Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study.

BACKGROUND: Cladribine is a synthetic deoxyadenosine analogue in development as an oral multiple sclerosis (MS) therapy. OBJECTIVE: To report in detail the safety findings from the 96-week, phase III, double-blind CLARITY study, which evaluated treatment with cladribine tablets in relapsing-remitting MS. METHODS: A total of 1,326 patients were randomized 1:1:1 to two short-course regimens of cladribine tablets (3.5 or 5.25 mg/kg cumulative dose over 96 weeks) or placebo. Safety assessments included monitoring for adverse events (AEs), routine physical and neurologic examinations and frequent laboratory parameter assessments. RESULTS: Of the randomized patients, 88.6% completed treatment with cladribine tablets versus 86.3% with placebo. Lymphopenia was the most commonly reported AE in patients treated with cladribine tablets and was anticipated based on the mechanism of action. The incidence of infections was 48.3% with cladribine tablets and 42.5% with placebo, with 99.1% and 99.0% rated mild-to-moderate by investigators. Herpes zoster infections developed in 20 (2.3%) cladribine-treated patients; all cases were dermatomal. There were no herpes zoster infections in the placebo group. Nine (1.0%) patients experienced events related to uterine leiomyomas in the cladribine tablets groups versus one (0.2%) with placebo. Three isolated cases of malignancy were reported in cladribine-treated patients during the study; a fourth was reported during post-study surveillance. A pre-malignant cervical carcinoma in situ was also reported. The incidence of malignancies during the study did not exceed the expected rate in a population standardized for country, gender and age. CONCLUSION: The safety and tolerability profile observed in the CLARITY study together with the reported efficacy support the potential for cladribine tablets as an MS therapy.

Pollen flow in the wildservice tree, Sorbus torminalis (L.) Crantz. I. Evaluating the paternity analysis procedure in continuous populations.

The joint development of polymorphic molecular markers and paternity analysis methods provides new approaches to investigate ongoing patterns of pollen flow in natural plant populations. However, paternity studies are hindered by false paternity assignment and the nondetection of true fathers. To gauge the risk of these two types of errors, we performed a simulation study to investigate the impact on paternity analysis of: (i) the assumed values for the size of the breeding male population (NBMP), and (ii) the rate of scoring error in genotype assessment. Our simulations were based on microsatellite data obtained from a natural population of the entomophilous wild service tree, Sorbus torminalis (L.) Crantz. We show that an accurate estimate of NBMP is required to minimize both types of errors, and we assess the reliability of a technique used to estimate NBMP based on parent-offspring genetic data. We then show that scoring errors in genotype assessment only slightly affect the assessment of paternity relationships, and conclude that it is generally better to neglect the scoring error rate in paternity analyses within a nonisolated population.

A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury.

OBJECT: The authors prospectively studied the efficacy of tirilazad mesylate, a novel aminosteroid, in humans with head injuries. METHODS: A cohort of 1120 head-injured patients received at least one dose of study medication (tirilazad or placebo). Eighty-five percent (957) of the patients had suffered a severe head injury (Glasgow Coma Scale [GCS] score 4-8) and 15% (163) had sustained a moderate head injury (GCS score 9-12). Six-month outcomes for the tirilazad- and placebo-treated groups for the Glasgow Outcome Scale categories of both good recovery and death showed no significant difference (good recovery in the tirilazad-treated group was 39% compared with the placebo group in which it was 42% [p=0.461]; death in the tirilazad-treated group occurred in 26% of patients compared with the placebo group, in which it occurred in 25% [p=0.750]). Subgroup analysis suggested that tirilazad mesylate may be effective in reducing mortality rates in males suffering from severe head injury with accompanying traumatic subarachnoid hemorrhage (death in the tirilazad-treated group occurred in 34% of patients; in the placebo group it occurred in 43% [p=0.026]). No significant differences in frequency or types of serious adverse events were shown between the treatment and placebo groups. CONCLUSIONS: Striking problems with imbalance concerning basic prognostic variables were observed in spite of the large population studied. These imbalances concerned pretreatment hypotension, pretreatment hypoxia, and the incidence of epidural hematomas. In future trials of pharmacological therapy for severe head injury, serious consideration must be given to alternative randomization strategies. Given the heterogeneous nature of head injury and the identification of populations that do relatively well with standard therapy, target populations with a higher risk for mortality and morbidity may be more suitable for clinical trials of such agents.

Double-blind, placebo-controlled, cross-over trial of progabide as add-on therapy in epileptic patients.

In a double-blind, cross-over trial, progabide (PGB) and placebo were compared as add-on therapy in 59 patients with moderate to severe epilepsy. Eight patients did not complete the study, 4 because of adverse drug reactions (elevation of liver transaminases, 2; gastritis, 1; and acute psychosis, 1) and 4 because of administrative reasons. Among the remaining 51 patients, seizure frequency was reduced greater than 50% in 18 patients with PGB treatment and in 8 patients with placebo (p less than 0.05). The number of days with seizures was significantly (p = 0.034) reduced during PGB treatment. Both patients' and physicians' preferences at the end of the trial were in favor (p less than 0.01) of PGB. Mild clinical side effects were present in 54.7% of the patients treated with PGB and in 37.7% with placebo. Increase in liver transaminases was observed in 2 patients during the double-blind study and in 1 during the follow-up period. Our data show that PGB, as previously reported, is useful in 30-40% of patients who are not responding completely to other antiepileptic drugs (AEDs). The compound is well tolerated, but liver function must be monitored.

Sleep laboratory studies on single dose effects of suriclone.

1. In a double-blind, placebo-controlled sleep laboratory study single doses of suriclone, a new non-benzodiazepine anxiolytic binding to benzodiazepine receptors, were investigated with respect to sleep and awakening. 2. Sixteen healthy young volunteers spent 10 nights in the sleep laboratory: 1 adaptation night, 1 baseline night and 4 drug nights (placebo; 0.2 mg, 0.4 mg suriclone; 2 mg lorazepam as reference drug) and 4 subsequent wash-out nights (drug-interval: 1 week). Somnopolygraphic investigations (22.30 h to 06.00 h) were commenced 0.5 h after drug-intake. A self-rating scale for sleep and awakening quality as well as psychometric tests were completed in the morning. 3. Hypnotic effects were most pronounced after lorazepam in regard to total sleep time and sleep efficiency. After lorazepam as well as after 0.4 mg suriclone nocturnal awakenings decreased significantly as compared with placebo, which was reflected in an improved subjective sleep quality after both dosages. Suriclone 0.2 mg did not induce any alterations in all night sleep. 4. In the morning, well-being, drowsiness and reaction time performance deteriorated after lorazepam as compared with placebo but not after suriclone. The latter was significantly superior to lorazepam with respect to subjective awakening quality, well-being, emotional rapport, drowsiness and attention. 5. Blood pressure and pulse remained unchanged after all of the drugs. Critical flicker frequency and muscle strength decreased only after lorazepam as compared with placebo.

Post marketing surveillance of zopiclone: interim analysis on the first 10,000 cases in a clinical study in general practice.

The tolerance of zopiclone, a hypnotic belonging to a new chemical group, the cyclopyrrolones, was studied in a follow-up trial in 23,000 insomniac outpatients treated for 3 weeks. The results from the interim analysis of the first 10,000 cases confirm the efficacy and safety of zopiclone under usual prescribing conditions. The average daily dose of zopiclone was 0.97 +/- 0.21 tablet (7.275 +/- 1.575 mg). The study population included 63.1% of female and 36.9% of male patients; the mean age was 52.3 +/- 16.6 years. 93.1% of the patients completed the trial. 8.2% of the patients experienced adverse reactions which resulted in drug discontinuation in only 2.8% of cases. In the global evaluation, the efficacy was rated excellent or good in more than 80% of the patients.

Zopiclone, the third generation hypnotic: a clinical overview.

Effective and safe hypnotics exist especially since the introduction of benzodiazepines (BZD) which appeared to bring major advantages over barbiturates. Ideally a new hypnotic should induce and maintain sleep without producing residual effect during the day and should be devoid of abuse and dependence potential. Zopiclone is a new hypnotic belonging to the cyclopyrrolone chemical class. Its elimination half-life is 5 to 6 h, no accumulation exists upon repeated administration, and its pharmacokinetic profile is not substantially modified in elderly and renal failure patients. Placebo-controlled studies have shown that zopiclone 7.5 mg is an effective hypnotic, and that it can improve all sleep variables in insomniacs. Its effects on sleep stages differ from those observed with BZD hypnotics: REM sleep is substantially unaffected by zopiclone and slow wave sleep is either unaffected or increased. Objective and subjective measurements during the day after bedtime administration of zopiclone, showed lack of residual effects and no residual impairment of cognitive functions. Zopiclone discontinuation is not accompanied by rebound effect and relevant withdrawal symptoms. Specific "craving effect" studies in alcoholics did not show an abuse potential for zopiclone. Side-effects are represented mainly by bitter taste and dry mouth with a minimal incidence of CNS depressant effects. Studies on the effects of zopiclone on respiratory functions failed to show detrimental effects. Efficacy and safety data on zopiclone suggest that this new drug can represent a useful alternative to existing hypnotics.

Clinical studies with the new anxiolytic alpidem in anxious patients: an overview of the European experiences.

Alpidem is a new imidazopyridine compound which has been selected in animal pharmacology for its anxiolytic and anticonvulsant activity, and for its high therapeutic index. In healthy volunteers, alpidem was well tolerated up to doses of 300 mg and appeared to be devoid of CNS toxic effects. An extensive clinical development plan has been carried out in Europe to test its efficacy and safety in anxious patients. In a series of 5 double-blind placebo controlled parallel group studies, alpidem was administered as a single dose in a situation of stress induced anxiety where the stress was represented by diagnostic investigations such as gastroscopy, cardiac catheterisation or minor surgical operations. In these studies, 188 patients received placebo and 188 received alpidem; their anxiety was assessed before and after the drug administration by means of visual analogue scales and state anxiety inventories. Alpidem at 50 and 75 mg was significantly better than placebo in reducing stress induced anxiety. Alpidem was then administered to patients suffering from severe generalized anxiety in doses from 50 to 150 mg/day for 3-4 weeks in 3 double-blind placebo controlled studies: 127 patients received alpidem and 80 received placebo. Patients were assessed by means of rating scales and visual analogue scales. Alpidem did show an anxiolytic activity in this patient population and was well tolerated especially with regard to CNS side-effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term treatment of epilepsy: open multicenter trial with progabide in epileptic patients.

A long-term open multicenter trial was carried out in 15 European centers with therapy-resistant epileptics to evaluate the efficacy and safety of progabide, a new antiepileptic GABA receptor agonist; 187 patients, suffering from partial epilepsy (57%), primary generalized epilepsy (20%), secondary generalized epilepsy (21%), and unclassified generalized epilepsy (2%), participated in the study. All patients had a total seizure frequency higher than one per month in spite of standard antiepileptic medication; 46% had a mean partial seizure frequency from daily to weekly. Progabide was administered at a mean daily dose of 30.5 mg/kg/day as an add-on to the standard antiepileptic drugs up to one year in 115 patients; 37 patients (19.8%) dropped out because of reasons which were not drug-related (bad compliance, lost to follow-up); in 12 patients (6.5%) progabide was withdrawn for side effects and in 20 (10.7%) for lack of efficacy. 71.3% of patients treated for one year (62% considering the 'cumulative' number of patients) experienced more than a 50% reduction in seizure frequency. This reduction was equally present in patients with partial epilepsy (63.9%) and with generalized epilepsy (62.2% of patients with primary and 57.1% with secondary generalized epilepsy). No signs of tolerance phenomena to the antiepileptic effect of progabide were observed. No side effects were reported in 56.7% of the patients. Clinical side effects were mild and transient, leading to progabide discontinuation in 6.5% of the patients only; an increase in SGPT was observed in 5.7% of the patients, these increases were transient and without any clinical symptom.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical activity of GABA agonists in neuroleptic- and L-dopa-induced dyskinesia.

It is well known that the therapeutic effect of neuroleptics is counterbalanced by the property of these drugs to induce serious neurological side-effects mainly represented by tardive dyskinesia. Several reports indicate that at the experimental level GABA agonists interact with dopamine neurons with effects on behavior, stereotyped and dyskinetic movements induced by either lesions or dopamine agonists. This action on dopamine-related events provides a basis for a possible therapeutic action of GABA agonists in dyskinesia. Previous results with the GABA agonists muscimol and THIP in tardive dyskinesia have not been encouraging. The present paper deals with clinical results obtained with the new GABA agonist progabide both in neuroleptic-induced dyskinesia and in L-dopa-induced dyskinesia from five studies conducted on a total of 57 patients. Twenty-nine patients suffering from neuroleptic-induced dyskinesia have been treated in three studies (two open, one double-blind cross over) with progabide at doses from 900 to 2400 mg/day; clinical evaluation and EMG testing are in favor of a therapeutic effect of progabide on dyskinesia. Twenty-eight patients with L-dopa dyskinesia have been studied in two double blind trials. At variance with studies in tardive dyskinesia progabide was not effective in this kind of dyskinesia but an increase in the "on" time has been observed in both studies. Attempts to treat tardive dyskinesia with various pharmacological tools are reviewed and discussed, showing that at present no established effective treatment exists for this frequent complication of neuroleptic use. The possible mechanism of action of progabide in dyskinesia is discussed in the light of its pharmacological properties. These results suggest that progabide can be useful in the treatment of neuroleptic-induced dyskinesia.

A comparison of the structure of small blood vessels in normal, denervated and dystrophic human muscle.

A light- and electron-microscopic study of the small arterial vessels and capillaries in muscle from 20 patients with Duchenne muscular dystrophy failed to adduce any direct morphological evidence that the necrobiotic muscle lesions in this disease are produced by muscle ischaemia. However the electron-microscopic studies showed that the basement membrane width in 3 out of 4 cases of Duchenne dystrophy so studied was significantly less than that or normal control material. In further case of Duchenne dystrophy, selected for study because some vessels in the biopsy muscle were surrounded by small round cell infilitrates, the basement membrane width was significantly greater than that in the normal control material. In the single case of spinal muscular atrophy studied, the basement membrane width was also significantly less than the control measurements. The possible relationship of these observations to the "ischaemic" theory of the pathogenesis of muscular dystrophy is discussed.