A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease

The adiponutrin (PNPLA3) rs738409 polymorphism has been found to be associated with susceptibility to non-alcoholic fatty liver disease (NAFLD) in various cohorts. We further investigated the association of this polymorphism with non-alcoholic steatohepatitis (NASH) severity and with histological features of NAFLD. A total of 144 biopsy-proven NAFLD patients and 198 controls were genotyped for PNPLA3 gene polymorphism (rs738409 C>G). The biopsy specimens were histologically graded by a qualified pathologist. We observed an association of G allele with susceptibility to NAFLD in the pooled subjects (OR 2.34, 95% CI 1.69–3.24, p < 0.0001), and following stratification, in each of the three ethnic subgroups, namely Chinese, Indian and Malay (OR 1.94, 95% CI 1.12–3.37, p = 0.018; OR 3.51, 95% CI 1.69–7.26, p = 0.001 and OR 2.05, 95% CI 1.25–3.35, p = 0.005, respectively). The G allele is associated with susceptibility to NASH (OR 2.64, 95% CI 1.85–3.75, p < 0.0001), with NASH severity (OR 1.85, 95% CI 1.05–3.26, p = 0.035) and with presence of fibrosis (OR 1.95, 95% CI 1.17–3.26, p = 0.013) but not with simple steatosis nor with other histological parameters. Although the serum triglyceride level is significantly higher in NAFLD patients compared to controls, the G allele is associated with decreased level of triglycerides (p = 0.029) in the NAFLD patients. Overall, the rs738409 G allele is associated with severity of NASH and occurence of fibrosis in patients with NAFLD

A Bioequivalence Comparison of Two Formulations of Rifampicin (300 mg vs 150 mg Capsules): An Open-Label, Randomised, Two-Treatment, Two-Way Crossover Study in Healthy Volunteers

Background: Rifampicin is a semisynthetic antibiotic derivative of rifamycin used worldwide for the treatment of various forms of tuberculosis. Objective: The objective of this study was to compare, under fasting conditions in healthy volunteers, the rate and extent of absorption of a generic rifampicin capsule in oral dosage form versus the proprietary equivalent formulation for the purpose of registration approval of the test formulation. Methods: This was an open-label, randomized, 2-treatment, 2-way crossover study with an 8-week washout period between the 2 study arms. Healthy volunteers received a 300-mg capsule of the test formulation (Idaman Pharma Manufacturing Sdn. Bhd.) or two 150-mg capsules of the reference formulation. Blood samples were collected predose and at 45 minutes and 1.25, 1.5, 2, 2.25, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours postdose. Plasma concentrations of rifampicin and its metabolite, 25-desacetyl rifampicin, were analyzed using a validated HPLC method. The formulations were considered bioequivalent if the 90 CIs for C(max) and AUC were within the predetermined bioequivalence range (80-125, according to the guidelines of the US Food and Drug Administration, or 75-133 for C(max) only, as set by the European Commission European Medicines Agency and the National Pharmaceutical Control Bureau of Malaysia). Tolerability was assessed by verbally questioning subjects regarding their well-being and any feelings of discomfort. All events reported by the subjects (serious or mild) were recorded on adverse-event forms. Results: Fourteen healthy subjects (10 males, 4 females) with a mean age of 22.6 years (range, 20-28 years) and a mean body mass index of 22.2 kg/m(2) (range, 18.3-29.9 kg/m(2)) were enrolled in the study; all 14 completed the trial as outlined in the protocol. The mean values for C(max), T(max), AUC(0-24), and AUC(0-infinity) with the test formulation of rifampicin were 7.20 mu g/mL, 1.32 hours, 37.12 mu g/mL . h, and 39.69 mu g/mL . h, respectively; for the reference formulation, the values were 7.65 mu g/mL, 1.71 hours, 38.92 mu g/mL . h, and 42.24 mu g/mL . h. For 25-desacetyl rifampicin, the mean values for C(max), T(max), AUC(0-24), and AUC(0-infinity) with the test formulation were 0.63 mu g/mL, 3.45 hours, 4.92 mu g/mL . h, and 6.27 mu g/mL . h; for the reference formulation, the values were 0.7 mu g/mL, 3.27 hours, 5.23 mu g/mL . h, and 6.84 mu g/mL . h. For rifampicin, the 90 CIs for the test formulation/reference formulation ratio for the logarithmic transformations of both C(max) and AUC(0-infinity). were within the bioequivalence limit of 80 to 125 (80.9-109.7 and 80.7-103.2, respectively). For 25-desacetyl rifampicin, the 90 CI for the test formulation/reference formulation ratio for the logarithmic transformations of AUC(0-24) (80.0-104.7) was within the bioequivalence limit of 80 to 125. However, the 90 CI for C(max) (78.4-102.2) was outside this limit but still within the acceptance limit for C(max) when adhering to the bioequivalence range of 75 to 133. No adverse events were reported during the study. Conclusions: This study found that the 300-mg test capsule and the 150-mg reference capsules of rifampicin met the regulatory criteria for assuming bioequivalence in these fasting healthy volunteers. Both formulations appeared to be well tolerated in the population studied. (Clin Ther. 2010;32:1822-1831) (C) 2010 Excerpta Medica Inc

Polyesters Based on Linoleic Acid for Biolubricant Basestocks: Low-Temperature, Tribological and Rheological Properties.

Presently, plant oils which contain high percentage of linoleic acid 1 are perceived to be a viable alternative to mineral oil for biolubricant applications due to their biodegradability and technical properties. In order to get biodegradable lubricant, triester derivatives compounds (1-5) were synthesized and characterized. The processes involved were monoepoxidation of linoleic acid 2, oxirane ring opening 3, esterification 4 and acylation 5. The structures of the products were confirmed by FTIR, 1H and 13C-NMR and LC-MS. The results that showed lowest temperature properties were obtained for triester 5, with a pour point value (PP) of -73°C, highest onset temperature (260°C) and lowest volatility at 0.30%. Viscosity index (VI) increased for the ester's synthetic compounds (2, 3, 4, 5), while the PP decreased. This behavior is the result of the increase of the chain length of the branching agents. Triester based linoleic acid has improved properties such as low-temperature and tribological properties. These results will make it feasible for plant oil to be used for biolubricants, fuels in chain saws, transmission oil and brake fluid

The main FTIR functional groups wavenumbers of linoleic acid and synthesis compounds.

<p>The main FTIR functional groups wavenumbers of linoleic acid and synthesis compounds.</p

Reaction scheme for the formation of triester.

<p>(2a, 2b) cis-9, 10-epoxy 12c- 18:1 and cis-12, 13 epoxy 9c- 18:1. (3a, 3b) 9,(12)-hydroxy-10,(13)-oleioxyoctadecanoic acid. (4a, 4b) oleyl 9,(12)-hydroxy-10,(13)-oleioxyoctadecanoate. (5a, 5b) oleyl 9,(12)-oleoyloxy-10,(13)-oleioxyoctadecanoate.</p

Physicochemical characteristics of synthesis compounds.

<p>Physicochemical characteristics of synthesis compounds.</p

LC-MS for the synthetic compounds and data used for their identification.

<p>LC-MS for the synthetic compounds and data used for their identification.</p

¹H NMR spectrums of linoleic acid and synthesis compounds.

<p>(1) Linoelic acid. (2) Monoepoxidation. (3) Oxirane ring opening. (4) Esterification. (5) Acetlyation.</p

Tribological characteristics of synthesis compounds.

<p>Tribological characteristics of synthesis compounds.</p

Variables and responses of synthesis compounds.

<p>Variables and responses of synthesis compounds.</p