Safety evaluation through genotoxicity and apoptotic markers following RISUG® induced contraception and its reversal in male rabbits

Ansari, Abdul S.; Badar, Ayesha; Lohiya, N. K.

doi:10.1016/j.reprotox.2018.07.083

Cited by 10 publications

(11 citation statements)

References 26 publications

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“…RISUG affects the sperm membrane including the acrosome which may have resulted in the sperm losing its fertilizing ability222324. Successful reversal of RISUG injection has been observed in rat, rabbit and langur monkeys’ studies without any side effects2526272829303132. However, reversibility of fertilizing ability of sperms was not attempted in this study.…”

Section: Discussionmentioning

confidence: 88%

Safety & efficacy of an intravasal, one-time injectable & non-hormonal male contraceptive (RISUG)

Sharma

Mathur

Singh

et al. 2019

Indian Journal of Medical Research

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Background & objectives:For improved male contraception, a new polymeric drug molecule – Reversible Inhibition of Sperm under Guidance (RISUG) has been synthesized and has been found to be effective, safe and reversible in various animal species. Phase-I and phase-II clinical trials have confirmed its safety and contraceptive efficacy. The present study was undertaken as a multicentric-limited phase-III clinical trial to test the efficacy and safety of RISUG in human volunteers.Methods:One hundred and thirty nine young males each having at least two children and living with wife were given 120 μl of RISUG as bilateral vas intraluminal injection. After the single-dose administration, the individuals were followed in respect of general health and semen parameters. Their wives were also followed particularly to determine onset of pregnancy.Results:During the six month follow up, the health of male volunteers and their wives was normal with no significant adverse effects. Temporary scrotal enlargement and mild scrotal and inguinal region pain were manifested in most individuals and resolved within one month without any routine activity impairment. In six individuals, there was injection procedure failure and azoospermia was not achieved. The other 133 individuals had either severe oligozoospermia or azoospermia at the first semen examination one month following RISUG injection; 82.7 per cent individuals had continued azoospermia in the month following first semen examination onwards and the rest 17.3 per cent manifested azoospermia within three to six months.Interpretation & conclusions:RISUG intravasal injection appears to be a safe clinical procedure with no significant adverse effects and has high sustained contraceptive efficacy. The localized intervention and continued contraceptive action on single-dose administration were significant features of the RISUG technology.

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Section: Discussionmentioning

confidence: 88%

Safety & efficacy of an intravasal, one-time injectable & non-hormonal male contraceptive (RISUG)

Sharma

Mathur

Singh

et al. 2019

Indian Journal of Medical Research

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“…5 Similarly, in rabbits, the overall results of genotoxicity and apoptotic markers indicated that no serious toxic effects were found related to any response of RISUG or its reversal. 11 In addition to apoptotic proteins, hormones have evident role in spermatogenesis. The present investigation based on reversal showed no significant fluctuations in the level of testosterone, prolactin, and cortisol.…”

Section: Discussionmentioning

confidence: 99%

“…5 Similarly, in rabbits, the overall results of genotoxicity and apoptotic markers indicated that no serious toxic effects were found related to any response of RISUG or its reversal. 11…”

Section: Discussionmentioning

confidence: 99%

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Toxicity and Mutagenicity Evaluation Following RISUG Contraception Reversal in Rats

Ansari

Hussain²,

Khan

et al. 2018

Int J Toxicol

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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.

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“…Rabbit: The results of reversal studies in rabbit suggested that DMSO and NaHCO 3 were feasible, with normal progeny, following short-and longterm contraception. The safety evaluation following vas occlusion with RISUG ® and its reversal using genotoxicity tests and apoptotic marker assays concluded that it has not been correlated with any toxicity [63,64]. iii.…”

Section: Advantages Of Risug ® Over Other Methods Of Male Contraceptionmentioning

confidence: 99%

RISUG® as a male contraceptive: journey from bench to bedside

Khilwani

Badar

Ansari

et al. 2020

Basic Clin. Androl.

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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 (NaHCO 3) in rats and rabbits with safety at F 1 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.

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Safety evaluation through genotoxicity and apoptotic markers following RISUG® induced contraception and its reversal in male rabbits

Cited by 10 publications

References 26 publications

Safety & efficacy of an intravasal, one-time injectable & non-hormonal male contraceptive (RISUG)

Safety & efficacy of an intravasal, one-time injectable & non-hormonal male contraceptive (RISUG)

Toxicity and Mutagenicity Evaluation Following RISUG Contraception Reversal in Rats

RISUG® as a male contraceptive: journey from bench to bedside

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