Efficacy and safety of BMY 21,502 in Alzheimer disease.

OBJECTIVE: To assess the efficacy and safety of BMY 21,502, a nootropic agent, in patients with mild-to-moderate Alzheimer disease. DESIGN AND PARTICIPANTS: Sixty-nine patients with Alzheimer disease (28 men, 41 women, mean age 72 y, range 54-92, mean Mini-Mental State Examination (MMSE) score 23.5) were randomized to receive either BMY 21,502 (n = 34) or placebo (n = 35) for 12 weeks of double-blind treatment followed by a 4-week placebo washout period. SETTING: Outpatient research facility. MEASUREMENTS: Primary efficacy assessments were the Alzheimer's Disease Assessment Scale (ADAS) and the Clinical Global Impressions Scale. The Computerized Neurological Test Battery and MMSE were performed as secondary efficacy measurements. RESULTS: Although overall effects were not statistically significant (p > 0.05), patients taking BMY 21,502 showed a mean change in the ADAS cognitive score of -1.5 points at week 12, compared with -0.5 in patients who received placebo. Patients with moderate dementia (MMSE < or = 20) showed a greater change at week 12 with BMY 21,502 (-2.7 points) compared with placebo (+0.3 points), but the difference was not statistically significant. Although BMY 21,502 was well tolerated in general, patients treated with BMY 21,502 experienced higher rates of abnormal liver enzyme concentrations and nausea than did those in the placebo group. There was also a higher rate of discontinuations in the BMY 21,502 group, with 12 of 34 (35%) patients in the BMY 21,502 group discontinuing, compared with 3 of 35 (9%) in the placebo group (p < 0.05). CONCLUSIONS: In this pilot study, BMY 21,502 was not found to be significantly superior to placebo during the treatment period. The compound was generally well tolerated, although 8 of 34 (24%) patients discontinued active drug treatment. Further evaluation of BMY 21,502 in a larger study population may be warranted.

BMS-181168 for protection of the human brain against hypoxia: double-blind, placebo-controlled EEG mapping studies.

In a double-blind, placebo-controlled, cross-over trial, the antihypoxidotic properties of BMS-181168 (previously BMY 21502)--a 1-[[1-[2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2- pyrrolidinone alleviating impairment of learning and memory in the animal--were studied utilizing EEG mapping under an experimental hypoxic hypoxidosis. The latter was induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (N2) (found at 6000 m altitude), which was inhaled for 23 minutes under normobaric conditions by 16 healthy male volunteers (aged 23-35 years, mean 27.2 years). After an adaptation session, they received in randomized order at weekly intervals oral single doses of placebo, or of 100 mg, 200 mg, and 400 mg BMS-181168. Evaluation of blood gases (PO2, PCO2, SO2), adverse events, and EEG mapping was carried out prior to drug administration and 2, 4, 6 and 8 hours post-drug, on each occasion under normoxic and transient hypoxic conditions. Hypoxemia was controlled by drawing arterialized capillary blood samples from the earlobes after hyperemization of the latter (after 0, 14, and 23 minutes of hypoxic gas inhalation) and by oximetry. After 23 minutes of inhalation, analysis showed a drop in PO2 from 98 to 48 mm Hg, in PCO2 from 41 to 31 mm Hg, and in SO2 from 97 to 80%. Descriptive statistical analyses of EEG mapping data demonstrated under hypoxia/placebo conditions an increase in delta/theta activity and a decrease in alpha activity as well as a slowing of the delta/theta centroid and an increase in the alpha and beta centroid, which suggests a marked deterioration in physiological vigilance.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition kinetics of buspirone in patients with renal or hepatic impairment after administration of single and multiple doses.

The single dose and steady-state pharmacokinetics of buspirone and its metabolite 1-pyrimidinyl piperazine (1-PP) have been evaluated in normal volunteers and patients with renal or hepatic impairment, using a parallel group design, with assignment of patients to study group on the basis of the degree of renal (mild, moderate, severe) or hepatic (compensated or decompensated) impairment. Each healthy volunteer or patient received a single dose of 10 mg buspirone on Day 1 of the study, and starting 36 h after the first dose, healthy volunteers and patients received 10 mg doses of buspirone every 12 hours for 9 days. On the morning of Day 10 they received the last dose. Serial blood samples were collected on Days 1, 5 and 10 and plasma was analysed for buspirone and 1-PP. The plasma concentrations of buspirone and 1-PP were highly variable regardless of the renal or hepatic function. The peak concentrations (Cmax) and area under the curves (AUC) of buspirone and 1-PP on Days D5 and 10 were higher than on Day D1. The trough levels (Cmin) and AUCs (D5 and 10) of buspirone and 1-PP indicated, that, regardless of renal or hepatic function, steady state was reached after 3 to 5 days of dosing. At steady-state, patients with renal or hepatic impairment had significantly higher Cmax and AUC values of buspirone than in normal volunteers. However, the intensity and frequency of adverse experiences in patients with renal or hepatic impairment were not significantly different from those observed in normal volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of the Computerized Neuropsychological Test Battery (CNTB) in an efficacy and safety trial of BMY 21,502 in Alzheimer's disease.

BMY 21,502 is a nootropic which protects memory and enhances long-term potentiation according to preclinical findings. Alzheimer's disease (AD) patients who were diagnosed by DSM-III-R and NINCDS-ADRDA criteria were enrolled in a 12-week double-blind investigation of BMY 21,502 vs. placebo at 300 mg tid. The study design included a 1-week placebo lead-in and a 4-week placebo washout in addition to the 12-week double-blind treatment period. Efficacy was assessed with the Alzheimer's Disease Assessment Scale (ADAS) and the Computerized Neuropsychological Test Battery (CNTB) at weeks 4, 8, 12, and 16. Clinical Global Impression (CGI) assessments were also performed biweekly. Sixty-nine patients (28M, 41F; mean age 72 years, range 54 to 92 years) were enrolled in the study. Baseline Mini-Mental Status Examination (MMSE) scores ranged from 16 to 26 (mean 23.5) in patients on active drug (n = 34), and from 15 to 26 (mean 22.5) in placebo patients (n = 35). Baseline efficacy scores were comparable for drug and placebo patients (p > 0.05). Twelve (35%) patients who received BMY 21,502 withdrew from the study, 8 (24%) due to adverse events. Three (9%) patients who received placebo withdrew from the study, all due to adverse events. Patients on active drug who were valid for analysis of efficacy (n = 22) showed a mean decrease in ADAS of -1.5 at week 12, vs. a mean change of -0.5 in patients who received placebo (n = 32), although there was no significant difference between the two (p > 0.05). Correlations between the CNTB summary scores and ADAS cognitive subscores were, nevertheless, highly significant at baseline (r = -0.83, p = 0.0001) and week 12 (r = -0.83, p = 0.0001). Correlations between the word list learning, spatial, and naming subtests of the ADAS and CNTB were also highly significant (p = 0.0001). Although modest, the findings for active drug vs. placebo response in this study suggest that BMY 21,502 should be further investigated, with a larger study population, in order to fully determine the compound's potential efficacy.

Buspirone therapy in anxious elderly patients: a controlled clinical trial.

Forty patients over 65 years of age with anxiety symptoms due to an anxiety state (N = 20) or secondary to neurotic depression (N = 20) took part in a double-blind, placebo-controlled trial conducted in a primary care practice. All patients were receiving concomitant drug therapy for chronic medical conditions; 70% were receiving two or more nonpsychotropic drugs in addition to the study medication. Patients were randomly assigned to treatment with buspirone 5-30 mg/day or placebo for 4 weeks, with clinical evaluations made weekly. One buspirone-treated and two placebo-treated patients discontinued treatment after 2 weeks because of lack of efficacy. Buspirone treatment resulted in significantly greater (p less than or equal to 0.05) improvement on the Hamilton Rating Scale for Anxiety, Hamilton Rating Scale for Depression, and Clinical Global Impression assessment than did placebo. Mild adverse experiences were reported by five buspirone-treated and nine placebo-treated patients. Buspirone (mean dose, 18 mg/day) proved equally effective for elderly patients suffering anxiety states or neurotic depression at doses similar to those used in younger patients, and was well tolerated by elderly patients receiving treatment for other chronic medical conditions.

Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression.

The azapirone class of anxiolytic drugs is being evaluated for clinical use in the treatment of depression. Buspirone, a serotonin (5-hydroxytryptamine, 5-HT) partial agonist active at the 5-HT1A receptor subtype, was evaluated in the treatment of depression in a series of five placebo-controlled, parallel group studies involving 382 patients with DSM-III major depression and significant associated anxiety symptoms (both Hamilton depression [HAM-D] and Hamilton anxiety [HAM-A] scales greater than or equal to 18). Buspirone therapy was initiated at 15 mg/day with individual dose titration to a maximum of 90 mg/day and resulted in marked improvement in both depressive and anxiety symptoms. Analyses of the composite data base from the five studies show significant (p less than 0.05) improvement in mean HAM-D, HAM-A, and Clinical Global Impression-Global Improvement scale ratings for buspirone-treated compared with placebo-treated patients. Of particular interest was significant improvement in cardinal depression symptoms, e.g., depressed mood, guilt, work and interest, anergia, and diurnal variation of mood. Subset analyses revealed that patients with melancholic-type major depression and patients with more severe symptoms (judged by higher initial HAM-D or HAM-A total scores) responded better to buspirone than did patients who were less ill. The buspirone dose most frequently associated with clinically significant improvement was 40 mg/day. Gepirone, an analogue of buspirone with highly selective binding affinity for the 5-HT1A receptor subtype, also shows promise of antidepressant efficacy in preliminary controlled clinical trials. These data suggest that azapirones, which as partial agonists modulate 5-HT1A receptor function, have clinically important antidepressant properties.

A double-blind comparison of buspirone, clobazam, and placebo in patients with anxiety treated in a general practice setting.

Sixty patients being treated for anxiety in a primary care facility received (double-blind) buspirone, the benzodiazepine drug clobazam, or placebo for 3 weeks. The mean daily dose at the end of treatment was 23 mg for buspirone and 21 mg for clobazam. Patients were assessed weekly using the Hamilton Rating Scale for Anxiety and Clinical Global Impression scale. Both active treatments produced significant improvement in anxiety symptoms compared with placebo as early as the first week of treatment, and there was progressive improvement over the subsequent 2 weeks. Response to buspirone was equally favorable in anxious patients who experienced depressive symptomatology.

Serotonergic anxiolytics and treatment of depression.

The serotonin 5-hydroxytryptamine-1A (5-HT1A) receptor agonists buspirone and gepirone have effects on serotonergic systems, including presynaptic and postsynaptic receptors, that predict both anxiolytic and antidepressant activity. Chronic administration of both drugs produces a down-regulation of 5-HT2 receptors, a finding common to most antidepressant drugs irrespective of mechanism of action. In addition, gepirone induces a full-blown serotonin syndrome in rodents and is active in the behavioral despair test mediated by an action on serotonergic neurons. Buspirone is active in this paradigm when injected directly into the serotonergic dorsal raphe nucleus. The therapeutic effects of both buspirone and gepirone have been assessed in placebo-controlled studies of patients with major depression. Findings in these studies support antidepressant efficacy in addition to anxiolysis. In double-blind studies of patients with major depression treated for 8 weeks, each drug was found to be superior to placebo in improvement in Hamilton Depression and Anxiety total scores as well as individual depressive symptoms. These clinical findings are consistent with preclinical pharmacology suggesting that 5-HT1A partial agonists may possess intrinsic antidepressant activity.

Serum prolactin levels after buspirone in man.

The acute effects of buspirone, an anxiolytic with mixed dopamine (DA) agonist-antagonist properties (achieved by blocking pre- and postsynaptic receptors) on serum prolactin (PRL) were studied in cross-over and double-blind trials in ten healthy young males. Sulpiride (200 mg) was used as a control drug; it raised PRL by almost 800%. Buspirone (25, 50 and 100 mg) raised serum PRL dose-dependently; the greatest increases (30, 70, and 320% from baseline, respectively) were seen 1 h after each dose. The results suggest that buspirone blocks postsynaptic DA receptors only at doses higher than those needed for anxiolysis.

Buspirone in Parkinson's disease.

Buspirone, an anxiolytic unrelated to benzodiazepines that may act at the presynaptic dopamine receptor, was given to 11 patients with Parkinson's disease in an open label study. Seven patients completed the initial 10 week study achieving doses of 50-70 mg/day without any significant change in their clinical status. Six patients continued for an additional 3-11 weeks with increases in dose to 65-100 mg/day. Two of the three most severely affected patients had mild worsening of parkinsonian symptoms. Buspirone is ineffective in the treatment of Parkinson's disease, but at anxiolytic doses (less than 40 mg/day) does not adversely affect parkinsonian disability.

Comparative effects of a repeated dose regime of diazepam and buspirone on subjective ratings, psychological tests and the EEG.

Two doses of buspirone (5 and 10 mg tds), 1 dose of diazepam (5 mg tds) and placebo were administered to 8 normal subjects for a period of 8 days. Each subject received each drug in a balanced order with a minimum interval of 1 week between courses. Psychotropic effects were assessed with a battery of physiological, psychomotor and subjective tests on the first, third and last days of treatment both before the first daily dose and at 1 h and 3 h after it. Diazepam showed a characteristic profile of action producing EEG changes and psychological impairment after a single dose which were still present after a week's treatment. Such effects were minimal after buspirone. Both drugs increased subjective ratings of drowsiness but these feelings tended to decrease after a week's treatment on the clinical doses. Buspirone (10 mg tds) produced some unpleasant side-effects initially but tolerance to these invariably developed after 3 days treatment.

Effects of alcohol on buspirone and lorazepam actions.

Psychomotor and psychologic effects of single doses of buspirone (10 and 20 mg) and lorazepam (2.5 mg) alone or combined with alcohol (1 gm/kg) were investigated in 12 healthy young men (crossover study). Lorazepam alone impaired psychomotor skills (tracking, body balance, extraocular muscle balance, and flicker recognition), the effects being maximal at 180 min. This impairment was not subjectively perceived by the subjects. Neither dose of buspirone alone impaired objective measurements, although buspirone, especially in the 20-mg dose, was felt to cause drowsiness, weakness, and faintness. Lorazepam, but not buspirone, interacted with alcohol.

Tofisopam, a novel 3,4-benzodiazepine: multiple-dose effects on psychomotor skills and memory. Comparison with diazepam and interactions with ethanol.

Twelve healthy male volunteers were treated (double-blind crossover design) with tofisopam (a new 3,4-benzodiazepine), diazepam, or placebo, on 2 consecutive days each. Psychomotor skills were impaired after a single dose of diazepam (10 mg) given on day 1. Measurements on day 2 showed that some tolerance had developed to the diazepam-induced impairment of reactive and coordinative skills, but not to its effects on flicker fusion or on the extraocular muscle balance. Tofisopam failed to impair performance both as a single dose (100 mg) and after repeated doses (100 + 50 + 50 + 100 mg). The subjects felt more fatigue, dizziness, calmness, and passiveness after diazepam than after tofisopam. When either drug was given together with 0.8 g/kg ethanol on day 2, the breath ethanol concentrations were 0.7--1.0 mg/ml and all psychomotor skills were impaired. Diazepam + ethanol particularly impaired memory and learning as well. After this combination the subjects were classified (time anticipation test) as 'disqualified drivers' more often than after placebo. It is concluded that diazepam, as well as either benzodiazepine with ethanol, may reduce the ability to drive vehicles or operate machinery.