Efficacy of almotriptan in early intervention for treatment of acute migraine in a primary care setting: the START study.

AIMS: The benefits of taking almotriptan early for acute migraine when pain is mild have clearly been demonstrated in the neurology setting. The aim of this study was to determine whether similar benefits with early intervention of almotriptan can be achieved in everyday general practice, where most migraineurs are managed. METHODS: In this European, prospective, observational study, patients were asked to treat up to three migraine attacks over a 2-month period with almotriptan 12.5 mg administered within 1 h of pain onset and when pain was mild (early + mild intervention group). RESULTS: A total of 501 patients were enrolled in primary care centres across Spain, France and Italy. The intention-to-treat analysis involved 454 patients who reported 1174 migraine attacks, with early intervention being used in 138 of these attacks. A greater proportion of patients who took almotriptan early + mild for their first migraine attack (n = 42) were pain free at 2 h compared with those in the non-early + mild intervention group (n = 410) (62% vs. 35%; p < 0.001). Similar results were obtained for all migraine attacks comparison [65% (n = 138) vs. 38% (n = 1036); p < 0.001]. Other secondary end-points were also significantly in favour of early + mild treatment, including sustained pain free (SPF), SPF with no adverse events (SNAE), and time lost because of migraine (all p < 0.001). Almotriptan was well tolerated with no serious adverse events reported. CONCLUSIONS: In the primary care setting, early intervention with almotriptan for treatment of migraine provides significant clinical benefits compared with delaying treatment and/or waiting until pain intensity has progressed beyond mild.

Paracetamol and phenacetin.

Since their synthesis in the late 1800s paracetamol (acetaminophen) and phenacetin have followed divergent pathways with regard to their popularity as mild analgesic/antipyretic drugs. Initially, paracetamol was discarded in favour of phenacetin because the latter drug was supposedly less toxic. Today the opposite is true, and paracetamol, along with aspirin, has become one of the two most popular 'over-the-counter' non-narcotic analgesic agents. This marked increase in the wide approval attained by paracetamol has been accompanied by the virtual commercial demise of phenacetin because of its role, albeit somewhat circumstantial, in causing analgesic nephropathy. Both paracetamol and phenacetin are effective mild analgesics, suitable for treating mild to moderate pain, and their actions are broadly comparable with those of aspirin and related salicylates, although they do not appear to possess significant anti-inflammatory activity. Since a major portion of a dose of phenacetin is rapidly metabolised to paracetamol, it seems possible that phenacetin owes some of its therapeutic activity to its main metabolite, paracetamol, whereas its most troublesome side effect (methaemoglobinaemia) is due to another metabolite, p-phenetidine. The mechanism of action of paracetamol is poorly defined, although it has been speculated that it may selectively inhibit prostaglandin production in the central nervous system, which would account for its analgesic/antipyretic properties. The lack of any significant influence on peripheral cyclooxygenase would explain the absence of anti-inflammatory activity. At therapeutic doses paracetamol is well tolerated and produces fewer side effects than aspirin. The most frequently reported adverse effect associated with paracetamol is hepatotoxicity, which occurs after acute overdosage (usually doses greater than 10 to 15g are needed) and, very rarely, during long term treatment with doses at the higher levels of the therapeutic range. Paracetamol damages the liver through the formation of a highly reactive metabolite which is normally inactivated by conjugation with glutathione. Overdoses of paracetamol exhaust glutathione stores, thus allowing the accumulation of this toxic metabolite which covalently binds with vital cell elements and can result in liver necrosis. Glutathione precursors (notably intravenous N-acetylcysteine) have proved remarkably successful in treating paracetamol overdose, as long as treatment is initiated within 10 hours.(ABSTRACT TRUNCATED AT 400 WORDS)

Aspirin and related derivatives of salicylic acid.

After almost 90 years of clinical use, aspirin remains one of the world's most extensively used 'over-the-counter' drugs, and it is still recognised as the standard analgesic/antipyretic/anti-inflammatory agent by which newer drugs are assessed. However, its pre-eminent position as the analgesic of choice for mild to moderate pain has been seriously challenged with the introduction of many 'new' non-steroidal non-narcotic analgesic drugs. Indeed, there is convincing scientific evidence that many of the 'newer' non-steroidal drugs such as diflunisal, ibuprofen, flurbiprofen etc. are significantly superior analgesics and, in many cases, have a longer duration of action. In recent years the salicylates, aspirin in particular, have been the focus of much attention regarding their side effect profiles. At usual dosages for relief of pain and during occasional use, aspirin is well tolerated by the vast majority of patients. Adverse reactions, of which there is a wide spectrum, most frequently accompany anti-inflammatory doses of aspirin, or may be the result of accidental overdosing (particularly in children and the elderly)--probably a reflection of the lay population's acceptability of aspirin's presumed safety. As with other non-steroidal analgesic drugs, gastrointestinal complaints are the most commonly reported side effects. The existence of many shared clinical, adverse and toxic effects of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is thought to be accounted for by a common mechanism--inhibition of the ubiquitous cyclo-oxygenase enzyme. Thus, suppression of prostaglandin biosynthesis is widely considered to explain the common properties of NSAIDS, although further research is still necessary to clarify some inconsistencies and to complete our understanding of the processes involved. Aspirin and salicylates have been reported to have a wide range of drug interactions but only relatively few seem to be clinically important. Many of the interactions are pharmacokinetic in nature. Drugs considered to produce the most significant interactions with salicylates include anticoagulants and thrombolytic agents, uricosuric agents, corticosteroids, methotrexate and sulphonylurea hypoglycaemic agents.

Tioconazole. A review of its antimicrobial activity and therapeutic use in superficial mycoses.

Tioconazole is a substituted imidazole antimicrobial agent structurally related to other drugs in this group. It has been shown to have a broad spectrum of activity in vitro against dermatophytes and yeasts, as well as against some chlamydia, trichomonads and Gram-positive bacteria. Both open and controlled clinical trials have clearly demonstrated the efficacy and safety of topical preparations of tioconazole for treating superficial dermatophyte or yeast infections of the skin and vaginal candidiasis. In comparative studies it was at least as effective as alternative imidazole antifungal drugs, and in a few trials significantly greater efficacy has been reported for tioconazole, compared with clotrimazole, miconazole, econazole and systemic ketoconazole. Preliminary studies in other clinical areas suggest tioconazole may be useful for treating onychomycosis (in a special nail formulation), napkin-rash due to Candida albicans, impetigo, and vaginal trichomoniasis, although comparative studies are needed in each of these settings to clearly assess its relative place in therapy. Thus, tioconazole is an effective and well tolerated treatment for vaginal candidiasis and superficial fungal infections of the skin.

Salbutamol in the 1980s. A reappraisal of its clinical efficacy.

Salbutamol (albuterol) is a beta 2-selective adrenoceptor agonist which accounts for its pronounced bronchodilatory, cardiac, uterine and metabolic effects. During the intervening years since salbutamol was first reviewed in the Journal (1971), it has become extensively used in the treatment of reversible obstructive airways disease. Numerous studies in this disease (including severe acute, childhood and exercise-induced asthma) have confirmed the bronchodilatory efficacy of salbutamol, and it has been shown to be at least as effective as most of the currently available bronchodilators, if not more effective. The onset of maximum effect of salbutamol is dependent on the formulation used and the route by which it is administered. In most patients inhaled salbutamol is a first-line therapy, since it offers rapid bronchodilation, usually relieving bronchospasm within minutes. Although oral salbutamol has often proved to be less efficacious than the inhaled formulation, it still affords clinically significant bronchodilation, and it is particularly useful in those patients unable to coordinate the use of inhalers. Parenteral formulations of salbutamol are generally reserved for the treatment of severe attacks of bronchospasm and they are one of the treatments of choice in these life-threatening situations. Studies of the concomitant use of salbutamol and other agents such as anticholinergics, methylxanthines and beclomethasone dipropionate have usually shown a complementary response in the majority of patients, as might be expected from the different mechanisms of action of these groups of drugs. Salbutamol is generally well tolerated and any side effects observed are a predictable extension of its pharmacology. Since the frequency of side effects is dose related, and therefore dependent on the route of administration, it is not surprising that they are much more common following intravenous and oral rather than inhalation therapy. Tremor, tachycardia and hypokalaemia are the most frequently reported adverse effects. After nearly 20 years of use, salbutamol is well established as a 'first-choice' treatment in reversible obstructive airways disease. Indeed, throughout this time many new bronchodilatory agents have been studied but none have proved more effective. Clinical evaluation of salbutamol in the treatment of premature labour, hyperkalaemia and cardiac failure awaits further studies, although to date some encouraging results have been reported.

Flutamide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer.

Flutamide is a non-steroidal antiandrogenic drug devoid of hormonal agonist activity. Flutamide appears to be a specific antiandrogen only at androgen-dependent accessory genital organs. Its pharmacological activity is due substantially to the principal metabolite, 2-hydroxyflutamide. In comparative trials involving small numbers of patients with previously untreated advanced prostatic cancer, flutamide 750mg daily is comparable with stilboestrol 1 or 3mg daily and with estramustine 560 or 840mg daily. Treatment of newly diagnosed advanced prostatic cancer with flutamide plus a luteinising hormone releasing hormone (LHRH) agonist has produced very promising results, and appears to prolong survival relative to that achieved with leuprolide alone. However, these results require confirmation in suitably designed prospective studies. In previously treated patients refractory to castration, flutamide 750mg daily appears comparable in efficacy to estramustine phosphate 600 mg/m2 daily. Apart from a high incidence (34 to 100%) of gynaecomastia flutamide monotherapy is usually well tolerated, and has the advantage of preserving libido and sexual potency in at least 80% of patients. Gynaecomastia is infrequent, however, when flutamide is used in conjunction with surgical castration or an LHRH agonist. Thus, flutamide is a suitable alternative to other systemic treatment in patients with advanced prostatic cancer who wish to preserve sexual potency. In combination with an LHRH agonist flutamide may become a first-line agent for previously untreated patients with cancer of the prostate.

Bifonazole. A review of its antimicrobial activity and therapeutic use in superficial mycoses.

Bifonazole is a substituted imidazole antifungal agent structurally related to other drugs in this group. It possesses a broad spectrum of activity in vitro against dermatophytes, moulds, yeasts, dimorphic fungi and some Gram-positive bacteria. Both non-comparative and comparative clinical trials have clearly demonstrated the efficacy and safety of various formulations of bifonazole 1% (cream, gel, solution and powder) applied once daily in the treatment of superficial fungal infections of the skin such as dermatophytoses, cutaneous candidiasis and pityriasis versicolor. In comparative studies bifonazole was significantly superior to placebo and at least as effective as alternative imidazole antifungal drugs including clotrimazole, econazole, miconazole, oxiconazole and sulconazole. Preliminary studies in other superficial skin and nail infections/dermatoses suggest that bifonazole may be useful for treating onychomycoses (in a combination cream; bifonazole 1% plus urea 40%), otomycoses, erythrasma, sebopsoriasis, seborrhoeic dermatitis and rosacea. However, controlled trials are needed in each of these clinical settings to assess accurately its relative place in therapy. Thus, bifonazole is an effective and well-tolerated treatment for superficial fungal infections of the skin. Compared with the majority of topical antifungal drugs, which need to be applied at least twice daily, bifonazole offers the convenience of once daily administration, which may improve patient compliance.

Transdermal hyoscine (Scopolamine). A preliminary review of its pharmacodynamic properties and therapeutic efficacy.

Hyoscine (scopolamine) is a competitive inhibitor of the muscarinic receptors of acetylcholine and it has been shown to be one of the most effective agents for preventing motion sickness. However, a relatively high incidence of side effects and a short duration of action has restricted the usefulness of this agent when administered orally or parenterally, and to counter this a novel transdermal preparation of hyoscine has been developed. Pharmacokinetic studies indicate that this new method for administering hyoscine controls the absorption process and the rate of drug entry into the systemic circulation over an extended period (72 hours), providing a means of delivery which is similar to a slow intravenous infusion. However, recent evidence suggests that the response to transdermal hyoscine treatment is variable and this may reflect pharmacokinetic differences between individuals. Controlled therapeutic trials have indicated that a single transdermal hyoscine patch is significantly superior to placebo and oral meclozine (meclizine) in preventing motion sickness. Trials comparing transdermal hyoscine with oral dimenhydrinate have failed to establish any significant differences in efficacy between the 2 drugs in small numbers of subjects, although there was always a more favourable trend towards the transdermal system. In patients with acute vertigo, transdermal hyoscine and oral meclozine were equally efficacious and both were significantly better than placebo in reducing the number of attacks of vertigo. Although transdermal hyoscine has been associated with a lower incidence of side effects than orally or parenterally administered hyoscine hydrobromide, adverse systemic effects have still been frequently reported. Most commonly cited have been dry mouth, drowsiness and impairment of ocular accommodation, including blurred vision and mydriasis (some ocular effects reported may be due to finger-to-eye contamination). Adverse central nervous system (CNS) effects, difficulty in urinating, rashes and erythema have been reported only occasionally. Thus, preliminary evidence suggests transdermal hyoscine may offer an effective and conveniently administered alternative for the prevention of motion-induced nausea and vomiting in certain situations. However, the duration of its clinical effectiveness, and its relative efficacy and tolerability compared with other agents needs to be confirmed in a few additional well-designed studies.

Budesonide. A preliminary review of its pharmacodynamic properties and therapeutic efficacy in asthma and rhinitis.

Budesonide is a non-halogenated glucocorticosteroid which has been shown to possess a high ratio of topical to systemic activity compared with a number of reference corticosteroids such as beclomethasone dipropionate, flunisolide, and triamcinolone acetonide. It appears to undergo extensive first-pass metabolism to metabolites of minimal activity which accounts for the low level of systemic activity. The majority of therapeutic trials in asthma have been of short term duration and have demonstrated that conventional doses of inhaled budesonide (200 to 800 micrograms/day) and beclomethasone dipropionate (400 to 800 micrograms/day) are of similar efficacy in both adults and children with moderate to severe asthma. Other studies have compared high doses of inhaled budesonide (400 to 3200 micrograms/day in 4 divided doses) with both alternate day (7.5 to 60 mg) and daily (7.5 to 40 mg) oral prednisone in patients with severe or unstable asthma. In the small number of such trials to date, inhaled budesonide was superior to prednisone with respect to the level of asthma control and the lesser influence on adrenal function. Long term open studies have similarly shown that inhaled budesonide can be gradually substituted for oral prednisone in steroid-dependent patients, often with a concomitant improvement in pulmonary function and asthma control. Intranasal budesonide (200 to 400 micrograms/day) relieves nasal symptoms in patients with seasonal allergic, perennial allergic and vasomotor rhinitis. In comparative studies in patients with seasonal rhinitis it has been shown to be of similar efficacy as intranasal flunisolide and intranasal beclomethasone dipropionate and superior to intranasal sodium cromoglycate (cromolyn sodium) and the antihistamine dexchlorpheniramine. Following inhalation, the most commonly reported side effects have been candidiasis, dysphonia and sore throat, while after intranasal administration the most frequent adverse reactions have been nasal stinging, throat irritation, dry nose and slight nasal bleeding. At usual dosages, both formulations of budesonide appear to have little or no effect on adrenal function. Thus, at this stage in its development budesonide has been shown to offer an effective alternative to oral or other inhaled corticosteroids in the management of asthma and rhinitis. However, its relative efficacy and tolerability during long term use, compared with beclomethasone dipropionate, remains to be clarified.

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

Piretanide is a potent 'loop' diuretic whose principal site of action is in the thick ascending limb of the loop of Henle. When administered orally or intravenously to healthy volunteers it rapidly increases diuresis and electrolyte excretion, and the effects are short-lived. In comparative studies, piretanide has generally been found to be 5 to 7 times more potent than frusemide (furosemide) but only one-tenth as potent as bumetanide, on a weight-for-weight basis. Piretanide 6 to 12 mg/day, in conventional or sustained release formulations, has been shown to significantly lower elevated blood pressure in a large proportion of patients with mild to moderate hypertension. Comparative trials of up to 3 months duration indicate that at this dosage piretanide is of comparable antihypertensive efficacy as hydrochlorothiazide 50 to 100 mg/day, but has significantly less effect on serum potassium levels. Short term studies in patients with oedema caused by renal, hepatic or cardiac failure demonstrated that piretanide 6 to 9 mg is of similar diuretic potency as frusemide 40 mg and bumetanide 1 mg. In medium term trials in patients with congestive heart failure piretanide 6 mg/day produced equivalent symptomatic improvement as frusemide 40 mg/day. When used to treat oedema caused by liver disease, piretanide 12 to 24 mg/day was successful in only about 50% of patients, but spironolactone added to the treatment regimen greatly increased the response rate. Generally, piretanide has been well-tolerated in clinical trials, although the conventional tablet formulation has caused a relatively high incidence of acute adverse effects--these were greatly reduced with the introduction of the sustained release formulation. Serum concentrations of most electrolytes have not shown any consistent adverse trends and hyperuricaemia and hypokalaemia have been encountered infrequently. Thus, piretanide appears to offer an effective alternative to other 'loop' diuretics for the treatment of oedematous diseases and to hydrochlorothiazide for the management of mild to moderate hypertension. However, its relative place in therapy remains to be clarified with wider clinical experience.

Brotizolam. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an hypnotic.

Brotizolam is a new thienotriazolodiazepine derivative with a pharmacological profile similar to that of benzodiazepines. It is indicated for use as an hypnotic in the management of insomnia, although it also has anticonvulsant, antianxiety and muscle relaxant properties in animals. In clinical trials brotizolam 0.125 to 0.5mg improved sleep in insomniacs similarly to nitrazepam 2.5 and 5mg, flunitrazepam 2mg and triazolam 0.25mg, whilst brotizolam 0.5mg was shown to be superior to flurazepam 30mg in some studies. Brotizolam is an effective hypnotic for hospital patients awaiting surgery, in whom it also reduces anxiety. Brotizolam has an elimination half-life of about 5 hours, which is 'intermediate' compared with the shorter-acting hypnotic, triazolam, and longer-acting benzodiazepines. Consequently, it is able to induce sleep without producing early morning rebound insomnia, and can also maintain sleep throughout the night. Brotizolam at dosages below 0.5mg at night usually produced minimal morning drowsiness; no residual impairment of psychomotor performance occurs following dosages within the recommended range of 0.125 to 0.25 mg/kg. No serious side effects have been reported to date and the most frequently observed adverse experiences are drowsiness, headache and dizziness. Mild rebound insomnia may occur in some patients when treatment is stopped. Thus, brotizolam is a useful hypnotic which can be used in patients who have difficulty in falling asleep and also in patients who are troubled by night-time awakenings. Used in the recommended dosage it may be particularly useful for patients in whom daytime impairment of performance is unacceptable.

Sulconazole. A review of its antimicrobial activity and therapeutic use in superficial dermatomycoses.

Sulconazole is a substituted imidazole antimicrobial agent structurally related to other drugs in this group. It possesses a broad spectrum of activity in vitro against dermatophytes, yeasts and some Gram-positive bacteria. The efficacy and safety of sulconazole 1% cream has been demonstrated in controlled clinical studies in patients with superficial dermatophyte or yeast infections. In these trials, sulconazole generally displayed similar efficacy to clotrimazole, econazole and miconazole, although in a few studies sulconazole produced better and/or quicker improvement than clotrimazole or miconazole in small numbers of patients with tinea pedis. Further studies in larger groups of patients are needed to confirm these encouraging preliminary findings. Thus, sulconazole is an effective and well tolerated alternative to other topical imidazole drugs in the treatment of superficial fungal infections of the skin.

Calcipotriol. A review of its pharmacological properties and therapeutic use in psoriasis vulgaris.

Calcipotriol (calcipotriene) is a vitamin D3 analogue which inhibits epidermal cell proliferation and enhances cell differentiation. In patients with chronic plaque psoriasis involved in short term studies of 6 to 8 weeks' duration, calcipotriol ointment applied twice daily was significantly more effective than betamethasone valerate and dithranol (anthralin). Pooled data from clinical trials show that calcipotriol is well tolerated, with the majority of adverse events being mild and transient local reactions. Topically applied calcipotriol has low hypercalcaemic potential and, in contrast to topical corticosteroids, oral retinoids and orally administered calcitriol, methotrexate and cyclosporin, calcipotriol does not appear to be associated with a risk of serious adverse events. Thus, at this early stage in its clinical development, calcipotriol appears to be an effective and well tolerated topical therapy for the management of psoriasis; if promising preliminary clinical findings are confirmed, calcipotriol will represent a major advance in this difficult area of therapeutics.

Controlled release metoprolol formulations. A review of their pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and ischaemic heart disease.

Conventional formulations of metoprolol have become well established in cardiovascular medicine and are particularly useful in the management of hypertension and ischaemic heart disease. Recently developed controlled release metoprolol delivery systems (metoprolol CR/ZOK and metoprolol OROS) were designed to overcome the drug delivery problems of matrix-based sustained release forms by releasing the drug at a relatively constant rate over a 24-hour period, and thus producing sustained and consistent metoprolol plasma concentrations and beta 1-blockade while retaining the convenience of once daily administration. Clinically and statistically significant reductions in blood pressure have been observed with metoprolol CR/ZOK and metoprolol OROS 24 hours after administration in mildly or moderately hypertensive patients. Studies in patients with mild to moderate hypertension have demonstrated that a similar or higher percentage of patients achieved a goal response with metoprolol CR/ZOK compared with matrix-based sustained release formulations of metoprolol, or conventional atenolol or bisoprolol, while metoprolol OROS achieved an equal or greater response rate compared with conventional or matrix-based sustained release metoprolol preparations. In patients with stable effort angina pectoris, once daily administration of metoprolol CR/ZOK provided at least equal antianginal efficacy as conventional metoprolol in divided doses, while metoprolol OROS reduced the mean number of anginal attacks by the same margin as atenolol. Controlled release metoprolol formulations have been well tolerated in clinical trials. Metoprolol CR/ZOK was associated with a similar or lesser degree of adverse effects related to the central nervous system compared with atenolol or long acting propranolol. Metoprolol CR/ZOK also demonstrated less pronounced beta 2-mediated bronchoconstrictor effects than atenolol in asthmatics, and less general fatigue and leg fatigue in healthy subjects. Metoprolol OROS produced less pronounced bronchoconstrictor effects than atenolol, matrix-based sustained release metoprolol or long acting propranolol in patients with asthma or obstructive airways disease, and healthy volunteers. These results are presumably due to the beta 1-selectivity of metoprolol in addition to the relatively low plasma concentrations maintained by metoprolol CR/ZOK and metoprolol OROS, and the avoidance of high peak plasma concentrations with these agents. Despite the relative safety of the controlled release forms of metoprolol, the use of all beta-adrenoceptor antagonists should be avoided in patients with a history of bronchospasm. Thus, controlled release metoprolol formulations offer the potential to maximise the confirmed benefits of this agent in the management of hypertension and angina, by maintaining clinically effective plasma concentrations within a narrow therapeutic range over a 24-hour dose interval.

Sumatriptan. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the acute treatment of migraine and cluster headache.

Sumatriptan is a serotonin1 (5-HT1) receptor agonist, which is effective in the acute treatment of migraine headache. Its antimigraine activity is believed to derive from selective vasoconstriction of cranial blood vessels which are dilated and distended during migraine headache and/or from inhibition of neurogenically mediated inflammation in the dura mater. In placebo-controlled comparative studies, sumatriptan reduced migraine headache from 'moderate or severe' to 'mild or none' within 2 hours in 50 to 73% of patients following oral administration of 100 or 200 mg, and within 1 hour in 70 to 80% of patients following subcutaneous doses of 6 to 8 mg or intranasal doses 20 mg into each nostril. In addition, sumatriptan alleviated the accompanying symptoms of nausea, vomiting, and photophobia/phonophobia more effectively than placebo, and permitted higher percentages of patients to resume normal daily activities. Sumatriptan 100 mg orally was more effective in the acute treatment of migraine than oral combination therapy consisting of ergotamine 2 mg plus caffeine 200 mg or aspirin 900 mg plus metoclopramide 10 mg. Pooled data from nearly 5000 patients treated with either oral or subcutaneous sumatriptan in clinical trials indicate that it is well tolerated. However, migraine recurrence within 24 or 48 hours of initial symptom resolution developed in approximately 40% of patients treated with sumatriptan, irrespective of route of administration. It is likely that migraine recurrence is related to the short half-life of the drug (approximately 2 hours). Future studies should attempt to ascertain whether additional doses of sumatriptan will help prevent migraine recurrence in patients with attacks of long duration and if so, should determine the optimum interval between dosages. In conclusion, sumatriptan is an important addition to the range of drugs currently available for acute treatment of migraine. It provides rapid relief from debilitating symptoms in a high percentage of patients, particularly after subcutaneous administration. At this stage in its development a number of questions remain to be answered - most notably whether repeat doses will help prevent recurrent attacks and which patients are most likely to respond to therapy. Nevertheless, sumatriptan presently offers a combination of efficacy and tolerability that is unique in this particular clinical setting.

Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential.

Clarithromycin is an acid-stable orally administered macrolide antimicrobial drug, structurally related to erythromycin. It has a broad spectrum of antimicrobial activity, similar to that of erythromycin and inhibits a range of Gram-positive and Gram-negative organisms, atypical pathogens and some anaerobes. Significantly, clarithromycin demonstrates greater in vitro activity than erythromycin against certain pathogens including Bacteroides melaninogenicus, Chlamydia pneumoniae, Chlamydia trachomatis, Mycobacterium chelonae subspecies--chelonae and--abscessus, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium avium complex, Legionella spp. and, when combined with its 14-hydroxy metabolite, against Haemophilus influenzae. However, bacterial strains resistant to erythromycin are also generally resistant to clarithromycin. The antimicrobial activity of clarithromycin appears to be enhanced by the formation in vivo of the microbiologically active 14-hydroxy metabolite. In combination, additive or synergistic activity against a variety of pathogens including Haemophilus influenzae, Moraxella catarrhalis, Legionella species (principally Legionella pneumophila) and various staphylococci and streptococci has been demonstrated. Clarithromycin has a superior pharmacokinetic profile to that of erythromycin, allowing the benefits of twice daily administration with the potential for increased compliance among outpatients where a more frequent regimen for erythromycin might otherwise be indicated. The clinical efficacy of clarithromycin has been confirmed in the treatment of infections of the lower and upper respiratory tracts (including those associated with atypical pathogens), skin/soft tissues, and in paediatrics. Clarithromycin was as effective as erythromycin and other appropriate drugs including beta-lactams (penicillins and cephalosporins) in some of the above infections. A most promising indication for clarithromycin appears to be in the treatment of immunocompromised patients infected with M. avium complex, M. chelonae sp. and Toxoplasma sp. Small initial trials in this setting reveal clarithromycin alone or in combination with other antimicrobials to be effective in the eradication or amelioration of these infections. Noncomparative studies have provided preliminary evidence for the effectiveness of clarithromycin in the treatment of infections of the urogenital tract, oromaxillofacial and ophthalmic areas. However, the promising in vitro and preliminary in vivo activity of clarithromycin against Mycobacterium leprae and Helicobacter pylori warrant further clinical trials to assess its efficacy in patients with these infections. Despite the improved pharmacokinetic profile and in vitro antimicrobial activity of clarithromycin over erythromycin, comparative studies of patients with community-acquired infections reveal the 2 drugs to be of equivalent efficacy. However, clarithromycin demonstrates greater tolerability, principally by inducing fewer gastrointestinal disturbances.(ABSTRACT TRUNCATED AT 400 WORDS)

Tenoxicam. An update of its pharmacology and therapeutic efficacy in rheumatic diseases.

Tenoxicam administered orally, rectally or parenterally is an effective analgesic and anti-inflammatory agent for the symptomatic treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and various rheumatic conditions such as tendinitis, bursitis, sciatica, back pain and gouty arthritis. In clinical trials its efficacy is at least equivalent to that of other NSAIDs and it is at least as well tolerated as piroxicam and probably better tolerated than diclofenac, indomethacin and ketoprofen. Compared with many other NSAIDs, tenoxicam offers certain advantages in that it is conveniently administered once daily and dosage adjustment is not required in the elderly or in patients with renal or hepatic impairment.

Doxacurium. A review of its pharmacology and clinical potential in anaesthesia.

Doxacurium, a benzylisoquinolinium diester, provides nondepolarising neuromuscular blockade (and thus surgical relaxation), without vagolytic or sympathomimetic effects. At equipotent doses, the duration of action of doxacurium is similar to that of the long-acting neuromuscular blocker pancuronium. Supplemental doses of doxacurium administered at approximately 25% recovery reliably increase the depth and duration of neuromuscular blockade without accumulation. Although patients will recover spontaneously from doxacurium neuromuscular blockade, pharmacological reversal with neostigmine is recommended in line with accepted clinical practice, and permits acceleration of recovery when necessary. Doxacurium may also be used to facilitate endotracheal intubation. However, even with large doses onset of action is delayed, suggesting more rapidly acting neuromuscular blocking agents will be preferred when rapid sequence induction and intubation is required. Doxacurium has been successfully used in children, the elderly, and in patients with renal failure, hepatic failure, or cardiovascular disease. The absence of clinically significant effects on cardiovascular parameters and relative lack of histamine release observed in clinical trials indicates that doxacurium is suitable for use in high-risk patient groups. Thus, while there are only a limited number of studies comparing doxacurium with other nondepolarising neuromuscular blockers, particularly other 'cardiostable' agents, its ability to produce sustained effective muscle relaxation without significantly affecting the cardiovascular system or inducing histamine release would seem to make it a preferred agent for surgery of longer duration, particularly in high-risk patient groups.

Paroxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness.

Paroxetine is a potent and selective inhibitor of the neuronal reuptake of serotonin, thereby facilitating serotoninergic transmission; this action appears to account for the antidepressant activity observed with this drug. A mean terminal elimination half-life of approximately 24 hours permits once daily administration. Results of short term clinical trials have shown paroxetine to be significantly superior to placebo, and comparable to amitriptyline, clomipramine, imipramine, dothiepin and mianserin in relieving symptoms associated with major depressive disorders. Paroxetine has shown some preliminary promise in the treatment of depressive illness resistant to tricyclic antidepressant therapy but further studies are required before any conclusions can be drawn. Paroxetine in therapeutic doses has been very well tolerated, and the favourable tolerability profile of this agent appears to be its primary advantage over traditional antidepressant agents. Paroxetine causes minimal anticholinergic-type adverse effects, and unlike tricyclic antidepressants, it does not precipitate cardiovascular effects or provoke cardiac conduction disturbances. Nausea has been the most frequently reported adverse event during short term use of paroxetine, but it is generally mild and transient and subsides with continued use. With longer term use headache, sweating and constipation were the most frequently reported side effects but the incidence rate was not significantly different from that noted for comparator antidepressants. Furthermore, the frequency of withdrawal due to adverse effects is less with paroxetine than with tricyclic antidepressant agents. Overall, available data appear to indicate that while the efficacy of paroxetine is similar to that of traditional antidepressant drugs, the newer agent possesses much improved tolerability. In addition, the wide therapeutic index of paroxetine may be beneficial when treating patients with an increased risk of suicide. Thus, paroxetine clearly looks to become a valuable addition to the range of drugs currently available to treat depressive illness. Future research may help to further define the relative place of this newer agent in antidepressant therapy and determine how its overall therapeutic efficacy compares with that of other related antidepressant agents such as fluoxetine.

Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis.

The pyrophosphate analogue, foscarnet, selectively inhibits the DNA polymerase of human herpes viruses, including cytomegalovirus, and the reverse transcriptase of HIV. Viral replication is therefore prevented, but resumes when the drug is cleared from infected cells. In vitro, the combination of foscarnet and zidovudine (azidothymidine) has an additive effect against cytomegalovirus and acts synergistically against HIV. An improvement in cytomegalovirus retinitis is obtained in over 85% of affected AIDS patients during foscarnet induction therapy, but relapse usually occurs within a month of ceasing treatment. There is a similar duration of remission during maintenance therapy given for 5 days each week, but this can be extended 4- to 5-fold with daily administration of higher doses. In allograft recipients, progression of retinitis can be halted by foscarnet until immune function recovers and eradicates the virus. The incidence of acute renal failure, which is common during foscarnet therapy, may be reduced by dosage adjustment and adequate prehydration. Anaemia, phlebitis, nausea and vomiting, and disturbances in serum calcium and phosphate levels, perhaps resulting from uptake of foscarnet into bone or chelation with ionised calcium, have also been associated with administration of the drug. Cytomegalovirus retinitis is difficult to treat, with few therapeutic options available. Although treatment with foscarnet produces some severe adverse effects, with care these can be minimised, and the drug produces clinical improvement in a large proportion of patients; this is a highly encouraging finding at this stage in its development. Preliminary comparative data indicate that foscarnet and ganciclovir are similarly effective, but foscarnet may have some theoretical advantages in AIDS patients since it can be used in combination with zidovudine without potentiating myelosuppression.