Paulino A. Alvarez

QT alterations in psychopharmacology: proven candidates and suspects.

Psychotropics are among the most common causes of drug induced acquired long QT syndrome. Blockage of Human ether-a-go-go-related gene (HERG) potassium channel by psychoactive drugs appears to be related to this adverse effect. Antipsychotics such as haloperidol, thioridazine, sertindole, pimozide, risperidone, ziprasidone, quetiapine, olanzapine and antidepressants such as amitriptyline, imipramine, doxepin, trazadone, fluoxetine depress the delayed rectifier potassium current (IKr) in a dose dependent manner in experimental models. The frequency of QTc prolongation (more than 456 ms) in psychiatric patients is estimated to be 8%. Age over 65 years, tricyclic antidepressants (TCA), thioridazine, droperidol, olanzapine, and higher antipsychotic doses were predictors of significant QTc prolongation. In large epidemiological controlled studies a dose dependent increased risk of sudden death has been identified in current users of antipsychotics (conventional and atypical) and of TCA. Thioridazine and haloperidol shared a similar relative risk of SCD. Lower doses of risperidone had a higher relative risk than haloperidol for cardiac arrest and ventricular arrhythmia. No increased risk was identified in current users of selective serotonin reuptake inhibitors (SSRI). Cases of TdP have been reported with thioridazine, haloperidol, ziprazidone, olanzapine and TCA. Evidence of QTc prolongation with sertindole is significant and this drug has not been approved by the Food and Drugs Administration (FDA). A large trial is ongoing to evaluate the cardiac risk profile of ziprazidone and olanzapine. Selective serotonin reuptake inhibitors have been associated with QTc prolongation but no cases of TdP have been reported with the use of these agents. There are no reported cases of lithium induced TdP. Risk factors for drug induced LQT syndrome and TdP include: female gender, concomitant cardiovascular disease, substance abuse, drug interactions, bradychardia, electrolyte disorders, anorexia nervosa, and congenital Long QT syndrome. Careful selection of the psychotropic and identification of patients risk factors for QTc prolongation is applicable in current clinical practice.

Adverse drug reactions as a reason for admission to an internal medicine ward in Argentina.

BACKGROUND Adverse Drug Reactions (ADR) are a major cause of morbidity and mortality worldwide. In spite of this, ADR are largely underreported and unrecognized. PURPOSE Identify and characterize ADR related admissions to our internal medicine ward using a proactive multidisciplinary pharmacovigilance approach. METHODS Within 24 hrs of admission 1045 patients admitted to the Internal Medicine Ward between August 2010 and February 2012 were screened for possible or probable ADR related admissions. RESULTS Probable ADR accounted for 112 of 1045 admissions (10.7%, 95% Confidence Interval [CI]: 8.8-12.6%), of which only 16 (14.3%) were classified as unavoidable. NSAIDs were the drug group more commonly implicated in probable ADR-related admissions (17.0%), followed by antiplatelets (16.1%). In-hospital mortality of patients admitted due to probable ADR was 8.0% (95% CI: 2.9-13.1%). During this study period, 6% of internal medicine ward and 4% of critical care unit beds were occupied by patients with probable ADR. The estimated cost of care of these patients was 641,000 US dollars (USD). CONCLUSION ADR are a frequent reason for admission to an Internal Medicine Ward in Argentina. The culprit drugs and interactions are similar to those reported in the literature. The cost is substantial and most of the ADR are potentially avoidable.

Brugada electrocardiographic pattern induced by fever

Brugada syndrome is a major cause of sudden death in young adults. Fever has been described to induce a Brugada-type electrocardiogram in asymptomatic patients with a negative family history, to disclose Brugada syndrome and to increase the risk of death and induce T wave alternans in patients with diagnosed Brugada syndrome. Risk stratification is challenging and demands a careful evaluation. Here we present 2 case reports and review the literature.

Severe neutropenia in a renal transplant patient suggesting an interaction between mycophenolate and fenofibrate.

OBJECTIVE To describe a patient in whom initiation of micronized fenofibrate precipitated mycophenolate induced neutropenia. CASE SUMMARY A 57-year-old man was admitted to the hospital because of febrile neutropenia. He had undergone kidney transplantation seventeen years ago. The patients immunosuppressive maintenance regimen consisted of mycophenolate mofetil (MMF) 500 mg three times a day, and meprednisone 4 mg daily. His medical history included, hypertension treated with losartan 50mg daily, and dyslipidemia treated with ezetimibe 10mg /simvastatin 20mg for four years (until 2 weeks before admission when micronized fenofibrate 200 mg per day was started because of persistently elevated triglycerides levels. On presentation temperature was 37.8°C and initial laboratory tests showed 3130 White Blood Cell Count(WBC)/μL with neutropenia (absolute neutrophil count (ANC) 313/μL) Fenofibrate and mycophenolate mofetil were discontinued, piperacillin tazobactam 4.5gr three times a day and granulocyte stimulation factor 300 μg/day were started. Three days after admission WBC was 7280/μL, neutrophils: 22%, ANC: 1160/mm(3). Mycophenolate mofetil was restarted and granulocyte stimulation factor was discontinued. One month after discharge his WBC was 4480/μL and ANC 1926/μL. DISCUSSION The initiation of fenofibrate in a patient on stable and therapeutic doses of mycophenolate may have precipitated mycophenolate induced neutropenia, a well described, dose dependent phenomenon. Mycophenolic acid (MPA) displays a complex pharmacokinetic profile susceptible to potential significant interactions with fenofibrate. Since approximately 99% of MPA and fenofibrate bind to albumin, displacement may occur, leading to increased free MPA. Second competition of fenofibric acid for UGT1A9 an enzyme implicated in conjugation of MPA may have decreased its metabolism. The combination of these two effects may increase the risk of dose dependent neutropenia. Using the Interaction Probability Scale (DIPS), the interaction was designated as probable. CONCLUSIONS Until further evidence is available, when fenofibrate is started in a renal transplant patient on mycophenolate careful monitoring should be considered to avoid potentially fatal complications.

Drug-Induced QTc Interval Prolongation: A Multicenter Study to Detect Drugs and Clinical Factors Involved in Every Day Practice

OBJECTIVE The actual prevalence of drug induced QTc prolongation in clinical practice is unknown. Our objective was to determine the occurrence and characteristics of drug-induced QT prolongation in several common clinical practices. Additionally, a subgroup of patients treated with dextropropoxyphene of particular interest for the regulatory authority was analysed. RESEARCH DESIGN AND METHODS Medical history and comorbidities predisposing to QT interval prolongation were registered for 1270 patient requiring medical assistance that involved drug administration. Three ionograms and ECGs were performed: baseline, intra- and after treatment; QT interval was corrected with Bazzet formula. RESULTS Among patients, 9.9% presented QTc >450/470 ms, 3% QTc > 500 ms, 12.7% ΔQTc >30 ms and 5.2% ΔQTc >60 ms. QTc prolongation associated with congestive heart failure, ischemic cardiopathy, diabetes, renal failure, arrhythmias, hypothyroidism, and bradycardia. At univariate analysis, clarithromycin, haloperidol, tramadol, amiodarone, glyceryl trinitrate, amoxicillin + clavulanic acid, amoxicillin + sulbactam, ampicillin + sulbactam, fentanyl, piperacillin + tazobactam, and diazepam prolonged QTc. Prolongation remained significantly associated with furosemide, clarithromycin, glyceryl trinitrate and betalactamase inhibitors after multivariate analysis. CONCLUSION QT interval prolongation in everyday practice is frequent, in association to clinical factors and drugs that can be easily identified for monitoring and prevention strategies.

Pharmacovigilance and the Cardiovascular System: Two Sides to Every Story

PURPOSE The objective of the present study was to quantify the reported cardiovascular adverse reactions and adverse reactions to cardiovascular drugs to help to design and implement monitoring and prevention strategies. METHODS The pharmacovigilance unit (PU) is a peripheral effector of National Pharmacovigilance Center and receives adverse drug reactions notifications from 10 teaching hospitals. Data on adverse reactions beginning in 2004 and notified to the PU were extracted from the database. Cardiovascular adverse drug reactions and adverse reactions to cardiovascular drugs were identified using Medical Dictionary for Regulatory Activities (MedDRA), and the Anatomical Therapeutic Chemical (ATC) Classification System respectively. The reports of adverse reactions were classified according to their seriousness. RESULTS From 2004 to 2010, 2516 notifications were received (2383 adverse reactions, 106 lack of efficacy, 26 quality failures). These notifications included 151 cardiovascular adverse reactions and 594 adverse reactions caused by cardiovascular drugs. In the first group, of the 151 cardiovascular adverse reactions through MedDRA SOC classification caused by all ATC group classes, 118 (78.2%) were caused by non cardiovascular drugs. Among them antimicrobials (27,2%) and neurologic drugs (21,2%) were the most frequent. 22 (14.6%) adverse reactions were serious. Long QT syndrome, peripheral edema, hypotension, tachycardia, and bradycardia, were the most frequent. In the second group, of the 594 reports identifying adverse reactions involving all MedDRA SOCs but caused only by cardiovascular drugs, 559 reports (94.1%) were non cardiovascular adverse reactions. Enalapril and furosemide accounted for 65.2% there were 33 (5.6%) serious adverse reactions. The most frequent adverse reactions were hyponatremia, impaired renal function, hypokalemia, metabolic alkalosis, asymptomatic elevation of liver enzymes, hyperkalemia, hyperglycemia, edema, and cough. CONCLUSION Non-cardiovascular adverse reactions were the most frequent manifestation of adverse drug reactions caused by cardiovascular drugs and cardiovascular adverse reactions were most often caused by non cardiovascular drugs. This report highlights the importance of systematic evaluation of adverse drug reactions.

Recent Advances in Understanding and Managing Cardiomyopathy

Cardiomyopathy is a disease of the heart muscle leading to abnormal structure or function in the absence of coronary artery disease, hypertension, or valvular or congenital heart disease. Currently, cardiomyopathy is the leading diagnosis of heart transplant patients worldwide. Incorporation of next-generation sequencing strategies will likely revolutionize genetic testing in cardiomyopathy. The use of patient-specific pluripotent stem cell-derived cardiomyocytes for disease modeling and therapeutic testing has opened a new avenue for precision medicine in cardiomyopathy. Stem cell therapy, gene therapy, interfering RNA, and small molecules are actively being evaluated in clinical trials.

A Systematic Approach to Assess the Burden of Drug Interactions in Adult Kidney Transplant Patients

AIM Renal transplant patients are frequently subject to polypharmacy and drug-drug interactions. However, no previous study has systematically assessed the risk of drug interactions and Adverse Drug Reactions (ADRs) in this population. METHODS A total of 138 consecutive adult kidney transplant recipients admitted to our hospital between August 2010 and February 2012 were prospectively and systematically assessed by our pharmacovigilance team, within 24 hours of admission, to identify potential drug-drug interactions and probable ADRs. RESULTS As a consequence of the high number of medications per patient (7.8±0.2 drugs), a considerable number of drugdrug interactions were observed in this population, with an average of 5.6±0.4 drug interactions per patient. Moreover, a significant percentage of admissions (~10%) of kidney transplant patients were related to probable ADRs. Almost all these patients had at least one drug interaction that could have potentially contributed to the probable ADR. Of note, clinically significant (i.e. severe) drug interactions were more frequent among patients with ADRs (29% vs. 15%, p<0.01). Also, patients with ADRs were more likely to have started a medication 30 days before admission (38.5% vs. 10.4%, p < 0.01). Non-immunosuppressive drugs most commonly involved in severe interactions were omeprazole, magnesium sulphate, and statins. The most commonly observed interactions were: tacrolimus and omeprazole, mycophenolate and omeprazole, sirolimus and enalapril, mycophenolate and antivirals, and mycophenolate and magnesium sulphate. CONCLUSION Drug interactions were extremely frequent among kidney transplant recipients, and responsible for potentially avoidable ADRs. They should be carefully considered when following kidney transplant recipients.

Atypical imaging findings in a renal transplant patient with reversible posterior leukoencephalopathy syndrome: a case report.

BackgroundAtypical clinical and imaging findings in Reversible Posterior Leukoencephalopathy Syndrome are recognized with increasing frequency.Case reportWe report a case of an adult in his 5th decade immunosupressed with methilprednisolone, tacrolimus and micophenolate who two months after renal transplantation, multiple infections and an episode of humoral rejection became hypertensive with severe headaches, visual field abnormalities, seizures, left hemiparesis and hemineglect.Computed Tomography scan of the brain showed a hypo dense lesion in the left occipital lobe. Ischemic stroke was diagnosed and aspirin and permissive hypertension were indicated. Twelve hours later he developed left sided motor seizures and cortical blindness. Magnetic Resonance Image showed hyper intensity in T2 and FLAIR in both occipital lobes and a small area of cortical restricted diffusion in Diffuson Weighted Images in the left occipital lobe. With a diagnosis of Reversible Posterior Leukoencephalopathy Syndrome his blood pressure was controlled with intravenous labetalol, and two days later the neurologic findings returned to baseline and most Computed tomography findings resolved.ConclusionThis case underscores that in the appropriate setting Reversible Posterior Leukoencephalopathy Syndrome should be suspected and the clinician should not be misled by atypical clinical or imaging findings. In contrast to other pathologies that resemble Reversible Posterior Leukoencephalopathy Syndrome, with the right and timely treatment, signs, symptoms and images can be completely reversible.

Burden and consequences of retained cardiovascular implantable electronic device lead fragments after heart transplantation

We performed a retrospective review of 402 consecutive patients who underwent heart transplantation at our institution between January 2009 and March 2017. A retained cardiovascular implantable electronic device (CIED) fragment was identified after transplantation in 49 of the 301 patients (16.2%) with CIED at baseline. Patients with retained fragments had leads with longer dwell times (median 2596 [1982, 3389] vs 1384 [610, 2202] days, P < .001), higher prevalence of previously abandoned leads (14.3% vs 2.8%, P = .003), and dual‐coil defibrillator leads (98% vs 81%, P = .001) compared with patients without retained fragments. Five patients (10%) with retained CIED fragments underwent magnetic resonance imaging without adverse events. There was no difference in overall mortality between patients with and without CIED fragments (12% vs 11%, P = .81) Patients with retained fragments located in the superior vena cava had significantly higher fluoroscopic times (3.3 vs 2.9 minutes, P = .024) during subsequent endomyocardial biopsies. In a competing risk analysis, presence of a retained CIED fragment was associated with upper extremity deep venous thrombosis (sub hazard ratio [HR] 2.19, 95% confidence interval [CI] 1.17‐4.10, P = .014) but not bloodstream infection after adjusting for potential confounders. In summary, retained CIED fragments are common after heart transplantation, and are associated with longer radiation exposure during biopsy procedures and upper extremity deep venous thrombosis.