Electron, phonon and thermoelectric properties of Cu7PS6 crystal calculated at DFT level.

The promising class of the environment-friendly thermoelectrics is the copper-based argyrodite-type ion-conducting crystals exhibiting just extraordinary low thermal conductivity below the glass limit associated with the molten copper sublattice leading to a softening of phonon modes. To explain why the argyrodite structure containing copper ions favors the low thermal conductivity, we have utilized the ab initio calculations of the electron, phonon, and thermoelectric properties of Cu7PS6 crystal in the framework of the density functional and Boltzmann transport theories. To obtain the reliable thermoelectric properties of Cu7PS6, we take into account the dependence of the electron effective mass m* on the redundant carrier concentration n. We propose to use the Burstein-Moss effect for the calculation of the electron effective mass m* of a semiconductor. We have found the strong nonlinear character of copper atom vibrations in Cu7PS6 which exceeds substantially the similar values for phosphorous and sulfur atoms. The large vibration nonlinearity of the copper atoms found in Cu7PS6 explains the diffusion-like heat transfer and the relatively low coefficient of the lattice thermal conductivity (κ = 0.7 W/(m K)), which is favorable to achieve the large thermoelectric figure of merit.

Elvitegravir concentrations in seminal plasma in HIV-1-infected men.

OBJECTIVES: The aim of the study was to quantify elvitegravir (EVG) concentrations in the semen of HIV-1-infected men receiving antiretroviral therapy (ART) consisting of an elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) single-tablet regimen. METHODS: A phase IV, cross-sectional study was carried out including HIV-1-infected male adults with suppressed plasma HIV-1 RNA who switched ART to EVG/COBI/FTC/TDF. Total EVG concentrations at the end of the dosing interval (C24 h ) and HIV-1 RNA were measured in paired seminal plasma (SP) and blood plasma (BP) samples 4 weeks after switching to EVG/COBI/FTC/TDF. Validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify EVG concentrations, and HIV-1 RNA was determined by real-time polymerase chain reaction (PCR). RESULTS: Ten men were included. Their median age was 40 years (range 24-47 years), the median time on ART was 50 months (range 10-186 months), the median time with plasma HIV-1 RNA < 40 copies/mL was 37 months (range 7-113 months), and the median CD4 count was 737 cells/µL (range 190-1122 cells/µL). Four weeks after switching to EVG/COBI/FTC/TDF, all subjects had HIV-1 RNA < 40 copies/mL in both BP and SP. Median EVG C24 h was 277 ng/mL (range 64.8-1790 ng/mL) in BP and 169 ng/mL (range 12.8-792 ng/mL) in SP. A significant correlation was observed between BP and SP EVG concentrations (Spearman rho 0.952; P < 0.001). The median SP:BP EVG concentration ratio was 0.39 (range 0.20-0.92). EVG C24 h in SP was at least 23-fold the in vitro protein-unbound 50% effective response (EC50 ) of HIV-1 clinical isolates (0.04-0.55 ng/mL). In all but one individual, EVG C24 h in SP was also higher than the blood plasma protein binding-adjusted 95% inhibitory concentration (IC95 ) of wild-type HIV-1 (45 ng/mL). CONCLUSIONS: Seminal EVG concentrations in HIV-infected men treated with EVG/COBI/FTC/TDF sufficed to contribute to maintaining HIV-1 RNA suppression in this compartment.

The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function.

Despite the extraordinary success of HIV-1 antiretroviral therapy in prolonging life, infected individuals face lifelong therapy because of a reservoir of latently-infected cells that harbor replication competent virus. Recently, compounds have been identified that can reverse HIV-1 latency in vivo. These latency- reversing agents (LRAs) could make latently-infected cells vulnerable to clearance by immune cells, including cytolytic CD8+ T cells. We investigated the effects of two leading LRA classes on CD8+ T cell phenotype and function: the histone deacetylase inhibitors (HDACis) and protein kinase C modulators (PKCms). We observed that relative to HDACis, the PKCms induced much stronger T cell activation coupled with non-specific cytokine production and T cell proliferation. When examining antigen-specific CD8+ T cell function, all the LRAs except the HDACi Vorinostat reduced, but did not abolish, one or more measurements of CD8+ T cell function. Importantly, the extent and timing of these effects differed between LRAs. Panobinostat had detrimental effects within 10 hours of drug treatment, whereas the effects of the other LRAs were observed between 48 hours and 5 days. These observations suggest that scheduling of LRA and CD8+ T cell immunotherapy regimens may be critical for optimal clearance of the HIV-1 reservoir.

Pharmacokinetics of two common antiretroviral regimens in older HIV-infected patients: a pilot study.

OBJECTIVES: The pharmacokinetics (PK) of antiretrovirals (ARVs) in older HIV-infected patients are poorly described. Here, the steady-state PK of two common ARV regimens [tenofovir (TFV)/emtricitabine (FTC)/efavirenz (EFV) and TFV/FTC/atazanavir (ATV)/ritonavir (RTV)] in older nonfrail HIV-infected patients are presented. METHODS: HIV-infected subjects ≥ 55 years old not demonstrating the frailty phenotype were enrolled in an unblinded, intensive-sampling PK study. Blood plasma (for TFV, FTC, EFV, ATV and RTV concentrations) and peripheral blood mononuclear cells [PBMCs; for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations] were collected at 11 time-points over a 24-hour dosing interval. Drug concentrations were analysed using validated liquid chromatography-ultraviolet detection (LC-UV) or liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Noncompartmental pharmacokinetic analysis was used to estimate PK parameters [area under the concentration-time curve over 24 h (AUC0-24h ) and maximal concentration (Cmax )]. These parameters were compared with historical values from the general HIV-infected population. RESULTS: Six subjects on each regimen completed the study. Compared with the general population, these elderly subjects had 8-13% decreased TFV AUC0-24h and Cmax , and 19-78% increased FTC and RTV AUC0-24h and Cmax . Decreased ATV AUC0-24h (12%) and increased Cmax (9%) were noted, while EFV exposure was unchanged (5%) with a 16% decrease in Cmax . Intracellular nucleoside/tide metabolite concentrations and AUC are also reported for these subjects. CONCLUSIONS: This study demonstrates that the PK of these ARVs are altered by 5-78% in an older HIV-infected population. Implications of PK differences for clinical outcomes, particularly with the active nucleoside metabolites, remain to be explored. This study forms the basis for further study of ARV PK, efficacy, and toxicity in older HIV-infected patients.

Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy.

Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.

Safety and pharmacokinetics of multiple-dose anidulafungin in infants and neonates.

Candida infections are common and often fatal in infants and neonates. Anidulafungin has excellent activity against Candida species, but the pharmacokinetics (PK) and safety of the drug in infants and neonates are unknown. The object of our study was to determine the PK and safety of anidulafungin in infants and neonates at risk for invasive candidiasis. Intravenous anidulafungin (1.5 mg/kg/day maintenance dose) was administered to 15 infants and neonates over 3 to 5 days. Plasma samples were collected after the first dose and again after the third to fifth doses. The pharmacokinetic parameters of the drug were determined by noncompartmental analysis. Safety was assessed using National Cancer Institute common toxicity criteria. The study showed that drug exposure levels were similar between neonates and infants; the median areas under the concentration-time curve (range) was 75 (30-109) µg·h/ml and 98 (55-278) µg·h/ml (P = 0.12) for neonates and infants, respectively. No drug-related serious adverse events were observed. The study results indicate that neonates and infants receiving 1.5 mg/kg/day have anidulafungin exposure levels similar to those in children receiving similar weight-based dosing and in adult patients receiving 100 mg/day.

Pharmacologic opportunities for HIV prevention.

Innovations in antiretroviral (ARV) treatment strategies have resulted in treated HIV-infected patients having life expectancies similar to those of uninfected individuals. Yet the number of individuals capable of HIV transmission is increasing-for every person in whom ARV treatment is initiated, four others are becoming newly infected with HIV. The limited progress with microbicides and vaccines for HIV prevention reinforce the need for a concentrated exploration of the utility of ARVs. Preliminary animal studies with topical and systemic ARVs show promising results. However, current clinical trials were designed without a comprehensive understanding of ARV pharmacokinetic-pharmacodynamic relationships in HIV prevention. This review focuses on current strategies for the prevention of HIV infection and on the ways in which the tools of pharmacology can be a valuable resource for determining pharmacodynamic targets, providing interspecies scaling of exposures, identifying the optimal drugs/drug combinations, doses, and dosing regimens, and designing efficient clinical trials.

Development of an LC-MS method for measuring TNF in human vaginal tissue.

A sensitive, accurate, and precise liquid chromatography-mass spectrometry assay for the determination of tenofovir (TNF) in human vaginal tissue was developed and validated. After homogenization of the tissue, solid-phase extraction on Varian Bond Elut-C(18) column was used for sample clean up. Chromatographic separation of TNF and the internal standard (tolbutamide) was achieved with a Varian Polaris 3C(18)-A reversed-phase analytical column (150 mm x 2 mm). A gradient method using 0.1% formic acid in water and 0.1% formic acid in acetonitrile was employed. Detection of TNF and tolbutamide was achieved by electrospray ionization mass spectrometry in the positive ion mode using 288.05 and 271.00 m/z, respectively. Linear TNF calibration curves were obtained between 1-1,000 ng/mL with a correlation coefficient (r(2)) greater than 0.999. Intra- and inter-day accuracy for TNF ranged from 89.7% and 109.4% and from 97.3% and 104.9%, and precision ranged from 1.3% and 10.9% and 2.6% and 9.0%, respectively. This is the first validated method developed to quantitate TNF in human tissues.

A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir.

The effects of tipranavir/ritonavir (TPV/r) on hepatic and intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP) enzyme activity were evaluated in 23 volunteers. The subjects received oral (p.o.) caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, and midazolam and digoxin (p.o. and intravenous (i.v.)) at baseline, during the first three doses of TPV/r (500 mg/200 mg b.i.d.), and at steady state. Plasma area under the curve (AUC)(0-infinity) and urinary metabolite ratios were used for quantification of protein activities. A single dose of TPV/r had no effect on the activity of CYP1A2 and CYP2C9; it weakly inhibited CYP2C19 and P-gp; and it potently inhibited CYP2D6 and CYP3A. Multiple dosing produced weak induction of CYP1A2, moderate induction of CYP2C19, potent induction of intestinal P-gp, and potent inhibition of CYP2D6 and CYP3A, with no significant effects on CYP2C9 and hepatic P-gp. Several P450/transporter single-nucleotide polymorphisms correlated with the baseline phenotype but not with the extent of inhibition or induction. Although mixed induction and inhibition are present, this approach offers an understanding of drug interaction mechanisms and ultimately assists in optimizing the clinical use of TPV/r.

Electric field induced magnetic anisotropy in a ferromagnet.

We report the first observation of a transient all electric field induced magnetic anisotropy in a thin film metallic ferromagnet. We generate the anisotropy with a strong (approximately 10(9) V/m) and short (70 fs) E-->-field pulse. This field is large enough to distort the valence charge distribution in the metal, yet its duration is too brief to change the atomic positions. This pure electronic structure alteration of the sample generates a new type of transient anisotropy axis and strongly influences the magnetization dynamics. The successful creation of such an anisotropy opens the possibility for all E-->-field induced magnetization reversal in thin metallic films--a greatly desired yet unachieved process.

Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects.

Limited data are available about the effect of steady-state lopinavir and ritonavir (LPV/r) on bupropion pharmacokinetics. As patients may benefit by using these two agents in combination, this study determined the extent and direction of this drug-drug interaction. Twelve healthy volunteers received a single 100 mg dose of sustained-release bupropion before and after 2 weeks of treatment with LPV/r 400 mg/100 mg twice daily. Pharmacokinetics profiles were determined on days 1 and 30 for bupropion and hydroxybupropion and days 29 and 30 for LPV/r. LPV/r administration significantly decreased bupropion maximum plasma concentration (C(max)) by 57% (90% confidence interval (CI), 38-76%; P<0.01) and area under the curve (AUC) infinity by 57% (90% CI, 32-83%; P<0.01). Hydroxybupropion C(max) and AUC infinity decreased by 31% (90% CI, 7-55%; P<0.01) and by 50% (90% CI, 34-65%; P<0.01), respectively. No significant changes in the pharmacokinetics of LPV/r were found following administration of a single dose of bupropion. Concurrent use of LPV/r and bupropion resulted in decreased exposure to bupropion and its active metabolite hydroxybupropion that may necessitate as much as a 100% dose increase of bupropion. A probable mechanism for this interaction is the concurrent induction of cytochrome P450 2B6 and UDP-glucuronosyltransferase enzymes. LPV/r exposure is unaffected by a single dose of bupropion.

Domain instability during magnetization precession.

Spin wave equations describing the nonequilibrium precessional state of a ferromagnetic system are given. The equations reveal a new type of spin wave instability (SWI) towards growing domains of uniform magnetization. In the developed stages of SWI a nonstationary picture of domain chaos is revealed by numerical simulations. SWI is capable of explaining recent experimental observation of stochastic switching in precessional magnetization reversal.

The ultimate speed of magnetic switching in granular recording media.

In magnetic memory devices, logical bits are recorded by selectively setting the magnetization vector of individual magnetic domains either 'up' or 'down'. In such devices, the fastest and most efficient recording method involves precessional switching: when a magnetic field B(p) is applied as a write pulse over a period tau, the magnetization vector precesses about the field until B(p)tau reaches the threshold value at which switching occurs. Increasing the amplitude of the write pulse B(p) might therefore substantially shorten the required switching time tau and allow for faster magnetic recording. Here we use very short pulses of a very high magnetic field to show that under these extreme conditions, precessional switching in magnetic media supporting high bit densities no longer takes place at well-defined field strengths; instead, switching occurs randomly within a wide range of magnetic fields. We attribute this behaviour to a momentary collapse of the ferromagnetic order of the spins under the load of the short and high-field pulse, thus establishing an ultimate limit to the speed of deterministic switching and magnetic recording.

Biological Correlates of Sexual Transmission of HIV Practical Consequences and Potential Targets for Public Health : Practical Consequences and Potential Targets for Public Health.

The probability of sexual transmission of HIV depends on the infectiousness of the index case and the susceptibility of the sexual contact. The risk of HIV transmission is heterogeneous and may be greatest during the initial sexual contacts in a steady partnership. Several factors, including systemic and mucosal acquired protective immune-response might be responsible for the apparent decrease of per-sex-act risk of transmission in a given partnership over time. Biological studies can be used to better understand the complex information obtained by epidemiological surveys. The infectiousness of HIV depends on the inoculum, and virologic factors. The genital tract viral load of the index case is likely the most important determinant of transmission. At the population level, interventions that reduce the genital shedding of HIV by reducing systemic blood viral load and/or local inflammatory processes are likely to have a beneficial impact on HIV incidence. Antiretroviral drugs are likely to reduce sexual transmission of HIV. However, these drugs may not all prove equally. Compartmentalized HIV replication in the male and female genital tract have been observed. Treatment with antiretroviral drugs that poorly penetrate the genital tract harbour the risk of local production and spread of resistant viruses. In addition, increased risk taking behaviour could offset the benefits of reduced probability of transmission at the population level. Biological data about HIV transmission must be used to inform public health policies and optimize HIV prevention strategies.

Use of midazolam urinary metabolic ratios for cytochrome P450 3A (CYP3A) phenotyping.

Midazolam (MDZ) total clearance (ClT) is widely used for cytochrome P450 3A (CYP3A) phenotyping, but requires up to eight blood samples. This study was conducted to compare the use of midazolam ClT to use of a midazolam urinary metabolic ratio for CYP3A phenotyping. Ten male and 10 female subjects received i.v. midazolam 0.025 mg/kg eight times over a 4-month period at approximately 2-week intervals. The first six phenotyping measures were used to estimate baseline CYP3A activity, then subjects received the moderate CYP3A inhibitor fluvoxamine 150 mg/day for the last 4 weeks (two phenotyping visits) of the study. Serial blood samples were obtained for calculation of ClT. Urine was collected for 6 h following each midazolam dose. Midazolam, 1'-hydroxymidazolam (1-OHMDZ), and 4-hydroxymidazolam were measured in plasma and urine by liquid chromatography with tandem mass spectrometry (LC/MS/MS). Analysis of 148 samples from 20 subjects revealed a weak overall correlation between the urinary ratio of 1-OHMDZ/MDZ to midazolam ClT of r(s) = 0.372 (P = 0.0001). There was no correlation when examining either baseline samples or fluvoxamine-inhibited samples alone (r(s) = 0.101, P = 0.289 and r(s) = 0.266, P = 0.123, respectively). The median (range) urinary ratio decreased significantly with fluvoxamine [219 (141-409) versus 127 (50-464); P = 0.005] and to a similar extent to the midazolam ClT (-33.6% versus -42.4%, respectively; P > 0.05). Median urinary recovery of the i.v. midazolam dose varied between 1.4% and 53% and was significantly lower in samples collected while patients were receiving fluvoxamine (34.3% versus 23.1%; P= 0.0004). Based on these results, although this midazolam urinary ratio was not very reflective of baseline CYP3A activity, it may be a useful indicator of CYP3A inhibition.

Domestic cat model for predicting human nucleoside analogue pharmacokinetics in blood and seminal plasma.

To establish whether a feline model can predict nucleoside analogue behavior in human semen, zidovudine (ZDV) and lamivudine (3TC) pharmacokinetic parameters (PKs) were determined in the blood and seminal plasma of healthy cats. Our results show considerable similarity in ZDV and 3TC PKs between cats and humans. As in humans, ZDV and 3TC tend to accumulate in feline seminal plasma. Area under the blood plasma concentration-time curve was predictive of seminal plasma excretion. The felid model offers a unique in vivo experimental alternative for investigating the pharmacokinetics of nucleoside analogues in the male genital tract.

Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method.

The CYP3A4 enzyme contributes to the disposition of more than 60 therapeutically important drugs and displays marked person-to-person variability of the catalytic function. However, the extent of genetic contribution to variability in CYP3A4 activity remains elusive. Recently, we showed that a comparison of between- (SDb2) and within-person (SDW2) variances provides an estimate of the genetic component of variability in drug disposition. The aim of the present analysis was to assess the genetic control of CYP3A4 activity in vivo. A computerized literature search was conducted covering 1966 to September 1999 to identify studies reporting repeated administration of CYP3A4 substrates. The genetic contribution (rGC) to disposition of each CYP3A4 substrate was obtained by the formula (SDb2-SDW2)/SDb2. The rGC values approaching 1.0, point to overwhelming genetic control, whereas those close to zero suggest that environmental factors dominate. A total of 16 studies with 10 different CYP3A4 substrates were identified (n = 161 subjects). The rGC for hepatic CYP3A4 activity as measured by midazolam plasma clearance or the erythromycin breath test was 0.96 (0.92-0.98) (95% Cl) and 0.89 (0.65-0.98), respectively (P < 0.05). The point estimates of rGC for composite (hepatic + intestinal) CYP3A4 activity measured after oral administration of cyclosporine, ethinylestradiol, ethylmorphine, nifedipine and nitrendipine, ranged from 0.66-0.98 (median: 0.83) (P < 0.05). Cyclosporine data suggested a higher genetic control of CYP3A4 at night than during the day. These data indicate that further molecular genetic investigations are warranted to identify genetic variants at CYP3A4 or elsewhere in the genome which contribute to regulation of CYP3A4 activity.

Nucleoside analogues achieve high concentrations in seminal plasma: relationship between drug concentration and virus burden.

Human immunodeficiency virus (HIV) can be transmitted in semen from a man to his sexual partners. Antiretroviral drugs are likely to affect the amount of HIV-1 in semen and perhaps transmission of the virus. The concentrations of zidovudine, lamivudine, and HIV-1 RNA in blood and seminal plasma were measured in 9 HIV-positive men over