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)

Eptastigmine is a new acetylcholinesterase (AChE) inhibitor currently under development for the symptomatic treatment of Alzheimer disease. This study was conducted to establish the maximum tolerated dose and the pharmacodynamics of eptastigmine in nine healthy elderly volunteers. Subjects received single oral doses of 8 mg, 20 mg, 32 mg, and 40 mg eptastigmine and placebo according to a double-blind, randomized, rising-dose, five-way crossover design. Adverse events, blood pressure, heart rate, body temperature, forced expiratory volume, salivary flow, and pupilar activity were closely monitored during treatment. Pharmacodynamic activity of eptastigmine was evaluated with an assay of AChE activity in red blood cells. Eptastigmine doses of 8 mg, 20 mg, and 32 mg were well tolerated. Two of four subjects receiving the 40-mg dose developed profound AChE inhibition (58-59%) and reported severe adverse events (nausea, vomiting, syncope, and bradycardia), precluding further administration in the remaining subjects. Eptastigmine administration produced a weak effect on supine heart rate, body temperature, and pupil diameter. There were no effects on blood pressure, forced expiratory volume, salivary flow, and near point of focus. Acetylcholinesterase activity was inhibited in a dose-related fashion according to a sigmoidal (logistic) function. The mean (+/- SEM) maximum inhibition of AChE activity (Imax) was 14.5+/-3.3%, 20.4+/-2.3%, 28.7+/-2.9%, 45.2+/-1.3% and 53.6+/-2.9% after placebo, 8 mg, 20 mg, 32 mg, and 40 mg of eptastigmine, respectively. The theoretical maximum response (Emax) was 72.9%, and the dose that produced half of the maximum response (ED50) was 29.5 mg. At 24 hours, residual AChE inhibition ranged from 9% to 15%, with a half-life of recovery of the enzyme of approximately 10 hours. The maximum tolerated dose of eptastigmine after single-dose oral administration in healthy elderly subjects is 32 mg. Single oral doses of eptastigmine produce sustained, dose-related inhibition of AChE activity. Adverse events are related to the degree of AChE inhibition.
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PMID:Maximum tolerated dose and pharmacodynamics of eptastigmine in elderly healthy volunteers. 970 45

We report our first 100 cases of Alzheimer's (AD) patients treated with tacrine (Cognex) for a period of one year. At the beginning of treatment the mean Mini-Mental-Status (MMS) score was 15.1. To date 71 patients are still under treatment (12 for more than 12 months). Forty-three instances of side-effects were observed, of which 31 involved hepatic side-effects with an increase in ALAT > IN (normal value) (6 cases > 3N), the mean date of appearance was 10.4 +/- 6.8 weeks, there were 16 cholinergic side-effects (nausea, vomiting, diarrhoea), plus 4 neurologic and 2 cutaneous side-effects. These side-effects led to the arrest of the treatment in 19 cases (16 for hepatic toxicity). Treatment was reattempted after interruption in 13 cases; successfully in 3 instances only. The measure of tacrine efficacy was based on 52 MMS score re-evaluations in week 18: there was an increase of the MMS score in 22 cases (3.3 points +/- 2.5), a stabilisation in 11 cases and a decrease in 19 cases (3.3 points +/- 2.2.). In week 30, the MMS scores (35 patients) increased in 9 cases (3.6 points +/- 2.4), stabilized in 5 cases and decreased in 21 cases (3.9 points +/- 3.3). At week 52, only 28 per cent of the patients were considered as either improved or stabilized. We conclude that there is a necessity for close follow-up of tacrine-treated patients, and that globally at 8 months there is an improvement or a stabilization in 40 per cent of patients and long term (at one year) a stabilizing effect on AD patients.
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PMID:[Balance sheet of tolerance-efficacy on the use of tacrine in 100 cases of Alzheimer's disease]. 977 2

Alzheimer's disease is characterized by degeneration of various structures in the brain, with development of amyloid plaques and neurofibrillary tangles. Deficiencies of acetylcholine and other neurotransmitters also occur. Pharmacologic treatment of the disease generally seeks to correct the histopathology, the biochemical derangements or their effects. The only drugs labeled to date for the treatment of cognitive symptoms in patients with Alzheimer's disease are two cholinesterase inhibitors that prevent the breakdown of acetylcholine in the synapse. Both medications are associated with modest improvements in cognitive function. However, all benefit is lost when these drugs are discontinued; the disease then progresses to the level seen in placebo-treated patients. Tacrine, the first cholinesterase inhibitor to be so labeled, must be taken four times daily and is associated with hepatic toxicity. Donepezil is taken once daily. Side effects of the cholinesterase inhibitors include nausea, vomiting and diarrhea, which tend to subside after the titration period. Other drugs that have shown some promise in the treatment of Alzheimer's disease are vitamin E, estrogen, selegiline and a mixture of ergoloid mesylates. Anti-inflammatory drugs and nicotine are also being studied for their effects as neuroprotectors or neurotransmitter enhancers. The caregivers of patients with Alzheimer's disease may see little effect from these or other investigational agents, but nursing home placement may be delayed.
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PMID:New drugs for Alzheimer's disease. 978 82

Cholinesterase inhibitors are currently the most established treatment strategy in Alzheimer's disease. The treatment effect appears mainly to be symptomatic. Effects on progression of the disease following long term treatment, and possible neuroprotective effects, have been investigated. Delay until nursing home placement has been reported. Three cholinesterase inhibitors, tacrine, donepezil and rivastigmine, are in clinical use. Other cholinesterase inhibitors, such as galantamine (galanthamine), metrifonate, physostigmine, eptastigmine, are currently under clinical evaluation. So far the efficacy appears to be comparable between the various cholinesterase inhibitors; treatment for up to 6 months has produced an improvement in Alzheimer's Disease Assessment Scale -- Cognitive Subscale score (ADAS-cog) of between 1.8 and 4.9 in patients with Alzheimer's disease. Tacrine, donepezil, galantamine and physostigmine are reversible inhibitors of acetylcholinesterase and butyrylcholinesterase, while metrifonate is considered to be an irreversible inhibitor and rivastigmine a pseudoirreversible inhibitor. Tacrine and physostigmine have lower bioavailability, 17 to 37% and 3 to 8%, respectively, than the other cholinesterase inhibitors such as rivastigmine, galantamine and donepezil (40 to 100%). The elimination half-life is considerably longer for donepezil (70 to 80h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12h). Donepezil is therefore administered once daily in comparison to rivastigmine which is administered twice daily and tacrine which is administered 4 times daily. Simultaneous food intake lowers the plasma concentration of tacrine and reduces the adverse effects of rivastigmine. Drugs like theophylline and cimetidine have been reported to change the pharmacokinetics of tacrine and donepezil. In contrast, concomitant medication with various drugs with rivastigmine does not seem to cause any drug interactions in patients with Alzheimer's disease. Tacrine, donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Active metabolites are known for tacrine and galantamine. Rivastigmine is not metabolised via CYP enzymes, but via esterases and is excreted in the urine. Tacrine is associated with hepatotoxicity while other cholinesterase inhibitors seem devoid this adverse effect. Increased liver enzyme values have been observed in 49% of patients with Alzheimer's disease treated with tacrine. Rechallenge with tacrine reduces the incidence of elevated liver enzyme levels. Peripheral cholinergic adverse effects are common for the cholinesterase inhibitors, with an incidence ranging between 7 to 30%. For some cholinesterase inhibitors, such as rivastigmine, the cholinergic adverse effects such as nausea, vomiting, dizziness, diarrhoea and abdominal pain can be reduced by slowing the rate of dose titration.
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PMID:Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology. 988 90

The purpose of the study was to evaluate the efficacy and safety of tacrine over 30 weeks in Chinese patients with probable Alzheimer's disease (AD). A total of 100 patients with mild to moderate AD were recruited and randomly assigned to active or placebo treatment. The active group received 30 mg/day of tacrine for the first 6 weeks, 60 mg/day for the next 6 weeks, 90 mg/day for 6 more weeks and then 120 mg/day for the remaining 12 weeks. Safety evaluations included biweekly determinations of alanine aminotransferase (ALT). The primary outcome measures were Cognitive Abilities Screening Instrument (CASI), Clinical Global Impression of Change (CGIC) by investigator and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Secondary outcome measures were Mini-mental State Examination (MMSE), Alzheimer's Deficit Scale (ADS) and CGIC by caregivers. Sixty-eight patients were included in an intent-to-treat analysis (48 active and 20 placebo); 56 patients had evaluable data at week 30 (36 active and 20 placebo). The results of the complete case analysis revealed a significant improvement in the CASI and MMSE scores of the active group in the 18th week (90 mg/day) and the 30th week (120 mg/day) (p < 0.01). In the intent-to-treat analysis, significant improvement of the active group was noted on CASI at week 30 (p = 0.05), but there was no significant difference in the measures of IQCODE, CGIC and ADS. The primary reasons for withdrawal of tacrine-treated patients (39 patients, 52%) were asymptomatic ALT elevation, anorexia and nausea/vomiting. These patients all recovered from the adverse events on discontinuation of treatment. Tacrine produced a statistically significant improvement in the CASI and MMSE in Chinese patients with mild to moderate AD using a lower dose than in western people.
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PMID:A double-blind, placebo-controlled study of tacrine in Chinese patients with Alzheimer's disease. 1036 47

A substantial body of evidence indicates that aged-related changes in the fluidity and lipid composition of the plasma membrane contribute to cellular dysfunction in humans and other mammalian species. In the CNS, reductions in neuronal plasma membrane order (PMO) (i.e., increased plasma membrane fluidity) have been attributed to age as well as the presence of the beta-amyloid peptide-25-35, known to play an important role in the neuropathology of Alzheimer's disease (AD). These PMO increases may influence neurotransmitter synthesis, receptor binding, and second messenger systems as well as signal transduction pathways. The effects of neuronal PMO on learning and memory processes have not been adequately investigated, however. Based on the hypothesis that an increase in PMO may alter a number of aspects of synaptic transmission, we investigated several neurochemical and behavioral effects of the membrane ordering agent, PF-68. In cell culture, PF-68 (nmoles/mg SDS extractable protein) reduced [3H]norepinephrine (NE) uptake into differentiated PC-12 cells as well as reduced nicotine stimulated [3H]NE release. The compound (800-2400 microg/kg, i.p., resulting in nmoles/mg SDS extractable protein in the brain) decreased step-through latencies and increased the frequencies of crossing into the unsafe side of the chamber in inhibitory avoidance training. In the Morris water maze, PF-68 increased the latencies and swim distances required to locate a hidden platform and reduced the time spent and distance swam in the previous target quadrant during transfer (probe) trials. PF-68 did not impair performance of a well-learned working memory task, the rat delayed stimulus discrimination task (DSDT), however. Studies with 14C-labeled PF-68 indicated that significant (pmoles/mg wet tissue) levels of the compound entered the brain from peripheral (i.p.) injection. No PF-68 related changes were observed in swim speeds or in visual acuity tests in water maze experiments, rotorod performance, or in tests of general locomotor activity. Furthermore, latencies to select a lever in the DSDT were not affected. These results suggest that PF-68 induced deficits in learning and memory without confounding peripheral motor, sensory, or motivational effects at the tested doses. Furthermore, none of the doses induced a conditioned taste aversion to a novel 0.1% saccharin solution indicating a lack of nausea or gastrointestinal malaise induced by the compound. The data indicate that increases in neuronal plasma membrane order may have significant effects on neurotransmitter function as well as learning and memory processes. Furthermore, compounds such as PF-68 may also offer novel tools for studying the role of neuronal PMO in mnemonic processes and changes in PMO resulting from age-related disorders such as AD.
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PMID:Plasma membrane ordering agent pluronic F-68 (PF-68) reduces neurotransmitter uptake and release and produces learning and memory deficits in rats. 1064 67

A randomized, double-blind, placebo-controlled, parallel-group study was undertaken to evaluate the safety and tolerability of a once-daily oral administration of metrifonate in patients with probable mild to moderate Alzheimer disease. Metrifonate was given as a loading dose of 125-225 mg based on weight (2.5 mg/kg) for 2 weeks, followed by a maintenance dose of 50-90 mg based on weight (1.0 mg/kg) for 4 weeks. Twenty-nine patients received metrifonate, and 10 patients received placebo. Metrifonate produced a mean erythrocyte acetylcholinesterase inhibition at the end of treatment of 86.3%. The proportion of patients who experienced at least one adverse event was comparable between the metrifonate (76%) and placebo (80%) groups. Selected adverse events in disfavor of metrifonate (defined as those for which the incidence in the metrifonate and placebo groups differed by at least 10%) were diarrhea, nausea, leg cramps, and accidental injury. Adverse events were predominantly mild in intensity and transient. No severe adverse events were experienced by any patient. The most notable hemodynamic change observed during metrifonate treatment was a clinically insignificant mean decrease in the heart rate (by electrocardiogram) of approximately 9 beats/min, compared with an approximate 3-beats/min decrease for the placebo group. No muscle weakness was observed in this study. No clinically relevant laboratory abnormalities, such as liver toxicity, or changes in exercise tolerance or pulmonary function tests were found with metrifonate treatment. This metrifonate dose provided a high level of acetylcholinesterase inhibition, which was associated in these patients with a favorable safety and tolerability profile. Indeed, the magnitude of the peripheral acetylcholinesterase inhibition is the highest tolerable inhibition level yet observed.
Alzheimer Dis Assoc Disord
PMID:Randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and tolerability of metrifonate in patients with probable Alzheimer disease. The Metrifonate Study Group. 1071 3

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.
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PMID:Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer's disease: review and current status. 1113 19

Donepezil is an acetylcholinesterase inhibitor indicated for the symptomatic treatment of mild to moderate Alzheimer's disease. It is reported to have a relatively favourable side-effect profile. We report here on a pharmacovigilance study carried out post-marketing in England. An observational cohort study using the technique of Prescription-Event Monitoring was carried out. Some 1762 patients (mean age 72.9 years; 42% male) were followed up for 6 months minimum. The commonest adverse events were nausea, diarrhoea, malaise, dizziness and insomnia. Aggression, agitation and abnormal dreams were uncommonly associated with the drug. There were no cardiac rhythm disturbances or liver disorders causally associated. The commonest adverse drug reactions are already reported in the product information. Given the relatively small size of this cohort, the signals of abnormal dreams and psychiatric disturbance as possible adverse drug reactions need further investigation in carefully planned studies.
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PMID:Adverse effects associated with the use of donepezil in general practice in England. 1119 60

The effectiveness of intensive post-remission chemotherapy regimens for adult patients with acute lymphoblastic leukemia (ALL) is limited by both a high rate of disease recurrence and a substantial incidence of treatment toxicity. To evaluate a potentially more effective and less toxic approach, we conducted a multicenter phase III trial of consolidation therapies comparing the standard L10M regimen with one combining the brief, intensive L17M regimen and escalating methotrexate (MTX) and L-asparaginase (L-asp). Patients over age 15 with previously untreated ALL were eligible. Induction therapy included vincristine, prednisone, doxorubicin, cyclophosphamide and intrathecal methotrexate administered over 36 days. Patients who achieved complete remission (CR) were randomized to receive consolidation with either the L10M regimen or with DAT (daunomycin, cytosine arabinoside, 6-thioguanine) and escalating MTX and L-asp. The randomization was stratified by age, WBC and Ph chromosome status. Maintenance therapy was the same in both arms. Of 353 eligible patients, 218 (62%) achieved CR and 195 were randomized. The treatment arms did not differ significantly with respect to disease-free survival (DFS; P= 0.46) or overall survival (P= 0.39). Estimated DFS at 5 years was 32% (95% confidence interval (CI) 23-42%) in the L10M arm and 25% (95% CI 16-33%) in the DAT/MTX/L-asp arm. In each arm, 4% of patients died of toxicities (infection in all but one case). Infections and nausea/vomiting were somewhat more common in the L10M arm (occurring in 68% and 53% of patients respectively) than the DAT/MTX/L-asp arm (56% and 33%). The DAT/MTX/L-asp consolidation regimen was associated with some reduction in nonfatal toxicities, but no significant improvement in DFS, overall survival or non-relapse mortality when compared to the standard L10M regimen.
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PMID:Comparison of the L10M consolidation regimen to an alternative regimen including escalating methotrexate/L-asparaginase for adult acute lymphoblastic leukemia: a Southwest Oncology Group Study. 1123 36


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