Safety Efficacy Studies Research Articles

Development of atropine sulphate nasal drops and its pharmacokinetic and safety evaluation in healthy human volunteers

Introduction The increased use of organophosphate (OP) insecticides and the ever increasing possibility of terror groups using nerve agents underscore the need to develop effective and safe antidotes against OP poisoning. While intramuscular administration of nerve gas antidotes like atropine sulphate has certain lacunae, intravenous route is neither practical nor feasible in the field conditions for mass casualties. The objective was to develop a novel atropine sulphate nasal drop formulation, evaluate and characterize it using scintigraphy and to carry out safety–efficacy study in human volunteers with a view to obtain early pharmacological effects in comparison to the existing options, particularly the conventional intramuscular route. Methods Permeability studies were done using atropine sulphate solution containing variable amount of chitosan. Radiometric method was developed for scintigraphy studies while standard spectroscopy was used for the quantification of atropine sulphate in fluids. Concentration of atropine sulphate in nasal drops to produce therapeutic concentration in blood was calculated. Six volunteers (age range 18–53 years) were administered the formulation delivering 6 mg of atropine sulphate each. Bioavailability and atropinization were noted serially. Results Based on the results of in vitro, human scintigraphy and analytical data, 1% atropine sulphate–0.5% chitosan was chosen as the final nasal formulation. Human bioavailability curve was created which showed that the therapeutic concentration of the drug in blood was reached within 5 min with nasal drops suggesting that drug delivery through the nasal route is significantly better than the intramuscular route. Unpaired t-test between the means of baseline value of heart rate and that of each time interval showed that increase in heart rate of all the volunteers became significant at 15 min ( P < 0.01) and extremely significant at 30 min ( P < 0.001). Correlation was evident from 5 min ( c > 0.7). Pupil diameter showed maximal increase at 30 min ( P < 0.01). Conclusions This novel product, 1% atropine sulphate–0.5% chitosan nasal drops might be a safe and efficacious emergency treatment of organophosphorous poisoning with several advantages over the present management, including early atropinization and capability of mass treatment in least amount of time.

Some suggested approaches to the analysis of chronic toxicity and chronic drug adminitration data

This paper discusses several methods for analyzing data emanating from chronic toxicity and safety-efficacy studies in which repeated measurements are obtained on the same subjects at regular intervals throughout a prolonged period of drug administration. The procedures recommended are described in some detail, and a completely worked example is given. In view of the general availability of high-speed data processing facilities, the routine application, where appropriate, of these or similar methods of analysis should significantly reduce the amount of experimentation necessary to detect various treatment effects over time.