Avian Response to Old-growth Maintenance Logging in the Swan River State Forest, Montana

Old-growth maintenance silvicultural treatment is a tool implemented to retain old-growth forest attributes, remove shade-intolerant trees, and create canopy gaps. Our objectives were to examine how these treatments affect avian diversity and density. We used a Before-After/Control-Impact Pairs study design by pairing old-growth stands proposed for harvest with nearby untreated stands, based on their pre-treatment forest structure and composition similarity. Logging reduced basal area by 40 percent (P < 0.05), overstory canopy cover by 31 percent (P < 0.05), and the density of trees >42 cm dbh (P < 0.05). No major changes in bird species composition or diversity were detected. Only the relative densities of evening grosbeaks changed (58% reduction in density, P < 0.05), likely due to the removal of insect-infested trees. All old-growth associated bird species continued to occupy treatment stands under the landscape conditions we observed. We did not evaluate avian survival or reproductive success, which would provide beneficial metrics for further interpretation of the potential effects of old-growth maintenance treatments

Ultrasensitive Liquid Chromatography–Tandem Mass Spectrometric Methodologies for Quantification of Five HIV‑1 Integrase Inhibitors in Plasma for a Microdose Clinical Trial

HIV-1 integrase strand transfer inhibitors are an important class of compounds targeted for the treatment of HIV-1 infection. Microdosing has emerged as an attractive tool to assist in drug candidate screening for clinical development, but necessitates extremely sensitive bioanalytical assays, typically in the pg/mL concentration range. Currently, accelerator mass spectrometry is the predominant tool for microdosing support, which requires a specialized facility and synthesis of radiolabeled compounds. There have been few studies attempted to comprehensively assess a liquid chromatography–tandem mass spectrometry (LC–MS/MS) approach in the context of microdosing applications. Herein, we describe the development of automated LC–MS/MS methods to quantify five integrase inhibitors in plasma with the limits of quantification at 1 pg/mL for raltegravir and 2 pg/mL for four proprietary compounds. The assays involved double extractions followed by UPLC coupled with negative ion electrospray MS/MS analysis. All methods were fully validated to the rigor of regulated bioanalysis requirements, with intraday precision between 1.20 and 14.1% and accuracy between 93.8 and 107% at the standard curve concentration range. These methods were successfully applied to a human microdose study and demonstrated to be accurate, reproducible, and cost-effective. Results of the study indicate that raltegravir displayed linear pharmacokinetics between a microdose and a pharmacologically active dose

Total Raltegravir Concentrations in Cerebrospinal Fluid Exceed the 50-Percent Inhibitory Concentration for Wild-Type HIV-1▿

HIV-associated neurocognitive disorders continue to be common. Antiretrovirals that achieve higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV and improved cognition. The objective of this study was to measure total raltegravir (RAL) concentrations in CSF and to compare them with matched concentrations in plasma and in vitro inhibitory concentrations. Eighteen subjects with HIV-1 infection were enrolled based on the use of RAL-containing regimens and the availability of CSF and matched plasma samples. RAL was measured in 21 CSF and plasma pairs by liquid chromatography-tandem mass spectrometry, and HIV RNA was detected by reverse transcription-PCR (RT-PCR). RAL concentrations were compared to the 50% inhibitory concentration (IC50) for wild-type HIV-1 (3.2 ng/ml). Volunteers were predominantly middle-aged white men with AIDS and without hepatitis C virus (HCV) coinfection. The median concurrent CD4+ cell count was 276/μl, and 28% of CD4+ cell counts were below 200/μl. HIV RNA was detectable in 38% of plasma specimens and 4% of CSF specimens. RAL was present in all CSF specimens, with a median total concentration of 14.5 ng/ml. The median concentration in plasma was 260.9 ng/ml, with a median CSF-to-plasma ratio of 0.058. Concentrations in CSF correlated with those in with plasma (r2, 0.24; P, 0.02) but not with the postdose sampling time (P, >0.50). RAL concentrations in CSF exceeded the IC50 for wild-type HIV in all specimens by a median of 4.5-fold. RAL is present in CSF and reaches sufficiently high concentrations to inhibit wild-type HIV in all individuals. As a component of effective antiretroviral regimens or as the main antiretroviral, RAL likely contributes to the control of HIV replication in the nervous system

Lack of a Significant Drug Interaction between Raltegravir and Tenofovir▿

Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase inhibitor with potent in vitro activity (95% inhibitory concentration of 31 nM in 50% human serum). This article reports the results of an open-label, sequential, three-period study of healthy subjects. Period 1 involved raltegravir at 400 mg twice daily for 4 days, period 2 involved tenofovir disoproxil fumarate (TDF) at 300 mg once daily for 7 days, and period 3 involved raltegravir at 400 mg twice daily plus TDF at 300 mg once daily for 4 days. Pharmacokinetic profiles were also determined in HIV-1-infected patients dosed with raltegravir monotherapy versus raltegravir in combination with TDF and lamivudine. There was no clinically significant effect of TDF on raltegravir. The raltegravir area under the concentration time curve from 0 to 12 h (AUC0-12) and peak plasma drug concentration (Cmax) were modestly increased in healthy subjects (geometric mean ratios [GMRs], 1.49 and 1.64, respectively). There was no substantial effect of TDF on raltegravir concentration at 12 h postdose (C12) in healthy subjects (GMR [TDF plus raltegravir-raltegravir alone], 1.03; 90% confidence interval [CI], 0.73 to 1.45), while a modest increase (GMR, 1.42; 90% CI, 0.89 to 2.28) was seen in HIV-1-infected patients. Raltegravir had no substantial effect on tenofovir pharmacokinetics: C24, AUC, and Cmax GMRs were 0.87, 0.90, and 0.77, respectively. Coadministration of raltegravir and TDF does not change the pharmacokinetics of either drug to a clinically meaningful degree. Raltegravir and TDF may be coadministered without dose adjustments

Lack of a Clinically Important Effect of Moderate Hepatic Insufficiency and Severe Renal Insufficiency on Raltegravir Pharmacokinetics▿ †

Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor with potent activity in vitro and in vivo. Raltegravir is primarily cleared by hepatic metabolism via glucuronidation (via UDP glucuronosyltransferase 1A1), with a minor component of elimination occurring via the renal pathway. Since the potential exists for raltegravir to be administered to patients with hepatic or renal insufficiency, two studies were conducted to evaluate the influence of moderate hepatic insufficiency (assessed by using the Child-Pugh criteria) and severe renal insufficiency (creatinine clearance, <30 ml/min/1.73 m2) on the pharmacokinetics of raltegravir. Study I evaluated the pharmacokinetics of 400 mg raltegravir in eight patients with moderate hepatic insufficiency and eight healthy, matched control subjects. Study II evaluated the pharmacokinetics of 400 mg raltegravir in 10 patients with severe renal insufficiency and 10 healthy, matched control subjects. All participants received a single 400-mg dose of raltegravir in the fasted state. In study I, the geometric mean ratios (GMR; mean value for the group with moderate hepatic insufficiency/mean value for the healthy controls) and 90% confidence intervals (CIs) for the area under the concentration-time curve from time zero to infinity (AUC0-∞), the maximum concentration of drug in plasma (Cmax), and the concentration at 12 h (C12) were 0.86 (90% CI, 0.41, 1.77), 0.63 (90% CI, 0.23, 1.70), and 1.26 (90% CI, 0.65, 2.43), respectively. In study II, the GMRs (mean value for the group with renal insufficiency/mean value for the healthy controls) and 90% CIs for AUC0-∞, Cmax, and C12 were 0.85 (90% CI, 0.49, 1.49), 0.68 (90% CI, 0.35, 1.32), and 1.28 (90% CI, 0.79, 2.06), respectively. Raltegravir was generally well tolerated by patients with moderate hepatic or severe renal insufficiency, and there was no clinically important effect of moderate hepatic or severe renal insufficiency on the pharmacokinetics of raltegravir. No adjustment in the dose of raltegravir is required for patients with mild or moderate hepatic or renal insufficiency