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:

Standard unfractionated heparin is a mixture of mucopolysaccharide chains of various length that may vary from 5000 to 30 000 daltons. Heparin is only effective as an anticoagulant in the presence of a plasma protein termed antithrombin III, with which it forms a complex. High- and low-affinity heparin are 2 types that readily bind or do not bind, respectively, to antithrombin III. The pharmacokinetics of unfractionated heparin are compatible with a model based on the combination of a saturable and a linear mechanism. The primary indication for intravenous infusion of conventional heparin is to prevent extension of an established arterial, venous or intracardiac thrombus. The average requirement is 400 U/kg/24h. Subcutaneous administration of 5000U of concentrated unfractionated heparin, administered every 8 or 12 hours, is effective and safe in the prevention of postoperative venous thrombosis and pulmonary embolism in patients at medium thrombotic risk. Adequate prophylaxis is also obtained in patients at high thrombotic risk if 5000U of heparin combined with 0.5mg dihydroergotamine is given subcutaneously 3 times daily, or by monitoring the 3 subcutaneous doses of heparin in order to maintain an adjusted activated partial thromboplastin time (APTT) of around 50 to 70 seconds.Low molecular weight heparins have been produced by a variety of techniques and their molecular weights range from 3000 to 9000 daltons. These preparations have a ratio of anti-factor Xa activity to anti-factor IIa activity of about 4, while the ratio for unfractionated heparin is 1. After intravenous administration of low molecular weight heparin, the half-life of the anti-factor Xa activity is considerably longer than for unfractionated heparin, while the anti-factor IIa half-lives are similar. In contrast to unfractionated heparin, low molecular weight heparin is completely absorbed after subcutaneous administration and its biological half-life is almost twice as long. In spite of certain differences with regard to the ratio between factor Xa and IIa inhibition, the various low molecular weight preparations show a rather similar absorption pattern. The bioavailability of all low molecular weight heparin fractions is substantially higher than that of unfractionated heparin, which renders their use more simple. Low molecular weight heparins less readily enhance platelet aggregation although there is no evidence that low molecular weight heparins are less antigenic or that they do not interact with platelet IgGFc receptor. A lower bleeding incidence for equivalent antithrombotic efficacy of fractionated heparins when compared to unfractionated heparins has yet to be established in humans.For prophylaxis of postoperative deep vein thrombosis, one daily subcutaneous injection of low molecular weight heparin results in satisfactory protection with almost no risk of bleeding. For the treatment of deep venous thrombosis, 2 daily injections of low molecular weight heparin are necessary. The presently recommended doses of each low molecular weight heparin differ and are less well established than for standard unfractionated heparin.After intravenous injection of 100U unfractionated heparin full neutralisation is obtained with 1mg protamine; the activities of low molecular weight heparins can be neutralised to a lesser extent.Several of the adverse effects of unfractionated heparin, such as thrombocytopenia and osteoporosis, have also been observed with low molecular weight heparins, but activation of lipoprotein lipase seems to occur to a minor extent with the latter.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Platelet destruction by antibodies is a common cause of thrombocytopenia. In this review, various treatments for immune thrombocytopenia are discussed, with emphasis on corticosteroids, splenectomy, danazol, high-dose immunoglobulin G, anti-Rhesus globulin, colchicine and cytotoxic, immunosuppressive agents such as cyclophosphamide and azathioprine. An approach to the treatment of adult idiopathic thrombocytopenic purpura (ITP) is reviewed in detail and the treatments for several other immune thrombocytopenic disorders are summarised.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisCadralazine is a peripheral arteriolar vasodilator which, unlike hydralazine or dihydralazine, has a protected hydrazino group. In hypertensive patients the optimal effect, based on the antihypertensive efficacy to tolerability ratio, is seen after a 15mg dose when the drug is administered as monotherapy. When administered in combination with other antihypertensive agents, a 10mg daily dosage seems appropriate. Noncomparative trials have shown that, in patients who had failed to respond adequately to a &bgr;-blocker and/or diuretic, the addition of cadralazine 10 to 30mg once daily reduced systolic/diastolic blood pressure by 11 to 19%/13 to 22%. This antihypertensive effect becomes evident over a 2-to 6-week period of therapy and persists during longer term administration.Comparative studies have shown that cadralazine is superior to placebo, and has a similar blood pressure lowering effect to hydralazine, dihydralazine and prazosin in patients not controlled by &bgr;-blocker and/or diuretic but who continued to receive these treatments. Similarly, cadralazine and chlorthalidone were equally effective in reducing blood pressure in resting hypertensive patients but cadralazine shows an advantage in reducing the pressor response in exercising patients.Cadralazine is well tolerated when administered with a &bgr;-blocker or diuretic. Most adverse effects become less frequent and severe with continued use, occur more frequently at dosages of 20 mg/day or more, and do not generally require withdrawal of therapy. Manifestations of the drug's vasodilating properties such as headache, asthenia, dizziness, palpitations and flushing are the most commonly reported symptoms during cadralazine monotherapy, but these may be reduced during combination therapy. The drug does not appear to induce a systemic lupus-like erythematosus syndrome, as may occur with hydralazine, but additional clinical experience is required to completely exclude this possibility.In conclusion, because of its efficacy as a second- or third-line antihypertensive agent, its simple once daily dosage regimen and favourable risk: benefit ratio, cadralazine may have a useful role, particularly in those hypertensive patients who do not respond adequately to established antihypertensive treatments. However, the therapeutic potential of cadralazine cannot be clearly established until the present limited clinical base is expanded to include comparisons with other classes of vasodilating drugs (ACE inhibitors and calcium antagonists), and its utility in the management of other indications such as severe hypertension during pregnancy has been adequately explored.Pharmacodynamic PropertiesCadralazine administered as a single oral 7.5 to 30mg dose reduces systolic and diastolic blood pressure in patients with essential hypertension by up to 20/25%, with a 15mg dose producing an optimum effect. Lowering of blood pressure is thought to be mediated via reduction of peripheral vascular resistance as a result of arterial smooth muscle relaxation; peripheral vascular resistance is reduced by 20 to 30% after a single cadralazine dose in hypertensive patients. Cadralazine produces reflex tachycardia which persists but tends to diminish during long term treatment, and it also increases cardiac output by about 16% in elderly hypertensive patients during long term therapy. The drug does not seem to cause significant sodium or water retention and, like other vasodilators, stimulates the renin-angiotensin system. Cadralazine appears to have a profound vasodilatory effect on renal blood vessels which enables renal blood flow and renal function to be maintained despite a marked fall in systemic blood pressure.Pharmacokinetic PropertiesCadralazine is rapidly absorbed in healthy volunteers, and in patients with hypertension or chronic heart failure. Peak plasma concentrations of 130, 210 and 379 &mgr;g/L occurred after administration of 5, 10 and 20mg doses in healthy volunteers and similar concentrations were reported in hypertensive patients (224 and 568 ug/L following 15 and 30mg doses). After 12 hours, cadralazine is almost undetectable in plasma. Following absorption, cadralazine undergoes limited metabolism to at least 7 metabolites, one of which, the hydrazinopyridazine metabolite, has antihypertensive activity.About 70 to 80% of an oral dose is recovered unchanged in urine within 24 hours. Faecal recovery represents about 5% of recovered drug. Elimination of cadralazine appears to be delayed in patients with hypertension or chronic heart failure compared with that reported in healthy volunteers; this may be due to impaired renal function in these patients.Therapeutic UseCadralazine has not been studied in large numbers of patients and comparative studies are few. Nonetheless, encouraging results from noncomparative studies show that cadralazine administered as a 10 to 30 mg/day dosage reduced supine and standing blood pressures when given as a second- or third-line antihypertensive therapy in hypertensive patients who had previously failed to respond satisfactorily to &bgr;-blockers and/or diuretics and who continued to receive this therapy. Blood pressure reductions of 11 to 19%/13 to 22% have been reported in such patients and at least 70%, and in some cases 100%, of patients achieved target blood pressure (diastolic blood pressure ≥ 95mm Hg). The antihypertensive effects of cadralazine were apparent within 2 weeks of starting treatment, persisted during longer term administration and were significantly superior to placebo.Combined treatment with a vasodilator plus a diuretic or &bgr;-blocker is significantly more effective than &bgr;-blocker monotherapy. Cadralazine and chlorthalidone show a similar antihypertensive efficacy in resting hypertensive patients who were also receiving a &bgr;-blocker. Both drugs reduce blood pressure within 2 weeks and this effect is maintained during treatment of up to 6 months. However, during exercise testing cadralazine is clearly superior to chlorthalidone in reducing the pressor response.In comparative clinical trials, cadralazine, hydralazine, dihydralazine and prazosin were similarly effective in hypertensive patients who had inadequate blood pressure control with previous diuretic or &bgr;-blocker therapy.Adverse EffectsCadralazine is well tolerated when administered with a diuretic and/or &bgr;-blocker with most adverse effects being mild to moderate in nature, occurring more frequently at higher dosages (≥ 20 mg/day), becoming less frequent with prolonged treatment, and rarely requiring withdrawal of therapy.The most common adverse effects are typical of a drug which produces peripheral vasodilation and include headache, asthenia, dizziness, oedema, palpitations and flushing; these generally may be less frequent and severe during combination therapy. Other less common symptoms are formication, dyspnoea, gastralgia, nausea and insomnia. Cadralazine appears to be better tolerated than dihydralazine and does not appear to produce a systemic lupus erythematosus-like syndrome in patients who had developed the syndrome under hydralazine treatment. However, more patients need to be treated with the drug before this possibility can be definitely excluded. Cadralazine has no clinically relevant effects on renal or thyroid function, routine laboratory tests, or ECG.Dosage and AdministrationAs a second- or third-line antihypertensive agent the usual oral dosage of cadralazine is 10 to 20mg once daily.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisThe estradiol transdermal therapeutic system is a cutaneous delivery device which delivers estradiol into the systemic circulation via the stratum corneum at a constant rate for up to 4 days. Physiological levels of estradiol (the major estrogen secreted by the ovaries in premenopausal women) can therefore be maintained in postmenopausal women with low daily doses because first-pass hepatic metabolism is avoided.In short term clinical studies, the beneficial effects of transdermal estradiol on plasma gonadotrophins, maturation of the vaginal epithelium, metabolic parameters of bone resorption and menopausal symptoms (hot flushes, sleep disturbance, genitourinary discomfort and mood alteration) appear to be comparable to those of oral and subcutaneous estrogens, while the undesirable effects of oral estrogens on hepatic metabolism are avoided. As with oral or injectable estrogen replacement therapy, concomitant sequential progestagen is recommended for patients with an intact uterus during transdermal estradiol administration, in order to reduce endometrial stimulation. Transdermal estradiol has been well tolerated in clinical trials, with local irritation at the site of application being the most common adverse effect. The incidence of systemic estrogenic effects appears to be comparable to that observed with oral therapy.Thus, transdermal estradiol offers near-physiological estrogen replacement in postmenopausal women in a convenient low-dose form which may avoid some of the complications of higher dose oral therapy. Long term epidemiological studies are warranted to determine whether transdermal estradiol therapy provides protection against osteoporosis and fractures and cardiovascular disease equivalent to that offered by oral and injectable estrogens. However, despite the importance of such data, it seems reasonable to conclude at this stage of its development that transdermal estradiol represents an important advance in hormone replacement therapy.Pharmacodynamic Properties17&bgr;-Estradiol is the predominant estrogen produced by the ovaries in premenopausal women. Administration of transdermal estradiol to postmenopausal women (in dosages of 0.05 to 0.2 mg/day) elevates plasma estradiol concentrations into the range observed in premenopausal women at the early to mid follicular stage. Plasma estrone concentrations are increased to a much lesser degree and a physiological plasma ratio of estradiol to estrone (approximately 1:1) is thus produced. As a result of the increased plasma estradiol concentrations, plasma concentrations of follicle-stimulating hormone (FSH) and luteinising hormone (LH) are decreased and vaginal cytology is converted to a pattern resembling that found in premenopausal women, with improvement of the maturation and karyopyknotic indices. Bone resorption is inhibited, as evidenced by a reduction in the urinary ratios of calcium and hydroxyproline to creatinine, and an increase in bone mineral density has been achieved in patients receiving long term treatment. Transdermal estradiol has a less marked effect than oral estrogens on lipid and lipoprotein metabolism; the plasma lipid profile does not appear to be significantly altered by short term treatment, but some studies of ≥ 6 months' duration have reported potentially beneficial changes in various lipid and lipoprotein fractions.Pharmacokinetic PropertiesThe estradiol transdermal therapeutic system is designed to deliver estradiol at a constant rate for up to 4 days. Currently, 3 sizes of delivery system are available, with nominal delivery rates of 0.025, 0.05 and 0.1 mg/24 hours. Following application of transdermal estradiol to intact skin, maximum plasma estradiol concentrations are attained in postmenopausal women within 2 to 8 hours. Steady-state plasma concentrations of estradiol are linearly proportional to the dose administered; mean levels of around 23, 40, 75 and 100 ng/L occur in women with pretreatment estradiol levels ≤ 10 ng/L from administration of 0.025, 0.05, 0.1 and 0.2 mg/day, respectively. Plasma levels of estradiol during transdermal therapy and reduction in menopausal symptoms, plasma FSH concentrations and urinary excretion of calcium are closely related.Estradiol is mainly metabolised in the liver, the major metabolites being estrone and estriol and their conjugates, which are considerably less potent than estradiol. The bulk of the metabolites are excreted in the urine as glucuronides and sulphates, although some enterohepatic recirculation may occur. Within 24 hours of removal of transdermal delivery systems, plasma concentrations of estradiol and estrone, and urinary excretion of estradiol and estrone conjugates, return to pretreatment levels. The plasma elimination half-life of estradiol is approximately 1 hour irrespective of the route of administration and the metabolic plasma clearance rate is between 650 and 900 L/day/m2.Therapeutic UseThe efficacy of transdermal estradiol as estrogen replacement therapy in peri- or postmenopausal women has been evaluated in noncomparative, placebo-controlled and comparative clinical trials. Dosages ranging from 0.025 to 0.2mg daily have been used. In studies of ≥ 2 months duration, treatment has generally been cyclical (3 weeks on, 1 week off) and sequential progestagen therapy has usually been administered for 5 to 12 days per cycle to patients with an intact uterus, in order to minimise endometrial proliferation. Climacteric symptoms - hot flushes, sweating, sleep disturbance, vaginal discomfort, poor concentration and irritability - have been eliminated or significantly improved during transdermal estradiol replacement therapy. In comparative studies transdermal estradiol has demonstrated efficacy in the control of climacteric symptoms at least equivalent to those of oral estradiol preparations, ethinylestradiol and conjugated estrogens, and subcutaneous estradiol implants or estradiol/prasterone depot injections.Data from preliminary studies suggest that transdermal estradiol, usually with sequential progestagen, is also effective in other indications for which estrogen therapy is prescribed, such as contraception and as hormone replacement therapy in patients with premature ovarian failure or bilateral oophorectomy participating in fertility programmes. Although transdermal estradiol inhibits bone resorption, few data are currently available regarding its effect on the incidence of osteoporosis and fractures in treated menopausal women.Analysis of patient acceptability of the transdermal route for estrogen replacement in several studies indicated that > 70% of patients preferred transdermal estradiol over oral or injectable therapies.Adverse EffectsA significant proportion of patients experience dermatological reactions to the transdermal delivery device. Although these mostly consist of transient erythema/itching at the site of application, which can be minimised by rotation of patch application sites, severe irritation leading to discontinuation of therapy occurs in about 2.5 to 7% of patients overall.Otherwise, transdermal estradiol therapy is generally well tolerated, the most common systemic adverse symptoms being typical estrogenic effects, such as breast tenderness and spotting/bleeding and general effects such as fatigue, abdominal bloating and nausea, which result in discontinuation of treatment in < 4% of patients. Estrogenic stimulation of the endometrium occurs with transdermal estradiol therapy and coadministration of a sequential progestagen (which may also produce a more acceptable bleeding pattern) is therefore recommended for patients with an intact uterus in order to minimise endometrial proliferation.Unlike oral estrogens, transdermal estradiol does not stimulate hepatic metabolism and consequently plasma concentrations of renin substrate, sex hormone-, thyroxine- and cortisol-binding globulins and clotting factors are not elevated.It has been suggested that transdermal estradiol might be associated with a lower incidence of adverse effects than oral estrogen replacement therapies because of the lower circulating estrogen concentrations involved and the lack of untoward effects on liver metabolism. However, this has not been confirmed in comparative studies to date; generally, adverse effects have been comparable in patients receiving transdermal estradiol and those receiving oral or injectable estrogens.Dosage and AdministrationThe recommended initial dosage of transdermal estradiol for the treatment of menopausal symptoms is 0.05mg daily, which may be increased in cases of inadequate response after 2 to 3 weeks' treatment, or decreased if breast discomfort or breakthrough bleeding occur. For maintenance therapy the lowest effective dose should be used. Treatment may be continuous or may be given in 4-week cycles (3 weeks on/1 off). Sequential progestagen treatment should be administered for 10 to 12 days per month to patients with an intact uterus.The transdermal estradiol delivery system should be changed twice weekly. Contraindications to the use of estradiol include carcinoma of the breast or endometrium, leiomyoma of the uterus, endometriosis, vaginal bleeding of unknown origin, severe renal, hepatic, or cardiac disease and active or previous thromboembolic disease.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisSimvastatin (epistatin; synvinolin; MK 733), an HMG-CoA reductase inhibitor, acts by decreasing cholesterol synthesis and by increasing low density lipoprotein (LDL) catabolism via increased LDL receptor activity. In patients with heterozygous familial and nonfamilial hypercholesterolaemia, orally administered simvastatin 10 to 40mg once daily reduces plasma total and LDL-cholesterol concentrations by about 30 to 45%. It also produces a beneficial moderate decrease in plasma triglycerides and a small, although significant, increase in high density lipoprotein (HDL)-cholesterol. Like many other hypocholesterolaemic agents simvastatin does not appear useful in patients with homozygous familial hypercholesterolaemia who lack LDL receptors.The hypocholesterolaemic activity of simvastatin is greater than of the bile acid sequestrants, probucol and the fibrates. Combined administration of simvastatin with bile acid sequestrants results in further reductions in plasma cholesterol levels beyond those seen with either drug alone. Simvastatin appears well tolerated in the short to medium term, but its long term tolerability needs to be confirmed. No comparisons of simvastatin and other HMG-CoA reductase inhibitors have been reported.As yet there have been few investigations to determine the impact of simvastatin or other HMG-CoA reductase inhibitors on cardiovascular events relative to their hypocholesterolaemic effects, but at least one such trial is ongoing. Simvastatin, like other HMG-CoA reductase inhibitors, has considerable potential advantages over other classes of hypocholesterolaemic agents, i.e. the magnitude of its cholesterol-lowering effect and convenience of administration. If further study confirms long term tolerability and an impact on cardiac mortality and morbidity, then simvastatin and others of its class should offer a significant new approach to the treatment of hypercholesterolaemia.Pharmacodynamic PropertiesSimvastatin, after absorption and hydrolysis in the liver to form the active &bgr;-hydroxyacid metabolite, acts as a potent reversible, competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an early and rate limiting enzyme in the biosynthesis of cholesterol.In vitrocell culture studies show that simvastatin is a potent inhibitor of cholesterol synthesis. Various studiesin vivoin rabbits and dogs have confirmed the ability of simvastatin to reduce plasma cholesterol levels, and there is some evidence the drug reduces the production of atherosclerotic lesions in rabbits. HMG-CoA reductase inhibition may decrease LDL synthesis and increase receptor-mediated LDL catabolism. The former mechanism appears to predominate in patients with nonfamilial hypercholesterolaemia and the latter in patients with heterozygous familial hypercholesterolaemia. The degree of cholesterol reduction is apparently similar in the 2 groups of patients.During therapy of hypercholesterolaemic patients with simvastatin there is an approximate 25 to 35% decrease in the mean plasma concentration of apolipoprotein B, the major LDL protein. Some studies have noted a mean increase of about 10% in apolipoproteins AI and AII, the major HDL proteins.In humans, simvastatin does not appear to influence adrenocortical function which theoretically might be affected as a result of HMG-CoA reductase inhibition reducing cholesterol concentrations. The cholesterol saturation index of gallbladder bile was significantly reduced in hypercholesterolaemic patients treated with simvastatin, suggesting the drug is unlikely to enhance cholesterol gallstone development.Pharmacokinetic PropertiesSimvastatin is a prodrug which undergoes rapid hydrolysis after absorption to form a number of active metabolites in humans. The major metabolite, &bgr;-hydroxyacid-simvastatin, is the most potent with respect to HMG-CoA reductase inhibition. After absorption in humans, simvastatin undergoes extensive first-pass metabolism in the liver, the primary site of action, with subsequent excretion of drug in bile. The systemic bioavailability of the drug is therefore low: the absolute bioavailability of &bgr;-hydroxyacid-simvastatin is less than 5%. The area under the plasma concentration-time curve for total HMG-CoA reductase inhibitors in the circulation is clearly related to dose over the range from 5 to 120mg in humans after the administration of single oral doses of simvastatin. Plasma inhibitor concentration is unaffected by coadministration of food with simvastatin. No accumulation appears to occur with repeated administration of normal therapeutic doses. Both simvastatin and &bgr;-hydroxyacid-simvastatin are >95% protein bound in human plasma. Distribution studies in rats indicate that simvastatin and lovastatin appear more selective for liver tissue than pravastatin. After oral administration of a radiolabelled dose of simvastatin, 13% of radioactivity is recovered in urine and 60% in faeces, the latter representing unabsorbed drug and that excreted as metabolites in bile.Therapeutic UseDose-finding studies have established that the maximal lipid changes induced by simvastatin occur within the range of 10 to 40mg once daily. Most subsequent studies have used dosages in this range, although in Japanese patients dosages begin at 5mg daily. After appropriate dietary control, monotherapy with simvastatin generally produces the following mean changes in circulating lipids in patients with heterozygous familial and nonfamilial hypercholesterolaemia (Fredrickson types IIa or b): total cholesterol is reduced by 30 to 35% and LDL-cholesterol by about 35 to 45%, triglycerides are reduced by about 20 to 40%, and HDL-cholesterol is increased by about 5 to 15%. With fixed dosages, the maximal effects are reached in about 4 to 8 weeks and are maintained during longer term therapy - up to 2 years in some patients, although most trials did not progress beyond 3 months. In percentage terms, simvastatin-induced changes in lipid levels appear similar in patients with familial and nonfamilial disease, and are not dependent on the severity of hypercholesterolaemia. However, patients with more severe hypercholesterolaemia (usually those with familial disease) are less likely to attain a desirable ‘normal’ level of plasma cholesterol.Limited information in patients with hypercholesterolaemia secondary to diabetes or nephrotic syndrome indicates that simvastatin produces similar lipid changes to those in patients with primary hypercholesterolaemia. Simvastatin may be useful in the treatment of primary dysbetalipoproteinaemia (Fredrickson type III) but is unlikely to offer any benefit in patients with homozygous familial hypercholesterolaemia unless there is some residual LDL-receptor function.In comparative studies, simvastatin produced significantly greater decreases in total and LDL-cholesterol concentrations than probucol, bile acid sequestrants (colestipol and cholestyramine), and the fibrates (bezafibrate, fenofibrate and gemfibrozil). However, the fibrates produced a greater increase in HDL-cholesterol levels, and were more effective in reducing triglyceride concentrations than simvastatin. Simvastatin is not indicated for the treatment of hypertriglyceridaemia, but its ability to reduce triglycerides to a moderate extent in hypercholesterolaemic patients can be considered as a secondary beneficial effect. Unlike probucol, simvastatin did not decrease HDL-cholesterol levels nor did it increase triglyceride levels, unlike cholestyramine. Simvastatin has not been compared with nicotinic acid, or with other HMG-CoA reductase inhibitors.The addition of colestipol or cholestyramine to simvastatin produces further decreases in total and LDL-cholesterol levels compared with simvastatin alone. With combination therapy the reduction in total and LDL-cholesterol may reach 50 to 60%, which means that patients with severe hypercholesterolaemia are more likely to attain a desirable cholesterol level.Adverse EffectsPublished information on the tolerability of simvastatin indicates that the drug is well tolerated in the short to medium term. Adverse effects are usually mild and transient, leading to drug withdrawal in less than 2% of patients. These most frequently include mild gastrointestinal complaints and more rarely fatigue, headache and rash. Mild, transient increases in serum transaminase levels may occur relatively frequently at the start of therapy, but more persistent, greater increases occur in 1 to 2% of patients and may require drug withdrawal. However, these changes have not been associated with signs or symptoms of hepatic disease. Simvastatin may cause minor increases in serum creatine phosphokinase; this has rarely been associated with myopathy, which appears to be a class-specific effect potentiated by drugs such as gemfibrozil, niacin and cyclosporin. Simvastatin has not demonstrated any cataractogenic potential in the short term. While the tolerability of simvastatin appears favourable compared with the established profiles of other hypocholesterolaemic agents, further monitoring is required to confirm its long term tolerability.Dosage and AdministrationSimvastatin is indicated for patients with primary hypercholesterolaemia when the response to diet and other nonpharmacological measures alone has proved inadequate. The usual starting dose is 10 mg/day given as a single dose in the evening; in Japanese clinical trials a starting dose of 5 mg/day has been favoured. Depending on the patient's response the dosage may be increased at 4-week intervals to a maximum of 40 mg/day given as a single dose in the evening. Regular monitoring of serum hepatic enzymes and creatine phosphokinase should be performed during therapy. The use of simvastatin in combination with fibrates, niacin and cyclosporin should be avoided to minimise the risk of myopathy. The drug is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases. Dosage reduction should not be required in patients with renal insufficiency.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisCefotaxime was the first ‘third generation’ cephalosporin to be marketed and is administered intramuscularly or intravenously. Similar to other agents of this class, it has a broad spectrum ofin vitroactivity, particularly against Enterobacteriaceae, including &bgr;-lactamase-producing strains. Cefotaxime forms a metabolite, desacetylcefotaxime, which is antibacterially effective against many bacteriaper seand acts additively or synergistically with cefotaxime against many strains. Since the first review of cefotaxime in the Journal, further studies have confirmed its value in the treatment of various infections: complicated urinary tract infections, lower respiratory tract infections, bacteraemia, meningitis, uncomplicated gonorrhoea, infections of skin and soft tissue and of bone and joints, and obstetric and gynaecological infections. Cefotaxime is effective as an empirical treatment of suspected infection due to susceptible organisms in immunocompromised patients and is of proven efficacy in serious, life-threatening infections in general. Cefotaxime reduces the incidence of postsurgical infection but the role of third generation cephalosporins in prophylaxis remains to be determined. The indications for which cefotaxime and other ‘third generation’ cephalosporins would be considered the most appropriate therapy remain largely dependent upon such factors as varied as cost, local medical custom, decisions of regulatory agencies and geographical patterns of bacterial resistance. Cefotaxime nevertheless represents a valuable ‘third generation’ cephalosporin of great clinical value in certain infectious conditions, in particular those which are serious and life-threatening and where resistance to therapies is creating a clinical problem.Antibacterial ActivityCefotaxime has a broad spectrum of activityin vitrowhich includes Gram-positive and Gram-negative aerobic and some anaerobic bacteria. Both penicillin-sensitive and penicillin-resistant strains ofStaphylococcus aureusare sensitive to cefotaxime, but methicillin-resistant strains are often resistant.Staphylococcus epidermidisis usually moderately sensitive to cefotaxime although penicillinase-producing strains are usually resistant. MostStreptococcusspecies (S. pneumoniae, S. pyogenes, S. agalactiae) are sensitive to cefotaxime, but most strains ofStreptococcus faecalisare resistant, as areListeria monocytogenesandNocardia asteroides.Cefotaxime is highly active against Gram-negative bacteria and in particular the Enterobacteriaceae, including penicillinase-producing strains. Notable exceptions where resistance may often be encountered includePseudomonasandEnterobacterspecies. Cefotaxime is active against many anaerobic bacteria (e.g.Peptococcus, PeptostreptococcusandVeillonellaspecies, andClostridium perfringens) and someBacteroidesspecies, butClostridium difficileis frequently resistant. Usually there is little difference between the bactericidal and inhibitory concentrations of cefotaxime for most bacteria.Cefotaxime is partially metabolised to desacetylcefotaxime, whichper sedemonstrates significant antibacterial activity. In addition, antibacterial and bactericidal synergy between cefotaxime and desacetylcefotaxime is seen against a high percentage of clinical isolates ofS. aureus, B. fragilisand Enterobacteriaeceae.Cefotaxime and desacetylcefotaxime are stable to inactivation by &bgr;-lactamases produced by many bacteria, and while cefotaxime is hydrolysed by &bgr;-lactamases produced byBacteroides fragilisand types IVc and Ic enzymes produced by some species ofKlebsiellaandProteus vulgaris,respectively, desacetylcefotaxime is relatively stable. Both compounds are hydrolysed by aMorganella morganii&bgr;-lactamase (type Ia), whereas desacetylcefotaxime alone is inhibited by aProteus penneritype Ic &bgr;-lactamase.Based on inhibitory and bactericidal activity, significant synergy occurs between cefotaxime and many other antibacterial agents, most notably the aminoglycosides. Antagonism has rarely been encountered except with the &bgr;-lactamase inhibitor clavulanic acid.Thein vivoantibacterial activity of cefotaxime has been clearly demonstrated in animal models of systemic infection caused by susceptible Enterobacteriaceae andS. aureus,but the drug was ineffective in inhibiting the proliferation ofE. faecalisin well established heart lesions in rabbits.Pharmacokinetic PropertiesThe disposition of cefotaxime is usually described by an open, 2-compartment model, with dose-dependent linear pharmacokinetics for single intravenous doses up to 2g. Mean peak plasma concentrations of about 100, 40 and 20 mg/L are achieved after a single 1g dose of cefotaxime as a bolus, 30-minute infusion and intramuscular injection, respectively. The bioavailability of the intramuscular dose is about 90 to 95%. Steady-state is achieved after several doses, and trough concentrations of cefotaxime and desacetylcefotaxime exceed 10 and 5 mg/L, respectively, after usual dosages.The apparent volume of distribution of cefotaxime is 20 to 30 L/1.73m2and it is 25 to 40% bound to human proteinin vitro.Following usual doses cefotaxime concentrations inhibitory for most susceptible organisms are achieved in most body tissues and fluids, although penetration is poor across noninflamed meninges, as with other &bgr;-lactam antibiotics. High concentrations of desacetylcefotaxime, the main metabolite, are also achieved in body tissues and fluids, sufficient to be antibacterially effectiveper seas well as acting additively or synergistically with cefotaxime. This may explain why cefotaxime is therapeutically effective when administered at longer dose intervals than would be theoretically predicted from the elimination pharmacokinetics of cefotaxime alone. Cefotaxime efficiently crosses the placenta, but penetration into breast milk is minimal.Cefotaxime undergoes hepatic metabolism to form desacetylcefotaxime. The latter undergoes further metabolism to inactive opened &bgr;-lactam ring lactones. About 80% of a radiolabelled dose of cefotaxime is excreted in urine; about 50 to 60% as unchanged drug and the remainder as metabolites. About 20% of the dose is recovered in faeces, as a small degree of biliary excretion of cefotaxime and desacetylcefotaxime occurs. Approximate values for plasma clearance, renal clearance and elimination half-life, respectively, are 15 L/h, 9 L/h and 1.2 hours for cefotaxime, and 45 L/h, 13.2 L/h and 1.6 hours for desacetylcefotaxime in subjects with normal renal function.The effects of age, disease and various other conditions on pharmacokinetics have been well studied. The main findings are that renal insufficiency or inadequate renal development in preterm and low birthweight neonates may decrease the clearance and increase the half-life of cefotaxime, and more particularly its metabolites. Dosage reduction (usually half the normal doses) is therefore required with severe renal insufficiency (creatinine clearance < 5 to 10 ml/min) or in low birthweight neonates. Hepatic impairment from cirrhosis or hepatitis did not affect the pharmacokinetics to a clinically significant degree.Therapeutic EfficacySince cefotaxime was first reviewed in the Journal, clinical trials have confirmed its therapeutic efficacy, in particular in comparisons with other standard treatments. Cefotaxime is as effective as other widely used antimicrobial agents in the treatment of mild uncomplicated urinary tract infection or upper respiratory tract infections, but the treatment of these common community-acquired infections is best achieved with more easily administered oral agents. Cefotaxime 2 to 6 g/day is highly effective in the treatment of complicated urinary tract infections, proving superior to usual dosages of cefoxitin, cefazolin, cefuroxime and gentamicin in some studies and equivalent to aztreonam, ampicillin plus netilmicin, ceftizoxime and ceftriaxone. The same dosage of cefotaxime is also highly effective in the treatment of lower respiratory tract infections, in particular pneumonia, proving equivalent to other first, second and third generation cephalosporins. In these areas as well as other conditions wherePseudomonas aeruginosais proven or suspected, combination with a specific antipseudomonal &bgr;-lactam or an aminoglycoside is necessary because of the generally poor activity of cephalosporins against this organism.Noncomparative studies in patients with bacteraemia indicate a high response rate with cefotaxime, particularly in infections caused by Enterobacteriaceae, but there are few comparative data. Cefotaxime is also effective in combination with an aminoglycoside or a quinolone in the empirical treatment of suspected infection in immunocompromised patients. However, in one study in such patients a combination of azlocillin plus amikacin was more effective than cefotaxime or ticarcillin each combined with amikacin while in another, the cure rate with ceftazidime alone was higher than with cefotaxime plus gentamicin in granulocytopenic patients. It should be noted that in this study the dosage of gentamicin was not titrated and it is not known whether therapeutic concentrations were achieved. More studies of cefotaxime in these circumstances are needed.Early clinical information on the use of cefotaxime in skin, soft tissue, bone and joint infections, intra-abdominal infections, and obstetric and gynaecological infections was largely from noncomparative data, but more recently comparative trials have confirmed the efficacy of cefotaxime. Cefotaxime 2g 8-hourly was similar in efficacy to the same dose of cefoxitin in acute salpingitis, to ceftizoxime 6g daily in pelvic inflammatory disease and to clindamycin plus gentamicin in patients with tubo-ovarian complex or abscess but tended to be less effective than ciprofloxacin in skin and soft tissue infections. Clinical and bacteriological response rates seem high, but at present there are insufficient comparative data to clearly define the place of cefotaxime in the treatment of these conditions. Certainly, in those conditions whereBacteroidesspecies might be encountered cefotaxime should be used in combination with another agent such as clindamycin or metronidazole.Cefotaxime has been particularly well studied in the treatment of meningitis, notably in paediatric patients. Its efficacy is at least equal to that of standard therapy with ampicillin plus chloramphenicol, and it may therefore be considered as suitable first-line agent when resistance to the latter is a clinical problem. Cefotaxime is highly effective against meningitis caused by Enterobacteriaceae andStreptococcus pneumoniae,although there were some failures whenPseudomonas, EnterobacterandSerratiaspecies were pathogens. Cefotaxime should therefore be used in combination with another appropriate antimicrobial agent when the latter infections are suspected or proven and certainly whenListeria monocytogenes, Enterococcus faecalisorStaphylococcus epidermidis,orStaphylococcus aureusare suspected. High dosages of cefotaxime should be used in meningitis: 50 to 100 mg/kg/day in 2 divided doses in low birthweight and premature neonates, up to 200 mg/kg/day in 3 or 4 divided doses in other infants and children, and 6 to 8 g/day in 3 or 4 divided doses in adults. There is some indication that cefotaxime can reduce the incidence of neurological morbidity and the duration of hospitalisation compared with that found following the use of ampicillin plus chloramphenicol. If confirmed, cefotaxime would definitely be proved a first-line agent for this serious condition.Cefotaxime has been well studied in the empirical treatment of severe life-threatening infections, proving equivalent to ceftazidime, ceftriaxone, imipenem/cilastatin and pefloxacin as monotherapy, and in combination with mezlocillin equivalent to the combination of gentamicin plus cefoxitin plus metronidazole. Cefotaxime monotherapy was clearly superior to a combination of an aminoglycoside and a penicillin, providing higher clinical and microbiological cure rates with a lower frequency of nephrotoxicity and superinfections.Cefotaxime as a single intramuscular dose of 1g is virtually 100% effective clinically and microbiologically in the treatment of uncomplicated gonorrhoea, being equally effective against non-penicillinase- and penicillinase-producing strains ofNeisseria gonorrhoeae.Single intramuscular injections of cefotaxime 500mg and ceftriaxone 250mg were similarly effective, as were single 1g doses of cefotaxime and ceftimazole. In a large study, cefotaxime 1g produced significantly fewer treatment failures than cefuroxime 1.5g. Cefotaxime may therefore be considered a suitable first-line agent when resistance to penicillin or spectinomycin presents a clinical problem.Cefotaxime 1 to 2g as a single preoperative dose or as a short course of 3 to 4 doses at 8-hourly intervals peri- and/or postoperatively has proven highly effective in the prevention of infection following a wide range of surgical procedures (urological, obstertrical and gynaecological, gastrointestinal, abdominal, and orthopaedic) with the notable exception of neurosurgery, as &bgr;-lactams in general show poor penetration across noninflamed meninges. Cefotaxime was at least as effective as other prophylactic regimens and in some studies superior to cefoxitin, ampicillin, metronidazole, neomycin plus erythromycin and benzylpenicillin plus cloxacillin and cefamandole. No clinical advantage has been clearly demonstrated during single-dose administration for those third-generation cephalosporins with a long elimination half-life, such as ceftriaxone.Cefotaxime for a few days in combination with ongoing selective digestive decontamination (SDD) with colistin (polymixin E), tobramycin and amphotericin B has been tested in the prevention of infection in intensive care patients. Cefotaxime reduced primary respiratory infection in selected patients and SDD was found to significantly reduce colonisation by aerobic Gram-negative bacilli and also the incidence of unit-acquired infection compared with no antibiotic prophylaxis.Adverse EffectsCefotaxime is generally well tolerated by adults and children following intravenous and intramuscular injection. The overall incidence of adverse events is about 5 to 8%, leading to discontinuation of treatment in about 1 to 2% of patients. The most commonly occurring adverse effects are typical of parenteral cephalosporins: gastrointestinal complaints (mostly diarrhoea, nausea and/or vomiting), dermatological reactions (rash and pruritus) and local reactions at the injection site such as pain and, less frequently, thrombophlebitis. More severe reactions have been reported in rare case reports involving only a few patients:Clostridium difficilepseudomembranous colitis, hypoprothrombinaemia, thrombocytopenia, encephalopathy, status epilepticus, eosinophilia, leucopenia and neutropenia. A causal relationship was not always clearly established in these isolated reports.Dosage and AdministrationThe recommended dosage of cefotaxime is 1 to 6 g/day given in divided doses 2 to 3 times daily intravenously or intramuscularly. The usual dosage is 1 to 2 g/day for urinary tract infections, 3 g/day for other moderate to serious infections, with the higher dosages of 6 g/day being reserved for life-threatening infections. The most appropriate regimen was 0.5 to 2g every 8 to 12 hours for highly susceptible organisms. Paediatric dosages are usually 50 mg/kg/day in neonates, and 100 to 150 mg/kg/day in older infants and children. With serious infections such as meningitis 150 to 200 mg/kg/day is recommended for neonates up to 7 days of age and 200 mg/kg/day for older children. Dose frequency is usually 2 to 3 times daily. A single intramuscular dose of 1g is recommended for the treatment of uncomplicated gonorrhoea. For the prevention of surgical infection a single preoperative dose of 1 to 2g is recommended which may be followed by 1 to 3 doses postoperatively at 8-hour intervals. The dosage should be halved but the frequency maintained in patients whose creatinine clearance is less than 10 ml/min.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS