Uses of of N-acetyl Cysteine in Medicine, obstetrics, gynecology and infertility

1. ABOUBAKR ELNASHAR

2. Chemistry and pharmacokinetics
Acetylated variant of the amino acid L-cysteine,
An excellent source of sulfhydryl groups
(Ziment, 1988).
A thiol (sulfhydryl-containing) compound
Absorption: rapidly from GIT
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3. Peak concentrations in the plasma:
in less than one hour
(Gregory, 1998).
Plasma half-life of free NAC:
2.15 hours.
No NAC is detectable 10-12 hours post-
administration.
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4. Mechanisms of action
The beneficial effects of NAC are a result of its
ability to
1. Reduce extra-cellular cystine to cysteine
2. Be a source of SH groups: so
stimulate glutathione synthesis,
enhance glutathione-s-transferase activity,
promote detoxification, and
act directly on reactive oxidant radicals
(De Vries et al., 1993).
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5. A. Hormonal
A significant fall in
testosterone levels and
FAI
(Fulghesu, el at 2002).
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6. B. Metabolic:
1. Antioxidant:
in non-insulin dependent diabetic patients (1.2 gm for
1 month) significantly reduced intra-erythrocyte
GSH disulfide (GSSG) levels and the GSH: GSSG
ratio
prevent endothelial damage after oxidative stress
(De Mattia, et al., 1998).
preserve vascular integrity
(Sekhon et al. 2003)
protect against focal ischemia.
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7. 2. Insulin sensitizer:
Increase peripheral insulin sensitivity, whereas the
hepatic insulin extraction was unaffected. NAC
improves insulin sensitivity in women with PCOS
(Moghetti et al., 2000).
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8. C. Biological effects:
Antiapoptotic
(Odetti et al., 2003).
Anticytokines (inhibit proinflammatory
cytokine release)
(Lappas et al. 2003)
Inhibition of
phosopholipid metabolism&
Protease activity.
NAC may exert the same effects at the
ovarian level which may be important in
inducing ovulation
Mucolytic.
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9. ABOUBAKR ELNASHAR

10. A. Medical
(1) Respiratory: -mucolytic
(2) HIV: -enhances the immune response of
peripheral blood T cells.
(3) Cancer: - Chemo-preventive agent.
(4) Heart disease: It protects against ischemic
and reperfusion damage
(5) Influenza: Reduces symptomatology (Deflora et
al., 1997)
(6) Cigarette smoking: inhibit cigarette smoking
(Rogers et al 1986).
(7) Acetaminophen overdose: The antidote of
choice (Gregory et al., 1998).
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11. B. In obstetrics
1)Habitual abortion
2)Gestational diabetes
3)Pre-eclampsia
4)To improve the outcome of preterm deliveries
associated with inflammation
5. During labor: prevents the oxidative stress and
change in hepatic GSSG that occurs in the fetal –
neonatal transition
C. In Gynecology
1.Survival factor in female germ cell, and other cells of
the ovarian cortex
2.Idiopathic oligospermia
3. In vitro maturation (IVM)
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12. D). Infertility
1. PCOS:
•NAC plus CC
effective , inexpensive, safe, tolerable adjuvant even
in the absence of insulin resistance
2. CC R PCOS:
•NAC plus CC
NAC 1.2 gm/ day with CC 100mg/day for 5 days.
Ovulation rate in 49.3 %
NAC plus HMG
decreases the number of consumed ampoules and
improves PR
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13. 3. Non PCOS undergoing ICSI.
NAC 1.2 gm/day plus CC 50 mg/day.
No significant statistical difference was found
between the 2 groups as regards: fertilization,
pregnancy, abortion rates, oocyte maturity
4. Unexplained infertility
NAC didn’t add to the ovulatory effect of the CC
Evidence suggests that in healthy individuals, NAC
might act as pro-oxidant and might lower the GSH
and increases the amount of oxidized GSH
#NAC is an effective cheap & safe adjuvant to CC in
long standing unexplained infertility undergoing IUI
ABOUBAKR ELNASHAR

14. A. Medical
(1) Respiratory: -
a mucolytic for use in chronic bronchitis, however
clinical results are equivocal
(Miller et al, 1985)
(2) HIV: -
NAC enhances the immune response of peripheral
blood T cells.
NAC blocks the suppression of T cell mitogenesis and
cytokine production by protease inhibitors
(Breithaupt et al., 1996)
protect hematopoietic progenitor cells from
zidovudine (AZT)-induced toxicity
(Gogu et al., 1996).
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15. (3) Cancer: -
Chemo-preventive agent.
Efficient in inhibiting the chemotactic and
invasive activities of the tumor cells of human
melanoma and murine origin melanoma.
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16. (4) Heart disease: -
•It protects against ischemic and reperfusion
damage, and enhance of the effectiveness of
nitroglycerine
•2 mg daily for four weeks followed by 4 gm daily for
four weeks to patients with elevated LP (a): 70%
reduction of LP
(Gavish and Breslow, 1991).
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17. (5) Influenza: -
Reduces symptomatology
(Deflora et al., 1997)
(6) Cigarette smoking: -
NAC inhibited cigarette smoking
(Rogers et al 1986).
Oral administration of NAC
(200 mg three times per day)
(7) Acetaminophen overdose: -
NAC is the antidote of choice
(Gregory et al., 1998).
ABOUBAKR ELNASHAR

18. B. In obstetrics
•Many pregnancy complications and birth defects
have been linked to oxidative stress and free
radical damage to the mother and fetus.
•Increased lipid peroxidation and reduced anti-
oxidant activity are associated with pregnancy
complications.
•The glutathione anti oxidant system has been
shown to play an important protective role in
reducing effects of oxidative stress in pregnancy
and childbirth.
•Several complications during pregnancy have
been linked to poor glutathion level
(Datta et al., 1994)
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19. 1) Habitual abortion
Women with habitual abortion are found to have
significantly lower levels of antioxidants like GSH,
vitamin E, A and beta carotene and higher levels of
lipid peroxidation
(Simsek et al., 1998).
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20. 3) Pre-eclampsia :
•Women with pre-eclampsia have antioxidant
activity that is markedly reduced by late gestation.
•Enhanced superoxide generation and impaired
glutathione metabolism may be involved in the
cause and outcome of pre-eclampsia
(Kharb, 2000).
•Supplementation with antioxidants is beneficial in
prevention of pre-eclampsia
(Knapen et al., 1998).
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21. 2) Gestational diabetes:-
Mothers with diabetes have abnormally high blood
sugar levels, which means that their embryos also
have high b1ood sugar levels. This excess blood
sugar produces damaging of free radicals in the
blood faster than antioxidants can eliminate them in
the under developed embryo, a process known as
oxidative stress.
Even mild oxidative stress can cause birth defects.
Oxidative stress also disrupts the expression of
specific genes in the embryos and may be a more
common cause of birth defects in the babies of
women with and without diabetes than is currently
appreciated
(Mengola et al., 1995).
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22. Hyperglycemia induced embryonic malformations
have been linked to an increase in free radical
formation and depletion of intracellular glutathione
(GSH) in embryonic tissues.
An excess of reactive oxygen species (ROS) has
been associated with the increased rate of
congenital malformation in experimental diabetic
pregnancy.
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23. Antioxidants may, hence be critical to prevent birth
defects in babies of women with diabetes.
Glutathione is the main defense against free radicals
in embryonic tissues, as it is in adult tissues.
Treatment with dietary GSH has a protective effect on
kidney function in diabetes, and suggests that dietary
GSH treatment may reduce diabetic complications
(Ueno et al., 2002).
Combined antioxidative treatment with NAC, vitamins
E and C has also been shown to decrease fetal
malformation rate and improve the outcome of the
pregnancy by reducing oxygen radical- related tissue
damage
(Cederberg et al., 2001).
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24. 4)To improve the outcome of preterm deliveries
associated with inflammation
Free radicals generated in large quantities during
inflammatory response are associated with maternal
and fetal GSH depletion, compromising the fetus.
Selective inactivation of free radicals with NAC,
glutathione precursors, has been found to improve
the outcome of preterm deliveries associated with
inflammation
(Buhimschi et al., 2003).
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25. 5. Cystic fibrosis
GSH is the most important antioxidant in the body
and a powerful mucolytic. Glutathione is also an
important regulator of inflammation.
This suggests that supplementation of the mother
with GSH improve GSH deficit that may start to
develop in the immune system cells of her fetus
and may lessen or even prevent the manifestations
of cystic fibrosis
(Utah Valley Institute).
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26. (6) During labor:
Animal studies found that oral administration of NAC
to the pregnant women partially prevents the
oxidative stress and change in hepatic GSSG that
occurs in the fetal – neonatal transition
(Sastre et al., 1994).
ABOUBAKR ELNASHAR

27. C. In Gynecology
(1)Survival factor in both male and female germ cell,
and also in other cell types of the ovarian cortex :
Ovarian tissue survival could be improved in the
short-term cultures by suppressing apoptosis
(Ahola, et al., 1999).
NAC may suppress cell death by protecting the cells
from increased levels of ROS, which have been
shown to lead to cell death.
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28. (2) Idiopathic oligospermia :
The antioxidant NAC and testosterone significantly inhibited
apoptosis in human testicular germ cells in vitro, thus
indicating the importance of antioxidative mechanisms for
germ cell survival in the seminiferous tubules during
spermatogenesis.
NAC is also suggested as a possible new therapeutic factor
in some men with idiopathic oligospermia
(Erkkila et al, .1997).
Sperm concentration increased in oligozoospermic men (7.4
to 12.5 million/ml)
(Comhaire et al, 2002)
Treatment significantly reduced ROS
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29. 3. In vitro maturation (IVM):
The chance of a successful IVF of egg cell was
dependant on activity of the selenium – containing
antioxidant enzyme glutathione peroxidase (GSHP)
in follicular fluid.
Supplementation of IVM medium with cystaine and
beta-mercapto-ethanol was found to increase
intracellular GSH content in oocytes, decrease in
peroxide level within oocytes and improve embryo
development and quality
(De Matos et al., 2002).
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30. 1. PCOS
NAC: 1.8 g/d for 5-6 W
Fulghesu et al (2002)
1. In hyperinsulinemic subjects:
Significant increase in insulin sensitivity
Significant reduction in insulin levels and secretion
after OGTT.
Significant reduction in T & FAI
2. In normoinsulinemie & placebo-treated subjects:
No significant changes
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31. Okman & Kucuk (2002)
N-acetyl-cysteine 0.6 mg t.i.d orally for 4 Weeks
Hormonal:
Significant reduction in T, DHEAS, and homocysteine.
Significant increase in SHBG
No significant change in FSH, LH, and E levels
Metabolic:
Significant reduction in basal insulin levels (significant
difference in HOMA-IR)
Significant decrease of cholesterol, triglyceride, and
LDL Significant increase in HDL.
No significant variation in fasting glucose
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32. ABOUBAKR ELNASHAR

33. A. Induction of ovulation
1. CC R PCOS
(CC 100mg for at least 3 cycles)
 NAC alone
(Elnashar et al ,2004)
Group I:
metformin (500 mg/ tablet) for 6 weeks from the first day of
the cycle in a dose 1500 mg/day orally.
Group II:
acetyl cysteine (SEDICO, SAE) (200 mg/sachet) 1.8 gm, orally,
on 3 divided doses (3 sachets /dose) for 6 weeks from the
first day of cycle. ABOUBAKR ELNASHAR

34. Metformin alone is effective drug in inducing
ovulation in C.C resistant PCOS while
NAC alone is not.
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35. •NAC plus CC
Group I:
NAC 1.2 gm/ day with CC 100mg/day for 5 days
Group II:
100 mg/day CC for 5 days starting at day 3 of the
cycle
(Rizk et al,2004)
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36. Results:
The combination of CC and NAC significantly
increased both ovulation and pregnancy rate in
women with CC resistant PCOS (49.3 % Vs 1.3 %
and 21.3 % Vs 0% respectively).
The NAC as an adjuvant to CC was more effective
than placebo for CC-resistant patients with PCOS.
It is safe and well tolerated.
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37. ABOUBAKR ELNASHAR

38. These results are due to
1.Reduction of both insulin levels and peripheral
insulin resistance
2. Reduction of testosterone
(Fulghesu et al., 2002).
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39. •NAC plus HMG
N acetylcystine with HMG is cost effective as it
decreases the number of consumed ampoules and
improves the pregnancy rate (18.7 Vs 23.8%)
(Metawie, 2005)
.
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40. 2. PCOS:
NAC is effective , inexpensive, safe, tolerable
adjuvant to the CC for ovulation induction in PCOS
patients even in the absence of insulin resistance
(Badawy, Elnashar, Totongy, 2005)
CC group
(N=470)
CC+NAC group
(N=470) P
Ovulation
Serum E2 (pg/ml)
Serum progesterone (ng/ml)
Endometrial thickness (mm)
Pregnancy
20 (4.3%)
110.0 ± 30.4
2.3 ± 1.2
4.3 ± 1.2
0
245 (52.1%)
452.1 ± 290.3
6.4 ± 2.3
7.8 ± 3.1
54 (11.4%)
S
S
S
S
S
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41. IR group
(N=260)
Non IR group
(N=210) P
Ovulation
Number of follicles
Serum E2 (pg/ml)
Serum progesterone (ng/ml)
Endometrial thickness (mm)
Pregnancy
129 (49.6%)
3.1 ± 0.89
468.0 ± 280.4
7.3 ± 1.2
8.3 ± 1.2
30(11.5%)
116 (47.3%)
3.2 ± 0.93
452.1 ± 290.3
6.4 ± 2.3
7.8 ± 3.1
24 (11.4%)
NS
NS
NS
NS
NS
NS
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42. 3. Non PCOS undergoing ICSI.
•Group A: CC 50 mg/day only
Group B: NAC 1.2 gm/day plus CC 50 mg/day.
No significant statistical difference was found
between the 2 groups as regards: fertilization,
pregnancy, abortion rates, oocyte maturity
(Toppozada et al, 2004)
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43. •20 infertile patients undergoing ICSI cycles:
NAC, 1,200 mg/day from day 3-7 of the cycle with
CC (100 mg /day) HCG (10,000 IU) was given when
leading follicle (s) were >/= 18 mm followed by ICSI.
Improved response to CC stimulation with NAC co-
treatment was evidenced by a number of mature
follicles
Clinical pregnancy was achieved in 3 cycles.
(Rizk et al, 2005)
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44. B. Unexplained infertility
The standard investigations of infertility are normal
(Semen analysis, Midluteal progesterone, HSG)
•NAC didn’t add to the ovulatory effect of the CC
(Badawy, Elnashar, Totongy, 2005)
Evidence suggests that healthy individuals, NAC might act as
pro-oxidant and might lower the GSH and increases the
amount of oxidized GSH
(Kleinveld et al. 1992)
CC group
(n=404)
CC+NAC
group
(n=400 )
P
Number of follicles
Serum E2 (pg/ml)
Serum progesterone (ng/ml)
Endometrial thickness (mm)
Pregnancy
3.1 ± 0.88
398.0 ± 230.4
8.3 ± 1.2
8.3 ± 2.2
90 (22.2%)
3.2 ± 0.97
452.1 ± 290.3
8.4 ± 2.3
8.8 ± 3.1
108 (27%)
NS
NS
NS
NS
NS
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45. •NAC is an effective cheap & safe adjuvant to CC in
long standing unexplained infertility undergoing IUI
(Rezik et al, 2004)
It improves pregnancy rates significantly in IUI cycles.
The multiple biological effects of NAC may explain its
ovulation induction prosperities
Clinical pregnancy rate: NAC+CC/IUI: 35%
CC/IUI: 22%
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46. Drug interactions
1. Concomitant oral administration of charcoal and
NAC is not recommended, {charcoal might
interfere with absorption of NAC}
(Renzi et al., 1985).
2. NAC enhance the blood pressure-lowering effects
of angiotensin-converting enzyme (ACE) inhibitors
(Marchetti et al., 1999).
3. The pharmacokinetics of NAC is altered in
patients with chronic liver disease. In general, these
individuals tend to have increased serum
concentrations and decreased ability to clear NAC
from the blood stream following an intravenous dose
(Jones et al., 1997).
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47. Side effects
 NAC is generally safe & well tolerated even in high doses .
 The most common side effects are :
1-Nausea & vomiting.
2-Diarrhea.
3- Infrequently, anaphylactic reaction.
 NAC has been safely administered during pregnancy. In
general there are no adequate studies of NAC administration
and pregnancy, so it should only used when clearly indicated
(Threlkeld etal., 1997).
 Contraindicated in active peptic ulcer disease.
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48. NAC is effective adjuvant to CC or HMG in
PCOS &
CC R PCOS
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49. ABOUBAKR ELNASHAR