A Proposed Methodology for In Vitro Evaluation of Bitterness in Drug Solutions and In Vitro Drug Release Samples

Purpose

Ethical and safety concerns, paediatric taste panels and predictivity in early drug development for strategic decisions are some of the reasons for seeking in vitro methods of bitterness evaluation for drugs and drug products. In this study, taste panel studies and in vitro drug release studies have been performed, correlated to each other and proposed as an analytical tool for evaluation of bitterness.

Methods

Bitterness threshold and bitterness scores for different solutions of ondansetron hydrochloride (ONS) were estimated by taste panel studies. In vitro drug release studies on taste-masked drug product in pharmacopoeial apparatus and an in-house-developed apparatus were performed and correlated to drug release studies in oral cavity.

Results

Concentration of 22 μg/ml and below was perceived bitterless by all the volunteers of taste panel. A second-order polynomial equation (y?=?0.6206x ²???0.2011x???0.7796; correlation coefficient R ²?=?0.991) was derived as a relationship between bitterness score and log ONS concentration. Drug release in in-house-assembled apparatus and oral cavity were not statistically different (α?=?0.05) at both 60 and 120 s.

Conclusions

Bitterness threshold and bitterness scores are helpful in evaluation of bitterness in drug solutions and samples obtained from drug release studies.     

Systematic formulation development of once-a-day gastroretentive controlled release tablets of rivastigmine using optimized polymer blends

Rivastigmine is a drug extensively prescribed for the treatment of Alzheimer’s disease. On therapeutic fronts, severe gastrointestinal (GI) adverse effects owing to a rapid rise and fall in drug plasma levels, and the high frequency of its dosing, tend to limit its usage. The present investigation, therefore, aimed at developing a gastroretentive floating-bioadhesive CR formulation for delivering rivastigmine in a sustained manner at the desired site of absorption. Employing 7-factor Taguchi design, the influential factors were embarked upon as Carbopol 971P and Methocel K15M CR. Effervescent floating-bioadhesive hydrophilic matrices were systematically formulated using a face-centered cube design (FCCD) and evaluated for in vitro drug release, floatation and ex vivo bioadhesive strength. Optimal composition of polymer blends systematically chosen using brute-force methodology, overlay plots and desirability function exhibited excellent bioadhesive and floatational characteristics besides possessing adequate drug release control (T₆₀ > 5 h). Pharmacokinetic studies carried out in rabbits showed the absence of any sharp peaks or troughs in the plasma drug levels, and various levels of in vitro/in vivo correlation (IVIVC) were successfully established. In vivo gamma scintigraphic studies in human volunteers ratified the gastroretentive characteristics of the optimized formulation with retention time of 6 h or more. Thus, besides unraveling the polymer synergism, the study helped in developing an optimal once-a-day gastroretentive drug delivery system exhibiting excellent swelling, floating, and bioadhesive characteristics.     

Pesticide bioaccumulation and plasma sex steroids in fishes during breeding phase from north India

The investigation was done to monitor the total hexachlorocyclohexane (∑HCH) and total dichlorodiphenyltrichloroethane (∑DDT), aldrin, endosulfan and chlorpyrifos in liver, brain and ovary, gonadosomatic index (GSI) and plasma levels of testosterone (T) and estradiol-17β (E2) during breeding season of captured catfishes and carps from the unpolluted ponds of Gujartal, Jaunpur (reference site) and polluted rivers Gomti, Jaunpur and Ganga, Varanasi. Results have indicated that catfishes have higher bioaccumulation of pesticides than the carps, which was beyond the permissible limits for ∑HCH whereas ∑DDT only by catfishes of polluted rivers. The GSI and plasma levels of T and E2 were lowered in the fishes captured from the polluted rivers. In conclusion, the fishes from river Gomti and Ganga showed a high degree of contamination and disrupted reproductive axis when compared to those from the reference site reflecting the degree of pesticide pollution present in those water bodies.     

Solubilized benzoyl peroxide versus benzoyl peroxide/clindamycin in the treatment of moderate acne

BACKGROUND: Benzoyl peroxide (BPO) is poorly soluble. A solubilized formulation of BPO has been developed to maximize its bioavailability and enhance follicular penetration. METHODS: Patients with acne vulgaris were randomly assigned to receive solubilized BPO 5% gel on one side of the face and a BPO 5%/clindamycin 1% combination product on the contralateral side, twice daily for 4 weeks. RESULTS: Of 23 patients enrolled, 100% completed the study. Reductions in lesion count with the solubilized BPO gel were at least as great as with BPO/clindamycin--and significantly greater (P< or =.05) for noninflammatory lesions at week 1 and inflammatory lesions at week 4. Both regimens were generally well tolerated and patient satisfaction was comparable. CONCLUSIONS: Solubilized BPO 5% gel monotherapy offers significantly greater efficacy, and comparable patient satisfaction, compared with BPO/clindamycin. The early reduction in lesion counts observed with the solubilized BPO gel in the absence of an antibiotic is clinically relevant.     

Assessment of differential doses of buprenorphine for long term pharmacotherapy among opiate dependent subjects

The aim of the present study was to evaluate, two different doses of sublingual buprenorphine (2 mg and 4 mg) among patients on maintenance treatment and to assess the relationship of steady state plasma level with craving. Twenty three male opioid dependent (ICD-10 DCR) subjects, were assigned to double blind randomized controlled trial of 2 and 4 mg/day doses of buprenorphine in an inpatient setting. They were evaluated thrice (2nd, 7th and 14th day) in 2 weeks for withdrawal symptoms (acute and protracted), sedation, euphoria, craving, side effects, global rating of well being and for measurement of plasma levels of buprenorphine. The data showed that there were no significant difference in scores of euphoria and sedation, protracted withdrawal symptoms and side effects, craving and overall well being and plasma level of buprenorphine among the subjects. However, both the groups had significant difference in score on almost all the measurements on final observation in comparison to initial observation. Both 2 mg/day and 4 mg/day dose of buprenorphine were effective in long term pharmacotherapy of opioid dependence without significant difference as compared by different measures used in the study.     

Evaluation of antidepressant activity of tramadol in mice

Objective:

To evaluate antidepressant like effect of tramadol in mice.

Materials and Methods:

Tramadol was administered at three different doses (10,20 and 40 mg/kg, i.p) once daily for 7 days to Swiss albino mice of either sex. The immobility period of control and drug treated mice were recorded in tail suspension test (TST).The antidepressant effect of tramadol was compared to that of fluoxetine (20 mg/kg, i.p), administered for seven days.

Results:

Tramadol produced significant antidepressant effect at all the doses, as indicated by reduction in immobility times as compared to control. The efficacy of tramadol at doses of 20 and 40 mg/kg was comparable with that of fluoxetine. Tramadol at 10 mg/kg dose showed significantly less antidepressant activity compared to fluoxetine.

Conclusion:

The results of the present study indicate antidepressant like activity of tramadol.     

Role of vitamin E in mitigating methomyl induced acute toxicity in blood of male Wistar rats

The present study was designed to evaluate the protective potential of vitamin E, if any, in attenuating the toxic effects induced by acute methomyl treatment in rats. Male Wistar rats, weighing between 230 and 250 g, received either a single oral dose of 9 mg/kg of methomyl, vitamin E alone injected intraperitoneally on alternate days (4 injections) at 50 mg/kg body for 1 week prior to methomyl treatment, or both methomyl plus vitamin E given in a similar manner. The effects of different treatments were studied on lipid peroxidation (LPO), reduced glutathione (GSH) and antioxidant enzymes, which included superoxide dismutase (SOD), glutathione-s-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GSHPx) and catalase and various hematological parameters, including total leucocytes count (TLC), differential leukocyte count (DLC), hemoglobin, platelets counts, red cell counts, and scanning electron microscopy (SEM). Acute 24-h treatment to rats resulted in a significant increase in the LPO. GSH levels and the activities of catalase, GST, and GSHPx were found to be significantly decreased following methomyl treatment. A significant elevation in the activity of SOD and in TLC was also observed after 24 h of methomyl treatment. Further, a significant increase in the neutrophils and eosinophil counts was also observed. However, lymphocytes showed a significant decrease following methomyl treatment. SEMs showed significant morphological changes following methomyl treatment. Vitamin E pretreatment to methomyl-treated rats effectively normalized the levels of LPO and GSH. Vitamin E could also significantly elevate the activity of catalase, increase platelets counts and TLC, and normalized the activities of SOD and GSHPx. Vitamin E pretreatment improved the morphology of the red blood cells. The study concludes that vitamin E affords protection in methomyl-induced toxicity in the rat.     

Radioprotection of Swiss albino mice by Emblica officinalis

The fruit pulp of Emblica officinalis (EO) is an important drug used in Indian systems of medicine for several diseases and as a tonic. In view of its multifarious uses, the plant extract (aqueous) was tested for its radioprotective properties against sublethal gamma radiation (9 Gy) in Swiss albino mice. Animals were divided into two groups and irradiated with gamma radiation externally, with or without EO extract, which was given orally at different doses before irradiation. The dose of fruit pulp extract found to be most effective against radiation was 100 mg/kg b.wt. This dose increased the survival time and reduced the mortality rate of mice significantly. Furthermore, body weight loss in EO administered irradiated animals was significantly less in comparison with animals who were given radiation only.     

The Ketone Body β-Hydroxybutyrate Does Not Inhibit Synuclein Mediated Inflammasome Activation in Microglia

Parkinson's disease (PD) is recognized as the most common neurodegenerative movement disorder and results in debilitating motor deficits. The accumulation and spread of neurotoxic synuclein aggregates in the form of Lewy bodies is a key pathological feature of PD. Chronic activation of the NLRP3 inflammasome by protein aggregates is emerging as a major pathogenic mechanism in progressive neurodegenerative disorders and is considered an important therapeutic target. Recently the ketone body, β-hydroxy butyrate (BHB), was shown to efficiently inhibit the NLRP3 inflammasome in macrophages, and in vivo models of inflammatory disease. Furthermore, BHB can readily cross the blood brain barrier suggesting that it could have therapeutic benefits for the management of PD. In this study, we evaluated if BHB could inhibit chronic microglial inflammasome activation induced by pathological fibrillar synuclein aggregates. Interestingly, we found that BHB treatment almost completely blocked all aspects of inflammasome activation and pyroptosis induced by ATP and monosodium urate (MSU) crystals, consistent with previously published reports in macrophages. Surprisingly however, BHB did not inhibit inflammasome activation and release of IL-1β or caspase-1 induced by synuclein fibrils. Our results demonstrate that BHB does not block the upstream pathways regulating inflammasome activation by synuclein fibrils and suggest that synuclein mediated inflammasome activation proceeds via distinct mechanisms compared to traditional NLRP3 activators such as ATP and MSU.