Brazilian Journal of Anesthesiology
https://bjan-sba.org/article/doi/10.1590/S0034-70942003000200013
Brazilian Journal of Anesthesiology
Special Article

O Conhecimento de diferenças raciais pode evitar reações idiossincrásicas na anestesia?

Could the understanding of racial differences prevent idiosyncratic anesthetic reactions?

Nilton Bezerra do Vale; José Delfino; Lúcio Flávio Bezerra do Vale

http://dx.doi.org/10.1590/S0034-70942003000200013 Braz J Anesthesiol, vol.53, n2, p.258-277, 2003
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Resumo

JUSTIFICATIVA E OBJETIVOS: No campo da variabilidade inter-étnica da resposta de drogas anestésicas e adjuvantes existem várias questões sem resposta. Estamos na iminência de sermos capazes de identificar diferenças raciais herdadas que podem prever a resposta de cada paciente aos anestésicos pelo atual desenvolvimento farmacogenético. CONTEÚDO: O conhecimento de fatores inter-étnicos que alteram a resposta à droga permitirá ao anestesiologista evitar reações idiossincrásicas: (1) Branco caucasiano - aumento do efeito diurético da dopamina; apnéia prolongada após succinilcolina ou mivacúrio; arritmias cardíacas após uso de halotano e catecolaminas na síndrome de Riley-Day; ataques agudos de porfiria após tiopental. (2) Negro americano: diferentes abordagens terapêuticas, hipertensão arterial essencial advêm da pior resposta aos anti-hipertensivos de IECA, inibidores do AT1, bloqueadores beta e à clonidina, contrastando com a melhor resposta anti-hipertensiva dos diuréticos, antagonistas de canais de cálcio e clarvedilol; ação vasodilatadora atenuada do isoproterenol (beta2) e uma maior resposta vasodilatadora à nitroglicerina sublingual; menor ação fibrinolítica do t-PA; recuperação mais lenta da anestesia venosa pela associação de remifentanil e propofol; menor glicuronidação do paracetamol e menos analgesia da codeína nos fracos metabolizadores (CYP2D6); a melanina retarda o início da analgesia epidérmica do creme anestésico EMLA; menor midríase pela adrenalina; maior broncoespasmo à metacolina em crianças asmáticas; deficit da G-6-PD nas hemácias eleva o risco de hemólise a drogas oxidativas (10% da população negra). (3) Asiáticos: alterações cinéticas tóxicas da meperidina e codeína; maior duração da ansiólise do diazepam; espasmo coronariano pela injeção de metilergonovina no pós-parto; inter-relação do receptor GABA, das desidrogenases e do comportamento de beber nipônico, contribui para sua maior sensibilidade etanólica. Isoenzimas do citocromo P450 apresentam polimorfismo genético no metabolismo de neuropsicotrópicos e a lenta acetilação da N-acetiltransferase na população equatorial (95%) aumenta a toxicidade de isoniazida e hidralazina. CONCLUSÕES: A presente revisão pretende dar algumas respostas específicas na área da idiossincrasia anestésica relacionada ao efeito da etnicidade sobre a farmacocinética, a farmacodinâmica das drogas e a segurança do paciente cirúrgico, objetivando otimizar uma neuropsicofarmacologia mais individualizada.

Palavras-chave

COMPLICAÇÕES, COMPLICAÇÕES

Abstract

BACKGROUND AND OBJECTIVES: There are several unanswered questions about the interethnic variability in anesthetic and adjuvant drugs responses. Current pharmacogenetic developments are taking us to the verge of being able to identify inherited racial differences which could predict individual patient’s anesthetic response. CONTENTS: The understanding of interethnic factors affecting drug response will allow anesthesiologists to prevent idiosyncratic reactions: (1) Caucasian: increased dopamine diuretic effect; prolonged apnea following succinylcholine or mivacurium; cardiac arrhythmias after halothane and catecholamines in Riley-Day syndrome; acute porphyria episodes after thiopental. (2) Afro-American: different therapeutic approaches, essential arterial hypertension caused by the poorert response to ACEI anti-hypertensives, AT1 blockers, beta-blockers and clonidine, contrasted with the best anti-hypertensive response of diuretics, calcium channel blockers, claverdilol; attenuated isoproterenol-mediated vasodilatation (beta2) and a better vasodilating response to sublingual nitroglycerine; lower t-PA-induced thrombolytic effect; slower recovery from intravenous anesthesia with propofol and remifentanil; less glycuronide conjugation of paracetamol and less pain relief by codeine in weak metabolizers (CYP2D6); melanin slows onset of epidermal analgesia with EMLA anesthetic cream; less epinephrine-induced mydriasis; major metacholine-induced bronchocospasm in asthmatic children; G-6-PD deficit in erythrocytes increases the risk for hemolysis to oxidative drugs in 10% of the Afro-American population. (3) Asians: toxic kinetic changes of meperidine and codeine; longer diazepam-induced anxiolysis; postpartum intravenous ergonovine-induced coronary artery spasm; inter-relationships of GABA receptor, dehydrogenases and Japanese drinking behavior contribute to their higher sensitivity to alcohol. Cytochrome P450 isoenzymes show genetic polymorphisms in neuropsychotropic drugs metabolism and the slow acetylation of N-acetyltransferase in equatorial populations (95%) increases isoniazid and hydrazine toxicity. CONCLUSIONS: This review aimed at answering specific questions in the area of anesthetic idiosyncrasy related to the effect of ethnicity on drugs’ pharmacokinetics and pharmacodynamics, in addition to surgical patients safety by optimizing a more individualized neuropsychopharmacotherapy.

Keywords

COMPLICATIONS, COMPLICATIONS

Referencias

Kalow W, Bertilsson L. Interethnic factors affecting drug response. Adv Drug Res. 1994;25:1-59.

Wood AJJ. Racial differences in the response to drugs: Pointers to genetic differences. N Engl J Med. 2001;344:1393-1396.

Vale NB. Iatrofarmacogenia na Anestesia Local. Controvérsias em Anestesiologia. 1990:107.

Epstein AM, Ayanian JZ. Racial disparities in medical care. N Eng J Med. 2001;344:1471-1473.

Amabis JM, Martho GR. Biologia das Populações. 1996.

Wrangham R, Peterson D. O Macho Demoníaco: As Origens da Agressividade Humana. 1998.

Marshall E. DNA studies challenge the meaning of race. Science. 1998;282:654-655.

Freyre G. Casa Grande & Senzala. 2001.

Eichelbaum M, Evert B. Influence of pharmacogenetics on drug disposition and response. Clin Exp Pharmacol Physiol. 1996;23:983-985.

Kalow W. Pharmacogenetics, pharmacogenomics and pharmacobiology. Clin Pharmacol & Ther. 2001;7:1-4.

Stewart WF, Lipton RB, Liberman J. Variation in migraine prevalence. Neurology. 1996;47:52-59.

Stoelting RK, Dierdof SF. Anesthesia and Co-existing Disease. 1993.

Matthews HW. Racial, ethnic and gender differences in response to medicines. Drug Metab and Drug Interact. 1995;12:77-91.

Marinac JS, Willsie SK, Dew M. Pharmacodynamic effects of dopamine stratified by race. Am J Therap. 2001;8:27-34.

Gokce N, Holbrock M, Duffy S. Effects of race and hypertension on flow-mediated and nitroglycerine-mediated dilatation of the brachial artery. Hypertension. 2001;38:1349-1354.

Forbat A, Lehmann H, Silk E. Prolonged apnea following injection of succinylcholine. Lancet. 1953;I:1067-1068.

Kalow W, Staron N. On distribution and inheritance of atypical forms of human serum cholinesterase as indicated by dibucaine numbers. Can J Biochem Physiol. 1957;35:1305-1317.

Davis L, Britten JJ, Morgan M. Cholinesterase: Its significance in anaesthetic practice. Anaesthesia. 1997;52:244-260.

Nociti JR. Apnéia prolongada pós-succinilcolina: Relato de caso. Rev Bras Anestesiol. 1992;42:315-318.

Ostergaard D, Jensen FS, Jensen E. Mivacurium-induced neuromuscular blockade in patients with atypical plasma cholinesterase. Acta Anaesthesiol Scand. 1993;37:314-318.

Jensen NF, Fiddler DS, Striepe V. Anesthetic considerations in porphyries. Anesth Analg. 1995;80:591-599.

Moyes DG. The Anaesthetic Implications in Porphyries. Lectures in Anaesthesiology. 1986.

Yeung LAC, McColl KEL. Management of attacks of acute prophyria. Drugs. 1987;34:604-616.

Meissner PN, Jarrison GG, Hift RJ. Propofol as an IV anaesthetic induction agent in variegate porphyria. Br J Anaesth. 1991;66:60-65.

Stir JA, Frantz RA, Gunz EF. Anesthesia, cathecolamines, and hemodynamics in autonomic dysfunction. Anesth Analg. 1982;61:701-704.

Vale NB, Delfino J. Anestesia na população negra. Rev Bras Anestesiol. 2003;43(3).

Moskowitz DW. Hypertension, thermotolerance and the "African gen": an hypothesis. Clin Exp Hypertension. 1996;1:1-9.

Sheifer SE, Escarce JJ, Schulman KA. Race and sex differences in the management of coronary artery disease. Am Heart J. 2000;139:848-857.

Timberlake DS, O’Connor DT, Parmer RJ. Molecular genetics of essential hypertension: recent results and emerging strategies. Cur Opin Nephrol Hypert. 2001;10:71-79.

Markovitz JH, Tucker D, Lewis C. Inversion relationship of urinary cyclic GMP (cGMP) to blood pressure reactivity in the CARDIA study: vasodilatadory regulation of sympathetic vasoconstriction. Psychosom Med. 1998;60:319-326.

O´Donnell CJ, Lindpaintner K, Larson MG. Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension an blood pressure in men but not women in the Framingham heart study. Circulation. 1998;97:1766-1772.

Dustan HP. Does keloid pathogenesis hold the key to understanding black/white differences in hypertension severity?. Hypertension. 1995;26:858-862.

Oates JA, Brown NJ. Antihypertensive Agents and the Drug Therapy of Hypertension. Goodman & Gilman´s: The Pharmacological Basis of Therapeutics. 2001:871.

Andersson B, Blange I, Sylven C. Angiotensin-II type 1 receptor gene polymorphism and long-term survival in patients with idiopathic congestive heart failure. Eur J Heart Fail. 1999;1:363-369.

Exner DV, Dries DL, Domanski MJ. Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med. 2001;344:1351-1357.

Wright Jr JT, Kusek JW, Toto RD. Design and baseline characteristics of participants in the African-American study of kidney disease and hypertension (AASK) pilot-study. Control Clin Trials. 1996;17:3S-16S.

Slater EE, Merrill DD, Guess HA. Clinical profile of angioedema associated with angiotensin-converting enzyme inhibition. JAMA. 1988;260:67-970.

Gibbs CR, Lip GYH, Beevers DG. Angioedema due to ACE inhibitors: increased risk in patients of African origin. Br J Clin Pharmacol. 1999;48:861-865.

Gainer JV, Nadeau JH, Ryder D. Increased sensitivity to bradykinin among African-Americans. J Allerg Clin Immunol. 1996;98:283-287.

Lang CC, Stein CM, He HB. Blunted blood pressure response to central sympathoinhibition in normotensive blacks: increased importance of nonsympathetic factors in blood pressure maintenance in blacks. Hypertension. 1997;30:157-162.

Cardillo C, Kilcoyne CM, Cannon RO. Racial differences in nitric oxide-mediated vasodilator response to mental stress in the forearm circulation. Hypertension. 1998;31:1235-1239.

Carlsson I, Sollevi A, Wennmalm A. The role of myogenic relaxation, adenosine and prostaglandins in human forearm reactive hyperaemia. J Physiol. 1987;389:147-161.

Yancy CW, Fowler MB, Colucci WS. Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med. 2001;344:1358-1365.

Kiowski W, Bühler FR, Fadayomi MO. Age, race, blood pressure, and renin: predictors for antihypertensive treatment with calcium antagonists. Am J Cardiol. 1985;56:81H-85H.

Bassett Jr DR, Duey WJ, Walker AJ. Racial differences in maximal vasodilatory capacity of forearm resistance vessels in normotensive young adults. Am J Hypertens. 1992;5:781-786.

Lang CC, Stein CML, Brown R. Attenuation of isoproterenol-mediated vasodilatation in blacks. N Eng J Med. 1995;333:155-160.

Liggett SB, Wagoner LE, Craft LL. The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest. 1998;102:1534-1549.

Wagoner LE, Craft LL, Singh B. Polymorphisms of the beta2-adrenergic receptor determine exercise capacity in patients with heart failure. Circ Res. 2000;86:834-840.

Cardillo C, Kilcoyne CM, Cannon RO III. Attenuation of cyclic nucleotide-mediated smooth muscle relaxation in blacks as a cause of racial differences in vasodilator function. Circulation. 1999;99:90-95.

Gillum RF. Risk factors for strokes in blacks: a critical review. Am J Epidemiol. 1999;150:1266-1274.

Faucett J, Gordon , Levine J. Differences on postoperative pain severity among four ethnic groups. J Pain Symptom Manage. 1994;9:383-389.

Sheffield D, Biles PL, Orom H. Race and sex differences in cutaneous pain perception. Psychosom Med. 2000;62:517-523.

Edwards RR, Fillingin R. Ethnic differences in thermal pain responses. Psychosom Med. 1999;61:346-354.

McCracken L, Mattheus AK, Tang TS. A comparison of blacks and whites seeking treatment for chronic pain. Clin J Pain. 2001;17:149-245.

Ortolani O, Conti A, Sall/Ka B. The recovery of Senegalese African blacks from intravenous anesthesia with propofol and remifentanil is slower than that of Caucasians. Anesth Analg. 2001;93:1222-1226.

Critchley JA, Nimmo GR, Gregson CA. Inter-subject and ethnic differences in paracetamol metabolism. Br J Clin Pathology. 1986;22:649-657.

Fagerlund TH, Braaten O. No pain relief from codeine?: An introduction to phamacogenomics. Acta Anaesthesiol Scand. 2001;45:140-149.

Taylor S. Skin color: biology, structure, function, and implications for dermatologic disease. J Am Acad Dermatol. 2002;46:S41-S62.

Robinson MK. Population differences in skin structure and physiology and the susceptibility to irritant and allergic contact dermatitis: implications for skin safety testing and skin assessment. Contact Dermatitis. 1999;41:65-79.

Robinson MK. Racial differences in acute and cumulative skin irritation responses between Caucasian and Asian population. Contact Dermatitis. 2000;42:134-143.

DeLeo VA, Taylor SC, Belsito DV. The effect of race and ethnicity on patch test results. J Am Acad Dermatol. 2002;46:S107-S112.

Brown RH, Schauble JF, Hamilton RH. Prevalence of latex allergy among anesthesiologists: identification of sensitized but asymptomatic individuals. Anesthesiology. 1998;89:292-299.

Gajraj NM, Pennant JH, Watcha MF. Eutectic mixture of local anesthetics (EMLA) cream. Anesth Analg. 1994;78:574-584.

Chen KK, Poth EJ. Racial differences as illustrated by the mydriatic action of epinephrine, euphthalmine and ephedrine. J Pharmacol Exp Ther. 1929;36:429-431.

Scott TG. The eye of the west African Negro. Br J Ophthalmol. 1945;29:12-15.

Deborah J. Racial groups respond differently to glaucoma treatment. Br Med J. 1998;317:164-168.

Li , Kushida K, Powell NB. Obstructive sleep apnea syndrome: a comparison between far-east Asian and white men in obstructive sleep apnea syndrome (OSAS). Laryngoscope. 2000;110:1689-1693.

Joseph CLM, Ownby DR, Peterson EL. Racial differences in physiologic parameters related to asthma among middle-class children. Chest. 2000;117:1336-1344.

Platts-Mills T, Carter MC. Asthma and indoor exposure to allergens. N Eng J Med. 1997;336:1382-1384.

Houghton IT, Chan K, Wong YC. Pethidine pharmacokinetics after intramuscular dose: a comparison in Caucasian, Chinese and Nepalese patients. Methods & Find Exp Clin Pharmacol. 1992;14:451-458.

Caraco Y, Sheller J, Wood AJ. Impact of ethnic origin and quinidine coadminstration on codeine’s disposition and pharmacokinetics effect. J Pharmacol Exp Ther. 1999;290:413-422.

Ghoneim MM, Kortilla K, Chiang CK. Diazepam effects and kinetics in Caucasians and Orientals. Clin Pharmacol Ther. 1981;29:749-756.

Kumana CR, Lauder IJ, Chan M. Differences in diazepam pharmacokinetics in Chinese and white Caucasians: relation to body lipid stores. Eur J Clin Pharmacol. 1987;32:211-215.

Goldstein JA. Clinical relevance of genetic polymorphism’s in the human CYP2C subfamily. Br J Clin Pharmacol. 2001;52:349-355.

Van Gerven JMA, Uchida M, Uchida N. Pharmacodynamics and pharmacokinetics of a single dose of nitrazepam in healthy volunteers: an interethnic comparative study between Japanese and European volunteers. J Clin Pharmacol. 1998;38:1129-1136.

Taylor G, Cohen B. Ergonovine-induced coronary artery spasm and myocardial infarction after normal delivery. Obstet Gynecol. 1985;66:821-822.

Yaegashi N, Miura M, Okamura N. Acute myocardial infarction associated with postpartum ergot alkaloid administration. Int J Gynecol Obstet. 1999;64:67-68.

Tsuai BCH, Stewart B, Fitzmaurice A. Cardiac arrest and myocardial infarction induced by postpartum intravenous ergonovine administration. Anesthesiology. 2001;94:363-364.

Auch-Schwelk W, Paetsch I, Krackhardt F. Modulation of contractions to ergonovine and methylergonovine by nitric oxide and thromboxane A2 in the human coronary artery. J Cardiov Pharmacol. 2000;36:631-639.

Pristipino C, Bletrame JF, John F. Major racial differences in coronary constrictor response between Japanese and Caucasians with recent myocardial infarction. Circulation. 2000;101:1102-1108.

Iwata N, Cowley DS, Radel M. Relationship between a GABA A, a 6 Pro385ser substitution and benzodiazepin sensitivity. Am J Psychiatr. 1999;156:1447-1449.

Gurling H, Cook C. The genetic predisposition to alcohol dependence. Cur Opinion Psych. 1999;12:269-275.

Higuchi S, Matsushita S, Maramatsu T. Alcohol and aldehyde dehydrogenate genotypes and drinking behavior in Japanese. Alcohol Clin Exp Res. 1996;20:493-497.

Iron A, Groppi A, Fleury B. Polymorphism of class I alcohol-desidrogenase in French, Vietnamese and Niger populations: genotyping by PCR amplification and RFLP analysis of dried blood spot. Ann Gen. 1992;35:152-156.

Shimoda T, Kohno S, Takao A. Investigation on the mechanism of alcohol-induced bronchial asthma. J Allerg & Clin Immunol. 1996;97:74-84.

Sellers EM, Tyndale RF. Mimicking gene defects to treat drug dependence. Ann N Y Acad Sci. 2000;909:233-246.

Irwin M, Miller C, Gillin JC. Polysomnographic and spectral sleep EEG in primary alcoholics: an interaction between alcohol dependence and African-American ethnicity. Alcoholism: Clin Exp Res. 2000;24:1376-1384.

Irwin M, Miller C. Decreased natural killer cell responses and altered interleukin-6 and interleukin-10 production in alcoholism: an interaction between alcohol dependence and African-American ethnicity. Alcoholism: Clin Exp Res,. 2000;24:560-569.

Chang GWM, Kam PCA. The physiological and pharmacological roles of cytochrome P450 isoenzymes. Anaesthesia. 1999;54:42-50.

Wilkinson GR. The Dynamics of Drugs Absorption, Distribution and Elimination. Goodman & Gilman´s The Pharmacological Basis of Therapeutics. 2001;3.

Perez-Stable EJ, Herrera B, Jacob P III. Nicotine metabolism and intake in black and white smokers. JAMA. 1998;280:152-156.

Pianezza ML, Sellers EM, Tyndale RF. Nicotine metabolism defect reduces smoking. Nature. 1988;393:750.

Moreira WR, Andrade CA, Silva GAV. Colecistectomia videolaparoscópica em paciente portador de anemia falcilforme: Complicações pela elevação da P ET CO2 e queda da SpO2. Rev Bras Anestesiol. 1996;46:26-34.

Wormhoudt LW, Commandeur JN, Vermeulen LP. Genetic polymorphism’s of human N-acethyltransferase, cytochrome P450, glutatione-S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol. 1999;29:59-124.

Wolf CR, Smith G, Smith RL. Pharmacogenetics. Br Med J. 2000;320:987-990.

Johnson JA. Predictability of the effects of race or ethnicity on pharmacokinetics of drugs. Intern J Clin Pharmacol Ther. 2000;2:53-60.

Xie HG, Kim RB, Wood AJ. Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol. 2001;41:815-850.

Kalow W. Ethnic differences in drug metabolism. Clin Pharmacokinet. 1982;7:373-400.

Majerus WM, Tollefsen DM. Anticoagulant, Thrombolytic and Antiplatelet Drugs. Gilman Goodman & Gilman´s The Pharmacological Basis of Therapeutics. 2001;1529.

Tanaka E. Clinical importance of non-genetic and genetic cytochrome P450 function tests in liver disease. J Clin Pharm Ther. 1998;23:161-170.

Daly AK, Brockmoller J, Broly F. Nomenclature for human CYP2D6 alleles. Pharmacogenetics. 1996;6:193-201.

Evans DAP, Manley KA, McKusick VA. Genetic control of isoniazid metabolism in man. Br Med J. 1960;2:485-491.

Poolsup N, Li Wan P, Knight TL. Pharmacogenetics and psychopharmacoterapy. J Clin Pharm & Therap. 2000;25:197-200.

Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphism’s: a comprehensive review of the in-vitro and human data. Pharmacogenetics. 2002;12:251-263.

Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol. 1998;45:525-538.

Aithal GP, Day CP, Kestaven PJL. Associations of polymorphism’s in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complication. Lancet. 1999;353:717-719.

Bertilsson L, Dahl ML, Dalen P. Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol. 2002;53:111-122.

Bernard AS, Bruera E. Drugs interactions in palliative care. J Clin Oncol. 2000;18:1780-1799.

Zhou HH, Wood AJ. Stereoselective disposition of carvedilol is determined by CYP2D6. Clin Pharmacol Ther. 1995;57:518-524.

Marez D, Legrand M, Sabbagh N. Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics. 1997;7:193-211.

DeVane CL, Nemeroff CB. Psychotropic drug interactions. The Economics Neuroscience (TEN). 1999;1:75-84.

Koizumi A, Nomiyama T, Tsukada M. Evidence on N-acetyltransferase allele-associated metabolism of hydrazine in Japanese workers. J Occupat & Environm Med. 1998;40:217-222.

Prows D, Prows CA. Optimizing drug therapy based on genetic differences: implications for the clinical setting. AACN Clinical Issues: Adv Prat Acute Crit Care. 1998;9:499-512.

Roses AD. Pharmacogenetics and the practice of medicine. Nature. 2000;405:857-865.

Ingelman SM. Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy. J Intern Med. 2000;250:186-200.

Nebert DW. Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist?. Clin Genet. 1999;56:247-258.

Wallace B. Essays in Social Biology: Genetics, Evolution, Race, Radiation Biology. 1979;123.

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