**Abstracts 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unpublished studies, conference proceedings, graduate theses, book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.