Use of CYP2D6 substrates and inhibitors during pain management with analgesic opioids: Drug-drug interactions that lead to lack of analgesic effectiveness.

BACKGROUND: Several opioids have pharmacogenetic and drug-drug interactions which may compromise their analgesic effectiveness, but are not routinely implemented into supportive pain management. We hypothesized that CYP2D6 phenotypes and concomitant use of CYP2D6 substrates or inhibitors would correlate with opioid analgesic outcomes. MATERIALS AND METHODS: An observational cross-sectional study was conducted with 263 adult chronic non cancer pain (CNCP) patients from a real-world pain unit under long-term CYP2D6-related opioid treatment (tramadol, hydromorphone, tapentadol or oxycodone). Metabolizer phenotype (ultrarapid [UM], normal [NM], intermediate [IM] or poor [PM]) was determined by the CYP2D6 genotype. The socio-demographic (sex, age, employment status), clinical (pain intensity and relief, neuropathic component, quality of life, disability, anxiety and depression), pharmacological (opioid doses and concomitant pharmacotherapy) and safety (adverse events) variables were recorded. RESULTS: The whole population (66 % female, 65 (14) years old, 70 % retired and 63 % attended for low back pain) were classified as PM (5 %), IM (32 %), NM (56 %) and UM (6 %). Multiple linear and logistic regressions showed higher pain intensity and neuropathic component at younger ages when using any CYP2D6 substrate (p = 0.022) or inhibitor (p = 0.030) drug, respectively, with poorer pain relief when CYP2D6 inhibitors (p=0.030) were present. CONCLUSION: The concomitant use of CYP2D6 substrates or inhibitors during opioid therapy for CNCP may result in lack of analgesic effectiveness. This aspect could be relevant for pharmacological decision making during CNCP management.

Co-prescription of metoprolol and CYP2D6-inhibiting antidepressants before and after implementation of an optimized drug interaction database in Norway.

PURPOSE: To compare the co-prescription of metoprolol and potent CYP2D6-inhibiting antidepressants before and during a 10-year period after implementation of an optimized drug interaction database into clinical decision support systems in Norway. METHODS: The study was a retrospective, cross-sequential nationwide analysis of drug-dispensing data retrieved from the Norwegian Prescription Database over a 1-year period before (2007) and two 1-year periods after (2012 and 2017) implementation of a drug interaction database providing recommendations on non-interacting alternative medications. Primary outcome was changes in co-prescription rates of metoprolol and the potent CYP2D6-inhibiting antidepressants fluoxetine, paroxetine, or bupropion relative to alternative antidepressants with no or limited CYP2D6 inhibitory potential. To control for potential secular trend bias, a comparison group consisting of atenolol/bisoprolol users was included. RESULTS: The co-prescription rate of metoprolol with potent CYP2D6 inhibitors declined following implementation of the optimized database, by 21% (P < 0.001) after 5 years and by 40% (P < 0.001) after 10 years. Compared with atenolol/bisoprolol users, patients treated with metoprolol had significantly reduced likelihood of being prescribed a CYP2D6-inhibiting antidepressant in the two post-implementation periods (OR 0.61 (95% CI 0.54-0.69) and OR 0.45 (95% CI 0.40-0.51), respectively, versus OR 0.84 (95% CI 0.74-0.94) prior to implementation). Small and mostly insignificant differences in average daily metoprolol dosage were found between patients treated with the various antidepressants. CONCLUSION: The present study suggests that implementation of a drug interaction database providing recommendations on non-interacting drug alternatives contributes to reduced co-prescribing of drug combinations associated with potentially serious adverse effects.

CYP2D6-inhibiting drugs and risk of fall injuries after newly initiated antidepressant and antipsychotic therapy in a Swedish, register-based case-crossover study.

Drug-drug interactions have been shown to affect the risk of fall injuries when opioids are used concomitantly with drugs inhibiting the cytochrome P450 2D6 (CYP2D6) enzyme in a previous pharmacoepidemiological study. The aim of this study was to determine whether CYP2D6-inhibiting drugs reinforce the risk of fall injuries when used concomitantly with antidepressants or antipsychotics. We identified all 252,704 adults with a first fall injury leading to hospitalisation from the National Patient Register in Sweden 2006-2013. Data on dispensed drugs was linked from the Swedish Prescribed Drug Register. We applied a case-crossover design to analyse newly dispensed (28 days preceding the fall injury, preceded by a 12-week washout period) antidepressants and antipsychotics, respectively, in relation to risk of a fall injury and according to concomitant use of CYP2D6-inhibiting drugs. Newly dispensed drugs were assessed correspondingly in a control period of equal length, 28 days prior to the 12-week washout period. Overall, the risk of fall injury was increased after newly initiated antidepressant and antipsychotic treatment. For antidepressants, concomitant CYP2D6 inhibitor use further elevated the risk estimates compared to non-use, most pronounced for the groups selective serotonin reuptake inhibitors (sertraline excluded) [OR = 1.47 (95% CI 1.19-1.80) vs. OR = 1.19 (95% CI 1.13-1.26)], and tricyclic antidepressants [OR = 1.71 (95% CI 1.17-2.51) vs. 1.27 (95% CI 1.11-1.47)] as well as for sertraline [OR = 1.61 (95% CI 1.05-2.38) vs. 1.12 (95% CI 1.00-1.26)]. For antipsychotics, the risk of fall injury was not altered by concomitant use of CYP2D6-inhibiting drugs. In conclusion, concomitant use of CYP2D6 inhibiting drugs tends to further increase the risk of fall injury in newly initiated antidepressant treatment, but not in antipsychotic treatment.

Saudi Heart Rhythm Society Task Force on Management of Potential Arrhythmogenicity Associated with Pharmacotherapy for COVID-19.

Evidence of cardiovascular complications associated with the COVID-19 global pandemic continues to evolve. These include direct and indirect myocardial injury with subsequent acute myocardial ischemia, and cardiac arrhythmia. Some results from a limited number of trials of antiviral medications, along with chloroquine/hydroxychloroquine and azithromycin, have been beneficial. However, these pharmacotherapies may cause drug-induced QT prolongation leading to ventricular arrhythmias and sudden cardiac death. Mitigation of the potential risk in these susceptible patients may prove exceptionally challenging. The Saudi Heart Rhythm Society established a task force to perform a review of this subject based on has recently published reports, and studies and recommendations from major medical organizations. The objective of this review is to identify high-risk patients, and to set clear guidelines for management of patients receiving these pharmacotherapies.

Psychiatric Aspects of Chloroquine and Hydroxychloroquine Treatment in the Wake of Coronavirus Disease-2019: Psychopharmacological Interactions and Neuropsychiatric Sequelae.

BACKGROUND: Chloroquine and hydroxychloroquine are among several experimental treatments being investigated in the urgent response to the coronavirus disease-2019. With increased use of these medications, physicians need to become knowledgeable of these drugs' neuropsychiatric side effects and interactions with psychiatric medications. OBJECTIVE: Clarify evidence base regarding the psychiatric side effects and psychiatric drug interactions of chloroquine and hydroxychloroquine. METHODS: A literature review was performed in PubMed from 1950 to 2020 regarding psychiatric topics and targeted pharmacological properties of chloroquine and hydroxychloroquine. RESULTS: First, chloroquine and hydroxychloroquine may mildly inhibit CYP2D6 metabolism of psychiatric medications, and psychiatric medications that interfere with CYP2D6 or CYP3A4 activity could alter chloroquine and hydroxychloroquine levels. Second, they may prolong the QT interval, warranting caution with concomitant prescription of other QT prolonging agents. Finally, neuropsychiatric side effects are very uncommon but possible and include a potentially prolonged phenomenon of "psychosis after chloroquine." Hydroxychloroquine has less information available about its neuropsychiatric side effects than chloroquine, with psychosis literature limited to several case reports. Weak evidence suggests a possible association of hydroxychloroquine exposure and increased suicidal ideation. It is not clear whether patients with psychiatric illness are more vulnerable to neuropsychiatric sequela of these medications; however, overdose of these medications by suicidal patients has high risk of mortality. CONCLUSION: The risk of neuropsychiatric side effects of chloroquine and hydroxychloroquine when used for coronavirus disease-2019 treatment is not known. Best practice may include suicide risk assessment for patients treated with hydroxychloroquine. However, delirium is expected to be a more likely etiology of neuropsychiatric symptoms in critically ill patients treated for coronavirus disease-2019, and adjustment disorder is a much more likely etiology of anxiety and depression symptoms than the side effects of chloroquine or hydroxychloroquine.

The impact of drug interactions on adverse effects of oral oxycodone in male geriatric patients.

WHAT IS KNOWN AND OBJECTIVE: With increased opioid use, drug-drug interactions (DDIs) and associated adverse events are growing among geriatric patients. However, the clinical significance of potential metabolic DDIs associated with opioid use has not been fully evaluated among geriatric patients. Particularly, cytochrome (CYP) P450 enzymes are important in drug metabolism of oxycodone and a black box warning for oxycodone reveals serious risks associated with drug-oxycodone interactions. This study focused on the use of oxycodone in geriatric patients to evaluate its adverse drug reactions (ADRs) and DDIs associated with CYP P450 enzymes. METHODS: A retrospective cohort study using patients treated at Korea Veterans Hospital was performed. Data from male patients aged 65 years and older who received oxycodone were analysed. Binomial variables describing patient-related characteristics, drug-related characteristics and CYP-mediating drugs were constructed. Associations between these variables and the frequency of ADRs were determined. The odds ratio (OR) and adjusted odds ratio (AOR) were calculated from univariable and multivariable analyses, respectively. RESULTS AND DISCUSSION: Among 111 patients, 32.4% experienced at least one ADR. The most common ADR was gastrointestinal-related (n = 21), followed by dizziness and drowsiness (n = 8). Use of either CYP2D6 inhibitors or CYP3A4 inhibitors increased the rate of ADRs by 20.4 and 25.4 times, respectively. In the case of patients taking both inhibitors, the adjusted OR was 48.6, and the attributable risk was 97.9%. WHAT IS NEW AND CONCLUSION: This study suggests that inappropriate combinations of oxycodone with CYP2D6 inhibitors and/or CYP3A4 inhibitors may warrant treatment modification to avoid ADRs in geriatric patients. Clinicians should monitor any signs of ADRs that may reflect DDIs while a geriatric patient is taking oxycodone.

Prevalência de coprescrição clinicamente significativa de psicofármacos inibidores da enzima CYP2D6 em usuários de um centro de atenção psicossocial / The prevalence of co-prescription of clinically relevant CYP enzyme inhibitor psychotropic drugs in psychosocial care center users

Objetivo: mensurar a prevalência da coprescrição de psicofármacos inibidores clinicamente significativos da enzima CYP2D6. Métodos: estudo transversal realizado com usuários do Centro de Atenção Psicossocial de um município da Amazônia Legal. Os dados foram coletados de prontuário (medicamentos e diagnóstico clínico) e questionário semiestruturado (sociodemográficos). As informações referentes às medicações (substrato/inibidor da CYP2D6) foram consultadas no Micromedex®, Drug Interaction Checker, Food and Drug Administration e The Pharmacogene Variation Consortium. Os dados foram interpretados utilizando estatística descritiva percentual simples, considerando a média e o desvio-padrão. Para a confecção do banco de dados, utilizou-se o Office Excel®2010. Estudo aprovado pelo Comitê de Ética em Pesquisa sob o Parecer nº 289.937. Resultados: participaram deste estudo 43 pessoas com média de idade de 40,98 (±11,04) anos, sendo 55,81% do sexo masculino, 81,39% solteiros, 88,37% não brancos (pretos/pardos), 58,14% estudaram até o ensino médio e 62,79% tiveram diagnóstico F20 (esquizofrenia e subdivisões). Entre a população estudada, 100% (43/43) faziam uso diário de haloperidol, e 95,34% (41/43) encontravam-se em uso rotineiro de mais de uma droga metabolizada pela enzima CYP2D6. Verificou-se que 93% (40/43) dos participantes continham coprescrição de substratos e inibidores da enzima CYP2D6, sendo a maior prevalência de prescrições envolvendo ácido valproico, clorpromazina, levomepromazina, prometazina e risperidona. Conclusão: o estudo pôde mensurar alta prevalência de coprescrição de psicofármacos inibidores clinicamente significativos da enzima CYP2D6.

Introduction: Clinically significant adverse drug reactions are seldomly frequent, but their incidence rises when there is co-prescription, especially psychoactive drugs metabolized by the enzyme CYP2D6. Objective: To measure the prevalence of co-prescription of clinically significant CYP2D6 enzyme inhibitors. Methods: Cross-sectional study conducted with users of the Center for Psychosocial Attention in a city of Legal Amazon. Sociodemographic, health and drug profile data were collected from patients' records. Possible enzymatic inductions or inhibitions were researched in Micromedex®, Drug Interaction Checker, Food and Drug Administration e The Pharmacogene Variation Consortium. The data were interpreted using simple percentage descriptive statistics, considering the mean and standard deviation. To make the database, Office Excel®2010 was used. The research has the approval of the Research Ethics Committee under opinion no. 289,937. Results: Forty-three people with a mean age of 40.98 (±11.04) years participated in this study, 24 (55.81%) men, 81,39% single, 88,37% non-white, 58,14% have high school and 62,79% were diagnosed with schizophrenia. Among the studied population, 100% (43/43) used haloperidol daily and 95.34% (41/43) used more than one drug inhibitor or metabolized by the CYP2D6 enzyme. It was found that 93% of the participants contained co-prescription of CYP2D6 substrates and inhibitors, with the highest prevalence of prescriptions involving valproic acid, chlorpromazine, levomepromazine, promethazine and risperidone. Conclusion: The study was able to measure the high prevalence of co-prescription of clinically significant CYP2D6 inhibitor drugs in the studied population.

Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia.

OBJECTIVE: To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD). METHOD: Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106). Patients began deutetrabenazine at 12 mg/day, titrating up to a dose that was tolerable and provided adequate dyskinesia control, based on investigator judgement, with a maximum allowed dose of 48 mg/day (36 mg/day for patients taking strong cytochrome P450 2D6 (CYP2D6) inhibitors). Safety measures included incidence of adverse events (AEs) and scales used to monitor parkinsonism, akathisia/restlessness, anxiety, depression, suicidality and somnolence/sedation. Efficacy endpoints included the change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 to 7) from baseline and the proportion of patients rated as 'Much Improved' or 'Very Much Improved' on the Clinical Global Impression of Change. RESULTS: A total of 343 patients enrolled in the extension study, and there were 331 patient-years of exposure in this analysis. The exposure-adjusted incidence rates of AEs with long-term treatment were comparable to or lower than those observed in the phase 3 trials. The mean (SE) change in AIMS score was -4.9 (0.4) at Week 54 (n = 146), - 6.3 (0.7) at Week 80 (n = 66) and -5.1 (2.0) at Week 106 (n = 8). CONCLUSIONS: Overall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD. TRIAL REGISTRATION NUMBER: NCT02198794.

How to Treat Hypertension in Venlafaxine-Medicated Patients-Pharmacokinetic Considerations in Prescribing Amlodipine and Ramipril.

BACKGROUND: Amlodipine (AMLO) and ramipril (RAMI) belong to the most prescribed drugs in patients with hypertension, a condition also encountered in depression. Venlafaxine may worsen hypertension because of noradrenergic properties. Although of special clinical relevance, data on pharmacokinetic interactions between AMLO, RAMI, and venlafaxine (VEN) are lacking. METHODS: Two TDM databases consisting of plasma concentrations of VEN and its active metabolite O-desmethylvenlafaxine (ODVEN) were analyzed. We considered a group of patients comedicated with AMLO, VAMLO (n = 22); a group comedicated with RAMI, VRAMI (n = 20); and a 4:1 control group age matched to the VAMLO group receiving VEN without confounding medications, V0 (n = 88). Plasma concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN); metabolic ratio (ODVEN/VEN); and dose-adjusted plasma concentrations (C/D) were compared using nonparametric tests. RESULTS: Groups did not differ in daily VEN dose, age, or sex. The metabolic ratio (ODVEN/VEN) was lower in the AMLO group (P = 0.029), whereas the RAMI group showed lower values for ODVEN (P = 0.029). All other parameters showed no significant differences. CONCLUSIONS: Significantly lower values for the metabolic ratio in the AMLO group are unlikely to be explained by cytochrome P450 (CYP) 3A4 and weak CYP2D6 inhibition by AMLO. Other factors such as differences in CYP2D6 polymorphisms and metabolizer status may better explain the findings. Ramipril showed modest effects with changes in ODVEN concentrations that did not remain significant after dose-adjusted comparisons.

The Underrated Risks of Tamoxifen Drug Interactions.

Tamoxifen is a prodrug, and most of the therapeutic effect in treating breast cancer stems from its metabolite, endoxifen. Since cytochrome P450 (CYP) 2D6 is the most important enzyme in the production of endoxifen, drugs that inhibit CYP2D6 would be expected to reduce tamoxifen efficacy. In addition to drug-drug interactions (DDI) involving CYP2D6, there is growing evidence that enzyme inducers can substantially alter the disposition of endoxifen, reducing tamoxifen efficacy. Although the clinical evidence on the impact of CYP2D6 inhibitors on tamoxifen efficacy is mixed, there were serious flaws in many of the studies. Thus, there is a reasonable chance that CYP2D6 inhibitors do in fact inhibit tamoxifen efficacy. Tamoxifen has extraordinarily complex pharmacokinetics, with more than a dozen drug-metabolizing enzymes and transporters involved in its disposition. Enzyme inducers may increase the activity of several of these pathways, including phase II enzymes, ABC transporters, and various CYP enzymes other than CYP2D6. Based on current clinical evidence, one could argue that enzyme inducers are potentially more dangerous than CYP2D6 inhibitors in patients taking tamoxifen. Moreover, early evidence suggests that the combination of CYP2D6 inhibitors plus enzyme inducers may produce catastrophic inhibition of tamoxifen efficacy. One could argue that, given the available evidence, an agnostic "wait and see" position on tamoxifen DDI is ethically untenable, and that many women with breast cancer are currently being subjected to an unnecessary risk of cancer recurrence. Specific recommendations to reduce the risk of adverse tamoxifen DDI are offered for consideration.

Clinical Outcomes of Concomitant Use of Warfarin and Selective Serotonin Reuptake Inhibitors: A Multidatabase Observational Cohort Study.

BACKGROUND: Patients treated with warfarin are often coprescribed selective serotonin reuptake inhibitors (SSRIs) for coexisting depression. Some SSRIs are potent CYP2C9 inhibitors that may increase warfarin plasma concentrations and the risk of bleeding. We aimed to examine the effect of the putative CYP2C9-mediated warfarin-SSRI interaction on clinical outcomes. METHODS: We conducted an observational cohort study among warfarin initiators who had a subsequent SSRI prescription in 5 US claims databases. Patients were followed for up to 180 days as long as they were exposed to both warfarin and their index SSRI groups. Cox regression models were used to estimate hazard ratios and 95% confidence intervals for bleeding events, ischemic or thromboembolic events, and mortality comparing patients treated with SSRIs that are potent CYP2C9 inhibitors (fluoxetine, fluvoxamine) with those treated with other SSRIs after propensity score matching. FINDINGS: The eligible cohort comprised 52,129 patients. Hazard ratios were 1.14 (95% confidence interval [CI], 0.94-1.38) for bleeding events, 1.03 (95% CI, 0.87-1.21) for ischemic or thromboembolic events, and 0.90 (95% CI, 0.72-1.14) for mortality. Results were consistent across individual component outcomes, different warfarin stabilization periods, and subgroup analyses. CONCLUSIONS: Patients concomitantly treated with warfarin and SSRIs that are potent CYP2C9 inhibitors had comparable rates of bleeding events, ischemic or thromboembolic events, and mortality as did patients cotreated with warfarin and other SSRIs, although small but potentially meaningful effects on bleeding cannot be completely excluded. SSRI inhibition of CYP2C9 does not appear to affect major safety or effectiveness outcomes of warfarin treatment in clinical practice, where patients may be closely monitored.

Delirium associated with concomitant use of duloxetine and bupropion in an elderly patient.

Delirium is common in daily practice. Drug-induced delirium constitutes approximately one-third of all cases of delirium. In cases characterized by the limited efficacy of a single antidepressant, a combination of two antidepressants is required, which may induce a complex drug-drug interaction. We reviewed a case of duloxetine- and bupropion-related delirium in an elderly male patient in our clinical practice. The patient was diagnosed with major depressive disorder and was treated with duloxetine. However, he developed delirium 10 days after bupropion was added to his treatment regimen. Three days after the cessation of bupropion, his delirious condition gradually improved. Duloxetine and bupropion are both cytochrome P450 2D6 inhibitors that may result in a higher level of hydroxybupropion. An increased level of hydroxybupropion may cause the elevation of dopamine and a risk of subsequent delirium. We should be aware of the risk of delirium induced by drug-drug interactions.

Antifungal agents for onychomycosis: new treatment strategies to improve safety.

Onychomycosis is a common and difficult-to-treat fungal infection of the nail unit that gradually leads to dystrophic changes of the nail plate and nail bed. If untreated, infection progresses and may lead to discomfort, reduced quality of life, and risk of complications in patients with comorbid conditions (eg, diabetes, human immunodeficiency virus, peripheral vascular disease). Onychomycosis treatments are designed to eradicate causative pathogens (most commonly Trichophyton rubrum and Trichophyton mentagrophytes), restore healthy nails, and prevent recurrence or spread of infection. Given the deep-seated nature of most cases of onychomycosis, an effective antifungal agent needs to achieve and maintain sufficient drug concentrations throughout the nail unit for the duration of healthy nail in-growth. Oral antifungal drugs are the most effective available therapy and are generally well tolerated, but may be limited by safety concerns and the potential for drug-drug interactions (DDIs). Thus, treating physicians and pharmacists must be cognizant of a patient's current medications; indeed, it may not be feasible to treat onychomycosis in patients with diabetes, heart disease, or depression because of the risk for DDIs. Current topical therapy is not associated with risk of DDIs. Tavaborole and efinaconazole, two recently approved topical agents, have demonstrated good nail penetration and high negative culture rates in clinical trials of patients with onychomycosis. This article provides the treating physician and pharmacist with information on the safety and effectiveness of current oral (allylamine, azole) and topical (ciclopirox, efinaconazole, tavaborole) treatment to aid in making informed treatment decisions based on the unique characteristics (medication history, comorbidities, nature of onychomycosis) of each patient.

Polimorfismos del gen CYP2D6 y su relación con la esquizofrenia / CYP2D6 gene polymorphisms and their relationship to schizophrenia

Introducción: La esquizofrenia es un trastorno psiquiátrico crónico notablemente heterogéneo, marcado por múltiples alteraciones biológicas sobre las cuales influyen numerosos factores genéticos y ambientales. Sin dudas los neurolépticos constituyen uno de los principales pilares en el tratamiento de esta afección. La enzima CYP2D6 participa en la fase I del metabolismo de estos fármacos.Objetivo: Mostrar el estado del conocimiento acerca de la relación entre los polimorfismos del gen CYP2D6 y la esquizofrenia. Métodos: Para esta revisión se llevó a cabo una búsqueda de artículos publicados en Pubmed/MEDLINE, que relacionaron la frecuencia de los genotipos CYP2D6 con la esquizofrenia y con el riesgo de reacciones adversas por el consumo de neurolépticos. Se utilizaron los artículos con texto completo e información novedosa sobre el tema. Desarrollo: Los individuos metabolizadores lentos tienen un riesgo incrementado de desarrollar reacciones adversas por el consumo de neurolépticos. Por otra parte, aunque los resultados que relacionan los genotipos metabolizadores lentos con el riesgo de esquizofrenia no coinciden en todos los casos, en algunas investigaciones se ha identificado como un factor protector para el desarrollo de esta enfermedad. Conclusiones: El estudio de polimorfismos del gen CYP2D6 puede contribuir a una terapia individualizada en el tratamiento de la esquizofrenia(AU)

Introduction: Schizophrenia is a chronic psychiatric disorder remarkably heterogeneous, marked by multiple biological alterations which influence on numerous genetic and environmental factors. Undoubtedly neuroleptics are one of the main pillars in the treatment of this condition. CYP2D6 is involved in phase I metabolism of these drugs. Objective: To show the state of knowledge about the relationship between polymorphisms of the CYP2D6 gene and schizophrenia. Methods: For this review was carried out a search of articles published in PubMed / MEDLINE, which linked the frequency of CYP2D6 genotypes with schizophrenia and the risk of adverse reactions from consumption of neuroleptics. Full text articles and new information on the subject were used.Development: slow metabolizers individuals have an increased risk of developing adverse reactions from consumption of neuroleptics risk. Moreover, although the results relating poor metabolizers genotypes with the risk of schizophrenia not match in all cases, in some research it has been identified as a protective factor for developing this disease. Conclusions: The study of gene polymorphisms of CYP2D6 can contribute to individualized therapy in the treatment of schizophrenia(AU)

Mirabegron: A new option in treating overactive bladder.

Antimuscarinic medications have long been the mainstay of drug treatment for overactive bladder. This article describes mirabegron, one of a new class of agents that relaxes the detrusor muscle directly via a beta3 adrenoceptor agonist. Mirabegron's efficacy on frequency, urgency, and urge incontinence was tested in several trials before its wide clinical introduction. However, caution is still needed as data are lacking on the drug's efficacy and safety in frail older adults and for long-term therapy.

Pharmacogenomics toward personalized tamoxifen therapy for breast cancer.

Tamoxifen has been used not only for the treatment or prevention of recurrence in patients with estrogen receptor positive breast cancers but also for recurrent breast cancer. Because CYP2D6 is known to be an important enzyme responsible for the generation of the potent tamoxifen metabolite, 'endoxifen', lots of studies reported that genetic variation which reduced its enzyme activity were associated with poor clinical outcome of breast cancer patients treated with tamoxifen. However, there are some discrepant reports questioning the association between CYP2D6 genotype and clinical outcome after tamoxifen therapy. Dose-adjustment study of tamoxifen based on CYP2D6 genotypes provides the evidence that dose adjustment is useful for the patients carrying reduced or null allele of CYP2D6 to maintain the effective endoxifen level. This review describes critical issues in pharmacogenomic studies as well as summarizes the results of the association of CYP2D6 genotype with tamoxifen efficacy.