Efficacy analysis of anti-platelet in the treatment of high-risk non-disabling ischemic cerebrovascular events guided by point-of-care testing of CYP2C19 gene / 中华神经科杂志

Objective:To explore the efficacy and safety of different anti-platelet regimens in the treatment of high-risk non-disabling ischemic cerebrovascular events (HR-NICE) guided by point-of-care testing of CYP2C19 gene. Methods:A single-centre, prospective, randomised, open-label, and blinded endpoint design was uesd in the study. From July 2020 to January 2022, HR-NICE patients were enrolled in the Stroke Green Channel and Department of Neurology of Xuzhou Central Hospital, and all patients were scraped the buccal mucosa for screening for CYP2C19 loss-of-function allele carriers by point-of-care testing . Patients with intermediate metabolism were defined as those who carried 1 loss-of-function allele and patients with poor metabolism were those who carried 2 loss-of-function alleles. This study reduced the test turnaround time to 1 hour by using a fully automated medical polymerase chain reaction analyzer for a point-of-care test of CYP2C19 genotype. CYP2C19 loss-of-function allele carriers were divided according to the random number table method into the conventional treatment group (clopidogrel 75 mg, once a day), the ticagrelor group (ticagrelor 90 mg, twice a day) and the intensive dose group (clopidogrel 150 mg, once a day) separately combined with aspirin (100 mg, once a day) dual antiplatelet for 21 days. Baseline information, Acute Stroke Org 10172 Treatment Trial staging, 90-day modified Rankin Scale score, occurrence of adverse events and severe adverse events were collected for all the 3 groups. The primary efficacy outcome was new stroke within 90 days, and the primary safety outcome was severe or moderate bleeding within 90 days. Results:A total of 716 patients were included: 240 in the conventional treatment group, 240 in the ticagrelor group and 236 in the intensive dose group. There was no statistically significant difference between the 3 groups at baseline (all P>0.05). There were 26 cases (10.8%) with new stroke events in the conventional treatment group, 11 cases (4.6%) in the ticagrelor group and 4 cases (1.7%) in the intensive dose group, with statistically significant differences among the 3 groups (χ 2=19.28, P<0.05), and the differences between the conventional treatment group and the ticagrelor group (χ 2=6.59, P=0.010) and between the conventional treatment group and the intensive dose group (χ 2=16.83, P<0.001) were statistically significant, whereas the difference between the ticagrelor group and the intensive dose group was not statistically significant ( P>0.05). In the 3 groups, there was 1 case (0.4%) of severe bleeding in the conventional treatment group, 6 cases (2.5%) in the ticagrelor group and none in the intensive dose group, which showed statistically significant differences (χ 2=7.23, P<0.05), and there was statistically significant difference between the ticagrelor group and the intensive dose group ( P=0.030). Among the patients with intermediate CYP2C19 metabolism, there were 13 cases (13/158, 8.2%) with 90-day recurrent stroke in the conventional treatment group, 4 cases (4/153, 2.6%) in the ticagrelor group, and 0 case (0/159) in the intensive dose group, with statistically significant difference (χ 2=16.04, P<0.001), and the differences between the intensive dose group and the conventional treatment group were statistically significant (χ 2=13.64, P<0.001), whereas there was no statistically significant difference between the intensive dose group and the ticagrelor group ( P>0.05). In the patients with 90-day recurrent stroke in the intensive dose group, there was 0 case (0/159) with intermediate metabolism and 4 cases (4/77,5.2%) with poor metabolism, with statistically significant differences ( P=0.011), whereas there were no statistically significant differences in the conventional treatment group and the ticagrelor group ( P>0.05). Conclusions:Screening carriers of CYP2C19 loss-of-function alleles by point-of-care testing can quickly and precisely guide the treatment of patients with non-cardiogenic HR-NICE. An intensive clopidogrel dose of 150 mg, once a day combined with aspirin was effective in reducing stroke recurrence with less occurrence of any bleeding and adverse events, and patients with intermediate CYP2C19 metabolism may be the best population to benefit.

Detoxification Mechanism of Combined Chebulae Fructus， Glycyrrhizae Radix et Rhizoma and Prepared Aconiti Kusnezoffii Radix Cocta in Regulating Cardiac Metabolic Enzyme CYP2J3 / 中国实验方剂学杂志

ObjectiveTo investigate the detoxification mechanism of Chebulae Fructus， Glycyrrhizae Radix et Rhizoma and Prepared Aconiti Kusnezoffii Radix Cocta， and their effective components ellagic acid， liquiritin and aconitine based on cardiac cytochrome P450 （CYP450） system. MethodIn in vivo experiments， rats were randomly divided into control group， prepared Aconiti Kusnezoffii Radix Cocta group （0.25 g·kg-1）， Chebulae Fructus group （0.252 g·kg-1）， Glycyrrhizae Radix et Rhizoma group （0.25 g·kg-1） and combination group （0.25 g·kg-1 Chebulae Fructus+0.25 g·kg-1 Glycyrrhizae Radix et Rhizoma+0.25 g·kg-1 prepared Aconiti Kusnezoffii Radix Cocta， with prepared Aconiti Kusnezoffii Radix Cocta as standard）. After 8 days of administration， creatine kinase （CK） and lactate dehydrogenase （LDH） in rats were detected to observe the pathological changes of heart tissue. Real-time PCR and Western blot were performed to detect the mRNA and protein expressions of CYP2J3， respectively. In in vitro experiments， control group， aconitine group， ellagic acid group， liquiritin group and combination group （aconitine+ellagic acid+liquiritin） were set， and their effects on cell number， DNA content， reactive oxygen species （ROS） and mitochondrial membrane potential （MMP） were detected by high content analysis. The changes in the mRNA and protein expressions of CYP2J3 were also observed. ResultIn vivo experiments， compared with the control group， the prepared Aconiti Kusnezoffii Radix Cocta group had increased CK and LDH in serum （P<0.05， P<0.01）， while the combination group had decreased activities of CK and LDH. Additionally， pathological staining results showed that Chebulae Fructus and Glycyrrhizae Radix et Rhizoma reduced the cardiac toxicity caused by prepared Aconiti Kusnezoffii Radix Cocta. Real-time PCR found that compared with the control group， prepared Aconiti Kusnezoffii Radix Cocta down-regulated the mRNA level of CYP2J3 （P<0.05）， while up-regulated that expression when used in combination with Chebulae Fructus and Glycyrrhizae Radix et Rhizoma （P<0.01）. The protein and mRNA translation levels were basically consistent. In vitro experiments， high content analysis revealed that there was a decrease in the cell number， DNA content and MMP fluorescence value of the aconitine group （P<0.01） and the combination group （P<0.05， P<0.01）， and the fluorescence value of the combination group was higher than that of the aconitine group. Moreover， aconitine down-regulated the mRNA level of CYP2J3 （P<0.05）， but the down-regulating ability of aconitine was reversed in the combination group （P<0.05）. ConclusionThe detoxification mechanism of combined Chebulae Fructus， Glycyrrhizae Radix et Rhizoma and prepared Aconiti Kusnezoffii Radix Cocta is mainly that the combination of ellagic acid， liquiritin and aconitine can up-regulate the expression of CYP2J3， and promote the metabolism of arachidonic acid （AA） to produce epoxyeicosatrienoic acids （EETs）， thus reducing the cardiac toxicity， and this effect may start from the transcriptional link.

The analysis on the correlation between CYP2C19 gene polymorphism and clopidogrel resistance in patients with acute coronary syndrome / 中国医师进修杂志

Objective:To analyze the relationship between CYP2C19 polymorphism and clopidogrel resistance (CR) in patients with acute coronary syndrome (ACS).Methods:One hundred and twenty-seven ACS patients treated with percutaneous coronary intervention (PCI) from June 2019 to June 2020 were enrolled, including 29 patients with CR(CR group) and 98 patients with none clopidogrel resistance (NCR, NCR group). The clinical data, coronary angiography results were compared between the two groups, the relationship of CYP2C19*2 and CYP2C19*3 polymorphisms and CR were analyzed.Results:The general data and coronary angiography between two groups had no significant differences ( P>0.05). There were differences in the distribution of isogenic genes and genotypes of CYP2C19 (rs4244285) and CYP2C19 (rs4986893) between the two groups ( P<0.05). Polymorphism of CYP2C19*2 and CYP2C19*3 was an important risk factor for CR ( OR = 14.688, 95% CI 3.652-59.063, P<0.01; OR = 7.228, 95% CI 2.412-21.663, P<0.01). Conclusions:CR is closely associated with CYP2C19*2 and CYP2C19*3 in ACS patients.

Testosterona inhibe la actividad de la aldosterona sintasa silvestre y quimérica in vitro

Background: Familial hyperaldosteronism type I is caused by the generation of a chimeric aldosterone synthase enzyme (ASCE) which is regulated by ACTH instead of angiotensin II. We have reported that in vitro, the wild-type (ASWT) and chimeric aldosterone synthase (ASCE) enzymes are inhibited by progesterone and estradiol does not affect their activity. Aim: To explore the direct action of testosterone on ASWT and ASCE enzymes. Material and Methods: HEK-293 cells were transiently transfected with vectors containing the full ASWT or ASCE cDNAs. The effect of testosterone on AS enzyme activities was evaluated incubating HEK-cells transfected with enzyme vectors and adding deoxycorticosterone (DOC) alone or DOC plus increasing doses of testosterone. Aldosterone production was measured by HPLC-MS/MS. Docking of testosterone within the active sites of both enzymes was performed by modelling in silico. Results: In this system, testosterone inhibited ASWT (90% inhibition at five pM, 50% inhibitory concentration (IC50) =1.690 pM) with higher efficacy andpotency than ASCE (80% inhibition at five pM, IC50=3.176 pM). Molecular modelling studies showed different orientation of testosterone in ASWT and ASCE crystal structures. Conclusions: The inhibitory effect of testosterone on ASWT or ASCE enzymes is a novel non-genomic testosterone action, suggesting that further clinical studies are needed to assess the role of testosterone in the screening and diagnosis of primary aldosteronism.

Eficácia terapêutica do Tacrolimo em pacientes pós-transplante hepático com polimorfismos genéticos do citocromo P450 3A5 (CYP3A5) / Tacrolimus therapeutic efficacy in post-liver transplant patients with Cytochrome P450 3A5 (CYP3A5) genetic polymorphisms

RESUMO Os polimorfismos genéticos do CYP3A5 têm sido apontados enquanto fatores influenciadores na eficácia farmacológica com tacrolimo em pacientes em terapia imunossupressora no pós-transplante hepático. O presente estudo objetiva realizar uma revisão da literatura acerca da influência dos polimorfismos genéticos do citocromo P450 3A5 (CYP3A5) na eficácia terapêutica com tacrolimo em indivíduos pós-transplante hepático. Revisão da literatura. Foi utilizada a combinação dos descritores "tacrolimo", "transplante de fígado", "inibidores do citocromo P-450 CYP3A" e "polimorfismo genético", nas bases de dados: PubMed, The Cochrane Library, Scopus e Scielo, sendo avaliados apenas estudos publicados entre 2009 e 2019 em inglês, português ou espanhol. Ao todo foi feita a sumarização de seis estudos, cada um avaliando uma diferente população. Inicialmente, foram abordados os aspectos farmacológicos do tacrolimo, incluindo detalhes sobre sua farmacodinâmica, farmacocinética e toxicidade. Na seção seguinte, foi realizada a avaliação de estudos que tratam da relação entre os polimorfismos genéticos do CYP3A5 e a eficácia farmacológica com o tacrolimo, incluindo as especificações étnicas e as limitações gerais dos estudos. Os polimorfismos genéticos do CYP3A5 têm apontado para alterações no metabolismo do tacrolimo de acordo com um recorte étnico e populacional, com destaque para os alelos *1 e *3*3, refletindo na necessidade de ajuste de dose ou até mesmo nas taxas de rejeição do órgão.

ABSTRACT Genetic polymorphisms of CYP3A5 have been pointed out as factors that influenciates tacrolimus immunosuppressive efficacy in post liver transplant patients. This study aims to review the literature on the influence of cytochrome P450 3A5 (CYP3A5) genetic polymorphisms of tacrolimus in post-liver transplant patients. This study is a literature review. A combination of the descriptors "tacrolimus", "liver transplant", "cytochrome P-450 CYP3A inhibitors" and "genetic polymorphism" were used in the databases PubMed, Cochrane Library, Scopus and Scielo, being evaluated only studies between 2009 and 2019 in English, Portuguese or Spanish. A total of six studies, each from a different population were summarized. Initially, the pharmacological aspects of tacrolimus were discussed, including details on its pharmacodynamics, pharmacokinetics and toxicity After that, we analyzed the studies that correlates CYP3A5 genetic polymorphisms and tacrolimus efficacy, including the ethnical specifications and the general limittions of the studies. The CYP3A5 polymorphisms have pointed to alterations in the metabolism of tacrolimus according to the ethnic and populational genotype, specially the *1 and *3*3 alleles, reflecting in the need for dose adjustment and also in post liver transplant rejection.

Living related donor liver transplantation for infant with Crigler-Najjar syndrome type Ⅰ: a report of one case and literature review / 器官移植

Objective To summarize the therapeutic effects of living related donor liver transplantation for Crigler-Najjar syndrome type Ⅰ (CNS type Ⅰ). Methods A 3-month-old male infant had appeared a progressive xanthochromia of the skin and sclera 4 d after birth without obvious cause. Other causative factors were eliminated after relevant tests were completed, and identified as CNS type Ⅰ by genetic testing. Living related donor liver transplantation was performed with his mother as the donor. An immunosuppression regimen was routinely applied postoperatively and tacrolimus doses were adjusted according to biochemical indicators and cytochrome P450 (CYP) 3A5 genotype of the recipient. Results The liver enzymes of the recipient returned to normal at 7 d postoperatively, and bilirubin decreased daily and fell to the normal range at 22 d postoperatively. Followed up to the submission date, the recipient's xanthochromia of skin and scleral faded with normal bilirubin and stable liver enzymes. The condition of the recipient was generally good with high quality of life. Conclusions Living donor liver transplantation can treat unconjugated hyperbilirubinemia and other diseases caused by CNS type Ⅰ, which greatly improve the quality of life of patients.

Effects of CYP2C9 and VKORC1 genetic polymorphisms in Chinese Han population on maintenance dosage of warfarin / 中华检验医学杂志

Objective@#To analyze CYP2C9 and VKORC1 gene polymorphisms in Chinese Han population and their correlation with the maintenance dosage of warfarin.@*Methods@#From October 2017 to April 2018, 458 Chinese Han patients (213 males and 245 females, aged from 26 to 94 years old) who underwent coagulation analysis in Peking University People′s Hospital were included in this retrospective study. PCR-Fluorescent probe method was applied to detect CYP2C9*3 and VKORC1-1639A>G gene polymorphisms in 458 patients, and among them, 130 patients who took warfarin for anticoagulant therapy and reached the international standard ratio of prothrombin time (INR) within the range of 2.0-3.0 were recorded. The basic information, dosage of warfarin and INR were also recorded. The statistical analysis data were compared with the reference table of recommended dosage of warfarin for different genotypes of patients recommended by FDA and the formula of predicted dosage of warfarin was simply verified by SPSS.@*Results@#Among the 458 patients who took anticoagulant therapy, the genotype frequencies of CYP2C9*1/*1(AA), CYP2C9*1/*3(AC) and CYP2C9*3/*3(CC) were 90.8%, 8.5%, and 0.7%; the genotype frequencies of VKORC1-1639GG and VKORC1-1639AG were 0.9% and 14.2%; the genotype frequencies of VKORC1-1639AA was 84.9%. After INR was reached, the results showed that the variant CYP2C9*1/*3 and CYP2C9*3/*3 required lower daily maintain dosage [(2.92±1.29) mg] than wild-type CYP2C9*1/*1 patients did [(3.91±1.63) mg], with statistically significant difference (P=0.018). And variant VKORC1-AA required lower daily maintain dosage [(3.68±1.64) mg] than variant VKORC1-AG patients did [(4.54±1.29) mg], with statistically significant difference (P=0.001). The application dosage of warfarin in patients with different VKORC1+CYP2C9 genotypes was consistent with the recommended dosage of the FDA reference table. The prediction accuracy of miao 2007 formula was lower than that of IWPC formula, and 94.1% of patients′ dosages of warfarin were underestimated.@*Conclusion@#Patients with CYP2C9*3 or VKORC1-AA genotype required lower warfarin dosage. The CYP2C9 and VKORC1 gene polymorphisms had a certain correlation with maintenance dosage of warfarin.

Nurse empowerment through Pharmacogenetics / Empoderamento do enfermeiro por meio da Farmacogenética / Empoderamiento del enfermero a través de la farmacogenética

Objective: to verify the existence of elements that justify the use of pharmacogenetics by the Brazilian nurse. Method: this is a quantitative, cross-sectional, observational, descriptive study, whose final sample was 67 individuals. The participants were healthy at the time of the study and reported a history of previous use and the occurrence of adverse effects by drugs commonly used and metabolized by CYP2C9. We collected 4 mL of venous blood for subsequent DNA extraction by salting out method and genotyping of the CYP2C9*2 and CYP2C9*3 polymorphisms, using Polymerase Chain Reaction in real time using Taqman assays. Results: the use of drugs metabolized by CYP2C9 was frequent (more than 75% of the individuals have already used between 2 or 4 of these drugs). Regarding adverse events, there were 19 perceived symptomatic occurrences associated with drugs metabolized by CYP2C9. The allele frequency of the polymorphism * 2 and * 3 in the population studied was 11.1% and 7.5%, respectively, and there was a coincidence between the presence of alleles of low enzyme activity and the occurrence of adverse effects. Conclusion: there are elements that justify the adoption of pharmacogenetics in the nursing care to reduce the occurrence of adverse reactions to drugs metabolized by CYP2C9.

Objetivo: verificar a existência de elementos que justifiquem o uso da farmacogenética pelo enfermeiro brasileiro. Método: trata-se de um estudo quantitativo, do tipo transversal, observacional descritivo, cuja amostra final foi de 67 indivíduos. Os participantes estavam saudáveis no momento do estudo e reportaram histórico de uso prévio e ocorrência de efeitos adversos por fármacos comumente utilizados e metabolizados pela CYP2C9. Coletamos 4 mL de sangue venoso para posterior extração de DNA por método salting out e genotipagem dos polimorfismos CYP2C9*2 e CYP2C9*3 através de Polymerase Chain Reaction em tempo real, utilizando ensaios Taqman. Resultados: o uso de fármacos metabolizados pela CYP2C9 foi frequente (mais de 75% dos sujeitos já utilizaram entre 2 ou 4 desses fármacos). A respeito dos eventos adversos, houve 19 ocorrências sintomáticas percebidas, associadas a fármacos metabolizados pela CYP2C9. A frequência alélica do polimorfismo *2 e *3 na população estudada foi de 11,1% e 7,5%, respectivamente, com coincidência entre a presença dos alelos de baixa atividade enzimática e ocorrência de efeitos adversos. Conclusão: existem elementos que justificam a adoção da farmacogenética no cuidado do enfermeiro com objetivo de redução da ocorrência de reações adversas a fármacos metabolizados pela CYP2C9.

Objetivo: verificar la existencia de elementos que justifiquen el uso de la farmacogenética por parte del enfermero brasileño. Método: se trata de un estudio cuantitativo, transversal, observacional, descriptivo, cuya muestra final fue de 67 individuos. Los participantes estaban sanos en el momento del estudio e informaron un historial de uso previo y la aparición de efectos adversos por fármacos comúnmente utilizados y metabolizados por el CYP2C9. Recolectamos 4 ml de sangre venosa para la posterior extracción de ADN mediante el método de salazón y genotipificación de los polimorfismos CYP2C9 * 2 y CYP2C9 * 3 a través de la reacción en cadena de la polimerasa en tiempo real utilizando ensayos Taqman. Resultados: el uso de drogas metabolizadas por el CYP2C9 fue frecuente (más del 75% de las personas ya han usado entre 2 o 4 de estas drogas). Con respecto a los eventos adversos, hubo 19 casos sintomáticos percibidos asociados con medicamentos metabolizados por el CYP2C9. La frecuencia alélica del polimorfismo * 2 y * 3 en la población estudiada fue de 11.1% y 7.5%, respectivamente, y hubo una coincidencia entre la presencia de alelos de baja actividad enzimática y la aparición de efectos adversos. Conclusión: existen elementos que justifican la adopción de la farmacogenética en el cuidado del enfermero para reducir la aparición de reacciones adversas a los medicamentos metabolizados por el CYP2C9.

Efecto de las variantes de CYP2C9 sobre la dosis de losartán en hipertensos chilenos / Association between cytochrome p4502c9 polymorphisms and losartan dosing in hypertensive patients

Background Losartan is widely used in many clinicals settings. Its dosage is related to the genetic characteristics of CYP2C9 enzymatic activity, which metabolizes losartan to its active form E-3174, responsible for the antihypertensive effect. Aims To identify the frequency of allelic variants CYP2C9*2 and CYP2C9*3 in hypertensive patients and to compare genotypes with a healthy Chilean population. To relate polymorphisms with the losartan dosing to obtain an optimal blood pressure. Material and Methods We studied 30 patients with controlled essential hypertension using losartan with normal liver function, and 202 healthy people. Peripheral blood DNA genotyping was performed by polymerase chain reaction to identify the polymorphisms. Allelic and genotypic frequencies were compared. Results In hypertensive patients, allelic frequencies were 0.85 (CYP2C9*1), 0.05 (CYP2C9*2) and 0.1 (CYP2C9*3). Genotypic frequencies were 73.3% (CYP2C9*1/*1), 6.7% (CYP2C9*1/*2), 16.7% (CYP2C9*1/*3) and 3.3% (CYP2C9*2/3); observing a significantly higher frequency of the allele CYP2C9*3 (p=0.041) and CYP2C9*1/*3 genotype (p=0.04). A non-significant tendency to need a larger dose of losartan was observed with the CYP2C9 * 3 allele, with an odds ratio (OR) of 1.46 (95% confidence intervals (CI) 0.01-18.64). The same tendency was observed with the need to use losartan twice a day, obtaining an OR of 5.88 (CI 0.54 -62.14). Conclusions There could be a relationship between the presence of CYP2C9 polymorphisms and the pathogenesis of hypertension. The presence of CYP2C9*3 is associated with the need for higher doses of losartan, possibly due to a decrease in the conversion of losartan to E-3174.

Polimorfismo do gene CYP2D6 1846 G/A em associação com o Acidente Vascular Encefálico/Aneurisma em uma população do Distrito Federal (Brasil) / CYP2D6 1846 G/A gene polymorphism in association with Hemorrhagic Stroke/Aneurysm in patients from the Federal District (Brazil)

Objetivo: Investigar uma possível associação do gene CYP2D6 1846 G/A em pacientes que possuem AVEH/Aneurisma, residentes no Distrito Federal (Brasil) além de cruzar as informações obtidas com as manifestações clinicas e o prognóstico. Método: Tratou-se de um estudo caso-controle de base populacional, envolvendo 81 casos com AVEH e/ou Aneurisma. Para a genotipagem dessas amostras utilizou-se a técnica laboratorial PCR-RFLP e adotou-se o nível de significância de 5%. Resultados: Ao associar as frequências genotípicas e alélicas em relação ao AVEH/Aneurisma, percebeu-se que não houve diferença estatística. Em relação à média de glicemia, participantes com genótipo GG, apresentavam índices elevados desse marcador no grupo caso quando comparado ao grupo controle. Conclusão: A presença do polimorfismo CYP2D6 1846 G/A deve ser amplamente estudada em pesquisas futuras, pois é necessário esclarecer se tais polimorfismos representam associações ao AVEH/Aneurisma.

Objective: To investigate a possible association of the CYP2D6 1846 G/A gene in HS/aneurysm patients residing in the Federal District (Brazil), as well as to crosscheck the information obtained with clinical manifestations and prognosis. Method: The investigation was a population-based case-control study involving 81 cases with HS/aneurysm. The samples genotyping employed the PCR-RFLP technique with a significance level of 5%. Results: The attempt to associate genotypic and allelic frequencies to the HVA/Aneurysm resulted in no statistical difference. Nevertheless, in patients with the GG genotype and hypertension, the risk for HS increased 44 times. Participants with GG genotype also had statistically higher glycemia mean levels in the case group. Conclusion: The presence of the CYP2D6 1846 G/A polymorphism should be extensively, as it is necessary to clarify whether such polymorphisms represent associations with HS and Intracerebral Aneurysm.

Estudio de las variantes alélicas CYP2C9*2 y CYP2C9*3 en muestras de población mestiza peruana / Study of the allelic variants CYP2C9*2 and CYP2C9*3 in samples of the Peruvian mestizo population

Resumen Introducción. El citocromo CYP2C9 metaboliza, aproximadamente, el 15 % de los fármacos prescritos. Su gen presenta alelos cuyas frecuencias difieren entre grupos étnicos y poblaciones. Los alelos CYP2C9*2 y CYP2C9*3 dan cuenta de una enzima con actividad disminuida cuya frecuencia no ha sido determinada en la población mestiza peruana. Objetivo. Caracterizar la frecuencia de las variantes *2 (rs1799853) y *3 (rs1057910) del gen CYP2C9 en muestras de población mestiza peruana provenientes de Lima, Tacna y Junín. Materiales y métodos. Se hizo un estudio descriptivo, observacional y prospectivo, con muestreo no probabilístico, por conveniencia e incidental. Se incluyeron 218 sujetos según los criterios de inclusión y exclusión; todos los participantes otorgaron su consentimiento informado. El ADN genómico se obtuvo mediante hisopado de mucosa oral, y la detección de los genotipos para los alelos CYP2C9*2 y CYP2C9*3 se hizo mediante reacción en cadena de la polimerasa (PCR) en tiempo real, utilizando sondas TaqMan™. Resultados. Las variantes de CYP2C9*2 y CYP2C9*3 están presentes en la población mestiza peruana con frecuencias de 0,046 y 0,062, respectivamente. El análisis de las frecuencias genotípicas observadas permitió predecir que la frecuencia de fenotipos metabolismo intermedio sería del 15,13 % (CYP2C9*1/*2: 5,96 %; CYP2C9*1/*3: 9,17 %), y la de fenotipos de metabolismo lento, del 3,22 % (CYP2C9*2/*2: 1,38 %; CYP2C9*3/*3: 1,38 %; CYP2C9*2/*3: 0,46 %). Conclusiones. Se lograron determinar las frecuencias genotípicas y alélicas para las variantes *2 y *3 del gen CYP2C9 en una muestra no probabilística de población mestiza peruana. Las frecuencias obtenidas (0,046 y 0,062, respectivamente) están entre las esperadas para una población mestiza sudamericana con ascendencia amerindia, europea, africana y asiática.

Abstract Introduction: CYP2C9 metabolizes approximately 15% of the prescribed drugs. Its gene has alleles whose frequencies differ between ethnic groups and populations. The alleles CYP2C9*2 and CYP2C9*3 account for an enzyme with decreased activity and their frequencies have not been determined in the Peruvian mestizo population. Objective: To characterize the frequencies of the allelic variants *2 (rs1799853) and *3 (rs1057910) of CYP2C9 gen in the Peruvian mestizo population from Lima, Tacna y Junín. Materials and methods: We conducted an observational, prospective cross-sectional study with non-probabilistic, by convenience, and incidental sampling. We included 218 subjects according to the inclusion and exclusion criteria, all of whom had signed the informed consent. We obtained the genomic DNA from oral mucosa swab. For the detection of the CYP2C9*2 and CYP2C9*3 genotypes, we used real-time-polymerase chain reaction with TaqMan® probes. Results: The genotyping revealed that CYP2C9*2 and CYP2C9*3 variants have low frequencies (0.046 and 0.062, respectively). The frequency of intermediate metabolizers was 15.13% (CYP2C9*1/*2: 5.96%; CYP2C9*1/*3: 9.17%) and that of slow metabolizers was 3.22% (CYP2C9*2/*2: 1.38%; CYP2C9*3/*3: 1.38%; CYP2C9*2/*3: 0.46%). Conclusions: It was possible to determine the genotypic and allelic frequencies for the variants *2 and *3 of the CYP2C9 gene in a non-probabilistic sample of the Peruvian mestizo population. The frequencies obtained (0.046 and 0.062, respectively) corresponded to those expected for a South American mestizo population with Amerindian, European, African and Asian ancestry.

Muscle strength and caffeine supplementation: are we doing more of the same? / Força muscular e suplementação de cafeína: estamos fazendo mais do mesmo? / Fuerza muscular y suplementación de cafeína: ¿estamos haciendo más del mismo?

ABSTRACT The purpose of this review was to examine in the current literature the advances made in terms of the effects of caffeine supplementation on maximum strength and its associated mechanisms since the publication of two important papers in 2010. Searches were carried out in the PubMed, Medline, Scielo and Web of Science databases for articles published after 2010. Sixteen studies were included based on inclusion and exclusion criteria. Five studies did not report changes in maximal voluntary strength (31.3%). Four of them used isometric muscle contractions, although this may not be a key factor because five other studies also used isometric contractions and reported ergogenic effects. Furthermore, these four studies evaluated small muscle groups and volunteers were not accustomed to consuming caffeine. Caffeine produced ergogenic effects in eleven of the sixteen studies analyzed (68.8%). None of the doses were clearly related to ergogenic effects; however, a dose of at least 3 mg/kg of caffeine is probably necessary. Caffeine ergogenicity was affected by various factors. There was a lack of standardized protocols and controls for intervening factors (e.g., circadian cycles and nutritional states), which could affect results. An ideal caffeine supplementation protocol that is useful for future research, athletes, and physical activity practitioners, has yet to be defined. A small advance made since 2010 involved a possible lack of gender difference; it would appear that caffeine supplementation affects men and women equally. Level of Evidence I; Systematic Review of Level I Studies.

RESUMO O objetivo desta revisão foi examinar na literatura atual os avanços feitos com relação aos efeitos da suplementação de cafeína sobre a força máxima e seus mecanismos associados a partir de 2010, ano em foram publicados dois importantes artigos. As buscas foram realizadas nas bases de dados PubMed, Medline, Scielo e Web of Science procurando-se artigos publicados após 2010. Dezesseis estudos foram incluídos com base nos critérios de inclusão e exclusão. Cinco estudos não relataram alterações da força voluntária máxima (31,3%). Quatro deles usaram contrações musculares isométricas, embora isso possa não ser um fator chave, porque outros cinco estudos também usaram contrações isométricas e relataram efeitos ergogênicos. Além disso, esses quatro estudos avaliaram pequenos grupos musculares e os voluntários não eram habituados à cafeína. A cafeína produziu efeitos ergogênicos em 11 dos 16 estudos analisados (68,8%). Nenhuma dose foi claramente relacionada com efeitos ergogênicos; contudo, há indícios da necessidade de uma dose de pelo menos 3 mg/kg de cafeína. A ergogenicidade da cafeína foi afetada por vários fatores. Havia uma falta de protocolos padronizados e controle de fatores intervenientes (por exemplo, ciclo circadiano e estado nutricional) que poderiam afetar os resultados. Ainda é preciso definir um protocolo ideal de suplementação de cafeína que seja útil para futuras pesquisas, atletas e praticantes de atividade física. Um pequeno avanço feito desde 2010 envolveu a possível falta de diferença de gênero - parece que a suplementação de cafeína afeta homens e mulheres igualmente. Nível de Evidência I; Revisão Sistemática de Estudos de Nível I.

RESUMEN El objetivo de esta revisión fue examinar en la literatura actuallos avances hechos con respecto a los efectos del suplemento de cafeína sobre la fuerza máxima y sus mecanismos asociados desde 2010, año en que se publicaron dos artículos importantes. Las búsquedas se realizaron en las bases de datos PubMed, Medline, Scielo y Web of Science, por artículos publicados después de 2010. Se incluyeron 16 estudios basados en los criterios de inclusión y exclusión. Cinco estudios no reportaron cambios de la fuerza voluntaria máxima (31,3%). Cuatro de ellos usaron contracciones musculares isométricas, aunque esto puede no ser un factor clave, porque otros cinco estudios también utilizaron contracciones isométricas y reportaron efectos ergogénicos. Además, estos cuatro estudios evaluaron grupos musculares pequeños y los voluntarios no tenían el hábito de consumo de cafeína. La cafeína produjo efectos ergogénicos en 11 de los 16 estudios analizados (68,8%). Ninguna dosis fue claramente relacionada con efectos ergogénicos, sin embargo, hay indicios de la necesidad de una dosis de al menos 3 mg/kg de cafeína. La ergogenicidad de la cafeína se vio afectada por varios factores. Hubo una falta de protocolos y controles estandarizados de factores intervinientes (por ejemplo, ciclo circadiano y estado nutricional) que podrían afectar los resultados. Todavía es necesario definir un protocolo ideal de suplemento de cafeína que sea útil para futuras investigaciones, atletas y practicantes de actividad física. Un pequeño avance hecho desde 2010 involucró la posible falta de diferencia de género - parece que el suplemento de cafeína afecta a hombres y mujeres igualmente. Nivel de Evidencia I; Revisión sistemática de estudios de Nivel I.

Correlation between CYP2D6 polymorphism and risperidone metabolism in schizophrenic patients / 中华检验医学杂志

Objective To investigate the effect of CYP2D6 gene polymorphism on risperidone (RISP) metabolism in schizophrenic patients. Methods CYP2D6 allele polymorphisms including*10,*4,*41 and *2 was detected by real-time fluorescent PCR in 120 schizophrenic patients who have taken risperidone continually. Alleles without SNP mutations were classified as wild-type (WT). At the same time, serum risperidone and 9-hydroxyrisperidone concentration of all patients were detected by mass spectrometric analysis. Some samples were selected for DNA sequencing of CYP2D6*10, which is the most common CYP2D6 allele in Oriental population. The 120 patients were divided into three groups according to their allele variants. Group 1 was defined as carriers of two functional alleles, group 2 was defined as carriers of one defective allele, group 3 was defined as carriers of two defective alleles. Genotype distributions, alleles frequencies, RISP, 9-oh-RISP, RISP+9-OH-RISP, 9-oh-RISP/RISP among three groups were calculated.Results Group 1 amount to 23 cases including 13 cases of WT/WT, 7 cases of*2/*2, 3 cases of WT/*2. Group 2 amount to 51 cases, including 38 cases of WT/*10, 8 cases of *2/*10, 1 case of *2/*41, 4 cases of WT/*41. Group 3 amount to 46 cases, including 44 cases of *10/*10, 2 cases of *10/*41. The*4 allele was not detected. The allele frequency of WT, *2, *10 and *41 was 29.6％, 10.8％, 56.7％ and 2.9％, respectively. The 9-hydroxyrisperidone/risperidone-ratio of three groups were 15.24±5.77, 11.06±4.56 and 2.39 ± 1.06, respectively. There was a significant difference in 9-hydroxyrisperidone/risperidone-ratio between Group 3 and the first two groups (P<0.001). Conclusions The frequency of *10 allele was the highest among the subjects. The frequency of WT and*2 allele was over 95％in the population. Individuals carrying one defective allele of CYP2D6 will decrease the rate of risperidone metabolism slightly, while individuals carrying two defective alleles of CYP2D6 may decrease the rate of risperidone metabolism significantly.

Correlation analysis between different genotypes of CYP2C19, ERCC2 and XRCC1 and pathological indexes of gastroesophageal reflux and hiatal hernia in Xinjiang / 中国医师杂志

Objective@#The aim of this study was to investigate the correlation between different genotypes of CYP2C19, ERCC2 and XRCC1 and clinical indexes of gastroesophageal reflux and hiatal hernia in Xinjiang.@*Methods@#The clinical data of 101 patients with gastroesophageal reflux and hiatal hernia clinically diagnosed by people′s hospital of Xinjiang Uygur Autonomous Region from January 2016 to December 2017 were prospectively studied, and Wilcoxon rank sum test was used to analyze the genotypes and relevant clinical indicators.@*Results@#There was statistically significant difference in the distance of hiatal hernia between patients with CYP2C19 containing A/A homozygous genotype and those with other two genotypes (A/G or G/G) (P<0.05), and there was statistically significant difference in intrabolus pressure (IBP) between patients with G/G homozygous genotype and those with A/G heterozygous genotype (P<0.05). Esophageal sphincter lower esophageal sphincter (LES) residual pressure, LES relaxation rate and percentage of invalid swallowing between patients with ERCC2 containing A/C heterozygous genotype and those with A/A homozygous genotype also has significant statistical difference (P<0.05). The more C contained in the genotype, the lower IBP maximum (on average), and this pattern has statistical significance (P<0.05); There was no statistical difference for all clinical indicators among different XRCC1 genotypes.@*Conclusions@#Different genotypes of CYP2C19 and ERCC2 are closely related to the clinical indexes of gastroesophageal reflux and hiatal hernia. CYP2C19 containing A/G or G/G genotype is correlated with gastroesophageal reflux disease (GERD) and the incidence of hiatal hernia. The population containing A/G and G/G genotypes of CYP2C19 may be with a high incidence of hiatal hernia. Homozygous G/G genotype may be a high risk factor for aggravating reflux esophagitis. A/C and C/C genotypes contained in ERCC2 genotype were correlated with the incidence of hiatal hernia. The more C bases contained in ERCC2 genotype, the greater the effect of reducing IBP, indicating that the more C bases contained in ERCC2 genotype may be negatively correlated with the prevalence of hiatal hernia.

Correlation analysis between different genotypes of CYP2C19, ERCC2 and XRCC1 and pathological indexes of gastroesophageal reflux and hiatal hernia in Xinjiang / 中国医师杂志

Objective The aim of this study was to investigate the correlation between different genotypes of CYP2C19,ERCC2 and XRCC1 and clinical indexes of gastroesophageal reflux and hiatal hernia in Xinjiang.Methods The clinical data of 101 patients with gastroesophageal reflux and hiatal hernia clinically diagnosed by people's hospital of Xinjiang Uygur Autonomous Region from January 2016 to December 2017 were prospectively studied,and Wilcoxon rank sum test was used to analyze the genotypes and relevant clinical indicators.Results There was statistically significant difference in the distance of hiatal hernia between patients with CYP2C19 containing A/A homozygous genotype and those with other two genotypes (A/G or G/G) (P ＜ 0.05),and there was statistically significant difference in intrabolus pressure (IBP) between patients with G/G homozygous genotype and those with A/G heterozygous genotype (P ＜0.05).Esophageal sphincter lower esophageal sphincter (LES) residual pressure,LES relaxation rate and percentage of invalid swallowing between patients with ERCC2 containing A/C heterozygous genotype and those with A/A homozygous genotype also has significant statistical difference (P ＜ 0.05).The more C contained in the genotype,the lower IBP maximum (on average),and this pattern has statistical significance (P ＜ 0.05);There was no statistical difference for all clinical indicators among different XRCC1 genotypes.Conclusions Different genotypes of CYP2C19 and ERCC2 are closely related to the clinical indexes of gastroesophageal reflux and hiatal hernia.CYP2C19 containing A/G or G/G genotype is correlated with gastroesophageal reflux disease (GERD) and the incidence of hiatal hernia.The population containing A/G and G/G genotypes of CYP2C19 may be with a high incidence of hiatal hernia.Homozygous G/G genotype may be a high risk factor for aggravating reflux esophagitis.A/C and C/C genotypes contained in ERCC2 genotype were correlated with the incidence of hiatal hernia.The more C bases contained in ERCC2 genotype,the greater the effect of reducing IBP,indicating that the more C bases contained in ERCC2 genotype may be negatively correlated with the prevalence of hiatal hernia.

Polimorfismos en los genes de la enzima alcohol deshidrogenasa (ADH1) y la citocromo P450 2E1 (CYP2E1) en pacientes con cirrosis y carcinoma hepatocelular / Polymorphisms in alcohol dehydrogenase (ADH1) and cytochrome p450 2E1 (CYP2E1) genes in patients with cirrhosis and/or hepatocellular carcinoma

Introducción. Uno de los principales factores de riesgo del carcinoma hepatocelular es el consumo crónico de alcohol. En estudios en diferentes poblaciones, se sugiere que las variantes genéticas de las enzimas que participan en el metabolismo del alcohol, como la alcohol deshidrogenasa (ADH) y la citocromo P450 (CYP2E1), estarían asociadas con riesgo de enfermedades hepáticas terminales. Objetivo. Identificar y caracterizar las variantes alélicas de los genes ADH1B, ADH1C y CYP2E1 en pacientes colombianos con diagnóstico de cirrosis y carcinoma hepatocelular. Materiales y métodos. Se incluyeron muestras de pacientes atendidos entre el 2005 y el 2007, y entre el 2014 y el 2016, en la unidad de hepatología de un hospital de Medellín. La genotipificación de las muestras se hizo mediante reacción en cadena de la polimerasa (Polymerase Chain Reaction, PCR) con análisis de los polimorfismos en la longitud de los fragmentos de restricción (Restriction Fragment Length Polymorphism, RFLP). Los resultados se compararon con los de dos grupos de control y con lo reportado en la base de datos del 1000 Genomes Project. Resultados. Se recolectaron 97 muestras de pacientes con diagnóstico de cirrosis y carcinoma hepatocelular. Los dos factores de riesgo más frecuentes fueron el consumo crónico de alcohol (18,6 %) y las colangiopatías (17,5 %). Los genotipos más frecuentes en la población de estudio fueron el ADH1B*1/1 (82 %), el ADH1C*1/1 (59 %) y el CYP2E1*C/C (84 %). Conclusiones. En este primer estudio de los polimorfismos en pacientes colombianos con diagnóstico de cirrosis y carcinoma hepatocelular, los genotipos más frecuentes fueron el ADH1B*1/1, el ADH1C*1/1 y el CYP2E1*C/C. No se observaron diferencias estadísticamente significativas en la frecuencia de los genotipos entre los casos y los controles. Se requieren estudios adicionales en población colombiana para evaluar el riesgo de la enfermedad hepática terminal por consumo crónico de alcohol y la asociación con los polimorfismos.

Introduction: One of the most important risk factors for hepatocellular carcinoma (HCC) is alcohol consumption: Studies in different populations suggest that the risk of liver disease could be associated with genetic variants of the enzymes involved in alcohol metabolism, such as alcohol dehydrogenase (ADH) and cytochrome P450 CYP2E1. Objective: To identify and characterize the allelic variants of ADH1B, ADH1C and CYP2E1 genes in Colombian patients with cirrhosis and/or HCC. Materials and methods: We included samples from patients attending the hepatology unit between 2005-2007 and 2014-2016 of a hospital in Medellin. Samples were genotyped using PCR-RFLP. We compared the results with two control groups and the 1000 Genomes Project database. Results: We collected 97 samples from patients with a diagnosis of cirrhosis and/or HCC. The two main risk factors were chronic alcohol consumption (18.6%) and cholangiopathies (17.5%). The most frequent genotypes in the study population were ADH1B*1/1 (82%), ADH1C*1/1 (59%), and CYP2E1*C/C (84%). Conclusions: This first study of polymorphisms in Colombian patients diagnosed with cirrhosis and/or HCC showed genotypes ADH1B*1/1, ADH1C*1/1 and CYP2E1*C/C as the most frequent. We found no significant differences in the genotype frequency between cases and controls. Further studies are necessary to explore the association between polymorphisms and the risk of end-stage liver disease from alcohol consumption.

Impacts of cytochrome P450 2D6 (CYP2D6) genetic polymorphism in tamoxifen therapy for breast cancer impactos do polimorfismo genético do citocromo P450 2D6 (CYP2D6) na terapia com tamoxifeno para câncer de mama

Abstract Tamoxifen (TMX) is the main drug used both in pre and postmenopausal women as adjuvant treatment for hormone receptor-positive breast cancer. An important barrier to the use of TMXis the development ofdrug resistance causedby molecular processes related to genetic and epigenetic mechanisms, such as the actions of cytochrome P450 2D6 (CYP2D6) polymorphisms and of its metabolites. The present study aimed to review recent findings related to the impact of CYP2D6 polymorphisms and how they can affect the results of TMX in breast cancer treatment. The keywords CYP2D6, tamoxifen, and breast cancer were searched in the PubMed, Scopus, The Cochrane Library, Scielo, and Bireme databases. Studies related to other types of neoplasms or based on other isoenzymes from cytochrome P450, but not on CYP2D6, were excluded. The impact of CYP2D6 polymorphisms in the TMX resistance mechanism remains unclear. The CYP2D6 gene seems to contribute to decreasing the efficacy of TMX, while the main mechanism responsible for therapy failure, morbidity, and mortality is the progression of the disease.

Resumo Otamoxifeno é a principal drogaque pode ser utilizada comotratamentohormonal adjuvante empacientesportadoras de câncer demamareceptor hormonal positivotanto na pré- quanto na pós-menopausa.Umadasmaiores barreirasemseu uso é o desenvolvimento de resistência medicamentosa causada por meio de processos moleculares relacionados a mecanismos genéticos e epigenéticos, como a ação dos polimorfismos do gene citocromo P450 2D6 (CYP2D6) e seus metabólitos.Opresente estudo busca revisar as descobertas recentes acerca dos impactos dos polimorfismos do gene CYP2D6 e de como eles podem afetar os resultados do tamoxifeno na terapêutica do câncer de mama. As palavras-chave CYP2D6, tamoxifeno e câncer de mama foram buscadas nas bases de dados Pubmed, Scopus, The Cochrane Library, Scielo e Bireme. Estudos relacionados com outros tipos de câncer ou relacionados a outras isoenzimas do citocromo P450 que não o CYP2D6 foram excluídos. O impacto do polimorfismo do CYP2D6 nos mecanismos de resistência ao tamoxifeno permanecem controversos. O gene CYP2D6 parece reduzir a eficácia do TMX; entretanto, os principais fatores associados a falha terapêutica são morbimortalidade e a progressão da doença

Relationship between metabolic rate of tacrolimus and BK virus infection early after renal transplantation / 器官移植

Objective To investigate the relationship between the metabolic rate of tacrolimus (FK506) and BK virus infection early after renal transplantation. Methods Eighty recipients undergoing allogenic renal transplantation in Institute of Organ Transplantation of the 309thHospital of Chinese People's Liberation Army were recruited in this study. The polymorphism of cytochrome P450 (CYP) 3A5 gene was detected in 80 recipients. All patients were divided into fast metabolism group ( CYP3A5*1/*3 and CYP3A5*1/*1 genotypes, n=38) and slow metabolism group ( CYP3A5*3/*3 genotype, n=42) based on the gene detection results. The distribution of CYP3A5 genotypes in 80 recipients was analyzed. The metabolic rate [concentration/dose ratio (C/D value)] of FK506 was statistically compared between two groups. The incidence of BK virus infection events [BK viruria, BK viremia and BK virus nephropathy(BKVN)] within postoperative 6 months were compared between two groups. Results Among 80 recipients, 5 cases (6%) were detected with CYP3A5*1/*1 genotype, 33 (41%) with CYP3A5*1/*3 genotype, and 42 (53%) with CYP3A5*3/*3 genotype. Among the 160 alleles in 80 recipients, 117 CYP3A5*3 allele were identified, suggesting that the mutation rate of CYP3A5*3 allele was 73.1%. In the fast metabolism group, the C/D values at postoperative 1, 3, and 6 months were significantly lower than those in the slow metabolism group (all P<0.01). The incidence rates of BK viruria in the fast and slow metabolism groups were 37% and 29%, 18% and 2% for BK viremia, and 3% and 0 for BKVN, respectively. In the fast metabolism group, the incidence of BK virenia was significantly higher than that in the slow metabolism group (P=0.02). The incidence of BK viruria and BKVN did not significantly differ between two groups (both P>0.05). Conclusions According to the CYP3A5 genotyping outcomes, the recipients with a high metabolic rate of FK506 have a high risk of BK viremia early after renal transplantation.

Effects of Triflusal and Clopidogrel on the Secondary Prevention of Stroke Based on Cytochrome P450 2C19 Genotyping / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: To compare the efficacy and safety of antiplatelet agents for the secondary prevention of ischemic stroke based on cytochrome P450 2C19 (CYP2C19) polymorphisms. METHODS: This study was a prospective, multicenter, randomized, parallel-group, open-label, blind genotype trial. First time non-cardiogenic ischemic stroke patients were enrolled and screened within 30 days. Participants were randomized to receive either triflusal or clopidogrel for secondary stroke prevention. The primary outcome was the time from randomization to first recurrent ischemic stroke or hemorrhagic stroke. RESULTS: The required sample size was 1,080 but only 784 (73%) participants were recruited. In patients with a poor CYP2C19 genotype for clopidogrel metabolism (n=484), the risk of recurrent stroke among those who received triflusal treatment was 2.9% per year, which was not significantly different from those who received clopidogrel treatment (2.2% per year; hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.60–2.53). In the clopidogrel treatment group (n=393), 38% had good genotypes and 62% poor genotypes for clopidogrel metabolism. The risk of recurrent stroke in patients with a good CYP2C19 genotype was 1.6% per year, which was not significantly different from those with a poor genotype (2.2% per year; HR, 0.69; 95% CI, 0.26–1.79). CONCLUSIONS: Whilst there were no significant differences between the treatment groups in the rates of stroke recurrence, major vascular events, or coronary revascularization, the efficacy of antiplatelet agents for the secondary prevention of stroke according to CYP2C19 genotype status remains unclear.

Hiccup Due to Aripiprazole Plus Methylphenidate Treatment in an Adolescent with Attention Deficit and Hyperactivity Disorder and Conduct Disorder: A Case Report

Our case had hiccups arising in an adolescent with the attention deficit and hyperactivity disorder (ADHD) and conduct disorder (CD) after adding aripiprazole treatment to extended-release methylphenidate. Actually, antipsychotics are also used in the treatment of hiccups, but studies suggest that they can cause hiccups as well. Within 12 hours of taking 2.5 mg aripiprazole added to extended-release methylphenidate at a dose of 54 mg/day, 16-year-old boy began having hiccups in the morning, which lasted after 3–4 hours. As a result, aripiprazole was discontinued and methylphenidate was continued alone because we could not convince the patient to use another additional drug due to this side effect. Subsequently, when his behavior got worsened day by day, his mother administered aripiprazole alone again at the dose of 2.5 mg/day at the weekend and continued treatment because hiccup did not occur again. But when it was administered with methylphenidate on Monday, hiccup started again next morning and lasted one hour at this time. In conclusion, we concluded that concurrent use of methylphenidate and aripiprazole in this adolescent led to hiccups.