Pharmacokinetics of trans-resveratrol in its aglycone (RES AGL )and glucuronide (RES GLU ) forms were studied following intravenous (15 mg/kg i.v.) and oral (50 mg/kg p.o.) administration of trans-resveratrol in a solution of ␤-cyclodextrin to intact rats. In addition, the enterohepatic recirculation of RES AGL and RES GLU was assessed in a linked-rat model. Multiple plasma and urine samples were collected and concentrations of RE-S AGL and RES GLU were determined using an electrospray ionization-liquid chromatography/tandem mass spectrometry method. After i.v. administration, plasma concentrations of RE-S AGL declined with a rapid elimination half-life (T 1/2 , 0.13 h), followed by sudden increases in plasma concentrations 4 to 8 h after drug administration. These plasma concentrations resulted in a significant prolongation of the terminal elimination half-life of RES AGL (T 1/2TER , 1.31 h). RES AGL and RES GLU also displayed sudden increases in plasma concentrations 4 to 8 h after oral administration, with T 1/2TER of 1.48 and 1.58 h, respectively. RES AGL bioavailability was 38% and its exposure was approximately 46-fold lower than that of RES GLU (AUC inf , 7.1 versus 324.7 mol⅐ h/l). Enterohepatic recirculation was confirmed in the linked-rat model since significant plasma concentrations of RES AGL and RES GLU were observed in bilerecipient rats at 4 to 8 h. The percentages of the exposures of RES AGL and RES GLU that were due to enterohepatic recirculation were 24.7 and 24.0%, respectively. The fraction of drug excreted in the urine over a period of 12 h was negligible. These results confirm that RES AGL is bioavailable and undergoes extensive first-pass glucuronidation, and that enterohepatic recirculation contributes significantly to the exposure of RES AGL and RES GLU in rats.Interest in the study of phenolic compounds present in red wine has grown since epidemiological studies have shown an inverse correlation between red wine consumption and the incidence of cardiovascular diseases (Nanji and French, 1986;Hegsted and Ausman, 1988). Resveratrol (3,5,4Ј-trihydroxystilbene), a molecule from the viniferin family of polymers, was identified as a biologically active compound in red wine in 1992 (Siemann and Creasy, 1992). Since then, numerous in vivo and in vitro studies have assessed the ability of resveratrol in preventing multiple pathophysiological processes. Resveratrol has the ability to inhibit the peroxidation of lipid membranes (Fauconneau et al., 1997), to decrease the concentration of low-and very-low-density lipoproteins (Frankel et al., 1993), and to inhibit platelet aggregation (Kimura et al., 1985), three conditions that help prevent cardiovascular diseases. Although significant estrogenic-like activity of resveratrol has been demonstrated in vitro (Gehm et al., 1997;Bhat et al., 2001), this was not proven in vivo in rats (Turner et al., 1999). Finally, trans-resveratrol was shown to have cancer chemoprotective properties and to induce apoptosis in leukemia and human breast carcinom...

Objective. To examine the concentration of glucosamine in the synovial fluid and its pharmacokinetics in serum in a large animal model following dosing with glucosamine HCl at clinically relevant levels.Methods. Eight adult female horses were studied. After an overnight fast, glucosamine HCl (20 mg/kg of body weight) was administered by either nasogastric (NG) intubation or intravenous (IV) injection. Blood samples were collected before dosing and at 5, 15, 30, 60, 120, 180, 240, 360, 480, and 720 minutes after dosing. Synovial fluid samples were collected from the radiocarpal joints 48 hours before dosing and at 1 and 12 hours after dosing. Glucosamine was assayed by fluorophoreassisted carbohydrate electrophoresis.Results. The maximum concentration of glucosamine in serum reached ϳ300 M (ϳ50 g/ml) following IV dosing and ϳ6 M (ϳ1 g/ml) following NG dosing. Synovial fluid concentrations reached 9-15 M with IV dosing and 0.3-0.7 M with NG dosing, and remained elevated (range 0.1-0.7 M) in most animals even at 12 hours after dosing. Following NG dosing, the median serum maximal concentration of 6.1 M (range 4.38-7.58) was attained between 30 minutes and 4 hours postdose. The mean apparent volume of distribution was 15.4 liters/kg, the mean bioavailability was 5.9%, and the mean elimination half-life was 2.82 hours.Conclusion. Clinically relevant dosing of glucosamine HCl in this large monogastric animal model results in serum and synovial fluid concentrations that are at least 500-fold lower than those reported to modify chondrocyte anabolic and catabolic activities in tissue and cell culture experiments. We conclude that the apparent therapeutic benefit of dietary glucosamine on pain and joint space width in humans and animals may be secondary to its effects on nonarticular tissues, such as the intestinal lining, liver, or kidney, since these may be exposed to much high levels of glucosamine following ingestion.Glucosamine is now widely taken in the US as a dietary supplement (recommended dosage 20 mg/kg/ day) to relieve the discomfort of osteoarthritis (OA)-related joint pain. In Europe, a patented formulation of glucosamine (glucosamine sulfate) is a prescription drug, which is also widely reported to achieve cartilageprotective effects in knee OA (1,2). A quality assessment and meta-analysis of 6 placebo-controlled clinical trials using both glucosamine HCl (2 studies) and glucosamine sulfate (4 studies) concluded that some degree of efficacy appears probable in treating symptoms of knee OA (3). More recently, 2 meta-analyses of a large number of randomized control trials with glucosamine sulfate consistently concluded that the drug is both safe and effective for the treatment of symptomatic OA (4,5).

IntroductionAutosomal dominant polycystic kidney disease is the most common hereditary kidney disease. TKV is a promising imaging biomarker for tracking and predicting the natural history of autosomal dominant polycystic kidney disease. The prognostic value of TKV was evaluated, in combination with age and eGFR, for the outcomes of 30% decline in eGFR and progression to ESRD. Observational data including 2355 patients with TKV measurements were available.MethodsMultivariable Cox models were developed to assess the prognostic value of age, TKV, height-adjusted TKV, eGFR, sex, race, and genotype for the probability of a 30% decline in eGFR or ESRD.ResultsTKV was the most important prognostic term for 30% decline in eGFR in autosomal dominant polycystic kidney disease patients with and without preserved baseline eGFR. For a 40-year-old subject with preserved eGFR (70 ml/min per 1.73 m2), the adjusted hazard ratios for a 30% decline in eGFR were 1.86 (95% CI, 1.65–2.10) for a 2-fold larger TKV (600 vs. 1200 ml) and 2.68 (95% CI, 2.22–3.24) for a 3-fold larger TKV (600 vs. 1800 ml), respectively. Hazard ratios for progression to ESRD for 2- and 3-fold larger TKV were 1.72 (95% CI, 1.49–1.99) and 2.36 (95% CI, 1.88–2.97), respectively.DiscussionThe capability to predict 30% decline in eGFR is a novel aspect of this study. TKV was formally qualified, both by FDA and EMA, as a prognostic enrichment biomarker for selecting patients at high risk for a progressive decline in renal function for inclusion in interventional clinical trials.

Glycerol phenylbutyrate (glyceryl tri (4-phenylbutyrate)) (GPB) is being studied as an alternative to sodium phenylbutyrate (NaPBA) for the treatment of urea cycle disorders (UCDs). This phase 2 study explored the hypothesis that GPB offers similar safety and ammonia control as NaPBA, which is currently approved as adjunctive therapy in the chronic management of UCDs, and examined correlates of 24-hour blood ammonia.Methods-An open-label, fixed sequence switch-over study was conducted in adult UCD patients taking maintenance NaPBA. Blood ammonia and blood and urine metabolites were compared after ClinicalTrials.gov: NCT00551200Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptMol Genet Metab. Author manuscript; available in PMC 2011 January 1. Published in final edited form as:Mol Genet Metab. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 7 days (steady state) of TID dosing on either drug, both dosed to deliver the same amount of phenylbutyric acid (PBA).Results-Ten subjects completed the study. Adverse events were comparable for the two drugs; two subjects experienced hyperammonemic events on NaPBA while none occurred on GPB. Ammonia values on GPB were ~30% lower than on NaPBA (time normalized AUC = 26.2 vs. 38.4 μmol/L; Cmax = 56.3 vs. 79.1 μmol/L; not statistically significant), and GPB achieved non-inferiority to NaPBA with respect to ammonia (time normalized AUC) by post hoc analysis. Systemic exposure (AUC 0-24 ) to PBA on GPB was 27% lower than on NaPBA (540 vs. 739 μg•h/mL), whereas exposure to phenylacetic acid (PAA) (575 vs. 596 μg•h/mL) and phenylacetylglutamine (PAGN) (1098 vs. 1133 μg•h/mL) were similar. Urinary PAGN excretion accounted for ~54% of PBA administered for both NaPBA and GPB; other metabolites accounted for < 1%. Intact GPB was generally undetectable in blood and urine. Blood ammonia correlated strongly and inversely with urinary PAGN (r=−0.82; p<0.0001) but weakly or not at all with blood metabolite levels.Conclusions-Safety and ammonia control with GPB appear at least equal to NaPBA. Urinary PAGN, which is stoichiometrically related to nitrogen scavenging, may be a useful biomarker for both dose selection and adjustment for optimal control of venous ammonia.

Capsaicin, a pungent compound in chili peppers, is a highly selective agonist for the transient receptor potential vanilloid 1 receptor expressed in nociceptive sensory nerves. A high-concentration (640 microg/cm2) capsaicin patch, designated NGX-4010, is in clinical evaluation for the management of peripheral neuropathic pain. To determine systemic capsaicin exposure after single 60- or 90-minute NGX-4010 applications, plasma samples were collected from 173 patients with postherpetic neuralgia (PHN), painful human immunodeficiency virus-associated neuropathy (HIV-AN), and painful diabetic neuropathy (PDN). The percentages of patients with quantifiable levels of capsaicin at any time point were 31% for PHN (30 of 96), 7% for HIV-AN (3 of 44), and 3% for PDN (1 of 33). The maximum plasma concentration observed in any patient was 17.8 ng/mL. Due to the limited number of quantifiable levels, a population analysis was performed to characterize the pharmacokinetics (PK) of capsaicin. Plasma concentrations were fitted adequately using a 1-compartment model with first-order absorption and linear elimination. Capsaicin levels declined very rapidly, with a mean population elimination half-life of 1.64 hours. Mean area under the curve and C max values after a 60-minute application were 7.42 ng x h/mL and 1.86 ng/mL, respectively. Only a few correlations between calculated PK parameters and patient characteristics were observed. Duration and area of application of the patch were detected as significant covariates explaining the PK of capsaicin. Ninety-minute applications of NGX-4010 resulted in capsaicin area under the curve and Cmax values approximately 1.78- and 2.15-fold higher than those observed in patients treated for 60 minutes. Treatment on the feet (patients with HIV-AN and PDN) produced far lower systemic exposure than treatment on the trunk (patients with PHN). Finally, larger treatment areas were associated with statistically higher Vc/F values. The low systemic exposure and very rapid elimination half-life of capsaicin after NGX-4010 administration are unlikely to result in systemic effects and support the overall safety profile of this investigational cutaneous patch.