Analytical methods and stability assessment of liquid yeast derived sucrase.

Two independent analytical methods for determining the activity and stability profile of liquid yeast derived sucrase (YS) were established and validated in order to conduct preliminary stability studies as a function of temperature. The methods included a hexokinase-based (HK) enzymatic assay for determining the formation of glucose upon hydrolysis of sucrose by YS, and a direct polarimetric procedure to quantitate YS hydrolysis of sucrose. Both assays were validated with respect to YS dilution, incubation time, sucrose or glucose concentration, linearity of response and within- and between-day variability. A preliminary stability study was conducted over a 24 week period with liquid YS samples stored at -20, 4, 30, 40 and 50 degrees C. Enzymatic activity was monitored as a function of time using both the HK and polarimetric assays. Liquid YS samples stored at -20, 4 and 30 degrees C retained 100% activity after 24 weeks storage, while the samples stored at 40 degrees C lost approximately 70% activity over the same storage period and samples stored at 50 degrees C lost approximately 95% activity after 12 weeks storage. The two methods of analysis gave consistent results over the course of the study.

A placebo-controlled trial of procaterol: a new long-acting oral beta 2-agonist in bronchial asthma.

Procaterol hydrochloride, a potent beta 2-adrenergic bronchodilator developed in Japan, was evaluated in a double-blind, placebo-controlled study for efficacy and safety in 45 patients (ages 18 to 55 yr) with chronic documented reversible airway disease. After a 1-week placebo washout period, patients were administered either 0.05 mg or 0.10 mg of procaterol or placebo twice daily for 2 wk. Spirometric determinations, vital signs, and ECGs were obtained at 1/2, 1, 2, 4, 6, and 8 hr after the first dose and at the same time intervals after 1 and 2 wk of treatment. Patients recorded on a daily basis peak flow rates, asthma symptoms, need for supplemental aerosol, concurrent medications, and side effects. Spirometry results indicated significant improvement in pulmonary function with both doses of procaterol compared with placebo (P less than 0.05). The larger dose was generally more effective. Bronchodilatation was evident 1/2 hr after dosing and peaked at 2 hr. At 8 hr after 0.10 mg of procaterol, FEV1 was still above predose values. Daily peak flow rates were significantly higher with 0.10 mg than with 0.05 mg (P less than 0.05) and placebo (P less than 0.001). Tremor and nervousness were the most frequent side effects. They occurred in a dose-related frequency, were mild and transient, and occurred early in treatment. No significant drug-related changes were noted in ECGs, heart rate, blood pressure, or clinical laboratory data. Procaterol was found to be an effective, well-tolerated oral bronchodilator with a long duration of action, especially at 0.10 mg twice daily.

Controlled comparison of trebenzomine with doxepin as an antidepressant-anxiolytic.

Trebenzomine, a new psychotropic drug, was compared with doxepin in the treatment of anxiety and depression. The study was a three-week, double-blind trial involving 26 psychoneurotic inpatients. Multiple ratings by physician, nurse, and patient all concurred that the 2 drugs produced significant improvement in both depressive and anxious symptomatology. No significant differences were found between the 2 drugs either in terms of rate or degree of improvement or incidence of side effects. Further investigation of trebenzomine for anxious depression is warranted.

Ripazepam (CI-683): double-blind comparison with placebo in anxious patients.

Thirty anxious, neurotic patients were treated in a general practice setting with single-blind placebo for one week followed by two weeks of double-blind treatment with either placebo or 40 or 80 mg/day ripazepam (CI-683), a new potential antianxiety agent of the pyrazolodiazepinone series. As rated by both physician and patient, ripazepam was found significantly superior to placebo at both dosage levels. Some evidence of greater improvement at 80 mg/day than at 40 mg/day was also obtained. The drug appeared to be well tolerated, with side effects reported by only four patients.

Tolerance development to the effect of delta9-tetrahydrocannabinol on conditioned behavior: role of treatment interval and influence of microsomal metabolism.

The importance of frequency of administration in the development of tolerance to delta9-tetrahydrocannabinol (delta9-THC) was studied with repeated administration of the drug prior to behavioral test sessions at 1-, 3-, 7- or 14-day intervals. Partial tolerance was seen to develop to the depressant effects of delta9-THC (10mg/kg i.p.) on food-motivated performance on a variable interval 60-sec (VI 60) schedule of reinforcement. The tolerance was most evident with the most frequent exposure to the drug. No signs of increasing responsiveness to delta9-THC were seen with any of the four inter-injection intervals. The role of hepatic metabolism in tolerance to delta9-THC was tested by pretreating animals with SKF-525A, a microsomal enzyme inhibitor, or phenobarbital, a microsomal enzyme inducer. The dosing schedules for SKF-525A and phenobarbital were sufficient to alter hexobarbital sleeping time significantly, but they did not affect the normal VI 60 sec performance. After a 5 mg/kg dose of SKF-525A the depressant actions of 3 and 10 mg/kg doses of delta9-THC appeared to show a slight but consistent enhancement during the course of tolerance development. Phenobarbital (80 mg/kg/day) pretreatment for seven days blocked the acute behavioral depressant effect of 3 mg/kg of delta9-THC and appeared to enhance the development of tolerance. A metabolic mechanism of tolerance development was suggested by the data, but not demonstrated definitively.