Reversible Inhibition Of Sperm Research Articles

New insights into molecular signaling pathways and current advancements in prostate cancer diagnostics & therapeutics.

Prostate adenocarcinoma accounts for more than 20% of deaths among males due to cancer. It is the fifth-leading cancer diagnosed in males across the globe. The mortality rate is quite high due to prostate cancer. Despite the fact that advancements in diagnostics and therapeutics have been made, there is a lack of effective drugs. Metabolic pathways are altered due to the triggering of androgen receptor (AR) signaling pathways, and elevated levels of dihydrotestosterone are produced due to defects in AR signaling that accelerate the growth of prostate cancer cells. Further, PI3K/AKT/mTOR pathways interact with AR signaling pathway and act as precursors to promote prostate cancer. Prostate cancer therapy has been classified into luminal A, luminal B, and basal subtypes. Therapeutic drugs inhibiting dihydrotestosterone and PI3K have shown to give promising results to combat prostate cancer. Many second-generation Androgen receptor signaling antagonists are given either as single agent or with the combination of other drugs. In order to develop a cure for metastasized prostate cancer cells, Androgen deprivation therapy (ADT) is applied by using surgical or chemical methods. In many cases, Prostatectomy or local radiotherapy are used to control metastasized prostate cancer. However, it has been observed that after 1.5 years to 2 years of Prostatectomy or castration, there is reoccurrence of prostate cancer and high incidence of castration resistant prostate cancer is seen in population undergone ADT. It has been observed that Androgen derivation therapy combined with drugs like abiraterone acetate or docetaxel improve overall survival rate in metastatic hormone sensitive prostate cancer (mHSPC) patients. Scientific investigations have revealed that drugs inhibiting poly ADP Ribose polymerase (PARP) are showing promising results in clinical trials in the prostate cancer population with mCRPC and DNA repair abnormalities. Recently, RISUG adv (reversible inhibition of sperm under guidance) has shown significant results against prostate cancer cell lines and MTT assay has validated substantial effects of this drug against PC3 cell lines. Current review paper highlights the advancements in prostate cancer therapeutics and new drug molecules against prostate cancer. It will provide detailed insights on the signaling pathways which need to be targeted to combat metastasized prostate cancer and castration resistant prostate cancer.

RISUG® offers early contraception: An experience during Phase III clinical trials

Objectives: An early contraceptive efficacy with reasonable assurance of reversibility has been a challenge in male contraception. With nearly four decades of research in reversible inhibition of sperm under guidance (RISUG®) as an intravasal male contraceptive, including pre-clinical trials in rats, rabbits, langur monkeys, and three phases of clinical trials, the present study aims to evaluate the additional parameters of a center of Phase III clinical trials. Material and Methods: Subjects were recruited following ICMR guidelines of inclusion and exclusion criteria. Samples were analyzed for sperm functional tests, namely, hypo-osmotic swelling, acrosomal intactness, nuclear chromatin decondensation, and sperm mitochondrial activity index. Furthermore, seminal biochemistry and serum hormones such as follicle-stimulating hormone, luteinizing hormone, testosterone, cortisol, and prolactin were assessed along with levels of anti-sperm antibodies and prostate-specific antigen (PSA). Results: The present study, on human subjects, emphasizes the efficacy of RISUG® with early onset of contraception and indication of a greater possibility of reversal. A significant decrease in all sperm functional parameters was observed following RISUG® injection along with increased sperm abnormalities. Semen biochemistry revealed no marked alterations in the concentration of fructose and acid phosphatase, while significantly decreased levels of glycerophosphorylcholine and neutral α-glucosidase were observed. No significant changes in the circulatory levels of hormones and the levels of PSA were observed. In addition, the development of anti-sperm antibodies, an adverse effect of other vas occlusive methods, was not indicated after RISUG® administration, implying the potential of reversibility in humans as observed earlier in different animal models. Conclusion: RISUG® presenting deleterious effects on spermatozoa and marked alterations in epididymal markers provides early contraception with a greater possibility of reversal. Although the progress of RISUG® toward development as an ideal male contraceptive is slow, the study implies a strong future possibility.

Studies on biochemical, oxidative and genotoxicity alterations following vas blockage with reversible inhibition of sperm under guidance and reversal in rats.

CONTEXT:Vas obstruction with reversible inhibition of sperm under guidance (RISUG) for contraception and its reversal, may cause oxidative stress or inimical effects on male reproductive functions.OBJECTIVE:To evaluate the biochemical and genotoxicity at the level of reactive oxygen species (ROS) following vas occlusion with RISUG and its reversal by Dimethyl sulphoxide (DMSO) and 5% NaHCO3 in Wistar albino rats.SETTINGS AND DESIGN:Animals were divided into seven groups (n = 10), namely sham-operated control, short-term vas occlusion with RISUG for 90 days, reversal with DMSO and 5% NaHCO3, long-term vas occlusion with RISUG for 360 days, reversal with DMSO and 5% NaHCO3.MATERIALS AND METHODS:Biochemical markers in reproductive tissues, hematology, serum biochemistry, serum electrolytes and ROS measuring indicators, e.g., lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase were examined.STATISTICAL ANALYSIS USED:One-way analysis of variance test was performed for analyses of data obtained in this study using the SPSS 10.0 software (SPSS Inc., Chicago, IL, USA).RESULTS:The tissue and clinical chemistry did not show appreciable alterations in RISUG injected and reversal Groups (II-VII) as compared to sham control. The genotoxicity and various ROS markers fluctuated within control limits following short- and long-term vas occlusion and reversal.CONCLUSIONS:The study suggested that the reversal procedures, following RISUG contraception, were not associated with any kind of toxicological manifestations.

Reversible inhibition of sperm under guidance as an intratubular and reversible contraception in female rats: An experimental study.

BackgroundReversible inhibition of sperm under guidance (“RISUGⓇ”) is a promising intravasal male contraceptive.ObjectiveAn exploratory study was conducted with a concept of non-invasive, transcervical, single-intervention and reversible contraception using RISUGⓇ in females.Materials and MethodsIn this experimental study, 60 adult Wistar albino female rats weighing 150-155 g, 3-4 months old were divided into four groups: group I: sham-operated control; group II: tubal occlusion with RISUG for 90 days; group III: tubal occlusion with RISUGⓇ for 90 days and reversal with dimethyl sulphoxide and group IV: tubal occlusion with RISUGⓇ for 90 days and reversal with 5% NaHCO. Animals were subjected to bilateral fallopian tube occlusion with RISUGⓇ and reversal with DMSO and NaHCO. The estrous cycle, fertility and histology of fallopian tube were evaluated.ResultsGroup I showed 100% fertility during all mating schedules. Animals of experimental groups indicated positive mating, but 0% fertility was evident following 30, 60, and 90 days of tubal occlusion. However, after reversal, fertility steadily increased to normalcy in groups III (50% at 45 days, 80% at 105 days, 100% at 150 and 195 days) and IV (70% at 45 and 105 days, 100% at 150 and 195 days) animals. Group II illustrated disorganized inner cell linings and eosinated RISUGⓇimplant-filled lumen. Reversal groups (III and IV) revealed complete restoration of cellular histo-architecture. Regular estrous cycle was noticed in all experimental groups. ConclusionRISUGⓇ is suitable for single intervention, intratubular, reversible contraception in female rats.

Non-surgical methods of regulation reproductive function and contraception males of domestic animals

The regulation of male reproductive function today is not limited to surgical castration; there are many other methods of controlling reproductive function. Non-surgical methods of controlling male reproductive function can be reversible and not reversible, i.e., reproductive function is preserved or completely suppressed. Castration of males or orchiectomy leads to irreversible sterility of the male, when the male completely loses the ability to reproduce. This operation can also entail some side effects: obesity, underdevelopment of the external genital organs, an increased risk of diabetes or hypothyroidism, problems with frequent urination and behavioral problems. Therefore, methods of non-surgical management of reproductive function and contraception in males are being actively developed. The article presents the latest methods of contraception and the management of the reproductive function of male domestic animals (cats, dogs): clinical application GnRH and agonists GnRH, Non-Peptide GnRH Antagonists, GnRH-Toxin Conjugate, GnRH Vaccines and other immune contraceptive vaccines, chemical sterilants for intratesticular injections, calcium chloride, zinc gluconate, chlorhexidine digluconate, hypertonic saline, sex steroids (progestines), gene silencing, kisspeptin and GnIH, targeting delivery of cytotoxins, single-dose hormonal male and female sterilianr, FSH – receptor ligand cytotoxin conjugates, Sperm Protein Reactive with Antisperm Antibodies (SPRASA) Reversible Inhibition of Sperm under Guidance(RISUG).

RISUG\xae as a male contraceptive: journey from bench to bedside

Even after decades of research men still lack reliable and reversible contraceptive methods comparable to female methods of contraception. Traditional methods of male contraception present a high failure rate and also involve high risk both when used for contraception and for protection against sexually transmitted diseases. Various chemical, hormonal, immunological, vas based and herbal methods of contraception have been examined by scientists world over during the past four decades. Among the possible lead approaches, exogenous hormonal contraception, either alone or in combination with progesterone or antiandrogen, is being viewed at low profile because of their insufficiency in inducing uniform suppression of spermatogenesis and steroid related long term complications. As an alternative to vasectomy, among various intravasal devices being examined, RISUG® (Reversible Inhibition of Sperm Under Guidance), a co-polymer of styrene and maleic anhydride offers long term contraception with safety, efficacy and it can be delivered by no-scalpel injection. Thus it is the only male contraceptive procedure currently under Phase- III Clinical Trial. The non-invasive reversal technique, successfully demonstrated in langur monkeys and functional reversal achieved with dimethyl sulphoxide (DMSO) and sodium bicarbonate (NaHCO3) in rats and rabbits with safety at F1 generation (first filial generation) have projected RISUG® as a better alternative to vasectomy. In this narrative review we revisit the long journey of RISUG® beginning with formulation on a bench towards reaching the market as a safe and effective contraceptive method, discussing various milestones and roadblocks of this expedition awaiting the mandatory regulatory clearance from the Government of India. Successful completion of ongoing phase III clinical trials with demonstration of reversal in human volunteers will give an indigenously developed male contraceptive to the world.

Toxicity and Mutagenicity Evaluation Following RISUG Contraception Reversal in Rats.

Reestablishment of fertility, after a male contraceptive method, is of great concern. In this context, RISUG (Reversible Inhibition of Sperm Under Guidance) has been evaluated for its mutagenicity following reversibility with dimethyl sulfoxide (DMSO)/sodium bicarbonate (NaHCO3) in Wistar albino rats. Animals were divided into 7 groups, namely, sham-operated control, vas occlusion with RISUG for 90 and 360 days, reversal with DMSO and NaHCO3 after 90 and 360 days, respectively. The testis, cauda epididymis, cauda epididymal spermatozoa, and serum were evaluated for apoptosis and hormonal status through various assays. RISUG was subjected to Ames test at dose levels of 10, 50, and 100 µL. Results of terminal deoxynucleotidyl transferase nick end labeling and caspase-3 assays in testes and cauda epididymis revealed that the percentage of positive cells in the experimental groups was comparable to sham-operated control. Annexin V assay in cauda epididymal spermatozoa showed slight elevation in group II ( P < 0.05), whereas in the remaining groups, minimum numbers of positive sperms were found. Hormone profile, namely, testosterone, prolactin, cortisol, prostate-specific antigen, and sperm antibody concentration, remained unchanged. In Ames test, no significant increase was observed in the number of revertant colonies on plates containing RISUG in the presence and absence of S9 mix in all 3 strains. Therefore, the reversal of RISUG-induced contraception by solvent vehicle DMSO/NaHCO3 was successful without any toxicity at the cellular levels.

Can the evolution of male contraception lead to a revolution? Review of the current state of knowledge.

IntroductionGreat advances in medical research concerning methods of contraception have been achieved in recent years, however, more than 25% of couples worldwide still rely on condoms – a method with poor efficacy. Even though there is a spectrum of 11 different contraceptive methods for women, there are only 4 commonly used by men (condoms, periodic abstinence, withdrawal and vasectomy). In this review, advances and present, state-of-the-art, both hormonal and non-hormonal male contraceptive methods will be presented and evaluated. Potential novel targets that warrant greater research will be highlighted.Material and methodsA comprehensive literature search without a time limit was performed using the Medline database on May 2017. The terms 'male contraception' in conjunction with ‘reversible inhibition of sperm under guidance’ (RISUG), 'hormonal', 'non-hormonal', 'vasectomy' or 'testosterone' were used. The articles were limited to those published in English, Polish or French.ResultsThere are various contraceptives currently available to regulate male fertility. Vasectomy is still the most effective permanent form of male contraceptive with a failure rate lower than 1%. Reversible, non hormonal methods of male contraception, like reversible inhibition of sperm under guidance, are very promising and close to being introduced into the market. In regards to hormonal contraception research, the use of testosterone injections has been widely studied yet they often harbor undesirable side effects and require further development.ConclusionsDespite continuous efforts worldwide, it seems that another several years of research is needed to provide safe, effective and affordable male contraceptives which will allow both men and women to participate fully in family planning.

Contraception with RISUG® and functional reversal through DMSO and NaHCO3 in male rabbits.

The study aimed to evaluate reversal of short- and long-term vas occlusion with reversible inhibition of sperm under guidance (RISUG) using dimethyl sulfoxide (DMSO) and sodium bicarbonate (NaHCO3) in male rabbits (Oryctolagus cuniculus). Animals were divided into seven groups containing five animals each. Fortnightly, semen analysis revealed that sperm concentration and output steadily declined after vas occlusion and complete azoospermia was attained at 30–60 days postinjection. Spermatozoa reappeared at 60–75 days of reversal and normozoospermia was noticed between 135 days and 150 days in the reversal groups. All spermatozoa were found nonmotile prior to azoospermia and a gradual recovery in sperm motility was observed between 105 days and 135 days of reversal. A significant decline in viability of sperms was noticed during vas occlusion up to 30–60 days which recovered at 60–75 days postreversal and normalized by 75–105 days in the reversal groups. A significant enhancement in the sperm abnormalities was recorded in all vas occluded animals as well as those in initial periods of reversal. Other parameters, namely, semen volume, ejaculation time, pH, color, and consistency, remained unaltered during all phases of the study. Fertility test, at the intervals of 15 days, demonstrated that animals exhibited complete sterility during the entire period of vas occlusion. A gradual recovery in fertility was observed with the appearance of spermatozoa following vas occlusion reversal and 100% fertility was observed following 135–150 days of reversal. F1 progeny of reversed animals was found normal. The results suggest that reversal with DMSO or NaHCO3 is feasible, with normal progeny, following short- and long-term contraception.

Relative suitability of DMSO and NaHCO3 for reversal of RISUG® induced long-term contraception.

Among the vas-based methods on trial, reversible inhibition of sperm under guidance (RISUG(®) ), a co-polymer of styrene and maleic anhydride is being projected as an effective alternative to No Scalpel Vasectomy. RISUG offers long-term contraception with safety, efficacy in human trials and can be delivered by no-scalpel injection. Currently, the procedure is under phase-III clinical trial. However, reversal of this vas-based drug-induced contraception needs to be established in animal models prior to clinical trials to ensure its claim as an effective alternative for vasectomy. In the present investigation, the relative suitability of dimethyl sulphoxide (DMSO) and NaHCO3 for RISUG induced long-term vas occlusion reversal was carried out in albino rats. Animals were allocated into four groups (n = 10), viz., sham-operated control (group-I), vas occlusion with RISUG for 360 days (group-II), vas occlusion with RISUG for 360 days and reversal with DMSO (group-III) and vas occlusion with RISUG for 360 days and reversal with NaHCO3 (group-IV). A variable response in fertility was observed in different groups. Absolute sterility in group III at all mating intervals, while, zero percent fertility in groups II and IV following 90 days of occlusion was observed. Following reversal restoration of fertility with DMSO at 45 days, whereas, reversal by NaHCO3 at 30 days was noticed. Ejaculated spermatozoa of RISUG injected and initial intervals of reversed animals exhibited various degrees of abnormalities. The testes exhibited focal degeneration in vas occluded animals. The occluded lumen of the vas deferens contained an eosinated polymer with exfoliated epithelium. Following vas occlusion reversal, a complete regeneration in the vas epithelium was seen. All other parameters remained unaltered. The reversal with NaHCO3 resulted into an early resumption of fertility when compared with DMSO and the procedure found to be successful, feasible and safe up to F1 generation. Thus, RISUG provides a hope for reversible male contraceptives.

Male contraception: a clinically-oriented review.

Despite the variety of available female contraceptive methods, many pregnancies (&#126;50%) are still undesired. Many men (&#62;60%) want to participate equally with their partner in family planning; however, male contraceptive methods (MCMs) account for only 14% of those used worldwide and no pharmaceutical MCM is available so far. The only two MCMs currently available are condoms, which despite protecting against sexually transmitted diseases have high failure rates (&#126;19%), and vasectomy, which though very efficient (99%) is poorly reversible (&#60;50%). Among MCMs under investigation, male hormonal contraceptives (MHCs) are those that have come closest to commercialization. The action of MHCs relies on the disruption of spermatogenesis that exogenous androgen administration evokes by suppressing the hypophyseal-gonadal axis. Various regimens of androgens as monotherapy or in combination with progestins have been tested in clinical trials achieving a Pearl Index &#60;1.0 (equal to that of the female oral contraceptive pill); however, concerns regarding the variable response rates observed (non-responders: 5-20%), the impracticality of parenteral administration and long-term prostate-associated or cardiovascular morbidity have deflected the interest of the pharmaceutical industry from further research. Non-hormonal contraception methods may be, at least theoretically, more specific by selectively disrupting spermatogenesis and sperm transport or fertilizing ability. Nevertheless, only a few have been tested in clinical trials (Reversible Inhibition of Sperm Under Guidance, RISUG, and Intra Vas Plugs); most of them are still in pre-clinical development or have been abandoned due to toxicity (gossypol). Consequently, until a reliable, safe and practical MCM is developed, women will continue to bear most of the contraception burden.

RISUG: A new perspective in non–hormonal male contraception

Abstract Currently there are several hormonal and non-hormonal methods of contraception available but due to long term side effects of hormonal contraceptives, a great research is undergoing to develop an effective and noninvasive non-hormonal male contraceptive. One of the product of this research is RISUG (an acronym for the Reversible Inhibition of Sperm Under Guidance). RISUG is a co-polymer of Styrene Maleic Anhydride (SMA) dissolved in Dimethyl Sulfoxide (DMSO) to form a gel. This gel is then introduced in the lumen of male vas deferens which results in the partial blockage of vas deferens. It causes the disruption of the membrane of spermatozoa and release of enzymes that are essential for the fertilization of ova. Thus the ejaculation after RISUG contains infertile spermatozoa.

Pharmaceutical Approaches and Advancements in Male Contraception

Currently available contraceptive methods offer a variety of options for women, but only very few for men which include surgical methods, condom and hormonal methods. Non-surgical and non-hormonal methods are under investigation. Among these, hormonal contraceptive approaches, including injections, oral and transdermal delivery systems of testosterone, have attracted the attention of investigators. Also non-hormonal approaches based on chemicals extracted from different plants such as cotton seed plant, Neem tree, Trypterigium wilfordii and Momordica Charantia seed, are known to have effect on male fertility. Additionally, alkylated imino sugars, Ca ++ channel blockers, indenopyridines, indazole-3-carboxylic acid analogues, reversible inhibition of sperm under guidance (RISUG) which involves injection of stericmaleic anhydride with dimethyl sulfoxide, spermicide‐ microbicide (including gel formulations) and vaccine approaches are intended to interfere in a certain fertilization step. Information obtained from multi-center studies in several countries on both men or women shows the necessity for additional reversible male contraceptive methods. Results from recent surveys clearly indicate that there is a market and a need for novel pharmaceutical preparations for male contraception.

Male contraception

Contraception is an accepted route for the control of population explosion in the world. Traditionally hormonal contraceptive methods have focused on women. Male contraception by means of hormonal and non hormonal methods is an attractive alternative. Hormonal methods of contraception using testosterone have shown good results. Non hormonal reversible methods of male contraception like reversible inhibition of sperm under guidanceare very promising. In this article we have reviewed the current available options for male contraception.

A Novel Two-Step Procedure for Plasma Surface Modification of Low-Density Polyethylene for Improved Drug Adhesion in Intra Uterine Devices (IUDs)

The Intrauterine Devices (IUDs) are unable to prevent STDs (Sexually Transmitted Diseases) and PIDs (Pelvic Inflammatory Diseases) which seriously restricts their usage. RISUG® (Reversible Inhibition of Sperm under Guidance), a potent spermicidal and antimicrobial drug is being coated over copper-T frame (made of polyethylene) by exposing it to vacuum plasma treatment twice to increase the adhesion property of polyethylene. First, the polyethylene alone is exposed to certain process conditions of RF (radiofrequency) plasma which increases the surface roughness by creating micro-and nano-pores (as indicated by scanning electron microscopy and atomic force microscopy). Thereafter RISUG® is smeared over the polyethylene of copper-T frame and subjected to the same plasma treatment again. The second plasma treatment causes a "micro-hammering" effect, pushing the drug in the pores and pits formed by the first plasma treatment, resulting in improved bonding. The present study shows that RF plasma treatment alters the surface properties of the copper-T frame without affecting its mechanical properties or primary fabrication.

Effect of γ-dose rate and total dose interrelation on the polymeric hydrogel: A novel injectable male contraceptive

Functional necessity to use a particular range of dose rate and total dose of γ-initiated polymerization to manufacture a novel polymeric hydrogel RISUG ® (reversible inhibition of sperm under guidance) made of styrene maleic anhydride (SMA) dissolved in dimethyl sulphoxide (DMSO), for its broad biomedical application explores new dimension of research. The present work involves 16 irradiated samples. They were tested by fourier transform infrared spectroscopy, matrix assisted laser desorption/ionization–TOF, field emission scanning electron microscopy, high resolution transmission electron microscopy, etc. to see the interrelation effect of gamma dose rates (8.25, 17.29, 20.01 and 25.00 Gy/min) and four sets of doses (1.8, 2.0, 2.2 and 2.4 kGy) on the molecular weight, molecular weight distribution and porosity analysis of the biopolymeric drug RISUG ®. The results of randomized experiment indicated that a range of 18–24 Gy/min γ-dose rate and 2.0–2.4 kGy γ-total doses is suitable for the desirable in vivo performance of the contraceptive copolymer.

RISUG ®: A potential candidate for the entry inhibitor group of antiretroviral drugs

Entry inhibitors are a group of antiretroviral drug which prevents HIV from entering human immune cells. They include both fusion and attachment inhibitors. A hypothesis is put forward in which a new male contraceptive drug with proven antimicrobial property is proposed as a possible candidate for the entry inhibitor group of antiretroviral drugs. The proposed mechanism of action involves (i) interaction with gp120 and thereby preventing binding to CD4 and (ii) competitive binding with the viral glycoprotein and inhibit the glycoprotein - cell surface glyocosaminoglycan Heparan Sulfate (HS) interaction. A new drug RISUG (Reversible Inhibition of Sperm Under Guidance) presently undergoing Phase III clinical trials throughout India for its contraceptive effect in male has also antimicrobial actions. RISUG is a chemical complex of styrene maleic anhydride (SMA(AN)) and dimethyl sulfoxide. On injection into the vas deferens, it reacts with the components of intravas fluid, the spermatic fluid and gets converted to styrene maleic acid (SMA(AC)) and breakdown products like mandelic acid. An anti HIV activity of RISUG is likely due to its electrical charge and mandelic acid generation. For experimental validation HIV in vitro assays can be performed which will involve infectivity assays, luciferase assay and soluble gp120 assays. A positive result from the studies will validate the hypothesis.

RISUG™ (reversible inhibition of sperm under guidance) – An antimicrobial as male vas deferens implant for HIV free semen

HIV transmission from the male to the female is a major health problem. A hypothesis proposing an intra vas deferens implant of an antimicrobial compound to prevent the infection spread is presented. Mechanisms of action for the inhibition could include inactivating HIV in sperms passing through the vas deferens; drug release from the implant to destroy HIV entering into semen from genital structures distal to the vas deferens; and sperm acrosome released hyaluronidase mediated reabsorption of HIV. A subcomponent of the implant flowing along sperm pathway may have a role in reducing the entry of HIV from a positive female into penile tissue. A new drug RISUG (reversible inhibition of sperm under guidance) presently undergoing clinical trials for its contraceptive effect in the male (because it disrupts the sperm acrosome by an electrical charge and pH lowering effects) has also antimicrobial action. The drug being a combination of styrene maleic anhydride (SMA) and dimethyl sulfoxide (DMSO) on being injected into the lumen of the vas deferens produces styrene maleic acid thereby lowering pH; induces electrochemical action leading to a stable electrical charge generation; releases mandelic acid; and induces acrosome reaction in sperms with consequent release of hyaluronidase and sperm inactivation. Moreover, one time administration into the lumen of the vas gives long term action. All these phenomena very well match with the needs for HIV clearance of semen and hence RISUG is here proposed as a possible candidate material for the HIV inhibiting vas deferens implant when delivered in below contraceptive threshold dosage. For experimental validation, after obtaining data on the semen HIV load under control conditions in the HIV positive males inducted into the study, 30 mg of SMA in 120 microl of DMSO (contraceptive dose being 60 mg SMA+120 microl DMSO) is to be injected into vasa deferens bilaterally. Thereafter at intervals of one month the viral load needs to be determined in semen obtained either by masturbation or in lubricant free condom at intercourse - the method of collection remaining the same throughout for a particular subject. A significant reduction in the semen viral load following RISUG administration will validate the hypothesis. Speculated reduced female to male HIV transmission is more difficult to test. Nonspecific indications will come from a population study of the incidence of RISUG treated men becoming HIV positive as compared to that in the general population.

A short-term evaluation of semen and accessory sex gland function in phase III trial subjects receiving intravasal contraceptive RISUG

Following the intravasal injection of a new male contraceptive RISUG (reversible inhibition of sperm under guidance) in volunteers, routine semen analysis, semen biochemistry and germ cell morphology were evaluated in comparison with the corresponding preinjection samples for a maximum period of 6 months. Sperm counts in all 25 subjects before injection varied from 45 to 120 × 10 6/ml. Out of 25 subjects, 6 became azoospermic after 1 month, 15 after 2 months, 3 after 3 months and 1 after 4 months of contraceptive injection. The mean volume of the ejaculates was found to be less as compared to preinjection samples. Occasional sperm or sperm heads and immature germ cells were identified in only a few postinjected subjects. However, no pregnancy was reported in these subjects during the study period. Abnormal morphology found in most of the sperm, but not in the accompanying immature germ cells, may be due to a charge-related effect on the former but not on the latter cells. Neutral α-glucosidase, the biochemical marker for epididymis, was estimated to be significantly lower in the seminal plasma of all the postinjected subjects. On the other hand, acid phosphatase activity and fructose levels in the seminal plasma were found to be in the normal range. Based on the above findings, it is concluded that at least for the present study period, RISUG, a new male contraceptive, is effective as a partially occluding agent in the vas deferens.