Identification of oxidative degradation impurities of olanzapine drug substance as well as drug product

Impurities found in stressed and stability studies of Olanzapine (polymorphic form-I) [1], [2], [3], [4], [5], [6] and [7] in both drug substance and drug product are described. These impurities are identified as 4-(4-methyl-1-piperazinyl)-3-hydroxymethylidene-1H-benzo[b][1,4]diazepine-2(3H)-thione (hydroxymethylidene thione) and (Z)-4-(4-methyl-1-piperazinyl)-3-acetoxymethylidene-1H-benzo[b][1,4]diazapine-2(3H)-thione (acetoxymethylidene thione). An oxidative degradation pathway of Olanzapine, for the formation of these impurities, has been proposed.     

Antioxidant potential of aqueous extract of Phyllanthus amarus in rats

Objective:

Increased levels of oxidative stress may be implicated in the etiology of many pathological conditions. Protective antioxidant action imparted by many plant extracts and plant products make them promising therapeutic drugs for free radical induced pathologies. In this study we assessed the antioxidant potential of Phyllanthus amarus (Euphorbiaceae).

Materials and Methods:

Experimental rats were divided into two groups: Control and Phyllanthus amarus (P. amarus) treated. Treated rats received P. amarus aqueous extract (PAAEt) at a dose of 200 mg/kg body wt/day for 8 weeks. After the treatment period of 8 weeks lipid peroxidation (LPO), vitamin C, uric acid and reduced glutathione (GSH) were estimated in plasma and antioxidant enzymes: Glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) were also assayed. Genotoxicity of PAAEt was assessed by single cell gel electrophoresis (SCGE) of lymphocytes under both in vitro and in vivo conditions. The protective role of PAAEt against hydrogen peroxide (H₂O₂), streptozotocin (STZ) and nitric oxide generating system induced lymphocyte DNA damage was also assessed by SCGE.

Results:

PAAEt treated rats showed a significant decrease in plasma LPO and a significant increase in plasma vitamin C, uric acid, GSH levels and GPx, CAT and SOD activities. SCGE experiment reveals that PAAEt was devoid of genotoxicity and had a significant protective effect against H₂O₂, STZ and nitric oxide (NO) induced lymphocyte DNA damage.

Conclusion:

The results suggest the non-toxic nature of PAAEt and consumption of PAAEt can be linked to improved antioxidant status and reduction in the risk of oxidative stress.     

Prevalence of Vitamin D Deficiency in Uninsured Women

Background Vitamin D deficiency, an important risk factor for osteoporosis and other chronic medical conditions, is epidemic in the United States. Uninsured women may be at an even higher risk for vitamin D deficiency than others owing to low intake of dietary and supplemental vitamin D and limited sun exposure. Objective Our goal was to determine the prevalence of vitamin D deficiency in this vulnerable population. Setting and Participants We enrolled 145 uninsured women at a County Free Medical Clinic in urban Michigan. Questionnaires were used to obtain information about demographics, medical history, vitamin supplementation, sunlight exposure, and dietary vitamin D intake. Results The 96 women who were tested for vitamin D status ranged in age from 21 to 65 years (mean 48 ± 11), and 67% were vitamin D deficient as indicated by a 25-hydroxyvitamin D [25(OH)D)] level <50 nmol/L (20 ng/mL). Non-Caucasians were 3 times more likely than Caucasians to be vitamin D deficient (P = .049). Mean dietary vitamin D intake was low (125 ± 109 IU/d) and only 24% of the participants used any supplemental vitamin D. Participants with total vitamin D intake <400 IU/day from diet and supplements were 10 times more likely to be vitamin D deficient than others (P < .001). Conclusions These results demonstrate a high prevalence of vitamin D deficiency in an uninsured, medically underserved female population. Uninsured women should be strongly encouraged to increase their vitamin D intake.     

Glutaraldehyde cross-linked chitosan microspheres for controlled delivery of zidovudine

Zidovudine-Chitosan microspheres were prepared by a suspension cross-linking method. The chitosan was dissolved in 2% acetic acid solution and this solution was dispersed in the light liquid paraffin. Span-80 was used as an emulsifier and glutaraldehyde as cross-linking agent. The prepared microspheres were slight yellow, free flowing and characterized by drug loading, infrared spectroscopy (IR), differential scanning colorimetry (DSC) and scanning electron microscopy (SEM). The in-vitro release studies are performed in pH 7.4 buffer solution. Microspheres produced are spherical and have smooth surfaces, with sizes ranging between 60-210 μm, as evidenced by SEM and particle size analysis. The drug loaded microspheres showed up to 60% of entrapment and release was extended up to 18-24 h. Among all the systems studied, the 35% Glutaraldehyde crosslinked, microspheres with 1 : 6 drug/chitosan ratio showed 75% release at 12 h. The infrared spectra and DSC thermograms showed stable character of zidovudine in the drug loaded microspheres and revealed the absence of drug-polymer interactions. Data obtained from in vitro release were fitted to various kinetic models and high correlation was obtained in the Higuchi model. The drug release was found to be diffusion controlled.     

Life style modification improves insulin resistance and liver histology in patients with non-alcoholic fatty liver disease

AIM: To study the effect of regular aerobic exercise on insulin resistance, serum aminotransferase and liver histology in nonalcoholic fatty liver disease (NAFLD) patients. METHODS: Sixty (mean age 40.0 ± 8.5 years, 75% male) NAFLD patients were included in the study. After baseline anthropometric measurement i.e., body mass index (BMI), waist circumference (WC); all patients were advised regular aerobic exercise for 30 min/d, for at least 5 d/wk and trained to achieve around 70% of his maximal heart rate. In addition, moderately energy restricted diet was advised to patients with high BMI (> 25 kg/m 2 ). Monthly follow up was done by measuring BMI, WC, aspartate aminotransferase, and alanine aminotransferase (ALT). Insulin resistance was calculated using homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) model, at baseline and after 6mo. Insulin resistance was arbitrarily considered altered when it was ≥ 2. Liver biopsy was done in a section of patients at baseline and after 6 mo. RESULTS: Seventy percent (42/60) patients were overweight or obese; 95% (57/60) had central obesity (WC > 90 cm in men, > 80 cm in women). In the 45 exercise compliant patients insulin resistance decreased from 6.4 ± 6.1 to 1.3 ± 1.0, BMI from 26.7 ± 3.3 kg/m 2 to 25.0 ± 3.3 kg/m 2 , WC from 95.7 ± 8.9 cm to 90.8 ± 7.3 cm and ALT from 84.8 ± 43.5 U/L to 41.3 ± 18.2 U/L (P < 0.01). In 15 exercise noncompliant patient’s insulin resistance, BMI, WC and ALT did not show significant change at 6 mo follow up. Six of 8 patients in compliant group on repeat liver biopsy showed significant change in steatosis and necroinflammation. Nonalcoholic steatohepatitis scores improved form 5.3 ± 1.5 to 3.35 ± 1.5. The decline in insulin resistance correlated with decline in ALT (P = 0.01, r s = 0.90) and liver histology (P = 0.03, r s = 0.73). CONCLUSION: Life style modification improves insulin resistance resulting in improvement in ALT and liver histology in NAFLD patients.