Dexfenfluramine. A review of its pharmacological properties and therapeutic potential in obesity.

Dexfenfluramine stimulates serotoninergic activity by inhibiting serotonin reuptake into presynaptic neurons and by enhancing its release into brain synapses. Based on the serotonin hypothesis of appetite control these effects would be expected to reduce food intake and thus body-weight. Studies in animal models and severely overweight patients have confirmed the effectiveness of dexfenfluramine as a weight-reducing agent which appears to be well tolerated. Permanent weight loss is the goal of weight-reducing strategies and, based on current clinical evidence, dexfenfluramine appears to exert a weight reducing effect over periods of up to 12 months without development of tolerance, a problem that has limited the long term use of other pharmacological agents used in the treatment of this disorder. Dexfenfluramine facilitated weight loss in patients who had not responded satisfactorily to other weight-reducing strategies, prevented relapse in those patients who had achieved weight reduction by other methods, and corrected disturbed eating patterns (and therefore reduced weight gain) in small studies involving patients with premenstrual syndrome, seasonal affective disorder and nicotine withdrawal syndrome. Follow-up of the longest study reported with dexfenfluramine suggests that continued therapy is required in severely overweight patients if weight loss is to be maintained. Dexfenfluramine has not been directly compared with nonpharmacological measures of weight control such as behaviour modification or exercise programmes. The decision that pharmacological means are indicated in overweight patients must be highly individualised, and must consider the many complex factors that often contribute to overweight states, as well as the anticipated magnitude of drug effect. Despite such a cautionary note, and the expected need (at this stage of its development) for an expanded clinical study programme in certain areas, dexfenfluramine is a clear advance in the pharmacological approach to improved management of overweight individuals.

Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). A review of its pharmacological properties and prospective role in the management of myelosuppression.

Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) is a polypeptide hormone produced through recombinant DNA technologies in glycosylated (yeast or mammalian expression systems) or nonglycosylated (Escherichia coli expression system) form. It is a multilineage haematopoietin which stimulates proliferation and differentiation of bone marrow myeloid progenitors and increases peripheral white blood cell counts when administered systemically. Treatment is generally well tolerated, although mild to moderate flu-like symptoms are common and rGM-CSF-induced fever and fluid retention may be problematic in occasional patients. rGM-CSF accelerates recovery of peripheral neutrophil counts after bone marrow transplantation, and results of a placebo-controlled randomised trial correlate this with reduced infectious episodes and shortened length of hospitalisation in patients with lymphoid malignancies. A substantial number of patients with graft failure after bone marrow transplantation also respond to rGM-CSF. The duration of myelosuppression secondary to cancer chemotherapy can be significantly reduced by rGM-CSF which has permitted investigation of antineoplastic dose-intensity escalation. In some haematopoietic disorders (e.g. aplastic anaemia, myelodysplasia and neutropenia secondary to HIV infection and antiviral therapy), rGM-CSF produces clinically useful increases in peripheral blood granulocyte counts, although the effect is generally not sustained after drug withdrawal. The potential for rGM-CSF to stimulate proliferation of the abnormal clone in myelodysplasia and in acute myelogenous leukaemia following induction therapy is of concern. Available data suggest, however, that with appropriate monitoring and exclusion of high-risk patients this serious potential risk can be avoided, and that myelopoiesis is enhanced in such patients by rGM-CSF treatment. Recombinant colony-stimulating factors are a new therapeutic modality; hence many aspects of their use remain to be clarified. Nonetheless, as one of a small group of novel agents rGM-CSF has major potential in the management of myelosuppression secondary to cytoreductive therapy with or without bone marrow transplantation, and in amelioration of disturbed myelopoiesis. It represents an important application of biotechnology to a difficult area of therapeutics.

Amiodarone. An overview of its pharmacological properties, and review of its therapeutic use in cardiac arrhythmias.

Amiodarone, originally developed over 20 years ago, is a potent antiarrhythmic drug with the actions of all antiarrhythmic drug classes. It has been successfully used in the treatment of symptomatic and life-threatening ventricular arrhythmias and symptomatic supraventricular arrhythmias. In patients with left ventricular dysfunction amiodarone does not usually produce any clinically significant cardiodepression and the drug has relatively high antiarrhythmic efficacy. Preliminary studies indicate that amiodarone may have a beneficial effect on mortality and survival in certain groups of patients with ventricular arrhythmias, an action probably related to both its antiarrhythmic and antifibrillatory effects. The adverse effect profile of amiodarone is diverse, involving the cardiac, thyroid, pulmonary, hepatic, gastrointestinal, ocular, neurological and dermatological systems. Interstitial pneumonitis and hepatitis are potentially fatal, but the vast majority of adverse events are less serious, and some may be dose dependent. Pretreatment monitoring, regular assessments and the use of minimum effective doses are, therefore, necessary. Thus, with appropriate monitoring to control its well recognised adverse effects amiodarone has an important place as an effective 'broad spectrum' antiarrhythmic drug which has, so far, been used when other treatments have proved ineffective. More recent preliminary data also suggest that it may also have a beneficial effect in the prevention of sudden death in some patients.

Enoximone. A review of its pharmacological properties and therapeutic potential.

Enoximone is an imidazolone derivative currently undergoing trials in patients with congestive heart failure refractory to conventional therapy. It is a phosphodiesterase inhibitor with both positive inotropic and vasodilator properties, and is active by both oral and intravenous routes of administration. While pharmacodynamic studies have documented beneficial haemodynamic effects after short term oral administration, and objective and subjective improvement relative to placebo during some short term trials, its clinical efficacy during continuous longer term therapy remains uncertain. Enoximone is of potential benefit as an adjunct in short term management of patients with end-stage cardiac failure awaiting cardiac transplantation. In the usually small studies reported to date enoximone was generally better tolerated at oral dosages of less than 2 mg/kg than at higher dosages. Thus, while its pharmacodynamic profile holds potential promise in a difficult therapeutic area, the long term clinical efficacy and tolerability of enoximone remain yet to be determined in controlled trials of adequate size and duration.

Omeprazole. An updated review of its pharmacology and therapeutic use in acid-related disorders.

Omeprazole is the first of a new class of drugs, the acid pump inhibitors, which control gastric acid secretion at the final stage of the acid secretory pathway and thus reduce basal and stimulated acid secretion irrespective of the stimulus. In patients with duodenal or gastric ulcers, omeprazole as a single 20 mg daily dose provides more rapid and complete healing compared with ranitidine 150 mg twice daily or 300 mg at nighttime, or cimetidine 800 or 1000 mg/day. Patients poorly responsive to treatment with histamine H2-receptor antagonists respond well to omeprazole--most ulcers healed within 4 to 8 weeks of omeprazole 40 mg/day therapy. Omeprazole 20 or 40 mg/day has been administered as maintenance therapy for peptic ulcer disease for up to 5.5 years with very few ulcer recurrences. In patients with erosive or ulcerative oesophagitis, omeprazole 20 or 40 mg/day produces healing in about 80% of patients after 4 weeks, and is superior to ranitidine with respect to both healing and symptom relief. Healing rates of greater than 80% are achieved after 8 weeks in patients with severe reflux oesophagitis unresponsive to H2-receptor antagonists. Maintenance therapy with a daily 20 mg dose prevents relapse in about 80% of patients over a 12-month period. Omeprazole is considered to be the best pharmacological option for controlling gastric acid secretion in patients with Zollinger-Ellison syndrome. Daily dosages of 20 to 360 (median 60 to 70 mg successfully reduce basal acid output to target levels (less than 10 mmol/h or less than 5 mmol/h in patients with severe oesophagitis or partial gastrectomy) during treatment for up to 4 years. Omeprazole is well tolerated in short term studies (up to 12 weeks); the reported incidence of serious side effects (about 1%) being similar to that seen in patients treated with an histamine H2-receptor antagonist. The longer term tolerability of omeprazole has been investigated in patients treated for up to 5.5 years. Slight hyperplasia, but no evidence of enterochromaffin-like (ECL) cell dysplasia or neoplasia or ECL cell carcinoids has been reported. ECL cell carcinoids have been observed in rats after life-long treatment with high doses of omeprazole or ranitidine, or in rats with partial corpectomy; the weight of experimental evidence indicates that this is a result of prolonged hypergastrinaemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Vigabatrin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control.

Vigabatrin was specifically designed to enhance gamma-aminobutyric acid (GABA) function in the CNS. By increasing brain concentrations of this inhibitory neurotransmitter the drug appears to decrease propagation of abnormal hypersynchronous discharges, thereby reducing seizure activity. At this stage in its development, clinical experience with vigabatrin is limited primarily to patients with refractory seizure disorders. In this difficult-to-treat population, 'add-on' therapy with vigabatrin greater than or equal to 2 g/day has shown impressive efficacy, reducing seizure frequency by greater than or equal to 50% in approximately half of patients. Clinical efficacy does seem to vary with seizure type with the best response reported in adults with complex partial seizures with or without generalisation and in children with cryptogenic partial epilepsy or symptomatic infantile spasm. Vigabatrin appears to have a negative effect on absences and myoclonic seizures. Some disorders of motor control may also be amenable to enhanced GABAergic function. In the small number of patients with tardive dyskinesia treated to date, vigabatrin produced mild to moderate improvement in hyperkinetic symptom scores but Parkinsonism or schizophrenic symptoms occasionally worsened. The best response was reported in a study of patients who had been withdrawn from neuroleptic therapy. In a small but well-controlled comparative trial, vigabatrin was as effective as baclofen in reducing spasm and improving some parameters of spasticity in patients with spinal cord lesions or multiple sclerosis. Most adverse reactions to vigabatrin are mild and transient with central nervous system (CNS) changes being reported most frequently. Of particular note, serial evoked potential studies and the few available histology reports have not found evidence of intramyelinic oedema during therapeutic use, as was reported in rats and dogs on chronic high-dose treatment. Thus, vigabatrin is a promising new anticonvulsant drug. Current evidence supports a trial of this agent as adjunctive therapy in patients with refractory seizure disorders, and future investigation of vigabatrin monotherapy and its efficacy relative to established agents is awaited with interest. Wider experience should help to clarify which patients - by seizure type and concurrent CNS pathology - are likely to benefit from vigabatrin and ongoing monitoring should further clarify the potential detrimental effects, if any, of long term use. In the meantime, it is a welcome addition in the difficult setting of resistant epilepsy.

Ondansetron. Therapeutic use as an antiemetic.

Ondansetron (GR 38032F) is a highly selective 5-HT3 receptor antagonist, one of a new class of compounds which may have several therapeutic applications. Animal and clinical studies show that ondansetron reduces the 24-hour incidence and severity of nausea and vomiting induced by cytotoxic drugs, including cisplatin, and by single exposure, high dose radiation. Ondansetron is more effective than high dose metoclopramide in the 24 hours following chemotherapy, and preliminary clinical evidence suggests that it is equally effective in the following 4 days. It is also more effective than the 'moderate' doses of metoclopramide used to suppress emesis following radiotherapy. The antiemetic efficacy of ondansetron is enhanced by dexamethasone in cisplatin-treated patients. Importantly, extrapyramidal effects have not been reported with ondansetron. Further comparisons are required with standard combination antiemetic therapy to complement the data presently available. Thus, ondansetron is a promising new agent for prophylaxis against nausea and vomiting in chemotherapy and radiotherapy. It may be particularly useful in young and elderly patients who are more susceptible to extrapyramidal symptoms induced by high dose metoclopramide. With its improved tolerability and clinical response profiles, ondansetron represents an important advance in a difficult area of therapeutics.

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

Amlodipine, a basic dihydropyridine derivative, inhibits the calcium influx through 'slow' channels in peripheral vascular and coronary smooth muscle cells, thus producing marked vasodilation in peripheral and coronary vascular beds. Short to medium term clinical trials indicate that amlodipine is effective as both an antianginal agent in patients with stable angina pectoris and an antihypertensive agent in patients with mild to moderate hypertension. In small comparative studies amlodipine was at least as effective as 'standard' agents, including atenolol, verapamil, hydrochlorothiazide or captopril in hypertension, and diltiazem or nadolol in angina pectoris. Amlodipine is well tolerated, and does not appear to cause some of the undesirable effects often associated with other cardiovascular agents (e.g. adverse changes in serum lipid patterns, cardiac conduction disturbances, postural hypotension). The most common adverse effects associated with amlodipine therapy--oedema and flushing--are related to the vasodilatory action of the drug, and are generally mild to moderate in severity. Thus, amlodipine seems to provide a useful alternative to other agents currently available for the treatment of essential hypertension and chronic stable angina pectoris, with certain pharmacodynamic and tolerability properties that should be advantageous in many patients.

Remoxipride. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in schizophrenia.

Remoxipride is a substituted benzamide of the same class as sulpiride, and has a pharmacodynamic profile consistent with central antidopaminergic activity. It is a weak, but relatively selective, central dopamine D2-receptor antagonist and appears to have preferential affinity for extrastriatal dopamine D2-receptors. It also has marked affinity for central sigma receptors. Clinical data from noncomparative and comparative studies show that remoxipride has antipsychotic acticvity in patients with chronic schizophrenia, and acute exacerbation of chronic schizophrenia, with activity on both positive and negative symptoms. Its overall efficacy in these studies was similar to that of haloperidol. Importantly, however, remoxipride produced a substantially lower incidence of extrapyramidal effects than haloperidol. Further long term comparative studies are required to ascertain the relative suitability of remoxipride for preventing relapse in psychotic patients, and to determine whether tardive dyskinesia occurs in remoxipride recipients--the latter has not been reported with remoxipride to date. Thus, while further experience (particularly of a long term comparative nature) is needed, at present remoxipride appears to offer an important tolerability advantage over haloperidol.

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.

Transdermal estradiol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausal complaints.

The estradiol transdermal therapeutic system is a cutaneous delivery device which delivers estradiol into the systemic circulation via the stratum corneum at a constant rate for up to 4 days. Physiological levels of estradiol (the major estrogen secreted by the ovaries in premenopausal women) can therefore be maintained in postmenopausal women with low daily doses because first-pass hepatic metabolism is avoided. In short term clinical studies, the beneficial effects of transdermal estradiol on plasma gonadotrophins, maturation of the vaginal epithelium, metabolic parameters of bone resorption and menopausal symptoms (hot flushes, sleep disturbance, genitourinary discomfort and mood alteration) appear to be comparable to those of oral and subcutaneous estrogens, while the undesirable effects of oral estrogens on hepatic metabolism are avoided. As with oral or injectable estrogen replacement therapy, concomitant sequential progestagen is recommended for patients with an intact uterus during transdermal estradiol administration, in order to reduce endometrial stimulation. Transdermal estradiol has been well tolerated in clinical trials, with local irritation at the site of application being the most common adverse effect. The incidence of systemic estrogenic effects appears to be comparable to that observed with oral therapy. Thus, transdermal estradiol offers near-physiological estrogen replacement in postmenopausal women in a convenient low-dose form which may avoid some of the complications of higher dose oral therapy. Long term epidemiological studies are warranted to determine whether transdermal estradiol therapy provides protection against osteoporosis and fractures and cardiovascular disease equivalent to that offered by oral and injectable estrogens. However, despite the importance of such data, it seems reasonable to conclude at this stage of its development that transdermal estradiol represents an important advance in hormone replacement therapy.

Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia.

Fenofibrate is a lipid-regulating drug which is structurally related to other fibric acid derivatives, such as clofibrate. At the recommended dosage of 200 to 400 mg daily, it produces substantial reductions in plasma triglyceride levels in hypertriglyceridaemic patients and in plasma total cholesterol levels in hypercholesterolaemic patients. High density lipoprotein (HDL)-cholesterol levels are generally increased in patients with low pretreatment values. Fenofibrate appears to be equally effective in diabetic patients with hyperlipoproteinaemia without adversely affecting glycaemic control. The influence of fenofibrate on the plasma lipid profile is sustained during long term (2 to 7 years) treatment. Comparative studies conducted to date have involved only small groups of patients--in overall terms fenofibrate was at least as effective as other fibrates, but larger comparative studies are needed before valid conclusions on its relative efficacy compared with nonfibrate lipid-lowering drugs can be drawn. The influence of fenofibrate on morbidity and mortality from cardiovascular disease has not been studied. Clinical adverse reactions to fenofibrate have mainly consisted of gastrointestinal disturbances, headache and muscle cramps. Transient elevations in transaminase and creatine phosphokinase levels commonly occur. Isolated cases of hepatitis with substantially elevated transaminase levels have been reported. Fenofibrate induces hepatomegaly, peroxisome proliferation and hepatic carcinomas in rodents, but this type of hepatotoxicity has not been observed in humans. The biliary lithogenic index is increased by fenofibrate, but this has not been shown to have increased the incidence of gallstones in treated patients. Thus, fenofibrate offers an effective and well tolerated alternative to clofibrate or other fibric acid derivatives, but its relative efficacy and tolerability compared with other types of lipid-lowering drugs, and its effect on cardiovascular morbidity and mortality, remain to be clarified.

Ganciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections.

Ganciclovir is a nucleoside analogue with antiviral activity in vitro against members of the herpes group and some other DNA viruses. It has demonstrated efficacy against human cytomegalovirus infections and should be considered a first-line therapy in the treatment of life- or sight-threatening cytomegalovirus infection in immunocompromised patients. Clinical efficacy varies with the underlying aetiology of immunocompromise and the site of disease, and prompt diagnosis and early treatment initiation appear to improve the response. In patients with cytomegalovirus pneumonia, particularly bone marrow transplant recipients, concomitant administration of cytomegalovirus immune globulin may significantly improve clinical outcome. Maintenance therapy to prevent recurrence is usually required by bone marrow transplant recipients until the recovery of adequate immune function, whereas AIDS patients may require indefinite ganciclovir maintenance therapy to prevent disease progression, as ganciclovir (like other antivirals) does not eradicate latent viral infection. Haematological effects occur relatively frequently during ganciclovir administration but are usually reversible. Ganciclovir has not been directly compared with other antiviral drugs because of the absence until recently of other effective treatments. However, comparative studies with foscarnet, particularly in cytomegalovirus retinitis, will be of considerable interest. Thus, ganciclovir represents a major advance in the therapy of severe cytomegalovirus infections in immunocompromised patients. Comparative studies, and investigation of ways of reducing toxicity (intravitreal administration; concomitant use of stimulants of haematopoiesis; use in conjunction with other antivirals with differing mechanisms of action), may further expand its eventual role.

Carboplatin. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of cancer.

Carboplatin is a 'second-generation' platinum compound advocated for use in the treatment of patients with ovarian cancer and it has also shown promise in small cell lung cancer, squamous cell carcinomas of the head and neck, and seminomas. Overall, it would appear to have a similar qualitative spectrum of activity to cisplatin. There have been few comparative trials with carboplatin, either alone or in combination with other chemotherapeutic agents, but the limited data suggest comparable efficacy with cisplatin in ovarian cancer. Importantly, the toxicity profile of carboplatin is markedly different from that of cisplatin, with nephrotoxicity, neurotoxicity and ototoxicity occurring only infrequently with carboplatin. As with cisplatin, nausea and vomiting occur in many patients after carboplatin administration, but symptoms are usually delayed for several hours and are mild to moderate in severity - dose-limiting nausea and vomiting are infrequent with carboplatin. The dose-limiting toxicity of carboplatin is myelosuppression, with severe thrombocytopenia and less often leucopenia, which may be more severe in older patients or in those with renal impairment or those who have had previous chemotherapy. Thus, preliminary data suggest that carboplatin is a therapeutically equivalent alternative to cisplatin, but with a differing toxicity profile that should offer advantages over cisplatin in many patients.

Lovastatin. A preliminary review of its pharmacodynamic properties and therapeutic use in hyperlipidaemia.

Lovastatin is the first of a new class of cholesterol lowering drugs that competitively inhibit HMG-CoA reductase. This new drug decreases cholesterol synthesis and apolipoprotein B concentrations, and increases LDL receptor activity without adverse effects on other products in the cholesterol pathway. In patients with heterozygous familial or polygenic (non-familial) hypercholesterolaemia, oral lovastatin 20 to 40 mg twice daily reduces plasma total cholesterol and LDL-cholesterol concentrations by 25 to 40% over a period of several weeks. Lovastatin also produces decreases in plasma triglyceride and VLDL-cholesterol concentrations, although to a lesser extent. In addition, small though significant increases in HDL-cholesterol concentrations have been observed. Combined administration of lovastatin with other lipid-lowering drugs results in further reductions in plasma total and LDL-cholesterol concentrations beyond those seen with either drug alone. From findings in short term studies, lovastatin appears to be well tolerated with a low incidence of side effects. However, liver function tests and eye examinations for possible lens opacities are advised, and further long term studies in larger groups of patients are necessary before the side effect profile of lovastatin will be clearly established. As would be expected at this relatively early stage of its clinical 'life,' lovastatin has not yet been studied in a manner that would determine its effect on cardiovascular mortality during long term administration. Nevertheless, if the substantial improvements to patients' lipid and lipoprotein profiles observed in short term studies are maintained during long term administration, then lovastatin will have an important role in the pharmacological management of hyperlipidaemia.

Propofol. A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic.

Propofol is an intravenous anaesthetic which is chemically unrelated to other anaesthetics. Induction of anaesthesia with propofol is rapid, and maintenance can be achieved by either continuous infusion or intermittent bolus injections, with either nitrous oxide or opioids used to provide analgesia. Comparative studies have shown propofol to be at least as effective as thiopentone, methohexitone or etomidate for anaesthesia during general surgery. The incidence of excitatory effects is lower with propofol than with methohexitone, but apnoea on induction occurs more frequently with propofol than with other anaesthetics. Additionally, a small number of studies of induction and maintenance of anaesthesia have found propofol to be a suitable alternative to induction with thiopentone and maintenance with halothane, isoflurane or enflurane. Propofol is particularly suitable for outpatient surgery since it provides superior operating conditions to methohexitone (particularly less movement), and rapid recovery in the postoperative period associated with a low incidence of nausea and vomiting. When used in combination with fentanyl or alfentanil, propofol is suitable for the provision of total intravenous anaesthesia, and comparative studies found it to be superior to methohexitone or etomidate in this setting. Infusions of subanaesthetic doses of propofol have been used to sedate patients for surgery under regional anaesthesia, and also to provide sedation of patients in intensive care. In the latter situation it is particularly encouraging that propofol did not suppress adrenal responsiveness during short term studies. If this is confirmed during longer term administration this would offer an important advantage over etomidate. Thus, propofol is clearly an effective addition to the limited range of intravenous anaesthetics. While certain areas of its use need further study, as would be expected at this stage of its development, propofol should find a useful role in anaesthetic practice.

Transdermal clonidine. A preliminary review of its pharmacodynamic properties and therapeutic efficacy.

The clonidine transdermal therapeutic system (TTS) is a cutaneous delivery device which provides therapeutically effective doses of clonidine at a constant rate over 7 days. In clinical trials it reduces blood pressure in patients with mild to moderate hypertension as effectively as oral clonidine but with greater stability of blood pressure control. Most patients find the transdermal system more convenient than oral treatments, and compliance may be improved. The side effects known to occur with orally administered clonidine, dry mouth and sedation in particular, are also produced with transdermal administration, but possibly at a lower incidence than during oral treatment. A proportion of patients experience adverse skin reactions with the transdermal system. At this stage of its development, transdermal clonidine has not been adequately compared with other 'standard' antihypertensive treatments such as diuretics or beta-adrenoceptor blocking drugs. However, despite the lack of such comparative studies, transdermal clonidine represents a worthwhile new approach to antihypertensive therapy, particularly in terms of patient convenience.

Human insulin. A review of its biological activity, pharmacokinetics and therapeutic use.

Human insulin, whether produced by recombinant DNA techniques (biosynthetic, insulin crb) or enzymatic modification of porcine insulin (semisynthetic, insulin emp) is equivalent in biological activity to porcine insulin following intravenous administration. Slight differences between human and porcine insulin in hypoglycaemic activity after subcutaneous injection appear to be related to differences in absorption, and are unlikely to be of major clinical importance. Similarly, reported minor differences in counterregulator hormone response to human insulin compared with porcine insulin need further study, but they are unlikely to have important clinical implications. In clinical use the therapeutic efficacy of human insulin is similar to that of porcine insulin. The lower antigenicity with human insulin relative to purified porcine insulin is of potential therapeutic value, and it is logical to use human insulin in newly diagnosed diabetics, in patients treated intermittently with insulin, in cases of immunological insulin resistance, and in patients with allergy and local reaction against animal insulin. Thus, human insulin seems to have no disadvantages compared with purified porcine insulin and may have some advantages. While there appears to be no compelling reason to change patients whose diabetes is presently well controlled with purified porcine insulin to human insulin, the availability of human insulin at a price equal to or less than that of animal origin makes such a change logical. In the meantime, human insulin should be considered the insulin of 'first choice' for newly diagnosed diabetics requiring insulin therapy and in carbohydrate intolerance and diabetes occurring during pregnancy.

Anisoylated plasminogen streptokinase activator complex (APSAC). A review of its mechanism of action, clinical pharmacology and therapeutic use in acute myocardial infarction.

APSAC is a new thrombolytic agent with advantages over conventional therapy such as streptokinase. In particular, it is suitable for intravenous administration over 4 to 5 minutes, in contrast with the prolonged infusion required with intravenous streptokinase, thus facilitating treatment of acute myocardial infarction outside a coronary care unit. Additionally, its fibrinolytic action is theoretically selective for fibrin associated with thrombi, which should minimise systemic fibrinolysis. However, in practice, systemic fibrinolysis does occur to some extent in most patients, but clinically significant haemorrhagic complications are rare. At the recommended dose of 30U injected intravenously over a period of 4 to 5 minutes in patients with acute myocardial infarction of less than 6 hours' duration, reperfusion of occluded coronary arteries occurs in about 72% of patients (range 53 to 91% in individual studies). Subsequent reocclusion has been reported in 0 to 20% of patients in most studies, with an average reocclusion rate of around 10%. The reperfusion rate compares favourably with that reported for intracoronary streptokinase and has tended to be superior to that with intravenous streptokinase. Thus, APSAC is an important advance in thrombolytic therapy for patients with acute myocardial infarction. Of particular importance is its relative ease of administration, reducing the dependence on coronary care units with catheterisation facilities, and the associated costs and delays in implementing treatment. APSAC should result in effective thrombolytic therapy being rapidly introduced after acute myocardial infarction in a wider proportion of patients than was previously feasible.

Topical minoxidil. A preliminary review of its pharmacodynamic properties and therapeutic efficacy in alopecia areata and alopecia androgenetica.

When minoxidil is administered orally for periods in excess of 1 month, hypertrichosis occurs as a side effect in a majority of patients. Consequently, topical minoxidil has been developed to try to improve hair growth in patients with alopecia areata and alopecia androgenetica. Preliminary studies have shown that topical minoxidil promotes cosmetically acceptable hair regrowth in a variable proportion of patients with alopecia areata. Data from a large multicentre trial indicate that cosmetically worthwhile results are achieved in about one-third of subjects with alopecia androgenetica after 1 year of treatment. A much higher proportion (about 80%) of patients with alopecia androgenetica exhibited some non-vellus hair regrowth after 1 year, and whether more of these patients would develop a cosmetically acceptable result with a longer treatment period is an important area of future investigation. Initial indications suggest that less severe disease is a predictor of likely response. Thus, topical minoxidil would seem to be a useful treatment modality for patients with alopecia androgenetica--a disease for which no other safe and effective drug therapy exists. Results from treating patients with alopecia areata with topical minoxidil, although encouraging, have been more variable and require further evaluation. Even though a number of questions remain to be answered about topical minoxidil (as would be expected at this stage in its development), it would seem to be the first available drug with the potential to promote substantial hair regrowth in these divergent diseases.