Extended Postexposure Protection Against Vaginal Simian/Human Immunodeficiency Virus Infection With Tenofovir Alafenamide Fumarate/Elvitegravir Inserts in Macaques.

Vaginal inserts that can be used on demand before or after sex may be a desirable human immunodeficiency virus (HIV) prevention option for women. We recently showed that inserts containing tenofovir alafenamide fumarate (TAF, 20 mg) and elvitegravir (EVG, 16 mg) were highly protective against repeated simian/human immunodeficiency virus (SHIV) vaginal exposures when administered to macaques 4 hours before or after virus exposure (93% and 100%, respectively). Here, we show in the same macaque model that insert application 8 hours or 24 hours after exposure maintains high efficacy (94.4% and 77.2%, respectively). These data extend the protective window by TAF/EVG inserts and inform their clinical development for on-demand prophylaxis in women.

Urchin-like CoP3/Cu3P heterostructured nanorods supported on a 3D porous copper foam for high-performance non-enzymatic electrochemical dopamine sensors.

In this study, we developed a high-performance non-enzymatic electrochemical sensor based on urchin-like CoP3/Cu3P heterostructured nanorods supported on a three-dimensional porous copper foam, namely, CoP3/Cu3P NRs/CF, for the detection of dopamine. Benefiting from the promising intrinsic catalytic activities of CoP3 and Cu3P, urchin-like microsphere structures, and a large electrochemically active surface area for exposing numerous accessible catalytic active sites, the proposed CoP3/Cu3P NRs/CF shows extraordinary electrochemical response towards the electrocatalytic oxidation of dopamine. As a result, the CoP3/Cu3P NRs/CF sensing electrode has a broad detection window (from 0.2 to 2000 µM), low detection limit (0.51 µM), high electrochemical sensitivity (0.0105 mA µM-1 cm-2), excellent selectivity towards dopamine in the coexistence of some interfering species, and good stability for dopamine determination. More importantly, the CoP3/Cu3P NRs/CF catalyst also exhibits excellent catalytic activity, sensitivity, and selectivity for dopamine detection under simulated human body conditions at a physiological pH of 7.25 (0.1 M PBS) at 36.6 °C.

Pharmacology of boosted and unboosted integrase strand transfer inhibitors for two-dose event-driven HIV prevention regimens among men.

BACKGROUND: Event-driven HIV prevention strategies are a priority for users who do not require daily pre-exposure prophylaxis (PrEP). Regimens containing integrase strand transfer inhibitors (INSTIs) are under evaluation as alternatives to daily PrEP. To better understand INSTI distribution and inform dosing selection we compared the pharmacology of two-dose boosted elvitegravir and unboosted bictegravir regimens in MSM. MATERIALS AND METHODS: Blood, rectal and penile secretions and rectal biopsies were collected from 63 HIV-negative MSM aged 18-49 years. Specimens were collected up to 96 h after two oral doses of tenofovir alafenamide and emtricitabine with elvitegravir boosted by cobicistat or unboosted bictegravir given 24 h apart. Antiretroviral drugs were measured by LC-MS. RESULTS: Mean bictegravir plasma concentrations remained above the 95% protein-adjusted effective concentration 96 h after dosing [273 (95% CI: 164-456) ng/mL] whereas elvitegravir plasma concentrations became undetectable 48 h after the second dose. Bictegravir and elvitegravir reached rectal tissues within 2 h after the first dose, and elvitegravir tissue concentrations [1.07 (0.38-13.51) ng/mg] were greater than bictegravir concentrations [0.27 (0.15-0.70) ng/mg]. Both INSTIs became undetectable in tissues within 96 h. Elvitegravir and bictegravir were not consistently detected in penile secretions. CONCLUSIONS: Whereas bictegravir plasma concentrations persist at least 4 days after a two-oral-dose HIV prophylaxis regimen, elvitegravir accumulates in mucosal tissues. Differing elvitegravir and bictegravir distribution may result in variable mucosal and systemic antiviral activity and can inform dosing strategies for event-driven HIV prevention.

Pharmacokinetics of vaginally applied integrase inhibitors in macaques.

OBJECTIVES: We conducted a detailed pharmacokinetic assessment in macaques treated with vaginal gels formulated with HIV integrase strand transfer inhibitors (INSTIs) to better understand drug distribution and identify INSTI concentrations associated with previously demonstrated in vivo protection against vaginal simian HIV challenge. METHODS: Six macaques received vaginal gel containing 1% raltegravir (30 mg) once-weekly over 6 weeks. Following a washout period, five macaques received once-weekly gel containing 0.23% L-870,812 (7 mg). Drug concentrations were measured in plasma, mucosal fluids and vaginal tissues at baseline and 2, 5 and 24 h post-dosing. RESULTS: The median maximum concentration (Cmax) for raltegravir and L-870,812 in plasma was below the limit of quantification and 41.1 ng/mL, respectively. The Cmax in vaginal fluids (1441 and 1250 µg/mL) and tissues (266.7 and 368.4 µg/g) was achieved 2-5 h after dosing, respectively. A similar half-life was observed for raltegravir and L-870,812 in vaginal fluids (8-10 h) and remained 3-4 orders of magnitude above the protein-adjusted IC95 (0.016 and 0.106 µg/mL, respectively) at 24 h. Drug concentrations in vaginal fluids correlated well with those in vaginal tissues (Pearson r ≥ 0.788). Both drugs were consistently detected in rectal fluids 2 h after vaginal dosing, albeit at much lower levels (31-92-fold) than those in vaginal fluids. CONCLUSIONS: To the best of our knowledge, this study provides the first data on INSTI levels in vaginal tissues associated with in vivo protection and demonstrates rectal drug distribution of INSTIs after vaginal dosing. These findings may inform dose selection for topical products with INSTIs for HIV prevention.

Antiretroviral drug exposure in urethral and glans surface sampling of the penis.

BACKGROUND: HIV exposure to penile tissues provides a risk of acquisition among men, yet studies evaluating penile antiretroviral (ARV) drug distribution have been lacking. We measured ARVs on urethral and glans surface swabs collected following a dose of tenofovir alafenamide, emtricitabine, elvitegravir, darunavir and cobicistat. METHODS: Thirty-five HIV-negative male participants provided urethral swabs, glans swabs, rectal swabs, blood and urine up to 96 h following a single dose of tenofovir alafenamide/emtricitabine/elvitegravir/cobicistat and darunavir. ARVs were measured by liquid chromatography-mass spectrometry with a lower limit of detection (LOD) of 1 ng/swab for swabs and 10 ng/mL for plasma and urine. Concentrations are reported as median and range. RESULTS: Urethral swab emtricitabine and darunavir concentrations peaked at 4 h for emtricitabine (36 ng/swab; 3-307 ng/swab) and 8 h for darunavir (25 ng/swab; 2-52 ng/swab). Glans swab emtricitabine and darunavir concentrations peaked 24 h after dosing (emtricitabine 14 ng/swab,

Long-Acting Cabotegravir Protects Macaques Against Repeated Penile Simian-Human Immunodeficiency Virus Exposures.

We used a novel penile simian-human immunodeficiency virus (SHIV) transmission model to investigate whether long-acting cabotegravir (CAB LA) prevents penile SHIV acquisition in macaques. Twenty-two macaques were exposed to SHIV via the foreskin and urethra once weekly for 12 weeks. Of these, 6 received human-equivalent doses of CAB LA, 6 received oral emtricitabine/tenofovir disoproxil fumarate, and 10 were untreated. The efficacy of CAB LA was high (94.4%; 95% confidence interval, 58.2%-99.3%) and similar to that seen with oral emtricitabine/tenofovir disoproxil fumarate (94.0%; 55.1%-99.2%). The high efficacy of CAB LA in the penile transmission model supports extending the clinical advancement of CAB LA preexposure prophylaxis to heterosexual men.

Effects of phytochemicals on cellular signaling: reviewing their recent usage approaches.

Most of the previous studies in last three decades report evidence of interactions between the different phytochemicals and the proteins involved in signal transduction pathways using in silico, in vitro, ex vivo, and in vivo analyses. However, extrapolation of these findings for clinical purposes has not been that fruitful. The efficacy of the phytochemicals in vivo studies is limited by parameters such as solubility, metabolic degradation, excretion, etc. Various approaches have now been devised to circumvent these limitations. Recently, chemical modification of the phytochemicals are demonstrated to reduce some of the limitations and improve their efficacy. Similar to traditional medicines several combinatorial phytochemical formulations have shown to be more efficient. Further, phytochemicals have been reported to be even more efficient in the form of nanoparticles. However, systematic evaluation of their efficacy, mode of action in pathway modulation, usage and associated challenges is required to be done. The present review begins with basic understanding of how signaling cascades regulate cellular response and the consequences of their dysregulation further summarizing the developments and problems associated with the dietary phytochemicals and also discuss recent approaches in strengthening these compounds in pharmacological applications. Only context relevant studies have been reviewed. Considering the limitations and scope of the article, authors do not claim inclusion of all the early and recent studies.

Efficacy of Oral Tenofovir Alafenamide/Emtricitabine Combination or Single-Agent Tenofovir Alafenamide Against Vaginal Simian Human Immunodeficiency Virus Infection in Macaques.

BACKGROUND: Tenofovir alafenamide (TAF)-based regimens are being evaluated for pre-exposure prophylaxis (PrEP). We used a macaque model of repeated exposures to simian human immunodeficiency virus (SHIV) to investigate whether TAF alone or the combination of TAF and emtricitabine (FTC) can prevent vaginal infection. METHODS: Pigtail macaques were exposed vaginally to SHIV162p3 once a week for up to 15 weeks. Animals received clinical doses of FTC/TAF (n = 6) or TAF (n = 9) orally 24 hours before and 2 hours after each weekly virus exposure. Infection was compared with 21 untreated controls. RESULTS: Five of the 6 animals in the FTC/TAF and 4 of the 9 animals in the TAF alone group were protected against infection (P = .001 and P = .049, respectively). The calculated efficacy of FTC/TAF and TAF was 91% (95% confidence interval [CI], 34.9%-98.8%) and 57.8% (95% CI, -8.7% to 83.6%), respectively. Infection in FTC/TAF but not TAF-treated macaques was delayed relative to controls (P = .005 and P = .114). Median tenofovir diphosphate (TFV-DP) levels in peripheral blood mononuclear cells (PBMCs) were similar among infected and uninfected macaques receiving TAF PrEP (351 and 143 fmols/106 cells, respectively; P = .921). CONCLUSIONS: Emtricitabine/TAF provided a level of protection against vaginal challenge similar to FTC/TFV disoproxil fumarate combination in the macaque model. Our results support the clinical evaluation of FTC/TAF for PrEP in women.

Effects of Sting Plant Extracts as Penetration Enhancers on Transdermal Delivery of Hypoglycemic Compounds.

Background and objectives: The percutaneous route is an interesting and inventive investigation field of drug delivery. However, it is challenging for drug molecules to pass through the skins surface, which is a characterized by its permeability barrier. The purpose of this study is to look at the effect of some penetration enhancers on in vivo permeation of insulin and insulin sensitizers (curcumin and rutin) through diabetes-induced mouse skin. Materials and Methods: Sting crude extracts of Dendrocnide meyeniana, Urtica thunbergiana Sieb. and Zucc, and Alocasia odora (Lodd.) Spach were used as the penetration enhancers. Mouse skin irritation was tested by smearing the enhancers for the measurements at different time points and the cell viability of the HaCaT human skin keratinocytes, which was determined by Trypan blue exclusion and MTT assays to evaluate human biosafety for these extracts after the mouse skin permeation experiments. Results: All enhancers induced a slight erythema without edema on the mouse skin that completely recovered after 6 h from the enhancer smears as compared with normal mouse skin. Furthermore, no damaged cells were found in the HaCaT keratinocytes under sting crude extract treatments. The blood sugar level in the diabetic mice treated with the insulin or insulin sensitizers, decreased significantly (p < 0.05) in the presence of enhancers. The area under the curve (AUC) values of transdermal drug delivery (TDD) ranged from 42,000 ± 5000 mg/dL x min without enhancers, to 30,000 ± 2000 mg/dL x min in the presence of enhancers. Conclusions: This study exhibited that natural plant extracts could be preferred over the chemically synthesized molecules and are safe and potent penetration enhancers for stimulating the transdermal absorption of drugs.

Efficacy of Vaginally Administered Gel Containing Emtricitabine and Tenofovir Against Repeated Rectal Simian Human Immunodeficiency Virus Exposures in Macaques.

Vaginal microbicides containing antiretrovirals (ARVs) have shown to prevent vaginally acquired human immunodeficiency virus (HIV), but these products may not protect women who engage in anal sex. Intravaginal dosing with ARVs has shown to result in drug exposures in rectal tissues, thus raising the possibility of dual compartment protection. To test this concept, we investigated whether intravaginal dosing with emtricitabine (FTC)/tenofovir (TFV) gel, which fully protected macaques against repeated vaginal exposures to simian human immunodeficiency virus (SHIV), protects against rectal SHIV exposures. Pharmacokinetic studies revealed rapid distribution of FTC and TFV to rectal tissues and luminal fluids, albeit at concentrations 1-2 log10 lower than those in the vaginal compartment. Efficacy measurements against repeated rectal SHIV challenges demonstrated a 4.5-fold reduction in risk of infection in macaques that received intravaginal FTC/TFV compared to placebo gel (P = .047; log-rank test). These data support the concept of dual compartment protection by vaginal dosing and warrants developing ARV-based vaginal products with improved bidirectional dosing.

Preparation, Characterization and Antifungal Properties of Chitosan-Silver Nanoparticles Synergize Fungicide Against Pyricularia oryzae.

Rice (Oryza sativa L.) is one of the major staple food crops of nearly two-third of the world's population. However, rice blast caused by fungus Pyricularia oryzae is generally considered the most serious disease of cultivated rice worldwide due to its extensive distribution and destructiveness under favourable climatic conditions. In this report, the combination between chitosan (CS) and silver (Ag), Ag@CS, was introduced for antifungal activity against Pyricularia oryzae extracted from blast-infected leaves. In detail, Ag@CS nanoparticles (NPs) were first synthesized and further mixed with Trihexad 700 WP (Tri), Ag@CS-Tri, against the fungus by agar diffusion method. The prepared Ag@CS-Tri NPs were characterized by Fourier transform infrared (FTIR), dynamic light scattering (DLS), transmission electron microscopy (TEM), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). In aqueous condition, Ag@CS-Tri NPs were successfully prepared and existed as spherical NPs with particle size of 17.26 ± 0.89 nm, which is an ideal size for their uptake into plant cells, indicating that the size of their parentally Ag@CS NPs is small enough to combine Tri, and their diameter is large enough to effectively penetrate the cellular membrane and kill fungi. More importantly, the antifungal property of Ag@CS-Tri NPs was significantly increased with inhibition zone around 25 nm compared with only around 12 nm of Ag@CS at the same concentration of Ag (2 ppm) and CS (4000 ppm). These results demonstrated that the synergistic effect of Tri and Ag@CS NPs can be a potential candidate with high antifungal activity for the use of antibiotics in agriculture.

FAK and S6K1 Inhibitor, Neferine, Dually Induces Autophagy and Apoptosis in Human Neuroblastoma Cells.

Human neuroblastoma cancer is the most typical extracranial solid tumor. Yet, new remedial treatment therapies are demanded to overcome its sluggish survival rate. Neferine, isolated from the lotus embryos, inhibits the proliferation of various cancer cells. This study aimed to evaluate the anti-cancer activity of neferine in IMR32 human neuroblastoma cells and to expose the concealable molecular mechanisms. IMR32 cells were treated with different concentrations of neferine, followed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess cell viability. In an effort to determine the molecular mechanisms in neferine-incubated IMR32 cells, cell cycle arrest, cell migration, and focal adhesion kinase (FAK), the 70-kDa ribosomal S6 kinase 1 (S6K1), poly (ADP-ribose) polymerase (PARP), caspase-3, Beclin-1, and microtubule-associated protein 1A/1B-light chain 3 (LC3) protein expressions were investigated. Neferine strongly disrupted the neuroblastoma cell growth via induction of G2/M phase arrest. Furthermore, neferine provoked autophagy and apoptosis in IMR32 cells, confirmed by p-FAK, and p-S6K1 reduction, LC3-II accumulation, Beclin-1 overexpression, and cleaved caspase-3/PARP improvement. Finally, neferine markedly retarded cell migration of neuroblastoma cancer cells. As a result, our findings for the first time showed an explicit anti-cancer effect of neferine in IMR32 cells, suggesting that neferine might be a potential candidate against human neuroblastoma cells to improve clinical outcomes with further in vivo investigation.

Repeated administration of high-dose depot medroxyprogesterone acetate does not alter SHIVSF162p3 viral kinetics and tenofovir pharmacokinetics when delivered via intravaginal rings.

BACKGROUND: Intravaginal rings (IVR) for HIV prevention will likely be used by women on depot medroxyprogesterone acetate (DMPA) hormonal contraception. We used pigtailed macaques to evaluate the effects of DMPA on tenofovir disoproxil fumarate (TDF) IVR pharmacokinetics and viral shedding. METHODS: Mucosal tenofovir (TFV) levels were compared in SHIVSF162p3 -negative DMPA-treated (n=4) and normally cycling (n=6) macaques receiving TDF IVRs. Plasma viremia and vaginal shedding were determined in groups of SHIVSF162p3 -positive DMPA-treated (n=6) and normally cycling (n=5) macaques. RESULTS: Similar median vaginal fluid TFV concentrations were observed in the DMPA-treated and cycling macaques over 4 weeks (1.2×105 and 1.1.×105  ng/mL, respectively). Median plasma viremia and vaginal shedding AUC of the DMPA-treated (2.73×107 and 8.15×104 copies/mL, respectively) and cycling macaques (3.98×107 and 1.47×103 copies/mL, respectively) were statistically similar. CONCLUSIONS: DMPA does not affect TDF IVR pharmacokinetics or SHIV shedding.

Integrin αIIbß3-Dependent ERK Signaling Is Regulated by Src and Rho Kinases in Both Leu33 and Pro33 Polymorphic Isoforms.

Platelet integrin αIIbß3 possesses a Leu/Pro polymorphism at residue 33 (Leu33/HPA-1a or Pro33/HPA-1b). The Pro33 isoform has been suggested to exhibit prothrombotic features. αIIbß3-expressing CHO (Chinese hamster ovary) cells on immobilized fibrinogen show activation of the MAP kinase family member ERK2, with an enhanced ERK2 activity in Pro33 cells compared to Leu33 cells. In our present work, we examined how the Leu/Pro polymorphism modulates the ERK2 activation stimulated by 2 differently triggered outside-in signalings. We either treated the CHO cells with Mn2+ or allowed them to adhere to fibrinogen. Moreover, we studied which signaling cascades are involved in ERK2 activation. In contrast to immobilized fibrinogen, Mn2+ did not significantly increase ERK2 activation. However, Mn2+ had a synergistic effect on ERK2 phosphorylation when combined with immobilized fibrinogen. Pro33 cells adherent to fibrinogen exhibited a significantly greater ERK2 activity than Leu33 cells in the presence of Mn2+, which peaked after 10 min of adhesion. Our data showed that Src family and rho kinases play a crucial role in the integrin αIIbß3-dependent outside-in signaling to ERK2.

Combination Emtricitabine and Tenofovir Disoproxil Fumarate Prevents Vaginal Simian/Human Immunodeficiency Virus Infection in Macaques Harboring Chlamydia trachomatis and Trichomonas vaginalis.

Genital inflammation associated with sexually transmitted infections increases susceptibility to human immunodeficiency virus (HIV), but it is unclear whether the increased risk can reduce the efficacy of pre-exposure prophylaxis (PrEP). We investigated whether coinfection of macaques with Chlamydia trachomatis and Trichomonas vaginalis decreases the prophylactic efficacy of oral emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). Macaques were exposed to simian/human immunodeficiency virus (SHIV) vaginally each week for up to 16 weeks and received placebo or FTC/TDF pericoitally. All animals in the placebo group were infected with SHIV, while 4 of 6 PrEP recipients remained uninfected (P= .03). Oral FTC/TDF maintains efficacy in a macaque model of sexually transmitted coinfection, although the infection of 2 macaques signals a modest loss of PrEP activity.

Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges.

Topical preexposure prophylaxis interrupts HIV transmission at the site of mucosal exposure. Intermittently dosed vaginal gels containing the HIV-1 reverse transcriptase inhibitor tenofovir protected pigtailed macaques depending on the timing of viral challenge relative to gel application. However, modest or no protection was observed in clinical trials. Intravaginal rings (IVRs) may improve efficacy by providing long-term sustained drug delivery leading to constant mucosal antiretroviral concentrations and enhancing adherence. Although a few IVRs have entered the clinical pipeline, 100% efficacy in a repeated macaque vaginal challenge model has not been achieved. Here we describe a reservoir IVR technology that delivers the tenofovir prodrug tenofovir disoproxil fumarate (TDF) continuously over 28 d. With four monthly ring changes in this repeated challenge model, TDF IVRs generated reproducible and protective drug levels. All TDF IVR-treated macaques (n = 6) remained seronegative and simian-HIV RNA negative after 16 weekly vaginal exposures to 50 tissue culture infectious dose SHIV162p3. In contrast, 11/12 control macaques became infected, with a median of four exposures assuming an eclipse of 7 d from infection to virus RNA detection. Protection was associated with tenofovir levels in vaginal fluid [mean 1.8 × 10(5) ng/mL (range 1.1 × 10(4) to 6.6 × 10(5) ng/mL)] and ex vivo antiviral activity of cervicovaginal lavage samples. These observations support further advancement of TDF IVRs as well as the concept that extended duration drug delivery devices delivering topical antiretrovirals could be effective tools in preventing the sexual transmission of HIV in humans.

Pharmacokinetic profile of raltegravir, elvitegravir and dolutegravir in plasma and mucosal secretions in rhesus macaques.

OBJECTIVES: Pharmacokinetic studies in animal models are important for assessing the prophylactic potential of antiretroviral drugs for HIV prevention. This study sought to identify clinically relevant doses of the marketed integrase inhibitors raltegravir, elvitegravir and dolutegravir in macaques and investigate drug penetration and antiviral activity in mucosal secretions. METHODS: Macaques received one oral dose of raltegravir, elvitegravir or dolutegravir alone or in combination with emtricitabine and tenofovir disoproxil fumarate followed by drug level measurements in blood and rectal and vaginal secretions. Antiviral activity was investigated in TZM-bl cells exposed to SHIV162p3 in the presence of rectal secretions collected from treated animals. RESULTS: Plasma drug concentrations with 50 mg/kg raltegravir or elvitegravir were within the range seen in humans receiving 400-800 mg of raltegravir or 800 mg of unboosted elvitegravir but lower than with 150 mg of elvitegravir boosted with cobicistat. AUC0-24 values for dolutegravir increased proportionally with the dose, with a calculated human-equivalent dose of 20 mg/kg. Elvitegravir showed the highest penetration in rectal and vaginal fluids despite the absence of pharmacological boosting, followed by raltegravir and dolutegravir. Rectal secretions collected at 24 h from treated macaques blocked infection of TZM-bl cells by 50% at dilutions of 1/1000 (raltegravir), 1/800 (dolutegravir) and >1/30 000 (elvitegravir). CONCLUSIONS: We defined macaque doses of HIV integrase inhibitors that recapitulate human clinical doses, which will facilitate efficacy and dose escalation studies in macaques. High and sustained drug concentrations and activity in mucosal secretions suggest that integrase inhibitors are promising candidates for HIV prevention.

Pharmacokinetics and preliminary safety study of pod-intravaginal rings delivering antiretroviral combinations for HIV prophylaxis in a macaque model.

Preexposure prophylaxis using oral regimens involving the HIV nucleoside reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) demonstrated efficacy in three clinical trials. Adherence was determined to be a key parameter for success. Incorporation of the TDF-FTC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase product adherence and efficacy compared with those of oral and vaginal gel formulations. A novel pod-IVR technology capable of delivering multiple drugs is described; this constitutes the first report of an IVR delivering TDF and FTC, as well as a triple-combination IVR delivering TDF, FTC, and the entry inhibitor maraviroc (MVC). The pharmacokinetics and preliminary local safety of the two combination pod-IVRs were evaluated in the pig-tailed macaque model. The devices exhibited sustained release at controlled rates over the 28-day study period. Median steady-state drug levels in vaginal tissues in the TDF-FTC group were 30 µg g(-1) (tenofovir [TFV], in vivo hydrolysis product of TDF) and 500 µg g(-1) (FTC) and in the TDF-FTC-MVC group were 10 µg g(-1) (TFV), 150 µg g(-1) (FTC), and 20 µg g(-1) (MVC). No adverse events were observed, and there were no toxicological findings. Mild-to-moderate increases in inflammatory infiltrates were observed in the vaginal tissues of some animals in both the presence and the absence of the IVRs. The IVRs did not disturb the vaginal microbiota, and levels of proinflammatory cytokines remained stable throughout the study. Pod-IVR candidates based on the TDF-FTC combination have potential for the prevention of vaginal HIV acquisition and merit clinical investigation.

Pharmacokinetic evaluation of tenofovir disoproxil fumarate released from an intravaginal ring in pigtailed macaques after 6 months of continuous use.

BACKGROUND AND METHODS: A reservoir intravaginal ring (IVR) eluting tenofovir disoproxil fumarate (TDF) was evaluated for 6 months of continuous use in normally cycling female pigtailed macaques with monthly IVR exchanges to define pharmacokinetics and safety. RESULTS AND CONCLUSIONS: Tenofovir levels in vaginal secretions and tissue remained consistent for 6 months with no adverse safety concerns.

LED dynamic electro-optical responses and light-fidelity-application optimization.

Commercial light-emitting diodes (LEDs) from different manufacturers were studied by means of impedance measurements in the frequency range between 75 kHz and 10 MHz. Electrical characteristics of these LEDs, such as impedance and resistance, were proven to be strongly influenced by the applied frequencies, the bias values, and the alternating-signal amplitudes. Through these measurements, a specific bias value, which later could be of great importance, was pointed out. Coupled with the optical signal-to-noise ratio measurements, this frequency-, bias-, and alternating-signal-amplitude-dependent impedance shows a close correlation between optical and electrical responses of LEDs, which turns out to be useful for visible light communication. Hence, a new and simple method of light-fidelity optimization through impedance measurements is proposed in this article.