ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

This article summarises current therapy and prophylaxis forPneumocystis carinii, Toxoplasma gondii, Leishmaniaspecies, African trypanosomes(Trypanosoma brucei gambienseandT. b. rhodesiense),and American trypanosome(Trypanosoma cruzi)infections. Each agent and the disease it causes is briefly reviewed, and current data on the structure, mode of action, indications for treatment, dosage, administration, duration of therapy, efficacy, toxicity, and necessary monitoring during therapy are discussed for each drug. Drugs considered include cotrimoxazole (trimethoprim + sulfamethoxazole), pentamidine, dapsone (diaphenylsulfone), trimetrexate, eflornithine (DFMO), and primaquine/clindamycin and pyrimethamine/sulphonamide combinations forPneumocystispneumonia; pyrimethamine/sulfadiazine, spiramycin, and clindamycin for toxoplasmosis; pentavalent antimonials (‘Pentostam’ and ‘Glucantime’), pentamidine, amphotericin B, allopurinol, ketoconazole, and itraconazole for leishmaniasis; suramin, pentamidine, melarsoprol, tryparsamide, Mel W, berenil, and eflornithine (DFMO) for African trypanosomiasis; and nifurtimox, benznidazole and gentian violet for American trypano-somiasis.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Estrogen deficiency, whether surgically induced or as a consequence of natural ovarian failure, has destructive effects on many organ systems. With current levels of life expectancy, untreated women may expect to spend a third of their lifetime in this state. Appropriate estrogen replacement therapy (ERT) can avert (if started promptly) or ameliorate these devastating consequences, some of which (osteoporotic fractures, increased cardiovascular morbidity) can be lethal. Nevertheless, from 10 to 20% of postmenopausal women may have significant contraindications to ERT. Treatment of symptoms and improving the quality of life is imperative, yet many physicians abjure intervention, for reasons which are not entirely clear. Recent studies of conventional intervention with sedatives or tranquillisers show results equivalent to placebo therapy. On the other hand, specific agents with demonstrated effectiveness are available for management of the major estrogen-deficiency effects, although none of them are truly adequate replacement for the effect of estrogen itself.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Sarcoidosis can affect almost every organ. It has diverse clinical presentations and a variable natural history. Lungs and intrathoracic lymph nodes are the most commonly involved tissues. A major challenge to clinicians is the early identification of those patients with aggressive disease in whom therapy might arrest progression. Although lung uptake of67Ga citrate, elevated serum angiotensin converting enzyme (ACE) levels and elevated T lymphocyte count in bronchoalveolar lavage fluid are all thought to reflect disease activity, they are by no means reliable markers.Because recent studies have shown that corticosteroid treatment does not avert pulmonary fibrosis and permanent impairment of pulmonary function, the use of these agents is restricted to the palliative treatment of disabling symptoms and physiological derangements. Corticosteroids are effective in reducing ocular inflammation, correcting hypercalcaemia, improving pulmonary function and alleviating symptoms related to hepatic, splenic, articular, myocardial, neural and cutaneous involvement.In the small proportion of patients who do not respond to moderate tolerable doses of steroids, alternative drug therapy such as immunosuppressives or immune modulators must be considered.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisTiclopidine inhibits platelet aggregation induced by adenosine diphosphate (ADP) and most other platelet agonists inex vivostudies of human platelets. The drug also improves other abnormalities of platelet function seen in patients with cerebrovascular disease, peripheral arterial disease, ischaemic heart disease or other conditions involving platelet hyperaggregation.Abnormal platelet activity has been implicated in a variety of clinical conditions in which patients are at high risk of thromboembolic events, and thus the effectiveness of ticlopidine has been investigated in such patients. Since the initial review of the drug appeared in the Journal, data from several large multicentre studies have shown that ticlopidine has a substantial benefit to offer patients who have experienced transient ischaemic attacks or stroke, and in those with peripheral arterial disease or ischaemic heart disease. Ticlopidine reduces the incidence of further stroke, myocardial infarction or vascular death, and is superior to placebo and aspirin in this regard in studies of patients with recent stroke or transient ischaemic attacks, or intermittent claudication. Ticlopidine is equally effective in both men and women and also improves symptoms of claudication in patients with peripheral arterial disease, and appears to reduce anginal pain.Patients with subarachnoid haemorrhage and sickle cell disease have shown some improvement with ticlopidine administration. The drug reduces thromboembolic events and re-stenosts in patients undergoing haemodialysis and cardiac surgery, and appears to prevent the progression of nonproliferative diabetic retinopathy.Ticlopidine in large clinical trials is associated with a higher incidence of adverse effects than placebo and an overall incidence similar to aspirin. Most adverse effects do not require withdrawal of treatment. Gastrointestinal symptoms (particularly diarrhoea) are most common, occurring almost twice as frequently with ticlopidine as with aspirin. Other adverse effects associated with ticlopidine include skin rash, haemorrhagic disorders, and haematological effects; these latter effects require careful monitoring of patients during the initial weeks of therapy.In conclusion, ticlopidine is a valuable addition to the prophylactic treatments available for the management of patients with cerebrovascular disease, peripheral arterial disease or ischaemic heart disease, who present a high risk of thromboembolic events. Although tolerability may be a problem for some patients, the overall benefit conferred by the drug would appear to outweigh this potential disadvantage. Because of its antiplatelet activity, ticlopidine has a promising role in other disorders mediated by platelet dysfunction. However, the precise role of the drug in these additional therapeutic indications awaits clarification with wider clinical experience.Pharmacological PropertiesTiclopidine is a thienopyridine derivative which has a broad spectrum antiaggregating activity. Inex vivostudies of platelets obtained from healthy volunteers and patients with cerebrovascular disease, peripheral arterial disease, ischaemic heart disease, or other conditions associated with platelet hyperaggregation, ticlopidine inhibits ADP-induced platelet aggregation. A maximal effect was seen 3 to 5 days after repeated administration in healthy volunteers and this can be seen for up to 10 days after withdrawal of drug treatment. Inhibition ofex vivoplatelet aggregation induced by other platelet agonists such as arachidonic acid, collagen, thrombin and platelet activating factor (PAF)-acether has also been reported, although this may not be a direct effect but rather a result of the inhibitory effect of ticlopidine on aggregation produced by ADP released by low concentrations of these agonists.Other ticlopidine-induced effects resulting from its interaction with ADP and platelets include a decrease in platelet deposition on atheromatous plaque in patients with cerebrovascular disease, reduced fibrinogen levels and blood viscosity in patients with peripheral arterial disease, and normalised platelet adhesiveness, erythrocyte deformability and &bgr;-thromboglobulin release in diabetic patients. Ticlopidine also prolongs bleeding time, with a maximal effect seen after 5 to 6 days in volunteers. The influence of ticlopidine on a variety of platelet agonists suggests a common site of action at an early stage of the platelet activating process. No comprehensive mechanism of action has been proposed, but inhibition of the ADP-induced exposure of the fibrinogen-binding site of the glycoprotein IIb-IIIa complex has been demonstrated.About 80 to 90% of an oral ticlopidine dose is absorbed, with plasma concentrations peaking at 1 to 3 hours. Steady-state peak and trough plasma concentrations of 0.9 mg/L and 0.2 mg/L, respectively, have been achieved after ticlopidine 250mg twice daily for 14 days. Ticlopidine is rapidly and extensively metabolised, with 1 metabolite more active than the parent drug. A terminal elimination half-life of 96h at steady-state has been reported in healthy volunteers. In the elderly the AUC and half-life of ticlopidine are significantly prolonged compared with younger volunteers after a single dose but this was not significant at steady-state. No studies evaluating the pharmacokinetics of ticlopidine in patients with major organ dysfunction have been published.Therapeutic TrialsSince the initial review of ticlopidine appeared in the Journal, attention has focused on the effectiveness of the drug in patients at high risk of thromboembolic events, i.e. those with transient ischaemic attacks and stroke, peripheral arterial disease or ischaemic heart disease. A large multicentre trial, the Canadian-American Ticlopidine Study (CATS) completed since the first review, has demonstrated that ticlopidine administered as a 250mg dose twice daily in patients who had had a recent stroke reduced the incidence of stroke, myocardial infarction or vascular death by 30.2% compared with placebo. Another large trial in more than 3000 patients [the Ticlopidine Aspirin Stroke Study (TASS)] has shown that ticlopidine has a more pronounced preventative effect on death from all causes or nonfatal stroke compared with aspirin. This was statistically significant within 1 year and was maintained over a 5-year period. Ticlopidine appears to be equally effective in women and men.Major clinical trials in patients with intermittent claudication resulting from peripheral arterial disease demonstrate that ticlopidine 250mg twice daily improves walking ability during treatment periods of 6 to 21 months. A reduction in the total mortality rate (by 29.1% compared with placebo), mainly because of its marked effect on ischaemic heart disease mortality, was seen in the Swedish Ticlopidine Multicentre Study (STIMS). In the same trial, the incidence of acute myocardial infarction, stroke, or transient ischaemic attack was significantly lowered by ticlopidine during an average period of 5.6 years.Results of another multicentre study show that ticlopidine 500 mg/day begun within 48 hours of admission reduces the risk of acute myocardial infarction, myocardial infarction and sudden death, and vascular mortality in patients with unstable angina. Ticlopidine also appears to reduce anginal pain to a similar extent to aspirin if administered within 24 hours of acute myocardial infarction.Other indications in which ticlopidine shows some benefit include the following: prevention of thrombotic events in patients undergoing haemodialysis, coronary artery bypass surgery, carotid endarterectomy or extracorporeal circulation; prevention of nonproliferative diabetic retinopathy; and prevention of cerebral vasospasm following subarachnoid haemorrhage. The effectiveness of the drug in Raynaud's phenomenon, sickle cell disease, ocular vein occlusion, glomerulonephritis and the prevention of post-operative thrombosis and bleeding remains uncertain.Adverse EffectsThe findings of a large placebo-controlled study in 1053 patients with a recent thromboembolic stroke show a higher incidence of adverse effects associated with ticlopidine compared with placebo: 54% of ticlopidine recipients and 34% of placebo recipients experienced an adverse symptom over a 3-year period. Of these patients, 12 and 3%, respectively, required withdrawal of treatment. The incidence of adverse effects was roughly similar in patients treated with ticlopidine or aspirin over a 2- to 6-year period, although ticlopidine recipients had almost twice the incidence of diarrhoea and skin rash whereas more peptic ulcers were reported in the aspirin group.The most common adverse effects associated with ticlopidine are gastrointestinal symptoms: diarrhoea is the most frequently reported, affecting about 20% of treated patients. Other effects are skin reactions (urticaria, pruritus, erythema), haemorrhagic disorders (epistaxis, ecchymoses, menorrhagia), and haematological disorders (leucopenia, thrombocytopenia, pancytopenia). These effects are generally not severe and resolve on discontinuation of ticlopidine treatment. The most potentially serious symptoms are haematological disturbances and close monitoring is therefore essential for at least the first 12 weeks of ticlopidine therapy. Abnormal liver function is rare with ticlopidine therapy but in instances where a definite causal relationship was determined, abnormal effects disappeared on withdrawal of treatment. Ticlopidine has also been associated with an increase in total cholesterol levels.Dosage and AdministrationA daily dosage of ticlopidine 500mg, administered orally as two 250mg tablets with food, is recommended. Up to 4 tablets (daily dosage 1000mg) can be administered for short term treatment but patients require careful monitoring. All patients receiving ticlopidine should be monitored during at least the first 12 weeks because of the risk of haematological disturbances. Ticlopidine is contraindicated in patients receiving high dose heparin, those with a history of bleeding disorders, gastroduodenal ulcer or those in the acute phase of haemorrhagic cerebral vascular accident.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisFenofibrate is a lipid-regulating drug which is structurally related to other fibric acid derivatives, such as clofibrate. At the recommended dosage of 200 to 400mg daily, it produces substantial reductions in plasma triglyceride levels in hypertriglyceridaemic patients and in plasma total cholesterol levels in hypercholesterolaemic patients. High density lipoprotein (HDL)-cholesterol levels are generally increased in patients with low pretreatment values. Fenofibrate appears to be equally effective in diabetic patients with hyperlipoproteinaemia without adversely affecting glycaemic control. The influence of fenofibrate on the plasma lipid profile is sustained during long term (2 to 7 years) treatment.Comparative studies conducted to date have involved only small groups of patients - in overall terms fenofibrate was at least as effective as other fibrates, but larger comparative studies are needed before valid conclusions on its relative efficacy compared with non-fibrate lipid-lowering drugs can be drawn. The influence of fenofibrate on morbidity and mortality from cardiovascular disease has not been studied.Clinical adverse reactions to fenofibrate have mainly consisted of gastrointestinal disturbances, headache and muscle cramps. Transient elevations in transaminase and creatine phosphokinase levels commonly occur. Isolated cases of hepatitis with substantially elevated transaminase levels have been reported. Fenofibrate induces hepatomegaly, peroxisome proliferation and hepatic carcinomas in rodents, but this type of hepatotoxicity has not been observed in humans. The biliary lithogenic index is increased by fenofibrate, but this has not been shown to have increased the incidence of gallstones in treated patients.Thus, fenofibrate offers an effective and well tolerated alternative to clofibrate or other fibric acid derivatives, but its relative efficacy and tolerability compared with other types of lipid-lowering drugs, and its effect on cardiovascular morbidity and mortality, remain to be clarified.Pharmacodynamic PropertiesFenofibrate is a lipid-regulating agent which reduces plasma levels of total cholesterol and triglycerides in healthy subjects and patients with hyperlipoproteinaemia.In hyperlipoproteinaemic patients substantial reductions occur in the atherogenic very low density lipoprotein (VLDL) fraction, while levels of low density lipoprotein (LDL) are consistently decreased in those with elevated baseline levels and HDL consistently increased when baseline levels are low (see Therapeutic Use, below). Changes in apolipoproteins appear to reflect changes in the relevant lipoprotein fractions; levels of apolipoproteins AI and AII are increased while those of apolipoproteins CII, CIII and E are decreased. Levels of apolipoprotein B are generally decreased when baseline LDL-cholesterol levels are elevated, but may be increased in patients with low pretreatment LDL-cholesterol levels.The underlying mechanisms by which fenofibrate influences lipid and lipoprotein patterns are not fully established. The drug has a wide range of effects on cholesterol and triglyceride metabolism, but it is not clear which are primary and which are secondary effects. However, the major effect of fenofibrate is to enhance triglyceride-rich lipoprotein catabolism by increasing lipoprotein lipase activity. In addition, fenofibrate appears to decrease cholesterol biosynthesis, which may in turn enhance LDL clearance by increased hepatic LDL receptor activity. Mobilisation of cholesterol deposited in peripheral tissues (including arterial walls) may occur: regression of xanthomas and xanthelasmas has been observed following fenofibrate treatment in clinical studies, and preliminary studies have reported evidence of regression of atherosclerosis following administration of fenofibrate and nicotinic acid. Platelet hyperaggregability and platelet-derived growth factor activity may be decreased, and esterification of cholesterol in plasma increased; all of these actions could contribute to inhibition of atherogenesis.In common with other fibrates. fenofibrate increases the lithogenic index of the bile by increasing cholesterol and decreasing bile acid concentrations. However, there is no clear link between fenofibrate administration and the occurrence of gallstones.Fenofibrate decreases serum uric acid levels in both healthy volunteers and in hyperlipoproteinaemic patients. This effect may be particularly beneficial in hyperuricaemic type IV patients, since elevated serum uric acid concentrations are considered a risk factor for cardiovascular disease.In rodent species fenofibrate induces hepatomegaly and peroxisome proliferation, with eventual hepatic tumour induction at very high doses, but these effects have not been observed in humans or other primates.Pharmacokinetic PropertiesFenofibrate is a prodrug which immediately after absorption is hydrolysed by tissue and plasma esterases to its active major metabolite, fenofibric acid. Peak plasma concentrations of around 6 to 9.5 mg/L are attained approximately 4 to 6 hours following a single 300mg dose of the commercially available dosage form in healthy fasting volunteers. Steady-state concentrations of approximately 10 mg/L were reached after 120 hours in healthy subjects given 300mg daily in 2 divided doses, although much lower steady-state values have also been reported.Fenofibric acid is more than 99% bound to plasma proteins and the volume of distribution has been reported as 0.89 L/kg in healthy subjects. The drug is eliminated mainly in the urine, in metabolised form, with some in the faeces, in varying proportions depending on the extent of absorption. The elimination patterns in animal species differ, a factor that may be important in interpreting toxicological findings. Mean elimination half-life values of 19.6 to 26.6 hours have been reported in healthy subjects.In patients with renal failure, the plasma half-life of fenofibric acid was considerably prolonged, with no correlation between the elimination half-life and serum creatinine level or creatinine clearance. Fenofibric acid is not removed by haemodialysis. The use of fenofibrate is therefore not recommended in patients with chronic renal failure, since marked accumulation of the drug is likely to occur, even at reduced dosage levels.Therapeutic UseThe lipid-regulating effects of fenofibrate have been evaluated in noncomparative and comparative studies, including some long term open trials of several years duration. These studies have mainly involved patients with the most commonly diagnosed forms of hyperlipoproteinaemia - types IIa, IIb and IV - although patients with type III or V disease have been included in a few trials, and a small number of children have been studied. Fenofibrate, at a dosage of 200 to 400mg daily (usually 100mg 3 times daily), has significantly reduced elevated total plasma cholesterol and triglyceride concentrations in such patients. Total plasma triglycerides are generally reduced by around 30 to 60% in type IIb patients, with substantial reductions also having been achieved in type III, IV and V patients. Total cholesterol levels are usually reduced by approximately 20 to 30% in type IIa and 13 to 32% in type IIb patients, with substantial decreases in the small number of type III patients studied. LDL-cholesterol levels (a major risk factor in coronary heart disease) are decreased in patients with high pretreatment levels, but may be increased in those with hypertriglyceridaemia, who often have abnormally low LDL levels. HDL-cholesterol is generally increased by fenofibrate, particularly in patients with low pretreatment levels, but may be decreased in some individuals.In small comparative studies, fenofibrate was approximately comparable overall with other lipid-lowering drugs such as ciprofibrate or bezafibrate although the effect on individual lipoprotein fractions varied among the drugs compared. Fenofibrate appeared to be more effective than clofibrate overall, but less effective than simvastatin in reducing plasma total and LDL-cholesterol in hypercholesterolaemic patients, but was more effective in decreasing triglyceride levels. However, further comparative studies in larger patient groups are needed before the relative efficacy of fenofibrate can be clearly described. The effects of fenofibrate on lipid and lipoprotein patterns are generally apparent after 1 month and have been sustained in small numbers of patients treated for several years. No studies on the long term effects of fenofibrate on morbidity and mortality from cardiovascular disease have been reported.Additive effects on some lipid and lipoprotein parameters have been observed in dyslipidaemic patients when fenofibrate treatment was combined with other lipid-regulating agents with different mechanisms of action, such as nicotinic acid (niacin) and the bile acid sequestrants colestipol and cholestyramine. Combination therapy of this type, may be particularly beneficial in patients in whom single-agent therapy does not sufficiently reduce plasma lipid levels.The influence of fenofibrate treatment on lipid and lipoprotein profiles in diabetic patients with hyperlipoproteinaemia is similar to that in nondiabetic patients; in patients receiving insulin or oral hypoglycaemic drugs, glycaemic control was maintained during fenofibrate therapy without the need for adjustment of antidiabetic medication.Adverse EffectsAdverse reactions attributable to fenofibrate appear to occur with an overall incidence of about 6% in short term studies and 11% in longer term trials. The most frequently reported adverse reactions have been gastrointestinal disturbances. accounting for approximately one-half of adverse effects observed in long and short term clinical trials. Other relatively common reactions include headache, muscle pains and rash.Hepatitis associated with markedly elevated transaminase levels has occasionally been reported, but appears generally to have slowly resolved after withdrawal of fenofibrate. Nonsymptomatic sporadic increases in alanine and/or aspartate aminotransferase have been reported in a number of studies. Elevations in plasma creatinine and urea are also frequently reported, as are increased creatine phosphokinase levels, which are sometimes associated with muscle cramps. Although fenofibrate increases the cholesterol saturation of bile, it has not been shown to be associated with an increased incidence of gallstones. A decrease in serum uric acid levels also generally occurs, which may be beneficial in hyperuricaemic patients.Dosage and AdministrationAs with other lipid-regulating drugs, fenofibrate therapy should only be instituted after dietary restrictions and other nonpharmacological interventions have proved inadequate for controlling lipid abnormalities. The recommended initial dosage of fenofibrate in adult patients with hyperlipoproteinaemia is 300mg daily in divided doses with meals. Patients with renal dysfunction require dosage reduction.The response to therapy should be determined by serum lipid monitoring and dosage adjusted where necessary within the range of 200 to 400mg daily. If an adequate response is not achieved within 3 months fenofibrate should be discontinued.Fenofibrate is contraindicated in severe hepatic or renal dysfunction or in gallbladder disease. Serum transaminases should be monitored during the first year of therapy and fenofibrate should be discontinued if ALT levels increase to more than 100 U/L.The dosage of concomitantly prescribed oral anticoagulants should be decreased by approximately one-third at the start of fenofibrate treatment and adjusted as required according to prothrombin time.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisZolpidem is an imidazopyridine, a chemically novel nonbenzodiazepine hypnotic agent which acts at the benzodiazepine ω1-receptor subtype in the brain. With a rapid onset of action and short elimination half-life, it reduces the latency to and prolongs the duration of sleep in patients with insomnia, yet has no major effects on sleep stages when given in dosages of 5 to 20mg nightly. Rebound effects on withdrawal of the drug have not been observed. Unlike benzodiazepines, zolpidem has no myorelaxant or anticonvulsant effects and its effects on anxiety appear to be minor. While zolpidem aids sedation, and may reduce memory or psychomotor function within the first 2 hours after administration of single oral doses, its use as a surgical premedicant remains to be established.Adverse effects are predominantly CNS and gastrointestinal in nature. Altered pharmacokinetics may lead to an increase in dose-proportionate adverse effects in the elderly and in patients with renal dysfunction. Limited evidence to date suggests that the dependence liability of zolpidem is minimal.Thus, zolpidem is an interesting alternative to benzodiazepines in the treatment of insomnia, with properties that potentially offer worthwhile advantages in this therapeutic area if they are confirmed with wider clinical experience.Pharmacodynamic PropertiesZolpidem is a nonbenzodiazepine sedative-hypnotic agent which binds selectively to the benzodiazepine ω1-receptor subtype in the central nervous system but possesses low affinities for ω2or ω3-receptor subtypes. It reduces the time to onset and increases the duration of sleep in healthy volunteers when administered in doses as low as 5 to 7.5mg at bedtime. In volunteers and patients with sleep disorders, zolpidem did not alter sleep stages until given in doses of 10 to 20mg or more, when it increased stage 2 sleep, slow wave sleep (stages 3 and 4) and latency to rapid eye movement (REM) sleep, and decreased the duration of REM sleep. Zolpidem does not appear to cause rebound insomnia or other withdrawal reactions after short term administration.The psychomotor effects of zolpidem are minor and transient, with slight impairment of function observed during the first 2 hours after administration and no significant changes noted the next day. Memory may also be impaired during the first 2 hours after administration of zolpidem as a surgical premedicant, a time during which anterograde amnesia has been observed, but memory deficits appear to be unusual in the morning following administration to humans. In rats, the strong sedative effects of zolpidem appear to mask any anxiolytic responses. Adequate anxiolysis has not been consistently observed in patients receiving zolpidem as a presurgical medication, and this effect has not been sufficiently well studied in humans to recommend zolpidem as an anxiolytic.Relatively little tolerance to zolpidem developed in rats, but tolerance was evident with midazolam, and while zolpidem did not sensitise rats to midazolam, the response to zolpidem was reduced after long term midazolam administration. No evidence of tolerance or dependence was observed in at least 138 geriatric and general practice patients with insomnia treated for up to 1 year; however, few studies have systematically investigated the dependence liability of the drug. Dose increases tended to occur early in therapy (within 30 days) and were usually the result of initial poor efficacy. Indeed, the efficacy of static dosages of zolpidem appeared to increase during the first 4 weeks of therapy.Zolpidem did not produce adverse respiratory effects in hospitalised patients with transient insomnia or chronic obstructive pulmonary disease or in patients receiving the drug as a surgical premedicant. However, zolpidem may reduce oxygen intake in patients with sleep apnoea. Studies in baboons have shown that the drug may reduce cerebral blood flow and oxygen consumption. Zolpidem does not possess significant anticonvulsant or myorelaxant properties.Pharmacokinetic PropertiesZolpidem is rapidly absorbed after oral administration, with peak plasma concentrations of about 200 &mgr;g/L attained approximately 2.2 hours after single oral 20mg doses and after 15 days of bedtime administration. First-pass metabolism occurs, resulting in a bioavailability of 70%. Although highly bound to plasma proteins, zolpidem concentrates initially in glandular and fatty tissues, but is rapidly eliminated, with only residual radioactivity observed in nonsecretory tissues 3 hours after administration. The drug is secreted in small amounts into breast milk.There are 3 major metabolites of zolpidem, which are all pharmacologically inactive. Unchanged zolpidem has been detected in only minute amounts (< 1%) in human excreta. The elimination half-life ranged from 1.5 to 2.4 hours in healthy volunteers; systemic clearance was 0.26 L/h/kg and the volume of distribution was 0.54 L/kg.Liver cirrhosis and renal disease both tend to reduce elimination of zolpidem and may necessitate dosage reductions. The drug is not removed by dialysis. Preliminary data suggest that zolpidem has a longer half-life in the elderly and shorter half-life in children; these changes may alter the duration of activity in these age groups. Gender may also affect zolpidem pharmacokinetics, as higher plasma concentrations and AUCs have been seen in women than in men and these may influence the incidence of adverse effects. Conversely, zolpidem pharmacokinetics appear to be unaffected by food, alcohol or caffeine consumption, or by race or ethnic origin.Therapeutic UseZolpidem has been tested in the treatment of insomnia and as a sedative/anxiolytic administered before surgery. A noncomparative trial has shown that zolpidem is well tolerated and effective in elderly and general practice patients with insomnia when given for up to 6 months. Dose-ranging studies in patients with insomnia have found a nightly dosage of 10 to 20mg achieved good results with optimum tolerability. At these dosages, zolpidem is superior to placebo and is generally similar to the benzodiazepines flurazepam, flunitrazepam, oxazepam and triazolam in inducing and maintaining sleep, minimising awakenings and maximising the duration of sleep in elderly, general practice or psychiatric patients with insomnia. The subjective quality of sleep and morning condition of patients with insomnia tended to be improved by zolpidem compared with placebo, and were similar or superior to improvements achieved by benzodiazepines. When used in 10 or 20mg nightly dosages to treat insomnia, zolpidem did not result in impairment of memory or motor skills on awakening.As an oral premedicant before surgery, zolpidem 10 or 20mg was significantly superior to placebo in causing sedation, and was preferred to placebo by both patients and anaesthetists. It reduced the anaesthetic dose required but tended to prolong recovery relative to placebo. Zolpidem produced only minor interference with psychomotor skills in the 3 hours post-recovery. When compared with midazolam 15mg or lorazepam 1 or 2.5mg, zolpidem 10 to 20mg produced a similar degree of sedation, although midazolam 15mg was a more powerful anxiolytic. Some anterograde amnesia was observed in each study group but it was significantly more common in recipients of lorazepam 25mg. Neither zolpidem dose prolonged the recovery of responses to visual and auditory stimuli, unlike lorazepam 2.5mg.Adverse EffectsWhen given in a nightly dosage of up to 20mg zolpidem is generally well tolerated by patients with insomnia. The most common adverse effects occurring in clinical trials were dizziness and lightheadedness (5.2%), somnolence (5.2%), headache (3.0%) and gastrointestinal upset (3.6%). Adverse events appeared to be more frequent in recipients of zolpidem 10 or 20mg than in patients administered triazolam 0.5mg or flunitrazepam 1mg, and although dependence, tolerance and withdrawal effects may be less common with zolpidem these factors have not been adequately studied. Falls and confusion occurred almost exclusively in elderly patients, especially those receiving higher dosages (> 20 mg/day) of the drug. Falls have not been reported in patients treated with zolpidem 5mg daily, although the population studied so far at this dosage is small. The incidence of amnesia was unrelated to age or dosage. Zolpidem resulted in double vision prior to anaesthesia induction in a small number of patients and tended to reduce blood pressure in patients administered the drug as a preoperative sedative.Dosage and AdministrationInitial zolpidem dosage in patients < 65 years experiencing acute insomnia is 10mg nightly, increased to 15 or 20mg nightly if the response is inadequate. For patients > 65 years experiencing insomnia, an initial 5mg dose may be increased to a 10mg maximum if needed. The lowest effective dose should be used. Dosage reduction is recommended in patients with renal or liver damage. Prolonged use is not recommended, and zolpidem recipients should be cautious when operating motor vehicles or machinery.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS