A screen of repurposed drugs identifies AMHR2/MISR2 agonists as potential contraceptives.

We identified the anti-Mullerian hormone (also known as Müllerian inhibiting substance or MIS) as an inhibitory hormone that induces long-term contraception in mammals. The type II receptor to this hormone, AMHR2 (also known as MISR2), represents a promising druggable target for the modulation of female reproduction with a mechanism of action distinct from steroidal contraceptives. We designed an in vitro platform to screen and validate small molecules that can activate MISR2 signaling and suppress ovarian folliculogenesis. Using a bone morphogenesis protein (BMP)­response element luciferase reporter cell­based assay, we screened 5,440 compounds from a repurposed drug library. Positive hits in this screen were tested for specificity and potency in luciferase dose­response assays, and biological activity was tested in ex vivo Mullerian duct regression bioassays. Selected candidates were further evaluated in ex vivo follicle/ovary culture assays and in vivo in mice and rats. Here, we report that SP600125, CYC-116, gandotinib, and ruxolitinib can specifically inhibit primordial follicle activation and repress folliculogenesis by stimulating the MISR2 pathway.

Biotransformation of contraceptive drug desogestrel with Cunninghamella elegans, and anti-inflammatory activity of its metabolites.

Biotransformation of an orally active contraceptive drug, desogestrel (1), with Cunninghamella elegans yielded a new metabolite, 13ß-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17ß-ol-3,6-dione (2), along with five known metabolites, i.e., 13ß-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-3ß,6ß,17ß-triol (3), 13ß-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-6ß,17ß-diol-3-one (4), 13ß-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17ß-ol-3-one (5), 13ß-ethyl-11-epoxy-18,19-dinor-17α-pregn-4-en-20-yn-17ß-ol-3-one (6), and 13ß-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-10ß,17ß-diol-3-one (7). The structure of new metabolite 2 was elucidated by using 1H-, 13C-, and 2D-NMR, EI-, and HREI-MS, IR, and UV spectroscopic data. Compounds 1-7 were evaluated for anti-inflammatory activities, i.e., inhibition of T-cell proliferation, and pro-inflammatory cytokine (TNF-α). Compounds 1 (IC50 = 1.12 ± 0.03 µg/mL), 2 (IC50 = 1.15 ± 0.05 µg/mL), 3 (IC50 = 1.15 ± 0.05 µg/mL), 4 (IC50 = 1.40 ± 0.03 µg/mL), 5 (IC50 = 1.78 ± 0.08 µg/mL), and 6 (IC50 = 1.36 ± 0.07 µg/mL) were identified as potent inhibitors of T-cells proliferation, in comparison to the standard drug, prednisolone (IC50 = 3.51 ± 0.03 µg/mL). Compound 7 (IC50 = 6.18 ± 0.04 µg/mL) showed a good activity. In addition, substrate 1 (IC50 ≤ 1 µg/mL), and its metabolites 2 (IC50 = 4.1 ± 0.60 µg/mL), and 6 (IC50 = 6.8 ± 0.8 µg/mL) also showed a potent inhibition of pro-inflammatory cytokine (TNF-α) production, as compared to the standards drug, pentoxifilline (IC50 = 94.8 ± 2.1 µg/mL). Whereas compounds 3 (IC50 = 57.9 ± 7.6 µg/mL), and 5 (IC50 = 27.2 ± 6.8 µg/mL) showed a moderate inhibition of TNF-α production, while compounds 4 and 7 showed no inhibition. Compounds 1-7 were found to be non-cytotoxic to 3T3 normal cell line (mouse fibroblast).

Factorial approach for the optimization and development of stability indicating study of the contraceptive suspension for injection(Depo-Provera®).

The study involves use of factorial design for optimization of forced degradation conditions and development of stability indicating method for medroxyprogestrone acetate (MPA) or depo-provera as known in the market. MPA is an important contraceptive and anticancer drug especially for treatment of breast cancer and it is the first time to study the different conditions affecting its stability. MPA was subjected to different variables such as solvent type, pH and the time subjected to UV light. Factorial design has been used during forced degradation to determine significant factors responsible for degradation and to optimize degradation conditions reaching maximum degradation. Factors responsible for forced degradation were statistically evaluated using Bubble and Surface plots. Variables proved to be significant (p < 0.05) and the suggested model represented a perfect example for indicating the efficiency of factorial designs in optimizing the degradation conditions that give maximum percent of degradation. We investigated also the solubility and stability profiles of MPA in aqueous solutions. Stability study results showed a very low stability profile of MPA in all the aqueous solutions with rapid degradation rate more than other solvents. The current research may contribute to enrich the knowledge of the physicochemical properties of this drug for exploring its full anticancer potential in the future.

A high resolution LC-MS targeted method for the concomitant analysis of 11 contraceptive progestins and 4 steroids.

In the context of hormonal contraception and hormone replacement therapy (HRT), many women are exposed to exogenous hormones. Current use of hormonal contraception with combined ethinyl estradiol and different progestins bestows a breast cancer relative risk (RR) of 1.2- while combined HRT has a RR of 2. Although these exposures present an important public health issue, little is known about the effects of individual progestins on the breast and other tissues. Increasing availability of large scale biobanks, high throughput analyses and data management tools enable ever expanding, sophisticated population studies. In order to address the impact of distinct progestins on various health indicators, it is desirable to accurately quantify progestins in clinical samples. Here we have developed and validated a high resolution liquid chromatography mass spectrometry (LC-MS) targeted method for the simultaneous quantification of 11 synthetic progestins widely used in oral contraceptives, gestodene, levonorgestrel, etonogestrel, chlormadinone acetate, cyproterone acetate, drospirenone, desacetyl norgestimate, medroxyprogesterone acetate, norethindrone, dienogest, nomegestrol acetate, and 4 endogenous steroid hormones, progesterone, testosterone, androstenedione, and cortisol in blood samples. This highly specific quantitative analysis with high resolution Orbitrap technology detects and quantifies 15 compounds using their internal standard counterparts in a single 12 min LC-MS run. Sensitivity is attained by the use of the instrument in targeted selected ion monitoring mode. Lower limit of quantitation ranges from 2.4 pg/ml for drospirenone to 78.1 pg/ml for chlormadinone acetate. The method provides comprehensive progestin panel measurements with as little as 50 µl of murine or human plasma.

Clinical relevance in present day hormonal contraception.

The contraceptive pill is an effective and very safe method to control pregnancies. It was developed 60 years ago, and despite that the composition has been the same since it was first developed (estrogen and progestogen), over the years the concentration of ethinyl estradiol has been reduced to improve tolerability. Nevertheless, progestogens are the basic active agent of hormonal contraception. The mechanism of progestogens is a multimodal one and basically three modes of contraceptive action can be distinguished: (a) A strong antigonadotrophic action leading to the inhibition of ovulation. The necessary dosage of ovulation inhibition per day is a fixed dosage that is intrinsic to each progestogen and independent of the dosage of estrogen used or the partial activities of the progestogen or the mode of application. (b) Thickening of the cervical mucus to inhibit sperm penetration and (c) desynchronization of the endometrial changes necessary for implantation. The on the market available progestogens used for contraception are either used in combined hormonal contraceptives (in tablets, patches or vaginal rings) or as progestogen only contraceptives. Progestogen only contraceptives are available as daily oral preparations, monthly injections, implants (2-3 years) and intrauterine systems (IUS). Even the long-acting progestogens are highly effective in typical use and have a very low risk profile. According to their introduction into the market, progestogens in combined hormonal contraceptives, have been described as 1st, 2nd, 3rd and 4th generation progestogens. The different structures of progestogens are derivatives from testosterone, progesterone and spironolactone. These differences in the molecular structure determine pharmacodynamic and pharmacokinetic differential effects which contribute to the tolerability and additional beneficial or therapeutic effects whether used in combined oral contraceptive (COC) or as progestogen only drugs. These differences enhance the individual options for different patient profiles. The new development of polymers for vaginal rings allowed on the one hand, the improvement of the estrogen/progestogen combination in these rings especially regarding the comfort of use for women (e.g. avoiding the use of cold chains or packages with up to 6-month rings) and on the other hand, the development of progestogen only formulations. Another future development will be the introduction of new progestogen only pills that will provide effective contraceptive protection with more favorable bleeding patterns and a maintenance of ovulation inhibition after scheduled 24-h delays in pill intake than the existing progestogen only pill (POP) with desogestrel (DES).

Reproductive drugs and environmental contamination: quantum, impact assessment and control strategies.

Industrial and municipal solid wastes, noise, pesticides, fertilizers and vehicular emission are visible pollutants responsible for environmental contamination and ill-effects on health of all living systems. But, environmental contamination due to drugs or medicines used for different purposes in humans and animals goes unseen largely and can affect the health of living system severely. During the last few decades, the usage of drugs has increased drastically, resulting in increased drug load in soil and water. Contraceptive and fertility drugs are extensively and effectively used in humans as well as animals for different purposes. Usage of these reproductive drugs in humans is increased manifold to manage reproductive problems and/or for birth control with changing lifestyles. These drugs are excreted in urine and faeces as metabolite or conjugated forms, leading to contamination of water, milk and animal produce, which are consumed directly by humans as well as animals. These drugs are not eliminated even by water treatment plant. Consumption of such contaminated water, milk, meat and poultry products results in reproductive disorders such as fertility loss in men and increase risk of different types of cancers in humans. Therefore, assessment of impact of environmental contamination by these drugs on living system is of paramount importance. The purpose of this review article is to provide a comprehensive analysis of various research and review reports on different contraceptive and fertility drugs used in human and animals, their occurrence in the environment and their ill-effects on living systems. The approaches to control this invisible menace have also been proposed.

Development of customised 3D printed biodegradable projectile for administrating extended-release contraceptive to wildlife.

Customisation of sustained and controlled release of contraceptives plays a key role in veterinary applications. A biodegradable projectile containing different doses of contraceptive progesterone was prepared using fused deposition modelling 3D printing. Three concentrations of progesterone (2, 5 and 10% w/w) with polylactic acid was prepared as a 1.75 mm filament by hot melt extrusion. Solvent dissolution tests confirmed the successful incorporation of progesterone in the polymer while microscopic (SEM) studies indicated the drug was melted and thoroughly mixed with the polymer matrix and pore-formation after dissolution. A significant suppression of melting temperature of polymer from 166 to 145 °C was noted by thermal analysis (DSC) studies of the drug loaded systems. Interaction between the contraceptive drug and the polymer via hydrogen bonding was revealed from the spectroscopic (FTIR) studies. In vitro release behaviour was assessed over a five-month period, for 2% and 5% progesterone loaded projectiles release profiles fitted zero order whereas 10% loaded projectiles fitted the Higuchi model. Penetration assessment confirmed the drug loaded PLA projectiles provided sufficient specific kinetic energy required to penetrate thin and medium-thickness skins. This work demonstrates the feasibility of fused deposition modelling 3D printing as suitable process for manufacturing ballistic customised drug delivery devices.

Antifertility effectiveness of a novel copper-containing intrauterine device material and its influence on the endometrial environment in rats.

This study was designed to investigate the antifertility effectiveness of a novel copper-containing intrauterine device material containing a composite of micro-copper (Cu), low-density polyethylene (LDPE), and methyl vinyl silicone rubber (MVQ) and its effects on the endometrial environment in rats. The contraceptive effectiveness was examined 12 days after pregnancy. The pathological changes; factors associated with bleeding, pain, and inflammation in the endometrium; and the surface condition of the implants were investigated after insertion for 90 days. Furthermore, the release rate of copper ions in simulated uterine solution (SUS) was investigated for 270 days. The contraceptive effectiveness was 100% in both the bulk Cu and micro-Cu/LDPE/MVQ groups, and that in the LDPE/MVQ group was 30%. On day 90 after insertion, histopathological observation and the ultrastructural changes in the endometrium showed that the damage caused by bulk Cu was much more severe than that caused by the Cu/LDPE/MVQ microcomposite and that the surface of the latter was much smoother than that of the former. Furthermore, compared with the sham-operated control group, the concentrations of tissue plasminogen activator and prostaglandin E2 were significantly increased 90 days after insertion in all of the experimental groups except for the LDPE/MVQ group (P < 0.05), and the parameters in the Cu/LDPE/MVQ group were significantly lower than those in the Cu group (P < 0.05). In addition, the expression levels of matrix metalloproteinase 9, metalloproteinase 1 tissue inhibitor, plasminogen inhibitor 1, CD34, vascular endothelial growth factor, substance P, and substance P receptor in the endometrium in all of the experimental groups were significantly lower than those in the Cu group 90 days after insertion (P < 0.05). The results of this study indicate that micro-Cu/LDPE/MVQ exhibits satisfactory contraceptive efficacy and causes fewer side effects than Cu.

Cunninghamella blakesleeana-mediated biotransformation of a contraceptive drug, desogestrel, and anti-MDR-Staphylococcus aureus activity of its metabolites.

Staphylococcus aureus is one of the most infectious agents among staphylococcal bacteria. Currently many strains of S. aureus have developed resistance against available antibiotics. Therefore, the treatment of infections caused by them is a major challenge. During current study, desogestrel (1), a contraceptive drug, was found to be a potent growth inhibitor of drug resistant strains of S. aureus. Therefore, in search of new and effective agents against multi-drug resistant S. aureus strains, whole-cell bio-catalytic conversion of desogestrel (1) by Cunninghamella blakesleeana ATCC 8688A at pH 7.0 and 25 °C was carried out, yielding three new metabolites, 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-6ß,15ß,17ß-triol (2), 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-3ß,6ß,17ß-triol (3), and 13-ethyl-11-methylene-18,19-dinor-17α-pregn-20-yn-3α,5α,6ß,17ß-tetraol (4), along with a known metabolite, 13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-6ß,17ß-dihydroxy-3-one (5). Among them, compounds 1-2 showed a potent activity against S. aureus EMRSA-17, S. aureus NCTC 13277 (MRSA-252), and S. aureus NCTC 13143, and clinically isolated Pakistani strain of S. aureus in an in vitro Microplate Alamar Blue Assay (MABA). Vancomycin was used as the standard drug in this assay. In addition, compound 1 also showed a significant activity against vancomycin-resistant S. aureus (VRSA) ATCC 700699. Compounds 1-5 were also evaluated against 3T3 normal cell line (mouse fibroblast) where they all were identified as non-cytotoxic. The present study thus provides new leads for the development of anti-bacterial drugs against MDR S. aureus.

Biotransformation of drospirenone, a contraceptive drug, with Cunninghamella elegans.

Biotransformation of an orally active contraceptive drug, drospirenone (1), by Cunninghamella elegans ATCC 36114 yielded four new metabolites, 6ß,7ß,15ß,16ß-dimethylene-3-oxo-14α-hydroxy-17α-pregn-4-ene-21,17-carbolactone (2), 6ß,7ß,15ß,16ß-dimethylene-3,11-dioxo-17α-pregn-4-ene-21,17-carbolactone (3), 6ß,7ß,15ß,16ß-dimethylene-3,12-dioxo-17α-pregn-4-ene-21,17-carbolactone (4), and 6ß,7ß,15ß,16ß-dimethylene-3-oxo-11ß,14α-dihydroxy-17α-pregn-4-ene-21,17-carbolactone (5), along with a known metabolite, 6ß,7ß,15ß,16ß-dimethylene-3-oxo-11α-dihydroxy-17α-pregn-4-ene-21,17-carbolactone (6). This study provides not only new analogues of orally active contraceptive drug, drospirenone, but also help in understanding the metabolism of this important drug.

Medicinal Plants Used in Iranian Traditional Medicine (ITM) as Contraceptive Agents.

BACKGROUND: In recent years, rapid population growth and unsafe abortions have emerged as controversial health issues in some countries. Hence, safe and effective contraceptive methods or agents have attracted a great deal of attention and the corresponding market has been widely expanded. OBJECTIVE: In this study, we present a review profiting from Iranian Traditional Medicine (ITM) to introduce expedient plants as efficient contraceptive agents. METHODS: Medicinal plants suggested as contraceptive agents were obtained from ITM text books and they were also investigated using search engines to confirm their in vitro and in vivo efficacy. RESULTS: According to credible Iranian medical literature a wide spectrum of plants possesses contraceptive activity and among them, Ruta graveolens, Ricinus communis, Piper nigrum, and Physalis alkekengi were found to be more efficient. CONCLUSION: Complementary and Alternative Medicine (CAM), particularly herbal remedies have received a lot of attention because of their truly healing properties. Focusing on ITM knowledge, there are various comments based on medicinal plants to reduce unsafe abortions leading to better public health in the society.

Microbial transformation of contraceptive drug etonogestrel into new metabolites with Cunninghamella blakesleeana and Cunninghamella echinulata.

Biotransformation of a steroidal contraceptive drug, etonogestrel (1), (13-ethyl-17ß-hydroxy-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-3-one) was investigated with Cunninghamella blakesleeana and C. echinulata. Five metabolites 2-6 were obtained on incubation of 1 with Cunninghamella blakesleeana, and three metabolites, 2, 4, and 6 were isolated from the transformation of 1 with C. echinulata. Among them, metabolites 2-4 were identified as new compounds. Their structures were deduced as 6ß-hydroxy-11,22-epoxy-etonogestrel (2), 11,22-epoxy-etonogestrel (3), 10ß-hydroxy-etonogestrel (4), 6ß-hydroxy-etonogestrel (5), and 14α-hydroxy-etonogestrel (6). Compounds 1-6 were evaluated for various biological activities. Interestingly, compound 5 was found to be active against ß-glucuronidase enzyme with IC50 value of 13.97±0.12µM, in comparison to standard compound, d-saccharic acid 1,4-lactone (IC50=45.75±2.16µM). Intestinal bacteria produce ß-glucuronidase. Increased activity of ß-glucuronidase is responsible for the hydrolyses of glucuronic acid conjugates of estrogen and other toxic substances in the colon, which plays a key role in the etiology of colon cancer. Inhibition of ß-glucoronidase enzyme therefore has a therapeutic significance. Compounds 1-6 were also found to be non cytotoxic against 3T3 mouse fibroblast cell lines.

Nanomaterial-dependent immunoregulation of dendritic cells and its effects on biological activities of contraceptive nanovaccines.

Nanovehicles are promising delivery systems for various vaccines. Nevertheless, different biophysicochemical properties of nanoparticles (NPs), dominating their in vitro and in vivo performances for vaccination, remain unclear. We attempted to elucidate the effects of NPs and their pH-sensitivity on in vitro and in vivo efficacy of resulting prophylactic nanovaccines containing a contraceptive peptide (FSHR). To this end, pH-responsive and non-responsive nanovaccines were produced using acetalated ß-cyclodextrin (Ac-bCD) and poly(lactic-co-glycolic acid) (PLGA), respectively. Meanwhile, FSHR derived from an epitope of the follicle-stimulating hormone receptor was used as the model antigen. FSHR-containing Ac-bCD and PLGA NPs were successfully prepared by a nanoemulsion technique, leading to well-shaped nanovaccines with high loading efficiency. The pH-sensitivity of Ac-bCD and PLGA nanovaccines was examined by in vitro hydrolysis and antigen release studies. Nanovaccines could be effectively engulfed by dendritic cells (DCs) via endocytosis in both dose and time dependent manners, and their intracellular trafficking was closely related to the pH-sensitivity of the carrier materials. Furthermore, nanovaccines could induce the secretion of inflammatory cytokines by DCs and T cells co-cultured with the stimulated DCs. In vivo evaluations demonstrated that nanovaccines were more potent than that based on the complete Freund's adjuvant, with respect to inducing anti-FSHR antibody, reducing the sperm count, inhibiting the sperm motility, and increasing the teratosperm rate. Immunization of male mice with nanovaccines notably decreased the parturition incidence of the mated females. Consequently, both in vitro and in vivo activities of FSHR could be considerably augmented by NPs. More importantly, our studies indicated that the pH-responsive nanovaccine was not superior over the non-responsive counterpart for the examined peptide antigen.

Chiral Separation of Ormeloxifene Hydrochloride, a Non-steroidal Contraceptive Agent.

Ormeloxifene hydrochloride (Centchroman) is once-a-week non-steroidal oral contraceptive agent marketed in India and other countries. In this study, we report a validated isocratic high-performance liquid chromatographic (HPLC) method for chiral separation of D- and L-ormeloxifene hydrochloride. This method is capable of baseline separation of its D- and L-isomers. HPLC separation was achieved on a Lux 5µ cellulose-1 with a mobile phase comprising hexane, isopropanol, methanol and triethylamine (90:10:1:0.5). Validation parameters such as limit of detection, limit of quantitation, linearity, precision, accuracy, specificity and preformulation studies were conducted according to new guidelines of International Conference on Harmonization.

Innovative Disulfide Esters of Dithiocarbamic Acid as Women-Controlled Contraceptive Microbicides: A Bioisosterism Approach.

In an ongoing effort to discover an effective, topical, dual-function, non-surfactant contraceptive vaginal microbicide, a novel series of 2,2'-disulfanediylbis(3-(substituted-1-yl)propane-2,1-diyl) disubstituted-1-carbodithioates were designed by using a bioisosterism approach. Thirty-three compounds were synthesized, and interestingly, most demonstrated multiple activities: they were found to be spermicidal at a minimal effective concentration of 1-0.001 %, trichomonacidal against drug-susceptible and resistant Trichomonas strains at minimal inhibitory concentration (MIC) ranges of 10.81-377.64 and 10.81-754.14 µM, respectively, and fungicidal at MIC 7.93-86.50 µM. These compounds were also found to be non-cytotoxic to human cervical (HeLa) epithelial cells and vaginal microflora (Lactobacilli) in vitro. The most promising compound, 2,2'-disulfanediylbis(3-(pyrrolidin-1-yl)propane-2,1-diyl)dipyrrolidine-1-carbodithioate (5), exhibited spermicidal activity 15-fold higher than that of the marketed spermicide Nonoxynol-9 (N-9) and also demonstrated microbicidal potency. To identify common structural features required for spermicidal activity, a 3D-QSAR analysis was carried out, as well as in vivo efficacy studies and fluorescent labeling studies to determine the biological targets of compound 5.

CatSper channel, sperm function and male fertility.

A number of physiological events, such as sperm hyperactivation, chemotaxis towards the egg, capacitation and acrosome reaction, are triggered by activation of sperm ion channels in response to a diverse range of chemical cues. Cation channel of sperm (CatSper), a sperm-specific ion channel, is unique in orchestrating the events for fertilization, and seems to be exclusively evolved for sperm function and male fertility. CatSper acts as a polymodal, chemosensory calcium channel and plays a vital role in the regulation of sperm hyperactivation. CatSper knockout models and application of patch clamp recordings have shown that it is indispensable for male fertility, and mutations and deletions in CatSper gene(s) may lead to infertility. In fact, mutations in CatSper1 and 2 have been identified in infertile individuals; however, CatSper3 and 4 have not been explored. Restricted localization and expression of CatSper in sperm offer an added advantage to developing gamete-based safe non-hormonal contraceptives. This review concisely covers identification, structure, function, and mechanism of action of CatSper channels. The functional importance of this complex ion channel in sperm motility and male fertility is highlighted for further research on male fertility, infertility, and contraception.

Does the contraceptive pill influence peak nasal inspiratory flow values?

BACKGROUND: Early oral contraceptive pills (OCP) had higher estrogen levels and have been thought to cause nasal obstruction in about 40% of women users. A recent small study conducted on women taking OCP showed no significant effects on nasal patency. The aim of the present study was to analyse in a large number of volunteers if Peak Nasal Inspiratory Flow (PNIF) values could be influenced by modern OCP. METHODOLOGY: PNIF was measured in 257 women (from 14 to 51 years old), divided into two groups: the study group composed of 109 healthy women taking modern OCP; the control group composed of 148 healthy women who did not take OCP. 9 women in the study group were excluded because of allergic disease, 248 females were finally considered. Data were statistically analysed and figures/tables were produced to see the effect of OCP on PNIF. RESULTS: The present study could not show any effect of OCP on nasal function. Moreover, while height influenced PNIF in both groups, age was not statistically significant. CONCLUSION: From the present study, it seems that OCP could have no effects on nasal airflow, confirming that modern OCP with lower estrogen doses should not affect nasal mucosa or nasal patency.

Male contraception: another Holy Grail.

The idea that men should participate in family planning by playing an active role in contraception has become more acceptable in recent years. Up to the present the condom and vasectomy have been the main methods of male contraception. There have been and continue to be efforts to develop an acceptable hormonal contraceptive involving testosterone (T) suppression. However the off target affects, delivery of the analogs and the need for T replacement have proven difficult obstacles to this technology. Research into the development of non-hormonal contraception for men is progressing in several laboratories and this will be the subject of the present review. A number of promising targets for the male pill are being investigated. These involve disruption of spermatogenesis by compromising the integrity of the germinal epithelium, interfering with sperm production at the level of meiosis, attacking specific sperm proteins to disrupt fertilizing ability, or interfering with the assembly of seminal fluid components required by ejaculated sperm for acquisition of motility. Blocking contractility of the vas deferens smooth muscle vasculature to prevent ejaculation is a unique approach that prevents sperm from reaching the egg. We shall note the lack of interest by big pharma with most of the support for male contraception provided by the NIH.

Drug-eluting fibers for HIV-1 inhibition and contraception.

Multipurpose prevention technologies (MPTs) that simultaneously prevent sexually transmitted infections (STIs) and unintended pregnancy are a global health priority. Combining chemical and physical barriers offers the greatest potential to design effective MPTs, but integrating both functional modalities into a single device has been challenging. Here we show that drug-eluting fiber meshes designed for topical drug delivery can function as a combination chemical and physical barrier MPT. Using FDA-approved polymers, we fabricated nanofiber meshes with tunable fiber size and controlled degradation kinetics that facilitate simultaneous release of multiple agents against HIV-1, HSV-2, and sperm. We observed that drug-loaded meshes inhibited HIV-1 infection in vitro and physically obstructed sperm penetration. Furthermore, we report on a previously unknown activity of glycerol monolaurate (GML) to potently inhibit sperm motility and viability. The application of drug-eluting nanofibers for HIV-1 prevention and sperm inhibition may serve as an innovative platform technology for drug delivery to the lower female reproductive tract.

Synthesis and acrosin inhibitory activities of substituted ethyl 5-(4-aminophenyl)-1H-pyrazole-3-carboxylate derivatives.

A series of novel ethyl 5-(4-aminophenyl)-1H-pyrazole-3-carboxylate derivatives were designed and synthesized and their in vitro acrosin inhibitory activities were evaluated. Most of the compounds exhibited acrosin inhibitory activities. Among them, three compounds (5l, 5n, and 5v) were more potent than that of the control TLCK. These provide a new structural type for the development of novel contraceptive acrosin inhibitory agents.