Radical transformation pathway towards sustainable electricity via evolutionary steps.

A transition towards long-term sustainability in global energy systems based on renewable energy resources can mitigate several growing threats to human society simultaneously: greenhouse gas emissions, human-induced climate deviations, and the exceeding of critical planetary boundaries. However, the optimal structure of future systems and potential transition pathways are still open questions. This research describes a global, 100% renewable electricity system, which can be achieved by 2050, and the steps required to enable a realistic transition that prevents societal disruption. Modelling results show that a carbon neutral electricity system can be built in all regions of the world in an economically feasible manner. This radical transformation will require steady but evolutionary changes for the next 35 years, and will lead to sustainable and affordable power supply globally.

The effect of hepatic impairment on the pharmacokinetics of asunaprevir, an HCV NS3 protease inhibitor.

BACKGROUND: It is necessary to evaluate the impact of hepatic impairment on the pharmacokinetic profile of direct-acting antiviral agents for the treatment of HCV infection. METHODS: In this open-label, parallel group, multiple-dose study subjects (aged 18-70 years with a body mass index <35 kg/m(2)) with mild (n=6), moderate (n=6) and severe hepatic impairment (n=4) received asunaprevir 200 mg twice daily; healthy subjects (n=12) were matched (age, weight, gender) 1:1 to the first 4 subjects in each hepatic impairment group to act as controls. Pharmacokinetic sampling and analyses were performed on days 1 and 7 of dosing. Pharmacokinetic parameters were derived by non-compartmental methods. Geometric mean ratios (GMRs) and 90% CIs were used to assess the impact of hepatic impairment on the pharmacokinetics of asunaprevir, relative to healthy matched controls. RESULTS: Compared with healthy subjects, mild hepatic impairment did not result in meaningful alterations in asunaprevir exposure (day 7 maximal plasma concentration [Cmax] GMR: 0.58 [90% CI 0.35, 0.98]; area under the plasma concentration-time curve in one dosing interval [AUCtau] GMR: 0.79 [90% CI 0.55, 1.15]); clinically significant increases in asunaprevir exposure were observed in subjects with moderate (Cmax GMR: 5.03 [90% CI 2.99, 8.47]; AUCtau GMR: 9.83 [90% CI 6.76, 14.28]) and severe hepatic impairment (Cmax GMR: 22.92 [90% CI 12.57, 41.81]; AUCtau GMR: 32.08 [90% CI 20.84, 49.40]). Correlation between increased asunaprevir exposure and all individual components of the Child-Pugh classification system was observed in subjects with moderate and severe hepatic impairment. CONCLUSIONS: Mild hepatic impairment does not meaningfully affect the pharmacokinetic profile of asunaprevir. The dosing of asunaprevir in patients with moderate-to-severe hepatic impairment is not recommended. Clinicaltrials.gov identifier NCT01019070.

Pharmacokinetics and inhibitory quotient of atazanavir/ritonavir versus lopinavir/ritonavir in HIV-infected, treatment-naive patients who participated in the CASTLE Study.

OBJECTIVES: To characterize the pharmacokinetics and inhibitory quotient (IQ) of atazanavir/ritonavir- and lopinavir/ritonavir-based regimens in HIV-infected, treatment-naive patients. METHODS: The CASTLE Study was a 96 week randomized study comparing 300 mg of atazanavir once daily with 400 mg of lopinavir twice daily, each with low-dose ritonavir (100 mg) plus tenofovir disoproxil fumarate/emtricitabine in HIV-infected, treatment-naive patients. A subset of patients participated in an intensive pharmacokinetic evaluation of the atazanavir regimen (n = 18) and the lopinavir regimen (n = 21) at week 4. (ClinicalTrials.gov NCT00272779) RESULTS: Atazanavir geometric mean (CV%) C(max), C(min) and AUC over the dosing interval were 2897 (46) ng/mL, 526 (57) ng/mL and 28 605 (46) ng ·â€Šh/mL, respectively, and for lopinavir they were 10 655 (51) ng/mL, 5944 (68) ng/mL and 90 946 (59) ng ·â€Šh/mL, respectively. The baseline protein binding-adjusted 90% effective concentration (PBA-EC(90)) was 16 (44) ng/mL for atazanavir and 173 (44) ng/mL for lopinavir. The median IQ (min, max), calculated as the ratio of C(min) to individual baseline PBA-EC(90), was 35 (4, 77) for atazanavir and 34 (11, 129) for lopinavir. The C(max) for ritonavir was 46% higher, while AUC(0-24) and C(min) were 16% and 72% lower in the atazanavir regimen compared with the lopinavir regimen. Tenofovir exposures were similar with both treatments. CONCLUSIONS: Atazanavir (300 mg once daily) and lopinavir (400 mg twice daily), each with low-dose ritonavir, achieved similar IQs in HIV-infected, treatment-naive patients. These results are supportive of the main clinical finding of the CASTLE Study, that the atazanavir/ritonavir-based regimen is non-inferior in antiviral efficacy to the lopinavir/ritonavir-based regimen in antiretroviral-naive subjects.

Effects of the H2-receptor antagonist famotidine on the pharmacokinetics of atazanavir-ritonavir with or without tenofovir in HIV-infected patients.

Significant pharmacokinetic interactions can result between acid-suppressing agents and some protease inhibitors (PIs) in the management of HIV infection. In healthy subjects, famotidine, an H(2)-receptor antagonist, reduces exposures of atazanavir by 4-28% at doses of 20-40 mg twice daily. This study evaluated the effect of famotidine 20-40 mg twice daily on the pharmacokinetics of atazanavir/ritonavir 300/100 mg once daily with and without tenofovir disoproxil fumarate (TDF) 300 mg in HIV-infected patients (n=40; 87.5% male; mean age 42, range 26-63 years; 55% white). Coadministration of famotidine 40 mg and atazanavir/ritonavir to HIV-infected patients reduced exposures of atazanavir by approximately 20%. This is comparable to reductions seen in HIV-uninfected subjects. Coadministration of famotidine 20 mg had less impact on atazanavir exposures, with no reduction of atazanavir geometric mean plasma concentration at 24 h postdose (C(min)). In the presence of TDF, administration of famotidine 20-40 mg twice daily 2 h after and 10 h before atazanavir/ritonavir reduced exposures of atazanavir by 19-25%. However, all individual atazanavir C(min) values remained at least five-fold above the population mean protein-binding adjusted 90% maximum effect (EC(90)) against wild-type HIV (14 ng/mL). No viral load rebound was observed at end of study. The results confirmed that coadministration of an H(2)-receptor antagonist with atazanavir/ritonavir in HIV-infected patients resulted in similar magnitude of reductions in atazanavir exposures as in healthy subjects. This supports the current dose recommendations for coadministration of an H(2)-receptor antagonist with atazanavir/ritonavir.

Hepatotoxicity and gastrointestinal intolerance when healthy volunteers taking rifampin add twice-daily atazanavir and ritonavir.

BACKGROUND: Rifampin is the cornerstone of antituberculosis therapy, but induction of hepatic cytochrome P4503A by rifampin markedly lowers HIV protease inhibitor plasma concentrations. METHODS: This phase 1, open-label, one-arm study was designed to assess pharmacokinetic interactions and safety of atazanavir, ritonavir, and rifampin among 14 evaluable HIV-seronegative volunteers. The study included 3 sequential periods of study drug dosing, with plasma sampling for pharmacokinetic analyses to occur on the last day of each period. During period 1, participants received rifampin 600 mg every 24 hours for 8 days. During period 2, participants continued rifampin 600 mg every 24 hours, and added atazanavir 300 mg and ritonavir 100 mg every 12 hours, to continue for at least 11 days. During period 3, atazanavir was to be increased to 400 mg every 12 hours. RESULTS: Upon adding atazanavir and ritonavir, the first 3 subjects developed vomiting and transaminase elevations resulting in study drug discontinuation. The study was therefore terminated. CONCLUSIONS: Coadministration of rifampin with HIV protease inhibitors may not be a viable treatment option if rifampin administration precedes protease inhibitor initiation. Future studies, which explore concomitant HIV protease inhibitors with rifampin must carefully consider the sequence in which drugs are initiated.

Effect of concomitantly administered rifampin on the pharmacokinetics and safety of atazanavir administered twice daily.

The potent induction of hepatic cytochrome P450 3A isoforms by rifampin complicates therapy for coinfection with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. We performed an open-label, single-arm study to assess the safety and pharmacokinetic interactions of the HIV protease inhibitor atazanavir coadministered with rifampin. Ten healthy HIV-negative subjects completed pharmacokinetic sampling at steady state while receiving 300 mg atazanavir every 12 h without rifampin (period 1), 300 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 2), and 400 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 3). During period 1, the mean concentration of drug in serum at 12 h (C(12 h)) was 811 ng/ml (range, 363 to 2,484 ng/ml) for atazanavir, similar to historic seronegative data for once-daily treatment with 300 mg atazanavir boosted with 100 mg ritonavir. During periods 2 and 3, the mean C(12 h) values for atazanavir were 44 ng/ml (range, <25 to 187 ng/ml) and 113 ng/ml (range, 39 to 260 ng/ml), respectively, well below historic seronegative data for once-daily treatment with 400 mg atazanavir without ritonavir. Although safe and generally well tolerated, 300 mg or 400 mg atazanavir administered every 12 h did not maintain adequate plasma exposure when coadministered with rifampin.

Lack of an effect of atazanavir on steady-state pharmacokinetics of methadone in patients chronically treated for opiate addiction.

BACKGROUND: Effective antiretroviral treatment of opiate-addicted drug users with HIV infection often requires concomitant substance abuse treatment, commonly with methadone. Pharmacological interactions between antiretroviral drugs and methadone may result in opiate withdrawal or increased side effects. OBJECTIVES: To determine if atazanavir, a once-daily protease inhibitor and moderate inhibitor of P450 CYP3A4, exhibited pharmacokinetic interactions with (R)-methadone. METHODS: Methadone pharmacokinetic parameters were measured in 16 patients on chronic methadone therapy prior to and after 14 days of daily administration of atazanavir. Steady-state pharmacokinetic values for total, (R)- (active) and (S)- (inactive) isomers of methadone were derived from plasma concentrations versus time data. Symptoms of opiate withdrawal and excess were monitored. RESULTS: For the active isomer (R)-methadone, the ratio of geometric means for coadministration with atazanavir relative to methadone alone were 1.03 [90% confidence interval (CI), 0.95-1.10] for the area under the concentration-time curve (AUC), 0.91 (90% CI, 0.84-1.00) for plasma maximal concentration and 1.11 (90% CI, 1.02-1.20) for plasma trough concentration. Confidence intervals for all three were within the no-effect or bioequivalence range of 0.80-1.25 for (R)-methadone. Inactive (S)-methadone was modestly reduced during atazanavir coadministration. Clinically relevant symptoms of opiate withdrawal or excess were not detected. Exposures to atazanavir were within range of previously reported values. CONCLUSIONS: No clinically relevant pharmacokinetic interactions were found between atazanavir and methadone. Dosage adjustment need not be recommended for either methadone or atazanavir when co-administered to patients treated for opiate abuse and HIV disease.

Manipulated stress and dispositional reinvestment in a wall-volley task: an investigation into controlled processing.

This field-based study examined the action of reinvesting in controlled processing on 14 university soccer players to assess skill breakdown under pressure. Based on scores on the Reinvestment Scale of Masters, Polman, and Hammond, two experimental groups of participants were inferred to be dispositionally High or Low in Reinvestment. They performed a wall-volley soccer task, which involved kicking a ball repeatedly against a wall target zone for 90 sec. as defined by McMorris, Gibbs, Palmer, Payne, and Torpey in a High and Low Stress environment. Prior to each condition performers were required to complete the Anxiety Rating Scale. A series of two-way (reinvestment x stress) analyses of variance with repeated measures on stress were conducted on the Anxiety and soccer scores. Players scoring High on the Reinvestment Scale reported significantly greater Intensity for Somatic Anxiety and lower Self-confidence than players who scored Low in the High Stress condition. Anxiety Direction scores indicated players scoring High on the Reinvestment Scale reported their increase in Somatic Anxiety and reduction in Self-confidence in the High Stress condition to be significantly more debilitating of performance than players who scored Low on the Reinvestment Scale. Soccer scores indicated players scoring High on the Reinvestment Scale were more prone to reinvesting in controlled processing and essentially experiencing greater decreases in performance under pressure than those Low in Reinvestment. Therefore, these findings support the predictive power of the Reinvestment Scale.