Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Donepezil (donepezil hydrochloride, E-2020, Aricept, Eisai), launched in March 1997, was the first drug to be marketed for the symptomatic treatment of Alzheimer's disease (AD) in the UK. It had been launched a year earlier in the US where clinicians had already had experience of tacrine (THA). Donepezil is a piperidine based, potent, specific, non-competitive and reversible inhibitor of acetylcholinesterase (AChE). It is structurally dissimilar from other established cholinesterase inhibitors, namely THA (an acridine compound) and the carbamates, physostigmine and rivastigmine and has a pharmacokinetic and tolerability profile distinct from these agents. Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70 h lending itself to once daily administration. The most common adverse events reported in clinical trials have been gastrointestinal, typically nausea, vomiting, diarrhoea and constipation. Headache, dizziness and sleep disturbance have also been reported; there has been no evidence of hepatotoxicity. Clinically a number of placebo-controlled trials have shown that donepezil 5 or 10 mg daily was associated with significant improvements in cognitive function, as assessed by the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS cog) after 12 or 24 weeks treatment. Significant improvements in global function and activities of daily living have also been demonstrated after 24 weeks treatment compared with placebo in patients with mild to moderate AD. Donepezil was the first rational treatment available in the UK for this disabling condition and as such received considerable attention. Much of the original attention was negative, ostensibly based on the scientific view that there was not enough published evidence to justify widespread use, but this was driven by concerns about the potentially high drug costs if all patients with AD were eligible to receive it. Considerable data have now been produced from Phase II, III and post-marketing surveillance. This drug evaluation will review the basic pharmacology of donepezil and place it in context with the trial data and the author's clinical experience with the drug.
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PMID:The pharmacology of donepezil: a new treatment of Alzheimer's disease. 1124 55

Ideally, treatment for Alzheimer's disease (AD) should prevent or cure the disease. Unfortunately, these goals appear unobtainable in the foreseeable future. Nevertheless, symptomatic relief is a feasible treatment option for AD patients and is available currently in the form of cholinesterase inhibitors such as tacrine, donepezil, metrifonate and rivastigmine. Donepezil is a second-generation, piperidine-class, selective and reversible acetylcholinesterase inhibitor. Four double-blind, placebo-controlled clinical trials of donepezil, involving over 1900 individuals with mild to moderate AD, have been published recently. In all trials, significant improvements in cognition were observed consistently for both therapeutic doses of donepezil (5 and 10 mg/d), relative to placebo. Similar donepezil-associated benefits were reported for global functioning. In addition, in one 24-wk, multinational clinical trial, patients receiving donepezil (10 mg/d) performed better than placebo-treated patients in their ability to perform complex daily functioning tasks. Donepezil was well tolerated in all trials, with approx. 79% of all donepezil-treated patients completing the studies compared with approx. 84% of placebo-treated patients. The most common adverse events associated with donepezil were generally cholinergic-induced and gastrointestinal in nature (e.g. nausea, diarrhoea, and vomiting) which were generally mild, transient and tended to occur after the dose was increased to 10 mg/d from 5 mg/d after 1 wk only. Sleep disturbances also occurred as the clinical trials utilized a bedtime dosing regimen. There was no evidence of organ toxicity or clinically significant treatment-emergent laboratory test abnormalities. Thus, donepezil appears to be a beneficial symptomatic treatment for patients with mild to moderate AD.
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PMID:Management of cognition and function: new results from the clinical trials programme of Aricept(R) (donepezil HCl). 1134 20

Studies have found that people with HIV have significant reductions in S-adenosylmethionine (SAMe). SAMe is an important ingredient in reactions used to make a substance that holds myelin, the coating on nerve fibers, together. SAMe also has been shown to have value in treating fibromyalgia and Alzheimer's disease. The drug may have potential use in fighting liver disease as well by increasing glutathione production and reducing the symptoms of cholestasis. Methionine, a substance made into SAMe by the body, might help improve HIV-related myelopathy. A study is currently enrolling patients with HIV to evaluate methionine's effectiveness in treating myelopathy. Side effects of methionine include nausea, vomiting, drowsiness, and irritability. Contact information is provided.
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PMID:SAMe as it ever was? 1136 83

Little is known about the effects of primary splenic irradiation (SI) in B-cell chronic lymphocytic leukemia (B-CLL) on subpopulations of lymphocytes, immunoglobulins, and the induction of autoantibodies against erythrocytes and platelets. Twenty-four untreated patients with B-CLL were studied prospectively. One patient was excluded from analysis because of intercurrent death. Of the remaining 23 patients, 7 were female and 16 were male, with an average age of 68.4 and 61.2 years, respectively. Treatment consisted of a weekly dose of I Gy up to a total dose of 10 Gy to the spleen. Standardized evaluation was done 2 weeks before and 6 weeks after SI. Twenty patients completed the course of SI. In 14 patients there was a partial response and in 9 patients the disease remained stable. The number of leukocytes decreased rapidly and significantly, with a decrease in the fraction of lymphocytes and an increase in the neutrophil count (all P<0.0001). There was a significant increase in platelet count, but not in hemoglobin level. Nausea, slight diarrhea, pleuropneumonia, granulopenia with fever (all n=1), urinary tract infection and high fever (n=1), and thrombocytopenia occurred (n=2). One patient received transfusion of packed cells because of upper digestive tract bleeding for which cessation of SI was not necessary. The number of malignant cells showed a significant decrease (P<0.01). No significant changes in CD4/CD8 ratio were found. The number of CD4+ and CD8+-cells, however, decreased significantly (P<0.01 and 0.03, respectively). DAT remained unchanged in most (93%) and tests for antibodies to platelets in 83% of the patients. No significant changes in immunoglobin levels were observed.
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PMID:Clinical and immunological evaluation of primary splenic irradiation in chronic lymphocytic leukemia: a study of 24 cases. 1140 Oct 87

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

(1) The reference symptomatic treatment for mild to moderate Alzheimer's disease is a cholinesterase inhibitor such as donepezil, but efficacy is only moderate and only about 10% of those patients treated actually benefit. (2) Galantamine is the fourth cholinesterase inhibitor to be marketed in France for Alzheimer's disease. The clinical file contains data from five double-blind placebo-controlled trials lasting 3-6 months, but no data comparing galantamine with other drugs. (3) These trials show that about 5-13% of patients treated with galantamine may be improved. (4) Adverse effects are very frequent, and are similar to those of other cholinesterase inhibitors, i.e. nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, etc. (5) For patients who are eligible for drug therapy, the reference treatment is still donepezil, for want of anything better.
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PMID:Galantamine: new preparation. The fourth cholinesterase inhibitor for Alzheimer's disease. 1182 42

The tolerability and safety of donepezil HCI in patients with mild to moderate Alzheimer's disease (AD) were examined in an integrated analysis of phase II/III placebo-controlled trials. Patients with mild to moderately severe AD (n=1,920) were randomised to receive donepezil (n=1,291) or placebo (n=629). Adverse events, physical examinations and clinical laboratory tests were assessed. A high completion rate (79%) was achieved in these trials. Of the 1,291 patients receiving donepezil only, 142 (11%) withdrew because of an adverse event compared with 43 of the 629 (7%) placebo patients. The most common adverse events included nausea, diarrhoea, headache, insomnia, dizziness, rhinitis, vomiting, asthenia/fatigue and anorexia. Donepezil had no clinically significant effect on any laboratory evaluations and was not associated with hepatotoxicity. These results demonstrate that donepezil is well tolerated and has a favourable safety profile at clinically effective, once-daily doses of 5 mg and 10 mg.
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PMID:Donepezil: tolerability and safety in Alzheimer's disease. 1246 88

Cholinesterase inhibitors (ChE-Is) are the standard of therapy for treatment of patients with Alzheimer disease (AD) and are the only class of drugs approved by the Food and Drug Administration (FDA) for treatment of this condition. This review provides evidenced-based recommendations for use of ChE-Is in clinical practice. The author searched computerized literature databases of the approved ChE-Is widely used in clinical practice (donepezil, rivastigmine, and galantamine), and extended the review with bibliographies from identified articles and package inserts of information reviewed by the FDA. Double-blind, placebo-controlled trials providing Class I evidence were used as data sources whenever possible. Articles with Class II and Class III data were used when Class I data were unavailable. In general, ChE-Is exert modest reproducible effects in patients with mild-to-moderate AD. Drug-placebo differences are evident on global and cognitive measures. Secondary outcomes, including measures of activities of daily living and behavior, also typically demonstrate drug-placebo differences in favor of the active agent. Head-to-head trials of ChE-Is are limited; existing trials suggest no major differences in efficacy. Observations from clinical trials imply that early initiation of therapy is associated with greater long-term benefits. Clinical trials with withdrawal periods indicate that withdrawal and re-initiation of treatment may result in loss of benefit. Open-label extensions of double-blind trials show that differences in level of functioning between treated populations and extrapolated for untreated populations continue for several years. Side effects of ChE-Is include nausea, vomiting, diarrhea, and anorexia, and are more frequent during dose escalation than maintenance therapy. Clinical-trial populations differ substantially from unselected populations of AD patients, and these selection biases demand that efficacy data from clinical trials be generalized with caution.
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PMID:Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. 1261 43

The pharmacology, dosage, adverse effects, efficacy, and economics of galantamine hydrobromide are discussed. Galantamine hydrobromide is a tertiary alkaloid that has been extracted from plant sources and is now synthesized for use in the treatment of mild to moderate Alzheimer's disease (AD). Galantamine acts both as a reversible competitive inhibitor of acetylcholinesterase (AChE) and as an allosteric modulator of nicotinic acetylcholine receptors. The recommended starting dosage is 4 mg (as the hydrobromide) twice daily. The dosage should be increased in increments of 8 mg/day in two divided doses after four weeks at a given dosage until a maintenance dosage of 16-24 mg/day in two divided doses is reached. Adverse effects are primarily mild and cholinergic and include nausea, vomiting, diarrhea, and dizziness. Five large clinical trials demonstrated that galantamine is more effective than placebo in controlling the symptoms of mild to moderate AD. Optimal therapy appears to require early initiation of the drug and a dosage-adjustment period of eight weeks. In one study, galantamine delayed full-time care by 10% and reduced the overall cost of care by $528. Because galantamine has not yet been compared directly with other AChE inhibitors, cost should be the principal factor weighed during formulary evaluations. Galantamine provides the clinician with another choice of an AChE inhibitor for use in treating AD.
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PMID:Galantamine hydrobromide: an agent for Alzheimer's disease. 1263 50

The objective of this study was to evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics of five fixed doses of ganstigmine (CHF 2819) in patients with probable Alzheimer's disease (AD). This randomized, double-blind, placebo-controlled trial evaluated five dose levels (5, 7.5, 10, 12.5, and 15 mg) administered orally once daily for 7 days. Adverse events and continuous telemetry were collected on successive panels of six patients (five active, one placebo). Acetylcholinesterase, butyrylcholinesterase, and plasma drug levels were measured. A total of 29 patients were randomized and 18 completed the study. A total of seven patients, including five of five in the 12.5-mg panel, discontinued because of adverse events. Four patients were withdrawn administratively from the first panel while an episode of atrial fibrillation (the only serious adverse event) was investigated. This panel was then repeated. Mild, transient headache or nausea were the most commonly reported adverse events. Multiple moderate adverse events in the 12.5-mg panel (including nausea, vomiting, and anorexia) led to the decision not to proceed with a 15-mg panel. Ten milligrams was determined to be the maximum tolerated dose. Ganstigmine exhibited nonlinear pharmacokinetics, was absorbed rapidly, and reached peak concentrations within 1 hour. Acetylcholinesterase inhibition was dose dependent and lasted as long as 24 hours. Ganstigmine, a novel cholinesterase inhibitor, was well tolerated within a dosing range of 5 to 10 mg. Once-daily dosing is supported by data on acetylcholinesterase inhibition.
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PMID:First clinical evaluation of ganstigmine in patients with probable Alzheimer's disease. 1278 20


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