Potential Drug-Drug and Herb-Drug Interactions in Patients With Cancer: A Prospective Study of Medication Surveillance.

J Oncol Pract. 2017 Jul;13(7):e613-e622

Authors: Ramos-Esquivel A, Víquez-Jaikel Á, Fernández C

Abstract
PURPOSE: Patients with cancer frequently use herbal supplements and concomitant medications along with antineoplastic agents. These patients are at high risk of herb-drug interactions (HDIs) and drug-drug interactions (DDIs). We aimed to determine clinically relevant DDIs and HDIs leading to pharmaceutical intervention.
METHODS: Patients starting a new anticancer therapy were asked to complete a questionnaire to identify concomitant use of any over-the-counter drug or herbal supplement. Potential DDIs and HDIs were identified using two different databases. If a potentially clinically relevant DDI was recognized by the clinical pharmacist, a notification was sent to the prescribing oncologist, who decided whether to carry out a suggested intervention. Regression analyses were performed to identify variables associated with clinically relevant DDIs.
RESULTS: A total of 149 patients were included in this study, with 36 potentially clinically relevant DDIs identified in 26 patients (17.4%; 95% CI, 11.3% to 23.5%), all of them leading to therapy modifications. In total, four patients (2.7%; 95% CI, 0.1% to 5.3%) had experienced clinical consequences from DDIs at the time of pharmacist notification. Additionally, 84 patients (56.4%; 95% CI, 48.4% to 64.4%) reported using concurrent herbal supplements, and 122 possible HDIs were detected. Concomitant use of two or more drugs was independently associated with high risk of a clinically significant DDI (odds ratio, 2.53; 95% CI, 1.08 to 5.91; P = .03).
CONCLUSION: Potentially clinically relevant DDIs and possible HDIs were frequently detected in this prospective study. A multidisciplinary approach is required to identify and avoid potentially harmful combinations with anticancer therapy.

PMID: 28628392 [PubMed - indexed for MEDLINE]

Informativeness of patient initial reports of adverse drug reactions. Can it be improved by a pharmacovigilance centre?

Eur J Clin Pharmacol. 2017 Aug;73(8):1009-1018

Authors: Kheloufi F, Default A, Rouby F, Laugier-Castellan D, Boyer M, Rodrigues B, Ponte-Astoul J, Jean-Pastor MJ, Blin O, Micallef J

Abstract
PURPOSE: Little is known about the informativeness of initial patient reports before they are reviewed by a pharmacovigilance centre (PVC). We aim to describe the patterns of patient adverse drug reaction (ADR) reporting in France and estimate the contribution of a review by a PVC assessor on the informativeness of these reports.
METHODS: A retrospective study was conducted on patient reports between July 2011 and July 2015. Informativeness of 16 key elements of information (including drug start and end date, duration of treatment, time to onset and duration of the ADR, outcome, medical history and concomitant medication) was assessed in initial reports before and after review by a pharmacovigilance assessor.
RESULTS: Overall, 240 reports concerning 522 ADR and involving 278 drugs were reported over this 4-year period. Mean number of available key elements of information in initial reports was increased from 11/16 to 15/16 after review of reports by the PVC. Time to onset and duration of the ADR were respectively available in only 51 and 58% of the reports before review compared to 83 and 90% after review. Medical history and concomitant medication were missing in 75% of the initial reports compared to less than 30% of the reports after review. Contacting the reporter enabled an increase of informativeness of most elements of information for more than 90% of the reports.
CONCLUSION: Patient reports often need to be completed on key elements of information that are required to assess reports. Both upstream education of patients and downstream intervention of a pharmacovigilance assessor to complete missing information could help to enhance the informativeness of such reports.

PMID: 28391408 [PubMed - indexed for MEDLINE]

A case report of nifedipine-induced hepatitis with jaundice.

BMC Res Notes. 2018 Apr 03;11(1):228

Authors: Yusuf D, Christy J, Owen D, Ho M, Li D, Fishman MJ

Abstract
BACKGROUND: Nifedipine is a generic, well-known and commonly-prescribed dihydropyridine calcium channel blocker used in the treatment of hypertension and Prinzmetal's angina. A known but very rare and serious adverse effect of nifedipine is clinically-apparent hepatitis which can take months to resolve.
CASE PRESENTATION: Here we present a case of nifedipine-induced hepatitis in a 78-year-old Caucasian female with no prior history of liver or autoimmune disease. We discuss our investigative and management approach, and present a review of prior cases. We offer an approach for patients who present with signs of acute liver injury with jaundice and high elevations in serum transaminases.
CONCLUSION: Not much is known about nifedipine-induced hepatitis due to its rare occurrence. Its prevalence is unknown. The disease appears to afflict older men and women. It can present acutely (within days) or subacutely (within 4-8 weeks after medication start) and in an idiosyncratic manner. Chronic or latent cases have also been described, some diagnosed as late as 3 years after medication start. Common symptoms include jaundice, nausea, chills, rigors, diaphoresis, fatigue, and abdominal pain. Laboratory investigations often reveal profound elevations in AST, ALT, GGT, and conjugated bilirubin. Peripheral blood smear may demonstrate eosinophilia. Histology from liver biopsy typically demonstrates infiltration of immune cells, cholestasis, and a picture of steatohepatitis. Treatment involves immediate discontinuation of the drug with supportive care. Thus far, all published instances of nifedipine-induced hepatitis were self-limiting without mortality due to fulminant liver failure. However, this disease can take months to resolve. There is no randomized evidence for other treatments such as corticosteroids.

PMID: 29615102 [PubMed - in process]

Workers' medication as occupational risk at construction site with formworks.

Work. 2017;57(3):389-395

Authors: López-Arquillos A, Rubio-Romero JC, López-Arquillos C

Abstract
BACKGROUND: Accidents in the construction sector are a cause for concern. The influence of many different factors in construction accidents have been studied (age, company size, length of service, deviation, drugs or alcohol consumption, etc.) but the influence of medicinal substances in specific construction activities has not been evaluated until now.
OBJECTIVE: The aim of the research presented here is to identify the effect of different medicinal substances on the occupational risk levels of construction activities with formworks.
METHODS: An expert panel was selected in order to quantify the individual risk of each medication for each individual construction activity.
RESULTS: Results showed that narcotics, antipsychotics, and hypnotics had the highest risk values, and the use of cranes and cutting materials were considered the most dangerous activities for a medicated worker.
CONCLUSIONS: Data obtained in this research can help reduce the negative effects of the substances studied on the occupational safety of construction workers. A better knowledge of the risk levels according to the current capabilities of workers under the effects of medication is a powerful tool in planning safer construction activities.

PMID: 28800352 [PubMed - indexed for MEDLINE]

Epidemic Use of Benzodiazepines among Older Adults in Israel: Epidemiology and Leverage Points for Improvement.

J Gen Intern Med. 2017 Aug;32(8):891-899

Authors: Steinman MA, Low M, Balicer RD, Shadmi E

Abstract
BACKGROUND: Benzodiazepines and benzodiazepine-receptor agonists (BDZRAs, often known as "Z-drugs") are commonly used in older adults despite well-documented harms.
OBJECTIVE: To evaluate patterns of benzodiazepine and BDZRA use in Israel, focusing on potential leverage points where quality improvement initiatives might effectively curtail new use or the transition from intermittent to chronic use.
DESIGN AND PARTICIPANTS: We used national electronic medical data to assess a 10% random sample of adults receiving care in Clalit Health Services, which serves half of Israel's population. The sample included 267,221 adults, of whom 56,808 (21%) were age 65 and older.
MAIN MEASURES: Medication use from 2013 to 2015 was ascertained using pharmacy dispensing data.
RESULTS: In 2014, 7% of adults age 21-64 and 32% of adults age 65 and older received at least one benzodiazepine/BDZRA, including 49% of adults age 85 and older (P < 0.001). The majority of older users (59%) were long-term users of the drugs, and 21% of older adults who were short-term users in 2014 transitioned to medium- or long-term use in 2015. Older Arab Israelis were much less likely to receive benzodiazepine/BDZRAs than older Jewish Israelis (adjusted OR 0.28, 95% 0.25-0.31), but within each community there was no major variation in prescribing rates across clinics. Depression diagnosis was associated with particularly high rates of benzodiazepine/BDZRA use: 17% of older adults with depression received a benzodiazepine/BDZRA but no antidepressant, and 42% received both. Recent hospitalization increased the risk of new benzodiazepine/BDZRA use (adjusted OR 1.41, 95% CI 1.01-1.96), but the absolute risk increase was only 3%.
CONCLUSIONS: Benzodiazepines/BDZRAs are used at exceptionally high rates by older Israeli adults, especially the oldest old. Important leverage points for quality improvement efforts include curtailing the transition from short-term to long-term use, reducing use in older adults with depression, and identifying reasons that explain large differences in benzodiazepine/BDZRA prescribing between different ethnic groups.

PMID: 28470549 [PubMed - indexed for MEDLINE]

Multifaceted interventions for improving spontaneous reporting of adverse drug reactions in a general hospital in China.

BMC Pharmacol Toxicol. 2017 Jun 26;18(1):49

Authors: Fang H, Lin X, Zhang J, Hong Z, Sugiyama K, Nozaki T, Sameshima T, Kobayashi S, Namba H, Asakawa T

Abstract
BACKGROUND: The present study investigates changes in spontaneous reporting (SR) compliance and ADR patterns following adoption of a new hospital SR system, and multiple interventions designed for its improvement use under modified drug administration guidelines.
METHODS: In total, 1389 ADR cases were reviewed. Cases were divided into two groups, cases from period 1 (n = 557, from January 2006 to June 2011) under the old SR system and cases in period 2 (n = 832, from July 2011 to December 2016) under the new SR system with multiple interventions to improve physician SR compliance. General information, drug information, and clinical manifestations were investigated and compared between periods.
RESULTS: Interventions for improved clinician training, education on knowledge, attitudes, and practices (KAP), and economic incentives substantially improved SR adherence. We also found that changing drug usage patterns (based on the new drug administration guidelines) greatly influenced ADR occurrence and type.
CONCLUSIONS: We found the SR compliance can be improved by multifaceted interventions. Drug usage patterns also influence ADR occurrence, so programs tailored for rational use are essential. These results could lead to further improvements in the SR system for ADRs in China, and provide guidance for establishing better methods of pharmacovigilance.

PMID: 28651624 [PubMed - indexed for MEDLINE]

How do smoking cessation medicines compare with respect to their neuropsychiatric safety? A protocol for a systematic review, network meta-analysis and cost-effectiveness analysis.

BMJ Open. 2017 Jun 17;7(6):e015414

Authors: Thomas KH, Caldwell D, Dalili MN, Gunnell D, Munafò MR, Stevenson M, Welton NJ

Abstract
INTRODUCTION: Cigarette smoking is one of the leading causes of early death in the UK and worldwide. Public health guidance recommends the use of varenicline, bupropion and nicotine replacement therapy (NRT) as smoking cessation aids in the UK. Additionally, the first electronic cigarette has been licensed for use as a smoking cessation medicine. However, there are ongoing concerns about the safety of these medicines. We present a protocol for a systematic review and network meta-analysis (NMA) to determine how these smoking cessation medicines compare to each other with respect to their neuropsychiatric safety in adult smokers. Secondary aims include updating the evidence regarding the effectiveness and cardiovascular safety of these medicines for use in a cost-effectiveness analysis.
METHODS AND ANALYSIS: We will include randomised controlled trials and observational studies with control groups comparing monotherapy with varenicline, bupropion, NRT or electronic cigarette and combination therapies to each other, placebo or usual care. The primary composite safety outcome will be serious adverse events, defined as events that resulted in death, were life threatening, required hospitalisation or resulted in significant disability or congenital/birth defect. The preferred effectiveness outcome will be sustained smoking cessation defined as abstinence for a minimum of 6 months as determined by biochemical validation. We will include trials identified by previous reviews and search relevant databases for newly published trials as well as contacting study authors to identify unpublished information. We will conduct fixed-effect and random-effect meta-analyses for each pairwise comparison of treatments and outcome; where these estimates differ, we will consider reasons for heterogeneity, quantified using the between-study variance (τ2). For each outcome, we will construct a NMA in a Bayesian framework which will be compared with the pair-wise results, allowing us to rank treatments. The effectiveness estimates from the NMA will be entered into a probabilistic economic model.
ETHICS AND DISSEMINATION: Ethics approval is not required for this evidence synthesis study as it involves analysis of secondary data from randomised controlled trials and observational studies. The review will make an important contribution to the knowledge base around the effectiveness, safety and cost-effectiveness of smoking cessation medicines. Results will be disseminated to the general public, healthcare practitioners and clinicians, academics, industry and policy makers.
PROSPERO REGISTRATION NUMBER: CRD42016041302.

PMID: 28624760 [PubMed - indexed for MEDLINE]

Data-driven prediction of adverse drug reactions induced by drug-drug interactions.

BMC Pharmacol Toxicol. 2017 Jun 08;18(1):44

Authors: Liu R, AbdulHameed MDM, Kumar K, Yu X, Wallqvist A, Reifman J

Abstract
BACKGROUND: The expanded use of multiple drugs has increased the occurrence of adverse drug reactions (ADRs) induced by drug-drug interactions (DDIs). However, such reactions are typically not observed in clinical drug-development studies because most of them focus on single-drug therapies. ADR reporting systems collect information on adverse health effects caused by both single drugs and DDIs. A major challenge is to unambiguously identify the effects caused by DDIs and to attribute them to specific drug interactions. A computational method that provides prospective predictions of potential DDI-induced ADRs will help to identify and mitigate these adverse health effects.
METHOD: We hypothesize that drug-protein interactions can be used as independent variables in predicting ADRs. We constructed drug pair-protein interaction profiles for ~800 drugs using drug-protein interaction information in the public domain. We then constructed statistical models to score drug pairs for their potential to induce ADRs based on drug pair-protein interaction profiles.
RESULTS: We used extensive clinical database information to construct categorical prediction models for drug pairs that are likely to induce ADRs via synergistic DDIs and showed that model performance deteriorated only slightly, with a moderate amount of false positives and false negatives in the training samples, as evaluated by our cross-validation analysis. The cross validation calculations showed an average prediction accuracy of 89% across 1,096 ADR models that captured the deleterious effects of synergistic DDIs. Because the models rely on drug-protein interactions, we made predictions for pairwise combinations of 764 drugs that are currently on the market and for which drug-protein interaction information is available. These predictions are publicly accessible at http://avoid-db.bhsai.org . We used the predictive models to analyze broader aspects of DDI-induced ADRs, showing that ~10% of all combinations have the potential to induce ADRs via DDIs. This allowed us to identify potential DDI-induced ADRs not yet clinically reported. The ability of the models to quantify adverse effects between drug classes also suggests that we may be able to select drug combinations that minimize the risk of ADRs.
CONCLUSION: Almost all information on DDI-induced ADRs is generated after drug approval. This situation poses significant health risks for vulnerable patient populations with comorbidities. To help mitigate the risks, we developed a robust probabilistic approach to prospectively predict DDI-induced ADRs. Based on this approach, we developed prediction models for 1,096 ADRs and used them to predict the propensity of all pairwise combinations of nearly 800 drugs to be associated with these ADRs via DDIs. We made the predictions publicly available via internet access.

PMID: 28595649 [PubMed - indexed for MEDLINE]

Repeated "Day 1" FOB testing in ICH S7A safety assessment protocols: The influence of within- and between-session learning.

J Pharmacol Toxicol Methods. 2017 May - Jun;85:61-72

Authors: Gauvin DV, Zimmermann ZJ, Dalton JA, Baird TJ

Abstract
A large number of CNS safety assessment studies using the standard Functional Observational Battery (FOB) are conducted each year at Contract Research Organizations throughout the globe. Study design characteristics are as varied as the Sponsors for whom they are contracted. Gender inclusion, sample sizes, and timing of the FOBs are generally negotiated during protocol development. The ICH S7A guidelines describe a dose-effect study design for CNS safety assessment to be conducted prior to the first dose administration in man. Additionally, some Sponsors attempt to use the CNS safety FOB to establish both time- and dose-related acute behavioral effects of their compound in this single critical safety study. In this review, we highlight the confounding influences of multiple postdose FOBs (Day 1) versus the more standard, single FOB scheduled near systemic Cmax of the compound. Within- and between-session learning, combined with changes in vigilance/alertness/fatigue in both the animals and raters, can limit the generalizability of the FOB to accurately assess CNS effects under the current guidelines. Rationale is provided as to the tenuous nature of conducting simultaneous time- and dose-effect behavioral assessments as part of the core safety pharmacology programs.

PMID: 28216425 [PubMed - indexed for MEDLINE]

Trigger factors of cutaneous lupus erythematosus: a review of current literature.

Lupus. 2017 Jul;26(8):791-807

Authors: Szczęch J, Samotij D, Werth VP, Reich A

Abstract
It is currently believed that autoimmune conditions are triggered and aggravated by a variety of environmental factors such as cigarette smoking, infections, ultraviolet light or chemicals, as well as certain medications and vaccines in genetically susceptible individuals. Recent scientific data have suggested a relevant role of these factors not only in systemic lupus erythematosus, but also in cutaneous lupus erythematosus (CLE). A variety of environmental factors have been proposed as initiators and exacerbators of this disease. In this review we focused on those with the most convincing evidence, emphasizing the role of drugs in CLE. Using a combined search strategy of the MEDLINE and CINAHL databases the following trigger factors and/or exacerbators of CLE have been identified and described: drugs, smoking, neoplasms, ultraviolet radiation and radiotherapy. In order to give a practical insight we emphasized the role of drugs from various groups and classes in CLE. We also aimed to present a short clinical profile of patients with lesions induced by various drug classes.

PMID: 28173739 [PubMed - indexed for MEDLINE]

Efficacy of olanzapine for the prophylaxis of chemotherapy-induced nausea and vomiting: a meta-analysis.

Br J Clin Pharmacol. 2017 Jul;83(7):1369-1379

Authors: Yang T, Liu Q, Lu M, Ma L, Zhou Y, Cui Y

Abstract
AIM: The aim of the present study was to evaluate the efficacy of olanzapine for the prevention of chemotherapy-induced nausea and vomiting (CINV).
METHODS: The literature was searched for randomized controlled trials (RCTs) evaluating the efficacy of olanzapine for the prophylaxis of CINV using PubMed, Embase, Central, as well as clinicaltrials.gov for unpublished studies. The endpoints of the study were the number of patients who achieved a complete response (CR; no emesis and no rescue) and no nausea in the acute, delayed and overall phases. Two authors independently selected studies, assessed the risk of bias and extracted data. The included RCTs were analysed using RevMan 5.3 provided by the Cochrane Collaboration.
RESULTS: Ten RCTs were identified for the meta-analysis. Compared with other antiemetic agents, olanzapine significantly improved the CR in the delayed and overall phases, but did not enhance the CR in the acute phase. For the control of CINV, olanzapine was better than and comparable with aprepitant in the acute phase and delayed phase, respectively. Compared with placebo, treatment with 5 mg and 10 mg olanzapine exhibited similar efficacy in terms of the CR in the delayed and overall phases.
CONCLUSIONS: Olanzapine is an excellent alternative for the prophylaxis of CINV. Olanzapine 5 mg per day should be recommended as the initial dose because of equivalent efficacy to a 10 mg dose but a lower potential risk of side effects. Further studies are needed to explore the optimal combination of medicines.

PMID: 28112422 [PubMed - indexed for MEDLINE]

The northeast regional SPS meeting update: Safety pharmacology innovations and applications.

J Pharmacol Toxicol Methods. 2017 May - Jun;85:82-86

Authors: Pannirselvam M, Brabham T, Botchway AW, Hodges DB, Traebert M, Pugsley MK

Abstract
The Safety Pharmacology Society (SPS) held a Northeast (NE) regional meeting in Boston, MA on May 13, 2016 at the Vertex Pharmaceuticals Incorporated site. There were 103 attendees from the pharmaceutical industry, contract research organizations (CROs), academia, and global regulatory agencies. An assortment of scientific topics were presented by 7 speakers that included broad topics in the cardiovascular (organ on chip, statistical power and translation of rat cardiovascular telemetry data and dual inhibition of IKr and IKs on QT interval prolongation) and central nervous system (in vitro platform for neurotoxicity, an integrated risk assessment of suicidal ideation and behavior, and EEG advances in safety pharmacology) and a novel topic discussing preclinical challenges faced in the development of a novel gene therapy. A highlight of the meeting was an in-depth discussion on the fatty acid acyl hydrolase (FAAH) inhibitor BIA 10-2474 which involved a comprehensive overview of the biology and pharmacology of FAAH followed by a presentation from the Biotrial (Rennes, France) team that conducted the clinical trial. An additional poster session was held that included 13 fascinating posters on cutting edge safety pharmacology topics.

PMID: 27913272 [PubMed - indexed for MEDLINE]

Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity.

J Vis Exp. 2018 Mar 16;(133):

Authors: Sheehan K, Sheth S, Mukherjea D, Rybak LP, Ramkumar V

Abstract
The systemic administration of protective agents to treat drug-induced ototoxicity is limited by the possibility that these protective agents could interfere with the chemotherapeutic efficacy of the primary drugs. This is especially true for the drug cisplatin, whose anticancer actions are attenuated by antioxidants which provide adequate protection against hearing loss. Other current or potential otoprotective agents could pose a similar problem, if administered systemically. The application of various biologicals or protective agents directly to the cochlea would allow for high levels of these agents locally with limited systemic side effects. In this report, we demonstrate a trans-tympanic method of delivery of various drugs or biological reagents to the cochlea, which should enhance basic science research on the cochlea and provide a simple way of directing the use of otoprotective agents in the clinics. This report details a method of trans-tympanic drug delivery and provides examples of how this technique has been used successfully in experimental animals to treat cisplatin ototoxicity.

PMID: 29608150 [PubMed - in process]

Comparison of Two Versions of the Beers Criteria and Adverse Outcomes in Older Hospitalized Patients.

Consult Pharm. 2017 Dec 01;32(12):752-763

Authors: Ozalas SM, Huang V, Brunetti L, Reilly T

Abstract
OBJECTIVE: To compare the performance of the 2003 and 2012 Beers criteria (BC) to predict negative clinical outcomes associated with potentially inappropriate medications in hospitalized older adults.
DESIGN: Retrospective cohort study.
SETTING: Acute Care of Elders (ACE) unit in a community-based teaching hospital.
PARTICIPANTS: All patients admitted to an ACE unit who were older than 65 years of age and prescribed at least one medication upon hospital admission.
MAIN OUTCOME MEASURE(S): The primary outcome was hospital length of stay (LOS). Secondary outcomes included likelihood of experiencing adverse drug events (ADEs) and in-hospital mortality.
RESULTS: A total of 340 patients were included in this study. Inpatients prescribed a BC drug at any time had a longer hospital LOS than those not prescribed a BC drug (2003 BC: adjusted geometric mean, 5.93 vs. 5.50 days, P = 0.003; 2012 BC: adjusted geometric mean, 5.87 vs. 4.21 days, P < 0.001). Patients prescribed a 2003 BC drug had an increased risk of experiencing an ADE compared with those not prescribed a BC drug (odds ratio [OR] = 1.86, 95% confidence interval [CI] 1.11-3.11); however, this outcome was not statistically significant after adjusting for confounders (OR = 1.51, 95% CI 0.870-2.63). There was no statistically significant difference in ADEs when using the 2012 BC (adjusted OR = 1.27, 95% CI 0.689-2.33). There was no difference in hospital mortality regardless of the BC version used.
CONCLUSION: Prescription of BC drugs in an acute care setting is associated with an increased hospital LOS; however, there is no difference in the risk of ADEs or in-hospital mortality.

PMID: 29467068 [PubMed - indexed for MEDLINE]

Clinical Alerts to Decrease High-Risk Medication Use in Older Adults.

J Gerontol Nurs. 2017 Jul 01;43(7):7-12

Authors: Lord-Adem W, Brandt NJ

Abstract
High-risk medications (HRMs) account for 14.6% to 54.6% of all medications used in older adults, and have been linked to >50% of adverse drug events (ADEs). HRM-related ADEs lead to increased morbidity and mortality, increased hospital length of stay, and financial costs for patients and health care systems. It has been well documented that incorporating information technology in patient care in the form of clinical alert systems can effectively decrease HRM use and improve patient safety. The current article seeks to identify and discuss clinical alert systems focusing on HRMs, their impact on prescribing for older adults, and challenges to the implementation of electronic decision systems. [Journal of Gerontological Nursing, 43(7), 7-12.].

PMID: 28651030 [PubMed - indexed for MEDLINE]

Personalized Medicine: New Perspectives for the Diagnosis and the Treatment of Renal Diseases.

Int J Mol Sci. 2017 Jun 10;18(6):

Authors: Gluba-Brzózka A, Franczyk B, Olszewski R, Banach M, Rysz J

Abstract
The prevalence of renal diseases is rising and reaching 5-15% of the adult population. Renal damage is associated with disturbances of body homeostasis and the loss of equilibrium between exogenous and endogenous elements including drugs and metabolites. Studies indicate that renal diseases are influenced not only by environmental but also by genetic factors. In some cases the disease is caused by mutation in a single gene and at that time severity depends on the presence of one or two mutated alleles. In other cases, renal disease is associated with the presence of alteration within a gene or genes, but environmental factors are also necessary for the development of disease. Therefore, it seems that the analysis of genetic aspects should be a natural component of clinical and experimental studies. The goal of personalized medicine is to determine the right drug, for the right patient, at the right time. Whole-genome examinations may help to change the approach to the disease and the patient resulting in the creation of "personalized medicine" with new diagnostic and treatment strategies designed on the basis of genetic background of each individual. The identification of high-risk patients in pharmacogenomics analyses will help to avoid many unwarranted side effects while optimizing treatment efficacy for individual patients. Personalized therapies for kidney diseases are still at the preliminary stage mainly due to high costs of such analyses and the complex nature of human genome. This review will focus on several areas of interest: renal disease pathogenesis, diagnosis, treatment, rate of progression and the prediction of prognosis.

PMID: 28604601 [PubMed - indexed for MEDLINE]

Optimistic bias, advertising skepticism, and consumer intentions for seeking information about the health risks of prescription medicine.

Health Mark Q. 2017 Apr-Jun;34(2):81-96

Authors: Park JS, Ahn HA, Haley EJ

Abstract
Based on a survey of prescription drug users (N = 408), this study revealed that: (a) the frequency of consumers' personal experience of prescription medicine adverse reactions negatively related to the extent of their optimistic bias about the chances of such events, (b) consumers' perceived personal control over adverse reactions positively related to optimistic bias, and (c) optimistic bias related more negatively to intentions to seek risk information when consumer skepticism toward direct-to-consumer advertising was high. When skepticism was low to average, optimistic bias did not inhibit such intentions. Implications and recommendations for the practice of direct-to-consumer advertising are provided.

PMID: 28590885 [PubMed - indexed for MEDLINE]

Potential drug-drug interactions in pediatric patients admitted to intensive care unit of Khyber Teaching Hospital, Peshawar, Pakistan: A cross-sectional study.

J Crit Care. 2017 Aug;40:243-250

Authors: Ismail M, Aziz S, Noor S, Haider I, Shams F, Haq I, Khadim F, Khan Q, Khan F, Asif M

Abstract
PURPOSE: To investigate frequencies, levels, clinical relevance and predictors of potential drug-drug interactions (pDDIs) in pediatric intensive care unit (PICU).
METHODS: Case notes of 411 patients were reviewed for pDDIs through Micromedex. Frequencies, levels and clinical relevance of pDDIs were reported. Logistic regression was applied to calculate the odds-ratios for predictors of pDDIs.
RESULTS: We recorded pDDIs in 59.4% patients. Major-pDDIs were found in 34.5% patients. Total 990 pDDIs were identified, of which, 37.8% were of moderate-severity and 30.6% of major-severity. Patient's case notes of top-ten pDDIs showed presence of signs/symptoms such as fever, jaundice, vomiting, anorexia, tachycardia, drowsiness, & lethargy; and abnormalities in labs such as total leukocytes count, blood urea nitrogen, alanine aminotransferase, & potassium-level. Odds of exposure to major-pDDIs were significantly higher in patients aged 6-12years (p=0.008); hospital stay of ≥7days (p=0.05); and ≥11 prescribed medicines (p<0.001).
CONCLUSION: Substantial numbers of patients in PICU are exposed to pDDIs. Major-pDDIs are of particular concern. Timely identification of pDDIs, preferably with computerized source, is crucial point for their management. Monitoring of clinically relevant parameters and identification of various predictors are needed to minimize or prevent the associated negative consequences of pDDIs.

PMID: 28458171 [PubMed - indexed for MEDLINE]

Pediatric Off-Label and Unlicensed Drug Use and Its Implications.

Curr Clin Pharmacol. 2017;12(1):18-25

Authors: Gore R, Chugh PK, Tripathi CD, Lhamo Y, Gautam S

Abstract
BACKGROUND: Worldwide, in the absence of standard pediatric prescribing information, clinicians often use medicines in children in a dosage form or for an indication that has not been approved for use. Inadequate clinical trials increase exposure to drugs that lack safety-efficacy data in pediatric population. Hence, off-label and unlicensed drug use must be regarded as a patient safety-issue that is known to be associated with increased risks of adverse drug reactions apart from under- or overdosing due to lack of pharmacokinetic data. This review aims to give an overview of the worldwide reported rates of off-label and unlicensed drug use in different patient populations in pediatric settings, with a brief summary of the related adverse drug reactions (ADRs) and a discussion of the existing regulatory provisions and possible solutions for ensuring safe use of medicines in children.
METHOD: Literature searches were conducted and we included studies that evaluated unlicensed or off-label drug use in various pediatric patient populations. The definition of off-label drug use and unlicensed drug varied between different studies.
RESULTS: Fourteen studies from different countries were included in the review and were grouped as: studies conducted in the patients admitted in neonatal intensive care units, in pediatric wards, in hospitalized children and in pediatric outpatient settings. The number of patients studied ranged from 34 in neonatal intensive care units to 355 409 hospitalized children. Many studies reported high rates of off-label (9% to 78.7%) and unlicensed (0.3% to 35%) drug use in different pediatric patient settings.
CONCLUSION: Given the prevalence of unlicensed and off-label drug use, the cooperation of various stakeholders including health professionals, pediatric population and their parents/caregivers, regulatory authorities, and the pharmaceutical industry is integral to instituting individual measures to avoid exposing children to unnecessary risks and avoid depriving them of potentially effective pharmacotherapy. Initiatives to encourage clinical trials for licensing drug use in children by providing market exclusivity and patent extension could aid in bridging the gap between approval and contemporary drug prescribing practices. Enforcement of legislations in the drug development process and subsequent pharmacovigilance could improve the quality of information and accountability of pharmaceutical industry to support and facilitate drug research in children.

PMID: 28322168 [PubMed - indexed for MEDLINE]

Cytochrome 2B6 polymorphism and efavirenz-induced central nervous system symptoms : a substudy of the ANRS ALIZE trial.

HIV Med. 2017 Sep;18(8):537-545

Authors: Gallien S, Journot V, Loriot MA, Sauvageon H, Morlat P, Reynes J, Reliquet V, Chêne G, Molina JM, ANRS 099 ALIZE trial study group

Abstract
OBJECTIVES: Single nucleotide polymorphisms in the cytochrome P450 (CYP) 2B6 gene have been associated with high interindividual variation in efavirenz pharmacokinetics. However, clinical data on the relationship of CYP2B6 polymorphisms with the occurrence of efavirenz-induced central nervous system (CNS) symptoms are limited.
METHODS: We analysed four polymorphisms in the CYP2B6 (516 G>T), CYP3A5 (6986 A>G) and ATP-binding cassette, sub-family B, member 1 (ABCB1) (2677 G>T/A and 3435 C>T) genes in HIV-infected adults virologically suppressed on a protease inhibitor-based regimen who switched to a regimen containing emtricitabine, didanosine and efavirenz in the setting of the ANRS ALIZE trial. Kaplan-Meier methods and Cox regression analysis were used to investigate their association with efavirenz plasma levels and CNS events up to 48 months after switching.
RESULTS: In total, 191 patients with a median age of 41 years, who were 87% male and 85% Caucasian, were enrolled in the study. Variant allelic frequencies were 0.49, 0.93, 0.59 and 0.63 for CYP2B6 516, CYP3A5 392, ABCB1 2677 and ABCB1 3435, respectively. The median efavirenz plasma concentration (MEPC) was 2.2 mg/L [interquartile range (IQR) 1.7-2.8 mg/L] and was significantly higher in patients with the deficient CYP2B6 516T. Overall, 242 CNS events were reported in 104 individuals (54%). No correlation was found between MEPC and CNS events. The occurrence of a first CNS event was lower in patients with the CYP2B6 516 G/G genotype vs. CYP2B6 516 T genotypes [50% (IQR: 40-60%) vs. 66% (IQR: 56-75%), respectively; P = 0.02]. In an adjusted Cox regression model, there was a tendency towards a higher risk of a first CNS event among carriers of the variant CYP2B6 516 T allele (relative risk 1.4 [95% CI, 0.99-2.1]; P?=?.06), compared with noncarriers.
CONCLUSIONS: The deficient CYP2B6 516 T allele is associated with higher efavirenz plasma drug levels and more frequent CNS-related symptoms.

PMID: 28145050 [PubMed - indexed for MEDLINE]