Carmelo Aguirre

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.

Selective Serotonin Reuptake Inhibitors and Gastrointestinal Bleeding: A Case-Control Study

Background Selective serotonin reuptake inhibitors (SSRIs) have been associated with upper gastrointestinal (GI) bleeding. Given their worldwide use, even small risks account for a large number of cases. This study has been conducted with carefully collected information to further investigate the relationship between SSRIs and upper GI bleeding. Methods We conducted a case-control study in hospitals in Spain and in Italy. Cases were patients aged ≥18 years with a primary diagnosis of acute upper GI bleeding diagnosed by endoscopy; three controls were matched by sex, age, date of admission (within 3 months) and hospital among patients who were admitted for elective surgery for non-painful disorders. Exposures to SSRIs, other antidepressants and other drugs were defined as any use of these drugs in the 7 days before the day on which upper gastrointestinal bleeding started (index day). Results 581 cases of upper GI bleeding and 1358 controls were considered eligible for the study; no differences in age or sex distribution were observed between cases and controls after matching. Overall, 4.0% of the cases and 3.3% of controls used an SSRI antidepressant in the week before the index day. No significant risk of upper GI bleeding was encountered for SSRI antidepressants (adjusted odds ratio, 1.06, 95% CI, 0.57–1.96) or for whichever other grouping of antidepressants. Conclusions The results of this case-control study showed no significant increase in upper GI bleeding with SSRIs and provide good evidence that the magnitude of any increase in risk is not greater than 2.

Dipeptidyl peptidase-IV inhibitors induced bullous pemphigoid: a case report and analysis of cases reported in the European pharmacovigilance database.

Bullous pemphigoid has been reported in association with gliptins. We describe a case, review the literature and analyse all cases of bullous pemphigoid recorded in the European pharmacovigilance database, EudraVigilance.

Serum protein binding of propofol in critically ill patients

Background: Disease‐induced modifications in the level of serum proteins may change the degree of binding of drugs highly bound to serum proteins.

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.

Influence of vitamin C on the absorption and first pass metabolism of propranolol

The effect of ascorbic acid on the availability of propranolol has been examined. After oral administration of propranolol 80 mg with or without ascorbic acid pretreatment (2 g), the plasma concentrations and urinary excretion of propranolol and its metabolites, 4-hydroxy-propranolol and propranolol-conjugated, were determined by HPLC. Compared to controls, vitamin C decreased the maximum concentration of propranolol from 463 to 334 nmol·l−1, and the area under the propranolol concentration-time curve (from 0 to 24 hours) from 3,13 to 1,96 μmol·l−1·h. The time to reach maximum propranolol concentration was increased from 1,9 to 2,7. The total amount of drug recovered in urine has also significantly diminished (from 12,6 to 4,29 mg). No change in elimination rate was observed, indicating that ascorbic acid had affected both the absorption process and the first pass metabolism. The heart-rate decreased less when propranolol was administered with ascorbic acid in comparison to control subjects, although this interaction has little biological importance.

Prevalence of CYP2C9 polymorphisms in the south of Europe

CYP2C9 is a major liver enzyme responsible of the metabolism of many clinically important drugs. The presence of CYP2C9 genetic polymorphisms has been associated with marked interindividual variability in its catalytic activity that could result in drug toxicity. Here we present frequencies of the most common CYP2C9 coding variants CYP2C9*2 (C430T) and CYP2C9*3 (A1075C) in representative samples of four regions from Spain (Basque Country, n=358; Catalonia, n=240; Central Spain, n=190 and Galicia, n=288) and one northern Italian region, (Verona, n=164), which range between 0.125 and 0.165 in the case of CYP2C9*2 and between 0.071 and 0.085 for CYP2C9*3. No significant differences between CYP2C9 allele frequencies were found comparing all the sampled populations. A more extensive comparative analysis using allele frequency data of populations widely spread over Europe was performed, showing significant differences in the CYP2C9*2 allele frequencies distribution between some of the regions, being quite homogeneous in the case of CYP2C9*3 variant. The results obtained show that above 40% of our samples carry a mutate allele, which can result in a poor metabolization of low therapeutic index drugs as oral anticoagulants (warfarin, acenocoumarol), oral antidiabetic drugs and some non-steroidal anti-inflammatory drugs. Our study constitutes both a large (n=1240) and robust allele frequency database on CYP2C9 polymorphisms, which represents one of the most numerous CYP2C9*2 and *3 database existing to date.

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.

Synergism between Prior Anisakis simplex Infections and Intake of NSAIDs, on the Risk of Upper Digestive Bleeding: A Case-Control Study

Background The aim of this study was to investigate the relationship between prior Anisakis infections and upper gastrointestinal bleeding (UGIB), and its interaction with non-steroidal anti-inflammatory drug (NSAID) intake. Methods/Principal Findings We conducted a hospital-based case-control study covering 215 UGIB cases and 650 controls. Odds ratios (ORs) with their confidence intervals (95% CIs) were calculated, as well as the ratio of the combined effects to the sum of the separate effects of Anisakis allergic sensitization and NSAIDs intake. Prior Anisakis infections were revealed by the presence of anti-Anisakis IgE antibodies specific to the recombinant Ani s 1 and Ani s 7 allergens used as the targets in indirect ELISA. Prior Anisakis infections (OR 1.74 [95% CI: 1.10 to 2.75]) and the intake of NSAIDs (OR 6.63 [95% CI: 4.21 to 10.43]) increased the risk of bleeding. Simultaneous NSAIDs intake and Anisakis allergic sensitization increased the risk of UGIB 14-fold (OR = 14.46 [95% CI: 6.08 to 34.40]). This interaction was additive, with a synergistic index of 3.01 (95% CI: 1.18–7.71). Conclusions Prior Anisakis infection is an independent risk factor for UGIB, and the joint effect with NSAIDs is 3 times higher than the sum of their individual effects.

CYP2C9 variants as a risk modifier of NSAID-related gastrointestinal bleeding: a case-control study.

Objective The aim of this study was to assess whether the CYP2C9*2 and/or *3 variants might modify the risk for NSAID-related upper gastrointestinal bleeding (UGIB) in NSAID users. Patients and methods We conducted a multicenter, case–control study in which cases were patients aged more than 18 years with a diagnosis of UGIB, and controls were matched (1 : 3) by sex, age, date of admission, and hospital. Exposure was defined as the mean number of defined daily doses (DDDs) of NSAIDs metabolized by CYP2C9 in the week preceding the index date. Three DDD categories were defined (0, ⩽0.5, and >0.5). Exposure was constructed taking both NSAID use and CYP2C9 polymorphisms into account. Patients of non-European origin were excluded from the analysis. Results A total of 577 cases and 1343 controls were finally included in the analysis: 103 cases and 89 controls consumed NSAIDs metabolized by CYP2C9, and 88 cases and 177 controls were CYP2C9*3 carriers. The adjusted odds ratios (aORs) of UGIB associated with the CYP2C9*2 and wild-type alleles proved to be similar [OR=8.79 (4.50–17.17) and 10.15 (2.92–35.35), respectively] and lower than those of the CYP2C9*3 allele [aOR=18.07 (6.34–51.53)] for consumers taking more than 0.5 DDDs of NSAIDs metabolized by CYP2C9. Grouping genotypes into carriers and noncarriers of the CYP2C9*3 variant resulted in aORs of 16.92 (4.96–57.59) for carriers and 9.72 (4.55–20.76) for noncarriers, where DDDs were greater than 0.5. Conclusion The presence of the CYP2C9*3 variant increases the risk for UGIB associated with NSAID for DDDs greater than 0.5. The presence of the CYP2C9*2 allele shows no such effect.