The quinolones. An overview of their pharmacology.

The fluoroquinolones represent a relatively new class of antibiotics with outstanding therapeutic potential, attributable to their broad spectrum of antimicrobial activity and favourable tissue distribution. They are highly active against most Gram-negative pathogens, as well as Staphylococcus aureus and coagulase-negative staphylococci. In addition, the fluoroquinolones have useful pharmacokinetic properties: they are orally active, and their lipophilicity and low degree of plasma protein binding allow for excellent tissue penetration and concentrations, as reflected in their particularly large apparent volumes of distribution. Infections due to aerobic Gram-negative pathogens are considered those most susceptible to the quinolones. Disease indications in which these agents appear to offer the greatest therapeutic advantage over currently available alternatives include the following: complicated urinary tract infections (particularly those caused by Pseudomonas aeruginosa or resistant Gram-negative microorganisms); suspected bacterial gastroenteritis; eradication of Salmonella typhi from the faeces in known carriers; P. aeruginosa-associated respiratory exacerbation in patients with cystic fibrosis; and chronic Gram-negative bacterial osteomyelitis. Direct comparisons of the various quinolones are too limited to date to provide clear therapeutic options. Nevertheless, this class of compounds is likely to play a major role in providing effective oral therapy for conditions that have previously required prolonged parenteral treatment.

Changes in body temperature and oxygen consumption rate of conscious mice produced by intrahypothalamic and intracerebroventricular injections of delta 9-tetrahydrocannabinol.

delta 9-Tetrahydrocannabinol (delta 9-THC) was injected into the preoptic area of the anterior hypothalamus or into the third or fourth cerebral ventricle of the conscious mouse through a chronically implanted cannula and the effects on body temperature and oxygen consumption rate were measured. At an ambient temperature of 22 degrees C, injections of delta 9-THC into the fourth ventricle (5 and 10 microgram) produced dose-dependent falls in rectal temperature. Hypothermia was also observed after injections of the drug into the hypothalamus (5 and 10 microgram) or into the third ventricle (10 microgram). The hypothermia produced by delta 9-THC was associated with a fall in oxygen consumption rate. Falls in rectal temperature and in oxygen consumption rate were significantly greater after injection of delta 9-THC than after injection of the drug vehicle, Tween 80. The falls in rectal temperature and oxygen consumption rate produced by injection of delta 9-THC into the fourth ventricle were abolished by elevation of the ambient temperature from 22 to 32 degrees C. A pretreatment that consisted of subcutaneous injections of delta 9-THC (20 mg/kg) given once daily for three days produced tolerance to the hypothermic effect of the drug when injected on day 4 either into the fourth ventricle (10 microgram) or into a lateral tail vein (2.0 mg/kg). The results suggest that delta 9-THC acts centrally to alter thermoregulation in mice not only when it is injected directly into the hypothalamus or cerebral ventricles but also when it is given intravenously. After intraventricular or intravenous administration the drug may act at extrahypothalamic as well as at hypothalamic sites. The data also support the hypothesis that in mice, tolerance to the hypothermic effect of A9-THC is pharmacodynamic and does not depend on changes in metabolism or distribution of the drug.

Pantoprazole. A review of its pharmacological properties and therapeutic use in acid-related disorders.

Pantoprazole is an irreversible proton pump inhibitor which, at the therapeutic dose of 40mg, effectively reduces gastric acid secretion. In controlled clinical trials, pantoprazole (40mg once daily) has proved superior to ranitidine (300mg once daily or 150mg twice daily) and equivalent to omeprazole (20mg once daily) in the short term (< or = 8 weeks) treatment of acute peptic ulcer and reflux oesophagitis. Gastric and duodenal ulcer healing proceeded significantly faster with pantoprazole than with ranitidine, and at similar rates with pantoprazole and omeprazole. The time course of gastric ulcer pain relief was similar with pantoprazole, ranitidine and omeprazole, whereas duodenal ulcer pain was alleviated more rapidly with pantoprazole than ranitidine. Pantoprazole (40mg once daily) showed superior efficacy to famotidine (40mg once daily) in ulcer healing and pain relief after 2 weeks in patients with duodenal ulcer in a large multicentre nonblinded study. In mild to moderate acute reflux oesophagitis, significantly greater healing was obtained with pantoprazole than with ranitidine and famotidine, whereas similar healing rates were seen with pantoprazole and omeprazole. Pantoprazole showed a significant advantage over ranitidine in relieving symptoms of heartburn and acid regurgitation. Reflux symptoms were similarly alleviated by pantoprazole and omeprazole. Preliminary results indicate that triple therapy with pantoprazole, clarithromycin and either metronidazole or tinidazole is effective in the treatment of Helicobacter pylori-associated disease; however, these findings require confirmation in large well-controlled studies. Pantoprazole appears to be well tolerated during short term oral administration, with diarrhoea (1.5%), headache (1.3%), dizziness (0.7%), pruritus (0.5%) and skin rash (0.4%) representing the most frequent adverse events. The drug has lower affinity than omeprazole or lansoprazole for hepatic cytochrome P450 and shows no clinically relevant pharmacokinetic or pharmacodynamic interactions at therapeutic doses with a wide range of drug substrates for this isoenzyme system. In conclusion, pantoprazole is superior to ranitidine and as effective as omeprazole in the short term treatment of peptic ulcer and reflux oesophagitis, has shown efficacy when combined with antibacterial agents in H. pylori eradication, is apparently well tolerated and offers the potential advantage of minimal risk of drug interaction.

Risperidone. A review of its pharmacology and therapeutic potential in the treatment of schizophrenia.

Risperidone, a benzisoxazol derivative, is a novel antipsychotic agent which combines potent serotonin (5-hydroxytryptamine) 5-HT2 and dopamine D2 receptor antagonism. Development of the drug was stimulated by reports that the selective serotonin 5-HT2 antagonist ritanserin improved the negative symptoms of schizophrenia and decreased extrapyramidal symptoms when combined with haloperidol. The relatively low incidence of extrapyramidal symptoms with risperidone may reflect a preferential action on mesolimbic rather than nigrostriatal dopaminergic pathways. Recent clinical investigation suggests that risperidone is of at least comparable efficacy to haloperidol and perphenazine in improving the symptoms of acute and chronic schizophrenia on short term administration. Advantages offered by risperidone over haloperidol include a faster onset of antipsychotic action, a lower incidence of extrapyramidal effects and possibly greater efficacy against the negative symptoms of schizophrenia. If these benefits prove to be maintained during long term therapy, risperidone is likely to make a significant contribution to the treatment of schizophrenia.

Pamidronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease.

Pamidronate [aminohydroxypropylidene diphosphonate disodium (APD), disodium pamidronate] is an orally and intravenously active amino-substituted bisphosphonate which produces potent and specific inhibition of bone resorption at doses devoid of any significant detrimental effect on bone growth and mineralisation. Clinical trials indicate that pamidronate is effective in a variety of conditions characterised by pathologically enhanced bone turnover, including Paget's disease, hypercalcaemia of malignancy, osteolytic bone metastasis, steroid-induced osteoporosis and idiopathic osteoporosis. Pamidronate is highly effective in restoring normocalcaemia in patients with hypercalcaemia of malignancy associated with bone metastases but, in common with other bisphosphonates, is marginally less effective against humoral hypercalcaemia of malignancy. Comparative studies in this area have suggested that, at therapeutic doses, pamidronate has a more pronounced calcium-lowering action than etidronate (etidronic acid) and clodronate (clodronic acid) and provides a longer period of normocalcaemic remission. In Paget's disease arrest and, in some patients, reversal of the progression of osteolytic lesions by pamidronate is associated with a sustained reduction in bone pain, improved mobility and a possible reduced risk of bone fracture. In patients with osteolytic bone metastasis pamidronate reduces skeletal morbidity and slows the progression of metastatic bone destruction. Long term use of low-dose pamidronate in conjunction with conventional antiosteoporotic therapy may halt bone loss in steroid-induced and idiopathic osteoporosis. Pamidronate appears to represent a valuable addition to the drugs currently available for the treatment of symptomatic Paget's disease and cancer-associated hypercalcaemia, and shows promise in the treatment of osteolytic bone metastasis and osteoporosis.

Isradipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease.

Isradipine, a dihydropyridine derivative, inhibits the inward calcium flux through 'slow' channels of cardiac and vascular tissue, thereby eliciting potent coronary, cerebral and peripheral vasodilatation. In comparison with other calcium channel blockers the drug offers the advantages of minimal cardiodepressant activity, a selective action on the coronary and skeletal muscle vasculature, and a prolonged vasodilatory action. Clinical trials indicate that isradipine is an effective antihypertensive agent, suitable as monotherapy or in combination with beta-blockers, diuretics or ACE inhibitors, for long term treatment of mild to moderate hypertension. Preliminary findings suggest that the drug has a potential role in the treatment of chronic stable angina and, possibly, congestive heart failure. Adverse effects associated with the vasodilatory action of isradipine are generally mild, transient and well-tolerated, and are similar to those encountered with other calcium channel blockers. Thus, isradipine appears to offer a useful alternative to other dihydropyridine derivatives currently employed for the treatment of mild to moderate hypertension and, to a lesser extent, chronic stable angina. While its relative freedom from serious adverse effects may prove of value, its place in therapy vis-à-vis the established calcium channel blockers requires further clarification.

Dopexamine hydrochloride. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in acute cardiac insufficiency.

Dopexamine hydrochloride is a novel synthetic catecholamine, structurally related to dopamine, with marked intrinsic agonist activity at beta 2-adrenoceptors, lesser agonist activity at dopamine DA1- and DA2-receptors and beta 1-adrenoceptors, and an inhibitory action on the neuronal catecholamine uptake mechanism. The drug is administered by intravenous infusion, and is characterized by a rapid onset and short duration of action. Short term haemodynamic studies in volunteers and patients with severe chronic heart failure have indicated that dopexamine hydrochloride reduces afterload through pronounced arterial vasodilatation, increases renal perfusion by selective renal vasodilation and evokes mild cardiac stimulation through direct and indirect positive inotropism. Preliminary small-scale noncomparative studies indicate that dopexamine hydrochloride displays beneficial haemodynamic effects in patients with acute heart failure and those requiring haemodynamic support following cardiac surgery, and that these effects are substantially maintained during longer term administration (less than or equal to 24 hours). Dopexamine hydrochloride appears to be generally well tolerated. Nausea and vomiting are the most frequently reported adverse effects, and respond to dosage reduction. Occasional reports of chest pain/angina pectoris precipitated by tachycardia indicates the need for caution in the use of dopexamine hydrochloride in patients with ischaemic heart disease. Thus, dopexamine hydrochloride may prove to be a useful alternative to dopamine and dobutamine in the treatment of acute heart failure and the postoperative management of low cardiac output states, although controlled studies are required to establish its efficacy and tolerability with respect to that of established therapies.

Lamotrigine. An update of its pharmacology and therapeutic use in epilepsy.

Lamotrigine is an antiepileptic agent which blocks voltage-dependent sodium channels, thereby preventing excitatory neurotransmitter release. Clinical evidence indicates that lamotrigine is effective against partial and secondarily generalised tonic-clonic seizures, as well as idiopathic (primary) generalised epilepsy. As monotherapy, lamotrigine 100 to 300 mg/day has similar medium term (30 to 48 weeks) efficacy to carbamazepine 300 to 1400 mg/day and phenytoin 300 mg/day against partial onset seizures and idiopathic generalised tonic-clonic seizures in adults with newly diagnosed epilepsy, and appears to be better tolerated than the older agents. As adjunctive therapy, lamotrigine (50 to 500 mg/day) has shown efficacy in short term ( < or = 6-months) placebo-controlled studies in adults with refractory partial epilepsy, reducing total seizure frequency (by < or = 60%) and producing improvement ( > or = 50% reduction in seizure frequency) in < or = 67% of patients. Both simple and complex partial seizures and secondarily generalised tonic-clonic seizures are reduced by lamotrigine, with generalised seizures (particularly absence seizures, atonic seizures and Lennox-Gastaut syndrome) tending to be more responsive than partial seizures. This reduction in seizure frequency is sustained on long term ( < or = 3 years) therapy and is reportedly accompanied by an improvement in psychological well-being. In children with refractory multiple seizure types, lamotrigine ( < or = 15 mg/kg/day; 400 mg/day) has proved effective as add-on therapy, with approximately equal to 40% of patients showing > or = 50% reductions in seizure frequency and approximately equal to 10 % achieving abolition of seizures after 3 months' treatment. Generalised seizures, including atypical and typical absence seizures, atonic and tonic seizures and Lennox-Gastaut syndrome are most responsive. The most common adverse events associated with lamotrigine are primarily neurological, gastrointestinal and dermatological. Maculopapular or erythematous skin rash, occasionally severe, occurs in approximately equal to 10% of patients and is the most common cause of treatment withdrawal. The risk of rash can, however, be minimised through adoption of a low, slow dosage titration schedule on initiating therapy. As monotherapy, lamotrigine produces less drowsiness than carbamazepine or phenytoin, and less asthenia and ataxia than phenytoin. Clinical experience would therefore suggest that lamotrigine is a particularly effective and generally well tolerated broad-spectrum agent for adjunctive treatment of both partial epilepsy and idiopathic generalised epilepsy in adults and children. Initial indications point to the drug filling an increasingly important future role in the monotherapy of newly diagnosed epilepsy.

Artesunate. A review of its pharmacology and therapeutic efficacy in the treatment of malaria.

Artesunate is an antimalarial agent, available in oral, rectal and parenteral formulations, that provides a rapid clinical effect in patients with Plasmodium falciparum malaria. The rapidity of effect, availability of an intravenous and intramuscular formulation and convenient dosage regimen make artesunate an ideal candidate for the treatment of severe malaria, including cerebral disease. While some results have been promising, there is no clear evidence to date that artesunate reduces mortality in patients with cerebral malaria to any greater extent than standard quinine therapy. When given as monotherapy, treatment should be continued for at least 5 to 7 days to prevent recrudescence. Combination therapy with mefloquine allows artesunate to be administered over 3 days or less, with a satisfactory clinical outcome maintained. Although optimal dosages remain to be determined, this combination continues to provide the rapid onset of clinical effect observed with artesunate monotherapy, but decreases the rate of recrudescence to 2% (i.e. radical cure rate of 98%) when used as treatment in patients with uncomplicated malaria from areas with a high risk of multidrug-resistance falciparum malaria. Although assessment of tolerability is complicated by the difficulty of distinguishing between disease- and treatment-related events, artesunate and artesunate-mefloquine combinations appear to be well tolerated in adults and children. Indeed, it is possible that prior administration of artesunate may reduce the incidence of mefloquine-induced vomiting. Clinical findings to date have not revealed any pattern of resistance to artesunate after use of the drug. However, given the history of the development of resistance to other antimalarial drugs, the use of artesunate should be restricted to areas of multidrug resistance, the drug should be used in combination with a longer acting agent such as mefloquine, and it should be used in regimens that provide radical cure rates of 90 to 100%. If used according to these treatment principles, artesunate will provide a well tolerated and valuable addition to the current extremely limited treatment options for multidrug-resistant falciparum malaria, a widespread parasitic disease associated with considerable mortality.

Rifabutin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacy.

Rifabutin is a derivative of rifamycin S with activity against mycobacteria including atypical organisms such as Mycobacterium avium and M. intracellulare, also referred to as Mycobacterium avium-intracellulare complex (MAC). To date, rifabutin is the only drug to have been studied in large prospective placebo-controlled trials that has been shown to significantly reduce the incidence of disseminated MAC infection when administered prophylactically as a single agent to patients with acquired immune deficiency syndrome (AIDS). Initial studies also indicate that rifabutin may be a useful component of multiple drug regimens for the treatment of MAC infection, although further studies combining rifabutin with other recently available antimycobacterial drugs are required to determine the most effective regimens. When rifabutin is combined with at least two other antimycobacterial drugs, the combination appears to be of similar efficacy to rifampicin (rifampin)-containing regimens in patients with newly diagnosed pulmonary tuberculosis. Since available therapy for MAC infection in patients with AIDS is still suboptimal, rifabutin, at present the only first-line agent for prophylaxis against disseminated MAC infection in patients with advanced human immunodeficiency virus (HIV) infection, has the potential to make a valuable contribution to the continuing attempts to preserve the quality of life of patients with AIDS.

Perindopril. A review of its pharmacological properties and therapeutic use in cardiovascular disorders.

Perindopril is a long acting angiotensin converting enzyme (ACE) inhibitor, which displays similar pharmacodynamic properties to other agents in this class. In common with enalapril, it is also a prodrug. After absorption, perindopril is hydrolysed to the active metabolite, perindoprilat, and with once daily administration adequate 24-hour inhibition of ACE is obtained. Perindopril 4 to 8mg once daily is usually effective for blood pressure control in patients with mild to moderate essential hypertension. Those patients who do not respond adequately to monotherapy with perindopril usually respond with the addition of a second agent, such as a thiazide diuretic. General practice trials indicate that perindopril is at least as effective and as well tolerated as usual therapeutic dosages of captopril, atenolol or hydrochlorothiazide plus amiloride in mild to moderate essential hypertension. Preliminary results indicate that perindopril may also be effective in patients with severe hypertension or congestive heart failure. Perindopril is generally well tolerated and has an adverse effect profile similar to that of other ACE inhibitors. It further clinical experience confirms initial findings, perindopril is likely to represent a useful alternative to other members of the ACE inhibitor class in all grades of hypertension and congestive heart failure.

Gallium nitrate. A review of its pharmacological properties and therapeutic potential in cancer related hypercalcaemia.

Gallium nitrate, a novel drug for the treatment of cancer-related hypercalcaemia, inhibits osteoclast activity but does not affect osteoclast morphology or viability. Limited clinical experience in patients with cancer-related hypercalcaemia indicates that gallium nitrate is effective in restoring normocalcaemia in 75 to 85% of patients and is well tolerated in those with preserved renal function, producing few clinically relevant adverse effects. In comparative clinical trials it proved a more effective antihypercalcaemic agent than calcitonin or etidronate and produced a longer lasting normocalcaemic response. Gallium nitrate would appear to be indicated in symptomatic patients with cancer-related hypercalcaemia who have failed to respond to adequate rehydration.

Sotalol. An updated review of its pharmacological properties and therapeutic use in cardiac arrhythmias.

Sotalol is a nonselective beta-adrenoceptor antagonist which prolongs cardiac repolarisation independently of its antiadrenergic action (class III antiarrhythmic properties). The antiarrhythmic action of sotalol appears to arise predominantly from its class III properties, and the drug exhibits a broader antiarrhythmic profile than the conventional beta-blockers. Sotalol is effective in controlling paroxysmal supraventricular tachycardias and the ventricular response to atrial fibrillation/flutter in Wolff-Parkinson-White syndrome, in maintaining sinus rhythm after cardioversion of atrial fibrillation/flutter, and in preventing initiation of supraventricular tachyarrhythmias following coronary artery bypass surgery. Sotalol shows promise in the control of nonmalignant and life-threatening ventricular arrhythmias, particularly those associated with ischaemic heart disease. It is effective in suppressing complex forms of ventricular ectopy, displaying superior antiectopic activity to propranolol and metoprolol. The acute efficacy of sotalol in preventing reinduction of sustained ventricular tachyarrhythmias and suppressing spontaneous episodes of these arrhythmias on Holter monitoring is translated into long term prophylactic efficacy against arrhythmia recurrence in approximately 55 to 85% of patients with refractory life-threatening ventricular arrhythmias. In addition, sotalol offers the advantage over the class I agents of reducing cardiac and all-cause mortality in the high risk population with life-threatening ventricular arrhythmias. The adverse effects of sotalol are primarily related to its beta-blocking activity and its class III property of prolonging cardiac repolarisation. Sotalol is devoid of overt cardiodepressant activity in patients with mild or moderate left ventricular dysfunction. The overall arrhythmogenic potential is moderately low, but torsade de pointes may develop in conjunction with excessive prolongation of the QT interval due to bradycardia, hypokalaemia or high plasma concentrations of the drug. In summary, sotalol displays a broad spectrum of antiarrhythmic activity, is haemodynamically well tolerated, and confers a relatively low proarrhythmic risk. It is likely to prove particularly appropriate in the treatment and prophylaxis of life-threatening ventricular tachyarrhythmias.

Flupirtine. A review of its pharmacological properties, and therapeutic efficacy in pain states.

Flupirtine is a novel non-opiate centrally acting analgesic agent with muscle relaxant properties, advocated for use in a number of pain states. Preliminary evidence suggests that flupirtine 100 to 200mg orally or 150mg rectally 3 to 4 times daily (maximum daily dose 600mg) is more effective than placebo in relieving moderate acute pain of various types. For the relief of pain due to surgery, traumatic injury, dental procedures, headache/migraine and abdominal spasms, flupirtine has proved at least as effective as the opiate analgesics codeine, dihydrocodeine and pentazocine, the nonsteroidal anti-inflammatory agents suprofen, diclofenac and ketoprofen, as well as dipyrone and paracetamol (acetaminophen). Although evidence to support a role in the treatment of chronic pain is limited, flupirtine has been found as effective as pentazocine in short term trials of patients with muscular or neuralgiform pain, dysmenorrhoea, soft tissue rheumatism or cancer pain. The safety profile of flupirtine has not yet been fully established, although initial evidence suggests that adverse reactions, while frequent, are usually minor in nature. The most common reactions are drowsiness, dizziness, dry mouth and various gastrointestinal complaints. In comparison with opiate drugs, flupirtine appears to produce fewer central nervous system effects, no respiratory or cardiovascular depression, and no overt tolerance or physical dependence on prolonged administration. If these initially favourable results are confirmed in larger long term trials, then flupirtine would appear to represent an effective analgesic for the relief of moderate pain, particularly that of musculoskeletal origin.

Azelaic acid. A review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary skin disorders.

Azelaic acid is a naturally occurring saturated dicarboxylic acid which, on topical application (usually as a 20% cream), has been shown to be effective in the treatment of comedonal acne and inflammatory (papulopustular, nodular and nodulocystic) acne, as well as various cutaneous hyperpigmentary disorders characterised by hyperactive/abnormal melanocyte function, including melasma and, possibly, lentigo maligna. In addition, azelaic acid has an antiproliferative and cytotoxic effect on the human malignant melanocyte, and preliminary findings indicate that it may arrest the progression of cutaneous malignant melanoma. The mechanism of this selective cytotoxic action of azelaic acid is unclear, but may possibly be related to its inhibition of mitochondrial oxidoreductase activity and DNA synthesis. In controlled studies, topical azelaic acid demonstrated comparable anti-acne efficacy to topical tretinoin, benzoyl peroxide, erythromycin and oral tetracycline, while in patients with melasma azelaic acid proved at least as effective as topical hydroquinone. On topical application azelaic acid is well tolerated, with adverse effects apparently limited to a generally mild and transient local cutaneous irritation. Thus, topical azelaic acid, employed either as monotherapy or in combination with other treatments, is likely to prove of value in the management of acne and several hyperpigmentary disorders, most notably melasma.

Olsalazine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in inflammatory bowel disease.

Olsalazine (sodium azodisalicylate; azodisal sodium) is an anti-inflammatory agent designed to deliver its active moiety, mesalazine (5-aminosalicylic acid; mesalamine), to the colon while avoiding the adverse effects associated with the use of a sulfapyridine carrier. As a prodrug, olsalazine is an effective oral treatment for both active ulcerative colitis and for maintenance of disease remission and may possibly be of benefit in patients with Crohn's colitis. Findings from both short and long term noncomparative and comparative studies demonstrate that olsalazine 1 to 3g daily in divided doses improves clinical signs and symptoms of colitis in approximately 60 to 80% of patients with acute ulcerative colitis of mild to moderate severity. This improvement rate was similar to that obtained with sulfasalazine. Lower doses of olsalazine, usually 1g daily in divided doses, also maintained remission in patients with chronic ulcerative colitis. While olsalazine effectively delivers mesalazine to the colon, the prodrug itself increases net luminal water secretion and accelerates gastrointestinal transit of a meal. The resulting diarrhoea (occurring in approximately 17% of patients and resulting in withdrawal from therapy in 6% of patients) is distinguishable from that associated with inflammatory bowel disease by the high water content and the absence of blood. Olsalazine-induced diarrhoea usually occurred soon after initiation of olsalazine therapy or dosage increase, was more frequent with higher doses and was usually transient. Dosage reduction, increases in frequency of dosing and concomitant administration with food reduced the severity in many patients with persistent olsalazine-induced diarrhoea. With the exception of diarrhoea, olsalazine was generally well tolerated. Fewer than 14% of patients allergic to or intolerant of sulfasalazine had similar reactions to olsalazine. Olsalazine appears to be a suitable therapy for the treatment of first attacks as well as acute exacerbation of mild to moderate acute ulcerative colitis, and for the maintenance of remission in patients with chronic ulcerative colitis.

Moricizine. A review of its pharmacological properties, and therapeutic efficacy in cardiac arrhythmias.

Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal re-entry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extra-cardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderality depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death.

Clozapine. A review of its pharmacological properties, and therapeutic use in schizophrenia.

Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug's wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics.

Nicorandil. A review of its pharmacology and therapeutic efficacy in angina pectoris.

Nicorandil belongs to the class of compounds known as potassium channel activators which are characterised by their arterial vasodilator properties. In addition, nicorandil has venodilating properties which are attributable to a nitrate group in its chemical structure. Therefore, by combining these two vasodilator mechanisms, nicorandil represents a novel type of compound for use in the treatment of angina pectoris. Furthermore, increasing experimental evidence suggests that potassium channel activation may also exert a direct cytoprotective effect by augmenting normal physiological processes which protect the heart against ischaemic events. Comparative studies of up to 3 months' duration suggest that nicorandil is equivalent in efficacy to isosorbide dinitrate, propranolol, atenolol, nifedipine or diltiazem in the treatment of stable angina. Preliminary evidence suggests that an improvement of anginal and ischaemic symptoms is maintained for up to 1 year. Whilst the efficacy of nicorandil in other types of angina has not been extensively studied, preliminary results indicate that intravenous nicorandil is as effective as isosorbide dinitrate in the treatment of unstable angina and is also effective in patients with variant angina. In addition, the limited data available indicate that nicorandil may be effective in patients with unstable and variant angina who are refractory to therapy with conventional antianginal agents, a potentially important area for further study. Headache, mostly of mild to moderate intensity was the most commonly reported adverse event, occurring in one-third of patients receiving the recommended therapeutic regimen of nicorandil 10 to 20mg twice daily. In comparative trials involving a total of 84 patients who received nicorandil, the incidence of headache was similar to that produced by isosorbide mononitrate and isosorbide dinitrate. Headache was most frequent on initiating therapy but declined with continued treatment. To date, approximately 5% of patients participating in European trials have withdrawn due to headache, although this rate may be reduced by using a lower starting dose of nicorandil (5 mg twice daily). In summary, clinical experience thus far indicates that nicorandil, with its novel combination of two distinct vasodilator mechanisms, offers an effective alternative to established vasodilator therapy with conventional nitrates and calcium antagonists in the long term treatment of stable angina pectoris. Further studies are warranted to establish whether the unique pharmacodynamic profile of nicorandil is advantageous for the treatment of other types of angina and/or the ischaemic myocardium.

Torasemide. An update of its pharmacological properties and therapeutic efficacy.

The pharmacological properties and therapeutic use of the high-ceiling loop diuretic torasemide (torsemide) were previously reviewed in Drugs in 1991, the following being a re-examination of the role of the drug in the light of data that have subsequently become available (particularly in the management of oedematous disorders). Torasemide produces a more prolonged water and electrolyte excretion than equipotent diuretic doses of furosemide (frusemide), but does not increase kaliuresis to the same extent. Dosages of torasemide of 2.5 to 5 mg/day do not affect plasma renin activity or aldosterone release to a clinically significant extent, although torasemide 20mg increases plasma renin levels, angiotensin II activity and urinary dopamine and prostaglandin E excretion. Studies published since the previous review have confirmed the efficacy of low dosages of torasemide (2.5 to 5 mg/day) in the treatment of hypertension, and have shown it to be effective when administered orally at a dosage of 5 to 20 mg/day in the management of congestive heart failure. Dosages of up to 400 mg/day increased urinary volume excretion and natriuresis in patients with chronic renal failure. Bodyweight and peripheral oedema were reduced by torasemide 10 to 200 mg/day as monotherapy, and 5 to 20 mg/day when coadministered with spironolactone, in patients with nephrotic syndrome. Dosages of 10 to 40 mg/day, either as monotherapy or in conjunction with an aldosterone antagonist, reduced ascites, oedema and bodyweight in patients with hydropically decompensated liver failure. Adverse effects due to torasemide are usually mild and transient in nature. No evidence of ototoxicity has been demonstrated in humans, and torasemide does not appear to affect blood glucose levels, serum uric acid concentrations, or serum potassium levels at dosages below 5 mg/day. Thus, additional evidence has accumulated for the clinical efficacy of torasemide in the management of mild to moderate essential hypertension and oedematous conditions which require diuretic therapy. Further studies are now required to confirm the long term efficacy and tolerability of torasemide, and to investigate the place of the drug in therapy relative to cardiovascular agents other than furosemide and the thiazide diuretics.