases apoptosis in leukemic cells cultured in serum-depleted media. Serum deprivation induced apoptosis in CEM-C7H2 (CEM) and to a lesser extent in CEM-9F3, a subline overexpressing Bcl-2. Addition of CoQ10 to serum-free media decreased apoptosis in both cell lines. Serum withdrawal induced an early increase of neutral-sphingomyelinase activity, release of ceramide, and activation of caspase-3 in both cell lines, but this effect was more pronounced in CEM cells. CoQ10 prevented activation of this cascade of events. Lipids extracted from serum-depleted cultures activated caspase-3 independently of the presence of mitochondria in cell-free in vitro assays. Activation of caspase-3 by lipid extracts or ceramide was prevented by okadaic acid, indicating the implication of a phosphatase in this process. Our results support the hypothesis that plasma membrane CoQ10 regulate the initiation phase of serum withdrawal-induced apoptosis by preventing oxidative damage and thus avoiding activation of downstream effectors as neutral-sphingomyelinase and subsequent ceramide release and caspase activation pathways. 22. Kagan, T., et al., Coenzyme Q10 can in some circumstances block apoptosis, and this effect is mediated through mitochondria. Ann N Y Acad Sci, 1999. 887: p. 31-47. The mitochondrial component coenzyme Q10 (CoQ10) has been used for many years as a dietary supplement intended to promote good health by trapping free radicals, thus preventing lipid peroxidation and DNA damage. We have tested its use as a generic anti-apoptotic compound and have found that its ability to protect against apoptosis varies depending on both cell type and mode of cell death induction. We have further established that this protection may be mediated by its effect on mitochondrial function and viability. We provide additional evidence that CoQ10's protective effect on mitochondrial membrane potential does not always result in altered mitochondrial enzyme activity and neither does it guarantee survival. These observations open the way for further investigations into the mechanisms involved in mitochondrial control of apoptosis. 23. Mosca, L., et al., Modulation of apoptosis and improved redox metabolism with the use of a new antioxidant formula. Biochem Pharmacol, 2002. 63(7): p. 1305-14. Oxidative stress is involved in the pathogenesis of a wide spectrum of diseases, implicating that strategies directed at counterbalancing oxidative processes could have a role in clinical medicine. There is also an evidence that oxidative stress acts as a major determinant of apoptotic cell death. Many studies have reported favourable effects of antioxidant formulas on several parameters of the oxidant-antioxidant balance, but none of them has focused whether antioxidant formulas could modulate apoptosis. We investigated in 20 healthy individuals the effect of supplementation with a formula containing alpha-tocopherol, alpha-lipoic acid, coenzyme Q(10), carnitines, and selenomethionine, on plasma oxidant status and peroxide levels, erythrocyte antioxidant enzymes, lymphocyte apoptosis, and generation of ROS at the mitochondrial level. Control subjects received only carnitines or an incomplete formula with alpha-tocopherol, alpha-lipoic acid, coenzyme Q(10), and selenomethionine. Supplementation with the complete formula resulted in a significant increase in the plasma antioxidant status that was mirrored by a decrease in blood peroxide levels and a reduced generation of ROS at the mitochondrial level. This was associated with a significant decrease in the frequency of peripheral blood lymphocytes, with either CD4 or CD8 phenotype, undergoing apoptosis. Less consistent results were found when either incomplete formula was used. Our study suggests that supplementation with antioxidant formulas can modulate the process of apoptosis under in vivo conditions. The clinical potential of this strategy in the treatment of diseases with an elevated commitment to apoptosis should be explored. 24. Schults, C.W., et al., Effects of coenzyme Q10 in early Parkinson disease. Evidence of slowing of the functional decline. Archives of Neurology, 2002. 59(10): p. 1541-50. Background:Parkinson disease (PD) is a degenerative neurological disorder for which no treatment has been shown to slow the progression. Objective:To determine whether a range of dosages of coenzyme Q10 is safe and well tolerated and could slow the functional decline in PD. Design:Multicenter, randomized, parallel-group, placebo-controlled, double-blind, dosage-ranging trial. Setting:Academic movement disorders clinics. Patients:Eighty subjects with early PD who did not require treatment for their disability. Interventions:Random assignment to placebo or coenzyme Q10 at dosages of 300, 600, or 1200 mg/d.Main Outcome Measure:The subjects underwent evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12-, and 16-month visits. They were followed up for 16 months or until disability requiring treatment with levodopa had developed. The primary response variable was the change in the total score on the UPDRS from baseline to the last visit. Results:The adjusted mean total UPDRS changes were +11.99 for the placebo group, +8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group, and +6.69 for the 1200-mg/d group. The P value for the primary analysis, a test for a linear trend between the dosage and the mean change in the total UPDRS score, was .09, which met our prespecified criteria for a positive trend for the trial. A prespecified, secondary analysis was the comparison of each treatment group with the placebo group, and the difference between the 1200-mg/d and placebo groups was significant (P = .04). Conclusions:Coenzyme Q10 was safe and well tolerated at dosages of up to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10 than in those assigned to placebo, and the benefit was greatest in subjects receiving the highest dosage. Coenzyme Q10 appears to slow the progressive deterioration of function in PD, but these results need to be confirmed in a larger study. 25. Haley, R.W., et al., Brain abnormalities in Gulf War syndrome: Evaluation with 1H MR spectroscopy. Radiology, 2000. 215: p. 807-817. PURPOSE: To test for neuronal brain damage in the basal ganglia and brainstem in Gulf War veterans by using magnetic resonance (MR) spectroscopy. MATERIALS AND METHODS: Twenty-two Gulf War veterans with one of three factor analysis-derived syndromes (case patients); 18 well veterans matched for age, sex, and education level (control subjects); and six Gulf War veterans with syndrome 2 from a different population (replication sample) underwent long echo time (272 msec) proton (hydrogen 1) MR spectroscopy on a 4 x 2 x 2-cm voxel in the basal ganglia bilaterally and a 2 x 2 x 2-cm voxel in the pons. Syndromes 1-3 are described as "impaired cognition," "confusion-ataxia," and "central pain," respectively. RESULTS: The N-acetylaspartate-to-creatine (NAA/Cr) ratio, which reflects functional neuronal mass, was significantly lower in the basal ganglia and brainstem of Gulf War veterans with the three syndromes than in those structures of the control subjects (P =.007). The finding was corroborated in the replication sample (P =.002). Veterans with syndrome 2 (the most severe clinically) had evidence of decreased NAA/Cr in both the basal ganglia and the brainstem; those with syndrome 1, in the basal ganglia only; and those with syndrome 3, in the brainstem only. CONCLUSION: Veterans with different Gulf War syndromes have biochemical evidence of neuronal damage in different distributions in the basal ganglia and brainstem. 26. Sinzinger, H., P. Schmid, and J. O'Grady, Two different types of exercise-induced muscle pain without myopathy and CK -elevation during HMG-Co-enzyme-A-reductase inhibitor treatment. Atherosclerosis, 1999. 143(11): p. 459-460. 27. Muller, D.P., J.K. Lloyd, and O.H. Wolff, Vitamin E and neurological function: abetalipoproteinaemia and other disorders of fat absorption. Ciba Found Symp, 1983. 101: p. 106-21. Evidence that vitamin E is important for normal neurological function in humans is presented. First, in abetalipoproteinaemia early therapy with vitamin E delays and may prevent the development of the neurological complications, and in patients with established lesions treatment can arrest or reverse the neuropathy. Second, in other chronic disorders of fat absorption with severe vitamin E deficiency, neurological manifestations which are very similar to those described in untreated abetalipoproteinaemia can be improved by vitamin E. Vitamin E supplementation is therefore advisable for all patients with chronic fat malabsorption who have low serum vitamin E concentration. Serum vitamin E concentrations should also be measured in patients with spinocerebellar disorders, whatever the aetiology. 28. Muller, D.P.R., J.K. Lloyd, and A. Bird, Long-term management of abetalipoproteinemia. Possible role for vitamin E. Arch Dis Child, 1977. 52: p. 209-14. 29. Iannaccone, S.T. and R.J. Sokol, Vitamin E deficiency in neuropathy of abetalipoproteinemia. Neurology, 1986. 36(7): p. 1009. 30. Hegele, R.A. and A. Angel, Arrest of neuropathy and myopathy in abetalipoproteinemia with high-dose vitamin E therapy. Can Med Assoc J, 1985. 132(1): p. 41-4. A 16-year-old girl, one of dizygotic twins, presented in 1976 complaining of a 1-year history of a lack of coordination and an inability to run. The results of biochemical tests confirmed the diagnosis of classic abetalipoproteinemia. In addition to the recognized neurologic features of this disorder, she had a reduced evoked motor unit potential and markedly elevated serum levels of muscle enzymes, which suggested myositis. The serum vitamin E level was markedly decreased. Oral therapy with vitamin E, 800 mg daily, was begun, and in 1981 the dosage was increased to 3200 mg daily. Over the 7 years of follow-up she improved clinically, there was an increase in the evoked motor unit potential, the serum levels of some of the muscle enzymes decreased to normal, and the serum and tissue vitamin E levels increased significantly. It was concluded that treatment with high doses of vitamin E was responsible for the arrest of the usually progressive neuropathy and myopathy. 31. Azizi, E., et al., Abetalipoproteinemia treated with parenteral and oral vitamin A and E and with medium chain triglycerides. Acta Pediatr Scand, 1978. 67: p. 797-801. 32. Morris, M.C., et al., Vitamin E and cognitive decline in older persons. Archives of Neurology, 2002. 59(7): p. 1125-1132. 33. Veltkamp, R. and J.F. Toole, Hyperbaric oxygen--a neuroprotective adjuvant for hyperacute ischemic stroke? Journal of the Neurological Sciences, 1997. 150(1): p. 1-2. 34. Clifton, G.L., Hypothermia and hyperbaric oxygen as treatment modalities for severe head injury. New Horizons, 1995. 3(3): p. 474-8. Abstract: Moderate systemic hypothermia has been shown to improve neurologic outcomes in both fluid-percussion and cortical contusion models of experimental brain injury. Based upon initial clinical work, it was concluded that at temperatures < 32 degrees C, patients with severe brain injury were at increased risk of ventricular arrhythmias, and that rapid rewarming immediately postinjury predisposed to intracranial pressure increases. Subsequent clinical studies of moderate hypothermia (32 degrees C) for 24- to 48-hr duration with slow rewarming in human brain injury showed indications of neurologic improvement and a low incidence of hypothermia-related complications. Based upon the strengths of both laboratory and clinical data, a multicenter (nine centers), randomized, prospective trial testing moderate systemic hypothermia in patients with severe brain injury has been organized. This trial, funded by National Institutes of Health, National Institute of Neurological Disorders and Stroke, began on October 20, 1994. Five hundred patients are to be treated in an intent-to-treat protocol using standard management at normothermia versus standard management at hypothermia. The trial is designed to detect an absolute shift of 12% in the percentage of patients achieving satisfactory outcome (good recovery/moderate disability) at a power of 85% at 6 months postinjury. The efficacy of hyperbaric oxygen administered every 8 hrs for 1-hr duration for a 2-wk period has also been tested in patients after severe brain injury. While the mortality rate was reduced in the treated group, the percentage of favorable outcomes was unchanged. Further studies are in progress. 35. Nighoghossian, N. and P. Trouillas, Hyperbaric oxygen in the treatment of acute ischemic stroke: an unsettled issue. Journal of the Neurological Sciences, 1997. 150(1): p. 27-31. Abstract: Therapy for acute ischemic stroke can be approached in two basic ways: first, by an attempt to restore or improve blood flow in an occluded vascular territory and, second, via therapy directed at the cellular and metabolic targets. As local anoxia and energy failure are the initiating cellular stage in ischemia, the inhalation of oxygen at increased atmospheric pressures might be effective. Treatment of acute focal cerebral ischemia with hyperbaric oxygen (HBO) has been reported in animals and humans. In general, the results of research in animals have suggested a promising role for the use of HBO. More than 400 cases of human ischemic stroke treated with HBO have been reported. In about half of the cases, improvement in status has been claimed on clinical or electroencephalographic grounds. In fact, the effectiveness of HBO in most disease processes other than carbon monoxide poisoning and decompression sickness is a subject of major ongoing debate. This short review will attempt: (1) to recall some early experiments involving HBO in the treatment of acute ischemia: (2) to point out some conflicting results regarding the role of HBO on cellular and metabolic disorders; and (3) to determine the possibility of a future role for HBO therapy in acute ischemic stroke. 36. Nighoghossian, N., et al., Hyperbaric oxygen in the treatment of acute ischemic stroke. A double-blind pilot study. Stroke, 1995. 26(8): p. 1369-72. Abstract: BACKGROUND AND PURPOSE: The effects of hyperbaric oxygen (HBO) therapy on humans are uncertain. Our study aims first to outline the practical aspects and the safety of HBO treatment and then to evaluate the effect of HBO on long-term disability. METHODS: Patients who experienced middle cerebral artery occlusion and were seen within 24 hours of onset were randomized to receive either active (HBO) or sham (air) treatment. The HBO patients were exposed daily to 40 minutes at 1.5 atmospheres absolute for a total of 10 dives. We used the Orgogozo scale to establish a pretreatment functional level. Changes in the Orgogozo scale score at 6 months and 1 year after therapy were used to assess the therapeutic efficacy of HBO. In addition, we used the Rankin scale and our own 10-point scale to assess long term-disability at 6 months and 1 year. Two sample t tests and 95% confidence intervals were used to compare the mean differences between the two treatment groups. Student's two-tailed test was used to compare the differences between pretherapeutic and posttherapeutic scores at 6 months and 1 year in the two treatment groups. RESULTS: Over the 3 years of study enrollment, 34 patients were randomized, 17 to hyperbaric treatment with air and 17 to hyperbaric treatment with 100% oxygen. There was no significant difference at inclusion between groups regarding age, time from stroke onset to randomization, and Orgogozo scale scores. Neurological deterioration occurred during the first week in 4 patients in the sham group, 3 of whom died; this worsening was clearly related to the ischemic damage. Treatment was also discontinued for 3 patients in the HBO group who experienced myocardial infarction, a worsening related to the ischemic process, and claustrophobia. Therefore, 27 patients (13 in the sham group and 14 in the HBO group) completed a full course of therapy. The mean score of the HBO group was significantly better on the Orgogozo scale at 1 year (P < .02). However, the difference at 1 year between pretherapeutic and posttherapeutic scores was not significantly different in the two groups (P < .16). Moreover, no statistically significant improvement was observed in the HBO group at 6 months and 1 year according to Rankin score (P < .78) and our own 10-point scale (P < .50). CONCLUSIONS: Although the small number of patients in each group precludes any conclusion regarding the potential deleterious effect of HBO, we did not observe the major side effects usually related to HBO. Accordingly, it can be assumed that hyperbaric oxygen might be safe. We hypothesize that HBO might improve outcome after stroke, as we detected an outcome trend favoring HBO therapy. A large randomized trial might be required to address the efficacy of this therapy. 37. Berrouschot, J., et al., [Hyperbaric oxygen therapy (HBO) after acute focal cerebral ischemia]. Nervenarzt, 1998. 69(12): p. 1037-44. Abstract: For a large number of patients with stroke no therapeutic option can be offered, even after approval of thrombolytic therapy for treatment of acute ischemic stroke in the US. In cerebral ischemia local anoxia and energy failure lead to further cellular damage and finally to complete stroke. All therapeutic concepts try to salvage structurally intact tissue which is at risk for irreversible damage (so-called penumbra). Hyperbaric oxygen (HBO) treatment has been reported in animal models of cerebral ischemia, and in a few clinical reports. In general, the results of these studies have been promising. This review focuses on the clinical perspective of HBO therapy and summarizes both the clinical and experimental data available on HBO therapy following ischemic stroke. 38. Krakovsky, M., et al., Effect of hyperbaric oxygen therapy on survival after global cerebral ischemia in rats. Surgical Neurology, 1998. 49(4): p. 412-6. Abstract: BACKGROUND: Hyperbaric oxygenation (HBO) has been considered for many years for the treatment of severe brain ischemia. However, its efficacy has not been proven. The aim of this study was to shed light on this question. METHODS: Acute global cerebral ischemia was induced in 18 rats using the four-vessel occlusion model. Regional cerebral blood flow (CBF) was determined by laser-Doppler flowmetry using a flexible 1 mm fiberoptic probe. Two stainless steel screws were used to measure the spontaneous electrical activity from the contralateral hemisphere. After ischemia monitored by laser-Doppler flowmetry and ECoG, the animals were divided into two groups: (1) control animals that breathed air at atmospheric pressure and (2) rats exposed to HBO at three atmospheres absolute pressure (ATA) for 1 hour. Survival time and rate were recorded for both groups of animals for 14 days. RESULTS: The survival rate in the study group was significantly higher (45%) than in the control group (0%). In the animals that did not survive the 14-day period, those exposed to HBO survived longer than the control animals (59.8+/-9.1 hour versus 17.9+/-2.7 hours, p < 0.05). CONCLUSION: This investigation demonstrates that HBO administered after global cerebral ischemia can increase survival in a rat stroke model. 39. Jain, Textbook of Hyperbaric Medicine. 1999. 40. http://www. yperbaric-therapy.com/ms/mscenter/index.html, Treating Multiple Sclerosis (MS) with Hyperbaric Oxygen Therapy (HBO). 2000. 41. Heuser, G. and J.M. Uszler, Hyperbaric oxygenation for cerebral palsy. Lancet, 2001. 357(9273): p. 2053-4. 42. O'Donnell, P., et al., The magnetic resonance imaging appearances of the brain in acute carbon monoxide poisoning. Clinical Radiology, 2000. 55(4): p. 273-80. AIMS: To describe the magnetic resonance imaging (MRI) appearances of the brain in acute carbon monoxide poisoning, the commonest cause of accidental poisoning in Europe and the U.S.A. To attempt to correlate the imaging findings with patient outcome as an aid to prognosis. MATERIALS AND METHODS: Brain MRI was performed on 19 consecutive patients, who had sustained acute carbon monoxide poisoning, as soon as possible after their referral to the regional Hyperbaric Unit at the Royal Hospital, Haslar. All patients were unconscious on arrival, and had received at least one treatment with hyperbaric oxygen by the time of first MR. The imaging findings were analysed independently by two experienced MR radiologists, with a third radiologist arbitrating on discrepant results. RESULTS: Thirteen male and six female patients, age range 21-70 years (mean 38.7 years) underwent MR an average of 35.6 h (range 6-126 h) following presentation at the referring centre. MR (at 0.5T) revealed abnormalities in the following areas: globus pallidus (n = 12); other basal ganglia [ n = 5: entire lentiform (globus pallidus and putamen), putamen alone, caudate nucleus, thalamus]; white matter (n = 6: periventricular, subcortical, other); cerebral cortex (n = 5), either localized or general; medial temporal lobe in the region of the hippocampus (n = 4). The majority of the patients with hyperintensity in the region of the hippocampus (n = 3) had no other area of cortical involvement. Two patients showed abnormalities in the cerebellum. Normal appearances were seen on the initial MR in seven patients. CONCLUSION: The appearances of the brain following acute CO poisoning are varied, and have previously been the subject of case reports or small studies, most of which have have addressed the delayed sequelae of this condition. This study, the first large series undertaken in the acute phase, confirms that, although the globus pallidus is the commonest site of abnormality in the brain, the effects of CO poisoning are widespread. The extent of damage correlates with clinical outcome, and therefore aids management and prognosis. 43. Stuppaeck, C.H., et al., Akathisia induced by necrosis of the basal ganglia after carbon monoxide intoxication. Movement Disorders, 1995. 10(2): p. 229-231. 44. Albin, R.L., Basal ganglia neurotoxins. Neurologic Clinics,, 2000. 18(3): p. 665-80. The epidemiology, clinical features, pathology, and mechanisms of action of basal ganglia neurotoxins are reviewed. Manganese, cyanide, hydrogen sulfide, methanol, carbon monoxide, 3-nitropropionic acid, MPTP, and annonaceae alkaloids are discussed. The probable mechanism of action for almost all basal ganglia neurotoxins is inhibition of mitochondrial function with destruction of the pallidum and putamen. MPTP produces selective loss of dopaminergic neurons because of selective uptake of a toxic metabolite in dopaminergic neurons. The basis for selective vulnerability of the putamen and pallidum is unknown. 45. Kao, C.H., et al., HMPAO brain SPECT in acute carbon monoxide poisoning. Journal of Nuclear Medicine, 1998. 39(5): p. 769-72. Technetium-99m-hexamethylpropylene amine oxime (HMPAO) brain images with fanbeam SPECT, in combination with surface three-dimensional display, were used to detect basal ganglion and cerebral cortex anomalies in the acute phase of carbon monoxide (CO) poisoning. METHODS: Ten patients, aged 16-29 yr, with acute CO poisoning and no past history of neurologic disorders were enrolled in this study. After oxygen treatment, all 10 patients were investigated using 99mTc-HMPAO brain images with fanbeam SPECT and surface three-dimensional display. Meanwhile, 6 of 10 patients also received a brain CT scan. RESULTS: CT scan findings were negative in all 6 patients. Fanbeam SPECT demonstrated unilateral or bilateral hypoactivity of basal ganglia in 6 patients. Local hypoactivity anomalies were found in the brain cortex of 7 patients, using surface three-dimensional display of the brain. Only 2 of 10 patients had normal 99mTc-HMPAO brain images. CONCLUSION: This study suggests that, in comparison with traditional brain imaging techniques, 99mTc-HMPAO brain imaging with fanbeam SPECT in combination with surface three-dimensional display is a better tool for early detection of regional cerebral anomalies in acute CO poisoning. 46. Weaver, L., et al., Carboxyhemoglobin half-life in carbon monoxide-poisoned patients treated with 100% oxygen at atmospheric pressure. Chest, 2000. 117(3): p. 801-8. STUDY OBJECTIVES: There are large reported differences for the carboxyhemoglobin (COHb) half-life (COHb t(1/2)) in humans breathing 100% atmospheric O(2) following CO inhalation in tightly controlled experiments compared to the COHb t(1/2) observed in clinical CO poisoning (range, 36 to 131 min, respectively). Other reports have suggested that the COHb t(1/2) may be affected by gender differences, age, and lung function. We wished to test the hypothesis that the COHb t(1/2) might also be influenced by CO poisoning vs experimental CO exposure, by a history of loss of consciousness (LOC), concurrent tobacco smoking, and by PaO(2). The purpose of the present study was to measure the COHb t(1/2) in a cohort of CO-poisoned patients and to determine if those listed factors influenced the COHb t(1/2). DESIGN: Retrospective chart review from 1985 to 1995. We calculated the COHb t(1/2) of CO-poisoned patients who were treated with high-flow supplemental atmospheric pressure O(2) delivered by nonrebreather face mask or endotracheal tube. SETTING: Hyperbaric medicine department of a tertiary-care teaching hospital. PATIENTS: Of 240 CO-poisoned patients, 93 had at least two COHb measurements > 2% (upper limit of normal) with recorded times of the measurements, permitting calculation of the COHb t(1/2). RESULTS: The COHb t(1/2) was 74 +/- 25 min (mean +/- 1 SD) with a range from 26 to 148 min. By stepwise multiple linear regression analysis, the PaO(2) influenced the COHb t(1/2) (R(2) = 0.19; p < 0.001), whereas the COHb t(1/2) was not influenced by gender, age, smoke inhalation, history of LOC, concurrent tobacco smoking, degree of initial metabolic acidosis (base excess), or initial COHb level. CONCLUSIONS: The COHb t(1/2) of 93 CO-poisoned patients treated with 100% O(2) at atmospheric pressure was 74 +/- 25 min, considerably shorter than the COHb t(1/2) reported in prior clinical reports (approximately 130 +/- 130 min) and was influenced only by the patient's PaO(2). 47. Golomb, B.A., A Review of the Scientific Literature as it Pertains to Gulf War Illnesses, Vol 2: Pyridostigmine Bromide. 1999, Santa Monica, CA: RAND. 385. 48. Cecchine, G., et al., A Review of the Scientific Literature as it Pertains to Gulf War Illnesses, Vol 8: Pesticides. 2000, Santa Monica, CA: RAND. 182. 49. Augerson, W., A Review of the Scientific Literature as it Pertains to Gulf War Illnesses, Volume 5: Chemical and Biological Warfare Agentsw. 2000, Washington, D.C.: RAND. 50. Nicolson, G.L., N.L. Nicolson, and M. Nasralla, Mycoplasmal infections and fibromyalgia/chronic fatigue illness (Gulf War Illness) associated with deployment to Operation Desert Storm. International Journal of Medicine, 1998. 1: p. 80-89. 51. Duerksen, S., Infection may hold clue to Gulf ills: Bacteria being found in many ailing vets, in San Diego Union Tribune. 2000. p. B1. 52. Fukuda, K., et al., Chronic multisymptom illness affecting Air Force veterans of the Gulf War. Jama, 1998. 280(11): p. 981-8. CONTEXT: Gulf War (GW) veterans report nonspecific symptoms significantly more often than their nondeployed peers. However, no specific disorder has been identified, and the etiologic basis and clinical significance of their symptoms remain unclear. OBJECTIVES: To organize symptoms reported by US Air Force GW veterans into a case definition, to characterize clinical features, and to evaluate risk factors. DESIGN: Cross-sectional population survey of individual characteristics and symptoms and clinical evaluation (including a structured interview, the Medical Outcomes Study Short Form 36, psychiatric screening, physical examination, clinical laboratory tests, and serologic assays for antibodies against viruses, rickettsia, parasites, and bacteria) conducted in 1995. PARTICIPANTS AND SETTING: The cross-sectional questionnaire survey included 3723 currently active volunteers, irrespective of health status or GW participation, from 4 air force populations.The cross-sectional clinical evaluation included 158 GW veterans from one unit, irrespective of health status. MAIN OUTCOME MEASURES: Symptom-based case definition; case prevalence rate for GW veterans and nondeployed personnel; clinical and laboratory findings among veterans who met the case definition. RESULTS: We defined a case as having 1 or more chronic symptoms from at least 2 of 3 categories (fatigue, mood-cognition, and musculoskeletal). The prevalence of mild-to-moderate and severe cases was 39% and 6%, respectively, among 1155 GW veterans compared with 14% and 0.7% among 2520 nondeployed personnel. Illness was not associated with time or place of deployment or with duties during the war. Fifty-nine clinically evaluated GW veterans (37%) were noncases, 86 (54%) mild-to-moderate cases, and 13 (8%) severe cases. Although no physical examination, laboratory, or serologic findings identified cases, veterans who met the case definition had significantly diminished functioning and well-being. CONCLUSIONS: Among currently active members of 4 Air Force populations, a chronic multisymptom condition was significantly associated with deployment to the GW. The condition was not associated with specific GW exposures and also affected nondeployed personnel. 53. May, K.P., et al., Sleep apnea in male patients with the fibromyalgia syndrome. Am J Med, 1993. 94(5): p. 505-8. PURPOSE: Fibromyalgia is a common pain syndrome that is often associated with sleep disturbances. The most characteristic pattern noted on formal sleep study is alpha-wave intrusion on delta-wave sleep. This nonrestorative sleep pattern may be endogenous, or caused by any of a number of sleep disturbances. Our goal was to determine the frequency of sleep apnea and its relationship to a nonrestorative sleep pattern in our patients with fibromyalgia syndrome. PATIENTS AND METHODS: All new fibromyalgia patients seen in the Rheumatology Clinic at Fitzsimons Army Medical Center were screened using history and physical examination for suspicion of sleep apnea. When this condition was suspected, the patients underwent formal polysomnography to delineate any sleep disturbance. RESULTS: Four of 92 women, and 13 of 25 men with the new diagnosis of fibromyalgia syndrome underwent polysomnography. Of the women, 2.2% (2 of 92) had significant sleep apnea at formal evaluation; both were obese and had obstructive findings. In contrast, 44% (11 of 25) of the men had significant sleep apnea. CONCLUSIONS: Sleep apnea is not a significant cause of fibromyalgia symptoms in females. In male patients with fibromyalgia, sleep apnea was observed in a large percentage. Fibromyalgia may be a marker for occult sleep apnea in males. 54. Molony, R.R., et al., Sleep, sleep apnea and the fibromyalgia syndrome. J Rheumatol, 1986. 13(4): p. 797-800. A patient who presented with primary fibromyalgia syndrome (PFS) was found to have sleep apnea. Since frequent wakening and nonrestorative sleep are prominent clinical complaints in both disorders, we hypothesized an etiologic relationship. A subsequent clinical survey of 11 additional sleep apneics revealed that 3 (27%) fulfilled proposed criteria for PFS. This was significantly greater than local and literature reported studies of nonrheumatologic patients and was comparable to reported prevalence of fibromyalgia in rheumatologic referral populations. A blinded sleep physiology study of 7 patients with PFS revealed a significantly increased percentage of transitional sleep and increased frequency of miniarousals/h, but no significant evidence of occult sleep apnea compared to matched normal controls. The frequent arousals of sleep apnea may be associated with fibromyalgia in some patients but do not explain the sleep disorder of PFS. 55. Alvarez Lario, B., et al., Fibromyalgia syndrome: overnight falls in arterial oxygen saturation. Am J Med, 1996. 101(1): p. 54-60. PURPOSE: Sleep alterations and muscular changes suggesting hypoxia have been reported in fibromyalgia syndrome (FS) pathophysiology. We tested the hypothesis that patients with FS show falls in the oxygen saturation of hemoglobin in arterial blood (SaO2%) during sleep. PATIENTS AND METHODS: Overnight SaO2% was measured by digital pulse oximetry in 28 randomly selected women who met 1990 American College of Rheumatology criteria for the diagnosis of FS and 15 similar controls. Considering the results of pulse oximetry and in order to evaluate the possible presence of a sleep apnea syndrome (SAS) as the reason for the nocturnal desaturations, the Epworth Sleepiness Scale (ESS) was mailed to the patients and controls. Patients and controls who had a score higher than 10 on the ESS underwent a polysomnographic study. RESULTS: Patients with FS showed lower overnight minimum SaO2% (86.8 +/- 1.3 versus 90.7 +/- 0.9 in controls, P < 0.05), greater number of desaturations (8.3 +/- 1.8 versus 2.7 +/- 0.8 in controls, P < 0.05) and more desaturations/hour (1.3 +/- versus 0.4 +/- 0.1 in controls, P < 0.05), more night minutes in SaO2% < 92% (56.3 +/- 12.9 versus 9.1 +/- 3.8 in controls, P < 0.01) and more minutes in SaO2% < 90% (14.7 +/- 3.7 versus 2.4 +/- 1.0 in controls, P < 0.05). There were no differences between patients with FS and controls in ESS scores. Five patients (19.2%) in the FS group and 2 (15.4%) in the control group had ESS scores higher than 10. One patient had 1 control subject showed on apnea-plus-hypopnea index higher than 5 (13 and 9, respectively) in polysomnographic study. CONCLUSIONS: Patients with FS showed small overnight falls in SaO2% and spent more time during the night in SaO2% below 92% and 90% than did the control group. These alterations that, as a whole, are not due to the presence of an associated SAS could be important in FS musculoskeletal pathophysiology. 56. Plantamura, A., J. Steinbauer, and J. Eisinger, [Sleep apnea and fibromyalgia: the absence of correlation does not indicate an exclusive central hypothesis]. Rev Med Interne, 1995. 16(9): p. 662-5. Fibromyalgia (FM) is a chronic painful syndrome characterized by widespread aching and points of tenderness, changed perception of pain and reduced brain serotonin. Abnormal EEG patterns have been reported in this condition. A study of FM occurrence in subjects with sleep abnormalities demonstrated by polysomnography was performed. Fifty patients (group 1:29 with sleep apnea and group 2:21 with poor sleep without sleep apnea) and 31 control subjects (without any sleep abnormalities) were submitted to the same clinical research of FM (ACR criteria). There was one 1 FM in group 1 (3.4%), one FM in group 2 (4.7%), and one FM in control group (3.2%). Sleep abnormalities and particularly sleep apnea are not significantly associated with FM. Other pathophysiological factors than central mechanisms are probably involved in the pathogenesis of FM. 57. Alvarez Lario, B., et al., Lack of association between fibromyalgia and sleep apnoea syndrome. Ann Rheum Dis, 1992. 51(1): p. 108-11. To determine whether sleep disorders can cause a fibromyalgia syndrome, 30 patients with sleep apnoea syndrome were studied. All presented an important reduction in deep sleep stages (-93.1 (SD 17.9)% of stage IV and -77.2 (45.7)% of stage III) and frequent episodes of wakening ('arousals'), factors which are involved in fibromyalgia. One patient (3%) met the criteria for fibromyalgia; the estimated prevalence of fibromyalgia for patients attending a general medical clinic is 6%. No significant correlation was found between the number of points which were tender upon pressure and the various sleep parameters studied. It is concluded that sleep disorders alone are not able to produce a fibromyalgia syndrome. 58. Jennum, P., et al., Sleep and other symptoms in primary fibromyalgia and in healthy controls. J Rheumatol, 1993. 20(10): p. 1756-9. OBJECTIVE. To evaluate sleep architecture and self-reported complaints in patients with fibromyalgia (FS). Forty patients and 10 age standardized healthy controls were included. All participants were women. METHODS. All patients and controls underwent a clinical examination and gave answers to a questionnaire. Polysomnography was done in 20 patients and in all controls. RESULTS. The percent arousal time and arousal index were higher (p < 0.05 and < 0.01, respectively) among FS compared to controls, but no other differences were found in sleep architecture. Ten of the patients with FS and 2 controls showed an apnea-hypoapnea index above 5/h (NS). The arousal time and arousal index were higher in patients with apnea-hypoapnea index > or = 5 compared to controls with apnea-hypoapnea index < 5 [mean (SD)] [arousal time: 4.5 (3.2) vs 0.7 (0.7), p < 0.001, arousal index: 14.9 (10.8) vs 2.4 (3.7), p < 0.001]. In patients with FS with apnea-hypoapnea index < 5 the arousal time was higher (2.0 (1.2), p < 0.05) and arousal index marginally higher (5.6 (3.2), p = 0.07) compared to the controls. No other differences were found in sleep structure. Insomnia (difficulties falling asleep, maintaining sleep, early morning awakening), tiredness, mood, cognitive disturbances and muscular pain were all reported more commonly by patients with FS than controls. A subdivision of the patients with FS into those with apnea-hypoapnea index < 5 and apnea-hypoapnea index > or = 5 did not change these findings. CONCLUSION. We conclude, that patients with FS show minor polysomnographic findings, with a higher occurrence of arousals. The arousals were in part explained by respiratory abnormalities. Patients with FS have several complaints, including insomnia. Some of these may relate to sleep fragmentation. Controlled studies are a requirement in investigations of sleep disorders in fibromyalgia. 59. Harding, S.M., Sleep in fibromyalgia patients: subjective and objective findings. Am J Med Sci, 1998. 315(6): p. 367-76. Fibromyalgia (FM) patients report early morning awakenings, awakening feeling tired or unrefreshed, insomnia, as well as mood and cognitive disturbances; they may also experience primary sleep disorders including sleep apnea. Longitudinal studies have demonstrated the chronic nature of these disturbances in patients with FM. A distinct relationship exists between poor sleep quality and pain intensity. Polysomnographic findings during sleep in these patients include an alpha frequency rhythm, termed alpha-delta sleep anomaly, which is also seen in normal controls during stage 4 sleep deprivation; deep pain induced during sleep in normal controls also causes this anomaly. Sleep architecture is altered in FM patients showing an increase in stage 1, a reduction in delta sleep, and an increased number of arousals. Before prescribing pharmacologic compounds aimed at modifying sleep, adequate pain control and sleep habits should be achieved; tricyclic antidepressants, trazadone, zopiclone, and selective serotonin reuptake inhibitors, however, may be required. More research is needed to elucidate the cellular and molecular mechanisms involved in the sleep disturbances occurring in patients with FM. 60. Fischler, B., et al., Sleep anomalies in the chronic fatigue syndrome. A comorbidity study. Neuropsychobiology, 1997. 35(3): p. 115-22. Polysomnographic findings were compared between a group of patients with the chronic fatigue syndrome (CFS; n = 49) and a matched healthy control (HC) group (n = 20). Sleep initiation and sleep maintenance disturbances were observed in the CFS group. The percentage of stage 4 was significantly lower in the CFS group. A discriminant analysis allowed a high level of correct classification of CFS subjects and HC. Sleep-onset latency and the number of stage shifts/hour contributed significantly to the discriminant function. The presence of these anomalies as well as the decrease in stage 4 sleep were not limited to the patients also diagnosed with fibromyalgia or with a psychiatric disorder. No association was found between sleep disorders and the degree of functional status impairment. The mean REM latency and the percentage of subjects with a shortened REM latency were similar in CFS and HC. 61. Paiva, T., et al., The relationship between headaches and sleep disturbances. Headache, 1995. 35(10): p. 590-6. The relationship between headaches and sleep disturbances is complex and difficult to analyze. Both symptoms may have causal relations, or may be associated in the same patient with mutual reinforcements. We studied 25 patients presenting with morning or nocturnal headaches. Standard headache diagnosis and polysomnography were performed. After polysomnography, the diagnoses were reevaluated. The main headache entities were cluster, chronic paroxysmal hemicrania, migraine, tension, combined headache, and chronic substance abuse headache. For each group, headache, sleep data, and changes in diagnosis are discussed. The diagnosis was changed in 13 patients; the final diagnoses were periodic movements of sleep, fibromyalgia syndrome, and obstructive sleep apnea. The diagnoses of cluster headache and chronic paroxysmal hemicrania were not modified by polysomnography. The migraine and tension headache groups had a relative male preponderance, and the diagnosis was changed in approximately half of the patients. This was also observed in combined headaches. Patients who had chronic substance abuse headaches had mainly insomnia, which in some cases, was relieved by stopping medication. Data were also analyzed in terms of simple models linking headache and sleep disturbances. Such an approach allowed the identification of several modes of mutual interaction. In summary, morning or nocturnal headaches are frequent indicators of a sleep disturbance and their presence might justify polysomnography, and the use of simple clinical models may be useful for understanding the complex relationship between headache and sleep. 62. Jelkmann, W., Use of recombinant human erythropoietin as an antianemic and performance enhancing drug. Curr Pharm Biotechnol, 2000. 1(1): p. 11-31. The glycoprotein hormone erythropoietin is an essential viability and growth factor for the erythrocytic progenitors in the bone marrow. Tissue hypoxia is the main stimulus for the synthesis of the hormone in the kidneys and the liver. Endogenous erythropoietin and recombinant human erythropoietin (rHu-EPO) are similar with respect to their biological and chemical properties except for some microheterogeneities in their 4 carbohydrate chains. Generic products and alternatives to rHu-EPO are in development. Renal anemia can be corrected by rHu-EPO in a dose-dependent and predictable way without major side effects apart from a possible increase in arterial blood pressure. The optimal target hematocrit still needs to be defined. There are rare reports of antibody formation towards rHu-EPO in humans. Patients suffering from non-renal anemias may also benefit from the prescription of rHu-EPO. The drug has been approved for treatment of tumor patients with platinum-induced anemia. The cost-effectiveness and medical justification of the administration of rHu-EPO in tumor patients with respect to its positive effects on tumor oxygenation, tumor growth inhibition and support of chemo- and radiotherapy is still a matter of debate. In surgical patients, the pharmacological application of rHu-EPO can increase the yield of blood units in autologous blood donation programs and lower the severity and duration of postoperative anemia, if applicated some days prior to surgery. While rHu-EPO is a godsend in medical practice, its abuse as an performance enhancing drug by athletes in endurance sports is an unethical and potentially dangerous procedure. Unequivocal methods for detection of rHu-EPO doping still need to be established. 63. Green, D., et al., Recombinant human erythropoietin: effect on the functional performance of anemic orthopedic patients. Arch Phys Med Rehabil, 1996. 77(3): p. 242-6. OBJECTIVE: To determine whether rapid correction of anemia improves the functional and cognitive performance of postoperative orthopedic patients. DESIGN: A randomized, double-blind, placebo-controlled clinical trial. SETTING: A rehabilitation institute. PATIENTS: Persons having orthopedic surgery at least 2 weeks previously, and a hemoglobin concentration < 10g/dL. INTERVENTIONS: Recombinant human erythropoietin (rH-EPO) or the EPO vehicle for up to 8 weeks. All patients received ferrous sulfate. MEASUREMENTS: Blood counts were performed at weekly intervals, and functional and cognitive tests at baseline and weeks 4 and 8. RESULTS: In patients receiving vehicle only, hemoglobin levels increased from a mean of 9.0 at baseline to 11.0 at 4 weeks and 11.7 at 8 weeks; corresponding values for rH-EPO were 8.8 (p = NS), 12.6 (p = .02), and 13.5 (p = .01). However, functional improvement in dressing, toileting, and mobility was similar between groups, and the results of neuropsychological tests showed no trends favoring rH-EPO. CONCLUSIONS: Although hemoglobin increases more rapidly in anemic orthopedic patients treated with rH-EPO, equally rapid functional improvement occurs in those who receive only iron therapy. 64. Ekblom, B., Blood doping and erythropoietin. The effects of variation in hemoglobin concentration and other related factors on physical performance. Am J Sports Med, 1996. 24(6 Suppl): p. S40-2. 65. Hengemihle, J.M., et al., Chronic treatment with human recombinant erythropoietin increases hematocrit and improves water maze performance in mice. Physiol Behav, 1996. 59(1): p. 153-6. Erythropoietin is a glycoprotein produced endogenously in the kidney, which stimulates red blood cell production. We evaluated the effects of chronic treatment with recombinant human erythropoietin (epoetin alfa: EPO) on the performance of 6-month-old male C57BL/6J mice in a spatial learning task, the Morris water maze. Mice were treated with either EPO (1.5 U injected SC every other day) or vehicle (PBS also injected SC every other day). Results indicated that the treatment had no effect on maze performance after 8 weeks, but after 19 weeks the EPO-treated mice showed better performance compared to controls as measured by mean distance (centimeters) to reach the goal platform. The improved performance in EPO-treated mice at 19 weeks was accompanied by an increased hematocrit. After 32 wk of EPO-treatment, the hematocrit returned to baseline levels even though the size and density of the red blood cells were increased. 66. Verbrugge, D.J. and L.T. Goodnough, The effect of recombinant human erythropoietin treatment on the endurance performance of Sprague-Dawley rats. Scand J Clin Lab Invest, 1994. 54(1): p. 55-9. Mild increases in haematocrit (Hct) have been shown to enhance aerobic performance, but the effects of more severe increases have not been studied. Recombinant human erythropoietin (rHuEPO), which can cause substantial increases in haematocrit, was used to study the effects of induced severe polycythemia on aerobic endurance performance. Sixteen Sprague-Dawley rats were aerobically trained on motorized running wheels. After 5 weeks, the baseline aerobic endurance of each animal was determined by measuring the running time to exhaustion (RTE). Then each rat was randomly assigned to an experimental group (EXP) which received 600 U kg-1 rHuEPO every 3 days, or a placebo group (PLC). Haematocrit and animal mass were monitored for 3 weeks while training and treatment continued, and then the RTE was determined a second time. Results indicated that the rats in the treatment group had a significantly higher Hct (62.2% vs. PLC value of 47.3%, p < 0.001), but did not have a different RTE (75 min vs. PLC value of 73 min, p > 0.05) when compared to the placebo group. The change in the Hct compared to the change in RTE for each animal showed an inverse relationship (r = -0.8212), indicating that greater increases in rHuEPO induced polycythemia resulted in a decreased performance level. We conclude that rHuEPO-induced severe polycythemia was not accompanied by an increase in aerobic endurance in this animal model. 67. Martin, G.R., et al., Recombinant erythropoietin (Epogen) improves cardiac exercise performance in children with end-stage renal disease. Pediatr Nephrol, 1993. 7(3): p. 276-80. To determine the effects of anemia in children with end-stage renal disease, we studied cardiac performance before and 1 and 6 months after recombinant erythropoietin (Epogen). Children with end-stage renal disease were included if they had significant anemia [hematocrit (Hct) < 30%]. Epogen 50 U/kg was given subcutaneously or intravenously three times per week until the Hct was > or = 33%. Echocardiography, cardiac output (acetylene rebreathing), and treadmill (modified Bruce) tests were performed. Boys (9) and girls (9), 11.9 +/- 5.6 years, were given Epogen and the Hct increased (from 21.7 +/- 2.7% to 33.4 +/- 2.1%, P = 0.001). Heart rate decreased (P = 0.04) and stroke volume did not change. Blood pressure did not change. Cardiac thickness, chamber dimensions, left ventricular wall stress, velocity of circumferential fiber shortening, and indices of diastolic function were normal and did not change after Epogen. Exercise time increased (from 10.3 +/- 1.9 to 11.2 +/- 1.9 min, P = 0.01) after 1 month of Epogen. Resting oxygen consumption (VO2) decreased (from 7.8 +/- 1.8 to 6.9 +/- 1.4 ml/min per kg, P = 0.01) 1 month after Epogen and peak exercise VO2 did not change after Epogen. There were no differences in exercise tests between the 1 and 6 month measurements. Exercise tolerance improves after the short-term correction of anemia and there is no further improvement after long-term correction. 68. McMahon, L.P., et al., Haemodynamic changes and physical performance at comparative levels of haemoglobin after long-term treatment with recombinant erythropoietin. Nephrol Dial Transplant, 1992. 7(12): p. 1199-206. Physical performance and haemodynamic parameters at rest and with exercise were compared in a prospective, cross-over fashion in 12 anaemic haemodialysis patients (Hb 6.4 +/- 0.5, mean +/- SEM) at two levels of haemoglobin (Hb 9 and 12 g/dl) before and after long-term treatment with recombinant human erythropoietin (rHuEpo). Patients were divided into two groups and measurements made prior to treatment, upon reaching, and after 4 months at the first target Hb (9 g/dl group A, 12 g/dl group B), and after 4 months at the alternative target Hb. Tests included an exercise radionuclide ventriculogram, Doppler echocardiogram, and respiratory function exercise test. Compared to pretreatment, there was a significant reduction in resting pulse rate (P < 0.001), and in pulse rate (P < 0.001) and arterial lactate (P < 0.01) concentrations at specified levels of exercise. Work capacity improved 60% (P < 0.001), and left ventricular mass fell by 26% (P < 0.001). Although cardiac output (CO) during and after exercise was reduced (P < 0.05), resting CO, cardiac index, stroke volume and ejection fraction (rest and exercise) were not significantly altered. There appeared little benefit in having the higher target Hb: no significant difference could be found between target levels for almost any measure. In addition, despite marked improvement from pretreatment levels, performance parameters were still below those of non-uraemic age-matched controls. These results demonstrate the beneficial but incomplete effect of rHuEpo on resting and exercise-related factors, and suggest that most improvement is achieved with modest increments in haemoglobin. 69. Adamson, J.W. and D. Vapnek, Recombinant erythropoietin to improve athletic performance. N Engl J Med, 1991. 324(10): p. 698-9. 70. Braumann, K.M., et al., Improved physical performance after treatment of renal anemia with recombinant human erythropoietin. Nephron, 1991. 58(2): p. 129-34. The physical performance of 12 anemic patients on renal dialysis was investigated following treatment of renal anemia with recombinant human erythropoietin (rhEPO; 40-120 U/kg, 3 times a week). Exercise intensity at a heart rate of 130 beats/min (PWC130) on a bicycle ergometer was assessed before rhEPO treatment, after reaching the target hematocrit (73 +/- 18 days), and in the maintenance phase (211 +/- 53 days). Hemoglobin concentrations measured at these time points were 7.3 +/- 1.2, 11.9 +/- 1.5, and 12.1 +/- 1.4 g/dl, respectively. PWC130 rose from 77 +/- 27 to 104 +/- 37 and 104 +/- 51 W, respectively. Aerobic threshold (i.e. blood lactic acid concentration of 2 mmol/l) shifted to higher workloads indicating improved muscle oxygen supply. 71. Scott, W.C., The abuse of erythropoietin to enhance athletic performance. Jama, 1990. 264(13): p. 1660. 72. Huppmann, M., et al., [Erythropoietin therapy in renal anemia. Effect on ergospirometry performance parameters]. Wien Med Wochenschr Suppl, 1989. 104: p. suppl 48-50. 73. Bocker, A., et al., Effect of erythropoietin treatment on O2 affinity and performance in patients with renal anemia. Contrib Nephrol, 1988. 66: p. 165-75. 74. Corey-Bloom, J. Ginkgo biloba slows cognitive decline in patients with multiple sclerosis. in Annual Meeting of the American Academy of Neurology. 2002. Denver, CO. 75. Joint National Committee, The Sixth Report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure (JNC VI). Arch Intern Med, 1997. 157: p. 2413-2446. 76. Matsubayashi, K., et al., Postural dysregulation in systolic blood pressure is associated with worsened scoring on neurobehavioral function tests and leukoaraiosis in the older elderly living in a community. Stroke, 1997. 28(11): p. 2169-73. BACKGROUND AND PURPOSE: Postural hypotension, which occurs frequently in community-living, apparently healthy elderly adults, is usually asymptomatic. However, the relation between postural changes in blood pressure and quantitative higher cerebral function or silent brain lesions remains unclear. We examined the association of exaggerated postural changes in systolic blood pressure with cognitive and quantitative neurobehavioral functions and with brain lesions on MRI in the community-dwelling older elderly. METHODS: The study population consisted of 334 community-dwelling elderly adults, aged 75 years or older (mean age, 80 years). Postural changes in systolic blood pressure (SBP) were assessed using an autosphygmomanometer (BP-203 I). By the difference between the mean of two measurements of SBP at standing and at supine position (dSBP = SBP at upright-SBP at supine position), we divided the subjects into three groups: (1) 20 subjects with postural hypotension (d-SBP < or = -20 mm Hg), (2) 29 subjects with postural hypertension (dSBP > or = 20 mm Hg), and (3) 285 subjects with postural normotension (20 < dSBP < 20 mm Hg). We defined the former two groups as the postural dysregulation group. Scores in four neurobehavioral function tests (Mini-Mental State Exam. Hasegawa Dementia Scale Revised, computer-assisted visuospatial cognitive performance score, and the Up and Go Test) and activities of daily living were compared among the three groups. Brain lesions on MRI, including number of lacunes and periventricular hyperintense lesions, were compared among 15 age- and sex-matched control subjects with postural hypotension, 15 with postural hypertension, and 30 with postural normotension. RESULTS: Twenty subjects (6.0%) exhibited postural hypotension and 29 (8.7%) postural hypertension. Scores in neurobehavioral functions and activities of daily living were significantly lower in the postural dysregulation group (both postural hypotension and hypertension groups) than in the postural normotension group. The postural dysregulation group exhibited significantly more advanced periventricular hyperintensities than the normotension group. CONCLUSIONS: Asymptomatic community dwelling elderly individuals with postural hypotension as well as those with postural hypertension had poorer scores on neurobehavioral function tests and more advanced leukoaraiosis demonstrated on MRI than those without exaggerated postural changes in SBP. 77. Korten, A.E., et al., Health, cognitive, and psychosocial factors as predictors of mortality in an elderly community sample. Journal of Epidemiology and Community Health, 1999. 53(2): p. 83-88. STUDY OBJECTIVE: To examine whether cognitive and psychosocial factors predict mortality once physical health is controlled. DESIGN: A prospective study of community dwelling elderly. Mortality was assessed over a period of 3-4 years after the baseline assessment of predictors. The data were analysed using the Cox proportional hazards model. SETTING: Canberra and Queanbeyan, Australia. PARTICIPANTS: A sample of 897 people aged 70 or over and living in the community, drawn from the compulsory electoral roll. RESULTS: For the sample as a whole, the significant predictors of mortality were male sex, poor physical health, poor cognitive functioning, and low neuroticism. Men had an adjusted relative risk of mortality of 2.5 compared with women. For the male sub-sample, poor self rated health and a poor performance on a speeded cognitive task were significant predictors, while for women, greater disability, low systolic blood pressure, and a low score on a dementia screening test were the strongest predictors. CONCLUSIONS: Mortality was predicted by physical ill health and poor cognitive functioning. Psychosocial factors such as socioeconomic status, psychiatric symptoms, and social support did not add to the prediction of mortality, once sex, physical health, and cognitive functioning were controlled. Mortality among men was more than twice that of women, even when adjusted for other predictors. 78. Guo, Z., et al., Blood pressure and performance on the Mini-Mental State Examination in the very old. Cross-sectional and longitudinal data from the Kungsholmen Project. American Journal of Epidemiology, 1997. 145(12): p. 1106-1113. The authors examined the association of blood pressure with cognitive function as assessed by the Mini-Mental State Examination (MMSE) in a community-based Swedish cohort of 1,736 people aged 75-101 years. Age, sex, education, antihypertensive medication use, heart disease, and stroke were considered as covariates. Multiple linear regression analysis indicated that both systolic and diastolic blood pressure, measured in 1987-1989, were positively and significantly related to baseline MMSE score; baseline systolic pressure was also positively and significantly related to follow-up MMSE score, measured after an average period of 40.5 months among subjects who were not taking antihypertensive medication at baseline. Furthermore, in the nontreated group, multiple logistic regression showed that individuals with a baseline systolic pressure less than 130 mmHg had an odds ratio of 1.88 (p = 0.05) for follow-up cognitive impairment (MMSE score < 24) compared with those whose systolic pressure was 130-159 mmHg. An increased but not statistically significant risk of cognitive impairment was associated with high blood pressure (systolic pressure > or = 180 mmHg or diastolic pressure > or = 95 mmHg) only in persons taking antihypertensive medication at baseline. Subjects with systolic pressure of 160-179 mmHg tended to be at lower risk of cognitive impairment. These results may support the view that a certain blood pressure level, particularly a systolic pressure of at least 130 mmHg, is important to the maintenance of cognitive functioning in the very old. They also suggest that severe hypertension that is not well controlled (systolic pressure > or = 180 mmHg or diastolic pressure > or = 95 mmHg) is still a threat to cognitive function in this age group. However, the use of blood pressure measurements made at a single visit and the relatively short follow-up period should be considered when interpreting these results. 79. Guo, Z., et al., Occurrence and progression of dementia in a community population aged 75 years and older: relationship of antihypertensive medication use. Archives of Neurology, 1999. 56(8): p. 991-6. OBJECTIVE: To examine whether antihypertensive medication use can affect the occurrence and progression of dementia. SUBJECTS AND METHODS: In a community cohort of 1810 persons aged 75 years and older, 225 prevalent cases of dementia were detected. Among the 1301 persons without dementia, 224 incident cases of dementia were identified during an average period of 3 years. Among the 225 prevalent cases of dementia, 79 were suitable for the analysis of cognitive decline. Information on drug use was collected for the 2 weeks preceding the baseline interview. RESULTS: Subjects taking antihypertensive medication (n = 651, 83.9% of whom took diuretics) had a lower prevalence of dementia than those not taking antihypertensive medication (P<.001). Subjects without dementia who were taking antihypertensive medication at baseline (n = 584) had a reduced incidence of dementia (adjusted relative risk, 0.7; 95% confidence interval, 0.6-1.0; P = .03). Furthermore, subjects taking diuretics (n = 484) had an adjusted relative risk of 0.7 (95% confidence interval, 0.5-1.0; P = .02) for all dementia, and subjects taking diuretic monotherapy (n = 345) had an adjusted relative risk of 0.6 (95% confidence interval, 0.4-0.9; P = .006). The use of other antihypertensive medication (calcium antagonists or beta-blockers), however, was related to a reduced risk of Alzheimer disease (adjusted relative risk, 0.6; 95% confidence interval, 0.3-1.2) only in the subpopulation with a higher baseline blood pressure (n = 458). Patients with dementia at baseline who were not taking diuretics had a 2-fold faster rate of decline in the score on the Mini-Mental State Examination than those taking diuretics. CONCLUSION: The use of diuretics may protect against dementia in elderly persons. 80. Zhu, L., et al., Blood pressure reduction, cardiovascular diseases, and cognitive decline in the mini-mental state examination in a community population of normal very old people: a three-year follow-up. Journal of Clinical Epidemiology, 1998. 51(5): p. 385-01. We observed the decline in cognitive functioning in a community cohort of 924 persons aged > or =75 years with initially good cognition. Cognitive performance was indexed with the Mini-Mental State Examination (MMSE) on two occasions, 3 years apart. The average decline in MMSE score was 0.4 points per year. However, 23.4% of the participants lost more than 10% of their baseline MMSE scores. Women declined more rapidly than men. Baseline advanced age, lower education, and stroke predicted the greater decline in women. It appears that the relation of lower education and stroke with cognitive decline was more pronounced in men, but age did not predict cognitive decline in men. In addition, there was a correlation between systolic pressure reduction and cognitive decline in women, which was not accounted for by other factors. In summary, although the cognitive ability is generally spared longitudinally, in terms of the entire population, a considerable proportion of individuals show substantial decline that is related to several factors such as advanced age, female gender, lower education, stroke, and systolic pressure reduction. 81. Guo, Z., et al., Low blood pressure and incidence of dementia in a very old sample: dependent on initial cognition. Journal of the American Geriatrics Society, 1999. 47(6): p. 723-6. OBJECTIVE: To examine whether initially low blood pressure is related to the incidence of dementia. DESIGN: A population-based prospective study. SETTING: The Kungsholmen district of Stockholm, Sweden PARTICIPANTS: Three hundred four nondemented subjects aged 75 to 96 years at baseline. MEASUREMENTS AND MAIN RESULTS: After an average of 3 years, 81 dementia cases were identified (67 with Alzheimer's disease cases). Compared with individuals with baseline systolic pressure of 141 to 179 mm Hg, those with systolic pressure < or = 140 mm Hg had a significantly higher risk of dementia (relative risk (RR) = 1.9, 95% confidence interval (CI), 1.2-3.2) and Alzheimer's disease (RR = 2.2, 95% CI, 1.2-3.8). However, the RR in relation to systolic pressure < or = 140 mm Hg was 1.3 (0.8-2.2) for all dementia and 1.5 (0.8-2.6) for Alzheimer's disease, when the baseline Mini-Mental State Examination (MMSE) score was included in the model as a dichotomous variable (< 24 vs > or = 24). Baseline MMSE < 24 significantly predicted the occurrence of dementia (RR = 6.9; 95% CI, 4.3-11.1). Systolic pressure < or = 140 mm Hg was significantly related to MMSE score < 24 at baseline. CONCLUSIONS: These data suggest that low blood pressure may be an early correlate of a dementing process although a causative effect cannot be definitely ruled out. 82. Kario, K., et al., Autonomic nervous system dysfunction in elderly hypertensive patients with abnormal diurnal blood pressure variation: relation to silent cerebrovascular disease. Hypertension, 1997. 30(6): p. 1504-10. To investigate the relationships among diurnal blood pressure (BP) variations and autonomic nervous system dysfunction, we assessed heart rate variability (HRV) using power spectral analysis of the 24-hour RR interval in 51 asymptomatic elderly hypertensive patients with various patterns of nocturnal BP fall. The extreme-dippers with marked nocturnal BP fall (n=16) had lower asleep low-frequency power (LF)/high-frequency power (HF) ratios (a relative index of sympathetic nervous system activity), while the nondippers without nocturnal BP fall (n=18) had lower awake LF/HF ratios and asleep/awake ratio for HF (an index of parasympathetic nervous activity), when compared with dippers with appropriate nocturnal BP fall (n=17). The incidence of multiple lacunar infarction detected by brain magnetic resonance imaging was 56% in the extreme-dippers and 38% in the nondippers, and both were markedly higher than that (6.3%) in the dippers (both P<.01). There was no significant relationship between the BP level and any HRV parameter for either the daytime or nighttime period. The asleep/awake ratio for systolic BP was significantly correlated with the asleep/awake ratio for HF (r= -.363, P<.01) and with the asleep/awake ratio for the LF/HF ratio (r=.540, P<.001), regardless of whether multiple lacunar infarction was present. In conclusion, the autonomic nervous system activity is not related to high BP level per se, rather its diurnal variation is more important as a determinant of the diurnal BP patterns, regardless of the presence or absence of cerebrovascular disease. 83. Watanabe, N., et al., Nocturnal blood pressure and silent cerebrovascular lesions in elderly Japanese. Stroke, 1996. 27(8): p. 1319-27. 84. Langer, R.D., T.G. Ganiats, and E. Barrett-Connor, Paradoxical survival of elderly men with high blood pressure. Bmj (Clinical Research Ed.), 1989. 298(6684): p. 1356-7. 85. Langer, R.D., T.G. Ganiats, and E. Barrett-Connor, Factors associated with paradoxical survival at higher blood pressures in the very old [published erratum appears in Am J Epidemiol 1993 Nov 1;138(9):774]. American Journal of Epidemiology, 1991. 134(1): p. 29-38. Paradoxically greater survival for persons aged 85 years and older with higher blood pressures has been reported in a Finnish population study (Br Med J 1988;296:887-9). In a previous report, the authors demonstrated improved 10-year survival with increasing diastolic blood pressure in men (but not in women) aged 75 years and older in the Rancho Bernardo Chronic Disease Study (Br Med J 1989;298:1356-7). However, few of the covariates which could potentially explain this effect were obtained at the visit used in that analysis. In an effort to confirm these reports of paradoxical survival and to explore possible reasons for them, the authors analyzed all-cause and cardiovascular mortality in 795 men and women aged 75-96 years (mean, 80.6), evaluated in 1984-1987 and followed prospectively for an average of 3 years after that comprehensive examination. Of 63 deaths, 48 (76%) were in men; 43 (68%) of all deaths were cardiovascular. Kaplan-Meier survival analyses showed a significant trend for improved survival with increasing diastolic pressure in men aged 80 years and older versus all-cause mortality (chi 2 p less than or equal to 0.01), and cardiovascular mortality (chi 2 p less than or equal to 0.00). These trends were not evident in men aged less than 80 years or in women in either age group. Results were not explained by differences in the use of antihypertensive medication, pulse pressure, history of hypertension, history of coronary heart disease, isolated systolic hypertension, interval change in diastolic pressure (over an average of 12 years), or by cholesterol, triglycerides, fasting plasma glucose, smoking, or body mass index. Thus, the paradoxical relation of improved all-cause and cardiovascular survival in men aged 80 years or older with higher diastolic pressure is not explained by a wide range of biologic and historical factors. 86. Langer, R.D., et al., Blood pressure change and survival after age 75. Hypertension, 1993. 22(4): p. 551-9. Higher diastolic pressure predicted better survival in men 75 years or older in two prior analyses in the Rancho Bernardo population. Diastolic change was implicated as a possible explanation. We studied this by assessing survival according to blood pressure change in 795 men and women aged 75 years and older at the time of a second measurement taken an average of 11 years after the first, who were then followed for 5 years. Sex-specific analyses compared participants with a diastolic decrease of 5 mm Hg or greater and participants with a systolic decrease of 10 mm Hg or greater with those whose blood pressure levels did not change or increased. In men, after adjustment for baseline pressure, a decrease in diastolic pressure of 5 mm Hg or greater was associated with higher all-cause mortality (relative risk, 2.33; 95% confidence interval, 1.39 to 3.91) and cardiovascular mortality (3.13, 1.47 to 6.66). The mortality risk was strongest in men who took antihypertensive medication and had a fall in diastolic pressure (12.33, 2.73 to 55.72) compared with treated men whose pressures did not decrease. Among men with isolated systolic hypertension, those treated whose diastolic pressure remained stable had the best survival. A systolic fall in men and a decrease in either diastolic or systolic in women was not associated with poorer survival after adjustment for baseline pressure. We conclude that a fall in diastolic pressure of 5 mm Hg was associated with poor survival in men after age 75. This risk was strongest in men who took antihypertensive medication. 87. Jancin, B., Blood pressure rise reperfuses stroke, in Internal Medicine News. 2002. p. 1-2. 15 subjects pilot study, NIH study, randomizede 2:1 to pharmacological blood pressure elevation or conventional management that included hydration, aspirin, and heparin, if appropriate [it is never appropriate!!]. The blood pressure increase was achieved by using intravenous phenylephrine as needed to raise mean arterial pressure by 10% increments up to 140mm Hg. Twentyfour hours after patients started showing improvement, they were weaned off this aggressive intravenous regimen and onto oral therapy with fludrocortisone, midodrine, and salt tablets. Patients in the treatment group had signifiant symptomatic improvements, going from a mean NIH Stroke Score of 10.2 at baseline on day 1 to 5.5 on day 3. THeir error ratre on objective cognitive testing fell from 48% on day 1 to 29% on day 33. And their mean volume of hypoperfused tissue on brain imaging dropped from 125 to 71 cc. These improvements were maintained at 6-8 weeks. None of these parameters significantly changed in the control group. In 7 of 9 treated patients, mean arterial pressure was strongly correlated with the results of daily cognitive testing, suggesting that the observed functional improvement was due to the changes in blood pressure, Dr. Ulatowski said. Deliberately raising blood pressure in a patient with vascular disease is contrary to standard care. No cardiac events occurred in the study subjects; however the trial did not include patients with heart failure, bradycardia, or recent myocardial ischemia. A couple of patients in the pilot trial developed symptoms during an attempt to wean them off oral therapy after one month, so investigators reinstituted the regimen. 88. De Lorenzo, F., J. Hargreaves, and V.V. Kakkar, Pathogenesis and management of delayed orthostatic hypotension in patients with chronic fatigue syndrome. Clin Auton Res, 1997. 7(4): p. 185-90. The relationship between orthostatic hypotension and chronic fatigue syndrome (CFS) has been reported previously. To study the pathogenesis and management of delayed orthostatic hypotension in patients with CFS, a case comparison study with follow-up of 8 weeks has been designed. A group of 78 patients with CFS (mean age 40 years; 49% men and 51% women), who fulfilled the Centre for Disease Control and Prevention criteria were studied. There were 38 healthy controls (mean age 43 years; 47% men and 53% women). At entry to the study each subject underwent an upright tilt-table test, and clinical and laboratory evaluation. Patients with orthostatic hypotension were offered therapy with sodium chloride (1200 mg) in a sustained-release formulation for 3 weeks, prior to resubmission to the tilt-table testing, and clinical and laboratory evaluation. An abnormal response to upright tilt was observed in 22 of 78 patients with CFS. After sodium chloride therapy for 8 weeks, tilt-table testing was repeated on the 22 patients with an abnormal response at baseline. Of these 22 patients, 10 redeveloped orthostatic hypotension, while 11 did not show an abnormal response to the test and reported an improvement of CFS symptoms. However, those CFS patients who again developed an abnormal response to tilt-test had a significantly reduced plasma renin activity (0.79 pmol/ml per h) compared both with healthy controls (1.29 pmol/ml per h) and with those 11 chronic fatigue patients (1.0 pmol/ml per h) who improved after sodium chloride therapy (p = 0.04). In conclusion, in our study CFS patients who did not respond to sodium chloride therapy were found to have low plasma renin activity. In these patients an abnormal renin-angiotensin-aldosterone system could explain the pathogenesis of orthostatic hypotension and the abnormal response to treatment. 89. Peroutka, S.J., Chronic fatigue disorders: an inappropriate response to arginine vasopressin? Med Hypotheses, 1998. 50(6): p. 521-3. Chronic fatigue disorders are characterized by a subjectively defined group of symptoms such as chronic fatigue, mental confusion, exertional malaise, weight changes, and/or diffuse multi-joint pains. Significant clinical overlap exists between chronic fatigue disorders and the syndrome of serum inappropriate anti-diuretic hormone (SIADH). Both chronic fatigue disorders and SIADH are characterized by lethargy and mental confusion. Both disorders can be induced or exacerbated by viral illnesses, physical exertion, emotional stress and/or hypotension. Both can be treated with salt loading and glucocorticoids. Therefore, altered water metabolism resulting from inappropriate release and/or response to arginine vasopressin (AVP) is proposed as a pathophysiological basis of certain chronic fatigue disorders. Moreover, these data suggest that salt loading and/or direct inhibition of AVP may be an effective therapeutic approach in individuals with chronic fatigue disorders. 90. Rowe, P.C., et al., Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial. Jama, 2001. 285(1): p. 52-9. CONTEXT: Patients with chronic fatigue syndrome (CFS) are more likely than healthy persons to develop neurally mediated hypotension (NMH) in response to prolonged orthostatic stress. OBJECTIVE: To examine the efficacy of fludrocortisone acetate as monotherapy for adults with both CFS and NMH. DESIGN: Randomized, double-blind, placebo-controlled trial conducted between March 1996 and February 1999. SETTING: Two tertiary referral centers in the United States. PATIENTS: One hundred individuals aged 18 to 50 years who satisfied Centers for Disease Control and Prevention criteria for CFS and had NMH provoked during a 2-stage tilt-table test. Eighty-three subjects had adequate outcome data to assess efficacy. INTERVENTION: Subjects were randomly assigned to receive fludrocortisone acetate, titrated to 0.1 mg/d (n = 50) or matching placebo (n = 50) for 9 weeks, followed by 2 weeks of observation after discontinuation of therapy. MAIN OUTCOME MEASURE: Proportion of subjects in each group with at least a 15-point improvement on a 100-point global wellness scale. RESULTS: Baseline demographic and illness characteristics between the groups were similar; CFS had been present for at least 3 years in 71%. Using an intention-to-treat analysis, 7 subjects (14%) treated with fludrocortisone experienced at least a 15-point improvement in their wellness scores compared with 5 (10%) among placebo recipients (P =.76). No differences were observed in several other symptom scores or in the proportion with normal follow-up tilt test results at the end of the treatment period. CONCLUSIONS: In our study of adults with CFS, fludrocortisone as monotherapy for NMH was no more efficacious than placebo for amelioration of symptoms. Failure to identify symptomatic improvement with fludrocortisone does not disprove the hypothesis that NMH could be contributing to some of the symptoms of CFS. Further studies are needed to determine whether other medications or combination therapy are more effective in treating orthostatic intolerance in patients with CFS. 91. Baschetti, R., Investigations of hydrocortisone and fludrocortisone in the treatment of chronic fatigue syndrome. J Clin Endocrinol Metab, 1999. 84(6): p. 2263-4. 92. Peterson, P.K., et al., A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome. Arch Intern Med, 1998. 158(8): p. 908-14. OBJECTIVE: To provide a preliminary assessment of the efficacy and safety of fludrocortisone acetate treatment of chronic fatigue syndrome. DESIGN: A placebo-controlled, double-blind, random-allocation crossover trial of 6 weeks of fludrocortisone. SETTING: An outpatient clinical trials unit. PATIENTS: Twenty-five participants with chronic fatigue syndrome (mean age, 40 years; 19 [76%] women; mean duration of illness, 7.0 years) were recruited from a research and clinic registry. Five patients withdrew from the trial. INTERVENTIONS: All participants were scheduled to receive fludrocortisone acetate (0.1-0.2 mg) or a placebo for 6 weeks in each treatment. MAIN OUTCOME MEASURES: Self-administered questionnaires were completed at the beginning and end of each treatment arm that asked patients to rate the severity of their symptoms on a visual analogue scale. The Medical Outcomes Study 36-Item Short-Form Health Survey, a reaction time test, and a treadmill exercise test were used to assess functional status. Blood pressure, heart rate, and plasma norepinephrine levels were obtained at baseline. Blood pressure and heart rate were recorded at the end of the exercise test and monitored at all subsequent visits. RESULTS: At baseline, the study participants reported symptom severity greater than 5 for most symptoms, and all had evidence of marked functional impairments. No improvement was observed in the severity of any symptom or in any test of function for the 20 participants who completed both arms of the trial. Blood pressure and heart rate readings were unaffected by treatment, and plasma norepinephrine levels did not differ from those of a healthy control group. The incidence of adverse experiences was similar in the fludrocortisone and placebo arms of the trial. CONCLUSION: Low-dose fludrocortisone does not provide sufficient benefit to be evident in a preliminary blinded trial of unselected patients with chronic fatigue syndrome. 93. Hanelt, W., Experience with atropine, 3*.000125g/d for chronic fatigue. Letter to Dr. Golomb dated 2-15-00. 2000. 94. Golomb, B.A., Illness in Persian Gulf War veterans: Evidence for a causal role for acetylcholinesterase inhibitors (pyridostigmine bromide, pesticides, and nerve agent). Submitted. 95. Rustam, H., et al., Evidence for a neuromuscular disorder in methylmercury poisoning. Arch Environ Health, 1975. 30: p. 190-195. Data suggestive of a neuromuscular disorder responsive to neostigmine was uncovered in the course of electrophysiological testing of Iraqi patients poisoned by methylmercury. Subsequent neostigmine therapy produced a remarkable clinical improvement of the patients. Placebo substitution resulted in a substantial loss of testable strength that was restored when drug therapy was resumed. 96. Braham, J., Drop attacks in the elderly: Effect of pyridostigmine. Postgraduate Medical Journal, 1994. 70(829): p. 848. 97. Trojan, D. and N. Cashman, Anticholinesterases in post-poliomyelitis syndrome. Ann NY Acad Sci, 1995. 753: p. 285-295. 98. Trojan, D. and N. Cashman, An open trial of pyridostigmine in post-poliomyelitis syndrome. Canadian J of Neurological Sciences, 1995. 22(3): p. 223-227. 99. Park, K., et al., Pyridostigmine toxicity: Electrophysiological study. Electromyogr Clin Neurophysiol, 1993. 33: p. 323-328. 100. Jancin, B., Blood pressure rise reperfuses stroke, in Internal Medicine News. 2002. p. 1-2. 15 subjects pilot study, NIH study, randomizede 2:1 to pharmacological blood pressure elevation or conventional management that included hydration, aspirin, and heparin, if appropriate [it is never appropriate!!]. The blood pressure increase was achieved by using intravenous phenylephrine as needed to raise mean arterial pressure by 10% increments up to 140mm Hg. Twentyfour hours after patients started showing improvement, they were weaned off this aggressive intravenous regimen and onto oral therapy with fludrocortisone, midodrine, and salt tablets. Patients in the treatment group had signifiant symptomatic improvements, going from a mean NIH Stroke Score of 10.2 at baseline on day 1 to 5.5 on day 3. THeir error ratre on objective cognitive testing fell from 48% on day 1 to 29% on day 33. And their mean volume of hypoperfused tissue on brain imaging dropped from 125 to 71 cc. These improvements were maintained at 6-8 weeks. None of these parameters significantly changed in the control group. In 7 of 9 treated patients, mean arterial pressure was strongly correlated with the results of daily cognitive testing, suggesting that the observed functional improvement was due to the changes in blood pressure, Dr. Ulatowski said. Deliberately raising blood pressure in a patient with vascular disease is contrary to standard care. No cardiac events occurred in the study subjects; however the trial did not include patients with heart failure, bradycardia, or recent myocardial ischemia. A couple of patients in the pilot trial developed symptoms during an attempt to wean them off oral therapy after one month, so investigators reinstituted the regimen. 101. Cupler, F.J., et al., Acetylcholine receptor antibodies as markers of treatable fatigue in HIV-1 infected individuals. Muscle and Nerve, 1996. 19: p. 1186-1188. 102. Robbins, T.W., et al., Cognitive enhancers in theory and practice: Studies of the cholinergic hypothesis of cognitive deficits in Alzheimer's disease. Behav Brain Res, 1997. 83(1-2): p. 15-23. 103. Davis, K.L., et al., Physostigmine: improvement of long-term memory processes in normal humans. Science, 1978. 201(4352): p. 272-4. Nineteen normal male subjects received 1.0 milligram of physostigmine or 1.0 milligram of saline by a slow intravenous infusion on two nonconsecutive days. Physostigmine significantly enhanced storage of information into long-term memory. Retrieval of information from long-term memory was also improved. Short-term memory processes were not significantly altered by physostigmine. 104. Mohs, R.C., et al., Cognitive effects of physostigmine and choline chloride in normal subjects, in Brain Acetylcholine and Neuropsychiatric Disease, K. Davis and P. Berger, Editors. 1979, Plenum Press: New York. p. 237-251. 105. Christie, J.E., et al., Physostigmine and arecoline: effects of intravenous infusions in Alzheimer presenile dementia. Br J Psychiatry, 1981. 138: p. 46-50. 106. Peters, B. and H. Levin, Memory enhancement after physostigmine in the amnesic syndrome. Arch Neurol, 1977. 34: p. 215. 107. Mohs, R., B. Davis, and et al, Oral physostigmine treatment of patients with Alzheimer's disease. Am J Psychiatry, 1979. 142: p. 28-33. 108. Wilson, A.L., et al., Nicotine patches in Alzheimer's disease: pilot study on learning, memory, and safety. Pharmacol Biochem Behav, 1995. 51(2-3): p. 509-14. In view of the cholinergic deficits present in patients with Alzheimer's disease (AD), a widely investigated treatment strategy for the cognitive deficits in AD is cholinergic stimulation. Although nicotinic cholinergic receptor binding has been demonstrated to be deficient in the AD brain, the predominant theoretical and therapeutic focus to date has been on muscarinic cholinergic receptors and systems. The purpose of the present study was to evaluate the effects of sustained nicotine administration on behavior, cognition, and physiology. A double-blind placebo-controlled trial was conducted in which six patients with probable AD were exposed to 7, 8, and 7 days of placebo, nicotine, and washout, respectively. Daily sessions evaluating learning, memory, and behavior were conducted. Global cognitive functioning, rest and activity levels, cardiac activity, and blood levels were also measured. Findings included improved learning during the nicotine condition, which persisted throughout washout. Memory, behavior, and global cognition were not significantly affected. Sustained administration of nicotine appeared to be safe, although sleep showed a significant decrease. 109. Westman, E.C., E.D. Levin, and J.E. Rose, Nicotine as a therapeutic drug. N C Med J, 1995. 56(1): p. 48-51. Current evidence about the therapeutic potential of nicotine is strongest for ulcerative colitis. The role, if any, of nicotine therapy in Parkinson's or Alzheimer's diseases is not clear, but further research appears warranted. We need more information about the tolerability and safety of nicotine administration in such diseases. At present, any therapeutic trials of nicotine therapy should occur only as part of research protocols. Further nonjudgmental examination of the perceived effects of tobacco use may lead to other uses of nicotine. However, given the widespread morbidity and mortality directly attributable to tobacco use, no form of tobacco should be used to deliver nicotine. We encourage everyone who uses tobacco products to quit. 110. Alagiakrishnan, K., W. Wong, and P.L. Blanchette, Use of donepezil in elderly patients with Alzheimer's disease--a Hawaii based study. Hawaii Med J, 2000. 59(2): p. 57-9. Donepezil (Aricept) is a reversible acetylcholinesterase inhibitor which is indicated for the treatment of mild to moderate dementia of the Alzheimer's type. We did a retrospective analysis of 41 elderly Alzheimer's subjects of different ethnic groups including a large number of Asian and Hawaiian patients. Donepezil appears to be clinically effective in patients of different ethnicities with mild to moderate Alzheimer's disease, even at advanced age. 111. Burov Iu, V., T.D. Baimanov, and N.I. Maisov, [Effects of amiridin and tacrine, drugs effective in Alzheimer's disease, on synaptosomal uptake of neuromediators]. Biull Eksp Biol Med, 1992. 113(4): p. 379-81. The study of the drugs effective in the treatment of cognitive deficits and memory loss associated with senile dementia of the Alzheimer's type--tacrine and amiridin, acetylcholinesterase inhibitor physostigmine and nootrop piracetam on uptake of 3H-serotonin (3H-5-HT), 3H-adrenaline (3H-AD), 3H-noradrenaline (3H-HA), 2H-dopamine (3H-DA), 3H-gamma-aminobutyric acid (3H-GABA), 3H-glutamic acid (3H-GLU), 3H-aspartic acid (3H-ASP) and 3H-glycine (3H-GLI) showed that tacrine and amiridin (5 x 10(-5) M) statistically significantly (P less than 0.05) inhibited the uptake of 3H-DA and 3H-5-HT. Physostigmine at concentration 5 x 10(-4) M statistically significantly (P less than 0.05) inhibited uptake of 3H-5-HT only. Piracetam at concentration range 1-5 x 10(-3) M had no effect on uptake of all investigated neurotransmitters. The above finding suggest that the uptake of neurotransmitter in nerve terminals is not the main target of amiridin and tacrine. 112. Coyle, J. and P. Kershaw, Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of Alzheimer's disease. Biol Psychiatry, 2001. 49(3): p. 289-99. Despite the proven efficacy of acetylcholinesterase inhibitors in Alzheimer's disease, there is a need for new and more effective treatments. Galantamine is a novel treatment for Alzheimer's disease that inhibits acetylcholinesterase and modulates nicotinic receptors. In randomized, double-blind, placebo-controlled studies of up to 6 months duration, galantamine significantly improved cognitive function. Galantamine also had beneficial effects on instrumental and basic activities of daily living, and postponed the progression of behavioral symptoms. Patients who completed one of the 6-month, placebo-controlled studies were eligible to enter a 6-month, open-extension study of the 24-mg/day dose of galantamine. At the end of 12 months, cognitive function and activities of daily living were preserved in those patients who had been treated throughout the study with galantamine 24 mg/day. At 12 months, this group of patients had significantly better cognitive functions than patients who had been treated with a placebo for 6 months before receiving galantamine. These studies indicate that galantamine postpones the progression of symptoms in Alzheimer's disease. Since galantamine shows the greatest benefits when treatment is started early, its long-term benefits may result from an effect on the underlying disease process; such an effect might be mediated by galantamine's concomitant action on nicotinic receptors. 113. Cummings, J.L., D.G. Gorman, and J. Shapira, Physostigmine ameliorates the delusions of Alzheimer's disease. Biol Psychiatry, 1993. 33(7): p. 536-41. Alzheimer's disease (AD) patients frequently manifest delusions, and the cholinergic deficiency of AD may contribute to this aspect of the psychopathology of the disorder. In a double-blind, crossover study involving two patients, we compared the antidelusional efficacy of physostigmine, an acetylcholinesterase inhibitor, with haloperidol, a widely used neuroleptic agent. Physostigmine ameliorated the delusions and produced fewer side effects. These preliminary observations suggest that the cholinergic deficiency contributes to the occurrence of delusions in AD and cholinergic therapy may have a role in the treatment of the delusional symptoms. 114. Fuschillo, C., et al., Cognitive deficits in Alzheimer's disease: Treatment with acetylcholinesterase inhibitor agents. Arch Gerontol Geriatr, 2001. 33 Suppl 1: p. 151-158. 115. Geib, S.J., W. Tuckmantel, and A.P. Kozikowski, Huperzine A--a potent acetylcholinesterase inhibitor of use in the treatment of Alzheimer's disease. Acta Crystallogr C, 1991. 47 ( Pt 4): p. 824-7. Huperzine A, 9-amino-13-ethylidene-11-methyl-4-azatricyclo [7.3.1.0(3,8)]trideca-3(8),6,11-trien-5-one, C15H18N2O, Mr = 242.32, monoclinic, P2(1)/n, a = 8.8574 (6), b = 12.1833 (7), c = 12.4278 (7) A, beta = 99.956 (5) degrees, V = 1320.9 (1) A3, Z = 4, Dx = 1.22 g cm-3, lambda(Cu K alpha) = 1.54178 A, mu = 5.75 cm-1, F(000) = 520, T = 296 K, RF = 6.30% for 1402 reflections with Fo greater than or equal to 5 sigma(Fo) and 183 parameters. The pyridone ring is planar and the stereochemistry of the C(11)--C(12) double bond is E. 116. Gottwald, M.D. and R.I. Rozanski, Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer's disease: review and current status. Expert Opin Investig Drugs, 1999. 8(10): p. 1673-1682. Alzheimer's disease is, in part, characterised by the loss of neurones in the basal forebrain cholinergic cells that project to the cerebral cortex and hippocampus. These impairments have correlated with the memory loss noted in dementia of the Alzheimer's type. This 'cholinergic hypothesis' has led to the rational design of drugs to enhance or stimulate acetylcholine-mediated neurotransmission. Early acetylcholinesterase inhibitors, such as tacrine and physostigmine, are poorly tolerated and have a short duration of action. Rivastigmine is a centrally-selective acetylcholinesterase inhibitor with a relatively long duration of action and is a 'pseudo-irreversible' cholinesterase inhibitor due to slow dissociation of a carbamoyl derivative from the esteratic site of acetylcholinesterase. Preclinical studies confirmed the central selectivity of the drug and its distribution into the cerebrospinal fluid (CSF). Early studies demonstrated that rivastigmine improved cognition and was relatively well-tolerated at moderate doses. Clinical investigations of rivastigmine administered at doses of 6 - 12 mg/day significantly improved cognition, as measured by the ADAS-Cog score, and activities of daily living, as measured by the Progressive Deterioration Scale. Significant global improvements were also noted as measured by the Clinician's Interview Based Impression of Change that required the use of caregiver information. The most frequent adverse effects noted in clinical trials were consistent with peripheral cholinergic stimulation and included nausea, vomiting, abdominal pain, dizziness and diarrhoea. These effects were dose-related and minimised by slow dose-escalation upon initiation of therapy. Rivastigmine undergoes minimal metabolism by the cytochrome P450 system. As a result, it has few drug interactions. The drug is currently marketed widely in over 60 countries worldwide. In the United States, the drug received 'approvable' status subsequent to the NDA filing, and should be available later this year. 117. Lopez-Pousa, S. and C. Lombardia Fernandez, [Treatment of Alzheimer's disease: acetylcholinesterase inhibitors]. Neurologia, 1999. 14(4): p. 180-8. AIM: The cognitive deficiency of Alzheimer's disease is attributed to a dysfunction in the cerebral cholinergic systems. Current drug treatments are directed at stimulating cholinergic transmission. The aim of this study was to evaluate the latest cholinergic drugs available an those about to appear in the market. METHODS: A review of the most recent studies published regarding the physiopathology of Alzheimer disease and the results following treatment with donepezil, rivastigmine and metriphonate was carried out. RESULTS: Donepezil is a specific, reversible acetylcholinesterase inhibitor of close to 100% absorption and a half-life of 70 h, achieving stable concentrations at approximately 3 weeks. Patients treated with a single daily dosis of 5 or 10 mg improve in the ADAS-Cog scale. The medication is initiated with a dosis of 5 mg/day. Rivastigmine is a competitive, pseudoirreversible inhibitor with a half-life of 2 h, although it acts for approximately 10 h. The Adas-Cog scale and the CIBIC-Plus improve in patients treated with a daily dosis of 6 or 12 mg taken in two doses. Administration should be initiated at low doses (3 mg/day) which are progressively increased. Metriphonate is a prodrug of short life which inhibits acetylcholinesterase through a metabolite (DDVP) with a half-life in the circulation of 2 h. Improvement is observed in the ADAS-Cog scale and the CIBIC-Plus and in behavior disorders at doses of 0.3 and 0.65 mg/kg/day. Doses between 30 and 60 mg/day are effective. CONCLUSIONS: Different studies carried out with the acetylcholinesterase inhibitors donepezil, rivastigmine and metriphonate have been effective in the control of the cognitive symptoms of Alzheimer disease in the initial or moderate phases of the disease. 118. Olin, J. and L. Schneider, Galantamine for Alzheimer's disease (Cochrane Review). Cochrane Database Syst Rev, 2002(3): p. CD001747. BACKGROUND: Galantamine (also called galanthamine, marketed by Janssen as Reminyl) was originally isolated from several plants, including daffodil bulbs, but is now synthesized. Galantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor. It is also an allosteric modulator at nicotinic cholinergic receptor sites potentiating cholinergic nicotinic neurotransmission. A small number of early studies showed mild cognitive and global benefits for patients with Alzheimer's disease (AD), and recently several multicentre clinical trials have been published with positive findings. Galantamine has received regulatory approval in 29 counties: Argentina, Australia, Canada, Czechia, the European Union (except for The Netherlands), Iceland, Korea, Mexico, Norway, Poland, Singapore, South Africa, Switzerland, Thailand, and the United States. OBJECTIVES: The objective of this overview is to assess the clinical effects of galantamine in patients with probable AD, and to investigate potential moderators of an effect. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 15 May 2002 using the terms galantamine and Reminyl. Published reviews were inspected for further sources. Additional information was collected from an unpublished investigational brochure for galantamine. SELECTION CRITERIA: Trials selected were randomized, double-blind, parallel-group, unconfounded comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks for people with AD. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers and pooled where appropriate and possible. The pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Intention-to-treat and observed cases data were both reported, if the data were available. ~bullet~Outcomes of interest include the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), clinical global impression of change (CIBIC-plus or CGIC), Alzheimer's Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL), Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI). ~bullet~Potential moderating variables of a treatment effect included trial duration and dose. MAIN RESULTS: Seven trials were identified that met criteria for entry, with six being Phase II or III industry-sponsored multicentre trials. Two were of 12 weeks duration; one of 13 weeks, one of 5 months; one of 29 weeks; and two of 6 months duration. Trials of 5 months or more were aggregated together in the analyses as '6 months.' Overall, galantamine showed significant treatment effects at daily doses of 16-32 mg for trials of 3- to 6-months duration. For global ratings, trials of 3 months duration with doses of 24-32mg/d (Odds Ratio (OR) 2.3; 95%CI 1.3 - 3.9) and 36mg/d (OR 3.4; 95%CI 1.2 - 9.5) were statistically significant in favour of treatment. For trials of 6 months duration (5-months to 29 weeks), only doses of 8mg/d failed to be associated with statistically significant benefit (16mg: OR 2.25; 95% CI 1.6 - 3.3; 24mg: OR 2.0; 95%CI 1.5 -2.5; 32mg: OR 1.9; 95%CI 1.4 - 2.5). For cognitive function over 6 months duration: at 16mg/d, improvements measured -3.3 points (k=1; 95%CI -4.4 - -2.1) on weighted mean difference on the ADAS-Cog scale; -3.5 points at 24mg/d (k=3; 95%CI -4.3 - -2.8), and -4.0 points at 32mg/d (k=2; 95%CI -5.0 - -3.0). The two 3-month trials with ADAS-Cog data also showed statistically significant improvement. Both observed cases (WMD 3.8; 95%CI 0.3 - 7.3) and intention-to-treat analyses using the Disability Assessment of Dementia scale gave statistically significant results in favour of treatment for daily doses of 32mg for 6 months duration (as did the single 3-month trial of 24-32mg/d treatment that used this scale). The small number of trials available for analysis, however, limited the power of subgroup analyses to detect differences. Galantamine consistently failed to show statistically significant treatment effects at doses of 8mg/day. Galantamine's adverse effects appear similar to those of other cholinesterase inhibitors, in that it tends to produce gastrointestinal symptoms acutely and with dosage increases. Overall, participants treated with galantamine at all doses for 3 months were more likely to discontinue that were those given placebo. Participants treated with galantamine at doses of 24-32 mg/d for 6 months were more likely to discontinue in most trials than were those treated with lower doses or placebo, with 32mg/d being associated with significantly higher withdrawal rates than was 24mg/d. However, in the one trial with a slower rate of titration the discontinuation rate was not significantly greater than placebo for the 16 mg/day dose. REVIEWER'S CONCLUSIONS: Patients in these trials were similar to those seen in earlier anti dementia AD trials, and consisted predominantly of mildly to moderately impaired outpatients. Galantamine's effects on more severely impaired people has not yet been assessed. Never the less, this review shows consistent positive effects for galantamine for trials of 3 months, 5 months and 6 months duration. In addition, although there was not a statistically significant dose-response effect, benefits associated with doses above 8mg/d were, for the most part, consistently statistically significant. There is therefore evidence for efficacy of galantamine on global ratings, cognitive tests, assessments of ADLs and behaviour. This magnitude for the cognitive effect is similar to that associated with other cholinesterase inhibitors including donepezil, rivastigmine, and tacrine. Galantamine's safety profile is similar to that of other cholinesterase inhibitors with regard to cholinergically mediated gastrointestinal symptoms. No information is available on adverse events that occurred less than 5% of the time. It appears that doses of 16 mg/d were best tolerated in the single trial where medication was titrated over 4-week periods, and because this dose showed statistically indistinguishable efficacy with higher doses, it is probably preferable initially. Longer-term use of galantamine has not been assessed in a controlled fashion. 119. Rogers, S.L., et al., Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med, 1998. 158(9): p. 1021-31. BACKGROUND: Donepezil hydrochloride (Aricept) is a selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer disease. This phase 3 study was 1 of 2 pivotal trials undertaken to establish the efficacy and safety of using donepezil in patients with mild to moderately severe Alzheimer disease. OBJECTIVES: To further examine the efficacy and safety of using donepezil in the treatment of patients with mild to moderately severe Alzheimer disease. To examine the relationships between plasma donepezil concentrations, inhibition of red blood cell acetylcholinesterase activity, and clinical response. METHODS: This was a 12-week, double-blind, placebo-controlled, parallel-group trial with a 3-week single-blind washout. Outpatients at 23 centers in the United States were randomized to receive placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride (5 mg/d during week 1 then 10 mg/d thereafter) administered once daily at bedtime. Primary efficacy was measured using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change including caregiver information (CIBIC plus). RESULTS: A total of 468 patients entered the study, more than 97% of whom were included in the intention-to-treat (end point) analyses. The use of donepezil produced statistically significant improvements in ADAS-cog, CIBIC plus, and Mini-Mental State Examination scores, relative to placebo. The mean drug-placebo differences, at end point, for the groups receiving 5 mg/d and 10 mg/d of donepezil hydrochloride were, respectively, 2.5 and 3.1 units for ADAS-cog (P<.001); 0.3 and 0.4 units for CIBIC plus (P< or =.008); and 1.0 and 1.3 units for Mini-Mental State Examination (P< or =.004). On the CIBIC plus scale, 32% and 38% of patients, respectively, treated with 5 mg/d and 10 mg/d of donepezil hydrochloride demonstrated clinical improvement (a score of 1, 2, or 3) compared with placebo (18%). The mean (+/-SEM) donepezil plasma concentrations at study end point were 25.9 +/- 0.7 ng/mL and 50.6 +/- 1.9 ng/mL in the groups receiving dosages of 5 mg/d and 10 mg/d, respectively. Corresponding mean (+/-SEM) percentages of inhibition of red blood cell acetylcholinesterase activity were 63.9% +/- 0.9% and 74.7% +/- 1.2% for these 2 dosages, respectively. There was a statistically significant positive correlation between plasma concentrations of donepezil and acetylcholinesterase inhibition; the EC50 (50% effect) was obtained at a concentration of 15.6 ng/mL. A plateau of inhibition (80%-90%) was reached at plasma donepezil concentrations higher than 50 ng/mL. The correlations between plasma drug concentrations and both ADAS-cog (P<.001) and CIBIC plus (P = .006) were also statistically significant, as were the correlations between red blood cell acetylcholinesterase inhibition and change in ADAS-cog (P<.001) and CIBIC plus (P = .005). The incidence of treatment-emergent adverse events with both dosages of donepezil (68%-78%) was comparable with that observed with placebo (69%). The use of 10 mg/d of donepezil hydrochloride was associated with transient mild nausea, insomnia, and diarrhea. There were no treatment-emergent clinically significant changes in vital signs or clinical laboratory test results. More important, the use of donepezil was not associated with the hepatotoxic effects observed with acridine-based cholinesterase inhibitors. CONCLUSION: Donepezil hydrochloride (5 and 10 mg) administered once daily is a well-tolerated and efficacious agent for treating the symptoms of mild to moderately severe Alzheimer disease. 120. Donnelly-Roberts, D.L., et al., ABT-594 [(R)-5-(2-Azetidinyl-methoxy)-2-Chloropyridine]: A novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization. J Pharmacol Exp Ther, 1998. 285(2): p. 777-786. 121. Damaj, M.I., et al., Pharmacological effects of epibatidine optical enantiomers. Brain Res, 1994. 662(1-2): p. 34-40. 122. Damaj, M.I. and B.R. Martin, Tolerance to the antinociceptive effect of epibatidine after acute and chronic administration in mice. Eur J Pharmacol, 1996. 300(1-2): p. 51-57. 123. Barlocco, D., et al., Mono- and di-substituted-3,8-Diazabicyclo[3.2.1] octane derivatives as analgesics structurally related to epibatidine: synthesis, activity, and modeling. J Med Chem, 1998. 41(5): p. 674-681. 124. Bannon, A.W., K.L. Gunther, and M.W. Decker, Is epibatidine really analgesic? Dissociation of the activity, temperature, and analgesic effects of (+/-)-epibatidine. Pharmacol Biochem Behav, 1995. 51(4): p. 693-698. The experiments in the present study were designed to determine if the activity, temperature, and analgesic effects of (+/-)-epibatidine treatment could be dissociated. Initially (i.e., 15 min) (+/-)-epibatidine treatment (0.1 mumol/kg = 28 micrograms/kg, IP) impaired rotorod performance, decreased activity, decreased temperature, and increased jump latency (e.g., analgesic effect). For the remaining time points measured (i.e., 30, 60, and 120 min), activity and temperature remained significantly reduced. In contrast, by 120 min (+/-)-epibatidine's effects on rotorod performance and analgesia (jump latency) were not observed. When administered after (+/-)-epibatidine (0.05 mumol/kg, IP), mecamylamine treatment (5 mumol/kg = 1 mg/kg, IP) produced a potentiation of analgesia. This potentiation effect was not observed on activity and temperature measures. The effect of (+/-)-epibatidine treatment (0.1 mumol/kg, IP) was also determined in mice with central nicotinic receptor blockade induced by treatment with chlorisondamine (23 mumol/kg = 10 mg/kg, IP). An (+/-)-epibatidine-induced reduction in activity was not attenuated in chlorisondamine-treated mice and only a minimal effect was observed on (+/-)-epibatidine-induced hypothermia in chlorisondamine-treated mice. In contrast, in chlorisondamine-treated mice (+/-)-epibatidine's analgesic effect was attenuated. Taken together, these data suggest that various centrally mediated effects of (+/-)-epibatidine can be dissociated. 125. Holladay, M.W., et al., Identification and initial structure-activity relationships of (R)-5-(2-Azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors. J Med Chem, 1998. 41(4): p. 407-412. Abstract: New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (i.p.) or oral (p.o.) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity. 126. Khan, I.M., T.L. Yaksh, and P. Taylor, Epibatidine binding sites and activity in the spinal cord. Brain Res, 1997. 753(2): p. 269-282. 127. Puttfarcken, P.S., et al., Evidence for nicotinic receptors potentially modulating nociceptive transmission at the level of the primary sensory neuron: Studies with F11 cells. J Neurochem, 1997. 69(3): p. 930-938. 128. Rao, T.S., et al., Evaluation of anti-nociceptive effects of neuronal nicotinic acetylcholine receptor (NAChR) ligands in the rat tail-flick assay. Neuropharmacology, 1996. 35(4): p. 393-405. 129. Rupniak, N.M., et al., Antinociceptive and toxic effects of (+)-epibatidine oxalate attributable to nicotinic agonist activity. Br J Pharmacol, 1994. 113(4): p. 1487-1493. 130. Jurna, I., P. Krauss, and J. Baldauf, Depression by nicotine of pain-related nociceptive activity in the rat thalamus and spinal cord. Clin Investig, 1993. 72(1): p. 65-73. 131. Ando, Y., Transdermal nicotine for ulcerative colitis [letter]. Ann Intern Med, 1997. 127(6): p. 491-2; discussion 492-3. 132. Baron, J.A., Beneficial effects of nicotine and cigarette smoking: the real, the possible and the spurious. Br Med Bull, 1996. 52(1): p. 58-73. Cigarette smoking is an established risk factor for cancer and cardiovascular disease, and is the leading cause of avoidable disease in most industrialized countries. Less well-known are possible beneficial effects, which are briefly considered in this survey. Preliminary data suggest that there may be inverse associations of smoking with uterine fibroids and endometriosis, and protective effects on hypertensive disorders and vomiting of pregnancy are likely. Smoking has consistently been found to be inversely related to the risk of endometrial cancer, but cancers of the breast and colon seem unrelated to smoking. Inverse associations with venous thrombosis and fatality after myocardial infarction are probably not causal, but indications of benefits with regard to recurrent aphthous ulcers, ulcerative colitis, and control of body weight may well reflect a genuine benefit. Evidence is growing that cigarette smoking and nicotine may prevent or ameliorate Parkinson's disease, and could do so in Alzheimer's dementia. A variety of mechanisms for potentially beneficial effects of smoking have been proposed, but three predominate: the 'anti-estrogenic effect' of smoking; alterations in prostaglandin production; and stimulation of nicotinic cholinergic receptors in the central nervous system. Even established inverse associations cannot be used as a rationale for cigarette smoking. These data can be used, however, to clarify mechanisms of disease, and point to productive treatment or preventive options with more narrowly-acting interventions. 133. Birtwistle, J. and K. Hall, Does nicotine have beneficial effects in the treatment of certain diseases? Br J Nurs, 1996. 5(19): p. 1195-202. Although tobacco smoking has long been associated with diseases of the lungs and cardiovascular system, numerous studies have demonstrated a negative association between tobacco smoking and ulcerative colitis, and the neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD). The evidence suggests that nicotine--the main pharmacologically active ingredient of tobacco--appears to be responsible for this effect. Pure nicotine has no known carcinogenic properties and can be administered in numerous ways including transdermal patches and tablets. As a therapeutic agent, its association with tobacco can be likened to morphine and opium smoking. There is ample clinical evidence to suggest that nicotine could be beneficial in the treatment of some patients with diseases. Pharmacologically, nicotine acts on cholinergic (nicotinic-specific) receptors which are depleted in AD and PD. Nicotinic receptors also interact closely with several neurotransmitters including dopamine, which is implicated in both PD and Gilles de la Tourettes's syndrome. There is no doubt that tobacco smoking can be harmful and no-one should be encouraged to smoke. However, although nicotine has many harmful side-effects, it may have therapeutic value or at the very least be a useful tool for future drug development. 134. Bonapace, C.R. and D.A. Mays, The effect of mesalamine and nicotine in the treatment of inflammatory bowel disease. Ann Pharmacother, 1997. 31(7-8): p. 907-13. OBJECTIVE: To characterize the usefulness of mesalamine and nicotine in the treatment of active ulcerative colitis and inactive Crohn's disease. DATA SOURCES: Citations were selected from the MEDLINE database. Only those involving human subjects, inflammatory bowel disease, and available in English were selected. STUDY SELECTION: Selection criteria of clinical trials and review articles assessing the effects of mesalamine and nicotine in active ulcerative colitis or inactive Crohn's disease and the utility of reducing steroid dependence or relapse rate. Less than 20% of the articles identified met the selection criteria. DATA SYNTHESIS: In patients with inactive Crohn's disease, mesalamine 2 g/d significantly reduced the risk of relapse in high-relapse-risk patients compared with placebo, reducing the relapse rate from 71% to 55%, but was ineffective in preventing recurrence of inactive Crohn's disease following surgical resection. Mesalamine 4 g/d was effective in decreasing weaning failure due to steroid dependence by 67%, although the relapse rate was not significant compared with placebo at the end of 12 months. Following surgical resection, mesalamine was unable to significantly reduce the incidence of recurrence compared with placebo at the end of 1 year. In patients with active ulcerative colitis, oral mesalamine 2 and 4 g/d was superior to placebo in inducing remission compared with placebo. Among patients with prior steroid of sulfasalazine treatment, rectal mesalamine 4 g hs achieved a remission rate of 78% in more than 12 weeks of therapy. Other studies have not found a dose-response relationship with lower dosages of mesalamine. Whereas nicotine 15-25 mg/d administered as a transdermal patch produced greater symptomatic improvement in active ulcerative colitis compared with placebo, nicotine 15 mg/16 h produced results no different from those with placebo in maintaining remission in active colitis. Nicotine appears to have an adverse effect on the course of Crohn's disease and is not recommended. CONCLUSIONS: Mesalamine has demonstrated clinical effectiveness as a therapeutic agent in the treatment of active ulcerative colitis and inactive Crohn's disease. Although its relationship to inflammatory bowel disease has been known for many years, the usefulness of nicotine for the treatment of active ulcerative colitis requires further exploration before it can be recommended as therapeutic agent. 135. Bonner, G.F., Current medical therapy for inflammatory bowel disease [see comments]. South Med J, 1996. 89(6): p. 556-66. Traditional medical therapy for inflammatory bowel disease (IBD) includes corticosteroids and sulfasalazine. In recent years, several mesalamine derivatives of sulfasalazine have become available. These allow delivery of increased dosages of active medication with minimal side effects. Newer steroid preparations, all investigational at this point, likely will offer efficacy similar to that of prednisone but with an improved side effect profile. Immunosuppressive agents, including 6-mercaptopurine, azathioprine, and likely also methotrexate, are beneficial in treating refractory IBD, particularly in patients with chronic steroid dependence. Cyclosporine has been shown to be remarkably effective in delaying colectomy for severe ulcerative colitis, but its long-term role remains uncertain. 136. Compton, R.F., et al., A dose-ranging pharmacokinetic study of nicotine tartrate following single-dose delayed-release oral and intravenous administration. Aliment Pharmacol Ther, 1997. 11(5): p. 865-74. BACKGROUND: Ulcerative colitis is predominantly a disease of non-smokers, and transdermal nicotine is therapeutic but often results in side-effects. Administration of nicotine tartrate as a liquid enema decreases systemic nicotine absorption and may be effective for treatment of active distal ulcerative colitis. Ileocolonic delivery of nicotine tartrate via a delayed release oral capsule would be the preferred route to deliver nicotine to the colon. AIM: To determine the bioavailability and pharmacokinetic parameters of delayed-release oral nicotine tartrate capsules (Eudragit S100 coated) at doses of 3 mg and 6 mg nicotine. METHODS: Twenty healthy human subjects received delayed-release oral nicotine tartrate at one of two doses (each group n = 10): 3 mg and 6 mg nicotine. All subjects also received intravenous nicotine tartrate (at a dose of 15 micrograms nicotine base/kg) during a separate study period. Serum nicotine concentrations were determined by gas chromatography-mass spectrometry. In addition, concentrations of serum cotinine (major nicotine metabolite) were determined by high-performance liquid chromatography in all samples for two subjects (both given 6 mg nicotine). Adverse reactions were determined by questionnaire. RESULTS: The mean bioavailabilities of nicotine after ileocolonic nicotine tartrate administration via delayed-release oral capsules at doses 3 mg and 6 mg nicotine were 41% and 42%, respectively. The ratios (after adjusting for nicotine dose) of cotinine area under the curve (AUC) for delayed-release oral nicotine to cotinine AUC for intravenous nicotine were 1.5 and 1.6 for the two subjects undergoing cotinine pharmacokinetics, demonstrating significant first-pass metabolism. Serum nicotine concentrations did not predict adverse reactions. CONCLUSIONS: Nicotine tartrate delivered to the ileocolon as a delayed-release oral capsule at doses of 3 mg and 6 mg nicotine considerably reduced systemic nicotine bioavailability. This reduction in bioavailability appears to be a result of first-pass hepatic metabolism rather than poor mucosal absorption of nicotine. The therapeutic potential of an ileocolonic delivery formulation of nicotine tartrate, which can potentially limit toxicity by local delivery of high doses of nicotine, should be investigated in patients with ulcerative colitis. 137. Finnie, I.A., et al., Stimulation of colonic mucin synthesis by corticosteroids and nicotine. Clin Sci (Colch), 1996. 91(3): p. 359-64. 1. We speculated that corticosteroids might cause beneficial stimulation of mucus synthesis, since this is a known action of carbenoxolone, itself a corticosteroid, and has also been proposed as a possible mechanism for the protective effect of smoking on ulcerative colitis. We have therefore compared the effects of corticosteroids including carbenoxolone, and nicotine on mucin synthesis, assessed by incorporation of N-[3H]acetylglucosamine into mucin by colonic epithelial biopsies in culture. 2. In histologically normal biopsies from the left colon, hydrocortisone and prednisolone caused a very marked concentration-dependent increase in mucin synthesis, with maximal effect (580 and 300% of control values respectively) at 6 mumol/l [P < 0.001, n = 35 biopsies (seven patients)] and 1.5 mumol/l [P < 0.001, n = 35 (seven patients)] respectively. The maximal effect of hydrocortisone was significantly greater than that of prednisolone (P < 0.05). Carbenoxolone, 0.17 mmol/l, also increased mucin synthesis in the left colon by 242% [P < 0.05, n = 15 (three patients)]. In contrast, these corticosteroids caused only a small, non-significant increase in mucin synthesis in the histologically normal right colon; fludrocortisone, 2 and 20 mumol/l, and aldosterone, 0.1-10 mumol/l, had no effect. Nicotine significantly increased mucin synthesis (180-220% of control values) between 62.5 nmol/l and 6.25 mumol/l (P < 0.05 at all concentrations) in both the right and left colon. In biopsies from the relatively uninvolved right colon of patients with ulcerative colitis, corticosteroids and nicotine caused relatively smaller increases in mucin synthesis. 3. The marked stimulation of mucin synthesis by corticosteroids suggests that this may account, at least in part, for their therapeutic effect in ulcerative colitis. 138. Green, J.T., et al., Nicotine enemas for active ulcerative colitis--a pilot study. Aliment Pharmacol Ther, 1997. 11(5): p. 859-63. BACKGROUND: Since transdermal nicotine is of value in the treatment of active ulcerative colitis but is often associated with side-effects, an alternative in the form of topical therapy with nicotine enemas has been developed. METHODS: In an open study, 22 patients with active colitis, all non-smokers, were asked to take a 100 mL enema containing 6 mg of nicotine every night for 4 weeks. Pre-trial treatment using mesalazine (n = 16), oral prednisolone (8), cyclosporin (1) and azathioprine (1) was kept constant for the month prior to assessment and during the study period. Symptoms, with stool frequency, were recorded on a diary card and an endoscopy was performed with rectal biopsy at the beginning of the study and after 4 weeks. RESULTS: Seventeen of the 22 patients completed 1 month of treatment. Mean duration of relapse was 29 weeks, range 3-94. Sixteen of 17 improved their St Mark's score. Urgency and stool frequency improved in 12 patients, sigmoidoscopic and histological scores in 10. Three patients had a full remission of symptoms with normal sigmoidoscopy. Six of 10 with a partial response continued with the enemas for a second month and five showed further improvement with full remission in two. The enema appeared effective when added to conventional treatment and produced few side-effects. CONCLUSION: Topical nicotine therapy for ulcerative colitis may have a place in future management, but controlled studies are needed. 139. Griffel, L. and K.M. Das, Nicotine and ulcerative colitis. Natl Med J India, 1994. 7(5): p. 222-3. 140. Guslandi, M. and A. Tittobello, Pilot trial of nicotine patches as an alternative to corticosteroids in ulcerative colitis. J Gastroenterol, 1996. 31(4): p. 627-9. In ten patients with mild to moderate clinical relapses of ulcerative colitis during treatment with mesalazine (1 g t.i.d.) and with a previous history of poorly tolerated steroid courses, transdermal nicotine (15 mg daily) was added for 4 weeks. Clinical findings were assessed by employing Rachmilewitz's activity index. In 7 of the patients, clinical remission was achieved, the results persisting for up to 3 months after nicotine withdrawal. Endoscopic and histological examination, when performed, confirmed the clinical findings. Nicotine patches may represent a good alternative to steroids in selected patients with mild to moderate relapses of ulcerative colitis. The precise mechanism of action remains unknown. 141. Guslandi, M. and A. Tittobello, Transdermal nicotine for ulcerative colitis [letter]. Ann Intern Med, 1997. 127(6): p. 492; discussion 492-3. 142. Kennedy, L.D., Nicotine therapy for ulcerative colitis. Ann Pharmacother, 1996. 30(9): p. 1022-3. Smoking has been associated with a decreased frequency of UC. Currently, the role of nicotine for the treatment of UC is not established. Several studies have evaluated nicotine gum and transdermal patches as supplemental therapy for stable UC, but nicotine has not been compared with other treatment modalities. Nicotine dosages in the studies have varied from 5 to 30 mg/d without apparent dose-related therapeutic effects, and many patients have found relief from placebo treatment. Patients often do not tolerate nicotine therapy's adverse effects, which can include nausea, light-headedness, and headache. Due to the cyclic disease course of UC and the potential addictiveness of nicotine, further large studies are warranted to assess the benefits of nicotine therapy for UC. These studies should be conducted using a randomized, double-blind design with an extensive follow-up period. Until further trials are conducted, nicotine should generally not be recommended for UC treatment. 143. Koop, I., [Nicotine for ulcerative colitis--a new therapeutic principle?]. Z Gastroenterol, 1994. 32(11): p. 656-7. 144. Paran, H., et al., Treatment of acute colonic pseudo-obstruction with neostigmine. J Am Coll Surg, 2000. 190(3): p. 315-8. BACKGROUND: Colonic pseudo-obstruction is a poorly understood syndrome, described by Ogilvie, and characterized by signs of large-bowel obstruction, without a mechanical cause. An imbalance in the autonomic nerve supply to the colon has been suggested as the pathophysiology. Recently, promising results with pharmacologic manipulation with neostigmine have been described. STUDY DESIGN: A prospective study was undertaken with 11 consecutive patients with clinical and radiologic signs of colonic pseudo-obstruction, in one general hospital, over a 1-year period. Patients were treated primarily with 2.5 mg of neostigmine in 100 mL of saline for 1 hour, under cardiac monitoring. Results were assessed by the clinical and radiologic responses. RESULTS: Rapid and effective spontaneous decompression of the colon was achieved in 8 patients after a single dose of neostigmine, within a mean of 90 minutes from the beginning of treatment. In another two patients decompression occurred only after a second dose was administered 3 hours after the first dose. In one patient, no changes were observed and colonoscopic decompression was performed. No significant bradycardia was observed in any of the patients. CONCLUSIONS: Neostigmine is a simple, safe, and effective therapy for treatment of colonic pseudo-obstruction. 145. Pierach, C.A., Neostigmine for acute colonic pseudo-obstruction. N Engl J Med, 1999. 341(21): p. 1622-3. 146. Ponec, R.J., M.D. Saunders, and M.B. Kimmey, Neostigmine for the treatment of acute colonic pseudo-obstruction. N Engl J Med, 1999. 341(3): p. 137-41. BACKGROUND: Acute colonic pseudo-obstruction -- that is, massive dilation of the colon without mechanical obstruction -- may develop after surgery or severe illness. Although it may resolve with conservative therapy, colonoscopic decompression is sometimes needed to prevent ischemia and perforation of the bowel. Uncontrolled studies have suggested that neostigmine, may be an effective treatment. METHODS: We studied 21 patients with acute colonic pseudo-obstruction. All had abdominal distention and radiographic evidence of colonic dilation, with a cecal diameter of at least 10 cm, and had had no response to at least 24 hours of conservative treatment. We randomly assigned 11 to receive 2.0 mg of neostigmine intravenously and 10 to receive intravenous saline. A physician who was unaware of the patients' treatment assignments recorded clinical response (defined as prompt evacuation of flatus or stool and a reduction in abdominal distention), abdominal circumference, and measurements of the colon on radiographs. Patients who had no response to the initial injection were eligible to receive open-label neostigmine three hours later. RESULTS: Ten of the 11 patients who received neostigmine had prompt colonic decompression, as compared with none of the 10 patients who received placebo (P<0.001). The median time to response was 4 minutes (range, 3 to 30). Seven patients in the placebo group and the one patient in the neostigmine group without an initial response received open-label neostigmine; all had colonic decompression. Two patients who had an initial response to neostigmine required colonoscopic decompression for recurrence of colonic distention; one eventually underwent subtotal colectomy. Side effects of neostigmine included abdominal pain, excess salivation, and vomiting. Symptomatic bradycardia developed in two patients and was treated with atropine. CONCLUSIONS: In patients with acute colonic pseudo-obstruction who have not had a response to conservative therapy, treatment with neostigmine rapidly decompresses the colon. 147. Sarna, S., et al., Effect of stress, meal and neostigmine on rectosigmoid electrical control activity (ECA) in normals and in irritable bowel syndrome patients. Dig Dis Sci, 1982. 27(7): p. 582-91. An intraluminal probe with two sets of bipolar electrodes (4 cm apart) was used to record electrical control activity (ECA) from the rectosigmoid of 17 normal subjects and 16 IBS patients in the resting state, during neutral and stressful interviews, and after a meal or neostigmine. Fast Fourier transform method was used for the frequency analysis of ECA. The ECA was present at all times in both the groups but was variable in frequency and amplitude and was phase-unlocked during all recording periods. Up to four frequency components were observed in the lower frequency range (LFR) of 2.0-9.0 c/min and up to two in the higher frequency range (HFR) of 9.0-13.0 c/min during all recording periods. The frequency and organization of ECA were not significantly different between the normal and the IBS groups in the resting state. Neutral and stressful interviews did not significantly affect the mean ECA frequency in either of the groups but the mean ECA frequency of the dominant frequency component in LFR was lower in IBS patients than in the normal subjects during the stressful interview. Meal and neostigmine did not significantly affect the ECA frequency or its organization in either of the groups. It appears from this study that alternations in colonic ECA may not form the basis of motility disorder in irritable bowel syndrome. 148. St John, P.H. and A.G. Radcliffe, Contraindication for the use of neostigmine in colonic pseudo-obstruction. Br J Surg, 1997. 84(10): p. 1481-2. 149. Trevisani, G.T., N.H. Hyman, and J.M. Church, Neostigmine: safe and effective treatment for acute colonic pseudo-obstruction. Dis Colon Rectum, 2000. 43(5): p. 599-603. BACKGROUND: Ogilvie's syndrome, or acute colonic pseudo-obstruction, is a common and relatively dangerous condition. If left untreated, it may cause ischemic necrosis and colonic perforation, with a mortality rate as high as 50 percent. Neostigmine enhances excitatory parasympathetic activity by competing with acetylcholine for attachment to acetylcholinesterase at sites of cholinergic transmission and enhancing cholinergic action. We hypothesized that neostigmine would restore peristalsis in patients with acute colonic pseudo-obstruction. METHODS: Twenty-eight patients at Fletcher Allen Health Care and The Cleveland Clinic Foundation were treated for acute colonic pseudo-obstruction with neostigmine 2.5 mg IV over 3 minutes while being monitored with telemetry. Mechanical obstruction had been excluded. RESULTS: Complete clinical resolution of large bowel distention occurred in 26 of the 28 patients. Time to pass flatus varied from 30 seconds to 10 minutes after administration of neostigmine. No adverse effects or complications were noted. Of the two patients who did not resolve, one had a sigmoid cancer that required resection and one patient died from multiorgan failure. CONCLUSION: This study supports the theory that acute colonic pseudo-obstruction is the result of excessive parasympathetic suppression rather than sympathetic overactivity. We have shown that neostigmine is a safe and effective treatment for acute colonic pseudo-obstruction. 150. Turegano-Fuentes, F., et al., Early resolution of Ogilvie's syndrome with intravenous neostigmine: a simple, effective treatment. Dis Colon Rectum, 1997. 40(11): p. 1353-7. PURPOSE: Our aim was to assess the value of a parasympathomimetic drug (neostigmine) in the early resolution of acute colonic pseudo-obstruction (Ogilvie's syndrome). METHODS: A prospective study was undertaken in 18 consecutive patients (mean age, 76 (range, 31-87) years) with acute colonic pseudo-obstruction. After a varying period of conservative treatment in all cases, 16 patients with persistent, massive abdominal distention were given intravenous neostigmine. RESULTS: A rapid and satisfactory clinical and radiologic decompression of the large bowel was obtained in 12 patients (75 percent) after a single dose of the drug; another patient had complete resolution after a second dose, and the other 3 patients had only partial resolution, in one of them after a second dose of the drug. No patient required surgical decompression of the bowel. CONCLUSION: These results give support to the theory of excessive parasympathetic suppression in most cases of Ogilvie's syndrome. The treatment with intravenous neostigmine has proved very effective, preventing in many cases prolonged periods of uncomfortable and potentially hazardous conventional conservative management and avoiding surgical treatment in a consecutive series of patients. 151. van der Spoel, J.I., et al., Neostigmine resolves critical illness-related colonic ileus in intensive care patients with multiple organ failure--a prospective, double-blind, placebo-controlled trial. Intensive Care Med, 2001. 27(5): p. 822-7. OBJECTIVE: Critical illness-related colonic ileus (CIRCI) is characterized by the non-passage of stools in critically ill patients as a result of the absence of prokinetic movements of the colon, while the upper gastrointestinal tract functions properly and mechanical ileus is absent: We investigated whether neostigmine resulted in defecation in patients with CIRCI. DESIGN: Double-blinded, placebo-controlled prospective study. SETTING: Eighteen-bed intensive care unit. PATIENTS: Thirty ventilated patients with multiple organ failure with CIRCI for > 3 days. INTERVENTION: Continuous intravenous administration of neostigmine 0.4-0.8 mg/h over 24 h, or placebo. MEASUREMENTS AND RESULTS: Time to first defecation and adverse reactions were recorded. Thirty patients were randomized, 24 could be evaluated. The mean prestudy time was 5 days, mean APACHE II score on admission was 23.2, and mean MOF score on the day of the study was 6.4. Of the 13 patients receiving neostigmine, 11 passed stools, whereas none of the placebo-treated patients passed stools (P < 0.001). After 24 h, the non-responders received in a cross-over fashion neostigmine or placebo respectively. Eight out of the 11 neostigmine patients now passed stools (mean 11.4 h), and none of the placebo patients. Overall, in none of the patients did passage of stools occur during placebo infusion, whereas 19 of the 24 neostigmine-treated patients had defecation (79%). No acute serious adverse effects occurred, but three patients had ischemic colonic complications 7-10 days after treatment. CONCLUSION: Continuous infusion of 0.4-0.8 mg/h of neostigmine promotes defecation in ICU patients with a colonic ileus without important adverse reactions. 152. Vavilala, M.S. and A.M. Lam, Neostigmine for acute colonic pseudo-obstruction. N Engl J Med, 1999. 341(21): p. 1622; discussion 1623. 153. Nicholson, D., Neostigmine for acute colonic pseudo-obstruction. N Engl J Med, 1999. 341(21): p. 1623. 154. Loffeld, R.J., [Neostigmine for the treatment of acute pseudo-obstruction of the colon (Ogilvie syndrome)]. Ned Tijdschr Geneeskd, 2001. 145(21): p. 1034. 155. Kreis, M.E., et al., Neostigmine increases postoperative colonic motility in patients undergoing colorectal surgery. Surgery, 2001. 130(3): p. 449-56. BACKGROUND: Gastrointestinal motility is frequently impaired after abdominal surgery. We investigated the effects of neostigmine on colonic motility in patients after colorectal surgery and in healthy volunteers. METHODS: Colonic motility was recorded by a manometry/barostat system in 12 patients after left colonic or rectal resection during baseline and after the intravenous administration of increasing doses of neostigmine on postoperative days 1, 2, and 3. In addition, colonic motility was recorded in 7 healthy volunteers. RESULTS: Neostigmine increased the colonic motility index. This increase was from 135 +/- 28 mm Hg/min at baseline to 574 +/- 219 mm Hg/min after administration of 5 microg/kg neostigmine on day 3 after surgery (mean +/- SEM, P <.05). In healthy volunteers, neostigmine at a dose of 5 microg/kg increased the colonic motility index from 184 +/- 73 to 446 +/- 114 mm Hg/min (P <.05). Barostat bag volumes decreased dose-dependently after neostigmine administration in patients as well as in volunteers, indicating an increase in colonic tone. CONCLUSIONS: Colonic motility and tone increased after neostigmine administration at a dose of 5 microg/kg in postoperative patients and in healthy volunteers. Neostigmine can be used to stimulate colonic motility after colorectal surgery and has a similar effect postoperatively as in healthy volunteers. 156. Koornstra, J.J., et al., [Neostigmine treatment of acute pseudo-obstruction of colon (Ogilvie syndrome)]. Ned Tijdschr Geneeskd, 2001. 145(12): p. 586-9. In a 77-year-old male patient with Parkinson's disease and with acute pseudo-obstruction of the colon (Ogilvie's syndrome) conservative therapy was ineffective. Neostigmine was recently shown to be effective and safe for the treatment of Ogilvie's syndrome. Intravenous neostigmine treatment caused a prompt clinical and radiological response in the patient. Early recognition of the condition and prompt neostigmine treatment if conservative measures fail is important to reduce the risk of bowel perforation. 157. Hasler, W.L., Neostigmine for acute colonic pseudo-obstruction: new use for an old drug? Gastroenterology, 2000. 118(2): p. 443-4. 158. Fink, S. and T.K. Chaudhuri, Neostigmine treatment for acute colonic pseudo-obstruction. Dis Colon Rectum, 2000. 43(10): p. 1454. 159. Daaboul, B. and E.Y. Eaker, Successful decompression of colonic pseudo-obstruction with neostigmine. Am J Gastroenterol, 1999. 94(11): p. 3371-2. 160. Cyba-Altunbay, S. and J. Bauer, [Therapy of prolonged postoperative intestinal atony following interventions on the aorto-iliac circulation. Results of a prospective randomized study with ceruletide lyophilysate versus neostigmine]. Fortschr Med, 1985. 103(16): p. 441-4. 161. Breccia, M., et al., Ogilvie's syndrome in acute myeloid leukemia: pharmacological approach with neostigmine. Ann Hematol, 2001. 80(10): p. 614-6. Acute colonic pseudo-obstruction, the so-called Ogilvie's syndrome, is a rare and life-threatening digestive complication usually observed in critically ill patients. It is characterized by signs of large-bowel obstruction, without a mechanical cause, and has been reported in various settings, including acute leukemias as a complication of neutropenic enterocolitis after intensive chemotherapy. We describe the case of a young woman who, during the neutropenic phase following autologous bone marrow transplantation for relapsed acute myeloid leukemia, developed neutropenic enterocolitis complicated by an acute pseudo-obstruction of descendent colon and sigma. This process was associated with sepsis and resolved with conservative therapy of the underlying condition, using granulocyte colony-stimulating factor and intravenous neostigmine. We discuss the management of this rare syndrome. 162. Amaro, R. and A.I. Rogers, Neostigmine infusion: new standard of care for acute colonic pseudo-obstruction? Am J Gastroenterol, 2000. 95(1): p. 304-5. This study was designed to assess the efficacy of i.v. infusion of neostigmine in patients with acute colonic pseudo-obstruction, which was defined as colonic distention with a cecal diameter of at least 10 cm on plain radiographs and no radiographic evidence of mechanical obstruction. Patients who failed to respond to conventional management (nothing by mouth, nasogastric suction, postural changes, i.v. fluids, electrolyte replacement, and discontinuation of any drugs that affect colonic motility) for 24 h were included in the study. Those with bradycardia (heart rate <60/min), hypotension (systolic blood pressure <90 mm Hg), active bronchospasm, clinical or radiographic evidence of perforation, history of partial colonic resection, active gastrointestinal bleeding, pregnancy, or serum creatinine >3 mg/dL were excluded. Twenty patients were included in this prospective, randomized, double-blind, placebo-controlled study. Eleven patients received neostigmine 2.0 mg i.v. over 3-5 min with electrocardiographic monitoring, and 10 received placebo. Patients were evaluated for immediate clinical response (passage of flatus or stools associated with decreased abdominal distention within 30 min) and sustained response with decreased abdominal girth and reduced colonic dilation on radiographs 3 h after infusion. Ten patients in the neostigmine group had an immediate clinical response (median time, 4 min) compared to none in the placebo group (p<0.001). Three patients in the neostigmine group (27%) and eight in the placebo group (80%) failed to show sustained improvement 3 h after infusion (p = 0.04). Eight patients (one-neostigmine; seven-placebo) who failed to respond received open-label treatment with neostigmine. Seven patients responded; one patient from the placebo group failed and eventually required colonic resection. In conclusion, from a total of 18 patients treated with neostigmine, 17 (94%) had immediate clinical response, and 16 (89%) did not have recurrent colonic dilation. The most common side effect was crampy abdominal pain reported in 13 patients, although usually mild (nine). Symptomatic bradycardia requiring atropine occurred in two patients. Two patients in the neostigmine group died, but death was felt not to be related to acute colonic pseudo-obstruction or its treatment. 163. Althausen, P.L., et al., The use of neostigmine to treat postoperative ileus in orthopedic spinal patients. J Spinal Disord, 2001. 14(6): p. 541-5. Ileus is a common complication of spinal surgery, affecting 5% to 12% of all patients. Often this ileus is secondary to acute colonic pseudo-obstruction. This study is a prospective clinical trial of neostigmine in seven spinal patients with ileus after surgery to demonstrate its efficacy. All patients had evidence of the Ogilvie syndrome that was unresponsive to 24 hours of conservative therapy. Patients received 2 mg neostigmine, and abdominal circumference, clinical response, and radiographic colonic measurements were recorded. Patients were followed for recurrence of ileus for their remaining time in the hospital. Six patients had prompt colonic decompression, and no patient had recurrence of colonic distension. Side effects were minimal. These results suggest that postoperative spinal patients with ileus secondary to acute colonic pseudo-obstruction that is unresponsive to conservative therapy benefit from treatment with neostigmine, resulting in safe, rapid decompression of the colon. 164. Abeyta, B.J., R.M. Albrecht, and C.R. Schermer, Retrospective study of neostigmine for the treatment of acute colonic pseudo-obstruction. Am Surg, 2001. 67(3): p. 265-8; discussion 268-9. Acute colonic pseudo-obstruction (ACPO) typically develops postoperatively or after severe illness. Studies suggest that pharmacologic manipulation with intravenous (i.v.) neostigmine (NSM) may be an effective and less invasive treatment modality for ACPO with minimal side effects. The purpose of this study was to retrospectively assess the efficacy and incidence of complications of an i.v. NSM bolus in patients with ACPO. Eight patients with ten episodes of ACPO were treated with a bolus dose of NSM. Rapid and effective decompression of the colon was achieved in six episodes after a single dose of NSM at a mean of 22.8 +/- 13.5 minutes. In three episodes decompression occurred after a second dose of NSM at a mean of 44.7 +/- 37.7 minutes. One patient failed NSM treatment but responded to a Cystografin enema. One patient experienced significant bradycardia. NSM is a simple, safe, and effective treatment for ACPO and based on result comparison of this study and previous studies both bolus and slow infusion dosing practices of NSM are effective. The NSM bolus dosing side effect profile has been shown to include significant bradycardia, whereas when NSM was infused over one hour significant bradycardic episodes requiring treatment have not been encountered. We propose that a prospective study evaluating NSM dosing as an i.v. bolus versus an i.v. infusion would be useful in determining whether NSM infusion can be proven safer than bolus dosing for the treatment of ACPO. 165. Abbasakoor, F., A. Evans, and B.M. Stephenson, Neostigmine for acute colonic pseudo-obstruction. N Engl J Med, 1999. 341(21): p. 1622; discussion 1623. 166. Sadjadpour, K., Pyridostigmine bromide and constipation in Parkinson's disease. Jama, 1983. 249(9): p. 1148. 167. Yellin, A.E., J. Newman, and A.J. Donovan, Neostigmine-induced hyperperistalsis. Effects on security of colonic anastomoses. Arch Surg, 1973. 106(6): p. 779-84. 168. Salin-Pascual, R.J., et al., Effects of transdermal nicotine on mood and sleep in nonsmoking major depressed patients. Psychopharmacology (Berl), 1995. 121(4): p. 476-9. The role of nicotine as an indirect cholinergic agent in sleep has been studied in normal subjects. There are no studies of its effects on sleep in depressed patients. Nicotine transdermal patches (17.5 mg), were studied in eight depressed patients (DSM-III-R) and eight normal volunteers. Subjects wore placebo and nicotine patches for 24 h. Depressed patients showed increased REM sleep without changes in other sleep variables. They also showed a short term improvement of mood. Normal volunteers had sleep fragmentation, and reduction of REM sleep time. No major side effects were reported in either group. 169. Davis, K.L., et al., Physostigmine in mania. Arch Gen Psychiatry, 1978. 35(1): p. 119-22. Seven men and one woman with primary affective disorder, mania, were given a slow intravenous infusion of physostigmine salicylate. In six patients, mood and thought content changed from mania toward depression as evaluated by either a visual analog mood scale or the Pettersen scale. Two other patients, who were the only predominantly irritable manics in the study, demonstrated little change in their hostility, although one became somewhat depressed. These findings are consistent with earlier reports of suppression of manic symptoms after physostigmine infusion in some but not all patients with mania. The pharmacologic mechanism of physostigmine reversal of manic symptoms may be the direct result of increased cholinergic activity or a result of the effect of increased cholinergic activity on other brain neurotransmitters. 170. Khouzam, H.R. and P.M. Kissmeyer, Physostigmine temporarily and dramatically reversing acute mania. Gen Hosp Psychiatry, 1996. 18(3): p. 203-4. 171. Shopsin, B., et al., Rebound phenomena in manic patients following physostigmine. Preliminary observations. Neuropsychobiology, 1975. 1(3): p. 180-7. The authors have administered physostigmine intravenously to three hospitalized manic patients on a double-blind basis. All three individuals showed clinical change both during and after the physostigmine period, which can be clearly delineated into three distinct phases. The behavioral modifications occurring during the physostigmine run did not qualitatively alter the underlying mania. The authors focus on 'rebound' phenomena, or post-physostigmine changes, as a possible clinical index with which chemically to characterize the initial state of amine imbalance responsible for a given affective illness. The data are considered consistent with an adrenergic-dopaminergic-cholinergic balance hypothesis of affective disorders, and may provide a relevant link in understanding the interface or crossover between manic and schizo-affective illness. 172. Hein, H., et al., [Nicotine as therapy of obstructive sleep apnea?]. Pneumologie, 1995. 49 Suppl 1: p. 185-6. In 8 smokers (age 57 +/- 6 years, BMI 26.4 +/- 3.8 kg/m2) with an apnea-hypopnea index of 22.2 +/- 19.5 and who wanted to give up smoking with the help of nicotine plaster, various characteristic values of respiratory disturbances (among others, average and longest duration of various apnea and hypopnea, average and minimum oxygen saturation) were investigated during nicotine and control nights. All characteristic values, with the exception of the average oxygen saturation (from 93.7 to 94.4%, p < 0.02), did not change significant. These results indicate that nicotine could be an effective drug. However, it cannot yet be recommended for the treatment of obstructive sleep apnea because of some still unanswered questions (efficacy for non-smokers, side-effects, risk of addiction). 173. Wirth, J.A., [Organic psychosyndrome and sleep apnea. Transdermal nicotine--a new therapy concept?]. Pneumologie, 1995. 49 Suppl 1: p. 183-4. We examined 11 patients (10 female, 1 male) of 73 to 79 years of age suffering from organic psychosyndrome (HOPS), using the apnoea screen system MESAM IV (1) and APNOE-SCREEN I. All examined patients had a sleep related disordered breathing (SBAS) with apnoea index (AI) between 10 and 52 (P/h). 3 patients (2 female, 1 male) had an increasing apnoea index under medication of theophyllin 375 mg/d. these theophyllin-nonresponsive patients received transdermal Nicotin in a concentration of 21 mg/d (during the night). The apnoea index decreased not significantly, while the tiredness was reduced significantly by 42.9%, the confusion by 40% and the nightly restlessness by 50%. 174. Davila, D.G., et al., Acute effects of transdermal nicotine on sleep architecture, snoring, and sleep-disordered breathing in nonsmokers. Am J Respir Crit Care Med, 1994. 150(2): p. 469-74. Previous research has suggested that nicotine may be therapeutically useful in the treatment of sleep-disordered breathing. The development of transdermal nicotine delivery systems has allowed us to test the overnight effectiveness of nicotine. Twenty nonsmoking subjects (10 men, 10 women) were recruited on the basis of a history of habitual snoring that was confirmed by overnight laboratory monitoring. Subjects were then randomized (double-blind crossover design) to receive either placebo or an active patch that delivers 11 mg of nicotine over a 24-h period. Patches were applied at 6 P.M. and removed at 6 A.M. the following morning, at which time venous blood was obtained for determination of serum nicotine concentrations. Polysomnography was performed using standard techniques to assess sleep architecture and sleep-disordered breathing. Snoring was monitored with a sound-level meter and quantitatively analyzed to determine the snoring index (SI) (number of snores per hour of sleep) and mean and maximum snoring intensities. The age of the subjects was 46.9 +/- 11.4 yr (mean +/- SD) and their mean body mass index (BMI) 33.3 +/- 4.6 kg/m2. A mean nicotine level was nondetectable with placebo and 7.8 +/- 2.3 ng/ml with wearing of an active patch. Nicotine decreased total sleep time (TST) by 33 min (p < or 0.01), sleep efficiency from 89.7 to 83.5% (p < or = 0.01), and percent rapid eye movement (REM) sleep from 18.8 to 15.1% (p < or = 0.01), and prolonged initial sleep latency (ISL) from 6.7 to 18.2 min (p < or = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS). 175. Obermeyer, W.H. and R.M. Benca, Effects of drugs on sleep. Neurol Clin, 1996. 14(4): p. 827-40. Many commonly prescribed medications and substances of abuse can have significant effects on sleep and wakefulness. Chronic use or abuse of certain drugs may lead to the development of substance-related sleep disorders. Primary sleep disorders, such as apnea, periodic movement disorders, and parasomnias, may be exacerbated by various drugs. This article summarizes the effects of widely used medications and recreational drugs on sleep. 176. Wilson, A.L., et al., Nicotine patches in Alzheimer's disease: pilot study on learning, memory, and safety. Pharmacol Biochem Behav, 1995. 51(2-3): p. 509-14. In view of the cholinergic deficits present in patients with Alzheimer's disease (AD), a widely investigated treatment strategy for the cognitive deficits in AD is cholinergic stimulation. Although nicotinic cholinergic receptor binding has been demonstrated to be deficient in the AD brain, the predominant theoretical and therapeutic focus to date has been on muscarinic cholinergic receptors and systems. The purpose of the present study was to evaluate the effects of sustained nicotine administration on behavior, cognition, and physiology. A double-blind placebo-controlled trial was conducted in which six patients with probable AD were exposed to 7, 8, and 7 days of placebo, nicotine, and washout, respectively. Daily sessions evaluating learning, memory, and behavior were conducted. Global cognitive functioning, rest and activity levels, cardiac activity, and blood levels were also measured. Findings included improved learning during the nicotine condition, which persisted throughout washout. Memory, behavior, and global cognition were not significantly affected. Sustained administration of nicotine appeared to be safe, although sleep showed a significant decrease. 177. Vazquez, J., et al., Transdermal nicotine on sleep and PGO spikes. Brain Res, 1996. 737(1-2): p. 317-20. There is conflicting evidence for the role of nicotine in sleep regulation. This study was undertaken to determine the effects of transdermal nicotine at doses of 17.5, 35 and 52.5 mg on sleep and PGO spike activity. Minor effects were observed on sleep with a general increase in waking. PGO spike activity was abolished by all patches. The results are discussed in terms of the mechanisms involved in the disappearance of PGO spikes as a result of nicotine. 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