Adinazolam sustained-release treatment of panic disorder: a double-blind study.

Two hundred six outpatients with panic disorder and agoraphobia were randomly assigned to receive 4 weeks of treatment with placebo or sustained-release adinazolam under double-blind conditions. Eighty-eight percent of patients receiving drug and 85% of patients receiving placebo remained in the study at week 4. This report describes the "intent-to-treat" analysis of 202 patients who made at least one follow-up visit after randomization at baseline. On the basis of the Clinical Global Impressions-Improvement Scale, 69.7% of the adinazolam-treated patients were much or very much improved compared with 39.6% of the placebo-treated patients at week 4 or end-point (p = 0.0001). At week 4, panic attacks were completely blocked in 57.1% of adinazolam-treated patients and in 39.2% of the placebo-treated patients (p = 0.009). Adinazolam sustained-release treatment was statistically more effective than placebo treatment on measures of global improvement, number of panic attacks, SCL-90 phobia severity, main phobia severity, and anticipatory and general anxiety. No drug-placebo differences were found for overall self-rated phobia severity, unexpected or situational panic attacks, or for work, family, or social disability.

Relationship between concentrations of adinazolam and its primary metabolite in plasma and therapeutic/untoward effects in the treatment of panic disorder.

Adinazolam mesylate, a triazolobenzodiazepine with antidepressant and anxiolytic activity, has been shown in several studies to treat panic disorder effectively. This report presents the results of analysis of concentrations in plasma of adinazolam and its primary metabolite, N-desmethyladinazolam (NDMAD), determined as a part of a flexible-dose, double-blind study of the efficacy of adinazolam mesylate sustained release tablets in the treatment of panic disorder with agoraphobia. Dosages administered in the study were titrated from 30 mg/day up to a maximum of 120 mg/day. Concentrations in plasma were determined by high-performance liquid chromatography at clinical evaluations at the end of treatment weeks 1, 2, and 4. The concentrations of both compounds were proportional to the administered dose. An inverted U-shaped concentration-response curve was apparent, where response was based on a priori definitions contained in the study protocol. However, this was probably a result of the flexible-dose study design used. By use of the post hoc definitions of response, as measured by the Clinician's Global Improvement Scale and the total panic attack frequency, logistic regression analysis resulted in more adequate predictions of actual response frequencies. Results indicate that NDMAD contributes to the therapeutic effects of adinazolam mesylate sustained release tablets in the treatment of panic disorder. The exact contributions of adinazolam and NDMAD to response in panic disorder could not be determined, because of the correlation between adinazolam and NDMAD concentrations on multiple dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative clinical profiles of triazolam versus other shorter-acting hypnotics.

The efficacy, safety, and performance of triazolam was compared with those of other shorter-acting hypnotics acting on the gamma-aminobutyric acid (GABA) receptor--zopiclone, zolpidem, midazolam, brotizolam, temazepam, lormetazepam, and loprazolam. In all, 5506 patients participated in 38 clinical and epidemiologic studies, of whom 2462 were treated with triazolam in parallel-design and crossover studies. To provide clinically relevant comparisons, only studies using comparator agents in doses equipotent to the triazolam doses were included. Two general findings emerged. First, "serious" central nervous system side effects, such as excitement and violence, were not demonstrated for any of the hypnotic agents, including triazolam. Other central nervous system side effects, such as depression and irritability, were reported with equal frequencies for all the hypnotics reviewed. Rebound insomnia, reported intermittently with most of these agents, was short-lived and not clinically significant. So-called early morning insomnia was noted only once and does not appear to be a valid clinical entity. Daytime anxiety was not observed in large numbers of triazolam-treated subjects studied, which is contrary to claims that the drug is anxiogenic. Second, a remarkable similarity was found among all of these shorter-acting agents in terms of efficacy, side effects, and performance-related effects. This was particularly of note for zopiclone and zolpidem. Although claims have been made suggesting differences, evaluation of the studies herein showed that these nonbenzodiazepine hypnotics were indistinguishable from triazolam and other benzodiazepine hypnotics in their clinical and pharmacologic activity. Thus, different chemical structures did not a priori predict different clinical profiles when drugs share a similar mechanism of action.

Effect of inhaled piriprost (U-60, 257) a novel leukotriene inhibitor, on allergen and exercise induced bronchoconstriction in asthma.

The leukotrienes, a group of oxidative metabolites of arachidonic acid, have potent pharmacological actions on human airways. We have investigated the effects of a leukotriene synthesis inhibitor, piriprost (U-60, 257) administered by inhalation on allergen and exercise induced bronchoconstriction in 12 subjects with allergic asthma. Subjects underwent diagnostic challenges with allergen and treadmill exercise to define the strengths of the stimuli required to reduce the FEV1 to about 25% of baseline (PS25). On separate study days subjects inhaled either piriprost 1 mg or vehicle placebo, followed 15 minutes later by the PS25 allergen or exercise. The FEV1 was measured at regular intervals before and after challenge up to 60 minutes. After allergen challenge in six subjects peak expiratory flow (PEF) was measured for the following 20 hours. When compared with placebo, inhalation of piriprost had no significant protective effect on the fall in FEV1 at any time point within 60 minutes of allergen or exercise challenge. In the four subjects with a documented late asthmatic reaction 2-12 hours after allergen challenge piriprost had no protective effect when compared with placebo. In the subjects who recorded PEF over 20 hours after allergen challenge there was no significant difference between piriprost and placebo. Piriprost was appreciably more irritant to the respiratory tract than was placebo. On the assumption that inhaled piriprost was bioavailable in the airways, this study casts doubt on any theory of a pivotal role for leukotrienes in the pathogenesis of acute exercise and allergen induced airway bronchoconstriction in asthma.

The characterization of lodoxamide, a very active inhibitor of mediator release, in animal and human models of asthma.

A most active biologue of disodium cromoglycate (DSCG) available, lodoxamide tromethamine (LT), has been studied and characterized pharmacologically, in animal and human models of asthma. It has self-tachyphylaxis, but has oral activity (lodoxamide ethyl) in rats, primates, and man. In rats (LT) was 2,500 X more active than DSCG (ID50 = 0.001 mg/kg), in primates the drug was also active by several routes (inhalation 1 microgram/kg, IV 0.001 mg/kg, and oral 10 mg/kg). In isolated rat peritoneal mast cells, the compound displayed a biphasic dose response inhibition to histamine release initiated by (48/80, anti-IgE, and the calcium ionophore A23,187) with IC50 values of 0.1-50 microM. The consistent finding relating to its mode of action was its ability to inhibit 45calcium flux into the mast cell in response to antigen or A23,187. Clinical evaluations of lodoxamide tromethamine showed that at aerosol doses of 1.0 mg or less, it demonstrated significant inhibitory activity against antigen or exercise induced bronchospasm. However, in pilot evaluation studies in clinical asthma settings, the compound could not be shown to spare bronchodilator usage, relative to placebo, or be shown to be more effective than placebo treated patients based on other clinical endpoints. The reason for rat and primate models not being predictive for human long-term clinical asthma in the characterization of anti-release compounds is not known.

Inhaled lodoxamide tromethamine in the treatment of perennial asthma: a double-blind placebo-controlled study.

The efficacy of lodoxamide tromethamine in the treatment of asthma was studied in a 16-week double-blind, placebo-controlled study of 68 perennial allergic subjects with asthma. Patients received either lodoxamide tromethamine, 0.25 mg four times daily, or placebo, administered by metered-dose inhaler. Response to treatment was assessed by analyzing changes in asthma symptoms, inhaled bronchodilator requirements, and pulmonary function when compared to a 2-week baseline period. Patients treated with lodoxamide tromethamine demonstrated an improvement in daytime breathing difficulty, cough, sputum production, and sleep (p less than 0.01 to 0.05), but improvement was not significantly different from that demonstrated by placebo-treated patients. Patients from both treatment groups were able to reduce their inhaled bronchodilators (p less than 0.01), but again no significant difference was apparent between lodoxamide tromethamine and placebo treatment, nor were there any differences in peak expiratory flow rate or FEV1 between the two groups. Seven patients who received lodoxamide tromethamine withdrew because of a sensation of heat and gastrointestinal symptoms. Thus, although lodoxamide tromethamine possesses potent mast cell-stabilizing activity in vitro, we have failed to demonstrate any useful long-term effect in the treatment of mild allergic asthma.

Bronchodilatory properties of 2-decarboxy-2-hydroxymethyl prostaglandin E1.

We evaluated in a double-blind study the bronchodilatory properties of 2-decarboxy-2-hydroxymethyl prostaglandin E1 (PGE1-carbinol), described recently as a nonirritant bronchodilator in animals. Fifteen asthmatic patients received by inhalation single doses of 1, 10, and 30 micrograms PGE1-carbinol, 55 micrograms PGE2, and placebo (10% ethanol in normal saline, which was also used as diluent for the PGs). Such pulmonary function tests as forced expiratory volume in 1 second, forced vital capacity, and maximal expiratory flow were monitored during 2 hours following inhalation of each compound. 10 and 30 micrograms PGE1-carbinol produced significant but short-acting bronchodilation, similar to that caused by 55 micrograms PGE2. One-third of the patients reported mild cough and throat irritation during and shortly after inhalation of 30 micrograms PGE1-carbinol or 55 micrograms PGE2. Placebo and 1 microgram PGE1-carbinol produced minimal side effects, but neither agent caused bronchodilation. In an adjunctive, unblinded trial, the same patients received 400 micrograms fenoterol. Fenoterol caused greater bronchodilation 15 and 30 minutes after inhalation than did the PGs in the double-blind study.