Clinical pharmacology and pharmacokinetic properties of topically applied corticosteroids. A review.

The development of topical corticosteroids since the 1950s has opened new doors for dermatologists previously faced with treating intractable dermatoses, so that the pharmacology of topically applied corticosteroids is now reasonably well described. Manipulation of the steroid molecule has produced compounds with greater lipophilicity, fewer mineralocorticoid properties and high potency. Potency is determined through various techniques, notably the vasoconstrictor assay as well as the mitotic index suppression method and atrophogenic potential assay. The mechanism of activity of corticosteroids is thought to result, at least in part, from binding of the drug to steroid receptors, with resultant effects on the synthesis of proteins responsible for specific effects. Corticosteroids are proposed to alter the inflammatory response, and thus provide therapeutic benefits, via actions on mediator release and function, inflammatory cell function and release of lysosomal enzymes. Disadvantages of corticosteroid activity include the possibility of adrenal suppression, epidermal and dermal thinning, and local effects such as purpura, striae, and steroid-induced rosacea and perioral dermatitis. The cutaneous pharmacokinetics, particularly of absorption of topical corticosteroids, must be examined in parallel with their pharmacodynamic effects to gain a more complete understanding of activity. Many factors can affect percutaneous steroid absorption: drug lipophilicity and solubility, drug concentration, anatomical site, age of the patient, presence of skin disease and use of occlusive dressings will each influence the degree to which topically applied corticosteroids achieve their intended therapeutic results. Cutaneous metabolism is a poorly understood process at present, but one which is acknowledged to have some impact on the biotransformation of corticosteroids applied topically. Thus, although some gaps still persist in present knowledge of the pharmacology and pharmacokinetics of this important class of drugs, there can be no denying the contribution of topical corticosteroids to the therapy of dermatoses.

Granisetron. A review of its pharmacological properties and therapeutic use as an antiemetic.

Granisetron (BRL 43694) is a highly selective 5-HT3 receptor antagonist which possesses significant antiemetic activity, likely mediated through antagonism of 5-HT3 receptors on abdominal vagal afferents and possibly in or near the chemoreceptor trigger zone. Clinical trials in cancer patients demonstrate that, compared with placebo, granisetron significantly reduces the incidence of nausea and vomiting for 24 hours after administration of high-dose cisplatin. In large comparative trials, 70% of patients who received granisetron prior to cisplatin or other chemotherapy experienced complete inhibition of vomiting with little or no nausea for 24 hours after antineoplastic administration; these results were similar to those obtained with high-dose metoclopramide plus dexamethasone, and superior to a combination of chlorpromazine plus dexamethasone, or prochlorperazine plus dexamethasone, or methylprednisolone monotherapy. The most frequently reported adverse event associated with granisetron administration is headache which occurs in about 10 to 15% of patients while constipation, somnolence, diarrhoea and minor transient changes in blood pressure have been reported less frequently. Extrapyramidal effects, which can occur with high-dose metoclopramide and may be a limiting factor in its use, have not been noted with granisetron administration. Thus, granisetron is an effective, well tolerated and easily administered agent for the prophylaxis of nausea and vomiting induced by cancer chemotherapy which appears to be devoid of extrapyramidal side effects associated with metoclopramide. As a member of a new class of drugs, the selective 5-HT3 receptor antagonists, granisetron provides the medical oncologist with a new, potentially more acceptable antiemetic therapy.

Levocabastine. A review of its pharmacological properties and therapeutic potential as a topical antihistamine in allergic rhinitis and conjunctivitis.

Levocabastine is a long acting, highly potent and selective histamine H1-receptor antagonist, which has been developed for nasal and ocular administration. In controlled trials performed to date levocabastine was effective and well tolerated in the treatment of allergic rhinitis and allergic conjunctivitis. Comparative studies have demonstrated that levocabastine is superior to placebo and at least as effective as sodium cromoglycate (cromolyn sodium) in alleviating symptoms associated with seasonal allergic conditions. Although levocabastine appears to be less effective than the topical corticosteroid beclomethasone with regard to relieving runny and blocked nose, further comparative trials between these 2 agents would be desirable. Similar to other antihistamines, levocabastine provides minimal relief of nasal blockage, but this symptom is believed to be mediated by receptors other than histamine H1. The prompt onset of antiallergic activity after application differentiates levocabastine from the reference topical antiallergic, sodium cromoglycate, which has an onset of efficacy characterised by a lag period, thereby necessitating maintenance treatment. The incidence of adverse effects associated with levocabastine therapy is low and is similar to that observed with placebo and sodium cromoglycate. Levocabastine provides prophylactic protection as well as acute relief from nasal and ocular symptoms in patients with seasonal allergic disorders. With the ever increasing trend towards topical therapy for the treatment of allergic rhinitis and allergic conjunctivitis, levocabastine is a useful addition to the range of drugs currently available. Possible avenues for additional research should include determining whether the antiallergic efficacy of topical levocabastine is superior to that of oral agents such as astemizole and terfenadine, and whether topical therapy is indeed preferred, considering the relative ease of administration of effective oral antiallergic agents.

Goserelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical use in sex hormone-related conditions.

Goserelin is a synthetic analogue of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH); or gonadorelin] which stimulates gonadotrophin and sex hormone release in the short term, and then causes suppression with continued administration. Goserelin is given as a subcutaneous biodegradable depot incorporating 3.6 mg of the drug, which is released continuously at an average rate of 120 micrograms/day over 4 weeks. Monthly goserelin depot therapy produces partial disease remission or stabilisation in about 75% of men with previously untreated prostatic cancer, a rate equivalent to that achieved with orchidectomy or diethylstilbestrol (stilboestrol). The response to goserelin is more rapid than to diethylstilbestrol, and goserelin is better tolerated. About 30 to 45% of premenopausal women with breast cancer responded to goserelin using objective assessment criteria, suggesting comparability to ovariectomy. In benign hormone-dependent conditions, preoperative goserelin aids surgical removal of uterine leiomyoma (fibroids) and reduces blood loss, and 6 months of therapy relieves the signs and symptoms of endometriosis. The elevation in testosterone at the beginning of goserelin therapy can result in disease 'flare' in men with prostate cancer, and sex steroid suppression with continued treatment results in hot flushes and loss of libido in most patients. Thus, goserelin is an effective alternative to surgery or estrogen therapy in prostatic cancer palliation, and possibly to ovariectomy in premenopausal breast cancer. Other gynaecological conditions reliant on the pituitary-gonadal axis also appear amenable to hormone manipulation with goserelin.

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

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

Nafarelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical potential in sex hormone-related conditions.

Nafarelin, a synthetic agonist of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LH-RH); gonadorelin] appears likely to join the other GnRH analogues currently used in a range of conditions reliant on gonadotrophins or sex hormones. With repeated administration, the pituitary becomes desensitised, and gonadotrophin release, and therefore sex hormone synthesis, are inhibited. Nafarelin has proved to be comparable to danazol in the management of women with endometriosis, with fewer potentially harmful adverse effects. Nafarelin has also been used effectively in in vitro fertilisation programmes, and in hirsute women and those with uterine leiomyoma, particularly to induce preoperative fibroid shrinkage. The drug shrinks hypertrophic tissue in men with benign prostatic hyperplasia, although treatment would need to be maintained indefinitely and therefore should probably be reserved for those unsuitable for prostatectomy. Preliminary data suggest that nafarelin is equivalent to diethylstilbestrol (stilboestrol) in terms of disease-free survival in men with prostate cancer. As a reliable method of contraception, nafarelin gives unpredictable results in men and the promising results in women may be offset by hypoestrogenic side effects. Nafarelin may join other GnRH agonists which are now routinely used in the management of children with central or combined precocious puberty. Nafarelin is readily and rapidly absorbed following intranasal delivery, and is protected to some extent from enzymatic degradation. The resultant relatively long elimination half-life allows once- or twice-daily administration. Estrogen depletion accounts for the most common side effects associated with nafarelin, including hot flushes and vaginal dryness, which are mild and tolerable in most patients. Reversible resorption of trabecular bone can occur during nafarelin therapy, perhaps necessitating cyclical treatment to enable bone mass to recover. Nafarelin, therefore, looks likely to find a role in the treatment of women with endometriosis, and results achieved in other conditions dependent on the pituitary-gonadal axis are promising.

Dilevalol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in hypertension.

Dilevalol, the RR-stereoisomer of labetalol, is a non-cardioselective beta-adrenoceptor antagonist with substantial partial beta 2-agonist and negligible alpha 1-blocking activity. Reduction in blood pressure during dilevalol administration is associated with peripheral vasodilatation, and heart rate remains essentially unchanged. Following oral administration, dilevalol is completely absorbed. Once-daily administration is possible, due to a long elimination half-life. Large well-controlled trials reveal that dilevalol is equivalent in antihypertensive efficacy to metoprolol, the ACE inhibitors captopril and enalapril, and the calcium antagonist nifedipine. Smaller noncomparative and comparative trials demonstrate the blood pressure-lowering effects of dilevalol and suggest an efficacy at least equivalent to that of the 'pure' beta-blockers atenolol and propranolol and the alpha 1-blockers urapidil and doxazosin. Dilevalol appears to be well tolerated, the most frequent adverse effects being dizziness, headache and diarrhoea in only about 7% of patients each. Unlike alpha 1-blockers and labetalol, dilevalol is not commonly associated with orthostatic hypotension. Thus, data suggest that dilevalol, with its distinctive pharmacological profile, is likely to be a useful addition to the options currently available for treating patients with mild to moderate essential hypertension.

Flumazenil. A preliminary review of its benzodiazepine antagonist properties, intrinsic activity and therapeutic use.

Flumazenil, a 1,4-imidazobenzodiazepine, is a specific benzodiazepine antagonist which is indicated for use when the effect of a benzodiazepine must be quickly attenuated or terminated. Following intravenous administration, the onset of clinically apparent benzodiazepine antagonism usually occurs within 1 to 5 minutes. Although flumazenil has a short elimination half-life of about 1 hour, a single intravenous dose of up to 1 mg is usually sufficient to attain and maintain for about 2 hours the desired level of consciousness after general anaesthesia or conscious to moderate sedation induced by benzodiazepines. After intoxication with high doses of benzodiazepines the initial single dose of flumazenil will require supplementing with repeated low intravenous doses or an infusion (0.1 mg/h) to maintain a state of wakefulness. Flumazenil is well tolerated, and since it reliably attenuates or reverses the central effects of benzodiazepines and is specific for these drugs, it facilitates diagnosis by eliminating benzodiazepine intoxication in patients in whom the cause of unconsciousness is unknown. While results of some studies suggested that flumazanil may have intrinsic benzodiazepine partial agonist or inverse agonist activity, this is unlikely to be clinically important with usual doses. Thus, flumazenil is a very promising, effective, short acting benzodiazepine antagonist which is well tolerated by most patients. Undoubtedly, its full clinical potential has yet to be realised.

Quazepam. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in insomnia.

Quazepam is a trifluoroethyl benzodiazepine hypnotic with a half-life of 27 to 41 hours, which has been shown to induce and maintain sleep in the short to long term (up to 4 weeks) treatment of patients with chronic or transient insomnia. Although its hypnotic efficacy has been well characterised against placebo, there are few clinical studies in comparison with established hypnotics, particularly over long term administration. However, preliminary evidence suggests that quazepam 15 to 30 mg is as effective as flurazepam and triazolam in usual therapeutic doses, and causes minimal rebound insomnia following its withdrawal, unlike rapidly eliminated benzodiazepines such as triazolam. The lack of rebound phenomena is likely to be attributable to the 'carryover' effects occurring after discontinuation of quazepam, which has pharmacologically active metabolites with half-lives of elimination similar to or longer than that of the parent drug. Probably because of the long half-lives of quazepam's metabolites, daytime sedation, fatigue and lethargy are the most frequently reported side effects. These side effects are most intense with the 30 mg dose and least with the 7.5mg dose, which has not been studied extensively. Hence, quazepam is an effective hypnotic which may be particularly suitable for short or medium term use in patients in whom withdrawal effects or rebound insomnia may be especially bothersome. Further definition of certain characteristics of its profile--such as its long term use and potential for development of tolerance or dependence, effects on psychomotor skills, efficacy of the 7.5mg dose, and suitability in elderly patients and patients with chronic organic diseases--will assist in more clearly defining its ultimate place in therapy.

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

Zopiclone is the first of the cyclopyrrolones, a new class of psychotherapeutic agents possessing a pharmacological profile of high efficacy and low toxicity similar to that of the benzodiazepines. Binding is thought to occur to the benzodiazepine receptor complex, or to a site closely linked to this complex. Although zopiclone exhibits anticonvulsant, muscle relaxant and anxiolytic properties in animals, it finds better use as an hypnotic because of marked sedating effects. In clinical trials, zopiclone (usually 7.5 mg) improved sleep in chronic insomniacs similarly to nitrazepam 5 mg, flurazepam 15 to 30 mg, triazolam 0.5 mg and temazepam 20 mg, but in a single study was slightly less effective than flunitrazepam 2 mg in some evaluation criteria. Sleep induction before surgical procedures in hospitalised patients is satisfactory with zopiclone, but when the drugs are administered a few hours before surgery, diazepam appears to be more effective in alleviating preoperative anxiety. Minimal impairment of psychomotor skills and mental acuity occurs in the morning after a bedtime dose of zopiclone, which has a short half-life of about 5 hours and no long acting metabolites. No serious side effects have been reported in the relatively small number of patients studied to date; the development of 'bitter taste' does not deter patients from continuing therapy. Thus, with its short duration of action zopiclone is a useful alternative to other hypnotics, especially in patients intolerant of residual effects the morning after taking an hypnotic.

Buspirone. A preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic.

Buspirone hydrochloride (HCl)1 is a new anxiolytic with a unique chemical structure. Its mechanism of action remains to be elucidated. Unlike the benzodiazepines, buspirone lacks hypnotic, anticonvulsant and muscle relaxant properties, and hence has been termed 'anxioselective'. As evidenced by a few double-blind clinical trials, buspirone 15 to 30 mg/day improves symptoms of anxiety assessed by standard rating scales similarly to diazepam, clorazepate, alprazolam and lorazepam. Like diazepam, buspirone is effective in patients with mixed anxiety/depression, although the number of patients studied to date is small. In several studies, a 'lagtime' of 1 to 2 weeks to the onset of anxiolytic effect has been noted; hence motivation of patient compliance may be necessary. Sedation occurs much less often after buspirone than after the benzodiazepines; other side effects are minor and infrequent. In healthy volunteers, buspirone does not impair psychomotor or cognitive function, and appears to have no additive effect with alcohol. Early evidence suggests that buspirone has limited potential for abuse and dependence. Thus, although only wider clinical use for longer periods of time will more clearly define some elements of its pharmacological profile, with its low incidence of sedation buspirone is a useful addition to the treatments available for generalised anxiety. It may well become the preferred therapy in patients in whom daytime alertness is particularly important.

Defibrotide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders.

Defibrotide is a deoxyribonucleic acid derivative extracted from mammalian organs, which has been developed for the treatment of a number of vascular disorders. It appears to increase fibrinolysis and may possess antithrombotic, antiatherosclerotic and anti-ischaemic actions, probably due to its ability to selectively increase prostaglandin I2 and E2 levels and to increase tissue plasminogen activator and decrease plasminogen activator inhibitor function. Defibrotide is available as an intravenous and intramuscular preparation, and also as an oral formulation for long term use. Trials performed to date have provided initial evidence that defibrotide is effective in the treatment of peripheral obliterative arterial disease and acute thrombophlebitis, while preliminary data suggest possible use in preventing fibrin deposition in the circuitry of renal haemodialysis equipment. Efficacy in preventing deep vein thrombosis after surgery has been demonstrated but defibrotide does not appear to offer any therapeutic advantage over heparin. Further clinical experience is required in other disorders, including acute myocardial infarction, Raynaud's phenomenon, renal thrombotic microangiopathy and renal transplant rejection, before adequate assessment of efficacy in these areas can be made. Defibrotide is well tolerated, as assessed in trials of up to 6 months duration, with a low global incidence of adverse events (< 1 to 9%). Mild allergic reactions and gastrointestinal disturbances have occasionally been described, and a hypotensive effect has also infrequently been observed. Thus, available data suggest that defibrotide is a well tolerated agent with little or no anticoagulant activity, which is conveniently available in both parenteral and oral formulations. Initial data indicate that the drug may be a useful alternative in the treatment of peripheral obliterative arterial disease and thrombophlebitis, while its therapeutic potential in other vascular disorders and efficacy relative to established agents remains to be fully determined.

Tamoxifen. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic use.

Tamoxifen, a non-steroidal antioestrogen, represents a significant advance in treatment of female breast cancer. In trials of tamoxifen as postsurgical adjuvant treatment of early breast cancer, disease-free survival is consistently prolonged, representing an enhanced quality of life in association with tamoxifen's favourable adverse effect profile. Moreover, overview analysis indicates a survival benefit of approximately 20% at 5 years for all women, most clearly evident in women over 50 years, while a survival benefit independent of menopausal, nodal or oestrogen receptor status has been demonstrated in some individual trials. Thus, for postmenopausal women, tamoxifen is clearly optimal adjuvant treatment, although the relative benefit of adjuvant chemotherapy in node-negative patients requires clarification. A survival benefit for women under 50 has not been clearly demonstrated in overview analysis, but is not precluded by these rather limited data, and adjuvant treatment of premenopausal women with tamoxifen may also warrant serious consideration. Response rates to tamoxifen in advanced breast cancer are around 30 to 35%, increasing with patient selection for oestrogen receptor positivity. Tamoxifen must be regarded as first-line endocrine treatment in postmenopausal women, and may represent an alternative to first-line ovarian ablation in premenopausal women. An emergent role in primary therapy of elderly and frail patients with operable disease is apparent. Tamoxifen is also of benefit following surgery in male breast cancer, and may have a role as first-line endocrine treatment. Tamoxifen also has a potential role in other hormone-sensitive malignancies such as pancreatic carcinoma, and in treatment of benign breast disease. Finally, tamoxifen has a place in treatment of male and female infertility. because of adverse effects is rarely necessary. The most frequent adverse effects are related to the drug's anti-oestrogenic activity, and include hot flushes, nausea and/or vomiting, vaginal bleeding or discharge, and menstrual disturbances in premenopausal patients. Thus, tamoxifen continues to play a major role in management of female breast cancer in both early and advanced stages of disease, with a place also in treatment of male breast cancer and of infertility.

Benazepril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension and congestive heart failure.

Benazepril is a nonsulfhydryl ACE inhibitor prodrug, which is converted in vivo to its active form, benazeprilat. Data from clinical studies have indicated that benazepril 5 to 80 mg (usually 10 to 20 mg), administered as a single daily dose, effectively decreases blood pressure in patients with mild to moderately severe hypertension. In a small number of comparative studies, the anti-hypertensive efficacy of benazepril appeared to be at least equivalent to that of captopril, enalapril, hydrochlorothiazide, nifedipine, nitrendipine or propranolol at usual therapeutic doses. Combinations of benazepril and hydrochlorothiazide or nifedipine achieved a greater lowering of blood pressure than benazepril alone, and this approach may be suitable for patients with more severe hypertension. Benazepril is reported to have beneficial effects on various indices of cardiac function and to improve clinical symptoms and exercise capacity in patients with congestive heart failure. The tolerability of benazepril in clinical trials has been very good, with an incidence of adverse effects similar to that observed in placebo recipients. Thus, benazepril appears to be an effective alternative to other members of its class for the management of hypertension, and further studies will accurately define its usefulness in congestive heart failure.

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

Citalopram is an antidepressant belonging to a new class of drugs which enhance serotoninergic neurotransmission through potent and selective inhibition of serotonin reuptake. Preliminary trials suggest that its short term therapeutic efficacy is significantly greater than that of placebo and mianserin, and comparable to that of amitriptyline, maprotiline and imipramine. It appears to be a weaker antidepressant agent than clomipramine, but better tolerated. Its elimination half-life of 33 hours permits once daily oral administration. Symptomatic improvement obtained with short term treatment has been maintained when therapy has been extended for up to 1 year; in the few patients studied for this extended period, the relapse rate was lower than with fluvoxamine, fluoxetine or imipramine. Compared to standard antidepressant agents, citalopram is well tolerated. It does not appear to be cardiotoxic, has not been associated with seizures in humans, and is relatively nonsedating. Unlike the tricyclic antidepressants, citalopram has minimal anticholinergic effects. Mild and transient nausea, with or without vomiting, is the most frequent adverse effect--occurring in 20% of patients--and increased perspiration, headache, dry mouth, tremor and insomnia are experienced by 15 to 18% of patients. Citalopram thus offers similar therapeutic efficacy and a more favourable tolerability profile than the tricyclic antidepressants. Preliminary data suggest that it may be particularly useful in patients who cannot tolerate the anticholinergic or cardiovascular side effects of tricyclic antidepressants and in those for whom sedation is not indicated.

Recombinant granulocyte colony-stimulating factor (rG-CSF). A review of its pharmacological properties and prospective role in neutropenic conditions.

Recombinant granulocyte colony-stimulating factor (rG-CSF) is a glycoprotein hormone which has been produced in mammalian cells and, in a nonglycosylated form, in the bacterium Escherichia coli through recombinant DNA technology. It stimulates proliferation, differentiation and activation of cells of the neutrophil-granulocyte lineage and has been investigated as therapy for patients with various neutropenic conditions, both iatrogenic and disease related. rG-CSF is well tolerated, the most frequently reported adverse effect being mild to moderate bone pain. A major use for rG-CSF therapy will be in ameliorating the neutropenia which follows cytoreductive chemotherapy. rG-CSF accelerates neutrophil recovery after chemotherapy, leading to a reduction in duration of the neutropenic phase. Consequently, infection rate is diminished, as is the associated usage of antibiotics and duration of hospitalisation. The implications are that rG-CSF may allow increased dose intensity and stricter adherence to chemotherapy schedules. The increase in neutrophils produced by rG-CSF renders it a useful treatment for conditions such as congenital, acquired and cyclic neutropenias for which current therapy is not very successful. rG-CSF may be an effective therapy in myelodysplasia, although there is concern about acceleration of the possible rate of conversion of this disease to acute myelogenous leukaemia. It is also likely that rG-CSF will be useful in accelerating the recovery of transplanted bone marrow in patients with leukaemia, lymphoma and solid tumour. Furthermore, there is great potential for expansion of the role of rG-CSF as monotherapy or in combination regimens with other cell factors in various haematological disorders such as aplastic anaemia. In summary, while many aspects of its use remain to be clarified, rG-CSF must be seen as an exciting advance in therapeutics. It should rapidly find an important place as an adjunct to cancer chemotherapy, and also appears to have substantial potential in a number of other neutropenic conditions which are currently difficult to treat.

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

Clodronate (clodronic acid, dichloromethylene bisphosphonate) is a bisphosphonate which has demonstrated efficacy in patients with a variety of diseases of enhanced bone resorption including Paget's disease, hypercalcaemia of malignancy and osteolytic bone metastases. In addition, early reports demonstrating potential efficacy of clodronate in the treatment of osteoporosis suggest a possible role in this debilitating disease. Short term intravenous administration (usually 300 mg/day for 5 days) or longer courses of oral clodronate (usually 1600 mg/day for 6 months) effectively reduced bone pain and/or improved mobility in most patients with Paget's disease, and these effects persisted for up to 12 months after discontinuing clodronate. When administered intravenously (300 mg/day for up to 12 days) to patients with malignant hypercalcaemia, serum calcium levels declined significantly within 2 days of starting treatment and approximately 70 to 95% of patients became normocalcaemic. While there is less experience with oral administration, clodronate (800 to 3200 mg/day) achieved normocalcaemia in the majority of patients, usually within 1 week, and serum calcium levels remained significantly reduced from baseline for up to 6 months with continued treatment. Clodronate is clearly superior to placebo and, based on a retrospective analysis, appears to produce greater and more sustained reductions in serum calcium levels than calcitonin in patients with malignant hypercalcaemia. The few available prospective comparative trials showed that clodronate is at least as effective as etidronate, but comparisons with alendronate and pamidronate produced results of questionable clinical relevance because of low bisphosphonate dosages used in these trials. Nevertheless, single intravenous doses of clodronate 600 mg or alendronate 7.5 mg (both agents repeated on day 3 if necessary) were comparable in efficacy, whereas a single intravenous dose of pamidronate 30 mg was more effective than a single intravenous dose of clodronate 600 mg. Normocalcaemic patients with osteolytic bone metastases due to advanced breast cancer experienced significant reductions in the number of episodes of hypercalcaemia and terminal hypercalcaemia, incidence of vertebral fractures and overall rate of morbid events, including the need for radiotherapy to treat bone-related pain, following treatment with clodronate 1600 mg/day for 3 years in a large placebo-controlled study. A similar large placebo-controlled trial in patients with multiple myeloma demonstrated that clodronate 2400 mg/day orally for 2 years significantly reduced progression of osteolytic bone lesions. Follow-up data from clinical trials revealed that the effects on development of fractures and hypercalcaemia persisted for at least 12 months after the drug was discontinued.(ABSTRACT TRUNCATED AT 400 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.

Fluoxetine: a review of its therapeutic potential in the treatment of depression associated with physical illness.

UNLABELLED: Fluoxetine is a potent and selective inhibitor of neuronal serotonin (5-hydroxytryptamine) reuptake. Fluoxetine reduces food, energy and carbohydrate intake and increases resting energy expenditure, which may account for the moderate and transient bodyweight loss observed with its use. Glucose tolerance and/or hypoglycaemia in patients with type 2 diabetes mellitus improve with fluoxetine therapy. The ability of fluoxetine to inhibit cytochrome P450 (CYP) isoenzymes (CYP2D6, CYP2C and CYP3A4), is potentially important for patients with physical illness who may be taking multiple concomitant medications. Fluoxetine was more effective than placebo in 2 double-blind, randomised trials, and according to limited data appears to be equally effective compared with other SSRIs and tricyclic antidepressants (TCAs), in the treatment of depression in patients with HIV/AIDS. The efficacy of fluoxetine is also superior to that of placebo in the treatment of depression in patients with diabetes mellitus and stroke as shown in double-blind randomised trials, although its efficacy relative to that of nortriptyline in stroke is uncertain. Fluoxetine had similar efficacy to that of desipramine in patients with cancer, with improved Hamilton Depression Rating Scale and quality-of-life scores from baseline; however, the drug was not more effective than placebo in a double-blind randomised trial. Medically healthy individuals tolerate fluoxetine well. Like other SSRIs, fluoxetine lacks the anticholinergic, cardiovascular, sedative and weight-increasing properties of TCAs, and is safer in overdose than TCAs and monoamine oxidase inhibitors. Rates of sexual dysfunction and suicidal ideation with fluoxetine appear similar to those seen with other SSRIs. CONCLUSION: Fluoxetine has shown superior efficacy compared with placebo in the treatment of depression in patients with HIV/AIDS, diabetes mellitus or stroke; however, it has not significantly improved depressive symptoms versus placebo in patients with cancer. The efficacy of fluoxetine appears similar to that of desipramine in patients with stroke, cancer or HIV, and is similar to that of sertraline or paroxetine in patients with HIV/AIDS; comparisons with nortriptyline give equivocal results. The potential for drug interactions with fluoxetine use should be carefully considered because most patients with comorbid physical illness will be receiving multiple comedications. Although fluoxetine has proved effective as an antidepressant in this population in several clinical trials, its drug interaction profile and long half-life are a potential limitation, and these properties should be carefully considered in relation to the status of each patient.

Zafirlukast: an update of its pharmacology and therapeutic efficacy in asthma.

UNLABELLED: Zafirlukast is a selective and competitive orally administered inhibitor of the cysteinyl leukotrienes LTC4, LTD4 and LTE4. The drug is indicated for the prophylaxis and treatment of chronic asthma, and has been developed in response to mounting evidence indicating the importance of the cysteinyl leukotrienes in the pathogenesis of this disorder. The efficacy of zafirlukast 20 mg twice daily has been shown in double-blind placebo-controlled studies of up to 13 weeks' duration in patients aged > or = 12 years. Zafirlukast was consistently superior to placebo in improving objective measures of lung function and subjective measures such as symptom scores and use of as-required bronchodilator therapy. This dosage is also as effective when added to low-dosage inhaled corticosteroid therapy as doubling of corticosteroid dosages. Recent studies indicate superior efficacy over zafirlukast of twice-daily inhaled fluticasone propionate 88 microg or salmeterol 42 microg, although zafirlukast was nevertheless associated with clinical improvement. Data also show zafirlukast 40 mg to be of similar efficacy to pranlukast 225 mg (both twice daily). Overall, preliminary pharmacoeconomic data suggest that healthcare costs are reduced by zafirlukast therapy, although superior cost effectiveness has been reported with inhaled fluticasone propionate. and further studies are needed. Data are available to show improvements in patient-rated quality of life, and preference for and high rates of compliance with zafirlukast. In clinical trials, zafirlukast has shown an adverse event profile similar to that of placebo. Isolated reports of hepatic dysfunction in a small number of individuals receiving the drug have been received, and recommendations for monitoring of patients are in place. Although no causal relationship has been established between zafirlukast and Churg-Strauss Syndrome, patients undergoing corticosteroid dosage reductions require careful surveillance. CONCLUSIONS: zafirlukast is an effective and well tolerated agent for preventive monotherapy in mild to moderate persistent asthma. Emerging data indicate benefit of the drug when added to low-dosage inhaled corticosteroids and show that it may be a viable alternative to inhaled adjunctive treatments and increased corticosteroid dosages in some patients. Although inhaled fluticasone propionate and salmeterol have been associated with greater clinical improvement than zafirlukast in clinical studies, compliance considerations and the confirmed clinical efficacy relative to placebo of the drug denote zafirlukast as an effective alternative in treatment programmes based on individualised therapy. As experience with zafirlukast accumulates, it is expected that the drug will be positioned more definitively in national and international treatment guidelines.