Montserrat García

Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation

We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentrations (C0)/dose and higher dose requirements than nonexpressers throughout the study. Among CYP3A5*1 carriers, those also carrying the CYP3A4*1B allele showed the lowest C0/dose, as compared with CYP3A4*1/CYP3A5*3 carriers (54.28 ± 26.45, 59.12 ± 24.00, 62.43 ± 41.12, and 57.01 ± 17.34 vs. 112.37 ± 76.60, 123.21 ± 59.57, 163.34 ± 76.23, and 183.07 ± 107.82 at 1 week, 1 month, 5 months, and 1 year after transplantation). In addition, CYP3A4*1B/CYP3A5*1 carriers showed significantly lower dose‐corrected exposure than CYP3A4*1/CYP3A5*1 carriers 1 year after transplantation (57.01 ± 17.34 vs. 100.09 ± 24.78; P = 0.016). Only the ABCB1 TGC (3435‐2677‐1236) haplotype showed a consistent association with PDs (nephrotoxicity; OR = 4.73; CI: 1.3–16.7; P = 0.02). Our findings indicate that the CYP3A4*1B‐CYP3A5*1 haplotype may have a more profound impact in tacrolimus PKs than the CYP3A5*1 allele. This study does not support a critical role of the CYP450 or ABCB1 single nucleotide polymorphisms in the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus.

Factors predicting hospital readmissions related to adverse drug reactions.

ObjectiveTo analyse the contribution of adverse drug reactions (ADR) to hospital readmissions.MethodsThis was a case–control study in which unscheduled admissions of patients who had been admitted to the hospital during the two previous months were assessed during a 21-month period. The patient was considered a case when the main diagnosis of readmission complied with the World Health Organisation’s definition of an ADR. For each case, two controls were selected from those patients that had been admitted for ADR without readmission (n = 177). Information on drugs and other risk factors was obtained from cases by interview and from controls by clinical record review.ResultsThere were 26,559 unscheduled admissions of which 81 were readmissions associated with ADR (4.5% of the unscheduled readmissions). There were no statistically significant correlations with sex, age or medical history, with the exception of arterial hypertension. The main drug products causing readmission were acenocoumarol (15, 18.5%), antihypertensive-diuretics (14, 17.3%), anticancer drugs (11, 13.6%) and digoxin (seven, 8.6%). In the multivariate logistic analysis, the variables predicting readmission were acenocoumarol [odds ratio (OR) 12.2, 95% confidence interval (CI) 3.8–38.3, P < 0.0001], a record of diabetes mellitus (OR 2.6, 95% CI 1.3–5.5, P < 0.01), the number of drugs taken at the moment of ADR (OR 1.2, 95% CI 1.1–1.4, P < 0.001) and high blood pressure (OR 0.3, 95% CI 0.2–0.6, P < 0.001) even though the latter was a negative predictor, preventing readmission. Of the 81 readmissions associated with ADR, 28 (34.6%) were preventable.ConclusionA medical record of diabetes mellitus, polypharmacy and acenocoumarol treatment were risk factors predicting hospital readmission related to ADR.

Adenosine triphosphate‐binding cassette B1 (ABCB1) (multidrug resistance 1) G2677T/A gene polymorphism is associated with high risk of lung cancer

P‐glycoprotein (P‐gp) is a transmembrane transporter that is encoded by the adenosine triphosphate‐binding cassette B1 (ABCB1) (multidrug resistance 1) gene, which plays a role in cell defense against environmental attacks, like those generated by xenobiotics. P‐gp is expressed in the lung, where it has been suggested to transport these compounds from the interstitium into the lumen.

Domperidone in Parkinson’s Disease: A Perilous Arrhythmogenic or the Gold Standard?

Domperidone, a dopamine antagonist that does not easily cross the blood-brain barrier, is considered the gold standard for treating gastrointestinal symptoms in patients with Parkinsons disease (PD) because the risk of developing extrapyramidal adverse effects is considered minimal. On the other hand, cardiotoxicity related to domperidone is not a new issue. In fact, arrhythmias, sudden death and cardiac arrest were reported with high intravenous doses in the 80s. Concern about the cardiotoxicity of oral domperidone has arisen more recently after the publication of two case-control studies which have questioned domperidones safety even further, especially in patients > 60 years and in doses >30 mg/day. Very little is known about domperidones cardiac effects in patients with PD. In addtion, pharmacoepidemiological data about specific antiemetic use in these patients is scarce, with almost anecdotal reports of inappropriate centrally acting antidopaminergic drugs like metoclopramide in the hospital setting. As a result, and even no cases of serious arrhythmias or sudden cardiac death associated with domperidone concerning patients with PD have been reported, no definitive conclusions can be drawn about its safety. In conclusion, despite domperidone is still recognized as the first choice for treating gastrointestinal symptoms PD, doses above 30 mg/daily should only be considered with special caution taking into account its potential cardiotoxic effects.

CYP2C8*3 Polymorphism and Donor Age are Associated With Allograft Dysfunction in Kidney Transplant Recipients Treated With Calcineurin Inhibitors

Epoxieicosatrienoic acids (EETs) play a protective role against damaging processes in the kidney. We have assessed the effect of polymorphisms in EETs‐producing enzymes (CYP2C8 and CYP2J2) and other proteins involved in calcineurin inhibitors (CNIs) disposition (CYP3A4, CYP3A5, and ABCB1) on graft function and clinical outcome in 166 renal transplant recipients treated with CNIs. Both CYP2C8*3 and donor age greater than 48 years were associated to a higher incidence of delayed graft function (DGF) [OR = 2.01 (1.1–4.1), P = .04 and 5.14 (2.4–10.9), P < .0001; respectively] and worse creatinine clearance 1 year after grafting (P < .05 and P < .001, respectively). In addition, carrying 4–6 variants in the 3 ABCB1 loci and older donor age were individually associated to higher incidence of calcineurin‐inhibitor‐induced nephrotoxicity [OR = 2.38 (1.1–5.4), P = .03 and OR = 1.03 (1.01–1.06), P = .038]. Regression analyses confirmed the relevant effect of both CYP2C8*3 and donor age on graft dysfunction. Carrying the 2C8*3 allele and having a donor older than 48 years was defined as a high‐risk status and observed to be highly related to DGF [OR = 3.91 (1.46–10.48), P < .01] and worse creatinine clearance (P = .033). Our results show that genetic and clinical parameters can be combined to identify risk factors for allograft dysfunction in renal transplant recipients.

Adverse reactions to antipsychotics in Parkinson disease: an analysis of the Spanish pharmacovigilance database.

PurposeAlthough antipsychotics are well known for causing a plethora of adverse drug reactions (ADRs), the main concern when used to treat psychosis in Parkinson disease (PD) has traditionally been motor function worsening. The limited number of patients included in clinical trials contributes to underreport less common ADR. The aims of this study were to describe ADR to antipsychotics occurring in patients with PD notified to the Spanish Pharmacovigilance System and to contrast them with published reports. MethodsAll notifications from the Spanish Pharmacovigilance System for the last 30 years (1984-2014) where an antipsychotic was considered suspicious of the ADR in patients who were also on dopaminergic therapy were reviewed.In addition, a systematic search of MEDLINE (1966-2014) was conducted with the following Medical Subject Headings (MeSH) terms: “Parkinson disease” and “antipsychotic agents” or “psychotic disorders” and “drug-related side effects” or “adverse reactions.” ResultsForty-four notifications were selected for evaluation. Quetiapine was the most frequently implicated drug since 2002, and previously clozapine was the drug implied in higher number of notifications. The most severe ADR was neuroleptic malignant syndrome, which was described in 5 patients (3 cases related to quetiapine, one to haloperidol, and another to olanzapine). ConclusionsSome previously unreported ADRs caused by antipsychotic drugs in patients with PD have been described for the first time in this study, although there are in general well-known antipsychotic adverse effects. It is remarkable that some notifications involve the use of drugs not recommended in these patients.

La notificación directa por los pacientes de reacciones adversas a medicamentos en España

The Spanish Pharmacovigilance System for Medicinal Products for Human Use, integrated by regional centers of pharmacovigilance coordinated by the Spanish Agency for Medicines and Health Products, is responsible for developing the Program of Spontaneous Reporting of Suspected Adverse Drug Reactions in our country. Although, until now, reports were only requesting to health professionals, the current understanding of the role of patients in the clinical setting and the experience gained in other countries of our environment, have demonstrated the convenience of developing active participation systems to patients in the reporting of suspected adverse drug reactions. In addition, this is taking into account in the new European legislation on pharmacovigilance.

Inadequate drug prescription and the rise in drug-induced acute tubulointerstitial nephritis incidence

Drugs are a frequent cause of acute tubulointerstitial nephritis (ATIN). Antibiotics, non-steroidal anti-inflammatory drugs and recently proton pump inhibitors stand among the most commonly responsible ones. However, their respective responsibility is not well known. This study reports 33 cases of drug-induced ATIN (DI-ATIN), the most frequent ones being metamizole and omeprazole. Clinicians often fail to diagnose DI-ATIN because its signs and symptoms are non-specific and differ from the now classic form observed with methicillin. Furthermore, drugs causing ATIN are too often prescribed unnecessarily. This study shows that in more than one-fifth of our cases, ATIN complicated prescription of a drug that was not justified by an adequate clinical indication. The consequences were noxious for the patients and costly in terms of public health expenses.

Aripiprazole and impulse control disorders: higher risk with the intramuscular depot formulation?

Dopamine agonists have been associated with an increased risk of developing impulse control disorders (ICDs). The US Food and Drug Administration (FDA) issued a safety warning in 2016 of a possible association between ICDs and aripiprazole. Recently, one large epidemiological study has confirmed this risk. In the present study, we aim to determine whether the safety signal of ICDs associated with aripiprazole detected by the FDA is replicated in the European pharmacovigilance database (EudraVigilance). We searched for all suspected spontaneous cases of ICDs associated with aripiprazole in EudraVigilance up to 23 February 2017. To assess the association between ICD cases and each dopamine agonist drug, we calculated the proportional reporting ratios (PRRs). Among 4 905 110 events of all types recorded in EudraVigilance, we found 160 cases of ICDs associated with aripiprazole. Aripiprazole fulfilled the criteria to generate a safety signal; PRR (95% confidence interval): 16.39 (13.97–19.24). Notably, the association seemed the strongest for the depot formulation of aripiprazole; PRR (95% confidence interval): 27.13 (17.22–42.75). Our analysis of the data contained in EudraVigilance confirms the safety signal detected last year by the FDA. Interestingly, for the first time, we show that the association seems the strongest for the intramuscular depot formulation of aripiprazole.

Possible interaction between letrozole and long-acting injectable zuclopenthixol

Abstract Mrs A, a 68-year-old woman with paranoid schizophrenia, was on long-term psychiatric treatment with long-acting intramuscular zuclopenthixol, quetiapine and alprazolam when, in April 2012, she was diagnosed with right breast infiltrating ductal carcinoma. After starting treatment with letrozole on 4 July, Mrs A progressively developed extrapyramidal symptoms and these were particularly evident after each zuclopenthixol administration. On 9 January, both quetiapine and alprazolam were stopped due to excessive lethargy. After the administration of the last dose of zuclopenthixol on 26 January, she presented with sedation, sialorrhea, festinant gait, axial dystonia and dysphagia, all of which were severe. The introduction of letrozole was the only change that had been made to her pharmacotherapeutic regimen in that period. The rest of the findings on neurological examination were normal. Renal function was adequate. Slow symptom onset and progressive worsening until full-blown clinical presentation after 6 months, and the dramatic improvement in the clinical picture achieved 2 days after treatment with biperiden, suggests a long-term insidious interaction leading to zuclopenthixol accumulation. To the best of our knowledge, this is the first report of a possible interaction between letrozole and zuclopenthixol. We consider that it warrants further investigation. In the meanwhile, physicians should be aware of the occurrence of this potentially serious drug–drug interaction.