Dornase alfa. A review of its pharmacological properties and therapeutic potential in cystic fibrosis.

By cleaving neutrophil-derived DNA present in the infected lungs of patients with cystic fibrosis (CF), dornase alfa (recombinant human deoxyribonuclease I) reduces the adhesiveness and viscoelasticity of CF sputum. Well designed clinical studies performed in patients with CF and mild to moderate pulmonary disease [forced vital capacity (FVC) > or = 40% of predicted value] show that aerosolised dornase alfa improves lung function, achieving a 6 to 7% increase from baseline in forced expiratory volume in 1 second (FEV1) after 6 months' therapy. Improvements in general well-being and CF-related symptoms were also noted by patients. Importantly, dornase alfa reduced the relative risk of respiratory exacerbations requiring parenteral antibiotics by 22 to 34% compared with placebo. Short term studies with dornase alfa in patients with more severe pulmonary disease (FVC < 40% of predicted value) and in those with acute infectious exacerbations did not reveal any significant improvements in pulmonary function, although long term studies are required to fully determine efficacy. Voice alteration, laryngitis or rash may develop with dornase alfa therapy, although more clinical experience with the agent is required to define its tolerability profile. Anaphylaxis has not been reported with dornase alfa to date. In summary, aerosolised dornase alfa offers modest improvements in lung function and, importantly, a reduced risk of respiratory exacerbations in patients with CF and an FVC > or = 40% of the predicted value, thus representing an important adjunct agent in this patient group.

Propofol. An overview of its pharmacology and a review of its clinical efficacy in intensive care sedation.

Propofol is a phenolic derivative that is structurally unrelated to other sedative hypnotic agents. It has been used extensively as an anaesthetic agent, particularly in procedures of short duration. More recently it has been investigated as a sedative in the intensive care unit (ICU) where it produces sedation and hypnosis in a dose-dependent manner. Propofol also provides control of stress responses and has anticonvulsant and amnesic properties. Importantly, its pharmacokinetic properties are characterised by a rapid onset and short duration of action. Noncomparative and comparative trials have evaluated the use of propofol for the sedation of mechanically ventilated patients in the ICU (postsurgical, general medical, trauma). Overall, propofol provides satisfactory sedation and is associated with good haemodynamic stability. It produces results similar to or better than those seen with midazolam or other comparator agents when the quality of sedation and/or the amount of time that patients were at adequate levels of sedation are measured. Patients sedated with propofol also tend to have a faster recovery (time to spontaneous ventilation or extubation) than patients sedated with midazolam. Although most studies did not measure time to discharge from the ICU, propofol tended to be superior to midazolam in this respect. In a few small trials in patients with head trauma or following neurosurgery, propofol was associated with adequate sedation and control of cerebral haemodynamics. The rapid recovery of patients after stopping propofol makes it an attractive option in the ICU, particularly for patients requiring only short term sedation. In short term sedation, propofol, despite its generally higher acquisition costs, has the potential to reduce overall medical costs if patients are able to be extubated and discharged from the ICU sooner. Because of the potential for hyperlipidaemia and the development of tolerance to its sedative effects, and because of the reduced need for rapid reversal of drug effects in long term sedation, the usefulness of propofol in long term situations is less well established. While experience with propofol for the sedation of patients in the ICU is extensive, there are still areas requiring further investigation. These include studies in children, trials examining cerebral and haemodynamic outcomes following long term administration and in patients with head trauma and, importantly, pharmacoeconomic investigations to determine those situations where propofol is cost effective. In the meantime, propofol is a well established treatment native to benzodiazepines and/or other hypnotics or analgesics when sedation of patients in the ICU is required. In particular, propofol possesses unique advantages over these agents in patients requiring only short term sedation.

Isradipine. An update of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of mild to moderate hypertension.

Since the earlier review in Drugs substantial additional data have accumulated regarding the antihypertensive efficacy of isradipine in various clinical situations, as well as data on its clinical effects in atherosclerosis. Recent therapeutic trials confirm that the efficacy of isradipine in the treatment of patients with mainly mild to moderate hypertension, when administered orally as a conventional or modified release preparation, is similar to that of titrated dosages of amlodipine, felodipine, nifedipine, diltiazem, captopril, methyldopa, metoprolol, prazosin and hydrochlorothiazide. A further decrease in blood pressure can be expected when isradipine is combined with another antihypertensive drug in patients who have not responded adequately to monotherapy. Initial studies have shown that intravenous isradipine is effective in controlling hypertension following coronary artery bypass graft surgery and that it appears useful in the treatment of intraoperative hypertension and hypertensive crisis, and in hypertensive disorders in pregnancy, when administered orally or intravenously. A large study, the Multicentre Isradipine Diuretic Atherosclerosis Study (MIDAS), was designed to compare the efficacy of isradipine and hydrochlorothiazide in reducing the rate of progression of carotid artery wall thickness, measured by B-mode ultrasound, as a surrogate for early atherosclerosis. Results indicated that wall thickness increased significantly less with isradipine than hydrochlorothiazide after 6 months of therapy. Thereafter the rate of progression remained parallel for the remainder of the 3-year trial. The confirmation of its antihypertensive efficacy, along with its favourable haemodynamic profile and reversal of left ventricular hypertrophy, minimal effect on glucose and lipid metabolism, preservation of quality of life and good tolerability, makes isradipine a suitable drug for the treatment of most patients with mild to moderate hypertension.

Nedocromil sodium. An updated review of its pharmacological properties and therapeutic efficacy in asthma.

Nedocromil sodium, the disodium salt of a pyranoquinoline dicarboxylic acid, has anti-inflammatory properties in vitro, in animal models of asthma, and in humans, as evidenced by inhibition of inflammatory cell activation and mediator release, early and late allergen-induced bronchoconstriction and airway hyperresponsiveness. Recent therapeutic trials confirm the safety and efficacy of inhaled nedocromil sodium as adjunctive therapy in adult patients whose asthma is not adequately controlled by beta-agonists alone. Nedocromil sodium has also been shown to improve symptoms when added to existing treatment with methylxanthines and corticosteroids. Some studies show nedocromil sodium to be successful replacement therapy for methylxanthines, in addition to enabling a modest reduction in inhaled corticosteroids in some patients. Thus, nedocromil sodium may be suitable in patients with asthma as an adjunct to existing therapy, as an alternative to regularly administered oral and inhaled beta-agonists and oral methyl-xanthines, and potentially, to low dose inhaled corticosteroids as maintenance therapy in patients with mild to moderate asthma being considered for corticosteroid therapy.

Zonisamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy.

Zonisamide is a 1,2 benzisoxazole derivative and the first agent of this chemical class to be developed as an antiepileptic drug. It has shown activity in various animal models of epilepsy, and although a detailed mode of action awaits clarification it appears to block the propagation/spread of seizure discharges and to suppress the epileptogenic focus. Clinical experience with zonisamide in Japan has documented its efficacy in the treatment of partial seizures (partial-onset generalised tonic-clonic, simple partial and/or complex partial seizures), and to a more variable extent, generalised tonic-clonic, generalised tonic (mainly seen in symptomatic generalised epilepsies including Lennox-Gastaut Syndrome) and compound/combination seizures (including those refractory to treatment with other antiepileptic drugs). Other generalised seizure types have also responded to therapy with zonisamide, although only small patient numbers were studied. Zonisamide has demonstrated efficacy equivalent to that of carbamazepine in patients with (mainly) partial seizures, and to that of valproic acid in a small study of children (n = 32) with generalised seizures. Animal studies suggest that zonisamide possesses a more favourable therapeutic index than most other antiepileptic drugs. However, clinical trials conducted to date, have not confirmed any overt tolerability advantage. Indeed, whereas the recommended therapeutic plasma zonisamide concentration is 20 mg/L, clinical investigations have associated adverse events with plasma zonisamide concentrations of > 30 mg/L, suggesting the usefulness of therapeutic drug monitoring. Moreover, although plasma concentrations of zonisamide are empirically regarded to be proportional to therapeutic doses in patients in Japan, nonlinear pharmacokinetics have been reported for this drug in patients in the US and may further complicate its use in this patient population. Additional pharmacokinetic studies will help to establish the change in pharmacokinetic profile that occurs with dosage titration in patients outside Japan. Among 700 patients treated with zonisamide in Europe/US, a high incidence of renal calculi (1.9%) has been noted, however, the causal relationship to zonisamide is disputed. Indeed, although urinary lithiasis has also been recorded for patients in Japan, the aetiology, incidence and spontaneous regression of this condition suggest that it is not a serious problem for this patient population. Until this difference is clarified, it is likely that zonisamide will find its greatest use in the treatment of patients in Japan. Like many other established antiepileptic drugs, available data suggest the propensity for zonisamide to alter the pharmacokinetic profile of other anticonvulsant agents, although severe interactions appear to be unlikely.(ABSTRACT TRUNCATED AT 400 WORDS)

Pravastatin. A review of its pharmacological properties and therapeutic potential in hypercholesterolaemia.

Pravastatin is an HMG-CoA reductase inhibitor which reduces plasma cholesterol levels by inhibiting de novo cholesterol synthesis and increasing the receptor-mediated catabolism of low density lipoprotein (LDL). Several large multicentre placebo-controlled trials have shown that pravastatin reduces total and LDL-cholesterol levels in a dose-proportional manner in patients with familial or nonfamilial hypercholesterolaemia. Reductions in LDL-cholesterol levels reported in the largest study were 18% (10 mg/day), 23% (20 mg/day) and 31% (40 mg/day) after 12 weeks. Once-daily administration appears to be as effective as two daily doses. Pravastatin consistently increases HDL-cholesterol levels and decreases levels of total triglycerides but these changes are not dose dependent. At the study dosages used, the antihypercholesterolaemic effects of pravastatin were superior to those of bezafibrate and clinofibrate, and were similar to those of simvastatin, lovastatin, gemfibrozil and cholestyramine although in some studies a trend towards a superior effect with pravastatin was seen. Pravastatin did not reduce HDL-cholesterol like probucol, or increase triglyceride levels like cholestyramine. Combined treatment with pravastatin and cholestyramine or colestipol enhances the cholesterol-lowering effects of either drug administered alone and offsets the increase in total triglyceride levels seen with cholestyramine or colestipol therapy. Pravastatin is well tolerated during treatment of up to 24 months but longer term tolerability has not yet been established. The effect of provastatin on cardiovascular events related to elevated plasma cholesterol levels is under investation in several large scale regression and primary and secondary prevention trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitrendipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension.

Nitrendipine is a calcium entry blocker shown to inhibit the movement of calcium through the 'slow channel' of cardiac and vascular smooth muscle, thus inducing peripheral vasodilation with consequent reductions in elevated blood pressure. As evidenced by clinical trials, nitrendipine promptly lowers blood pressure in patients with mild to moderate hypertension, and sustains this effect during long term administration. Combining nitrendipine with other antihypertensive agents such as diuretics or beta-blockers often results in successful treatment in patients unresponsive to nitrendipine monotherapy. Headache, oedema, flushing and palpitations commonly occurring during treatment with nitrendipine are generally mild, usually subsiding with continued therapy. Thus, although additional long term studies are required to properly assess the relative merits of the drug compared with other antihypertensives, by providing the clinician with an effective and safe alternative to traditional therapies, nitrendipine represents a step forward in the treatment of mild to moderate hypertension.

Nisoldipine. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of angina pectoris, hypertension and related cardiovascular disorders.

Nisoldipine is an orally administered calcium entry blocking drug structurally related to nifedipine. In limited clinical trials it has been shown to be effective and relatively well tolerated in the treatment of patients with chronic stable angina pectoris and mild to moderate essential hypertension. As for all dihydropyridine-calcium antagonists, its major properties include potent peripheral and coronary vasodilation and improvement in myocardial oxygen supply relative to demand. These actions occur without depression of cardiac conduction or left ventricular function. Short term clinical trials have shown nisoldipine to produce both symptomatic and objective improvements in patients with chronic angina of effort and have suggested a benefit in vasospastic angina. A small number of comparative trials indicate that nisoldipine is equally as effective as nifedipine. In addition, in combination with beta-adrenoceptor blockade nisoldipine appears to offer additional benefit compared with beta-blockade alone and is well tolerated. In patients with mild to moderate essential hypertension nisoldipine monotherapy, in 1 or 2 daily doses, has maintained blood pressure control and has also been a useful addition to diuretics and beta-adrenoceptor blocking drugs in patients with poorly controlled disease. Side effects appear to be dose related, generally mild and transient, and are primarily those resulting from potent peripheral vasodilation - headache, flushing and pretibial or ankle oedema. Although studies to date are promising, there are no published long term studies (greater than 1 year) of nisoldipine in comparison with other calcium entry blockers and other drugs currently in clinical use for the treatment of angina pectoris or hypertension. Until such studies are completed the exact place of nisoldipine in the treatment of these diseases remains to be established.

Diclofenac sodium. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy.

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) advocated for use in painful and inflammatory rheumatic and certain non-rheumatic conditions. It is available in a number of administration forms which can be given orally, rectally or intramuscularly. Conveniently, dosage adjustments are not required in the elderly or in those patients with renal or hepatic impairment. The drug has a relatively short elimination half-life, which limits the potential for drug accumulation. In numerous clinical trials the efficacy of diclofenac is equivalent to that of the many newer and established NSAIDs with which it has been compared. As an analgesic it has a fast onset and long duration of action. When administered intramuscularly it is at least comparable to, and frequently superior to, many narcotic and spasmolytic combinations in renal and biliary colic. Extensive clinical experience has been gained with diclofenac, clearly establishing its safety profile. It is well tolerated compared with other NSAIDs and rarely produces gastrointestinal ulceration or other serious side effects. Thus, diclofenac can be considered as one of the few NSAIDs of 'first choice' in the treatment of acute and chronic painful and inflammatory conditions.

Indoramin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension and related vascular, cardiovascular and airway diseases.

Indoramin is a postsynaptic selective alpha 1-adrenoceptor antagonist used in the treatment of hypertension. In contrast to some other alpha-blockers, animal studies suggest that its blood pressure lowering effect results from relaxation of peripheral arterioles as a consequence of blockade of postsynaptic alpha 1-adrenoceptors. Furthermore, unlike some other alpha-blockers, this lowering of blood pressure is rarely associated with reflex tachycardia or postural hypotension. Therapeutic trials have shown indoramin to be effective in lowering blood pressure in all grades of hypertension: mild and moderate hypertension when used alone, but generally in combination with a thiazide diuretic, and in moderate to moderately severe hypertension when used in combination with a beta-blocker and diuretic. In a few small comparative studies, no significant difference was found in the blood pressure lowering effects between indoramin and methyldopa, propranolol and prazosin. Side effects were similar for indoramin, propranolol and methyldopa; however in the 1 comparative study with prazosin, prazosin produced a lower incidence of sedation. Indeed, the most common side effect with indoramin therapy has been sedation of a mild to moderate and/or transient nature, reported in about 19% of cases. Other side effects which have sometimes led to a withdrawal of indoramin treatment have been dry mouth, dizziness, and in males, failure of ejaculation; however, side effects may be reduced by starting therapy with smaller doses and titrating more gradually.

Esmolol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy.

Esmolol is a relatively cardioselective beta-adrenoceptor antagonist. Since esmolol is rapidly metabolised by blood-borne esterases, it has a very short half-life (about 9 mins) and a short duration of action. In this respect esmolol is unique amongst currently available beta-adrenoceptor antagonists, and it is anticipated that it will be particularly useful in critical care situations where administration by continuous intravenous infusion should permit a level of control over beta-adrenoceptor antagonism that has previously been unattainable. In perioperative settings, esmolol attenuates tachycardia induced by a variety of surgical stimuli such as endotracheal intubation, sternotomy and aortic dissection, suggesting a clinical use of the drug to prevent potentially serious complications in surgical patients with cardiovascular disease. Additionally, clinical studies have shown that titrated dosages of esmolol achieved therapeutic response rates of 66 to 79% in patients with supraventricular tachyarrhythmias, which favourably compared with response rates achieved with propranolol. In most of these patients esmolol produced a reduction in ventricular rate which was well maintained during infusion but disappeared within 30 minutes following esmolol withdrawal. Preliminary studies involving small numbers of patients have reported that esmolol exerts significant antihypertensive effects in patients with postoperative hypertension, and beneficial effects in patients with myocardial ischaemia and infarction, but support for these results is required from additional large, well-controlled studies. Esmolol has been generally well tolerated, and although hypotension has occurred in up to 44% of patients it resolved during or soon after the infusion of esmolol. Thus, esmolol is the first titratable beta-adrenoceptor antagonist able to be rapidly 'switched on' and 'off', a property that is expected to offer a major contribution to safety in critical care patients requiring beta-adrenoceptor antagonism for short durations.

Guanfacine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension.

Guanfacine, a phenylacetyl-guanidine derivative, is a centrally acting alpha-adrenoceptor agonist, with a mechanism of antihypertensive action similar to that of clonidine. It reduces blood pressure in patients with essential hypertension at least as effectively as clonidine or methyldopa. Like lower doses of clonidine, guanfacine can be given once daily due to its relatively long elimination half-life. Although dry mouth and sedation occur frequently with higher doses of guanfacine, their incidence is lower than with other centrally acting antihypertensives; in addition, other troublesome side effects such as orthostatic hypotension or sexual dysfunction also occur much less with guanfacine than with other centrally acting antihypertensive agents. While a withdrawal syndrome may occur on abruptly discontinuing guanfacine administration, the symptoms are generally mild, and the incidence of withdrawal symptoms appears lower than occurs with abrupt withdrawal of clonidine. Thus, guanfacine is an effective and well tolerated alternative to other centrally acting antihypertensive drugs. Whether its final place in therapy will be as an alternative 'second-line' drug, or as initial monotherapy in patients with mild to moderate hypertension, remains to be clarified in comparative studies with diuretics, calcium antagonists, and beta-adrenoceptor blocking drugs.

Spirapril. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertension.

Spirapril is a non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor prodrug which is converted to the active metabolite spiraprilat following oral administration, and which has been evaluated primarily for the treatment of hypertension. In dose-finding studies of patients with mild to severe hypertension, spirapril > or = 6 mg once daily produced reductions in blood pressure of approximately 10 to 18 mm Hg (systolic) and 7 to 13 mm Hg (diastolic) [24-hour postdose trough readings at the end of the treatment period]. Blood pressure normalisation (trough diastolic blood pressure < or = 90 mm Hg) had occurred in 29 to 50% of patients at the end of these investigations. The dose-response curve for spirapril appears to be flat for doses of 6 to 24 mg once daily. Comparisons with other ACE inhibitors are limited in number, and further studies are required before the relative antihypertensive efficacy of spirapril can be fully evaluated. However, in single, well controlled clinical trials, spirapril produced similar reductions in blood pressure to those seen with enalapril or captopril. When given as monotherapy or in combination with hydrochlorothiazide, spirapril may offer potential advantages over the calcium antagonist nitrendipine. Spirapril is generally well tolerated and produces an adverse event profile similar to that of other ACE inhibitors. Data from small studies suggest that spirapril can be used without dosage adjustment in patients with renal impairment, as a consequence of its dual renal and hepatic clearance mechanisms. This is in contrast to most ACE inhibitors, which are eliminated by a predominantly renal mechanism that results in accumulation of the active metabolite when renal function is impaired. However, the utility of spirapril in this patient group has yet to be fully determined because of conflicting data regarding its effects on renal function. Thus, spirapril is an effective antihypertensive agent which is well tolerated. Further comparative trials are needed to fully determine its efficacy with respect to other ACE inhibitors, and a better understanding of its effects on renal function will clarify its role in hypertensive patients with renal failure.

Azelastine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential.

Azelastine is an antiallergic agent which demonstrates histamine H1-receptor antagonist activity and also inhibits histamine release from mast cells following antigen and non-antigen stimuli. Azelastine antagonises histamine- and leukotriene-induced bronchospasm in animal studies and reduces airway responsiveness to inhaled antigen or distilled water, and exercise challenge. In comparative studies, orally administered azelastine in doses up to 4 mg/day consistently relieved symptoms in patients with seasonal or perennial rhinitis - comparable to inhaled sodium cromoglycate (cromolyn sodium) 80 mg/day, oral chlorpheniramine (chlorphenamine) and oral terfenadine 120 mg/day. In addition, azelastine administered as an intranasal spray was as effective as oral terfenadine 120 mg/day and intranasal budesonide 0.4 mg/day in alleviating symptoms of rhinitis. Azelastine is also a potent antiasthmatic agent which produces significant and long lasting bronchodilation in patients with bronchial asthma. The drug is superior to placebo and comparable to oral ketotifen 2 mg/day and sustained release theophylline 700 mg/day when administered as a twice daily oral 4 mg dose. Azelastine is generally well tolerated: the most common adverse effects are altered taste perception and drowsiness. Adverse effects are mild and transient and result in withdrawal of treatment in less than 2% of patients. In a comparative study oral azelastine 2 or 4 mg/day produced no more sedation than terfenadine 120 mg/day. Thus, barring unexpected findings with wider clinical use, azelastine offers an effective and well tolerated choice of treatment for patients with allergic rhinitis and/or bronchial asthma, which may be particularly beneficial in patients in whom inhaled drug treatment is contraindicated.

Pentostatin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in lymphoproliferative disorders.

Pentostatin, a potent inhibitor of adenosine deaminase, is an antineoplastic agent which has been studied in the treatment of a variety of lymphoproliferative disorders. It is particularly effective in the treatment of hairy cell leukaemia, achieving complete remissions in 33 to 92% of patients, and has useful activity in treating B cell chronic lymphocytic leukaemia, prolymphocytic leukaemia, adult T cell leukaemia/lymphoma and cutaneous T cell lymphoma refractory to conventional chemotherapy. Initial results suggest that in the treatment of hairy cell leukaemia pentostatin achieves a more rapid response and higher frequency of complete remission with longer duration than interferon-alpha 2a, although it is still not known if some patients experiencing complete remission have been cured. The drug has yet to be directly compared with other promising purine analogues such as cladribine and fludarabine, and results of such comparisons are required before the ultimate role of pentostatin in the treatment of hairy cell leukaemia can be clearly established. However, pentostatin does produce a substantial response in a difficult therapeutic area and should be considered for initial treatment of hairy cell leukaemia.

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.

Cladribine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies.

Cladribine (2-chloro-2'-deoxyadenosine) is an adenosine deaminase-resistant analogue of deoxyadenosine. In the treatment of hairy cell leukaemia, cladribine has demonstrated excellent efficacy (complete response in 33 to 92% of patients) in noncomparative studies. Cladribine appears to compare favourably with other systemic agents in this indication as it achieves a high degree of efficacy after a single 7-day course, with an acceptable tolerability profile. However, long term data and direct comparative studies with interferon-alpha and pentostatin (deoxycoformycin) are required to confirm the finite advantages offered by cladribine. Preliminary results obtained in other indications including chronic lymphocytic leukaemia, non-Hodgkin's lymphoma, cutaneous T cell lymphoma, Waldenström's macroglobinaemia and acute myeloid leukaemia in children have been sufficiently encouraging to warrant further study. Early pharmacokinetic data suggest that cladribine may be administered by oral and subcutaneous routes, both of which permit convenient outpatient therapy. Myelosuppression, the dose-limiting toxicity of cladribine, and culture-negative fever are the most common adverse effects associated with therapy. However, cladribine appears to be only rarely associated with many of the other adverse effects that characterise antineoplastic therapy. In the weeks post-treatment, there is a small but definite risk of serious infection; infections with a fatal outcome have been reported in a number of studies with cladribine. In conclusion, preliminary data concerning cladribine have been extremely encouraging. Should early response rates in patients with hairy cell leukaemia be sustained, the efficacy of the drug, together with a short treatment regimen, a favourable tolerability profile, and the possibility of oral therapy, suggest that cladribine is likely to supersede other agents available for this indication.

Enoxaparin. A review of its pharmacology and clinical applications in the prevention and treatment of thromboembolic disorders.

Enoxaparin (PK 10169) belongs to the group of low molecular weight heparins which have a greater bioavailability and longer half-life than unfractionated heparin, permitting less frequent subcutaneous administration. In well controlled trials in surgical patients at high risk of deep venous thrombosis (DVT), enoxaparin has demonstrated prophylactic efficacy against venographically confirmed DVT at least equal to that observed with unfractionated heparin. Efficacy has also been demonstrated in patients at moderate risk and in limited investigations using 125I-fibrinogen scanning in nonsurgical patients at risk of DVT; in addition, enoxaparin appears to provide effective treatment of established DVT. In clinical studies, enoxaparin has also prevented coagulation of extracorporeal circulation, maintaining the patency of the circuit in patients undergoing haemodialysis. Thus, enoxaparin represents an effective alternative in the prophylaxis and treatment of thrombosis, with the convenience of less frequent administration than unfractionated heparin and the possible advantage of a lesser propensity for bleeding complications.

Finasteride. A review of its potential in the treatment of benign prostatic hyperplasia.

Finasteride is a novel therapeutic agent that selectively inhibits the enzyme 5 alpha-reductase, thereby reducing prostatic dihydrotestosterone (DHT) levels and prostate size. In men with symptomatic benign prostatic hyperplasia (BPH), these effects have been associated with improvements in peak urinary flow rate and urological symptoms; withdrawal from therapy, however, results in regrowth of the adenoma and long term therapy is therefore necessary. Although the magnitude of clinical improvement seen with finasteride has been perceived to be modest [especially when compared with that associated with transurethral resection of the prostate (TURP)], it has been maintained in the medium term (up to 2 years) and thus may represent significant reversal of disease progression. Such beneficial effects, however, may not become apparent until completion of at least 6 months of therapy. Furthermore, since clinical studies have been unable to proactively identify a responsive subgroup, a trial period of 6 or possibly 12 months is necessary to assess patient responsiveness. Despite these potential shortcomings, the benefits of therapy appear to outweigh the risks. Indeed, finasteride is well tolerated; most adverse events have been related to sexual dysfunction (decreased libido, ejaculation disorders and impotence) and occurred in only a small proportion (about 2 to 3%) of patients. Moreover, although there has been concern that finasteride might mask the detection of prostate cancer through its decremental effects on serum prostate specific antigen (PSA) levels, careful monitoring in clinical trials appears to have avoided this problem. Thorough pretreatment assessment and periodic follow-up examinations for malignancy are therefore required in clinical practice. The role of finasteride in the treatment of patients with BPH is still emerging and will no doubt gain in clarity with further planned investigations. TURP (or other invasive procedures such as the insertion of prostatic stents in patients unsuitable for resection), continues to be the mainstay of therapy for those patients with severe symptomatic BPH. However, available data support a first line role for finasteride in the treatment of patients with uncomplicated symptomatic BPH. Within this setting, finasteride appears to offer a needed additional treatment option for those patients in whom surgery is not indicated, and may be of special benefit to the considerable proportion of patients who opt not to undergo prostatectomy.

Bisoprolol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension and angina pectoris.

Bisoprolol is a beta 1-adrenoceptor antagonist with no partial agonist (intrinsic sympathomimetic) activity or membrane stabilising (local anaesthetic) activity. The oral bioavailability of bisoprolol is high (90%) and the drug has a long elimination half-life which allows once-daily administration; in addition, it is hepatically and renally cleared in equal proportions. In non-comparative studies, and comparative trials, bisoprolol proved effective, and as efficacious as atenolol, low doses of metoprolol, diuretics and nifedipine SR in hypertension, and atenolol and verapamil in stable angina pectoris. Bisoprolol has been well tolerated in most patients. Thus, bisoprolol is an effective alternative to other beta-adrenoceptor antagonists in patients with mild to moderate essential hypertension or stable angina pectoris. Furthermore, its unique pharmacokinetic properties may offer advantages in selected patients. However, the results of further comparative studies with established agents in the treatment of hypertension and angina pectoris are still awaited so that a final assessment of the relative place in therapy of bisoprolol in these disease states may be made.