Site of action of low dose ketoconazole on androgen biosynthesis in men.

Ketoconazole inhibits testosterone biosynthesis in men, but the exact site of its action on the androgen pathway remains to be established. To examine this question, we measured several steroids in the androgen and glucocorticoid pathways in normal men before and after receiving either a single dose of 200 mg ketoconazole or placebo in a cross-over randomized trial. Total and free plasma testosterone fell to levels 60% below basal within 4-8 h (P less than 0.02 in all) and then returned to control concentrations by 24 h after drug administration. The transient alterations of plasma testosterone correlated well with ketoconazole blood levels, which peaked at 2 h and fell exponentially thereafter. A compensatory increase in plasma LH at 24 h in the drug but not placebo group was consistent with the decrease in plasma testosterone. The levels of plasma androstenedione paralleled those of testosterone in the ketoconazole-treated subjects. In marked contrast, plasma 17 alpha-hydroxyprogesterone increased at 4-8 h (all P less than 0.02) before returning to basal values at 24 h. This rise in precursor with fall in product steroid implicated an effect of ketoconazole on the C17-20 lyase enzyme. This conclusion was supported by the highly significant increase in the ratio of plasma 17 alpha-hydroxyprogesterone to androstenedione observed between 2 and 24 h after drug administration. The effect of ketoconazole at this dose level appeared relatively specific, since no decrements in plasma cortisol or 11-desoxycortisol were found. During chronic administration of 200 mg ketoconazole daily, decrements of plasma testosterone 2-4 h after drug administration were minimal and documented only by paired comparisons within subjects but not by unpaired tests between normal men and men receiving drug. The lack of major effects on testosterone levels long term at this dosage probably explain why few androgen-related side effects with this drug were previously reported. Ketoconazole, therefore, represents another compound with relatively selective effects on a cytochrome P-450-mediated steroid hydroxylation step, namely that involved with C17-20 lyase.

Hepatic reactions during ketoconazole treatment.

Silent and symptomatic hepatic reactions have occurred during ketoconazole treatment. The silent reactions (transient asymptomatic elevations of serum transaminase or alkaline phosphatase levels) may occur at any time during ketoconazole treatment. Asymptomatic increases in liver enzymes may also occur in a sizeable number of patients with fungal disease without any treatment. Symptomatic hepatic reactions have occurred mainly during the first few months of treatment. The estimated incidence of symptomatic reactions is of the order of 1 in 10,000.

Modulation of immunity in multiple sclerosis: a double-blind levamisole-placebo controlled study in 85 patients.

Levamisole seems to regulate cell-mediated immunity by restoring T-cell function. Since a deficiency of T lymphocytes has been described by various authors in multiple sclerosis patients. Of the 85 patients involved in the trial, evaluation of functional and neurological scores was possible in 54 (32 with placebo and 22 with levamisole). The mean follow-up period was 2 years. This double-blind controlled study indicates that both neurological function and disability significantly deteriorated in the placebo-treated patients, but remained fairly stable in the levamisole-treated group. Since the difference between both groups was not significant, no levamisole effect was demonstrated on progression in multiple sclerosis. With the exception of one case of granulocytopenia (which had no clinical effect), no drug-related changes could be demonstrated. This contrasts with the general impression that this immunomodulator agent might be harmful to patients with multiple sclerosis. The fact that during this blind study both annual relapse rate and disability score remained more stable in treated patients with severe disability suggests that, while waiting for a more effective treatment, long-term levamisole therapy could be useful in patients with multiple sclerosis.

Ketanserin: a novel cardiovascular drug.

Ketanserin is the archetype of a new class of cardiovascular drugs, the 5HT2 (S2) serotonergic receptor antagonists. In humans, ketanserin inhibits serotonin-induced vasoconstriction and platelet activation. In addition, it reduces platelet hyperactivity, blood viscosity and total serum cholesterol. The antihypertensive effect of ketanserin is more pronounced in older people, in whom it decreases blood pressure gradually to normal levels. It lowers systemic vascular resistance resulting in a reduction of pre- and afterload. It improves vascular compliance and reduces left ventricular hypertrophy. Ketanserin improves the microcirculation of the skin, in particular capillary blood flow. Placebo-controlled studies have established that ketanserin prevents amputations in patients with atherosclerosis, enhances ulcer healing in patients with scleroderma and reduces the frequency and duration of attacks in patients with Raynaud's disease. In a placebo-controlled trial the on-treatment analysis of 3071 patients with intermittent claudication (the PACK-trial) showed a 23% reduction of severe cardiovascular events with ketanserin, suggesting that ketanserin may prevent complications of atherosclerosis. The accumulated clinical evidence indicates that serotonergic antagonism opens new perspectives in the treatment of cardiovascular disease. Current clinical research with ketanserin further explores its potential as a vascular protective agent.

Plethysmographic registration of volume changes in a hand vein. Effects of serotonin and of a specific antagonist.

The influence of serotonin on a selected dorsal hand vein can be evaluated by changes in tangential wall tension, volume, and pressure. A plethysmographic method has been used to record the changes in venous capacitance at constant pressure after IV injection of small doses of serotonin. R 41 468, a specific serotonin antagonist, has been given orally (10, 20, or 40 mg) or intravenously (2.5 or 10 mg) to healthy volunteers. A reduction or a complete blockade of activity of serotonin was observed after all doses of R 41 468. Duration and strength of the antagonism were dose-dependent. This pharmacologic in vivo model allows investigations into substances with an effect on vascular smooth muscles.

Double-blind comparison of ketanserin with placebo in patients with essential hypertension.

Two double-blind multicenter trials were performed to compare the antihypertensive action of ketanserin, at an oral dosage of 20 mg three times daily, with that of placebo over a period of four to six weeks. A subset of patients was treated in a crossover fashion for either four weeks (36 patients) or six weeks (24 patients). The patients had essential hypertension, with a diastolic blood pressure greater than or equal to 95 mmHg measured in sitting position at the end of a placebo run-in period of at least one week. In a first trial, 78 of 82 patients completed the four-week study period, where the mean drop of the systolic/diastolic blood pressure was -14/-12 mmHg in the ketanserin group (n = 32) versus -8/-5 mmHg in the placebo group (n = 46). This difference is statistically significant (p = 0.05/p less than 0.01). In 13 patients who after the initial ketanserin treatment were further treated with placebo in crossover for four weeks, the blood pressure rose slightly (+1/+3 mmHg). In the alternative group (n = 23), the blood pressure fell by -10/-7 mmHg after placebo and decreased further by -10/-8 mmHg after ketanserin. In a second trial, 24 patients completed a two by six week crossover treatment. In 12 patients assigned to the sequence placebo-ketanserin, there was a drop of the systolic/diastolic blood pressure by -7/-4 mmHg after placebo and an additional drop by -26/-10 mmHg after ketanserin.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of Pityrosporum pachydermatis in otitis externa of dogs: evaluation of a treatment with miconazole.

The bacterial and mycotic flora were assessed in 158 ears of dogs with otitis externa and in 101 ears of healthy control dogs. Pityrosporum pachydermatis occurred in 57 per cent of ears with otitis externa and in 17 per cent of clinically healthy ears. Staphylococci and Pseudomonas aeruginosa were the predominant bacteria in otitic ears, micrococci and Bacillus spp were the most frequent isolates from clinically healthy ears. P pachydermatis, Ps aeruginosa and Candida tropicalis occurred in monoculture in a significant number of mainly chronic cases of otitis externa. A combination preparation, containing miconazole, polymyzin B and prednisolone, was highly effective in controlling the clinical signs of otitis externa and eliminating flora from the affected ears. The data presented suggest that yeasts, and especially P pachydermatis, may be significant pathogens in otitis externa and that antimycotic treatment is an essential part of the treatment of otitis externa in dogs.

Levamisole in rheumatoid arthritis--a multivariate analysis of a multicentric study.

Statistical analysis of the data from a multicentric study of six months of treatment with levamisole in rheumatoid arthritis involved two steps. In a first step, the differences between observations before and after treatment have been made independent of their initial values. Differences after treatment have been transformed into responses to treatment using a proportionality factor that is related to the initial values before treatment. The second step involved a reduction of the various responses into a single global response by means of a discriminant analysis between two classes. Class membership has been defined by the type of treatment (either placebo or drug) predicted by the investigators at the end of treatment and before breaking of the code of the double-blind study. This method of analysis allows for the combination of multiple clinical observations with a subjective evaluation. Its results can be easily represented graphically and tested for statistical significance. The use of global responses to treatment is illustrated with a comparison of placebo and drug treatments and can be extended to comparisons between investigators or between different dose and time regimens.

Degree of responsiveness to levamisole and factors influencing responsiveness and adverse reactions.

The individual response to treatment, and factors influencing this response, were evaluated by means of Lewi's mathematical model in patients with rheumatoid arthritis. Patients showed a graded response to anti-inflammatory agents ranging from deterioration through moderate to marked improvement. Levamisole was superior to anti-inflammatory agents in preventing deterioration or inducing marked improvement. Patients in an early stage of disease were the best responders and had fewest idiosyncratic reactions. The responses were independent of the treatment schedule used. A threshold dose of levamisole exists, but it is not critically dependent on body weight.

Ketanserin compared to nifedipine and methyldopa in patients aged above 50 years: two international multicentre studies. For the International Study Group.

The antihypertensive properties and adverse reactions of ketanserin, nifedipine and methyldopa were compared in hypertensive patients aged above 50 years in two international studies. After a placebo run-in period, patients received for 3 months, either ketanserin or nifedipine retard in study 1, and either ketanserin or methyldopa in study 2. After 1 month of monotherapy, a diuretic was added if necessary. Study 1 had 117 subjects, with 119 in study 2. The changes in systolic and diastolic blood pressure were similar for ketanserin and nifedipine although more patients switched to combination therapy in the ketanserin group. The overall response rate was comparable with ketanserin and nifedipine (96% for both drugs). The decrease in diastolic blood pressure was significantly greater in the ketanserin group compared to methyldopa and more patients responded to ketanserin (82%) than to methyldopa (65%). No rebound hypertension was observed on discontinuation of therapy with any of the drugs. The total incidence of adverse reactions in monotherapy was lower with ketanserin than with nifedipine (34 and 47%) and similar for ketanserin and methyldopa (40 and 45%). For ketanserin no consistent adverse reaction pattern was seen.

[Immunopharmacology of levamisole]. / Immunpharmakologie des Levamisol.

Levamisole, a simple chemical, first introduced as a broad spectrum anthelmintic, is an immunotherapeutic agent with anti-anergic properties. It is the first member of a potential new class of immunologically active, probably thymomimetic compounds. The present knowledge from studies on isolated cells, experimental animals, healthy volunteers and patients with various diseases shows that levamisole behaves physiologically as a thymus hormone and restores to normal the functions of phagocytes and T-lymphocytes in compromised hosts and induces T-cell differentiation. The biochemical mechanism of action remains still unclear. The various mechanisms by which levamisole might act are not mutually exclusive. Levamisole is well tolerated in doses of 2,5 mg/kg. Side-effects are markedly more frequent in patients with rheumatoid arthritis than with other diseases. The only potentially fatal adverse reaction is agranulocytosis.

The host and the parasite.

The role of the host in the management of patients with mycotic infection is considered. In vivo studies with ketoconazole indicate the importance of the host and the possibility of stimulating host immune mechanisms by an immune modulator.