Lamotrigine. A review of its pharmacological properties and clinical efficacy in epilepsy.

Lamotrigine is an antiepileptic drug which is believed to suppress seizures by inhibiting the release of excitatory neurotransmitters. Efficacy has been demonstrated for lamotrigine as add-on therapy to existing regimens in patients with resistant partial seizures. Total seizure frequency was reduced by 17 to 59% compared with placebo, and 13 to 67% of patients experienced reductions of > or = 50% in seizure frequency. Secondarily generalised tonic-clonic seizures respond well to lamotrigine, and there is preliminary evidence of improvement in patients with primary generalised seizures, Lennox-Gastaut syndrome and in children with multiple seizure types. Seizure control has been maintained in patients who have continued to receive lamotrigine as monotherapy after discontinuation of other medications. Results of one trial suggest similar efficacy for lamotrigine monotherapy as for carbamazepine, but confirmation of its use in this setting awaits more extensive controlled comparisons with established agents. Adverse events associated with lamotrigine as add-on therapy are typical of antiepileptic drugs, namely dizziness, ataxia and other CNS-related symptoms. Rash, which has occurred in 10% of patients in placebo-controlled trials, may be severe and its appearance has led to discontinuation of therapy in 1% of patients. Lamotrigine appears well tolerated in the longer term, but this facet of its profile requires further monitoring. Influences of valproic acid and enzyme-inducing anti-epileptics on lamotrigine eliminate necessitate dosage modification of lamotrigine. Conversely, lamotrigine has little apparent influence on the pharmacokinetics of other agents, although it may increase plasma concentrations of the active metabolite of carbamazepine during concomitant administration. Thus, lamotrigine permits improved seizure control in some patients with refractory partial seizures, and may prove to be especially effective in secondarily generalised tonic-clonic seizures. As is usual at this stage in a drug's development, several aspects of the profile of lamotrigine are incompletely defined, notably its efficacy in other seizure types, in children, as monotherapy, and its longer term tolerability. Nonetheless, lamotrigine presently offers a worthwhile alternative for the physician confronted with the challenge of treating patients with intractable partial seizures with or without secondarily generalised seizures, and shows potential for broader applications in other areas of epilepsy management.

Nilutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer.

Nilutamide is a nonsteroidal antiandrogen with affinity for androgen receptors but not for progestogen, estrogen, or glucocorticoid receptors. Consequently, nilutamide blocks the action of androgens of adrenal and testicular origin which stimulate the growth of normal and cancerous prostatic tissue. Nilutamide has a long half-life which permits once-daily administration. Nilutamide is usually given in combination with surgical or chemical castration using gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH)] agonists. In castrated patients the addition of nilutamide improves objective response rates, bone pain, urinary symptoms, tumour markers and time to disease progression. The tolerance of nilutamide is generally acceptable. Adverse effects are usually mild and reversible and consistent with androgen depletion. Unexpected but reversible adverse effects of nilutamide include delayed adaption to dark after exposure to bright light, transient increases in transaminases, and more severe but rare interstitial pneumonitis. Thus, nilutamide is a welcome treatment option that may be particularly useful in patients to whom the convenience of once-daily administration is seen as a worthwhile benefit.

Moxonidine. A review of its pharmacology, and therapeutic use in essential hypertension.

Interest in centrally acting antihypertensive agents has recently been renewed with the development of drugs that are associated with fewer central adverse effects (e.g. sedation, dry mouth) than the older drugs in this class. Moxonidine reduces sympathetic outflow and hence lowers blood pressure through stimulation of central imidazoline receptors. Blood pressure is decreased by 10 to 20% during moxonidine treatment, with about 70% of patients with mild to moderate hypertension achieving a diastolic pressure of < 90mm Hg. The relatively few published comparative studies demonstrate that moxonidine has efficacy comparable with that of clonidine, prazosin, atenolol, nifedipine, captopril and hydrochlorothiazide. It is at least as well tolerated as these agents in trials and, importantly, appears to cause less sedation and dry mouth than clonidine. Compliance may be aided by the once- or twice-daily administration schedule with moxonidine, and dosage adjustment is only necessary in patients with moderate renal impairment. While its published clinical data base needs further expanding, moxonidine thus appears to be a more attractive option than oral clonidine, and may be considered along with the other classes of drug used to treat patients with mild to moderate hypertension.

Ocular diclofenac. A review of its pharmacology and clinical use in cataract surgery, and potential in other inflammatory ocular conditions.

Diclofenac sodium is a potent nonsteroidal anti-inflammatory drug with analgesic activity. When instilled as a topical 0.1% solution in a limited number of patients undergoing cataract surgery, diclofenac limits surgically induced miosis, reduces signs of ocular inflammation, does not cause elevations in intraocular pressure, and reduces the occurrence and severity of cystoid macular oedema. Preliminary findings suggest a niche for topical diclofenac in other ocular inflammatory conditions such as iritis, episcleritis and conjunctivitis, although its efficacy in these areas awaits confirmation. The drug appears well tolerated, apart from a transient burning sensation after instillation in some patients. Ocular diclofenac thus appears well suited as a local anti-inflammatory adjunct to cataract surgery, and may be useful in some other inflammatory ocular conditions.

Selegiline: an appraisal of the basis of its pharmacoeconomic and quality-of-life benefits in Parkinson's disease.

Selegiline (deprenyl) is a selective, irreversible cerebral monoamine oxidase type B inhibitor (MAO-B) that is used in the treatment of Parkinson's disease. It has a relatively mild adverse effect profile without risk of the tyramine ('cheese') reaction at normal therapeutic doses. In about half to two-thirds of patients with mild levodopa response fluctuations, selegiline improves overall disability and 'end-of-dose' fluctuations, with a levodopa-sparing effect. Selegiline thus may improve patient quality of life, although formal cost-utility analyses are required to establish the costs of these benefits. Cost-effectiveness studies may help characterise the relative pharmacoeconomic benefits of selegiline and the dopamine agonists, agents which can also be administered as adjuvant therapy at this stage of the disease. There is also evidence to suggest that selegiline may delay the need for levodopa therapy by up to 11 months in patients with early Parkinson's disease, although the relative contribution of neuroprotective and symptomatic effects of selegiline in these patients has yet to be clarified. From a societal perspective, a theoretical analysis indicates that the economic benefits of selegiline therapy are likely to be substantial. An agent which slowed progression of disability by around 10% would realise savings, through reduction in both direct and indirect costs, in the order of $US330 million per annum in the United States. Available data suggest that selegiline slows progression of symptoms well in excess of 10%. Further, if a simple and inexpensive method is developed to identify preclinical Parkinson's disease before nigrostriatal damage is advanced, selegiline may be useful in a broader patient population with possible financial benefits to society through reduction of the considerable indirect costs of Parkinson's disease.

Co-dergocrine mesylate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in age-related cognitive decline.

Co-dergocrine mesylate is a combination of the mesylated forms of dihydroergocornine, dihydroergocristine, dihydro-alpha-ergocryptine and dihydro-beta-ergocryptine. In animal models and healthy elderly volunteers the compound improves indices of cognitive function such as memory and learning. The mechanism(s) behind such action remains under investigation. Nonetheless, it has been proposed that co-dergocrine mesylate has a dual effect on central monoaminergic neurotransmitter systems, compensating for both hyperactivity and deficits of the adrenergic, serotoninergic and dopaminergic systems. The compound also appears to have a normalising effect on the power of electroencephalogram frequencies, and may improve cerebral metabolism. Results from controlled studies of elderly patients with age-related cognitive decline have established that co-dergocrine mesylate is well tolerated and, in some studies, had statistically significant positive effects on symptoms of cognitive dysfunction. However, there is considerable controversy over the clinical relevance of these results as there was wide variability in the number and type of cognitive and neuropsychological assessments used in individual studies and there may have been considerable overlap in diagnosis of patients with varying degrees of dementia. In addition, the drug has not been compared with most other, more recently developed, centrally active agents. Thus, the specific place of co-dergocrine mesylate in the treatment of age-related cognitive decline remains undetermined, despite many years of clinical use.

Imipenem/cilastatin: a pharmacoeconomic appraisal of its use in intra-abdominal infections.

Imipenem/cilastatin possesses a very broad spectrum of antibacterial activity that encompasses the range of Gram-negative and Gram-positive aerobes and anaerobes usually associated with intra-abdominal and other polymicrobial infections. Its therapeutic efficacy is comparable to that of aminoglycoside/antianaerobe combination regimens, and the most commonly reported adverse effects are similar to those of other beta-lactam antibacterials and are generally of a non-serious nature. The acquisition cost of imipenem/cilastatin is generally greater than that of aminoglycoside/antianaerobe combination regimens, but treatment with the latter incurs the additional costs of multiple intravenous administration, aminoglycoside pharmacokinetic and other monitoring, and possible nephrotoxicity and ototoxicity. The available pharmacoeconomic studies show a trend towards lower total treatment costs with imipenem/cilastatin compared with gentamicin plus clindamycin. Results from other sources suggest that imipenem/cilastatin may achieve further cost savings through reduced duration of hospitalisation. Although further study is required to confirm these trends, it appears that the total treatment cost of imipenem/cilastatin does not exceed that of usual combination therapy and the risk of aminoglycoside-induced toxicity is avoided.

Ocular carteolol. A review of its pharmacological properties, and therapeutic use in glaucoma and ocular hypertension.

Carteolol is a relatively potent nonselective beta-adrenoceptor antagonist with partial agonist activity. It is used topically to reduce elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension. Twice-daily ocular administration of carteolol 1 or 2% lowers IOP by approximately 32% on average in patients with these conditions, an efficacy equivalent to that of timolol 0.25 or 0.5%. Carteolol eyedrops lack local anaesthetic activity, appear to cause less local irritation than timolol, and produce less pronounced decreases in heart rate or dyspnoea, possibly due to partial agonist activity. The latter activity may also improve retinal perfusion. Thus, although additional comparative trials are needed to accurately assess the precise place of carteolol in therapy, this drug offers a useful alternative to timolol in the management of conditions associated with a raised IOP, and may have advantages in older patients with regard to its tolerability profile, although careful monitoring is still wise.

Simvastatin: a pharmacoeconomic evaluation of its cost-effectiveness in hypercholesterolaemia and prevention of coronary heart disease.

Epidemiological and intervention study results support reduction of coronary heart disease (CHD) risk, and hence direct and indirect costs, by lowering plasma lipids. Cost-effectiveness of a lipid-lowering strategy thus depends significantly on the extent of plasma lipid decrease achieved. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin is a well tolerated and highly effective antihyperlipidaemic agent. Despite a current lack of direct evidence that simvastatin reduces CHD incidence, the cost-effectiveness of the drug {in terms of years of life saved (YOLS)} has been studied, based on findings of epidemiological trials. Simvastatin 20 mg/day is more cost-effective than cholestyramine 4g 3 times daily, particularly in men and in those with a higher pretreatment cholesterol level ( greater than 8 mmol/L) and other risk factors. Cost-effectiveness is also enhanced if treatment is started at a younger age (35 to 45 years) and maintained for a defined period rather than lifelong. Thus, while additional direct comparative studies are needed to confirm this finding, present evidence suggests simvastatin is a cost-effective intervention in appropriately selected patients.

Leuprorelin. A review of its pharmacology and therapeutic use in prostatic disorders.

Leuprorelin (leuprolide acetate) is a synthetic analogue of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH)] which initially stimulates luteinising hormone (LH) and hence testicular androgen release; continuous administration then results in profound suppression of these hormones. Testosterone levels associated with castration are attained within 3 to 4 weeks. A biodegradable subcutaneous or intramuscular depot formulation of leuprorelin 3.75 or 7.5 mg, which releases the drug at a constant rate over 28 days, is available and may be preferred over daily subcutaneous injections. The progression of previously untreated advanced prostatic cancer is delayed in 70 to 90% of men receiving leuprorelin, with median survival of approximately 2 years. The efficacy of leuprorelin is equivalent to that of estrogen therapy, but the tolerability of the GnRH analogue is far better. In contrast to most other studies of GnRH agonists, a slight survival advantage has been reported for combined treatment with leuprorelin and the antiandrogen flutamide. Small noncomparative trials reveal that leuprorelin also causes regression of benign hyperplastic prostate tissue with corresponding relief of obstructive, but not irritative, symptoms although continuous treatment is necessary to maintain remission. Impotence and flushing occur in most leuprorelin recipients but, unlike diethylstilbestrol (stilboestrol), cardiovascular toxicity and gynaecomastia are not significant problems. Symptom flare, usually manifested as bone pain in prostate cancer patients and exacerbation of obstructive symptoms in those with benign prostatic hypertrophy, can occur in 4 to 29% at the beginning of treatment. Leuprorelin treatment is therefore an established effective palliative measure in men with previously untreated advanced prostatic cancer, and may have a role in those with benign hypertrophy who are unfit for surgery.

Intranasal salmon calcitonin. A review of its pharmacological properties and potential utility in metabolic bone disorders associated with aging.

Salmon calcitonin, a polypeptide hormone secreted by the parafollicular C cells of the thyroid gland, lowers serum calcium levels by decreasing bone resorption and renal tubular calcium reabsorption. An analgesic action, possibly mediated via beta-endorphins, is also evident. In the past, parenteral formulations of salmon calcitonin have been used in the management of metabolic bone disorders, but their routine use has been limited by the inconvenience of this route of administration and by poor tolerability. The development of an intranasal preparation of salmon calcitonin will provide a more convenient means of administering the drug. In clinical trials published to date intranasal salmon calcitonin has been effective and well tolerated in small numbers of recently postmenopausal women at risk of developing osteoporosis, and in patients with established osteoporosis, Paget's disease, or osteoporosis secondary to corticosteroid usage, multiple myeloma or ovariectomy. For periods of up to 2 years the drug reduces bone resorption and improves bone architecture, relieves pain and increases functional status. Further research is needed to confirm longer term efficacy (in particular, effects on fracture rate), optimal dosage schedules and the role of intermittent and combination treatment regimens.

Levamisole/fluorouracil. A review of their pharmacology and adjuvant therapeutic use in colorectal cancer.

The combination of the antimetabolite fluorouracil plus the immunomodulator levamisole is used as adjuvant therapy following surgical tumour removal in patients with Dukes' stage C colon cancer. Fluorouracil given alone in this setting results in only a modest improvement in survival rate, and levamisole monotherapy is clinically ineffective. Well controlled studies, however, demonstrate that combined levamisole/fluorouracil reduces the recurrence rate by between 31 and 41% and the total mortality rate by between 13 and 33% compared with surgery alone in patients with Dukes' stage C colon cancer after median follow-up of 3 or 7.75 years. The median time to recurrence and median survival time are also extended significantly by levamisole/fluorouracil compared with fluorouracil alone or no adjuvant treatment. Thus, levamisole/fluorouracil has been recommended as the standard adjuvant therapy for patients with Dukes' C colon cancer, against which new investigative regimens should be compared. Methods for optimising the impressive results already achieved with this combination, and using this as a basis for further progress should be the thrust of future trials.

Selegiline. A review of its pharmacology, symptomatic benefits and protective potential in Parkinson's disease.

Selegiline (deprenyl) is a selective inhibitor of cerebral monoamine oxidase type B at the dosage (10 mg/day) used in patients with Parkinson's disease. Through this activity, the drug increases nigrostriatal dopamine levels, and may protect neurons against damage by free radicals and possibly exogenous neurotoxins. Selegiline also inhibits dopamine reuptake from the synaptic cleft. Because of its selectivity, selegiline 10mg daily does not prevent the breakdown and exacerbate the indirect pressor effects of dietary amines such as tyramine; it is devoid of the 'cheese' effect. Following oral administration, selegiline is rapidly metabolised to L-methamphetamine and L-amphetamine, which may account for the euphoria and insomnia seen in many patients, although potentiation of dopaminergic activity with concurrent levodopa appears more likely. The drug is a useful adjunct to levodopa in Parkinsonism, improving 'end-of-dose' fluctuations, producing modest improvements in motor function, and allowing a reduction in levodopa dosage. Indeed, if levodopa dosages are not decreased when selegiline is added to the therapeutic regimen, peak concentration dyskinesias due to levodopa are often exacerbated. However, symptomatic benefits are rarely maintained for more than a year and selegiline is relatively ineffective in allaying the abrupt swings in response to levodopa ('on/off' effects). When used alone in patients with mild disease, selegiline appears to slow the rate of symptom progression and may extend survival, through either neuroprotection or symptom relief. Whichever mechanism(s) is responsible, there is strong evidence to suggest that selegiline should be considered both in patients newly diagnosed with Parkinson's disease in an attempt to delay symptom progression, and in those experiencing dose-dependent fluctuations in response to levodopa.

Adenosine. An evaluation of its use in cardiac diagnostic procedures, and in the treatment of paroxysmal supraventricular tachycardia.

Adenosine (adenine riboside), administered either as the free base or as the 5'-triphosphate (ATP) by rapid intravenous bolus, depresses atrioventricular (AV) nodal conduction, resulting in transient AV block. Adenosine is the active agent and ATP is rapidly converted to adenosine after exogenous administration. By blocking the anterograde AV nodal limb of a re-entrant circuit, adenosine 6 to 12 mg (or ATP 10 to 20 mg) converts almost all episodes of paroxysmal supraventricular tachycardia (PSVT) involving the AV node within 30 seconds of administration. This is at least equivalent in efficacy to verapamil in adults, and superior to lanatoside C in children, with a considerably more rapid onset of action. Furthermore, if a dose of adenosine is ineffective, the exceptionally short plasma half-life of the adenyl nucleosides (less than 10 sec) allows rapid upward dosage titration until PSVT is terminated. Because the induced conduction block primarily affects the AV node, adenosine is a useful diagnostic tool in patients with broad or narrow QRS complex tachycardia; it terminates arrhythmias dependent on the AV node, unmasks other supraventricular mechanisms during transient AV block, but almost always has no effect on ventricular tachycardia. Noncardiac adverse effects, i.e. flushing, dyspnoea and chest pain, may occur during acute arrhythmia termination or diagnosis with adenosine, and arrhythmias may develop; however, these effects are usually transient (lasting less than 1 minute). Adenosine has also been used to induce coronary vasodilation in patients undergoing thallium-201 single photon emission computed tomography (201Tl SPECT), 2-dimensional echocardiography or positron emission tomography to evaluate suspected coronary artery disease. Intravenous infusion of adenosine 140 micrograms/kg/min for 6 minutes was generally associated with only mild adverse effects. These usually resolved within 1 to 2 minutes of discontinuing adenosine, although occasionally patients required aminophylline and/or nitroglycerin (glyceryl trinitrate). Diagnoses based on the results of scintigraphy were of a sensitivity, specificity and predictive accuracy comparable to those achieved with exercise- or dipyridamole-201Tl SPECT. Adenosine is therefore particularly suitable for the diagnosis of tachycardias and the acute management of PSVT involving the AV node in all age groups, without the risks of cardiac arrest and hypotension associated with verapamil. Furthermore, intravenous adenosine infusion may be used to induce coronary vasodilation in patients unable to perform exercise stress tests for 201Tl scintigraphy, and is well tolerated.

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

Flutamide, a nonsteroidal antiandrogenic drug devoid of hormonal agonist activity, is used in the treatment of advanced prostate cancer. In previously untreated patients, flutamide 750 mg daily given alone is of comparable efficacy to diethylstilbestrol (stilboestrol) 1 or 3 mg daily and estramustine 560 or 840 mg daily, but has the potential advantages of fewer cardiovascular effects and maintenance of some sexual potency. Its greatest therapeutic potential is as a component of combination androgen blockade, where administration with an agonist analogue of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LH-RH)] in both initial uncontrolled and randomised studies increased survival time relative to GnRH agonist monotherapy or orchidectomy. Subsequent multicentre trials, however, have been unable to confirm an improvement in survival time. Thus, while there seems to be little doubt that flutamide prevents the initial disease flare caused by GnRH agonists, an improvement in remission rate and survival remains contentious. Flutamide is generally well tolerated and is suitable monotherapy in patients with previously untreated advanced prostatic cancer who wish to preserve sexual potency. However, full assessment of the role of combination androgen blockade awaits publication of the final results of ongoing multicentre trials.

Mitoxantrone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer.

Mitoxantrone is a dihydroxyanthracenedione derivative which as intravenous mono- and combination therapy has demonstrated therapeutic efficacy similar to that of standard induction and salvage treatment regimens in advanced breast cancer, non-Hodgkin's lymphoma, acute nonlymphoblastic leukaemia and chronic myelogenous leukaemia in blast crisis; it appears to be an effective alternative to the anthracycline component of standard treatment regimens in these indications. Mitoxantrone is also effective as a component of predominantly palliative treatment regimens for hepatic and advanced ovarian carcinoma. Limited studies suggest useful therapeutic activity in multiple myeloma and acute lymphoblastic leukaemia. Regional therapy of malignant effusions, hepatic and ovarian carcinomas has also been very effective, with a reduction in systemic adverse effects. Mitoxantrone inhibits DNA synthesis by intercalating DNA, inducing DNA strand breaks, and causing DNA aggregation and compaction, and delays cell cycle progression, particularly in late S phase. In vitro antitumour activity is concentration- and exposure time-proportional, and synergy with other antineoplastic drugs has been demonstrated in murine tumour models. Leucopenia may be dose-limiting in patients with solid tumours, whereas stomatitis may be dose-limiting in patients with leukaemia. Other adverse effects are usually of mild or moderate severity although cardiac effects, particularly congestive heart failure, may be of concern, especially in patients with a history of anthracycline therapy, mediastinal irradiation or cardiovascular disease. Mitoxantrone displays an improved tolerability profile compared with doxorubicin and other anthracyclines, although myelosuppression may occur more frequently. Thus, mitoxantrone is an effective and better tolerated alternative to the anthracyclines in most haematological malignancies, in breast cancer and in advanced hepatic or ovarian carcinoma. Further studies may consolidate its role in the treatment of these and other malignancies.

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.

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.

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.