Showing papers on "Tolerability published in 1989"

Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients.

Abstract: 4-Hydroxyandrostenedione (CGP32349; 4-OHA) is a clinically effective treatment for advanced postmenopausal breast cancer by both the parenteral and p.o. routes, as a result of its inhibition of aromatase and consequent suppression of plasma estrogen levels. Thirty patients were randomized to treatment with 250 mg 4-OHA orally once, twice, and 4 times daily for 2 weeks and 29 of these plus a further 11 patients were then randomized to treatment with 250 or 500 mg i.m. every 2 weeks to determine the optimal dose for each route according to the suppression of serum estradiol levels. There was no significant difference between the 3 oral doses in their suppression of estradiol levels indicating that the maximum required p.o. dose of 4-OHA is probably 250 mg daily. Suppression by the parenteral dose of 250 mg every 2 weeks was marginally suboptimal but clinical considerations of response and tolerability indicate this as the optimal dose for i.m. injection. 4-OHA had no effect on serum levels of androstenedione, testosterone, or 5 alpha-dihydrotestosterone when given by either route but p.o. treatment with 4 doses of 250 mg daily reduced sex hormone-binding globulin levels by a mean of 34%. Serum levels of estrone as measured by gas chromatography-mass spectrometry were suppressed to approximately 40% of baseline by parenteral treatment. The half-life of 4-OHA p.o. was approximately 3 h, whereas the apparent half-life of injected drug was between 5 and 10 days after a more rapid clearance during the first 4 days after injection.

Ranitidine

Abstract: Synopsis Ranitidine, a histamine H2-receptor antagonist, is now well established as a potent inhibitor of gastric acid secretion effective in the treatment and prophylaxis of gastrointestinal lesions aggravated by gastric acid secretion. Therapeutic trials involving several thousands of patients with peptic ulcer disease confirm that ranitidine 300mg daily administered orally in single or divided doses is at least as effective as cimetidine 800 to 1000mg daily in increasing the rate of healing of duodenal and gastric ulcers. Similar dosages of ranitidine have been shown to relieve the symptoms of reflux oesophagitis and heal or prevent gastrointestinal damage caused by ulcerogenic drugs. Ranitidine 150mg orally at night maintains ulcer healing in the long term. Ranitidine has also demonstrated good results in the treatment of Zollinger-Ellison syndrome and in the prevention of aspiration pneumonitis when given prior to surgery and to pregnant women at full term. It may also have a place in the management of acute upper gastrointestinal bleeding and in the prevention of stress ulcers in the intensive care setting, although these areas require further investigation. Ranitidine has been used safely in obstetric patients during labour, in children, the elderly, and in patients with renal impairment when given in appropriate dosages. The drug is very well tolerated and is only infrequently associated with serious adverse reactions or clinically significant drug interactions. Even at high dosages, ranitidine appears devoid of antiandrogenic effects. Ranitidine is clearly comparable or superior to most other antiulcer agents in the treatment and prevention of a variety of gastrointestinal disorders associated with gastric acid secretion. With its favourable efficacy and tolerability profiles, ranitidine must be considered a first-line agent when suppression of gastric acid secretion is indicated.

Oxcarbazepine: a new drug in the management of intractable trigeminal neuralgia.

Abstract: The efficacy and tolerability of oxcarbazepine, a keto derivative of carbamazepine, has been assessed in six patients (two males, four females; mean age 61 years, range 42-77), with trigeminal neuralgia refractory to carbamazepine therapy, over a period of 6 months. An excellent therapeutic response to oxcarbazepine was seen in all patients with pain control correlating well with serum drug concentrations of oxcarbazepine and its primary active metabolite 10-OH-carbazepine. Onset of the effect was observed within 24 hours in all cases. An overall serum therapeutic concentration range, in the six patients, of 50-110 mumol/l of 10-OH-carbazepine corresponding to a daily effective dose range of 1200-2400 mg (14.6-35.6 mg/kg body weight) oxcarbazepine, was observed. There was a significant correlation between oxcarbazepine dose and serum oxcarbazepine (r = 0.695, p less than 0.05) and 10-OH-carbazepine (r = 0.957, p less than 0.001) concentrations. Oxcarbazepine was well tolerated and no significant side effects were identified, though a mild hyponatraemia was observed during high doses (greater than 28 and greater than 35 mg/kg/day) in two patients. It is concluded that oxcarbazepine has potent antineuralgic properties in the absence of significant side effects and therefore may be useful in the management of intractable trigeminal neuralgia.

Efficacy and tolerability of moclobemide compared with imipramine in depressive disorder (DSM-III): an Austrian double-blind, multicentre study.

Abstract: The antidepressant efficacy, tolerability, and safety of moclobemide, a reversible, monoamine oxidase-A inhibitor, were compared with those of imipramine in parallel groups of patients with a major depressive episode, in a 4-week, multicentre (17 centres), randomised study. A total of 381 patients were randomly allocated to either treatment; they were not required to avoid tyramine-rich foods. Drop-out rates were comparable in both groups at about 17%. Judged primarily on the HRSD, no significant differences in efficacy were observed between the groups, but the number of patients presenting with adverse events, as well as the total number of adverse events, was greater with imipramine. Cardiovascular tolerability was satisfactory and physical examination, body weight, and laboratory values were essentially unaffected in both groups.

Effectiveness and tolerability of long term treatment with cabergoline, a new long-lasting ergoline derivative, in hyperprolactinemic patients.

Abstract: Cabergoline (CAB) is a new oral dopaminergic compound showing a very long-lasting PRL-lowering activity and reported to be well tolerated The efficacy and tolerability of chronic treatment with CAB in 30 female hyperprolactinemic patients, aged 18-52 yr (6 microadenomas, 3 macroadenomas, and 21 functional hyperprolactinemias), were studied In a group of 10 patients who received CAB (08 mg once weekly or 04 mg twice weekly) for 8 weeks PRL levels normalized while on treatment and remained normal (8 patients) or greatly reduced (1 patient) for 1-2 months after discontinuation of the drug Twenty-six patients underwent chronic treatment (6-12 months) with an initial dose of 05 mg once weekly, subsequently increased to 1-2 mg in 10 patients and decreased in the other 2 Due to severe side-effects CAB was discontinued in 3 patients, in 1, 8, and 12 weeks A significant reduction of PRL levels was already observed after the first week of treatment (mean +/- SEM basal values, 901 +/- 133 vs 295 +/- 63 micrograms/L; P less than 0001) Twenty-two patients had normal PRL levels in 1-36 weeks (mean, 6 weeks) with 05-2 mg CAB Twenty-two patients resumed regular menses; 2 patients became pregnant after 3-11 months of treatment Thirteen patients complained of side-effects (nausea, hypotension, headache, gastric pain, dizziness, and weakness) that disappeared with time in 10 of them The comparison with a previous bromocriptine treatment regimen in 20 patients had shown that the number of patients requiring discontinuation of the latter drug was significantly higher (7 vs 3 patients; P less than 0001) However, 2 patients who needed to discontinue CAB were able to tolerate bromocriptine therapy A computed tomographic scan performed after 12 months of therapy in 7 patients showed a significant reduction (50%) of the adenoma in 5 In conclusion, our results show that CAB is a well tolerated new dopamine agonist with long-lasting activity that represents an advance in chronic medical treatment of hyperprolactinemic conditions

Overview of initial clinical studies with intravenous and oral GR43175 in acute migraine

Abstract: The novel 5-HT 1-like receptor agonist GR43175 has been evaluated as a treatment for acute migraine in a series of open, dose-ranging and controlled clinical trials. Patients with severe attacks of migraine have attended special pain or headache clinics for treatment and assessment. Given intravenously as a bolus, GR43175 is capable of aborting all migraine symptoms within 10-30 min in over 90% of cases at a dose of 64 micrograms/kg. Characteristic transient and reversible side effects with such a regimen include feelings of heaviness, pressure and occasionally warmth or tingling which can be diminished by extending the duration of drug administration to a short infusion. Initial dose-ranging studies with a dispersible tablet formulation of GR43175 have revealed an efficacy of 70-85% within 2 h with doses of 70-280 mg. Furthermore, tolerability is excellent. These encouraging early results warrant larger-scale controlled studies of GR43175 in acute migraine.

Efficacy and safety of vigabatrin in the long-term treatment of refractory epilepsy

Abstract: 1. The long term safety and efficacy of vigabatrin has been studied in 254 patients with refractory epilepsy (82% with partial seizures) in 23 different clinics in eight European countries. 2. This was an open multicentre study in which patients who had experienced a significant benefit from vigabatrin and had continued to take the drug for 1 year or longer were eligible for evaluation. The mean duration of therapy in the 254 patients was 22.7 months; 72 patients received vigabatrin for more than 2 years. 3. Patients were severely affected by epilepsy with a median monthly seizure frequency of 15.7 despite taking an average of 2.2 antiepileptic drugs. On vigabatrin, the median seizure frequency was about 35% of baseline, remaining stable over time despite a 10% reduction in the number of concurrent medications. 4. The lack of tachyphylaxis to the antiepileptic effect of vigabatrin is shown by the small number of patients who discontinued for insufficient efficacy (11%), two thirds of them during the first 6 months of follow-up. Maintenance of efficacy is also clearly demonstrated by analysis of 2 year and 3 year cohorts of patients. 5. Clinical and biological tolerability was excellent. There was a very low rate of drop out for adverse events (1.6%). Adverse events, mainly sedation, irritation and weight gain were mostly mild and transient. 75% of patients reported no adverse event at all. 6. Safety evaluation included serial neurological, ophthalmological and general examinations: no new abnormal clinical feature or adverse event emerged with long term therapy.

A placebo-controlled, double-blind, clinical trial of paroxetine in depressed outpatients.

Abstract: A placebo-controlled, randomized, double-blind study was carried out in outpatients suffering from major unipolar depressive disorder to assess the efficacy and tolerability of paroxetine in the treatment of depression. The study lasted for six weeks. After a placebo washout period of 4 to 14 days patients took 20mg of paroxetine or matched placebo as a morning dose for one week; thereafter the dose of paroxetine could be titrated between 10 and 50mg/day. Patients were evaluated at baseline, weekly during the first four weeks of the study, and at the end of six weeks; patients who entered a six-week extension phase were evaluated at 9 and 12 weeks. Evaluations were carried out using HAMD (including ECDEU factors), MADRS, HSCL, Covi anxiety and Raskin depression scales, CGI, and a seven-point rating of global improvement. Adverse events and laboratory values were also recorded at each assessment. One hundred and eleven patients entered the study, and efficacy data were available for 102 of these (49 on paroxetine and 53 on placebo). Efficacy measurements demonstrated significantly greater clinical improvement with paroxetine than placebo after two weeks of treatment, and this became even more marked after six weeks. Patients who continued treatment for a further six weeks maintained their clinical improvement. When adverse events were examined, statistically significant differences between paroxetine and placebo were seen only for sweating, diarrhoea, nausea, and somnolence. No significant changes were seen in any of the laboratory parameters measured. If these results are confirmed in future studies, paroxetine will represent an important addition to the treatments available for depression.

Paroxetine: pharmacokinetic and antidepressant effect in the elderly

Abstract: To evaluate the pharmacokinetic properties, efficacy, and tolerability of paroxetine in elderly depressed patients, a clinical study was set up - initially at Aalborg Psychiatric Hospital in Denmar ...

Long-term tolerability, pharmacokinetic and preliminary efficacy study of lamotrigine in patients with resistant partial seizures.

Abstract: Four adult men with resistant partial seizures underwent an intensive open-label protocol designed to evaluate long-term add-on lamotrigine (LTG) therapy. Following an 8-week baseline, LTG was added to their background medication(s) (carbamazepine in three; carbamazepine and phenytoin in one). Incremental LTG doses of 50, 100, 150, and 200 mg every 12 h were given on days 58-60, 61-63, 64-127, and 128-176, respectively. The patients were hospitalized during and after each of the dose increases for a total of 25 days. Frequent outpatient visits were performed biweekly, weekly, or monthly, depending on the phase of the protocol. Frequent clinical, electrocardiographic (ECG), and laboratory evaluations were performed. Serial blood levels and 24-h urine collections were performed sequentially. In patients 1, 2, and 3, LTG was well tolerated at 200 mg b.i.d. Patient 4 did not tolerate 150 mg, b.i.d., but tolerated and maintained complete seizure control on 100 b.i.d. All four patients tolerated LTG and continued to receive it for 39, 46, 105, and 104 weeks, respectively. Serial 12-h plasma LTG levels were obtained on days 63, 70, and 133. On these days, the mean (+/- SD) LTG clearances (dose/AUC) were 0.0436 +/- 0.0171, 0.0468 +/- 0.0093, and 0.0575 +/- 0.0160 L/h/kg, respectively. Some 43-87% of the LTG was recovered in the urine, predominantly as the glucuronide metabolite. In the four patients, the mean weekly seizure frequency per patient was 6.5 in baseline, 5.0 on submaximal LTG doses, and 3.5 on the maximum administered doses. Three of the four patients eventually experienced a greater than 50% decrease in seizure frequency. In conclusion, when given for long periods of time (9.5 months to 2 years), LTG was well tolerated in doses up to 400 mg/day and mean trough levels of 3.0 +/- 0.6 microgram/ml; LTG has a favorable pharmacokinetic profile and appears to exhibit first-order linear kinetics during long-term chronic dosing; LTG shows preliminary evidence of efficacy during long-term administration; and to date, our patients represent the longest reported experience of continuous and closely monitored LTG therapy in the literature.

Review of comparative clinical trials. Moclobemide vs tricyclic antidepressants and vs placebo in depressive states.

Abstract: Moclobemide is a reversible monoamine oxidase inhibitor (MAOI) which preferentially inhibits type-A MAO. In the present communication the results obtained with moclobemide in various clinical trials are reviewed. To this day, the antidepressant efficacy of moclobemide has been compared to that of placebo in four trials. The antidepressant efficacy of moclobemide (300-600 mg/d; N = 164) was found to be superior to that of placebo (N = 162) and comparable to that of imipramine (100-200 mg/d; N = 164) in a 6-w., double-blind, multicentre study, in patients suffering from a Major Depressive Episode (DSM-III). Two smaller trials, strongly suggest that moclobemide is more efficacious than placebo for the treatment of endogenous depression (ICD-9) and for the treatment of Dysthymic Disorders (DSM-III). The antidepressant efficacy of moclobemide was compared to that of imipramine, desipramine, clomipramine and amitriptyline. The antidepressant efficacy of moclobemide (300-600 mg/d; N = 189) was found to be comparable to that of imipramine (100-200 mg/d; N = 192) in a 4-w., double-blind, multicentre study, in patients suffering from a Major Depressive Episode. This finding is supported by the results obtained in 12 other smaller studies, using either imipramine, desipramine, clomipramine or amitriptyline as comparator drug. When the tolerability of moclobemide, as judged by reported and observed adverse events, is compared to that of placebo, it appears that only nausea is reported significantly more frequently with moclobemide than with placebo (9.5% vs 4.8%). In the trials comparing moclobemide to tricyclic antidepressant drugs (TCAs), the tolerability of moclobemide was constantly found to be superior to that of the TCAs; in particular the incidence of anticholinergic side effects was low with moclobemide and was significantly higher with the TCAs. The cardiovascular tolerability of moclobemide tended to be superior to that of the TCAs. Physical examination, hematology and clinical chemistry did not seem to be affected by treatment in any of the studies summarized in this review.

Placebo-controlled trial of potassium supplements in black patients with mild essential hypertension

Abstract: Forty-eight black patients with mildly increased blood pressure (BP) that had not yet been subjected to treatment took part in a double-blind clinical trial of the efficacy and tolerability of oral potassium supplements (64 mmol daily) versus a matching placebo (made of starch with coating) in a 16-week study. Potassium supplements produced a significant decrease in mean supine and standing BP within 4 weeks after treatment inception. Urinary potassium excretion increased significantly in the 24 patients who received potassium supplements (p less than 0.001). No significant changes occurred in plasma sodium and potassium concentrations or in urinary excretion of sodium during the study. All patients completed the trial without experiencing any notable untoward effects. These results are consistent with the premise that oral potassium supplements may exert hypotensive effects of clinically significant degree in patients with mild hypertension.

A double-blind, long-term study of tizanidine ('Sirdalud) in spasticity due to cerebrovascular lesions

Abstract: A double-blind study was carried out in 30 patients suffering from spasticity due to cerebrovascular lesions to compare the long-term efficacy and tolerability of tizanidine hydrochloride with that of baclofen. A 2-week titration phase identified the optimum dose of tizanidine (max. 20 mg/day) or baclofen (max. 50 mg/day) in each patient. Patients were then treated with this dose for a 50-week maintenance phase. Efficacy and tolerability parameters were evaluated first on a monthly and then on a bimonthly basis. Both tizanidine and baclofen caused an improvement in the symptoms associated with spasticity. In end-point analysis, 87% of patients showed an improvement (p less than 0.01) in excessive muscle tone - the major efficacy parameter in this study - in the tizanidine group, while 79% improved (p less than 0.01) in the baclofen group. Side-effects in the tizanidine group were mild and transient and no patients discontinued the study; in the baclofen group, 3 patients discontinued the study due to severe side-effects. However, both drugs were assessed as effective and fairly well tolerated in the long-term. Although there were no statistically significant differences between the two drugs, the global assessment of antispastic efficacy revealed a nearly significant difference (p = 0.057) in favour of tizanidine and the global assessment of tolerability was also in favour of tizanidine.

A controlled single-dose study of the efficacy, dose response and duration of action of nicorandil in angina pectoris.

Abstract: Nicorandil is a vasodilator that acts on the venous and arterial beds of the systemic circulation. It reduces both cardiac preload and afterload, as well as improving coronary blood flow. The present study assessed the efficacy, tolerability, duration of action and optimal single dose of nicorandil in patients with stable angina pectoris. Treadmill exercise tests were undertaken by 8 patients at 2 and 6 hours after single oral doses of 20, 40, and 60 mg of nicorandil, and placebo. Doses were administered at weekly intervals in this double-blind, cross-over study. The duration of exercise to onset of angina was increased by 58, 96 and 125 seconds over baseline values (p less than 0.01) with the 20-, 40- and 60-mg doses of nicorandil, respectively. Significant improvement in exercise capacity compared with the effects of placebo was maintained at 6 hours after administration. The antianginal activity was accompanied by a marked reduction in blood pressure both at rest and during exercise, which resulted in severe dizziness and fainting in 2 of 6 patients after the 60-mg dose. However, significant reflex tachycardia occurred only at 2 hours after the 60-mg dose. Plasma concentrations of nicorandil correlated with percent reductions in blood pressure at 2 hours after administration (p less than 0.001) and with increasing total exercise work load (p less than 0.01). The incidence of adverse events appeared to be dose related. Headache and dizziness accounted for most of the reported events. The 20-mg single dose of nicorandil was considered to provide the best combination of antianginal activity and tolerability in this study.

Clinical activity and tolerability of trazodone, mianserin, and amitriptyline in elderly subjects with major depression: a controlled multicenter trial.

Abstract: The aim of this multicenter study was to compare trazodone (TRA) with two reference drugs, amitriptyline (AMI) and mianserin (MIA), under double-blind conditions, in an elderly population, to ascertain age-related patterns for efficacy and tolerability. One hundred six elderly depressed inpatients, ranging in age from 60 to 83 years, diagnosed as having major depression according to DSM-III, were treated with 75 mg AMI (37 patients), 60 mg MIA (33 patients) or 150 mg TRA (36 patients) p.o.t.i.d. for 5 weeks. There were no differences in the clinical outcome among the three groups of patients at the end of the trial, with a significant amelioration (p less than 0.01) for the Hamilton Rating Scale for Depression (HRS-D) and the Geriatric Depression Scale (GDS). TRA showed a lower overall prevalence of side effects than AMI or MIA, particularly for anticholinergic (p = 0.03 vs. AMI) and cardiovascular (p = 0.05 vs. MIA) effects. For these data GDS seems to be most reliable in detecting changes in elderly depressive symptomatology; moreover a comparable therapeutic response (among the three drugs) but a better tolerance for atypical antidepressants, particularly TRA, make advisable the use of the latter drug in the elderly population.

Efficacy and tolerability of combined topical treatment of acne vulgaris with tretinoin and erythromycin in general practice.

Abstract: Efficacy and tolerability of a gel preparation with 0.025% tretinoin and 4% erythromycin in acne vulgaris was evaluated in an open multicentre study. A total of 1337 patients of either sex, aged 8 to 68 years, were enrolled in the study; 13 had to be excluded from analysis. Some 499 patients had received former acne treatment; this was described as non-efficient or poorly efficient in 90% of the patients. The treatment period lasted up to 14 weeks. Efficacy was determined by counting the acne lesions (comedones, papules and pustules) before drug administration and every second week during the treatment period. Lesions had diminished after 2 weeks in about 35% of the patients. At the end of the treatment period, comedones were eliminated in 47.0% and improved in another 41.4%. Papules were eliminated and improved in 58.2% and 32.6%, pustules in 74.3% and 18.3% respectively. Side-effects (erythema, burning, pruritus, scaling and dryness of the skin) occurred in 203 patients (15.3%). Treatment was stopped in 25 subjects (1.9%) due to intolerance reactions. The results of the present study thus confirm the high efficacy and tolerability of the fixed combination observed previously in more selected patients. The fixed combination of tretinoin and erythromycin makes retinoic acid treatment possible even by a general practitioner.

Efficacy and tolerability of a new antipsychotic compound (risperidone): results of a pilot study.

Abstract: Risperidone is a new benzisoxazole derivative displaying a very potent serotonin antagonism and a potent dopamine antagonism in pharmacological studies. These properties suggest the hypothesis that risperidone may exert antipsychotic effects and be superior to classic neuroleptics in its beneficial effects on negative and affective symptoms and its low extrapyramidal side-effect propensity. In an open pilot study 13 patients suffering from acute schizophrenic psychosis were treated with risperidone within an individually adapted dose range from 1 to 10 mg per day. A good antipsychotic efficacy could be demonstrated in 6 of the 8 patients who completed the trial. Risperidone was very well tolerated. The substance possesses a low EPS-inducing profile. Future research has to test the suggested advantage of risperidone over other neuroleptic drugs and its performance in the treatment of chronic schizophrenic patients.

Quinapril: a double-blind, placebo-controlled trial in essential hypertension.

Abstract: Quinapril HCl is a novel, nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor. The Study Group evaluated its efficacy (20, 40, 80 mg daily with forced dose titration determination at trough blood pressure) once daily versus twice daily versus placebo, as well as its tolerability and safety, in 270 patients with mild to moderate essential hypertension (WHO Stages I and II, sitting diastolic blood pressure [DPB] greater than or equal to 95 mm Hg), for twelve weeks. Reductions in DBP of up to 13 mm Hg were obtained, and in full dosage more than 65% of patients achieved a reduction in DBP of 10 mm Hg or more from baseline or reduced their DBP to 90 mm Hg or less. Quinapril was well tolerated, and reported adverse effects were scarcely more frequent than in the placebo group. Once daily doses of quinapril were as safe and effective as twice-daily doses. Quinapril is likely to exhibit good therapeutic utility in the management of essential hypertension.

European Osteosarcoma Intergroup

Abstract: A preliminary analysis is made of 307 patients who were entered into a randomized study comparing the tolerability and efficacy of two chemotherapies is done. Special attention is given to the surgical part of this study. Amputation was done in 31.6% of cases and conservative surgery in 58%. Local recurrences appeared in 17 cases after a period of 10 months. There were postoperative complications in 34 patients. There was no significant difference in the recurrences in the two chemotherapy. The recurrences were as frequent in the ampuation group as in the group which receiving conservative treatment.

Tolerability of long term clozapine treatment.

Abstract: Tolerability of long term clozapine treatment (7-8 years) was investigated in 27 female patients (age 34-77 years). Diagnosis according to ICD 9 was schizophrenia in 21 patients, severe psychomotor agitation with mental deficiency in 4 patients and an "endogenous" depression in 2 patients. All patients had previously been treated with different neuroleptics but with inadequate response or distressing side effects. The duration of the disorder was 10-36 years, duration of hospitalisation 10-36 years. At the day of investigation the total dose of clozapine ranged from 52-826 g, the average total dose being 385 g. The daily dose of clozapine ranged from 75 to 600 mg, the average daily dose being 225 mg. Only 2 patients were treated exclusively with clozapine, the other 25 patients were also receiving other neuroleptics. Seventy eight per cent of the investigated patients complained about hypersalivation and 63% showed overweight. In 37% of the patients the EEG demonstrated abnormalities. Mild parkinsonism was reported in 15% and akathisia in 11% of the patients, all these patients being on combined treatment. Clozapine did not induce tardive dysakinesia (TD) in any of the patients within a treatment period of 7-8 years. It is concluded that a potential benefit of clozapine includes a low incidence of neurological side effects even after long term administration.

Early studies with the novel 5-HT1-like agonist GR43175 in healthy volunteers:

Abstract: A series of single dose studies has been undertaken after intravenous, subcutaneous and oral administration to healthy volunteers to determine safety, tolerability and pharmacokinetics of GR43175, a novel 5-HT 1-like receptor agonist. GR43175 proved to be well tolerated using all routes of administration. Minor side effects were reported including scalp tingling, sensations of bodily warmth, lightheadedness and heavyheadedness. In addition, short-lasting vasopressor effects were encountered, although no drug-related changes were seen in heart rate and ECG or in laboratory safety screens. The drug was rapidly absorbed after oral dosing and had a mean absolute bioavailability of 14% due at least in part to first-pass metabolism. Plasma concentrations in healthy volunteers fell within the range for producing relief of headaches in migraine patients. GR43175 had a high mean plasma clearance (1313 ml/min), the majority of which was due to non-renal clearance and a large volume of distribution (2351). The mean half-lives were 1.7 h and 2.3 h after intravenous and oral doses, respectively.

Efficacy and Tolerability of Ebastine at Two Dose Levels in the Treatment of Seasonal Allergic Rhinitis

Abstract: The efficacy and tolerability of 2 different dose levels of the selective H1-antagonist, ebastine (10 and 20mg once daily), were compared in 101 patients with acute seasonal allergic rhinitis in a randomised double-blind parallel study. The causative allergens were Parietariae, Gramineae or ash tree pollen. The results from nasal provocation tests and assessment of symptom intensities before and after treatment for 7 days showed that both doses of ebastine provided significantly greater clinical improvement and protection against the causative allergen than placebo. Treatment was considered effective by the physician in 64% of patients receiving ebastine 20mg, in 72% of those receiving ebastine lOmg and 33% of placebo recipients. Ebastine was well tolerated, with similar numbers of patients reporting side effects in each treatment group. No statistically significant differences were found between treatment with ebastine 10 and 20mg in terms of efficacy or tolerability. The results of this study suggest that the therapeutic efficacy of ebastine lOmg once daily is not surpassed by that of 20mg once daily in the treatment of patients with acute seasonal allergic rhinitis.

Tolerability of enalapril in congestive heart failure.

Abstract: This report reviews the tolerability profile of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, in the treatment of patients with congestive heart failure. Data have been collected from 546 patients treated with enalapril for up to 9 months in clinical trials other than the Cooperative North Scandinavian Enalapril Survival Study. Results in patients treated with enalapril (n = 193) or placebo (n = 195) in double-blind, controlled clinical trials show that the incidences of death, serious adverse experiences, and adverse experiences requiring discontinuation of double-blind therapy, as well as the overall incidence of such experiences, were similar in the 2 groups. However, certain adverse experiences that are related to the mechanism of action of ACE inhibitors were seen more often after enalapril than after placebo treatment. Dizziness and hypotension were the most frequent adverse experiences reported in patients with heart failure treated with enalapril. The most frequent laboratory adverse experiences were increases in blood urea nitrogen and serum creatinine levels. hyperkalemia was also seen in patients receiving enalapril. It is possible to identify patients at risk of these experiences before initiating treatment with enalapril and to take certain measures (such as withholding or reducing the dose of diuretic drugs and discontinuing potassium supplements or potassium-sparing diuretic drugs) to reduce the likelihood that hypotension, increases in blood urea nitrogen and serum creatinine levels, or hyperkalemia will occur. Angioedema, a recognized adverse effect of ACE inhibitors, was not seen in the clinical trials reviewed here. Cough , another recognized adverse effect of these agents, was seen infrequently and rarely resulted in the discontinuation of enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxiracetam in the treatment of primary degenerative and multi-infarct dementia: a double-blind, placebo-controlled study.

Abstract: A multicentre, double-blind, between-patient study was carried out to evaluate the efficacy and tolerability of oxiracetam (800-mg tablets), in comparison with placebo, each given twice daily for 12 w

Therapeutic and side-effect profile of a selective and reversible MAO-A inhibitor, brofaromine. Results of dose-finding trials in depressed patients.

Abstract: Brofaromine (CGP 11 305 A), a new reversible and selective MAO-A inhibitor, was studied in two multicentre, (Trial A and Trial B) double-blind, dose-finding trials in a total of 124 depressed in-patients. Doses of 25, 50 and 75 mg bid were compared, to determine which was the most effective. The duration of the trials was four weeks. The comparative drugs were nomifensine (100 mg/day) and tranylcypromine (20 mg/day). The majority of patients in the Trial A was classified as "endogenous" depression. Diagnosis of depression was based on DSM-III or ICD-9 criteria. Conversely, most of the patients in Trial B were "non-endogenous" depressives. In "endogenous" depression, a statistically significant linear dose-response relationship was found in all the efficacy variables assessed. The most effective dose was 150 mg/day. This dose gave a mean drop of 25.3 +/- 11.9 (S.D.) points in the total Hamilton Depression Rating Scale (HAMD) scores and provided successful treatment in 83% of the patients treated, success being defined as a drop of at least 50% in the initial HAMD score at the end of the trial period. In "non-endogenous" depression, no statistical difference was found between the four treatment groups in any of the efficacy variables assessed. Response rate in all brofaromine groups averaged 59% (tranylcypromine group 60%). Tolerability was good in 90% or more of the brofaromine patients in both trials, regardless of the dose administered. The side effects reported most frequently were sleep disturbances, nausea, and headaches.