Cyclandelate in the prophylaxis of migraine: a placebo-controlled study.

The prophylactic action of cyclandelate was investigated in a multicentre, randomized, placebo-controlled, parallel group study. A 4-week baseline period was followed by a 4-week placebo phase and a 16-week treatment period with either 1600 mg cyclandelate or placebo. Patients (n = 251) with two to six migraine attacks/month were randomized. Neither the primary study endpoint (reduction of migraine days from baseline to the last 28 days) nor most of the secondary endpoints (reduction in the number of migraine attacks, severity or duration of attacks, frequency of autonomic disturbances, medication for treatment of attacks) showed a difference between cyclandelate and placebo. Cyclandelate, however, was superior to placebo in a global impression of efficacy rated by the patients and the treating physicians. Both treatments were well tolerated. In conclusion, cyclandelate was not superior to placebo in the prophylaxis of migraine with regard to parameters usually used in migraine prophylaxis trials.

Safety of oral terbinafine: results of a postmarketing surveillance study in 25,884 patients.

OBJECTIVE: To broaden the safety database for oral terbinafine by determining the incidence of adverse events, particularly rare risks, that accompany its uncontrolled use in actual clinical practice. DESIGN: Four open, prospective, uncontrolled, postmarketing surveillance studies were conducted in unselected patients in 4 countries. No exclusion criteria were applied. The only treatment instructions participating physicians received were the manufacturer's product information. Physicians monitored patients for adverse events at baseline, during treatment, and at the end of treatment. Serious events were identified according to study protocol, which was consistent for all 4 studies, allowing data to be pooled and analyzed collectively. SETTING: Patients were recruited from dermatology, general, and family practices in the United Kingdom, the Netherlands, Germany, and Austria. PATIENTS: Of the 25884 patients who entered the study, 38.6% had concomitant diseases, 42.8% were taking other medications, and 22.7% were older than 60 years. The predominant indication for terbinafine treatment was onychomycosis (72.2%). INTERVENTIONS: Data on treatment duration was available for 25091 patients. Median duration of treatment was 12 weeks (mean, 13.2 weeks). Treatment extended beyond 6 weeks in 76.0% of patients and for at least 12 weeks in 59.3%. MAIN OUTCOME MEASURES: The incidence of adverse events as reported by physicians, with their opinions regarding relationship to terbinafine therapy. RESULTS: The incidence of adverse events was 10.5%; the majority involved the gastrointestinal system (4.9%) or skin (2.3%). These tended to be mild, transient, and reversible. Terbinafine was considered a possible or probable cause of 11 (0.04%) serious adverse events. No drug interactions were reported, even in patients taking oral antidiabetic agents, astemizole, terfenadine, or cimetidine hydrochloride. CONCLUSIONS: The positive safety profile established during controlled clinical trials of oral terbinafine extends to its uncontrolled use in clinical practice. No previously unrecognized risks were identified.

Acute overdosage with thioridazine: a review of the available clinical exposure.

Two hundred and twenty-three cases of acute overdosage associated with thioridazine were reviewed. The most frequent feature was impairment of consciousness which was linearly dose-related and occasionally resulted in life-threatening complications. Arrhythmia was the most frequently reported serious toxic effect. Patients presenting with anoxia were at risk for arrhythmia, as were patients ingesting a high dose. Arrhythmia may, by decreasing cardiac output, predispose to the occurrence of all other observed complications (ie, pulmonary edema, severe hypotension and renal failure). Therefore, treatment of arrhythmias should be the keystone of management of thioridazine overdosage. Torsade de pointes was reported only once with overdosage. Isolated ventricular arrhythmias (VA) occurred at high doses (median 12 g). At lower doses (median 5 g), VA were frequently associated with conduction disturbances, which were not, as such, statistically predictive of arrhythmias. Since thioridazine in high doses exhibits a beta-adrenoceptor and a verapamil-like calcium channel blocking effect, drugs with these types of properties are contraindicated. VA may be refractory to lidocaine or recur after such therapy. Transient cardiac pacing appears to be the most appropriate management of VA. Although its efficacy is established for the treatment of phenothiazine-induced arrhythmias, its use remains rare (only 3/50 cases).

Malignancies in rheumatoid arthritis patients treated with cyclosporin A.

More than a thousand RA patients have been treated with cyclosporin A (CyA) in clinical trials. In seventeen of them, tumours developed after treatment with the drug. An indirect approach used to calculate the relative risk associated with the use of CyA in clinical trials suggested that: (i) RA itself increases the risk of cancer development; (ii) the use of CyA further increases the risk by approximately the same degree as DMARDs; and (iii) neither the pattern of malignancies nor the risk associated with CyA seems to be different from that observed with conventional DMARDs. Nevertheless, patients treated with CyA should be carefully monitored while more experience is gathered.

Acute ketotifen overdosage. A review of present clinical experience.

Ketotifen (Zaditen) is a widely used prophylactic antiasthmatic drug with pronounced antianaphylactic properties and a specific H1-antihistaminic effect. This article summarises the available information on acute overdosage of this drug, which was reported in 13 adults and 8 children. The symptoms of acute overdosage observed with ketotifen are similar to those described for antihistaminic agents. However, it would appear that the acute toxicity of ketotifen is rather low, since no serious effects have been reported either in children or in adults after the intake of up to 20mg of ketotifen, which is 10 times the recommended dose. No lethal outcome of acute overdosage has been described in association with this drug. Ketotifen seems to be better tolerated in children than in adults. Based on present clinical experience, management of acute overdosage includes gastric lavage within 2 to 4h after ingestion or activated charcoal after this period. Symptomatic treatment is indicated if arrhythmias, hypotension or seizures develop, and the patient should be kept under surveillance for at least 6 to 8h.

Clozapine-associated agranulocytosis: risk and aetiology.

This paper reviews the epidemiology and pathogenesis of clozapine-associated agranulocytosis. According to present clinical experience, granulocytopenia can be expected in approximately 3% of patients during clozapine treatment. The risk of serious sequelae of granulocytopenia can be minimised by regular white blood cell count monitoring. Although research suggests that some patient groups may be at higher risk of developing this serious adverse reaction, we cannot yet predict the susceptible patients, so all patients exposed to clozapine should receive regular blood monitoring throughout treatment. Because of the risk of agranulocytosis, clozapine should only be used in schizophrenic patients who are resistant to, or intolerant of, conventional antipsychotic medications. Unless compliance with blood monitoring is assured, clozapine treatment should not be recommended.

HLA-associations in Leponex/Clozaril (clozapine)-induced granulocytopenia and agranulocytosis. Statistical viewpoints.

This paper describes a statistical analysis of the simultaneous occurrence of 48 human leucocyte antigens (HLAs) in an attempt to predict whether a patient treated with clozapine will develop granulocytopenia or agranulocytosis. Whereas the numerical results show that use of HLAs does not appear to satisfy the intended purpose, emphasis is placed on the statistical methodology recommended for a problem of this type. Other work in this area is critically discussed.

No direct clinical relevance of the human leucocyte antigen (HLA) system in clozapine-induced agranulocytosis.

The clinical use of clozapine in psychiatry is restricted by the associated risk of agranulocytosis. This risk is significantly higher than that associated with conventional antipsychotic medications. In order to identify a possible parameter to detect susceptible individuals before treatment, 103 patients with a history of clozapine-induced granulocytopenia or agranulocytosis and 95 matched control patients were typed for human leucocyte antigen (HLA)-A, -B, -C, -DR, -DQ and for a number of neutrophil-specific alloantigens. No significant association between certain HLA alleles or neutrophil antigens and susceptibility to clozapine-induced granulocytopenia or agranulocytosis was observed.

Transient cardiac pacing is insufficiently used to treat arrhythmia associated with thioridazine.

All cases of arrhythmias associated with thioridazine were reviewed (177 cases). No case of severe ventricular arrhythmia was reported in children. In adults, at therapeutic doses, ventricular tachycardia or fibrillation (VT/VF) or torsade de pointes was observed mainly in patients with concomitant risk factors. At doses higher than 800 mg, atrioventricular (A-V) and bundle branch blocks were associated with VT/VF. Mortality was higher in patients with A-V blocks. Although transient cardiac pacing is known to be efficacious to control phenothiazine-induced arrhythmias, it was rarely used.

Acute cyclosporin overdose. A review of present clinical experience.

Although cyclosporin is widely used in transplant patients, experience regarding the consequences of an overdose is limited. This article summarises the data available on 27 patients with oral (n = 20) or parenteral (n = 7) overdosage of cyclosporin. The available clinical data are consistent with predictions derived from animal toxicological studies, suggesting a low acute toxicity of the drug in humans. Acute oral overdoses result in minimal clinical manifestations and/or mild degrees of renal dysfunction, primarily in patients with previously impaired kidney function. Acute parenteral overdoses may have more serious consequences, premature neonates being at particular risk of developing life-threatening reactions. Determinations of blood concentrations of cyclosporin are of limited use in the management of patients with acute overdose. Guidelines are suggested for the management of such patients.