Although CO
insertion is a predominant phenomenon in diamine-functionalized Mg
(dobpdc) (dobpdc
=4,4-dioxidobiphenyl-3,3'-dicarboxylate) adsorbents, a high-performance metal-organic framework for ...capturing CO
, the fundamental function of the diamine carbon chain length in the mechanism remains unclear. Here, Mg
(dobpdc) systems with open metal sites grafted by primary diamines NH
-(CH
)
-NH
were developed, with en (n=2), pn (n=3), bn (n=4), pen (n=5), hn (n=6), and on (n=8). Based on CO
adsorption and IR results, CO
insertion is involved in frameworks with n=2 and 3 but not in systems with n≥5. According to NMR data, bn-appended Mg
(dobpdc) exhibited three different chemical environments of carbamate units, attributed to different relative conformations of carbon chains upon CO
insertion, as validated by first-principles density functional theory (DFT) calculations. For 1-hn and 1-on, DFT calculations indicated that diamine inter-coordinated open metal sites in adjacent chains bridged by carboxylates and phenoxides of dobpdc
. Computed CO
binding enthalpies for CO
insertion (-27.8 kJ mol
for 1-hn and -20.2 kJ mol
for 1-on) were comparable to those for CO
physisorption (-19.3 kJ mol
for 1-hn and -20.8 kJ mol
for 1-on). This suggests that CO
insertion is likely to compete with CO
physisorption on diamines of the framework when n≥5.
Although CO2 insertion is a predominant phenomenon in diamine‐functionalized Mg2(dobpdc) (dobpdc4−=4,4‐dioxidobiphenyl‐3,3′‐dicarboxylate) adsorbents, a high‐performance metal‐organic framework for ...capturing CO2, the fundamental function of the diamine carbon chain length in the mechanism remains unclear. Here, Mg2(dobpdc) systems with open metal sites grafted by primary diamines NH2−(CH2)n−NH2 were developed, with en (n=2), pn (n=3), bn (n=4), pen (n=5), hn (n=6), and on (n=8). Based on CO2 adsorption and IR results, CO2 insertion is involved in frameworks with n=2 and 3 but not in systems with n≥5. According to NMR data, bn‐appended Mg2(dobpdc) exhibited three different chemical environments of carbamate units, attributed to different relative conformations of carbon chains upon CO2 insertion, as validated by first‐principles density functional theory (DFT) calculations. For 1‐hn and 1‐on, DFT calculations indicated that diamine inter‐coordinated open metal sites in adjacent chains bridged by carboxylates and phenoxides of dobpdc4−. Computed CO2 binding enthalpies for CO2 insertion (−27.8 kJ mol−1 for 1‐hn and −20.2 kJ mol−1 for 1‐on) were comparable to those for CO2 physisorption (−19.3 kJ mol−1 for 1‐hn and −20.8 kJ mol−1 for 1‐on). This suggests that CO2 insertion is likely to compete with CO2 physisorption on diamines of the framework when n≥5.
A question of length: A correlation between CO2 insertion mechanism and the carbon chain length of diamine NH2−(CH2)n−NH2 in the Mg2(dobpdc) (dobpdc4−=4,4‐dioxidobiphenyl‐3,3′‐dicarboxylate) system is established. Results suggest that CO2 insertion is likely to compete with CO2 physisorption on diamines of the framework when n≥5.
Multipurpose prevention technologies (MPTs), which prevent sexually transmitted infection(s) and unintended pregnancy, are highly desirable to women. In this randomized, placebo-controlled, phase I ...study, women used a placebo or tenofovir (TFV) and levonorgestrel (LNG) intravaginal ring (IVR), either continuously or cyclically (three, 28-day cycles with a 3 day interruption in between each cycle), for 90 days. Sixty-eight women were screened; 47 were randomized to 4 arms: TFV/LNG or placebo IVRs used continuously or cyclically (4:4:1:1). Safety was assessed by adverse events and changes from baseline in mucosal histology and immune mediators. TFV concentrations were evaluated in multiple compartments. LNG concentration was determined in serum. Modeled TFV pharmacodynamic antiviral activity was evaluated in vaginal and rectal fluids and cervicovaginal tissue ex vivo. LNG pharmacodynamics was assessed with cervical mucus quality and anovulation. All IVRs were safe with no serious adverse events nor significant changes in genital tract histology, immune cell density or secreted soluble proteins from baseline. Median vaginal fluid TFV concentrations were >500 ng/mg throughout 90d. TFV-diphosphate tissue concentrations exceeded 1,000 fmol/mg within 72hrs of IVR insertion. Mean serum LNG concentrations exceeded 200 pg/mL within 2h of TFV/LNG use, decreasing quickly after IVR removal. Vaginal fluid of women using TFV-containing IVRs had significantly greater inhibitory activity (87-98% versus 10% at baseline; p<0.01) against HIV replication in vitro. There was a >10-fold reduction in HIV p24 antigen production from ectocervical tissues after TFV/LNG exposure. TFV/LNG IVR users had significantly higher rates of anovulation, lower Insler scores and poorer/abnormal cervical mucus sperm penetration. Most TFV/LNG IVR users reported no change in menstrual cycles or fewer days of and/or lighter bleeding. All IVRs were safe. Active rings delivered high TFV concentrations locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. Trial registration: ClinicalTrials.gov #NCT03279120.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Daily oral emtricitabine (FTC, F)/tenofovir disoproxil fumarate (TDF) combination is approved for HIV pre-exposure prophylaxis (PrEP) in men and women. Tenofovir alafenamide fumarate (TAF) is a ...newer, more potent prodrug of tenofovir (TFV), and in combination with FTC, has recently been approved for prevention of HIV through rectal transmission.
This Phase I, prospective, interventional, randomized study was conducted in three clinical sites: PROFAMILIA, Santo Domingo, Dominican Republic; University of Pittsburgh and Eastern Virginia Medical School. We assessed the multi-compartmental pharmacokinetics (primary outcome) and safety (secondary outcome) among HIV uninfected women randomized to F/TDF (200mg/300mg) or F/TAF (200mg/25mg; F/TAF25) (n=24) in a single dose phase (SDP) and F/TDF, F/TAF (200mg/10mg; F/TAF10), or F/TAF25 (n=75) in a multiple dose (14 daily doses) phase (MDP). We described PK parameters in plasma, peripheral blood mononuclear cells (PBMCs), and cervicovaginal (CV) and rectal fluids and tissues. ClinicalTrials.gov #NCT02904369, completed.
Recruitment for the study began on 5 October 2016. The first participant was enrolled on 6 October 2016 and the last participant completed the study 21 November 2017.
TFV concentrations area under curve (AUC) were ~20 fold lower following F/TAF versus F/TDF. TFV-diphosphate (TFV-DP) AUC concentrations in PBMCs were 7-fold higher with F/TAF25 versus F/TDF. Median TFV-DP concentrations in vaginal tissue (4hours post last dose) were approximately 6-fold higher with F/TAF25 versus F/TDF. TFV and TFV-DP were lower with F/TAF versus F/TDF in rectal tissue. Concentrations of FTC and FTC-triphosphate (FTC-TP) were similar across matrices and treatment arms. Gastrointestinal adverse events (AEs) occurred more frequently in F/TDF users (44.0%) than in either F/TAF group (11.5 and 12.0%).
F/TAF was safe and well-tolerated. TFV-DP concentrations were higher in PBMCs and similar or higher (4h post dose) in female genital tract tissues for F/TAF versus F/TDF. High FTC and FTC-TP concentrations in all compartments support the potential of F/TAF as a new PrEP combination for women.
United States Agency for International Development (USAID)/the President's Emergency Plan for AIDS Relief (PEPFAR) through Cooperative Agreement AID-OAA-A-14-00011 with CONRAD/Eastern Virginia Medical School. This publication resulted in part from research supported by the University of North Carolina at Chapel Hill Center for AIDS Research (CFAR).
Background
Adherence to topical microbicides for HIV prevention has been a challenge for women using them and those developing novel products. The Quatro Clinical Crossover Study investigated user ...preference and acceptability of four different placebo‐based vaginal delivery forms among young African women. The objective of this sub‐study was to test the ability of objective adherence measures in assessing placebo product usage.
Methods
A total of two hundred women from Zimbabwe and South Africa used placebo vaginal gel, insert, and film once per week, with or without sex, for 1 month and an intravaginal ring continuously for one month (Months 1–4). Women then chose their preferred product and used it with sex each week during Month 5. Women self‐collected vaginal swabs after using the gel, insert and film. Collected vaginal swabs and used intravaginal rings were analysed for placebo‐based adherence measures using spectroscopy and excipient‐based analyses to determine product use. Vaginal insertion and semen exposure was determined using previously developed and published adherence biomarkers. Intravaginal rings were extracted for residual excipient (glycerin) and penetrated bioanalytes.
Results
Both methodologies showed that women used gel the most during Months 1–4 (75% by excipient methods, 85% by spectroscopy). The methodologies also determined that nearly all swabs from both sites were vaginally inserted, and 51–86% had detectable placebo product. Semen was detected in more swabs collected during Month 5 from women in Zimbabwe than the swabs from women in South Africa, and most of those swabs had placebo product present as well. The majority of women used the ring for the required four weeks. Sixty‐eight per cent of women who used the ring for the required 4 weeks increased to 78% during Month 5.
Conclusion
This sub‐study demonstrated how these objective placebo‐based measures of adherence determined product use of various microbicide delivery forms.
Abstract
Background
Strict adherence to antiretroviral-based microbicide use is important for effective HIV prevention. We previously developed a composite measure of product adherence, protocol ...compliance, and semen exposure for determining vaginal use of tenofovir (TFV) 1% gel applicators through biomarkers and residual drug analyses. In this study, we tested the ability of the composite measure in vaginally used TFV gel applicators from a Phase III HIV prevention clinical trial.
Methods
Used vaginal gel applicators from the FACTS 001 study were swabbed for detection of vaginal bacterial markers (vaginal insertion), semen DNA markers (semen exposure), and residual TFV gel (product use).
Results
Of 1,098 evaluable TFV and placebo applicators, 80% had detectable vaginal insertion biomarkers and 52% had semen biomarkers. Ninety-nine percent of vaginally inserted applicators TFV applicators had detectable residual TFV as measured by liquid chromatography with tandem mass spectroscopy (LC–MS/MS). Residual TFV levels were also successfully detected using Fourier Transform Infrared (FTIR)-based spectroscopy.
Conclusions
Vaginal insertion and semen exposure biomarkers were detectable on used TFV 1% gel applicators. Residual TFV on these gel applicators was detectable by LC–MS/MS and FTIR-based spectroscopy, which has potential to be a more convenient and quicker method for detecting drug use. With continual improvements, this composite measure of product adherence, protocol compliance, and semen exposure has potential to assess use of not only TFV gel but also other topical microbicides or products.
Background
Adherence is critical for successful topical, vaginally delivered anti-retroviral (ARV)-based HIV pre-exposure prophylaxis (PrEP). Quantitating systemic or tissue ARV levels through ...LC–MS/MS is currently viewed as the most reliable measure of adherence. However, for placebo-controlled trials, this is a high cost analysis that measures adherence only in the drug treatment group. A desirable marker of adherence is one that is measured in both placebo and drug treatment groups using a simple on-site clinical laboratory test, which allows necessary interventions for supporting participant adherence. Our objective was to develop adherence markers for four vaginal placebo products currently used as microbicide delivery systems: gel, film, insert, and intravaginal ring. Excipient and spectroscopy-based approaches were used for preclinical development of the placebo markers and subsequently validated by the CONRAD 135 study. The study collected vaginal swabs collected each day for 1 week post vaginal application of gel, film, or insert in the clinic with or without sex. Intravaginal rings were collected after 1 day, 7, and 30 days of use.
Results
Placebo gel, film, and insert in vaginal swabs were successfully detected by specific excipient colorimetric or probe-based assays for hydroxyethylcellulose, glycerin, and sorbitol respectively, as well as spectroscopy-based prediction models. The range of detection for gel, film, and insert in swabs collected up to 16 h post vaginal application was 70-100% of the total swabs per time point, with some markers showing potential for longer duration. Decreasing residual glycerin levels and increasing bioanalyte penetration of vaginally used intravaginal rings showed significant changes between 1 and 30 days of use.
Conclusions
We demonstrated clinical proof-of-concept that adherence markers for placebo product can be measured using simple, lower cost approaches. Measuring adherence in both placebo and drug arms of a HIV PrEP study would better inform future trial designs.
NH3, essential for producing artificial fertilizers and several military and commercial products, is being produced at a large scale to satisfy increasing demands. The inevitable leakage of NH3 ...during its utilization, even in trace concentrations, poses significant environmental and health risks because of its highly toxic and reactive nature. Although numerous techniques have been developed for the removal of atmospheric NH3, conventional NH3 abatement systems possess the disadvantages of high maintenance cost, low selectivity, and emission of secondary wastes. In this context, highly tunable porous materials such as metal–organic frameworks, covalent organic frameworks, hydrogen organic frameworks, porous organic polymers, and their composite materials have emerged as next‐generation NH3 adsorbents. Herein, recent progress in the development of porous NH3 adsorbents is summarized; furthermore, factors affecting NH3 capture are analyzed to provide a reasonable strategy for the design and synthesis of promising materials for NH3 abatement.
This review affords a comprehensive overview of porous materials and their composites to capture NH3 gas.
Women worldwide face risks from pregnancy, HIV, and other sexually transmitted infections (STIs). To date, highly effective contraceptive methods provide no HIV/STI protection, and HIV prevention ...products, excluding condoms, provide no pregnancy protection. Intravaginal rings (IVRs) delivering antiretrovirals and contraceptives are a promising multipurpose prevention technology (MPT).
Embedded within a Phase I randomized, placebo-controlled trial, we examined acceptability of continuous versus interrupted use of a 90-day MPT IVR among 47 low-risk women in Norfolk, Virginia and the Dominican Republic. A baseline survey assessed menstruation attitudes, risk perceptions and trial-related motivations. Follow-up surveys (M1/M3) examined user experiences with and preferences for IVR attributes; 18 women also participated in two in-depth interviews.
Most women rated the IVR's flexibility and smoothness (86%) and ease of insertion/removal (76%) as very acceptable. Fewer women similarly rated the IVR size (57%) and changes in color from menstruation (52%). Most participants experienced no changes or less bleeding. Those reporting more/heavier bleeding (20% M1, 15% M3) disliked the change. Overall, women preferred a 3-month (75%) to a 1-month IVR (7.5%) or a bimonthly injectable (10%). In qualitative interviews, women were willing to continuously use an IVR for 6-12 months, providing it did not "
" inside the body. Reasons for trial participation and prevention preferences, menstrual attitudes, and perceived IVR benefits and doubts varied by site.
Findings provide strong evidence of demand for an MPT IVR that protects from pregnancy and HIV/STIs, lasts longer than 1 month, minimally disrupts menstrual bleeding, and is in women's control. numberClinicalTrials.gov: #NCT03279120.
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