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Background: Previous reports on the pharmacokinetic of tipranavir (TPV) and buprenorphine (BUP)/ naloxone found that coadministration resulted in an 80% reduction in the area under the curve AUC of the primary BUP metabolite, norBUP, without any pharmacodynamic consequences. This study was conducted to characterize how tipranivir/ritonavir effects the glucuronide metabolites of BUP and may explain the reduction in the norBUP.Methods: HIV-seronegative subjects stabilized on at least 3 weeks of BUP/naloxone sequentially underwent baseline and steady-state pharmacokinetic evaluation of twice daily TPV 500?mg coadministered with ritonavir 200?mg (TPV/r).Results: Twelve subjects were enrolled and ten completed the study. The steady-state pharmacokinetics for BUP-3-glucuronide (BUP-3G) and norBUP-3-glucuronide (norBUP-3G) in the presence and absence of steady-state TPV/r were analyzed. The C(max) of BUP-3G was 8.78???5.23?ng/mL without TPV/r and increased to 12.7???11.7 after steady state of TPV/r was achieved. The AUC of BUP-3G was 31.1???19.4?(ng/mL)?(h) without TPV/r and increased to 58. 6???49.5 after steady state of TPV/r was achieved (p?=?.0966). In contrast, steady-state norBUP-3G AUC(0?24?h) (p?=?.0216) and C(max) (p?=?.0088) were significantly decreased in the presence of steady-state TPV/r.Conclusions and Scientific Significance: This study further elucidates the effects of TPV/r on glucuronidation. The current evaluation of glucuronide metabolites of BUP and norBUP are suggestive of combined inhibition of Uridine diphosphate (UDP)-glucuronosyltransferase of the 1A family and cytochrome P450 3A4 that spares UGT2B7 leading to a shunting of BUP away from production of norBUP and toward BUP-3G as seen by a statistically significant increase in the AUC of BUP-3G. [ABSTRACT FROM AUTHOR]

Background: Serum cystatin C was proposed as a potential replacement for serum creatinine in glomerular filtration rate (GFR) estimation. We report the development and evaluation of GFR-estimating equations using serum cystatin C alone and serum cystatin C, serum creatinine, or both with demographic variables.Study Design: Test of diagnostic accuracy.Setting& Participants: Participants screened for 3 chronic kidney disease (CKD) studies in the United States (n = 2,980) and a clinical population in Paris, France (n = 438).Reference Test: Measured GFR (mGFR).Index Test: Estimated GFR using the 4 new equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both with age, sex, and race. New equations were developed by using linear regression with log GFR as the outcome in two thirds of data from US studies. Internal validation was performed in the remaining one third of data from US CKD studies; external validation was performed in the Paris study.Measurements: GFR was measured by using urinary clearance of iodine-125-iothalamate in the US studies and chromium-51-EDTA in the Paris study. Serum cystatin C was measured by using Dade-Behring assay, standardized serum creatinine values were used.Results: Mean mGFR, serum creatinine, and serum cystatin C values were 48 mL/min/1.73 m(2) (5th to 95th percentile, 15 to 95), 2.1 mg/dL, and 1.8 mg/L, respectively. For the new equations, coefficients for age, sex, and race were significant in the equation with serum cystatin C, but 2- to 4-fold smaller than in the equation with serum creatinine. Measures of performance in new equations were consistent across the development and internal and external validation data sets. Percentages of estimated GFR within 30% of mGFR for equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both levels with age, sex, and race were 81%, 83%, 85%, and 89%, respectively. The equation using serum cystatin C level alone yields estimates with small biases in age, sex, and race subgroups, which are improved in equations including these variables.Limitations: Study population composed mainly of patients with CKD.Conclusions: Serum cystatin C level alone provides GFR estimates that are nearly as accurate as serum creatinine level adjusted for age, sex, and race, thus providing an alternative GFR estimate that is not linked to muscle mass. An equation including serum cystatin C level in combination with serum creatinine level, age, sex, and race provides the most accurate estimates. [ABSTRACT FROM AUTHOR]

Background: Injection drug use (IDU) accounts for 70 percent of HIV cases in Ukraine. Until buprenorphine maintenance therapy (BMT) was introduced, few effective strategies aimed at achieving reduction in illicit drug use were available as a conduit to anti-retroviral therapy (ARV) among IDUs.Description: In October 2005, BMT was scaled-up using Global Fund resources in six regions within Ukraine. Entry criteria included opioid dependence, HIV-1 seropositivity, age >or=18 years and reported interest in BMT. All sites included a multidisciplinary team. To date, 207 patients have been initiated on BMT.Lessons Learned: The existing infrastructure allows for further scale-up of and administration of BMT and the possibility of co-administration with ARV. The process for prescription and administration of buprenorphine and ARV is at times cumbersome and constrained by current regulations.Recommendations: More IDU need BMT to improve overall health outcomes. Central to expanding access will be legislative changes to existing drug policy. Moreover, the cost of buprenorphine is prohibitively expensive. Sustainable substitution therapy in Ukraine requires lower negotiated prices for buprenorphine, the addition of methadone, or both to the existing formulary for HIV+ drug users. [ABSTRACT FROM AUTHOR]