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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. Keywords Contraceptive; RISUG; Vas deferens; SMA; Fertilization; DMSO
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159
Document heading
doi:
10.1016/S2305-0500(13)60138-4
RISUG: A
new perspective in non-hormonal male contraception
V
ikas
T
hakur
1
,
M
anjusha
C
houdhary
1
*
,
V
ineet
M
ehta
1
,
D
inesh
K
umar
1
,
N
itesh
2
1
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra-136119 Haryana, India
2
R. I. Inderprastha Institute of Technology, Karnal-132001, Haryana, India
ARTICLE INFO ABSTRACT
Article history:
Received 22 March 2013
Received in revised form 23 April 2013
Accepted 25 April 2013
Available online 20 June 2013
Keywords:
Contraceptive
RISUG
V
as deferens
SMA
F
ertilization
DMSO
*Corresponding author: Mrs. Manjusha choudhary, Institute of Pharmaceutical
Sciences, Kurukshetra University, Kurukshetra, Haryana, India.
Tel: +91-9991146283
E-mail: manjushachoudhary@gmail.com
1. Introduction
Today the huge growth of world population is one of the
biggest challenges faced by the human race.
In 1997 the
world population was
5.8 billion and currently it is around
7 billion and it is expected that it will be 8 billion by 2025,
9.1 billion in 2050 and 19 billion by the end of twenty first
century
[1,2]
. As the global population continuously increasing
very sharply, there is an urgent need to increase the choice
of effective contraception methods.
Indeed today we have
both hormonal and non-hormonal methods available for the
male contraception.
However the long term use of hormonal
contraceptives (androgen, progestin) might associate
with serious adverse reactions such as cancer, obesity,
hypertension and blood clotting.
Thus the non-hormonal
contraceptives might be more suitable than hormonal
contraceptives because they do not affect the functioning
of male sex organs such as prostate gland.
Currently many
non-hormonal male contraceptives are under various stages
of researc
h and development
[3]
.
2. Reversible inhibition of sperm under guidance
RISUG (Reversible Inhibition of Sperm Under Guidance),
is an injectable compound which has completed its phase
I and II clinical trial and now under phase III clinical trial
in
India
[4,5]
. It consists of a co-polymer of Styrene Maleic
Anhydride (SMA) dissolved in Dimethyl Sulfoxide (DMSO)
to form a gel.
This compound is injected into the lumen
of vas deferens by no scalpel
technique and provides
contraception for at least
8 to 10 years
[6]
.
3. Mechanism of action
RISUG is a poly electrolytic compound. It is introduced
in the lumen of vas deferens, where it comes in contact
with the spermatozoa
[7]
. On contact with the spermatozoa,
due to its poly-electrolytic nature, it cause ionic imbalance
on the human sperm membrane which results in swelling
and rupture of the sperm head
(Acrosome) and leakage
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.
Asian Pacific Journal of Reproduction 2013; 2(2): 159-162
Asian Pacific Journal of Reproduction
Journal homepage: www.apjr.net
160
Vikas Thakur et al./ Asian Pacific Journal of Reproduction (2013)159-162
of enzymes (Hyaluronidase and Acrosin) necessary for the
fertilization of ova
[8]
. RISUG results in partial blockage
of vas deferens associated with the flow of functionally
inactive cells
[9]
. The RISUG ejaculates consist of partially
or completely damaged spermatozoa which functionally
become unable to fertilize the ova.
The earlier studies
carried over langur monkeys have shown that vas deferens
with
SMA results in severe oligospermia or azoospermia
in first two ejaculations and continuous azoospermia in
subsequent ejaculations
[10]
. Release of enzymes necessary
for fertilization is discussed in
Figure 1.
Sperm membrane disruption after interaction
with RISUG
Neck
Acrosome
Head
Midpicec
tail
Figure 1.
Membrane disruption and release of enzymes which are
necessary for fertilization.
4.
RISUG
administration
The RISUG is administered into the vasa deferens by
using a non-scalpel method and requires only
15 minutes
to complete the procedure.
Once the RISUG administered
into the lumen of vas deferens, it fixed firmly to very small
folds on the inner surface of vas deferens with in
72 hour
of injection
[11]
. In first clinical trial of RISUG, it is found
that the therapeutic dose of the drug
is 60 milligram
[12]
. The
persons who had administered the drug in second clinical
trial have now been using the drug for more than
10 or 15
year without any problem.
After the proper implantation of
the drug, there is no pregnancy found to occur during the
1-3 year of the clinical study
[4]
. RISUG injection into vas
deferens has been described diagrammatically in
Figure 2.
Bladder
Vas deferens
Penis
Scrotum
Seminal vesicle
Rectum
Urethral sphincter
Sperms in vas deterens
interact with RISUG and
loose their capacity to
fertilize the egg
Sperm
Figure 2.
RISUG injection into vas deferens.
5.
RISUG
reversal
Earlier studies in primates have shown that RISUG is
easily reversible.
The studies have been shown that multiple
injections and reversal is effective in primates
[13]
. The
noninvasive reversal of
RESUG is obtained by flushing
it out from the lumen of vas deferens by dissolving in an
appropriate solvent
[14]
. It can also be removed by stimulating
the vas deferens percutaneously
[15]
. In one of study it is
reported that an injection of baking soda
dissolved in water
flush out the drug from the vas deferens effectively
[14]
.
Another study showed the effective removal of the RISUG
from the lumen by massage, vibration and low electrical
current
[16]
. The study on primates put forward that it
would take some months for the whole reversal of
RISUG
s
contraceptive effects
[17]
. Unlike vasectomy, RISUG does not
cause any kind of auto-immune response and its reversal is
very much trustworthy
[18]
.
6. Other reported activity
In addition to contraception, RISUG has also shown to
possess antimicrobial activity.
The research has proven
that
RISUG possesses potent antimicrobial activity against
a number of microorganisms such as
C
andida albicans,
P
seudomonas aeruginosa,
S
taphylococcus aureus,
E
scherichia
coli, and
N
eisseria gonococci
[20]
. The viruses are more
susceptible to its antimicrobial action than the vegetative
form of bacteria such as
S
taphylococcus and
P
seudomonas.
The drug has shown to possess anti-HIV activity due to its
electrical charge effect
[19,20]
.
7. Future prospective
RISUG is a polymeric complex of SMA and DMSO
[8,21]
. On
its administration
into the lumen of vas deferens, it reacts
with the water molecule, lipids and proteins present in the
spermatic fluid resulting in gel formation.
Progressively the
SMA gets converted into styrene maleic acid and mandelic
acid.
The mandelic acid and styrene maleic acid (SMAac)
which are released from the
RISUG implant gradually
moves with the spermatic fluid along the vas deferens to the
ejaculato
ry duct and to the semen. The SMA and mandelic
acid mix with the spermatic fluid and deactivate the
HIV
present in the semen
[20]
. The anti-HIV activity of mandelic
acid has been already proven
[21]
. Thus it helps to clear
the semen from
HIV virus. Another proposed additional
161
Vikas Thakur et al./ Asian Pacific Journal of Reproduction (2013)159-162
action is through hyaluronidase, released during the
acrosome reaction.
An increase in the number of acrosome
reacted sperms result in increase in the concentration of
hyaluronidase enzyme in spermatic fluid. Hyaluronidase
acts over tissue collagen protein and facilitates the entry
of
HIV virus into tissue
[20,22]
. Hyaluronidase increases the
penetration of
HIV virus into the tissues thus HIV absorbs in
to the surrounding tissue from the seminal fluid.
Ultimately
the seminal
HIV load will further reduce and the whole
semen will be free from the
HIV. The foremost problem
of antiretroviral therapy is
that most of the host body
reservoir are resistant to the entry of anti-
HIV drugs. The
hyaluronidase will increase the absorption of virus into the
nearby tissue and not to the structures from which the virus
is instigated.
Now the tissue containing the virus is likely to
be less protected to the action of anti-
HIV drugs and results
in the greater exposure of the virus to the drug at low dose
and thereby produces lesser side effects
[20]
.
8. RISUG: as an entry inhibitor for HIV
Entry inhibitors are the type of antiretroviral drug that
inhibit the entry of
HIV into the host immune cells. A
hypothesis is set forward in which a new non-hormonal male
contraceptive,
RISUG with confirmed antimicrobial activity
is recommended as a potential entrant for entry inhibitor
group of antiretroviral drugs.
The suggested mechanism
of action of
RISUG includes (1) it interacts with the gp120
(a viral surface protein) and thus prevents the binding of
the virus to the cell surface of
CD4 helper T cells and (2)
competitively binds with viral surface glycoprotein and thus
prevents the glycoprotein
-
cell surface glycosaminoglycan
Heparan Sulfate(HS)
[23]
. Possible mechanism of action of
RISUG as an entry inhibitor, anti-retroviral drug is given in
Figure 3.
Figure 3.
Possible mechanism of action of RISUG as an entry inhibitor, anti-retroviral drug.
9. Expected side effects of RISUG
In phase II clinical trial some participants showed minor
swelling of testes with no concomitant pain.
The swelling
resolved within
2 weeks after injection of RISUG without
any treatment
[24]
. Unlike vasectomy RISUG does not show
autoimmune response and granulomas
[18]
. Another fear
accompanying vas deferens occlusion is declined prostate
gland health.
But men from phase II clinical trial 8 years
after receiving the
RISUG had healthy prostate
[25]
.
10. Conclusions
Today the RISUG is under extensive research and
development and in clinical phase
III trial in India. The
conventional hormonal contraceptives produce numerous
side
effects on their long term use. The non-hormonal male
contraceptive RISUG provides effective contraception
without producing any type of serious adverse reactions. In
addition to contraceptive activity it is proposed that the drug
may be having anti-
HIV activity. Thus RISUG might be a
potential non-hormonal contraceptive in upcoming years.
Conflict of interest statement
We declare that we have no conflict of interest statement.
HIV-1(gp120)
RISUG
interaction with cell
suface HSPG
accomulation of
viruses cell surface
RISUG
CD4 helper cell
CD4/gp120 interaction
Fusion with cell
infected cell with HIV
Cell death
162
Vikas Thakur et al./ Asian Pacific Journal of Reproduction (2013)159-162
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RISUG a polyelectrolytic hydrogel (styrene maleic anhydride and dimethyl sulfoxide) has proven to be efficacious as a contraceptive for a long term when injected into the lumen of vas deferens. Currently it is in advanced phase III clinical trials in India. Present investigation analyzes the swelling characteristics of RISUG hydrogel in different pH buffers and various biological fluids to understand its retention in the vas deferens as reported in previous studies. Significant variation in degree of swelling and equilibrium swelling ratio with transformation of Fickian to non-Fickian mode of diffusion was observed with increased pH. This might be due to ionization of carboxylic groups at high pH resulting in increased electrostatic repulsive force and high osmotic pressure inside the hydrogel network affecting its physical cross-linking and increases the free volume. Conversely, at low pH the dissociation of carboxylic group is limited making the hydrogel more stable. Interaction with various biomolecules present in various biological fluids was also studied. SEM, AFM and FTIR were used to analyze the topological and structural parameters of the polymer in different mediums. Loosening of structure and increasing porosity with significant adsorption of various biomolecules was observed. AFM revealed a significant change in overall roughness of polymer surface on interaction with different biological fluids. These observations suggest that the swelling and increased roughness will lead to increased resistance to sperm movement in the vas deferens.
Article
Earlier studies on the rat and the monkey had demonstrated that an injection of styrene maleic anhydride (SMA) in a solvent vehicle of dimethyl sulphoxide (DMSO) into the lumen of the vas deferens is toxicologically safe and has contraceptive action. Phase I clinical trial was therefore undertaken on 38 male volunteers giving varying doses of SMA, ranging between 5 mg and 140 mg, into each vas deferens. A dose of 70 mg is the predicted therapeutic dose based on animal data. That the compound is within the vas deferens lumen during the period of the safety assessment is inferred from the effect on the spermatozoa count in ejaculates which reach azoospermic levels in the higher dose ranges. The treatment is well tolerated with only minimal side effects in a few cases and no long-term adverse effects.
Article
Following up on an earlier clinical trial demonstrating the safety of an intra-vas deferens injection of a contraceptive drug named Risug, comprised of styrene maleic anhydride (SMA) in a solvent vehicle of dimethylsulphoxide (DMSO), a study to assess the contraceptive effectiveness of a specific dose (60 mg) of SMA bilaterally was planned and implemented. Male subjects and their wives with normal reproductive profiles were the volunteer subjects. The wives were not using any contraceptives. The results reconfirm the safety and show that for a period of at least 1 year, the treatment leads to azoospermia in the male and gives pregnancy protection. PIP A Phase I clinical trial documented the safety of an intra-vas deferens injection of a contraceptive agent (Risug) containing up to 140 mg of styrene maleic anhydride (SMA) in a solvent vehicle of dimethylsulfoxide. This Phase II study sought to determine whether a single injection of a fixed dose of SMA into the lumen of the vas deferens controls fertility for a period of at least 12 months. 12 male subjects whose wives were not using a contraceptive method were administered 60 mg of SMA bilaterally. This regimen produced sustained azoospermia in all 12 subjects, with no changes in other parameters over the course of the 12-month study period. Spermatozoa all along the length of the vas deferens appeared to be inactivated immediately following injection. No pregnancies were reported. The findings confirm the safety of this method and indicate that the treatment leads to azoospermia for at least 1 year.
Article
A copolymer of styrene and maleic anhydride (SMA) was dissolved in dimethyl sulphoxide (DMSO) and injected into the lumen of the vas deferens of rats. The polymer was retained in the lumen for a period of more than 90 days. Sodium bicarbonate (10%), pH 8.9, was used to flush the polymeric material from the vas deferens lumen. The reversibility and patency of the vas deferens was thus obtained. Sodium bicarbonate proved to be an effective alternative to dimethyl sulphoxide for reversal.
Article
The feasibility of a spacing method for contraception, using Styrene Maleic Anhydride (SMA) as a vas occlusive agent, has been assessed in male langur monkeys. The vas deferens of 6 animals were occluded with 60 mg SMA in 120 microL DMSO. After 150 days, the occlusion was reversed by a technique which involved palpation, percutaneous electrical stimulation, forced vibratory movement, suprapubic percussion and per-rectal digital massage of the vas segments. The vas deferens were then re-occluded with SMA and reversed by the non-invasive method after three consecutive azoospermic samples. The second vas occlusion resulted in uniform azoospermia after the third ejaculation and reversal caused the reappearance of spermatozoa in the semen to severe oligozoospermic levels in the first two ejaculations and rising to normospermia in the subsequent ejaculations. Ultrastructure of the spermatozoa by SEM and TEM and sperm function tests revealed that the spermatozoa had recovered normal morphology. Vas morphology also regained a normal pseudostratified columnar epithelium containing basal and principal cells. The results suggest that the SMA-based spacing technique for male contraception could be extrapolated to the human by use of no-scalpel injection and non-invasive reversal.