Severe Drug Interactions Research Articles

Hepatitis C virus reinfection after liver transplant: New chances and new challenges in the era of direct-acting antiviral agents.

The first interferon-free regimens have been approved for the treatment of patients with chronic hepatitis C virus (HCV). In the liver transplant (LT) setting, these regimens are expected to have an important effect, because graft loss due to HCV recurrence is a serious problem after LT. The response to the hitherto conventional treatment with pegylated interferon and ribavirin is poor. The significantly better response rates achieved with boceprevir-based and telaprevir-based triple therapy have led to better graft and patient survival rates, but severe drug interactions with immunosuppressants limit the feasibility of this therapy for LT patients. With the approval of sofosbuvir in January 2014, of simeprevir in May 2014, and of daclatasvir in August 2014, three antiviral agents are now available and promise to be applicable without relevant adverse effects or negative interactions with immunosuppressants. Thus, 2014 marks the beginning of a new era of treatment options for HCV recurrence after LT. Although safety and efficacy studies of several interferon-free regimens for patients with HCV recurrence after LT have achieved good preliminary results, reports of clinical experiences with LT patients are scarce. The lack of randomized studies, the small number of enrolled and carefully selected patients, and the heterogeneity of these studies make the results questionable. Real-life experiences are eagerly awaited so that clinicians can estimate the usefulness and the pitfalls of these new regimens. Additionally, the high costs of these agents may limit their accessibility for many patients. The aim of this review is to summarize the current experience with and the expectations of the new direct-acting antiviral agents for LT patients.

Gestion des interactions médicamenteuses

The risk of drug interactions in patients increases with the increasing number of drugs in the therapeutic regimens. To avoid or reduce them, management of these interactions is imperative. This management is to identify potential drug interactions by using the appropriate resources, to judge the clinical relevance, and to act accordingly with the prescriber. This article discusses the levels of severity of drug interactions and highlights the need for their management by presenting a part of the experience of the department of Pharmacovigilance EHU Oran. The intervention of the pharmacologist turns out beneficial by helping the clinician to manage risk associations in favor of better therapeutic efficacy and minimal side effects.

Pharmacotherapy of type 2 diabetes mellitus: an update on drug-drug interactions.

The incidence of type 2 diabetes mellitus is increasing rapidly, as are the associated co-morbidities. Consequently, it has become necessary for a diabetic patient to take multiple medications at the same time to delay progression of the disease. This can put patients at an increased risk of moderate to severe drug interactions, which may threaten patients' life or may deteriorate the quality of their life. Hence, managing drug-drug interactions is the cornerstone of anti-diabetic therapy. Most of the clinically important drug-drug interactions of anti-diabetic agents are related to their metabolic pathways, but drugs that compete for renal excretion or impair renal status can also play an important role. In this review, we have examined the clinical implications and underlying mechanisms of drugs that are likely to alter the pharmacologic response of or cause adverse events with antidiabetic drugs, and we have outlined safe and efficacious treatment modalities.

164P - Impact of Statins for the Treatment of Non-Small Cell Lung Cancer

ABSTRACT Aim: Lung cancer is still the leading cause of cancer mortality world-wide. Erlotinib is a novel EGFR tyrosine kinase inhibitor that has shown promising results in the treatment of patients with advanced NSCLC. HMG-CoA-reductase inhibitors (statins) have shown promising in-vitro activity against a large number of tumour cell lines. However, most statins are metabolized in the liver by CYP3A4 and therefore can lead to severe drug interactions when co-administered with drugs using the same pathway, like erlotinib. Fluvastatin and pitavastatin are metabolized by different pathways and are therefore no matter of drug interactions with erlotinib. Aims of this study were to investigate the cytostatic effects of fluvastatin, pitavastatin and simvastatin alone and in combination with erlotinib on 6 different NSCLC cell lines. Methods: Experiments were carried out with human NSCLC cell lines A549 (K-RAS mutation), Calu-6 (K-RAS mutation, P53 mutation), H1650 (EGFR mutation, erlotinib resistant), H1975 (EGFR mutation, erlotinib resistant), HCC 827 (EGFR mutation, erlotinib sensitive), H1993 (MET oncogene amplification).We investigated the activity of caspase 3 upon statin treatment by cleavage of specific flourescent caspase substrates. Inhibition of growth was assessed by MTS assays. Results: Statins lead to growth inhibition in all 6 NSCLC cell lines investigated in a dose dependant manner. Our data indicate that A549 and Calu-6 cells which harbour K-RAS mutations are most susceptible for this statin effect. Moreover statins induce caspase 3 activation which is accompanied by morphological changes typical for apoptosis. Interestingly, K-RAS mutated cells showed increased sensitivity to statins. Strikingly the combination of erlotinib and pitavastatin proved to be more effective in NSCLC cells harbouring K-RAS mutations, as this treatment led to a more pronounced inhibition of growth in contrast to each drug alone. A trend to additional effects was observed in H1650, H1975 and H1993 cells however, these effects were not statistically significant. Conclusions: Our data indicate, that especially NSCLC cell lines with K-RAS mutations are most susceptible to statin induced apoptosis and growth inhibition. Furthermore co-treatment with statins led to a higher sensitivity to erlotinib in K-RAS mutated cell lines. Disclosure: All authors have declared no conflicts of interest.

New Antiretroviral Therapies and Potential Drug Interactions in HIVInfected Drug Abusers

Substance abuse remains a major obstacle in treating HIV-infected patients. The high prevalence of drug use is responsible for lack of adherence and severe drug interactions to antiretroviral therapy in HIV positive individuals. Over the past decade, newer therapies for HIV have been developed by targeting different stages of HIV life cycle. Of importance, targeting initial binding with receptor and genome integration by CCR5 antagonists and integrase inhibitors, respectively have been effective in reducing viral loads in clinical trials. However, most of these recently approved or investigational antiretroviral drugs are also metabolized by cytochrome P450 (CYP) enzymes. Thus, substance abuse mediated changes in level of CYP enzymes (induction or inhibition) may result in severe drug interactions, failure of therapy, rapid progression to AIDS, and increased mortality in HIV patients who are treated with regimens containing CCR5 antagonists and integrase inhibitors. In this review, we have discussed the pharmacokinetic data, efficacy, lack of adherence to these therapies in drug abusers, and CYP-mediated potential drug interactions for CCR5 antagonists and integrase inhibitors in HIV-infected drug abusers.

Drug-drug interactions and their predictors: results from Indian elderly inpatients

In view of the multiple co-morbidities, the elderly patients receiving drugs are prone to suffer with drug interactions since they receive a greater number of drugs. The study was undertaken to determine the prevalence of drug interactions, as well as their predictors. The prescriptions of a total of 1510 inpatients were collected prospectively for 1.5 years from inpatients wards of public tertiary care teaching hospital. All the prescriptions were checked for drug interactions using the Micromedex® Drug-Reax database-2010 and Stockley's Drug Interactions. Regression analyses sought to determine predictors for the drug interaction. The patients, with the average age of 67.2 ±0.2 years, were prescribed an average of 9.15 ±0.03 medications. It was found that out of 1510 prescriptions of inpatients, 126 (8.3%) prescriptions had one or more than one drug interaction. All the identified interactions were severe in nature. The top most interacting drugs were acetylsalicylic acid and anticoagulant (n=59). The second top most interacting drug combination was clopidogrel and proton pump inhibitors (n=51). The most commonly involved drugs in interactions were C (cardiovascular system) and A (alimentary tract and metabolism). Using multivariate binary logistic regression, multiple drugs (Odds Ratio=4.5; 95% Confidence Interval: - 2.38 -9.47) and multiple diagnoses (Odds Ratio=2.6; 95%CI: -1.40 -5.57) were found to be significant predictors for drug interaction. The results of this study substantiate the occurrence of severe drug interactions among Indian elderly inpatients. In order to provide safer pharmaceutical care, the active involvement of clinical pharmacists is a potential option.

Polypharmacy and the management of the older cancer patient

Aging is associated with polymorbidity and polypharmacy. In the absence of a consensual definition, polypharmacy has been defined according to the number of drugs that an individual takes or to the presence of the risk of at least one severe drug interaction. In older cancer patients, polypharmacy is at least as common as it is in individuals of the same age without cancer. The management of cancer itself may result in the addition of more medications to counteract the adverse effects of antineoplastic treatment. Polypharmacy may be necessary to control the multiple health conditions of the older person, but it may represent a risk factor for more complications from antineoplastic therapy, and it may affect the outcome of cancer treatment. Polypharmacy is also associated with increased cost. The criteria proposed for the management of polypharmacy include the assessment that all medical conditions are properly treated, the avoidance of drug interactions, and of drugs that may compromise the outcome of antineoplastic treatment and the choice of drugs with the lowest risk of complications in older individuals.

Effects of Fatty Acids and Glycation on Drug Interactions with Human Serum Albumin

The presence of elevated glucose concentrations in diabetes is a metabolic change that leads to an increase in the amount of non-enzymatic glycation that occurs for serum proteins. One protein that is affected by this process is the main serum protein, human serum albumin (HSA), which is also an important carrier agent for many drugs and fatty acids in the circulatory system. Sulfonylureas drugs, used to treat type 2 diabetes, are known to have significant binding to HSA. This study employed ultrafiltration and high-performance affinity chromatography to examine the effects of HSA glycation on the interactions of several sulfonylurea drugs (i.e., acetohexamide, tolbutamide and gliclazide) with fatty acids, whose concentrations in serum are also affected by diabetes. Similar overall changes in binding were noted for these drugs with normal HSA or glycated HSA and in the presence of the fatty acids. For most of the tested drugs, the addition of physiological levels of the fatty acids to normal HSA and glycated HSA produced weaker binding. At low fatty acid concentrations, many of these systems followed a direct competition model while others involved a mixed-mode interaction. In some cases, there was a change in the interaction mechanism between normal HSA and glycated HSA, as seen with linoleic acid. Systems with only direct competition also gave notable changes in the affinities of fatty acids at their sites of drug competition when comparing normal HSA and glycated HSA. This research demonstrated the importance of considering how changes in the concentrations and types of metabolites (e.g., in this case, glucose and fatty acids) can alter the function of a protein such as HSA and its ability to interact with drugs or other agents.

Geriatric Pharmacotherapy and Adverse Events

Geriatric Pharmacotherapy and Adverse Events

Mycobacterium tuberculosis Infections in Solid Organ Transplantation

Mycobacterium tuberculosis Infections in Solid Organ Transplantation

POSSIBLE TOXIC EFFECTS OF BENZODIAZEPINES;

Introduction: Benzodiazepines and its derivatives are used widely as anxiolytics, hypnotics, seizure control and as musclerelaxants. Design: The prescriptions of 270 patients were evaluated for moderate to severe drug interactions using drug interactiondetection software. Setting: Teaching hospital in Gujrat, Pakistan. Objective: This study is used to evaluate the possible toxic effects ofbenzodiazepine related drug-drug interactions in prescriptions of indoor patients. Material & Methods: The prescriptions wereprocessed through a software program named, The Medical Letter Adverse Drug Interaction program. The randomly collected patientchart profiles included both male and female patients ranging from age of few months old children to old aged patients. Result: Out of 270patients medication charts 210 medication charts were having at least one or more drug interactions ranging from moderate to severe.Out of 80 interacting drug combinations found, 15 were benzodiazepine related drug interactions. So, percentage of benzodiazepinesrelated drug interactions was 18.75%.Moreover, the data also showed that the percentage of DDIs increases as the prescription sizeincreases. Our results indicate that hospitalized patients in Pakistan are at risk of ADRs caused by potential DDIs. Moreover, there arechances that the safe therapeutic doses of benzodiazepines may become toxic or ineffective due to drug-drug interactions andpolypharmacy. Conclusions: So, the use of DDIs detection software programs in hospitals and pharmacies should be promoted in orderto minimize drugs especially benzodiazepines related injuries and to ensure patient safety.

Prevalência de interações medicamentosas em unidades de terapia intensiva no Brasil

OBJETIVO: Determinar a prevalência de interações medicamentosas em unidades de terapia intensiva e analisar a significância clínica das interações identificadas. MÉTODOS: Estudo multicêntrico, transversal e retrospectivo desenvolvido com 1124 pacientes em sete unidades de terapia intensiva (UTI) de hospitais de ensino no Brasil. As informações sobre os medicamentos administrados com 24 horas e 120 horas de internação foram obtidas nas prescrições. RESULTADOS: Em 24 horas 70,6% dos pacientes apresentaram pelo menos uma interação medicamentosa. O número de interações medicamentosas detectadas em 24 horas foi 2299 e em 120 horas foi 2619. Midazolam, fentanil, fenitoína e omeprazol foram os fármacos com maior frequência de interações medicamentosas. CONCLUSÃO: Nesta amostra, interações medicamentosas moderadas e graves foram mais prevalentes. Diante desses resultados, todas as ações dos profissionais de saúde que prestam assistência ao paciente devem ser integradas visando identificar e prevenir possíveis eventos a medicamentos.

Agreement among four drug information sources for the occurrence of warfarin drug interactions in Brazilian heart disease patients with a high prevalence of Trypanosoma cruzi infection

The aim of this study was to assess the agreement of four renowned interaction lists on potentially severe warfarin drug interactions (DI) in outpatients at a university hospital in Brazil, specifically in subgroups of Trypanosoma cruzi-infected and non-infected patients and those with previous bleeding episodes. This was a cross-sectional study in which adult outpatients with heart disease and indications for chronic warfarin use were enrolled. The occurrence of potentially severe warfarin DI was evaluated based on the lists provided by three compendia, i.e., Drug Interaction Facts (DIF), Drug Interactions: Analysis and Management (DIAM) and DRUG-REAX, and by the World Health Organization (WHO) Model Formulary. A kappa coefficient was used to calculate the agreement among the sources. A total of 280 patients were studied. Most patients were female (54.6 %) with an average age of 56.8 (standard deviation 13.1) years. The agreement among the four sources was fair (Fleiss' kappa coefficient = 0.295). T. cruzi-infected individuals were less likely to have severe warfarin DI than non-infected patients (p < 0.05 for DIAM, DRUG-REAX and the WHO Model Formulary). Potentially severe DI were more frequent in patients with previous bleeding episodes, based on the DIF compendia (p = 0.007). This evaluation of warfarin DI revealed that the disagreement between compendia is also observed in clinical practice. T. cruzi infection is associated with a lower prevalence of potentially severe warfarin DI, but with a wider variation in its detection. Our results suggest a wide spectrum of discrepancies in detecting heart disease patients at higher risk for severe warfarin DI and a possible heterogeneity in clinical guidance.

Analysis of cytochrome P450 gene polymorphism in a lupus nephritis patient in whom tacrolimus blood concentration was markedly elevated after administration of azole antifungal agents

Both itraconazole (ITCZ) and voriconazole (VCZ) are potent inhibitors of cytochrome P450 (CYP) 3A, and their effects have been reported to be equal. However, ITCZ is metabolized by CYP3A, whereas VCZ is mainly metabolized by CYP2C9 and CYP2C19 and only partially by CYP3A. We experienced the case of a patient who showed a 5-fold increase in trough levels of tacrolimus (FK) level after switching from ITCZ to VCZ. Our objective is to discuss the mechanism of the increase drug-drug interaction in terms of serum concentration of the azole drugs and patient pharmacogenomics. A 53-year-old woman was treated with FK (1 mg/day) for lupus nephritis. Because fungal infection was suspected, she received ITCZ (100 mg/day). When ITCZ was replaced with VCZ (400 mg/day), the blood concentration of FK increased markedly from 6·1 to 34·2 ng/mL. During coadministration with FK, the levels of ITCZ and VCZ were 135·5 ng/mL and 5·5 μg/mL, respectively, with the VCZ level around 3-fold higher than the previously reported level (1·4-1·8 μg/mL). Her CYP genotypes were CYP2C19*1/*2, CYP3A4*1/*1 and CYP3A5*3/*3. The patient was a CYP2C19 intermediate metabolizer (IM) and deficient in CYP3A5. The increase in plasma VCZ level appears to have been at least in part, associated with the CYP2C19 IM phenotype. One possible explanation for the marked increase in blood FK concentration was increased inhibition of CYP3A because of the impaired metabolism and subsequent increased plasma concentration of VCZ. This case shows that the severity of drug interactions may be influenced by metabolic gene polymorphism.

Rational drug prescribing for elderly inpatients in a Brazilian hospital: A pilot study

Inadequate prescriptions are one of the biggest causes of adverse events related to medications. The aim of this study was to evaluate rational drug prescribing for elderly inpatients. A cross-sectional study was conducted to monitor the quality of drug prescriptions of patients admitted from May to August 2009, in a cardiovascular ward in Brazil. The quality evaluation of drug prescribing for elderly inpatient medication appropriateness was assessed by detection of potentially inappropriate medications, therapeutic duplicity and drug interactions. A total of 62 elderly inpatients were included, 71% were female, median age was 77.5 years. Number of medications prescribed was 3818, ranging from 3 to 25 medications per prescription. Polypharmacy was highly common (86%) in analyzed prescriptions. 370 prescriptions were analyzed (6 prescriptions per patient). We reviewed 370 medication orders (3818 prescribed drugs), 34% of which had at least one potentially inappropriate medication for the elderly, 70% presented therapeutic duplicity. Drug interactions were detected in 77% of prescriptions. Positive associations were observed between therapeutic duplicity and potentially inappropriate medications and between therapeutic duplicity and severe drug interactions. Our study show high rate of inappropriate prescriptions, which can influence the effectiveness of pharmacotherapy as much as the elderly safety. Key words: Rational drug prescribing, elderly, inpatients.

Towards Safer and More Predictable Drug Treatment - Reflections from Studies of the First BCPT Prize Awardee

This MiniReview is a personal recollection of selected research topics, which the author in collaboration with colleagues has studied, aiming to improve the predictability of drug therapy. In early studies, we found bi- and trivalent cations to reduce the absorption of various tetracyclines and fluoroquinolones. Certain antacids elevated the bioavailability of some non-steroidal anti-inflammatory drugs and sulphonylureas. Various brands of phenytoin tablets revealed great differences in their bioavailability, causing clinical consequences. Numerous factors affecting the antidotal effect of activated charcoal were also studied, with charcoal compared to other gastrointestinal decontamination methods, including ipecac and gastric lavage. Effect of age and diseases on the pharmacokinetics of drugs was a research topic. Acute sotalol intoxications revealed its QT-prolonging properties, and even small mixed overdoses of moclobemide with serotonergic drugs proved fatal. Itraconazole and other potent inhibitors of CYP3A4 could drastically increase exposure to drugs like midazolam, triazolam, buspirone, lovastatin, simvastatin and oxycodone, whereas rifampicin greatly reduced their plasma concentrations. A change from potent inhibition to induction caused a 400-fold change in the exposure to oral midazolam. CYP2C8 was revealed to be crucial in the metabolism and interactions of several drugs. Many interactions affecting statins are CYP3A4-mediated, but transporters are important in certain interactions. Tizanidine is very susceptible to CYP1A2 inhibition. Fruit juices such as grapefruit juice can raise or lower exposure to different drugs. Both drug interactions and pharmacogenetics can modify the activity of cell membrane transporters and cause variability in the pharmacokinetics of and response to their substrate drugs.

Prevalence of potential drug interactions in an Iranian general hospital

The hazards of prescribing many drugs, including side-effects, drug-drug interactions and difficulties of compliance have long been recognized as particular problems when prescribing. This study estimates the rate and factors associated with potential drug-drug interactions in prescriptions from wards of An Iranian General Hospital. Data were retrieved from the pharmacy of a general hospital (200 beds) during one year period 2010. Potential drug-drug interaction were identified using a computerized drug-drug interaction database system (Prescription Analyzer 2000, Sara Rayane Co., Iran). Patients of both genders and 15 years-old or more were included in this study. Prescriptions with two or more drugs prescribed were selected during one year period 2010. Gender number of drugs and therapeutic drug classes on prescriptions were explored as associated factors to drug-drug interaction. The overall prevalence of potential drug-drug interaction was 20.3%. The risks of severe potential drug interactions were relatively high and the rate of potential drug-drug interaction was significantly higher in women (60.6%) and the patients aged over 60 years old (57.1%). The frequency of the potentially severe drug-drug interaction was 10.8% with digoxin-furosemide as the most common interacting pair (5.91%). A positive correlation was found between drug-drug interaction, patient's age, number of drugs and drugs acting on cardiovascular system. So cardiology women inpatients, age more then 60 years old, and patients prescribed digoxin and angiotensin-converting enzyme inhibitors should be closely monitored for adverse outcomes from drug-drug interaction.

Managing atrial fibrillation in the elderly: critical appraisal of dronedarone

Atrial fibrillation is the most commonly seen arrhythmia in the geriatric population and is associated with increased cardiovascular morbidity and mortality. Treatment of the elderly with atrial fibrillation remains challenging for physicians, because this unique subpopulation is characterized by multiple comorbidities requiring chronic use of numerous medications, which can potentially lead to severe drug interactions. Furthermore, age-related changes in the cardiovascular system as well as other physiological changes result in altered drug pharmacokinetics. Dronedarone is a new drug recently approved for the treatment of arrhythmias, such as atrial fibrillation and/or atrial flutter. Dronedarone is a benzofuran amiodarone analog which lacks the iodine moiety and contains a methane sulfonyl group that decreases its lipophilicity. These differences in chemical structure are responsible for making dronedarone less toxic than amiodarone which, in turn, results in fewer side effects. Adverse events for dronedarone include gastrointestinal side effects and rash. No dosage adjustments are required for patients with renal impairment. However, the use of dronedarone is contraindicated in the presence of severe hepatic dysfunction.

Drug interactions in palliative care – it’s more than cytochrome P450

Objective: This study aims to identify the combination of substances with high potential for drug interactions in a palliative care setting and to provide concise recommendations for physicians. Methods: We used a retrospective systematic chart analysis of 200 consecutive inpatients. The recently developed and internationally advocated classification system OpeRational ClAssification of Drug Interactions was applied using the national database of the Federal Union of German Associations of Pharmacists. Charts of patients with potential for severe DDIs were examined manually for clinical relevance. Results: In 151 patients (75%) a total of 631 potential drug interactions were identified. Opioids (exception: methadone), non-opioids (exception: non-steroidal anti-inflammatory drugs), benzodiazepines, proton-pump inhibitors, laxatives, co-analgesics (exception: carbamazepine) and butylscopolamine were generally safe. High potential for drug interactions included combinations of scopolamine, neuroleptics, metoclopramide, antihistamines, non-steroidal anti-inflammatory drugs, (levo-) methadone, amitriptyline, carbamazepine and diuretics. The manual analyses of records from eight patients with risk for severe drug interactions provided no indicator for clinical relevance in these specific patients. Drug interactions attributed to the cytochrome pathway played a minor role (exception: carbamazepine). Conclusion: Most relevant drug interactions can be expected with: (i) drugs (inter-) acting via histamine, acetylcholine or dopamine receptors; and (ii) Non-steroidal anti-inflammatory drugs. Even in last hours of life the combination of substances (e.g. anticholinergics) may produce relevant drug interactions (e.g. delirium). Perspective: Data on the potential for drug–drug interactions in palliative case is extremely scarce, but drug interactions can be limited if a few facts are considered. A synopsis of the findings of these studies is presented as concise recommendation to minimize drug interactions.

Gout Deserves Tender Treatment in Elderly

Gout Deserves Tender Treatment in Elderly