The aim of our study was to study the relationship between the CYP2C19 genetic polymorphism and the efficacy and safety of diazepam in patients with alcohol withdrawal syndrome in order to develop algorithms for optimizing the therapy of diazepam to reduce the risk of dose-dependent adverse drug reactions and pharmacoresistance.Materials and methods. The study was conducted on 30 Russian male patients suffering from alcohol withdrawal syndrome. For the treatment of anxiety, fear and emotional tension, patients received diazepam in injections at a dosage of 30,0 mg / day for 5 days. Genotyping was performed by real-time polymerase chain reaction with allele-specific hybridization. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions: the Clinical Institute Withdrawal Assessment for Alcohol scale, the visual-analogue scale of the craving for alcohol, and the side-effect scale.Results. Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP2C19 -806C>T genotypes: (CC) –12,0 [–15,0; –8,0], (CT + TT) –7.0 [–14,0; –5,0], p = 0,001. The scores on the UKU scale, which was used to evaluate the safety of therapy, were also different: (CC) 8,0 [6,0; 12,0], (CT + TT) 6,0 [6,0; 12,0], p = 0,006.Conclusion. The relationships between the CYP2C19 genetic polymorphism and the efficacy and safety of diazepam were demonstrated. This should be taken into consideration when prescribing this drug to such patients in order to reduce the risk of adverse drug reactions and pharmacoresistance.
Background Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are the two principal ingredients of natural cannabis with counteracting functions. Synthetic cannabinoids (SCs) are much more potent than natural cannabis, since they act as a more potent full agonist at the cannabinoid subtype 1 receptor than THC, and they also lack cannabinoids such as CBD that may otherwise counteract psychoactive properties of THC. Therefore, SCs may induce a more severe clinical presentation than natural cannabis does: the use of SCs may be associated with agitation, anxiety, tachycardia, hallucinations, irritability, memory and cognitive impairment, violent behavior, unresponsiveness, and psychosis. Clinical characteristics, specificity of the disease course and patient profile of the SC-induced psychoses are still poorly characterized in the scientific literature. The present study was therefore designed to evaluate the psychotic disorders in patients with synthetic cannabinoid use disorder in terms of patient profile and clinical characteristics with reference to their follow-up. Methods A total of 60 male patients (n=60; mean (standard deviation [SD]) age: 23.6 (3.5) years) diagnosed with psychotic disorder induced by the SC use who were hospitalized at the intensive care unit or emergency department of the Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare were included in this single-centre, longitudinal, observational cohort study. The catamnestic follow-up period was up to 2 years. Results We evaluated different clinical cases of SC-induced psychoses and identified four clinical types of them on the ground of leading psychopathological syndrome during the patient’s entire length of hospitalization: Then we performed a catamnestic follow-up of patients to reveal the possible schizophrenic process manifestation in patients who use SC. Catamnestic follow-up revealed that manifestation of the schizophrenic process was present in 8 patients (13% of cases). Discussion Our results revealed that SC-induced psychoses affect young adults primarily. Consistent with the statement that the majority of first-time SC users are experienced marijuana smokers, SC was used following other transitional substances rather than as the first substance in the majority of our patients, with cannabis being the most popular antecedent substance. SC was not the first substance used in the majority of our patients, and it had been preceded by use of other transitional substances, such as cannabis in most cases. Despite the exogenous nature, structurally such psychoses are often endoformic. For instance, even the delirium is atypical and includes the elements of Kandinsky-Clerambault’s syndrome. Psychopathologically hallucinations and delusions dominate in the clinical presentation of the psychoses (with predominant hallucinatory symptoms or affective paranoid symptoms). Development of substance-induced psychoses is often associated with the manifestation of the schizophrenic process (in our study it was revealed in 13% of cases). It is extremely difficult to create a differential diagnosis between such psychotic disorders and a primary endogenous psychotic episode. In such cases the appearance of deficit symptoms specific for schizophrenia becomes crucial.
Введение: Имплементация систем поддержки принятия решений, способных формировать рекомендации по выбору лекарствен- ного средства и его дозы в соответствии с результатами фармакогенетического тестирования, является актуальной задачей, так как решение ее позволит повысить эффективность терапии и снизить риск развития нежелательных лекарственных реакций.Материалы и методы: В исследовании принимал участие 51 пациент (21 - основная группа, получавшая назначения в соответ- ствии с рекомендациями, основанными на результатах фармакогенетического тестирования, а 30 - группа сравнения, получавшая назначения без них) мужского пола с синдромом отмены алкоголя. Для оценки эффективности и безопасности терапии синдрома отмены алкоголя, которую осуществляли с использованием бензодиазепинового транквилизатора феназепама (бромдигидрохлор- фенилбензодиазепина), а также стандартной дезинтоксикационной и витаминотерапии, применялись международные психоме- трические шкалы и шкалы оценки выраженности нежелательных реакций. Определение полиморфизмов генов CYP2D6*4 (1846G>A, rs3892097), CYP2C19*2 (681G>A, rs4244285), CYP2C19*3 (636G>A, rs4986893), CYP2C19*17 (-806C>T, rs12248560), CYP3A5*3 (6986A>G, rs776746) и ABCB1*6 (3435C>T, rs1045642) осуществлялось методом полимеразной цепной реакции в реальном времени с аллель-специфиче- ской гибридизацией. Интерпретацию результатов фармакогенетического тестирования осуществляли с использованием свободно распространяемого программного обеспечения PharmacoGenomeX2 (www.pgx2.com).Результаты: Получены статистически значимые различия в количестве баллов по всем психометрическим шкалам у пациентов основной группы и группы сравнения. Например, по шкале оценки тяжести синдрома отмены алкоголя к 3-му дню исследования количество баллов в основной группе составляло 13,5 [11,2; 16,0], а в группе контроля - 18,0 [17,0; 22,0] (p < 0,001); к 5-му в основ- ной группе - 6,5 [4,2; 8,0], в группе контроля - 15,0 [14,0; 16,0] (p < 0,001). По шкале безопасности UKU также была получена стати- стически значимая разница. К 3-му дню исследования количество баллов по шкале UKU в основной группе составило 6,0 [5,0; 7,0], а в группе контроля - 7,0 [6,0; 8,0] (p = 0,030); к 5-му дню разница возрастала. В основной группе - 5,5 [3,0; 9,0], в группе контроля - 14,0 [12,0; 19,0] (p < 0,001). Группы были репрезентативны (при включении в исследование разница в количестве баллов отсутствовала). Выводы: Персонализация дозы лекарств в соответствии с фармакогенетическими алгоритмами у пациентов с синдромом отмены алкоголя, способна снизить риск развития нежелательных реакций и фармакорезистентности, что позволяет рекомендовать исполь- зование фармакогенетических систем поддержки принятия решений для подбора дозы лекарств. Introduction: Implementation of the clinical decision support systems capable of forming the recommendations on drug and dose selec- tion according to the results of pharmacogenetic testing is an urgent task. Fulfillment of this task will allow increasing the efficacy of ther- apy and decreasing the risk of undesirable side effects.Materials and methods: The study involved 51 patients (21 - the main group receiving appointments in accordance with the recommenda- tions based on the results of pharamogenetic testing, and 30 - the comparison control group receiving appointments without them) male with alcohol withdrawal syndrome. In order to assess the effectiveness and safety of alcohol withdrawal syndrome, which was performed with the benzodiazepine tranquilizer of phenazepam (bromodihydrochlorophenylbenzodiazepine), as well as standard detoxification and vitamin therapy, international psychometric scales and scales of assessment in expressions of adverse reactions. Genotyping Determination of genetic polymorphisms CYP2D6*4 (1846G>A, rs3892097), CYP2C19*2 (681G>A, rs4244285), CYP2C19*3 (636G>A, rs4986893), CYP2C19*17 (-806C>T, rs12248560), CYP3A5*3 (6986A>G, rs776746) and ABCB1*6 (3435C>T, rs1045642) were realized using real-time polymerase chain reaction with allele specific hybridization. Interpretation of the results of pharmacogenetic testing was carried out with the help of free soft- ware PharmacoGenomeX2 (www.pgx2.com)Results: Statistically significant differences in the number of scores for all psychometric scales in the patients of the main group and the comparison group were obtained. For example, on the scale of assessing the severity of alcohol withdrawal syndrome by the 3rd day of the study, the score in the main group was 13.5 [11.2; 16,0], and in the control group - 18,0 [17,0; 22.0] (p <0.001); to the 5th in the main group - 6.5 [4.2; 8.0], in the control group - 15.0 [14.0; 16.0] (p <0.001). On the UKU security scale, a statistically significant difference was also obtained. By the 3rd day of the study, the UKU score in the main group was 6.0 [5.0; 7,0], and in the control group - 7,0 [6,0; 8.0] (p = 0.030); by the 5th day the difference increased. In the main group, 5.5 [3.0; 9.0], in the control group - 14.0 [12.0; 19.0] (p <0.001). The groups were representative (when included in the study, the difference in the number of points was absent).Conclusion: Personalization of the dose of drugs in accordance with pharmacogenetic algorithms in patients with alcohol withdrawal syn- drome, can reduce the risk of unwanted reactions and pharmacoresistance, which allows to recommend the use of pharmacogenetic deci- sion support systems for drug dosage selection.
Тревожные расстройства, занимая важное место в психиатрии, нередко коморбидны и с другими заболеваниями. При этом актуальным становится изучение факторов, влияющих на индивидуальные различия в эффективности препаратов и выраженности их побочных эффектов у разных пациентов. Одним из важнейших таких факторов является генетический. В данной работе исследовалось влияние полиморфизма 1846G>A гена CYP2D6 на показатели эффективности и безопасности препарата лексотана у пациентов с тревожными расстройствами и алкогольной зависимостью. Аnxiety disorders are considered a serious problem of psychiatry being comorbid with other states. In this context investigation of factors responsible for unequal drug efficiency and safety in different patients is needed. Among these factors, genetics is considered to be one of the most important. This study assessed the role of CYP2D6 gene polymorphism 1846G>A in Lexotan efficiency and safety in patients with anxiety disorders comorbid with alcoholism.
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