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According to the cholinergic hypothesis, the impairment of cognitive function and the behavioural disturbances that affect patients with Alzheimer's disease are mainly due to cortical deficiencies in cholinergic transmission. Numerous cholinesterase inhibitors have been investigated for treatment of this disease, the rationale being to support the cholinergic system by blocking the degradation of acetylcholine released from presynaptic neurons. These drugs can be classified as reversible (tacrine, donepezil and galantamine), pseudo-reversible (physostigmine, eptastigmine and rivastigmine) or irreversible (metrifonate) enzyme inhibitors. This article reviews efficacy and tolerability results from 6-month placebo-controlled studies of 7 cholinesterase inhibitors: tacrine (80 to 160 mg/day), donepezil (5 to 10 mg/day), rivastigmine (1 to 12 mg/day), metrifonate (30 to 80 mg/day), eptastigmine (30 to 60 mg/day), physostigmine (30 to 36 mg/day) and galantamine (8 to 32 mg/day). All these agents have demonstrated a statistically significant, although modest, effect versus placebo on the cognitive and global performance of patients with Alzheimer's disease. Dramatic clinical response has been seen in only 3 to 5% of patients. There are no major differences in terms of efficacy between the different drugs. The mean difference between drug and placebo effects on standardised psychometric scales is about 2 to 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog; a 70-point cognitive scale) and 0.2 to 0.5 points on the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus; a 7-point global scale), or 5 to 14% of the average value of the scales. The most common adverse effects observed after administration of cholinesterase inhibitors are nausea, vomiting, diarrhoea, dizziness, asthenia and anorexia, all symptoms linked to cholinergic overstimulation. These effects are dose related and largely depend on the degree of cholinesterase inhibition. Also important is the rate of onset of cholinesterase inhibition, which depends on the kinetics of enzyme inhibition, the presence and rate of titration, and the pharmacodynamic peak-to-trough fluctuations. A model predicting the incidence of nausea based on acetylcholinesterase inhibition and the half-life of acetylcholinesterase recovery is proposed. In conclusion, cholinesterase inhibitors are the only pharmacological agents proved to be effective for the treatment of Alzheimer's disease in large, long term, double-blind, placebo-controlled trials. While the efficacy of different cholinesterase inhibitors is similar, their tolerability profiles differ. For example, the incidence of nausea (in excess of that seen with placebo) at cognitively effective dosages ranges from 1% with eptastigmine 60 mg/day to 53% with physostigmine 30 mg/day. Differences in tolerability profile may be due to the extent of peripheral acetylcholinesterase inhibition needed to reach clinical efficacy. Other contributing pharmacodynamic factors are the rate of onset of and fluctuations in acetylcholinesterase inhibition at steady state.
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PMID:Pharmacodynamic-tolerability relationships of cholinesterase inhibitors for Alzheimer's disease. 1147 43

A 73-year-old man consumed a decoction of the medicinal herb Erycibe henri Prain ("Ting Kung Teng"), as recommended in traditional Chinese medicine for arthritis. Shortly, he developed a cholinergic syndrome that included dizziness, diaphoresis, chills, lacrimation, salivation, rhinorrhea, nausea, and vomiting. He was also hypothermic and hypotensive. Notable laboratory values included a normal serum cholinesterase and transiently elevated blood urea nitrogen, creatinine, and glucose. There is no previous report on the toxicity due to this herb in the literature. Active constituents of the herb include a number of tropane alkaloids, one of which possesses cholinergic rather than anticholinergic activities. A study conducted on mice, with a related herb, has demonstrated renal, hepatic, and erythrocyte toxicity.
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PMID:Medicinal herb Erycibe henri Prain ("Ting Kung Teng") resulting in acute cholinergic syndrome. 1212 92

Pesticides, such as parathion, are metabolized by cytochrome p-450 system to paraoxon, which is a potent cholinesterase inhibitor. Paraoxonase (PON) catalyzes the hydrolysis of these toxic metabolites and protects against pesticide toxicity. A glutamine/arginine (Gln/Arg) polymorphism at amino acid position 192 of PON has been described. The Arg/Arg genotype is associated with higher serum paraoxonase activity compared to Gln/Gln. The Arg/Gln genotype is associated with intermediate serum PON activity. The potential association between PON genotype and symptoms of chronic pesticide toxicity was examined among 100 farm workers. As part of a cross-sectional study of pesticide toxicity among mixed-race farm workers in the Western Cape. South Africa, 100 farm workers were genotyped for polymorphism of the paraoxonase gene at amino acid position 192. Subjects with two or more of the following symptoms were considered to have evidence of chronic toxicity: abdominal pain, nausea, rhinorrhea, dizziness, headache, somnolence, fatigue, gait disturbance, limb numbness, paresthesias, limb pain, or limb weakness. In multivariable logistic regression analysis, the independent predictors of chronic toxicity were previous history of head trauma resulting in loss of consciousness (OR 2.8, 95% CI = 1.7-6.7), having worked as a pesticide applicator (OR 5.4, 95% CI = 3.2-8.9), and having one of the two "slow metabolism" (Gln/Gln or Gln/Arg) genotypes (OR 2.9, 95% CI = 1.7-6.9). Furthermore, the prevalence of chronic toxicity increased in a stepwise fashion from 15% among pesticide nonapplicators with a "fast metabolism" (Arg/Arg) genotype, to 42.9% among pesticide nonapplicators with "slow metabolism" (Gln/Gln or Gln/Arg) genotypes, to 58.8% among pesticide applicators with "fast metabolism" genotype, and 75.0% among pesticide applicators with "slow metabolism" genotypes (P = 0.001). Age, number of years on the job, smoking history, alcohol history, education level, plasma or red blood cell cholinesterase level, or previous history of acute organophosphate poisoning were not statistically significant predictors of chronic toxicity. The PON genotype is an important determinant of a farmworker's susceptibility to chronic pesticide poisoning.
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PMID:Association between human paraoxonase gene polymorphism and chronic symptoms in pesticide-exposed workers. 1262 27

Psychosis only rarely occurs in patients with untreated Parkinson's disease. Much more commonly, psychosis is induced by drug therapy for Parkinson's disease and is the strongest known risk factor for nursing home placement. Delusions are less frequent than hallucinations, but are more concerning as they are often paranoid in nature. Treatment begins with a search for correctable infectious, toxic, and metabolic aetiologies. If symptoms persist, anti-Parkinson's disease medications are slowly reduced. However, withdrawal of these drugs usually worsens parkinsonism and is often not tolerated. Certain atypical antipsychotics can be used to treat psychosis without compromising motor function. The choice of atypical antipsychotic is largely based on ease of use and adverse effect profile as most have comparable efficacy in improving psychosis. Currently, there are five marketed atypical drugs - clozapine, risperidone, olanzapine, quetiapine and ziprasidone. Ziprasidone is the only agent whose adverse effect profile has not been reported in Parkinson's disease. The most common adverse effects of clozapine in Parkinson's disease are sedation, orthostatic hypotension and sialorrhoea. Sedation is generally helpful since these patients are frequently awake at night and tend to have worse behavioural problems then. Clozapine does not induce deterioration of motor function, but it has the potential to cause agranulocytosis, which is idiosyncratic and not dose-related. In risperidone-treated Parkinson's disease patients, reported adverse effects include somnolence, sialorrhoea, dizziness, palpitations, constipation, delirium, fatigue, leg cramps, depression, urinary incontinence and hypotension. Although in some Parkinson's disease studies, risperidone has been well tolerated, others have shown that many patients are unable to tolerate the drug due to deterioration of motor function. While an initial study of olanzapine in Parkinson's disease psychosis showed the drug to be effective without deterioration of motor function, succeeding reports demonstrated a deleterious effect of the drug on motor functioning. The most common adverse effects of quetiapine in Parkinson's disease patients are sedation and orthostatic hypotension. There is a lack of double-blind trials; however, cumulative reports involving >200 Parkinson's disease patients strongly suggest that quetiapine is well tolerated and effective. Unlike clozapine, it does not improve tremor and may induce mild deterioration of motor function. Recently, cholinesterase inhibitors have been reported to alleviate psychosis in Parkinson's disease. Although ondansetron, an antiemetic with antiserotonergic properties, has been reported to relieve psychosis in Parkinson's disease, its prohibitive cost has prevented further study in this population. Electroconvulsive treatment is generally reserved for the patient with psychotic depression who is unable to tolerate any pharmacological therapy.
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PMID:Treatment of psychosis in Parkinson's disease: safety considerations. 1281 32

A 42-year-old pregnant woman (26 weeks of gestation, G(4)P(0+3)) presented at the emergency department with a two-hour history of dizziness, blurred vision and repeated vomiting. These symptoms started during the use of an undiluted insecticide liquid (diazinon 60 EC) while cleaning a small non-aired bathroom. After clinical and laboratory confirmation for organophosphate poisoning (plasma pseudocholinesterase levels 161 U/l), treatment with atropine and pralidoxime was started. She recovered within 7 days and delivered a healthy baby 12 weeks later (Apgar score 9 and 10) by elective cesarean section. The child showed no signs or symptoms of organophospate, atropine or pralidoxime exposure.
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PMID:Organophosphate poisoning in pregnancy: a case report. 1585 33

Reminyl (galantamine)-- a cholinesterase inhibiting component--was used in treatment of 15 patients with dementia featured by the presence of Levi bodies in brain neurons. The treatment duration was 16 weeks with elevation of the drug dosage every 4 weeks--from 8mg to 12 mg twice a day. Treatment evaluation was conducted clinically and by psychometrical tests and scales. Reminyl improved patient's state reducing cognitive, behavioral and psychotic disturbances. The highest effect was achieved in 2/3 patients. Side-effects (nausea, dizziness, dyspepsia, general sickness, etc) were observed in 47% cases. Only in 2 patients they caused treatment withdrawal. The absence of aggravation of extrapyramidal disorders is emphasized.
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PMID:[Reminyl efficacy in dementia with Levi bodies]. 1628 74

Accidental or intentional ingestion of carbofuran can produce a life-threatening syndrome that requires prompt diagnosis and treatment. This paper investigates unintentional carbofuran poisoning in farm workers. Thirteen patients were admitted to the emergency department with carbofuran poisoning between January 2002 and August 2004 (2 female, 11 male). The patients had been poisoned while mixing the liquid form of carbofuran with seeds. Their hands were red on admission. Complaints most commonly reported by the patients on admission were nausea, vomiting, headache, weakness, dizziness and blurred vision. The most commonly observed signs were tachycardia, tachypnea, salivation, miosis, elevated blood pressure, and fasciculation. Three patients were agitated and one was lethargic on admission. We reviewed the patients' medical charts retrospectively, as well as the demographic data, intoxication route, clinical and laboratory presentations, and outcomes. We made the diagnosis according to a compatible exposure history and clinical findings. The most commonly observed laboratory finding was hyperglycemia, which was found in 6 patients. Serum pseudocholinesterase level was low in only one patient. All the patients were cured and discharged from the hospital in good physical condition. Rapid onset, mild illness and quick recovery are typical characteristics of acute occupational carbofuran poisoning. We conclude that public health efforts should educate farm workers about the dangers of pesticide application so that its threat can be diminished.
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PMID:Carbofuran poisoning among farm workers. 1635 64

Methyl parathion - MP (C[8]H[10rsqbNO[5rsqbPS) is a restricted-use pesticide that has been widely used as an agricultural insecticide. It belongs to the class of organophosphate chemicals characterized by their ability to inhibit acetylcholinesterase activity. The main route of human exposure is inhalation, but dermal contact and inadvertent ingestion can also be substantial. Populations that are susceptible to MP exposure primarily are applicators, manufacturers and individuals living near application and/or disposal sites. Exposure has also been reported as a result of illegal indoor application. MP related health effects include headaches, nausea, night-waking, diarrhea, difficulty breathing, excessive sweating and salivation, incoordination, and mental confusion. Other symptoms including behavior problems, motor skill problems and impairment of memory recall have also been reported. The primary targets of toxicity are the hematopoietic system (serum cholinesterase inhibition), the cardiovascular system (cardiovascular lesions, abnormalities in heart rate and increase in heart-to-body ratio), the reproductive system (placental morphology, fibrosis and hemorrhage, and inhibition of DNA synthesis in seminiferous tubules), and the nervous system (headache, muscle weakness, insomnia, dizziness, and impaired memory). MP is believed to not have any carcinogenic effects. In an attempt to update its toxicologic profile, we hereby provide a critical review of MP-related environmental and toxicologic effects, with a special emphasis on their potential implications for public health.
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PMID:Environmental toxicology and health effects associated with methyl parathion exposure--a scientific review. 1681 98

Donepezil is a reversible inhibitor of acetylcholinesterase. Its commonest adverse events are nausea, diarrhoea, malaise, dizziness, and insomnia. Symptomatic cardiac rhythm disturbances associated with the use of donepezil are extremely unusual. An 82 year old patient with Alzheimer's disease (AD) developed complete atrioventricular block and ventricular tachyarrhythmia 1 month after starting treatment with donepezil, and was admitted to the emergency department because of dizziness and syncope. Immediately after admission, a temporary ventricular pacing catheter was placed in the right ventricle. Rhythm was observed to return to a normal sinus rhythm on the fourth day after implantation. Treatment of AD with cholinesterase inhibitors carries a risk of cardiac disturbances. In addition to sinusal bradycardia, it may lead to such major dysrhythmias as complete atrioventricular block and ventricular tachyarrhythmia, as in our case. In this report, we describe symptomatic complete atrioventricular block and ventricular tachyarrhythmia associated with the use of donepezil.
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PMID:Complete atrioventricular block and ventricular tachyarrhythmia associated with donepezil. 1685 1

Caregivers play a determining role in choosing treatments for persons with Alzheimer's disease. The objective of this study was to examine caregivers' willingness to have persons with Alzheimer's disease continue taking cholinesterase inhibitors in the event that any 1 of 11 adverse effects was to occur. Data were gathered via postal questionnaire from 375 caregivers in Montreal. Sixty-four per cent of caregivers responded ( n = 201), and most (> or =59%) were willing to continue treatment if persons with Alzheimer's disease suffered from weight loss or loss of appetite. However, most (> or =53%) were not willing to continue treatment in the event of headache, dizziness, nausea, diarrhea, vomiting, drop in blood pressure, insomnia, muscle cramps, or stomach bleeding. The use of cholinesterase inhibitors by persons with Alzheimer's disease was positively associated with caregivers' willingness to accept greater numbers of adverse effects (adjusted relative risk = 1.97; 95% CI = 1.11 to 3.61). Caregivers appear to make a risk-benefit assessment when they decide whether or not care-recipients should continue pharmacotherapy in the event of adverse effects.
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PMID:Caregiver acceptance of adverse effects and use of cholinesterase inhibitors in Alzheimer's disease. 1823 27


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