Pharmacokinetic, bioavailability, metabolism and plasma protein binding evaluation of NADPH-oxidase inhibitor apocynin using LC-MS/MS.

Apocynin is a major active constituent of Picrorhiza kurroa that exhibits potent anti-inflammatory activity by inhibiting superoxide-generating NADPH oxidase enzyme. To elucidate detailed pharmacokinetic profile of apocynin, high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed in rat and human plasma. To the best of our knowledge, this is the first method for complete validation of apocynin in biological matrix using LC-MS/MS. Apocynin was rapidly absorbed after oral administration at 50mg/kg in rats and peak plasma level achieved within 5min. Moreover, plasma levels were observed up to 48h. The bioavailibity of apocynin was found to be 8.3%. In vitro plasma protein binding was found to be 83.41-86.07% and 71.39-73.34% in rat and human plasma, respectively. Apocynin was found stable in gastric (pH 1.2), intestinal (pH 6.8) and physiological (pH 7.4) fluids including microsomal (rat and human) stability studies. Further, apocynin did not convert to its dimeric form diapocynin in any of these studies. The data presented here provide crucial information about apocynin to support its pharmacological efficacy and further development as a potential anti-inflammatory drug candidate.

Corneal targeted nanoparticles for sustained natamycin delivery and their PK/PD indices: an approach to reduce dose and dosing frequency.

Natamycin is the only approved medication for the treatment of mycotic keratitis. Current dosage regimen include one drop of natamycin suspension (5% w/v) instilled in the conjunctival sac at hourly or two hourly intervals for several days which has poor patient compliance. The purpose of the present study was to design a corneal targeted nanoformulation in order to reduce dose and dosing frequency of natamycin and evaluate its pharmacokinetic/pharmacodynamic indices in comparison with clinical marketed preparation. The nanoparticles prepared by nanoprecipitation method were in nanometer size range with high entrapment efficiency and positive surface charge. In-vitro release studies indicated prolonged release of natamycin up to 8h. In-vitro antifungal activity was comparable with marketed preparation. The performance of nanoformulations was evaluated in rabbit eyes. The concentration of natamycin in tear fluid was determined by using LC-MS/MS. The pharmacokinetic parameters such as area under the curve, t½ and mean residence time were significantly higher and clearance was significantly lower for nanoformulations with that of marketed preparation. The optimized dosing schedule to maintain natamycin concentration above tenfold of MIC90 was one instillation in every 5h. Moreover, 1/5th dose reduction of nanoformulation was also effective.

Synthesis, structure-activity relationships, and biological studies of chromenochalcones as potential antileishmanial agents.

Antileishmanial activities of a library of synthetic chalcone analogues have been examined. Among them, five compounds (11, 14, 16, 17, 22, and 24) exhibited better activity than the marketed drug miltefosine in in vitro studies against the intracellular amastigotes form of Leishmania donovani. Three promising compounds, 16, 17, and 22, were tested in a L. donovani/hamster model. Oral administration of chalcone 16, at a concentration of 100 mg/kg of body weight per day for 5 consecutive days, resulted in >84% parasite inhibition at day 7 post-treatment and it retained the activity until day 28. The molecular and immunological studies revealed that compound 16 has a dual nature to act as a direct parasite killing agent and as a host immunostimulant. Pharmacokinetics and serum albumin binding studies also suggest that compound 16 has the potential to be a candidate for the treatment of the nonhealing form of leishmaniasis.