An overview of therapeutic interventions in myocardial infarction. Emphasis on secondary prevention.

The high risk of subsequent mortality and morbidity following the occurrence of a myocardial infarction (MI) underlies the importance of instituting effective preventive regimens as part of the overall management of these patients. The aim of such treatment is to prolong survival by preventing sudden and non-sudden death and further major cardiovascular events. Currently available data from randomised, controlled clinical trials in MI patients indicate that early treatment with thrombolytic agents [streptokinase, anisolyated plasminogen streptokinase activator complex (APSAC) or recombinant tissue-type plasminogen activator (rt-PA)] in the first few hours after onset of symptoms significantly reduces the short term mortality following MI, with follow-up studies at 1 year indicating that the early benefits persist long term. The optimum time for initiation of thrombolytic therapy is within 6 hours of onset, but treatment started between 7 and 24 hours after onset can also be beneficial. Similarly, there is good evidence that beta-blockers (e.g. propranolol, timolol, metoprolol, atenolol) and aspirin are effective in reducing both the mortality and reinfarction rate following MI. With beta-blockers, a policy of starting treatment early intravenously and continuing orally for 2 to 3 years seems likely to save more lives than either strategy alone; however, contraindications to beta-blockade reduce the number of patients eligible to receive this treatment. In the case of aspirin, the optimum dosage has yet to be determined, but on the basis of present evidence, it seems reasonable to start treatment early with doses of 160 to 325 mg daily and continue for a year or 2 after recovery. Other studies have shown that long term oral anticoagulant therapy is also effective in reducing the mortality and reinfarction rate after MI. Subcutaneous heparin therapy given for 10 days in patients with acute anterior MI reduces the frequency of left ventricular mural thrombosis, while intravenous heparin given for greater than or equal to 4 days improves coronary artery patency rates following administration of a thrombolytic agent. In a comparison with low dose aspirin, intravenous heparin proved more effective in maintaining coronary artery patency rates after rt-PA thrombolysis. There is also evidence that oral nitrates may reduce mortality in MI patients, especially in those with heart failure. However, current data on the use of antiarrhythmic drugs do not support the routine of these drugs following MI. Similarly, with lipid-lowering agents, the evidence that lowering cholesterol is beneficial in reducing mortality after MI is at present inconclusive. Further studies with these groups of drugs are awaited with interest.(ABSTRACT TRUNCATED AT 400 WORDS)

Piroxicam. A reappraisal of its pharmacology and therapeutic efficacy.

Piroxicam is a chemically different non-steroidal anti-inflammatory drug with a long half-life which enables it to be administered once daily. This member of the oxicam series of compounds is now well established in the treatment of rheumatoid arthritis and osteoarthritis and has been shown to be a suitable alternative to aspirin, indomethacin, naproxen, ibuprofen, ketoprofen, sulindac, phenylbutazone and diclofenac in the treatment of rheumatic diseases. Open trials in many thousands of patients in hospital clinics and in general practice have demonstrated its analgesic and anti-inflammatory efficacy in a wide cross-section of patients with rheumatic diseases, when administered once daily either at night or in the morning, and recent studies have demonstrated its usefulness in musculoskeletal disorders, dysmenorrhoea and postoperative pain. Such studies have also demonstrated the generally good tolerability of piroxicam 20mg daily. As with other non-steroidal anti-inflammatory drugs, gastrointestinal complaints are the most frequently reported side effects. The frequency and severity of these effects are dose related. Thus, piroxicam is now well established in the treatment of rheumatic diseases and offers an alternative to other analgesics in various pain states.

Indapamide. A review of its pharmacodynamic properties and therapeutic efficacy in hypertension.

Indapamide is an orally active sulphonamide diuretic agent. Although some evidence appears to indicate that the antihypertensive action of indapamide is primarily a result of its diuretic activity, only a limited diuresis occurs with the usual antihypertensive doses of 2.5 mg daily, and in vitro and in vivo data suggest that it may also reduce blood pressure by decreasing vascular reactivity and peripheral vascular resistance. In mild to moderate hypertension it is as effective as thiazide diuretics and beta-adrenergic blocking agents in lowering blood pressure when used as the sole treatment. Indapamide has been successfully combined with beta-adrenergic blocking agents, methyldopa, and other anti-hypertensive agents. While such findings need confirmation, it appears that indapamide shares the potential with other diuretic agents to induce electrolyte and other metabolic abnormalities, although it may do so with less frequency or severity. Thus, indapamide appears to offer a suitable alternative to more established drugs as a 'first-line' treatment in patients with mild to moderate hypertension. Whether it differs significantly from other diuretics when used as antihypertensive therapy, either in its mode of action or its side effect profile, needs further clarification.

Beclomethasone dipropionate. A reappraisal of its pharmacodynamic properties and therapeutic efficacy after a decade of use in asthma and rhinitis.

Inhaled beclomethasone dipropionate is now well established in the management of asthma. Studies conducted over the last decade, and since the drug was previously reviewed in the Journal, have confirmed that inhaled beclomethasone dipropionate 400 to 800 micrograms daily can reduce the need for oral maintenance corticosteroids in the majority of asthmatic patients requiring such therapy, and that increasing the dosage to 2000 micrograms daily may provide additional clinical benefit in some patients unresponsive to usual therapeutic dosages. Follow-up over a period of several years has confirmed that the initial response to inhaled beclomethasone can be maintained in most patients. Recent studies indicate that beclomethasone dipropionate 400 micrograms daily is equally effective when administered in 2 or 4 divided doses in patients with stable asthma, but it is likely that the lower frequency of administration will be less effective when the asthma is unstable. Recent studies have established the usefulness and good tolerability of intranasal beclomethasone dipropionate in the treatment of perennial and seasonal rhinitis, where the drug has been shown to be more effective than intranasal sodium cromoglycate and similar in efficacy to flunisolide. Nasal polyps decrease in size during continuous treatment with intranasal beclomethasone dipropionate, but enlarge again during periods of respiratory infection. After a decade of treatment with inhaled and intranasal beclomethasone dipropionate, there is no evidence that the drug damages the tracheobronchial lining or the nasal mucosa. Thus, the initial promise of beclomethasone dipropionate has been fulfilled. It has had an important role in asthma therapy over the past decade, which will continue into the future.

Astemizole. A review of its pharmacodynamic properties and therapeutic efficacy.

Astemizole is an H1-histamine receptor antagonist with a long duration of action permitting once daily administration. Its efficacy in seasonal and perennial allergic rhinitis has been convincingly demonstrated, and several comparative studies suggest that astemizole is at least as effective as some other H1-histamine receptor antagonists. A few smaller studies have shown beneficial effects on the symptoms of allergic conjunctivitis and chronic urticaria (but not atopic dermatitis). While astemizole appears to share with other H1-histamine receptor antagonists a tendency to increase appetite and cause weight gain after prolonged use, it offers the important advantage of an absence of significant central nervous system depression or anticholinergic effects with usual doses. Thus, astemizole offers a worthwhile improvement in side effect profile over 'traditional' H1-histamine receptor antagonists, especially in patients bothered by the sedative effects of these drugs.

Isotretinoin. A review of its pharmacological properties and therapeutic efficacy in acne and other skin disorders.

Isotretinoin is a new orally active retinoic acid derivative for the treatment of severe refractory nodulocystic acne. The pharmacological profile of isotretinoin suggests that it acts primarily by reducing sebaceous gland size and sebum production, and as a result alters skin surface lipid composition. Bacterial skin microflora is reduced, probably as a result of altered sebaceous factors. Isotretinoin 1 to 2 mg/kg/day for 3 to 4 months produces 60 to 95% clearance of inflammatory lesions in patients with severe, recalcitrant nodulocystic acne, with evidence of continued healing and prolonged remissions in many patients after treatment withdrawal. Doses as low as 0.1 mg/kg/day have also proven successful in the clearance of lesions; however, with such low doses the duration of remission after discontinuation of therapy is usually shorter. Encouraging results have also been seen in small numbers of patients with rosacea, Gram-negative folliculitis, Darier's disease, ichthyosis and pityriasis rubra pilaris, the response in keratinising disorders resembling that with the related drug etretinate. While long term follow-up studies in these patients have not been reported, prolonged remission after withdrawal of isotretinoin in disorders of keratinisation is unlikely, as with other drugs used in these conditions. Isotretinoin is only partially effective in psoriasis, in contrast to etretinate which is very effective in psoriasis but ineffective in severe acne. Some encouraging results have also been reported with isotretinoin in patients with squamous and basal cell carcinomas, but isotretinoin has proven unsuccessful in non-squamous cell epithelial and non-epithelial cancer. Side effects affecting the mucocutaneous system occur in nearly all patients receiving isotretinoin, but rarely lead to drug withdrawal. Raised serum triglyceride levels are also commonly reported. The possibility of long term spinal or skeletal bone toxicity may restrict the use of isotretinoin in severe disorders of keratinisation requiring prolonged administration. Isotretinoin is strictly contraindicated in women of childbearing potential due to its severe teratogenic properties, unless an effective form of contraception is used. Thus, isotretinoin offers an effective advance on the treatment options available in a difficult therapeutic area - those patients with severe, nodulocystic acne not responding to 'traditional' therapy.

Ceftriaxone. A review of its antibacterial activity, pharmacological properties and therapeutic use.

Ceftriaxone is a new 'third generation' semisynthetic cephalosporin with a long half-life which has resulted in a recommended once daily administration schedule. It is administered intravenously or intramuscularly and has a broad spectrum of activity against Gram-positive and Gram-negative aerobic, and some anaerobic, bacteria. The activity of ceftriaxone is generally greater than that of the 'first' and 'second generation' cephalosporins against Gram-negative bacteria, but less than that of the earlier generations of cephalosporins against many Gram-positive bacteria. Although ceftriaxone has some activity against Pseudomonas aeruginosa, on the basis of present evidence it cannot be recommended as sole antibiotic therapy in pseudomonal infections. Ceftriaxone has been effective in treating infections due to other 'difficult' organisms such as multidrug-resistant Enterobacteriaceae. Ceftriaxone was effective in complicated and uncomplicated urinary tract infections, lower respiratory tract infections, skin, soft tissue, bone and joint infections, bacteraemia/septicaemia, and paediatric meningitis due to susceptible organisms. In most of these types of infections once-daily administration appears efficacious. Results were also encouraging in a few patients with ear, nose and throat, intra-abdominal, obstetric and gynaecological infections, and adult meningitis, but conclusions are not yet possible as to the efficacy of the drug in these indications due to limited experience. A single intramuscular dose of ceftriaxone has been compared with standard therapy for gonorrhoea due to non-penicillinase-producing and penicillinase-producing strains of Neisseria gonorrhoeae and shown to be highly effective. In a few small trials the comparative efficacy of ceftriaxone and other antibacterials has been assessed in other types of infections and in perioperative prophylaxis in patients undergoing surgery. Few significant differences in response rates were found between therapeutic groups in these comparative studies, but larger well-designed studies are needed to more clearly assess the comparative efficacy of ceftriaxone and other antimicrobials, especially the aminoglycosides and other 'third generation' cephalosporins, and to confirm the apparent lack of serious side effects with ceftriaxone. If more widespread use confirms the safety and efficacy of ceftriaxone, it will offer an important alternative, particularly for the treatment of serious infections due to multidrug-resistant Gram-negative bacteria and in situations where the long half-life of the drug could result in worthwhile convenience and cost benefits.

Auranofin. A preliminary review of its pharmacological properties and therapeutic use in rheumatoid arthritis.

Auranofin is the first orally active gold compound for the treatment of rheumatoid arthritis. Like other chrysotherapeutic agents, its exact mechanism of action is unknown, but it probably acts via immunological mechanisms and alteration of lysosomal enzyme activity. Although long term clinical experience with auranofin is limited, its efficacy appears to approach that of sodium aurothiomalate. Further comparative studies with aurothioglucose, hydroxychloroquine and D-penicillamine are required before definitive statements can be made regarding the relative efficacy of auranofin and these agents. While patients have demonstrated clinical remission of rheumatoid arthritis in response to auranofin therapy, radiological studies have been inconclusive regarding its effect on the occurrence or progression of erosive lesions. Auranofin is relatively well tolerated in most patients, but diarrhoea, skin rash, and pruritus are sometimes troublesome, and thrombocytopenia and proteinuria are potentially serious side effects which may occur during therapy. Whereas mucocutaneous side effects are more frequent with injectable gold compounds, gastrointestinal reactions are the most common adverse effect seen with auranofin. The frequency of side effects has been similar with auranofin and sodium aurothiomalate, but they are generally less severe with auranofin. While some of the side effects are controlled by a reduction in dosage, temporary or permanent withdrawal of auranofin may be necessary. Auranofin is clearly a useful addition to the limited list of agents with disease-modifying potential presently available for the treatment of rheumatoid arthritis. It will doubtless generate much interest as its final place in therapy becomes better defined through additional well-designed studies and wider clinical experience.

Gliclazide. A preliminary review of its pharmacodynamic properties and therapeutic efficacy in diabetes mellitus.

Gliclazide is a 'second generation' oral hypoglycaemic agent. The particular interest with this drug is that it has shown certain effects on the blood for which it is hoped there may be some clinical benefit in diabetic angiopathies. Both in animal and human studies it has demonstrated a reduction in platelet adhesiveness and aggregation, whilst possible enhancement of platelet metabolism, reduction of coagulant factors, as well as increased fibrinolytic activity, are still being investigated. Initial trials have suggested that gliclazide therapy may reverse or at least slow down the progression of diabetic retinopathy. However, a few additional well-designed long term controlled studies are needed to confirm these findings, and to clarify whether any beneficial effect on diabetic retinopathy is unique to gliclazide or also occurs with other oral hypoglycaemic drugs. Both newly diagnosed maturity onset diabetics as well as those previously treated with sulphonylureas respond well to gliclazide therapy. In the small comparative studies which have been reported, gliclazide was of comparable efficacy to other oral hypoglycaemic agents.

Oxatomide. A review of its pharmacodynamic properties and therapeutic efficacy.

Oxatomide is an orally active H1-histamine receptor antagonist which, as appears to occur with some other antihistamines, also inhibits mast cell degranulation. Oxatomide has demonstrated response rates similar to those with other more established members of its drug class in a few studies of chronic urticaria and allergic rhinitis. Interestingly, some patients responding to oxatomide were said to be unresponsive to previously administered antihistamines. The effect of oxatomide was little different from placebo in clinical trials of bronchial asthma in adults. While somewhat more encouraging results have been reported in children with bronchial asthma when higher than presently recommended dosages were employed, and in follicular conjunctivitis, atopic dermatitis and food allergy, reports to date are largely preliminary in nature and additional well-controlled studies are needed to clarify the efficacy of oxatomide in such conditions. The drug has been generally well tolerated, but shares some of the familiar H1-histamine receptor antagonist side effects. As with other similarly acting drugs, the 2 primary side effects with oxatomide are drowsiness and weight gain. Thus, on the basis of present evidence, a trial with oxatomide seems a potentially useful alternative in patients with conditions known or thought to be allergic in nature, in whom more established treatments were ineffective or poorly tolerated.

Sucralfate. A review of its pharmacodynamic properties and therapeutic use in peptic ulcer disease.

Sucralfate is a basic aluminium salt of sulphated sucrose which is advocated for use in peptic ulcer disease. It is minimally absorbed after oral administration and is believed to act primarily at the ulcer site by protecting the ulcer from the effects of pepsin, acid and possibly bile salts. Controlled therapeutic trials have demonstrated that sucralfate 1g 4 times daily is effective in increasing the rate of healing of duodenal and gastric ulcer over a period of 4 to 8 weeks. Trials comparing sucralfate and cimetidine have not found any significant difference in efficacy between the drugs in small numbers of patients. A dosage of 2g daily given prophylactically decreases the rate of recurrence of duodenal ulcers, but the efficacy of sucralfate in preventing relapse of gastric ulcers has yet to be clearly demonstrated. Sucralfate is particularly well tolerated. Constipation, the most common side effect, occurs in 2% of patients. Thus, sucralfate offers an effective and well tolerated alternative for the management of peptic ulcer disease.

Ursodeoxycholic acid: a review of its pharmacological properties and therapeutic efficacy.

Ursodeoxycholic acid is the 7 beta-hydroxy epimer of chenodeoxycholic acid and is normally present in only trace amounts in the bile. Oral administration of pharmacological doses markedly decreases biliary cholesterol saturation. Complete or partial dissolution of radiolucent gallstones located in a functioning gallbladder occurred in about 40 to 55% of patients treated with ursodeoxycholic acid in controlled studies of 6 months duration. Patients showing partial gallstone dissolution at that time are likely to continue improving possibly to complete gallstone dissolution with continued therapy. The success rate with ursodeoxycholic acid may be increased top about 80% if more stringent patient selection criteria are applied to include only those with non-calcified floating cholesterol stones of less than 10 to 15 mm diameter. Those with calcified stones or stones greater than 15 mm diameter or unlikely to respond to ursodeoxycholic acid therapy. The optimal dose in published studies was about 8 to 10 mg/kg/day, which is about half to two-thirds the dose of chenodeoxycholic acid (15 mg/kg/day) achieving approximately equivalent results. Ursodeoxycholic acid appears to be remarkably well tolerated, with diarrhoea occurring in only a very small proportion of patients. While surgery is clearly the preferred treatment in many patients with symptomatic gallstones, in a carefully selected subgroup of such patients gallstone dissolution therapy with ursodeoxycholic acid offers an important and worthwhile alternative.

Flunarizine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use.

Flunarizine is a 'selective' calcium entry blocker with a similar chemical structure and pharmacological profile to the related compound, cinnarizine. However, in contrast to cinnarizine it has a long plasma half-life and need only be given once a day. The majority of therapeutic trials in the prophylaxis of migraine, occlusive peripheral vascular disease and vertigo of central or peripheral origin have been placebo-controlled, and have shown that the drug produces significantly greater beneficial effects than placebo as evaluated by subjective and objective criteria. A small number of comparative studies have shown flunarizine to be at least as effective as pizotifen in migraine prophylaxis, and in a longer term study as effective as cinnarizine in vertigo of central origin. However, it has not been compared with other drugs which may be useful in these areas, such as methysergide in migraine prophylaxis, some antihistamines or phenothiazines in vertigo, or (understandably at this stage of its evolution) with surgical revascularisation in severe occlusive peripheral vascular disease. In preliminary placebo-controlled studies there was some evidence that flunarizine may improve impaired cognitive function in patients with cerebrovascular disorders, but such findings need further confirmation in additional carefully conducted studies. With a very long half-life, flunarizine may be given once daily; and drowsiness, the main side effect, can be minimised by taking the daily dose in the evening. Thus, it appears that flunarizine will offer a useful alternative in some therapeutic areas that can be difficult to manage with previously available therapy. However, a definitive statement on its relative place in therapy of such conditions must await a few well-controlled comparative studies.

Amrinone. A preliminary review of its pharmacological properties and therapeutic use.

Amrinone is a bipyridine derivative with positive inotropic effects and vasodilatory properties. However, in the clinical setting of congestive heart failure, the relative contribution of these factors remains a matter of conjecture. Its mode of action appears to be related to alterations in extracellular and intracellular calcium balance, probably mediated by increased levels of tissue cyclic adenosine monophosphate and possibly involving a sodium-dependent pathway. Clinical experience has mostly been short term and is limited to a relatively small number of patients with severe congestive heart failure, refractory to conventional treatment. Amrinone rapidly improves cardiac performance by decreasing systemic vascular resistance (afterload), decreasing the determinants of left ventricular filling pressure (preload) and improving the cardiac contractility. Improvements in exercise performance and clinical symptomatology occur without an increase in heart rate or decrease in mean arterial pressure. Amrinone has been compared with dopamine, dobutamine, pirbuterol and prazosin in preliminary short terms studies in patients with severe congestive heart failure, although more studies are needed before any relative clinical advantages or disadvantages can be ascribed to amrinone. Initial experience suggests that the addition of vasodilators such as hydralazine and isosorbide dinitrate to amrinone therapy may confer additional haemodynamic benefits. Preliminary medium term studies suggest that tolerance to the haemodynamic effects of amrinone does not usually occur, but long term studies are needed to determine whether amrinone alters the normal progression of the disease and whether overall mortality is affected. Amrinone has usually been administered as intravenous bolus doses (totalling 1.5 to 3.6 mg/kg/day) and/or continuous intravenous infusion, with varied results. Generally, an oral dose greater than the intravenous dose is required to achieve an equivalent level of response. Reversible, usually asymptomatic, thrombocytopenia occurs in about 20% of patients treated with amrinone. Arrhythmias and gastrointestinal disturbances have been reported, but wider clinical experience is required to determine the side effect profile of the drug.

Acyclovir. A review of its pharmacodynamic properties and therapeutic efficacy.

Acyclovir (aciclovir) is a nucleoside analogue antiviral drug related to cytarabine, idoxuridine, trifluridine and vidarabine. In common with these earlier antivirals, acyclovir is active against some members of the herpesvirus group of DNA viruses. The efficacy of topical acyclovir has been convincingly demonstrated in ocular herpetic keratitis, and in initial and primary initial genital herpes infection, but little or no clinical benefit was seen when non-primary initial genital infections were assessed separately. Acyclovir ointment demonstrated little benefit in recurrent genital herpes but topical acyclovir cream decreased the course of the infection by 1 to 2 days. Orally and intravenously administered acyclovir were beneficial in initial genital herpes infections, and oral therapy shortened the duration of recurrent infections by 1 to 2 days but did not ameliorate pain. In non-immunocompromised patients with recurrent herpes simplex labialis, generally little clinical benefit was seen with the use of topical acyclovir ointment even when therapy was initiated during the prodromal phase, while topical acyclovir cream effected small but significant improvements in the clinical but not the symptomological course of the disease. However, in immunocompromised patients, both intravenous and topical acyclovir shortened the clinical course of herpes simplex virus infections occurring mainly on the lips, oral mucosa and face, and prophylaxis with either oral or intravenous acyclovir suppressed the appearance of recurrent lesions from latent virus for the period of drug administration, but acyclovir did not eradicate latent herpesviruses. In non-immunocompromised patients, intravenous acyclovir was shown to decrease the acute pain of zoster, especially in the elderly, but postherpetic neuralgia was not ameliorated. When immunocompromised patients were studied, intravenous acyclovir inhibited the progression of zoster infections and shortened the healing time and duration of viral shedding in patients with cutaneous disseminated zoster. However, acute and post-herpetic pain were not significantly affected. Well designed controlled studies are underway to establish the efficacy of acyclovir in herpes simplex encephalitis and cytomegalovirus infections in immunocompromised patients, infections due to Epstein-Barr virus, and neonatal herpesvirus infections. Despite some aspects of the drug's use which require further clarification, acyclovir will make a major impact on the treatment of herpesviral infections. Barring unexpected findings with wider clinical use, it will become the agent of choice in several conditions.

Moxalactam (latamoxef). A review of its antibacterial activity, pharmacokinetic properties and therapeutic use.

Moxalactam (latamoxef) is a new synthetic oxa-beta-lactam antibiotic administered intravenously or intramuscularly. It has a broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, is particularly active against Enterobacteriaceae and is resistant to hydrolysis by beta-lactamases. Moxalactam has moderate activity against Pseudomonas aeruginosa, but on the basis of present evidence can not be recommended as sole antibiotic treatment of known or suspected pseudomonal infections. Like the related compounds, the cephalosporins, moxalactam is effective in the treatment of complicated urinary tract infections and lower respiratory tract infections caused by Gram-negative bacilli. As moxalactam is also active against Bacteroides fragilis it has considerable potential in the treatment of intra-abdominal infections in patients with normal immunological mechanisms, as well as in immunocompromised patients, when used alone or in combination with other antibiotics. Likewise, its ready penetration into the diseased central nervous system, its high level of activity against Gram-negative bacilli, and the lack of necessity to monitor drug plasma concentrations, indicate its potential value in the treatment of neonatal Gram-negative bacillary meningitis. Further clinical experience is needed before it can be determined whether moxalactam alone can be used in the treatment of conditions for which the aminoglycosides are drugs of choice, but if established as equally effective, moxalactam has the advantage of being devoid of nephrotoxicity. Bleeding is a potentially serious problem, however, particularly in the elderly, malnourished and in the presence of renal impairment.

Guanabenz. A review of its pharmacodynamic properties and therapeutic efficacy in hypertension.

Guanabenz is an orally active central alpha 2-adrenoceptor agonist. Its antihypertensive action is thought to result from a decrease in sympathetic outflow from the brain to the peripheral circulatory system as a result of stimulation of central alpha 2-adrenoceptors. In mild to moderate hypertension it is as effective as methyldopa and clonidine in lowering blood pressure when used as the sole treatment. As with these drugs, guanabenz may be combined with a diuretic to increase its blood pressure-lowering effect. The overall incidence of side effects seen with guanabenz was at least as high as with methyldopa or clonidine, and side effects such as drowsiness or dry mouth have been bothersome enough to lead to discontinuation of guanabenz therapy in some patients. However, particularly troublesome effects such as sodium retention, depression or sexual dysfunction which may occur with methyldopa or clonidine have not been reported with guanabenz.

Tocainide. A review of its pharmacological properties and therapeutic efficacy.

Tocainide is an antiarrhythmic drug structurally related to lignocaine with similar electrophysiological, haemodynamic and antiarrhythmic effects. In contrast to lignocaine (lidocaine) it is well absorbed after oral administration and has a plasma half-life of about 15 hours. In several open and controlled therapeutic trials in patients with ventricular arrhythmias, often following a myocardial infarction, tocainide has been relatively effective and usually well tolerated. In treating ventricular ectopic beats and/or ventricular tachycardia tocainide has demonstrated effective suppression in 60 to 70% of patients in both open and controlled studies. It has an acute effect when infused in patients with ventricular arrhythmias complicating myocardial infarction, as well as a prophylactic effect when given orally. The majority of these studies have demonstrated tocainide to be more effective than placebo, but trials against other antiarrhythmic agents are few in number and vary in design. One study combining an infusion of tocainide with oral therapy compared to a bolus injection of lignocaine followed by a constant infusion in patients after myocardial infarction, found the two agents to be of similar efficacy. The most common adverse effects are neurological and gastrointestinal in nature, nausea and dizziness occurring most frequently. Adverse effects resulting in termination of therapy have been reported in about 16% of patients. Aggravation of pre-existing heart failure, increased ventricular arrhythmia, deterioration of conduction disturbances, convulsions, and cases of lupus erythematosus syndrome have occasionally been reported. Thus, tocainide appears to offer a worthwhile addition to the other antiarrhythmic agents available for ventricular arrhythmias. However, its relative place in therapy compared with other antiarrhythmic drugs is not yet clearly established.

Etretinate. A review of its pharmacological properties and therapeutic efficacy in psoriasis and other skin disorders.

Etretinate (Ro 10-9359) is a new aromatic retinoic acid derivative for the treatment of severe psoriasis and other dyskeratoses. The pharmacological profile of etretinate suggests that it acts by normalizing pathological changes in epidermal and dermal skin, particularly inhibiting hyperkeratinization and cell differentiation, although its specific mode of action in different disorders remains to be elucidated. Etretinate is rapidly and presystemically metabolised to an active metabolite which appears in plasma at about the same time as parent drug. A 'deep' storage compartment with a very extended elimination half-life gives rise to detectable plasma levels of drug for at least 3 to 4 months after discontinuation of long term therapy. Studies suggest that etretinate at an initial dose of 1 mg/kg/day, reducible during maintenance therapy, is an effective alternative to PUVA and other conventional therapy in severe psoriasis. Its greatest immediate value is in the control of eruptive and treatment-resistant psoriasis, and in its potential for use in combination with other therapy to improve the response. In Darier's disease it appears to be the treatment of choice, and preliminary studies also suggest its usefulness in ichthyosis, and most other dyskeratoses and possibly in basal cell carcinoma. Side effects affecting the mucocutaneous system occur in nearly all patients, but rarely lead to drug withdrawal. When withdrawal does become necessary, the primary reason is usually hair loss. A few paradoxical observations of raised and lowered liver enzyme levels have been reported, and also a few cases of suspected liver damage. Etretinate is strictly contraindicated in women of child-bearing potential due to its severe teratogenic properties.

Cefotaxime. A review of its antibacterial activity, pharmacological properties and therapeutic use.

SYNOPSIS: Cefotaxime is a new 'third generation' semisynthetic cephalosporin administered intravenously or intramuscularly. It has a broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, and is generally more active against Gram-negative bacteria than the 'first' and 'second generation' cephalosporins. Although cefotaxime has some activity against Pseudomonas aeruginosa, on the basis of present evidence it cannot be recommended as sole antibiotic therapy for pseudomonal infections. However, cefotaxime has been effective in treating infections due to other 'difficult' organisms, such as multidrug-resistant Enterobacteriaceae. Like other cephalosporins, cefotaxime is effective in treating patients with complicated urinary tract and lower respiratory tract infections, particularly pneumonia caused by Gram-negative bacilli. High response rates have also been achieved in patients with Gram-negative bacteraemia. Although favourable clinical results have been obtained in patients with infections caused by mixed aerobic/anaerobic organisms (such as peritonitis or soft tissue infections), the relatively low in vitro activity of cefotaxime against Bacteroides fragilis may restrict its usage in situations where this organism is the suspected or proven pathogen. In preliminary studies, males and females treated with a single intramuscular dose of cefotaxime for uncomplicated gonorrhoea caused by penicillinase-producing strains of Neisseria gonorrhoeae responded very favourably. Encouraging results have also been reported in open studies in children including neonates, treated with cefotaxime for meningitis and various other serious infections. In some situations, cefotaxime has been given in combination with another antibiotic such as an aminoglycoside, but the merits of such a combination have not been clearly established. Whether cefotaxime alone is appropriate therapy for conditions previously treated with aminoglycosides (other than pseudomonal infections) also needs additional clarification, but if established as equally effective in such conditions cefotaxime offers potentially important clinical and practical advantages in its apparent lack of serious adverse effects and freedom from the need to undertake drug plasma concentration monitoring.