Sildenafil Citrate ( Viagra) Effect on the Pattern of Controlled Hypotension Induced by Sodium Nitroprusside Or Nitroglycerin M

The Egyptian Journal of Hospital Medicine Vol., 7 : 76 – 86 June 2002 I.S.S.N: 12084

Sildenafil Citrate ( Viagra) effect on the pattern of controlled hypotension induced by sodium nitroprusside or nitroglycerin

Mona M. Radwan and Nemat El Baz Mohamed Department of Pharmacology, Faculty of Medicine for Girls Al-Azhar University, Cairo

Abstract: Oral sildenafil Citrate (viagra) is an effective treatment for erectile dysfunction (ED) . There are reports of serious hypotension when sildenafil citrate is given to patients taking certain vasodilators . This study was designed to assess the effects of sildenafil citrate (viagra) therapy on the dose, efficacy and safty of I.V. infusion of nitrovasodilators; sodium nitroprusside or nitroglycerin, to induce controlled "delibrate" hypotension (55-60 mmHg). Sodium nitroprusside (SNP; l / ug/kg/min) or nitroglycerin (NTG. 2ug/kg/min.) was intravenously given to induce hypotension in control cats and in cats treated with sildenafil (l.9 mg/kg) single oral dose. Some heamodynamic variables; mean arterial blood pressure "MAP" and "ECG" pattern, were monitored. In control groups it was found that, ( SNP) infusion achieved a rapid induction of controlled hypotension accompanied by reflex hypertension after drug infusion discontinuation. However, (NTG) infusion failed to decrease the (MAP) to the target level, and upon discontinuation of its infusion, return of arterial blood pressure to control values, was moderately slower. Comparison between the effect of the two drugs revealed a significant difference in mean arterial blood pressure after infusion. Treatment with sildenafil citrate (viagra) , augmented the (MAP) reduction caused by (SNP), and improved the lack of potency of (NTG) induced hypotension . Comparison between the effect of the two drugs revealed a significant difference during drug infusion, and after drug infusion discontinuation. Doses of (SNP) or (NTG) required to induce delibrate hypotension in groups treated with sildenafil were decreased when compared to that in control groups. Sodium nitroprusside (SNP) infusion induced increase in the mean heart rate (HR) without ECG changes in control or treated groups. Sildenafil citrate treatment increased significantly the initial HR in comparison to control group. In contrast, nitroglycerin (NTG) infusion, did not change significantly the (HR) in control group. However, in sildenafil citrate treated group, (NTG) infusion induced significant increase in the HR throughout the study , and there was also changes in PR QRS, and QT interval in one case.

Introduction: Induced "controlled, deliberate" technique of induced hypotension. hypotension, as an adjunct to anest - Sodium nitroprusside (SNP) and hesia, is frequently used to minimize nitroglycerin (NTG) have been used to blood loss and to improve the quality of induce hypotension because they are the surgical field (Sivarajan et al., rapid in onset and have short duration l980). Cottrell et al. (l980) reported of action ( Friederich and Butterworth, that, most reviews suggests an MAP of 1995) . The vasodilator effect of both 50-60 mmHg, as the lower limit of (SNP) and (NTG) is mediated by a blood pressure while using the release of nitric oxide (NO), which

Refree : Prof ; Dr. Raga Abaza 76 Sildenafil Citrate ( Viagra) effectć..

diffuses into vascular smooth muscle controlled hypotension. So, this study and mediates vasodilation by was designed to evaluate the effects of stimulating soluble guanylate cyclase to sildenafil citrate treatment on some produce guanosine 3'-5 cyclic (SNP) and (NTG) heamodynamics in monophosphate (cGMP) , thereby cats; mean arterial blood pressure causing smooth muscle relaxation (MAP) and ECG pattern. (Ignarro et al. l983 and Ignarro, l989) . cGMP and cAMP are inactivated by Materials And Methods: phosphodiesterases by hydrolytic cleav Drugs used in this study were: -age of the 3'-ribosephosphate bond. sildenafil citrate (Viagra 50 mg tablet; More than nine different families and Pfizer, Egypt), sodium Nitroprusside subfamilies of phosphodiesterases; dihydrate (Nipride 50 mg vial ; phosphodiesterase PDE2, PDE3. Warwick U.K.), and Nitroglycerin PDE4, PDE5 that differ in their spec - (Tridil 5 mg /ml vial, Merck pharma). ificity, have been identified ( Kuthe et Doses corresponding to human al.,l999). Beavo, (l995) reported that therapeutic doses were calculated type 5 phosphodiesterase (PDE5) is according to the method reported by abundant in human circulation. Paget and Barnes (l964) and statistical The introduction of effective analysis of the data was performed by oral treatment of erectile dysfunction student "t" test of significance. (ED) by means of agents with a Mean arterial pressure (MAP) = peripheral (sildenafil) or central diastolic + (systol-diastol/3) mmHg. (apomorphine) site of action has Heart rate ( beats/min.) was also occurred as a result of active research calculated from the recorded ECG. on the mechanisms of erection (Anderson, l993, Anderson and Methods: Wagner,l995, McKenna, l998). Four groups of cats, each of six Sildenafil citrate "viagra", which has animals were used. The first group was been recently introduced into clinical treated with intravenous infusion practice for the treatment of erectile (I.V.I.) of sodium nitroprusside (l dysfunction, is a selective inhibitor of ug/kg/min.), and the second group type 5 phosphodierterase (Jeremy et with I.V.I. of nitroglycerin (2 al.,l997) . After oral administration, ug/kg/min.) Both infusions were Moreland, et al. (l999) found that titrated as needed to achieve the target blood sildenafil level peaked in 60-120 (MAP) 55-60 mmHg. Heamodynamic minutes, and its plasma half-life was informations collected for both drugs estimated to be 4-4.5 hours. The effects included MAP ; before, during , and of sildenafil are in part mediated by after drug infusion discontinuation, drug enhancing the action of nitric oxide and requirement ( ug/kg), and ECG ( lead II) accompanied by a fall in systemic changes. These two groups were blood pressure (Mahmud et al., 200l). considered as control groups . The blood pressure-lowering effect of The third and fourth groups were sildenafil did not differ significantly in treated with sildenafil citrate " viagra" the normotensive and hypertensive (l.9 mg/kg) single oral dose one hour patients (Vardi et al., 2002). before experiment. Animals in the third Therefore , there may be a group were given (SNP), and the fourth potential interaction between sildenafil group were given (NTG), in the same and (NO) donors, used for induction of way mentioned in the first and second

Mona M. Radwan & Nemat El Baz Mohamed

groups. The same parameters mentioned failed to induce the target decrease in above were recorded and compared the MAP ( Table l , Figs. 1,3). Slow with that of the control groups. repound of blood pressure without reflex hypertension after (NTG) Results: infusion discontinuation, was observed . Effect on mean arterial pressure The average dose required to induce (MAP): the decrease in blood pressure was 200- Sodium nitroprusside (SNP) was 400 ug/kg. Table 1 and Fig. 1 shows the successful and rapid in achieving a comparison between (SNP) and (NTG) significant decrease in the MAP to the effects on mean arterial pressure . target level (55-60 mmHg) from base Sildenafil citrate "viagra" (l.9 line values as shown in (Table l , Figs. mg/kg) oral treatment, augmented 1,2). Rapid return of blood pressure significantly the decrease in MAP with reflex increase was observed after induced by (SNP) or (NTG) infusion its infusion discontinuation. The (Table 2 , Figs. 4,5,6). Fig. (7) shows average dose required to induce the the mean arterial pressure of (SNP) and decrease in blood pressure was 300-350 (NTG) in control and sildenafil treated ug/kg . On the other hand (NTG) groups. infusion showed a slow decrease and

Table (1): Mean arterial pressure (MAP) mmHg ± SEM values before, during, and after discontinuation of SNP (1ug/kg/min.) or NTG (2 ug/ kg/ min.) infusion, in control cats. Mean arterial pressure (MAP) mmHg ± SEM Drug Group Before During infusion After infusion requirement to infusio 1 min. 2 min. 3 min. 2 min. 4 min. 8 min. induce n hypotension SNP Mean 82.5 55.5* 54.75* 53.75* 61.75* 81.25 90.5* 300-350 ug/kg ± SEM 0.96 1.85 0.48 0.48 1.11 2.75 1.26

NTG Mean 84 73.25*° 68*° 63.25*° 67.75*° 71.5*° 75.75*° 200-400 ug/kg ± SEM 0.82 1.44 1.1 1.25 1.32 1.32 1.49

* Significant difference between the MAP values caused by SNP or NTG in comparison to the initial values. ° Significant difference between the MAP caused by NTG when compared to that caused by SNP.

Sildenafil Citrate ( Viagra) effectć..

Figure ( 1): Mean arterial pressure (MAP) mmHg ± SEM values before, during, and after discontinuation of SNP ( 1 ug/ kg/ min.) or NTG ( 2 ug/ kg/ min.) infusion, in control cats

100 90 80 70 60 50 40 30 20 10 0 b d e u D D A A A fo r u u ft ft ft r in ri ri e e e e g n n r r r i g g in in in n in i i f f f f f n n . . . u . f. f. ( ( ( si ( ( ( 2 4 8 o 1 n 2 3 m m m m m m i i i i i n n n n n in ) ) ) ) ) )

Mean NTG Mean SNP

90 mm Hg

80 mm Hg 9 0 mm Hg

8 0 mm Hg

Fig. (2) : Controlled hypotension induced by Fig. (3) : Controlled hypotension induced by sodium nitropresside (SNP) (l µg/kg/min.) nitroglycerin (NTG) ( 2 µg/kg/min.) infusion in control cats. infusion in control cats.

Mona M. Radwan & Nemat El Baz Mohamed

Table (2): Mean arterial pressure (MAP) mmHg ± SEM values before, during, and after discontinuation of SNP (1ug/kg/min.) or NTG (2 ug/ kg/ min.) infusion, in sildenafil citrate —viagra“ (1.9mg/kg) treated cats. Mean arterial pressure (MAP) mmHg ± SEM Drug Group Before During After drug discontinuation requirement to infusion infusion 2 min. 4 min. 8 min. induce 1 min. hypotension

SNP Mean 82.25 23.5* 63.25* 81.75 97.5* 60-70 ug/kg ± SEM 1.18 0.87 2.25 2.25 0.87

NTG Mean 84.5 56*° 62* 71.25*° 80.25*° 100-200ug/kg ± SEM 1.26 0.58 1.08 1.25 0.63 * Significant difference between the MAP values caused by SNP or NTG in comparison to the initial values. ° Significant difference between the MAP caused by NTG when compared to that caused by SNP

Fig. (4): Mean arterial pressure (MAP) mmHg ± SEM values before, during, and after discontinuation of SNP (1 ug/ kg/ min.) or NTG (2 ug/ kg/ min.) infusion, in sildenafil citrate "viagra"(1.9mg/kg) treated cats

120 100 80 60 Mean NTG 40 Mean SNP 20 0

) ) ) ) on in in in in si u m 2m m m f (1 ( (4 (8 in . f. . . e f n f f r in i in in fo g er g r e n t n te b ri f ri f u A u A d D

Sildenafil Citrate ( Viagra) effectć..

90 mm Hg

80 mm Hg

Fig. (5): Controlled hypotension induced by ( SNP) ( lug/kg/min.) infusion in sildenafil citrate "viagra" ( l.9 mg/kg) single oral dose treated cats.

90 mm Hg

80 mm Hg

Fig. (6) : Controlled hypotension induced by (NTG) ( 2ug.kg/min.) infusion in sildenafil citrate "Viagra" (l.9 mg/kg) single oral dose treated cats.

Fig. (7): Mean arterial pressure (MAP) mmHg ± SEM values before, during, and after discontinuation of SNP ( 1 ug/ kg/ min.) or NTG ( 2 ug/ kg/ min.) infusion, in control and sildenafil citrate ( 1.9mg/kg) pretreated cats:

120 100 80 60 40 20 0

n ) ) ) ) ) ) io in in in in in in us m 2m m m m m f ( 1 ( ( 3 ( 2 ( 4 ( 8 in . f. . . . . e nf in nf nf nf nf or i g i i i i ef g n g er er er b in ri in ft ft ft ur u ur A A A d D D

Mean NTG (control Mean SNP (control) Mean SNP (pretreated) Mean NTG (pretreated)

Mona M. Radwan & Nemat El Baz Mohamed

Effect on heart rate (HR) and ECG (HR) of (SNP ) and (NTG) groups . In pattern (SNP) group there was no change in In control groups (SNP) infusion induced significant reflex increase in (HR) throughout the infusion. (HR), in contrast to (NTG) infusion However, in (NTG) group sildenafil which caused insignificant change in (HR). Normal PR, QRS, and ST pattern treatment caused significant increase were recorded in both groups (Table 3, in (HR) (Table 3, Fig. 8 ). There was Fig. 8). Sildenafil citrate treatment also changes in PR , QRS and QT caused significant increase in the initial intervals in one case. Table (3): Effect of treatment with Sildenafil citrate (viagra) (1.9mg/kg) on mean heart rate (HR) beats/min, ± SEM caused by SNP (1ug/kg/min) or NTG (2ug/kg/min) infusion.

Groups Mean HR ± SEM Changes Initial during target after drug Arterial pressure discontinuation

Control SNP 300 ± 7.1 430 ± 7.1* 375 ± 7.1* Normal RR, QRS, ST NTG 300 ± 7.1 310 ± 7.1° 300 ± 7.1° Normal RR, QRS, ST Sildenafil treated SNP 335 ± 7.1 • 430 ± 7.1* 375 ± 7.1* Normal RR, QRS, ST • NTG 325 ± 7.1 355 ± 7.1*°• 345 ± 7.1°• PR (0.06sec), QRS (0.04sec), prolonged QT interval in one case *Significant difference between the mean HR values caused by SNP or NTG in comparison to the initial values. ° Significant difference between the mean HR values caused by NTG when compared to that caused by SNP.

• Significant difference in mean HR of cats in treated groups when compaired to that in control groups

Fig. (8)Effect of treatment with Sild enafil citrate (viagra) (1.9mg/kg) on mean heart rate (HR) beats/min, ± SEM caused by SNP (1ug/kg/min ) or NTG (2ug/kg/min) infusion.: 500

400

300 200

100 0 Initial HR HR durinHg Rta rdguerti nagr taerrti.a Pl rP esrse.mure. HR after drug discont. Control SNP Control NTG Sild. Pretreat.SNP Sild. Pretreat. NTG

Sildenafil Citrate ( Viagra) effectć..

Discussion: on (SNP) and (NTG) induced hypote - Nitric oxide doners; (SNP) and nsive effect. The results demonstrated (NTG), are often used to induce that, sildenafil treatment augmented the deliberate hypotension. However, each effect of (SNP) infusion and caused drug alone is associated with its own life-threatening hypotension within one limitations, such as cyanide poisoning minute. In contrast, the lack of potency with (SNP) large doses (Friederich and of (NTG) infusion, was significantly Butterworth, l995), and 1ack of potency enhanced by sildenafil. The dose with (NTG) (Porter et al., l988). required to induce hypoten -sion by This study demonstrated that both drugs was reduced. (SNP) infusion was successful in The most common adverse events achieving the target decrease in (MAP). of sildenafil such as headache and However this effect was accompanied hypotension, results from its vasodila - by rebound hypertension after abrupt ting properties (Rosenkranz and discontinuation of its infusion. In Erdmann, 200l) . The authors reported contrast, (NTG) infusion failed to that, the concomitant use of sildenafil decrease the blood pressure to the target and organic nitrates is contraindicated level, and upon discontinuation of its because it may lead to a potentiation of infusion, return of arterial pressure to the decrease in blood pressure and control values was moderately slower. cause life-threatening hypotension. This results shows conformity with the Sakuma et al. (2002) reported also that, study of Yaster et al. (l986) who the relaxant effect of the vasodilators reported that (SNP) was the agent of with an (NO) donor property, was choice for the reliable and sustained significantly enhanced, and the cGMP induction of deliberate hypotension, level of the tissue was elevated, after however, (NTG) was ineffective as an adding sildenafil . Sildenafil alone agent to produce rapid predictable and increased the plasma cGMP concentr - sustained decrease in arterial pressure ations (37%-40% over the basal) which below 55 mmHg. The authors was augmented by (SNP) (60 %) over attributed the effect of (SNP) to its the value achieved by sildenafil alone action on both resistance and (Yoo et al., 2002). A synergistic capacitance vessels, whereas (NTG) is interaction between (NTG) and thought to affect primarily the venous sildenafil was also observed in consci - capacitance vessel. ous chronically instrumented dogs by Sildenafil citrate "viagra"; Schwemmer et al. (200l) . The intera - phosphodiesterase type 5-inhibitor, is ction between sildenafil and (NTG) , currently used to treat erectile furthermore, was not affected by the dysfunction (ED) in millions of route of administration of the two patients (Goldstein et al., l998). drugs (Webb et al., 2000). Previously, a synergistic interaction With regards to the effect of between sildenafil and (NO) doners , (SNP) or (NTG) infusion on the ECG of has indeed been demonstrated in cats in the present study, (SNP) isolated human vessels (Medina et exhibited significant reflex increase in al.,2000), in patients with stable angina (HR) of cats in both control and treated (Webb et al., 2000), as well as in isola - groups, whereas sildenafil increased ted rabbit aorta (Wallis et al.,l999). significantly only the initial (HR) in the In the present study, we investi - treated group. In contrast (NTG) gated the effect of sildenafil treatment induced insignificant effect in (HR) of

Mona M. Radwan & Nemat El Baz Mohamed

cots in the control group, while in risk of marked vasodilation unless the sildenafil treated group, (NTG) infusion dose is decreased and hence the increased signifciantly the (HR) potential for cyanide toxicity. In throughout the study . Phillips et al. contrast, the concomitant use of (2000) have demo -nstrated that sildenafil and (NTG) may improve the sildenafil increases the sympathetic decrease in blood pressure caused by neural activity in humans. (NTG) infusion. It is likely that the increase in the initial (HR) of cats induced by sildenafil References: may reflect a positive inotropic effect, 1. Andersson KE (l993): Pharmacology of induced by sildenafil therapy (Yoo et lower Urinary tract smooth muscles and al.,2002). Furthermore this tachycardia Penile erectile tissues. Pharmacol. Rev. can be explained by an acute activation 45: 254 2. Andersson KE. and Wagner G. (l995): of the baroreflex control mechanism, Physiology of penile erection. Physiol. which follows the decrease of blood Rev. 75: 191. pressure and buffers it around the new 3. Beavo JA.(l995): Cyclic nucleotide level of set point (Young et al.,l984). phosphodiesterases: Functional In conclsuion sildenafil citrate implications of multiple isoforms. "viagra', which has been recently Physiol. Rev. 75: 725-48. introduced into clinical practice for 4. Cottrell JE., Gupta B., and Turndorf H. treatment of erectile dysfunction, is a (l980): Induced hypotnesion, anesthesia selective inhibitor of type 5-phospho - and Neurosurgery. Edited by Cottrell diesterase. Sodium nitroprusside (SNP) J.E., Turndorf H. St. Louis, CV Mosby; and nitroglycerine (NTG), are often 386-400. 5. Friederich JA and Butterworth JF used to induce deliberate hypote -nsion (l995): I.V. sodium nitroprusside: (50-60 mmHg). However, each drug is Twenty years and counting . Anesth associated with its own limitat -ions as Analg.; 81 : 152-62. cyanide poisoning with (SNP) large 6. Goldstein I, Lue TF, Padman -Nathan doses, and lack of potency with (NTG). H et al. (l998): Oral sildenafil in the The vasodilator effect of (SNP) or treatment of erectile dysfunction. N. (NTG) is mediated by the release of Engl. J. Med.; 338 : 1397-404 (NO) which mediates vasodilation by ."Abstract". stimulating the production of cGMP . 7. Ignarro LJ (l989): Biological actions Therefore ,there may be a potential and Properties of endothelium-derived interaction between sildenafil and (NO) nitric oxide formed and released from artery and vein. Circ. Res., 65: l-21. doners in the systemic circulation where 8. Ignarro LJ; Burke TM; Wood KS et al. type 5 phosphodiesterase is abundant. (l983): Association between cyclic We observed that, (SNP) induced GMP accumulation and acetylcholine- hypotension was augmented by elicited relaxation on bovine sildenafil, and the lack of potency intrapulmonary artery . J. Pharmacol., (disadvantage) with (NTG) was impro - Exp. Ther., 228: 682-90. ved. The doses of both drugs required to 9. Jeremy JY; Ballard SA and Naylor AM induce deliberate hypotension was et al. (l997): effects of sildenafil, a decreased after sildenafil treatment . type -5cGMP phosphodiesterase So we suggest that the use of inhibitor , and papaverine on cyclic sodium nitroprusside to induce hypote - GMP and cyclic AMP levels in the rabbit corpus cavernosum in vitro. Br. nsion during anesthesia in combination J. Urol. 79: 958-63. with sildenafil can be limited by the

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10. Kuthe A.; Stief CG and Magert H.J. et various coronary vasodilators in al. (l999): Molecular biological isolated porcine coronary artery. Eur. J. characterisation of phosphodiesterases Pharmacol. 22; 437 (3): 155-63. 3 and 5 in human corpus cavernosum 20. Schwemmer M; Bassenge, E.; Stoeter penis [ abstract 405] . Eur Urol. 35 M., et al. (2001): Potentiation of (suppl 2): l02 Abstrract. sildenafil-induced hypotension is 11. Mahmud A; Hennessy M. and Feely J. minimal with nitrates generating a (200l): Effect of sildenafil on blood radical intermediate. J. Cardiovasc. pressure and arterial wave reflection in Pharmacol; 38: 149-55. treated hypertensive men. J. of Human 21. Sivarajan M.; Amory DW; Everett GB hypertension, 15(10): 707-13. et al. (l980): blood pressure, not 12. McKenna KE (l998): Central control of cardiac output, determiens blood loss penile erection, Int. J. Impot. Res. 10 during induced hypotension. Anesth (suppl I): S25 , Abstract. Analg; 59: 203-6. 13. Medina P., Segarra G., Martinez et 22. Vardi Y.; Klein L.; Nssar S. et al. al.(2000): Relaxation induced by (2000): Effects of sildenafil citrate cGMP phosphodiesterase inhibitors (viagra) on blood pressure in sildenafil and Zaprinast in human normotensive and hypertensive men. vessels. Ann. Thorac. Surg.;70: 1327 - Urology, 59 (5): 747-52. 31. 23. Wallis RM, Corbin JD, Francis SH et 14. Moreland RB, Goldstein I, Kin NN et al. (l999): Tissue distribution of al.(1999): Sildenafil citrate, a selective phosphodiesterase, platelet function, phosphodiesterase type 5 inhibior: and the contractile responses of Research and clinical implication in trabeculae corneae and Aortic rings in erectile dysfunction. Trends vitro. Am .J. Cardiol.; 83: 3C-12C. Endocrinol. Metab; 10, 97-l04. 24. -Webb DJ, Muirhead GJ; Wulff M. et. 15. Paget G.E. and Barnes J.M. (l964): al.(2000): Sildenafil citrate potentiates Toxicity test. In : Evaluation of drug the hypotensive effects of nitric oxide activities, pharmacometrics. Edited by donor drugs in male patients with stable Laurence DR and Bacharach AL; Vol. angina. J. Am. Coll. Cardiol.; 36: 25- I; Chap. 6; P. 135; Academic Press; 31. London and New York. 25. -Yaster M., simmons R.S., R.C.P.T. et 16. Phillips B.C.; Kato M., Pesek C.A. et al.(l986): A comparison of al. (2000): Sympathetic activation by Nitroglycerin and Nitroprusside for sildenafil. Circulation; 102: 2068 -73. inducing hypotension in children: A 17. Porter SS, Asher M, and Fox DK double-blind study. Anesth. 65: 175- (l988): Comparison of intravenous l79. nitroprusside, nitroprusside-captopril, 26. Yoo K.Y., Kim . H.S., Moon J. et al. and nitroglycerin for deliberate (2002): Sildenafil( Viagra) Augments hypotension during posterior spine sodium nitroprusside induced. But not fusion in adults. J. Clin. Anesth.; I: 87- Nitroglycerin-induced hypotension in 95. dogs. Anesth. Analg.; 94: l505-9. 18. Rosenkranz S. and Erdmann E.(200l): 27. Young M.A.; Watson R.D.S. and Littler Interaction between sildenafil and W .A. (l984): Baroreflex setting and antihypertensive drugs: What is sensitivity after acute and chronic evidence based? DTsch Med. nicardipine therapy . Clinical Scie; 66, Wochenschr; 126 (41): 1144-9. 233-235. 19. Sakuma I., Akaishi Y., Tomioka H. et al. (2002): Interactions of sildenafil with

Mona M. Radwan & Nemat El Baz Mohamed

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