Pharmacogenomics and adverse drug reactions: Primetime and not ready for primetime tests.

J Allergy Clin Immunol. 2016 Oct;138(4):943-955

Authors: Khan DA

Abstract
Adverse drug reactions (ADRs) are a relatively common cause of morbidity and mortality. Many factors can contribute to ADRs, including genetics. The degree to which genetics contributes to ADRs is not entirely clear and varies by drug, as well as the type of ADR. Pharmacogenetics and, more recently, pharmacogenomics have been applied to the field of ADRs for both predictable ADRs and hypersensitivity drug reactions. Evaluations for glucose-6-phosphate dehydrogenase and thiopurine S-methyltransferase are commonplace clinical tests to reduce hematologic problems associated with drugs, such as dapsone and azathioprine, respectively. Numerous pharmacogenetic associations have been discovered for immediate hypersensitivity reactions to β-lactams, aspirin, and nonsteroidal anti-inflammatory drugs; however, the clinical utility of testing for these genetic associations has not been established. In contrast, pharmacogenetic testing for HLA-B*1502 before carbamazepine in patients of certain Asian ethnicities and testing for HLA-B*5701 before abacavir treatment are recommended. This review will focus on pharmacogenetics and pharmacogenomics and their role in reducing ADRs, especially those caused by drug hypersensitivity reactions.

PMID: 27720019 [PubMed - indexed for MEDLINE]

Efficacy of adoptive cellular therapy in patients with gastric cancer: a meta-analysis.

Immunotherapy. 2016 Jul;8(8):971-81

Authors: Shen D, Liu ZH, Xu JN, Xu F, Lin QF, Lin F, Mao WD

Abstract
AIM: To systemically evaluate the efficacy and safety of adoptive cellular therapy for the treatment of gastric cancer (GC).
MATERIALS & METHODS: We performed a systemic review and meta-analysis of nine eligible trials with GC and evaluated the effect of adoptive cellular therapy on the overall survival (OS) rate, T-cell subsets and adverse events.
RESULTS: Overall, 829 patients were involved in the analysis. Adoptive cellular therapy significantly improved the OS rate compared with the control group. Meanwhile, we observed greatly increased percentages of CD3(+), CD4(+) and CD4(+)/CD8(+) in cellular therapy groups.
CONCLUSION: Adoptive cellular therapy combined with adjuvant therapy resulted in significantly better OS rates, progression-free survival and T-lymphocyte responses in patients with GC.

PMID: 27381688 [PubMed - indexed for MEDLINE]

Immune checkpoint inhibitors side effects and management.

Immunotherapy. 2016 Jun;8(7):799-807

Authors: Kourie HR, Klastersky J

Abstract
The next decade in cancer therapy will be marked by the expansion of immunotherapies, namely immune checkpoint inhibitors. The increasing number and combination of checkpoint inhibitors and the variety of their mechanisms of action and indications will most likely multiply the side effects associated with these therapies and make their management more complicated and diversified. Given the growing rate of approval of different checkpoint inhibitors in different cancers in multiple settings, a review summarizing the major side effects of the new agents in use today and their management seems to be appropriate. Highlighting these adverse events and their management in a single review might help the daily practice of the physicians and consequently contribute the patient's safety and quality of life.

PMID: 27349979 [PubMed - indexed for MEDLINE]

Pembrolizumab in a BRAF-mutant metastatic melanoma patient following a severe immune-related adverse event with ipilimumab.

Immunotherapy. 2016 Jun;8(6):687-92

Authors: Aya F, Fernández-Martínez A, Gaba L, Victoria I, Tosca M, Carrera C, Prat A, Arance A

Abstract
Currently, limited data exist on the safety of pembrolizumab in patients with metastatic melanoma who have developed severe immune-related adverse events following treatment with ipilimumab. We report a 45-year-old male patient with BRAF-mutant metastatic melanoma who discontinued treatment with ipilimumab due to treatment-related grade 3 colitis and was subsequently treated with the anti-programmed cell death 1 protein (PD-1) antibody pembrolizumab. He has been on treatment with pembrolizumab for more than 20 months with no major toxicities and has achieved an objective partial response, which is ongoing.

PMID: 27115320 [PubMed - indexed for MEDLINE]

Safety assessment and attenuation of cisplatin induced nephrotoxicity by tuberous roots of Boerhaavia diffusa.

Regul Toxicol Pharmacol. 2016 Nov;81:341-352

Authors: Karwasra R, Kalra P, Nag TC, Gupta YK, Singh S, Panwar A

Abstract
Cisplatin (Cis-diaminedichloroplatinum II) is a chemotherapeutic agent having well documented adverse effect as nephrotoxicity. This study was designed to evaluate the nephroprotective role of Boerhaavia diffusa in cisplatin-induced acute kidney injury. Wistar rats (n = 6) were allocated into six groups constituting normal control, cisplatin-induced, Boerhaavia diffusa root extract in doses 50, 100 and 200 mg/kg and Boerhaavia diffusa per se group, administered orally for a period of ten days. Intraperitoneal injection of cisplatin was administered on day 7, to all groups except normal control and Boerhaavia diffusa per se group. On day 10, cisplatin resulted in substantial nephrotoxicity in Wistar rats with significant (p < 0.001) elevation in serum creatinine and blood urea nitrogen, decline in the concentrations of reduced glutathione and superoxide dismutase, elevation in TNF-α level in renal tissues. Boerhaavia diffusa at a dose of 200 mg/kg body weight significantly (p < 0.001) ameliorates increased in serum creatinine, blood urea nitrogen, oxidative stress and inflammatory markers. In parallel to this, it also exhibits antiapoptotic activity through the reduction of active caspase-3 expression in kidneys. Findings indicate that Boerhaavia diffusa is effective in mitigating cisplatin-induced nephrotoxicity and thus, for this the acute and sub-acute toxicity studies conducted to evaluate the safety profile of Boerhaavia diffusa. The no-observed adverse effect level (NOAEL) of tuberous roots of Boerhaavia diffusa root extract was 1000 mg/kg.

PMID: 27667768 [PubMed - indexed for MEDLINE]

Hot Topics in Primary Care: The Cardiovascular Safety of Nonsteroidal Anti-Inflammatory Drugs: Putting the Evidence in Perspective.

J Fam Pract. 2017 Apr;66(4 Suppl):S52-S57

Authors: Quan M

Abstract
The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, published in 2000, was the first to raise concerns that NSAIDs (specifically, the COX-2 selective inhibitor rofecoxib) might be associated with a higher risk for cardiovascular (CV) events. As discussed in this article, subsequent trials and meta-analyses have demonstrated a higher CV risk with use of not only COX-2 inhibitors (coxibs) but also certain tNSAIDs. These investigations have contributed to actions by the US Food and Drug Administration (FDA), most recently in July 2015, requiring strengthening of CV risk warnings on labels for all prescription and over-the-counter NSAIDs, despite evidence suggesting that differences in CV risk may exist among the NSAIDs.

PMID: 28375409 [PubMed - indexed for MEDLINE]

Safety and Efficacy of Radiation Therapy in Advanced Melanoma Patients Treated With Ipilimumab.

Int J Radiat Oncol Biol Phys. 2016 Sep 01;96(1):72-7

Authors: Qin R, Olson A, Singh B, Thomas S, Wolf S, Bhavsar NA, Hanks BA, Salama JK, Salama AK

Abstract
PURPOSE: Ipilimumab and radiation therapy (RT) are standard treatments for advanced melanoma; preclinical models suggest the potential for synergy. However, limited clinical information exists regarding safety and optimal timing of the combination.
METHODS AND MATERIALS: We reviewed the records of consecutive patients with unresectable stage 3 or 4 melanoma treated with ipilimumab. Patients were categorized as having received RT or not. Differences were estimated between these 2 cohorts.
RESULTS: We identified 88 patients treated with ipilimumab. At baseline, the ipilimumab-plus-RT group (n=44) had more unfavorable characteristics. Despite this, overall survival, progression-free survival, and both immune-related and non-immune-related toxicity were not statistically different (P=.67). Patients who received ipilimumab before RT had an increased duration of irradiated tumor response compared with patients receiving ipilimumab after RT (74.7% vs 44.8% at 12 months; P=.01, log-rank test). In addition, patients receiving ablative RT had non-statistically significantly improved median overall survival (19.6 vs 10.2 months), as well as 6-month (95.1% vs 72.7%) and 12-month (79.7% vs 48.5%) survival rates, compared with those treated with conventionally fractionated RT.
CONCLUSIONS: We found that both ablative and conventionally fractionated RT can be safely administered with ipilimumab without a clinically apparent increase in toxicity. Patients who received ipilimumab before RT had an increased duration of irradiated tumor response.

PMID: 27375168 [PubMed - indexed for MEDLINE]

IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer.

Int J Radiat Oncol Biol Phys. 2016 Aug 01;95(5):1367-77

Authors: Landau DB, Hughes L, Baker A, Bates AT, Bayne MC, Counsell N, Garcia-Alonso A, Harden SV, Hicks JD, Hughes SR, Illsley MC, Khan I, Laurence V, Malik Z, Mayles H, Mayles WP, Miles E, Mohammed N, Ngai Y, Parsons E, Spicer J, Wells P, Wilkinson D, Fenwick JD

Abstract
PURPOSE: To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer.
PATIENTS AND METHODS: Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumor doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined.
RESULTS: Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years.
CONCLUSIONS: IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.

PMID: 27296040 [PubMed - indexed for MEDLINE]

Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy.

Eur J Cancer. 2016 Jun;60:190-209

Authors: Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, Schmidgen MI, Gutzmer R, Utikal JS, Göppner D, Hassel JC, Meier F, Tietze JK, Thomas I, Weishaupt C, Leverkus M, Wahl R, Dietrich U, Garbe C, Kirchberger MC, Eigentler T, Berking C, Gesierich A, Krackhardt AM, Schadendorf D, Schuler G, Dummer R, Heinzerling LM

Abstract
BACKGROUND: Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.
METHODS AND FINDINGS: In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis.
CONCLUSION: Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

PMID: 27085692 [PubMed - indexed for MEDLINE]

Phase I Study of Neoadjuvant Chemotherapy with Capecitabine and Oxaliplatin for Locally Advanced Gastric Cancer.

Anticancer Res. 2017 Jul;37(7):3703-3710

Authors: Satake H, Kondo M, Mizumoto M, Kotake T, Okita Y, Ogata T, Hatachi Y, Yasui H, Miki A, Imai Y, Ichikawa C, Murotani K, Kotaka M, Kato T, Kaihara S, Tsuji A

Abstract
AIM: To determine the recommended dose of neoadjuvant chemotherapy of combined capecitabine and oxalipatin (G-XELOX) for locally advanced gastric cancer.
PATIENTS AND METHODS: Patients received two cycles of neoadjuvant chemotherapy with oxaliplatin on day 1 and capecitabine (2,000 mg/m(2)/day, b.i.d.) on days 1-14, repeated every 3 weeks. They then underwent gastrectomy with curative D2/3 lymph-node dissection followed by adjuvant therapy with S-1 for 1 year. De-escalation of oxaliplatin dose was planned (starting at level 1, oxalipatin 130 mg/m(2)).
RESULTS: Six patients were enrolled. The maximum tolerated dose was not reached at level 1. Oxaliplatin at 130 mg/m(2) combined with capecitabine at 2,000 mg/m(2)/day, b.i.d. had acceptable toxicity. No treatment-related death occurred. Most frequent drug-related adverse events during neoadjuvant G-XELOX were nausea and peripheral sensory neuropathy. One patient declined surgical resection, leaving five undergoing resection with curative intent, of whom four achieved pathological down-staging after neoadjuvant G-XELOX.
CONCLUSION: Neoadjuvant G-XELOX was feasible in patients with locally advanced gastric cancer.

PMID: 28668863 [PubMed - in process]

Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials.

BMC Nephrol. 2017 Jun 30;18(1):206

Authors: Liu Y, Ma X, Zheng J, Jia J, Yan T

Abstract
BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reducing risk of cardiovascular events (CVEs) and preserving kidney function in patients with chronic kidney disease is well-documented. However, the efficacy and safety of these agents in dialysis patients is still a controversial issue.
METHODS: We systematically searched MEDLINE, Embase, Cochrane Library and Wanfang for randomized trials. The relative risk (RR) reductions were calculated with a random-effects model. Major cardiovascular events, changes in GFR and drug-related adverse events were analyzed.
RESULTS: Eleven trials included 1856 participants who were receiving dialysis therapy. Compared with placebo or other active agents groups, ARB therapy reduced the risk of heart failure events by 33% (RR 0.67, 95% CI 0.47 to 0.93) with similar decrement in blood pressure in dialysis patients. Indirect comparison suggested that fewer cardiovascular events happened during treatment with ARB (0.77, 0.63 to 0.94). The results indicated no significant differences between the two treatment regimens with regard to frequency of myocardial infarction (1.0, 0.45 to 2.22), stroke (1.16, 0.69 to 1.96), cardiovascular death (0.89, 0.64 to 1.26) and all-cause mortality (0.94, 0.75 to 1.17). Five studies reported the renoprotective effect and revealed that ACEI/ARB therapy significantly slowed the rate of decline in both residual renal function (MD 0.93 mL/min/1.73 m(2), 0.38 to 1.47 mL/min/1.73 m(2)) and urine volume (MD 167 ml, 95% CI 21 ml to 357 ml). No difference in drug-related adverse events was observed in both treatment groups.
CONCLUSIONS: This study demonstrates that ACE-Is/ARBs therapy decreases the loss of residual renal function, mainly for patients with peritoneal dialysis. Overall, ACE-Is and ARBs do not reduce cardiovascular events in dialysis patients, however, treatment with ARB seems to reduce cardiovascular events including heart failure. ACE-Is and ARBs do not induce an extra risk of side effects.

PMID: 28666408 [PubMed - in process]

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Evaluation of the Potential Risk of Drugs to Induce Hepatotoxicity in Human-Relationships between Hepatic Steatosis Observed in Non-Clinical Toxicity Study and Hepatotoxicity in Humans.

Int J Mol Sci. 2017 Apr 12;18(4):

Authors: Goda K, Kobayashi A, Takahashi A, Takahashi T, Saito K, Maekawa K, Saito Y, Sugai S

Abstract
In the development of drugs, we sometimes encounter fatty change of the hepatocytes (steatosis) which is not accompanied by degenerative change in the liver in non-clinical toxicity studies. In this study, we investigated the relationships between fatty change of the hepatocytes noted in non-clinical toxicity studies of compound X, a candidate compound in drug development, and mitochondrial dysfunction in order to estimate the potential risk of the compound to induce drug-induced liver injury (DILI) in humans. We conducted in vivo and in vitro exploratory studies for this purpose. In vivo lipidomics analysis was conducted to investigate the relationships between alteration of the hepatic lipids and mitochondrial dysfunction. In the liver of rats treated with compound X, triglycerides containing long-chain fatty acids, which are the main energy source of the mitochondria, accumulated. Accumulation of these triglycerides was considered to be related to the inhibition of mitochondrial respiration based on the results of in vitro mitochondria toxicity studies. In conclusion, fatty change of the hepatocytes (steatosis) in non-clinical toxicity studies of drug candidates can be regarded as a critical finding for the estimation of their potential risk to induce DILI in humans when the fatty change is induced by mitochondrial dysfunction.

PMID: 28417920 [PubMed - indexed for MEDLINE]

Adverse event-related costs for systemic metastatic breast cancer treatment among female Medicaid beneficiaries.

J Med Econ. 2016 Nov;19(11):1027-1033

Authors: Irwin DE, Masaquel A, Johnston S, Barnett B

Abstract
OBJECTIVE: This retrospective study compared the real-world incidence and costs of systemic treatment-related adverse events (AEs) in patients with metastatic breast cancer in a Medicaid population.
METHODS: Insurance claims data for adult women who received biologic or chemotherapy (± hormonal therapy) for metastatic breast cancer between 2006-2013 were extracted from the Truven Health MarketScan(®) Multi-State Medicaid database. Incidence of AEs (per 100 person years) and average monthly AE-related healthcare costs (per-patient-per-month) during each line of therapy (first or later lines) were estimated. The association between AEs and total all-cause healthcare costs was estimated using multivariable regression.
RESULTS: A total of 729 metastatic breast cancer patients were analyzed. Hematological (202.3 per 100 person years) and constitutional AEs (289.6 per 100 person years) were the most common class of AEs reported. Unadjusted per-patient-per-month AE-related expenditure by class were highest for hematological AEs ($1524), followed by gastrointestinal ($839) and constitutional AEs ($795), with anemia ($942), nausea/vomiting ($699), and leukopenia/neutropenia ($550) having incurred the highest total AE-related costs. Adjusted total all-cause monthly costs increased with the number of AEs ($19,701 for >7 AEs, $16,264 for 4 - 6 AEs, and $13,731 for 1 - 3 AEs) compared to no AEs ($5908) (all p < 0.01).
CONCLUSIONS: Among metastatic breast cancer patients treated with systemic therapy in a Medicaid population, AEs were associated with significant increases in costs, which increased with the number of AEs experienced. Therapies associated with a lower incidence of AEs may reduce cost burden and improve patient outcomes.

PMID: 27206801 [PubMed - indexed for MEDLINE]

Clinical pharmacists' opportunities to reduce inappropriate prescription of QT-prolonging medications: calls to action.

Int J Pharm Pract. 2017 Apr;25(2):176-179

Authors: Dhanani TC, Mantovani EH, Turner JR

Abstract
All biologically active agents carry the potential to lead to adverse reactions in certain individuals, including serious cardiac adverse reactions. Since 2005, there has been an international regulatory landscape governing the investigation of a new drug's propensity to lead to the polymorphic ventricular tachycardia Torsades de Pointes (Torsades), a rare but potentially fatal occurrence. When a regulatory agency considers it appropriate, warning information is placed in a medicine's patient information leaflet (label) concerning drug-induced QT interval prolongation, a phenomenon associated with Torsades. In busy hospital settings, however, prescribers, including cardiologists, make injudicious prescribing decisions that put patients at risk. The science of cardiac safety, including the clinical trials that generate the information about QT prolongation in patient information leaflets, is frequently not part of the curriculum at Schools of Pharmacy. Given that medication-induced cardiotoxicity is extremely serious, we advocate that schools integrate the science of cardiac safety into existing therapeutics/therapeutic medication monitoring courses. Given their expert knowledge of pharmacology, pharmacists working as part of a hospital's clinical team would then be even better placed to review prescribing decisions concerning medications that prolong the QT interval, and alert prescribers in cases where reassessing their decisions seems prudent. National pharmacy societies or other pertinent professional societies could create practice guidelines to support graduates once employed as clinical pharmacists. Clinical pharmacists are well placed to be influential arbiters of safer prescribing decisions. Cardiac safety education during their pharmacy training and practice guideline support from professional societies during their careers can optimize this role.

PMID: 27677250 [PubMed - indexed for MEDLINE]

The economic burden of common adverse events associated with metastatic colorectal cancer treatment in the United States.

J Med Econ. 2017 Jan;20(1):54-62

Authors: Latremouille-Viau D, Chang J, Guerin A, Shi S, Wang E, Yu J, Ngai C

Abstract
AIMS: Adverse events (AEs) associated with treatments for metastatic colorectal cancer (mCRC) may compromise the course of treatment, impact quality-of-life, and increase healthcare resource utilization. This study assessed the direct healthcare costs of common AEs among mCRC patients in the US.
METHODS: Adult mCRC patients treated with chemotherapy or targeted therapies were identified from administrative claims databases (2009-2014). Up to the first three mCRC treatment episodes per patient were considered and categorized as with or without the AE system/organ category during the episode. Total healthcare costs (2014 USD) were measured by treatment episode and reported on a monthly basis. Treatment episodes with the AE category were matched by treatment type and line of treatment to those without the AE category. Adjusted total cost differences were estimated by comparing costs during treatment episodes with vs without the AE category using multivariate regression models; p-values were estimated with bootstrap.
RESULTS: A total of 4158 patients with ≥1 mCRC treatment episode were included (mean age = 59 years; 58% male; 60% with liver and 14% with lung metastases; 2,261 [54%] with a second and 1,115 [27%] with a third episode). On average, two treatment episodes were observed per patient with an average length of 166 days per episode. Adjusted monthly total cost difference by AE category included hematologic ($1,480), respiratory ($1,253), endocrine/metabolic ($1,213), central nervous system (CNS; $1,136), and cardiovascular ($1,036; all p < .05).
LIMITATIONS: Claims do not include information on the cause of AEs, and potentially less severe AEs may not have been reported by the physician when billing the medical service. This study aimed to assess the association between costs and AEs and not the causation of AEs by treatment.
CONCLUSIONS: The most costly AEs among mCRC patients were hematologic, followed by respiratory, endocrine/metabolic, CNS, and cardiovascular.

PMID: 27603498 [PubMed - indexed for MEDLINE]

How much information about the benefits of medicines is included in patient leaflets in the European Union? - A survey.

Int J Pharm Pract. 2017 Apr;25(2):147-158

Authors: Dickinson R, Raynor DK, Knapp P, MacDonald J

Abstract
INTRODUCTION: Patient information leaflets (PILs) are required with all licensed medicines throughout the European Union (EU) and they must include information about all side effects and their likelihood. This has led to criticism of a lack of balance, with little information included about potential benefits. Recent European Medicines Agency guidance proposed the inclusion of benefit information, and this study examined the current prevalence and type of such information in PILs in the EU.
METHODS: A survey and content analysis of the English translation of PILs in the EUwas carried out. Random quota sampling was used on the most frequently dispensed (n = 50) and newly licensed medicines (n = 50) in 2011/2. Leaflets were searched for benefit information meeting predefined criteria, and data synthesised and categorised into 10 categories.
RESULTS: Eighty-five (85%) leaflets described how the medicine works, with 45 providing information about the rationale for treatment (more commonly for newly licensed (32/50) than most commonly dispensed medicines (13/50; P < 0.001). Nearly half (47) did not describe whether the medicine was curative, symptomatic or preventative. The terms used to communicate uncertainty were imprecise (such as 'may help'). None communicated numerical benefit information.
CONCLUSION: Current PILs do not appropriately communicate information about benefit. At the basic level, around a half did not include information about treatment rationale or whether the treatment was to treat symptoms, curative or preventative. However, for true informed decision making, patients need quantitative information about benefits and none of the leaflets provided this.

PMID: 27405658 [PubMed - indexed for MEDLINE]

Drug-related problems and medication reviews among old people with dementia.

BMC Pharmacol Toxicol. 2017 Jun 27;18(1):52

Authors: Pfister B, Jonsson J, Gustafsson M

Abstract
BACKGROUND: Drug-related problems, including medication errors and adverse drug events, are common among old people. Due to, for example, greater susceptibility to side effects, people with dementia are even more at risk of drug-related problems. The objectives of this study were to assess the occurrence and character of drug-related problems found among old people with dementia or cognitive impairment.
METHODS: Data from a randomized controlled clinical trial exploring the effects of a pharmacist intervention as part of a hospital ward team in patients 65 years and older with dementia or cognitive impairment were used. The study was conducted between 2012 and 2014 in the orthopedic and medicine wards in two hospitals located in Northern Sweden. Drug-related problems identified in this patient group were classified and described, and associations with different factors were investigated.
RESULTS: Clinical pharmacists identified at least one DRP in 66% (140/212) of participants in the intervention group, for a total of 310 DRPs. Ineffective drug/inappropriate drug and unnecessary drug therapy were the most common drug-related problems. Discontinuation of drug therapy was the most common action carried out. Drug-related problems were more common among people prescribed a larger number of drugs and among people with an earlier stroke.
CONCLUSIONS: Drug-related problems are common among people with dementia and cognitive impairment. Comprehensive medication reviews conducted by clinical pharmacists as part of a health care team might be important to prevent, identify and solve these problems.

PMID: 28655357 [PubMed - in process]

Treatment outcomes of fixed-dose combination versus separate tablet regimens in pulmonary tuberculosis patients with or without diabetes in Qatar.

BMC Infect Dis. 2017 Feb 02;17(1):118

Authors: Al-Shaer MH, Mansour H, Elewa H, Salameh P, Iqbal F

Abstract
BACKGROUND: Tuberculosis is considered the second most common cause of death due to infectious agent. The currently preferred regimen for treatment of pulmonary tuberculosis (PTB) is isoniazid, rifampin, pyrazinamide, and ethambutol, which has been used either as separate tablets (ST) or as fixed-dose combination (FDC). To date, no studies have compared both regimens in Qatar. We aim to evaluate the safety and effectiveness of FDC and ST regimen for treating PTB, in addition to comparing safety and efficacy of FDC and ST regimens in patients with diabetes treated for TB.
METHODS: A retrospective observational study was conducted in two general hospitals in Qatar. Patients diagnosed with PTB received anti-tuberculosis medications (either as FDC or ST) administered by the nurse. Sputum smears were tested weekly. We assessed the time to negative sputum smear and incidence of adverse events among FDC and ST groups.
RESULTS: The study included 148 patients. FDC was used in 90 patients (61%). Effectiveness was not different between FDC and ST regimens as shown by mean time to sputum conversion (29.9 ± 18.3 vs. 35.6 ± 23 days, p = 0.12). Similarly, there was no difference in the incidence of adverse events, except for visual one that was higher in ST group. Among the 33 diabetic patients, 19 received the FDC and had faster sputum conversion compared to those who received ST (31 ± 12 vs. 49.4 ± 30.9 days, p = 0.05). Overall, diabetic patients needed longer time for sputum conversion and had more hepatotoxic and gastric adverse events compared to non-diabetics.
CONCLUSION: ST group had higher visual side effects compared to FDC. FDC may be more effective in diabetic patients; however, further studies are required to confirm such finding.

PMID: 28152986 [PubMed - indexed for MEDLINE]

Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation.

J Am Coll Cardiol. 2016 Oct 18;68(16):1756-1764

Authors: Lorberbaum T, Sampson KJ, Chang JB, Iyer V, Woosley RL, Kass RS, Tatonetti NP

Abstract
BACKGROUND: QT interval-prolonging drug-drug interactions (QT-DDIs) may increase the risk of life-threatening arrhythmia. Despite guidelines for testing from regulatory agencies, these interactions are usually discovered after drugs are marketed and may go undiscovered for years.
OBJECTIVES: Using a combination of adverse event reports, electronic health records (EHR), and laboratory experiments, the goal of this study was to develop a data-driven pipeline for discovering QT-DDIs.
METHODS: 1.8 million adverse event reports were mined for signals indicating a QT-DDI. Using 1.6 million electrocardiogram results from 380,000 patients in our institutional EHR, these putative interactions were either refuted or corroborated. In the laboratory, we used patch-clamp electrophysiology to measure the human ether-à-go-go-related gene (hERG) channel block (the primary mechanism by which drugs prolong the QT interval) to evaluate our top candidate.
RESULTS: Both direct and indirect signals in the adverse event reports provided evidence that the combination of ceftriaxone (a cephalosporin antibiotic) and lansoprazole (a proton-pump inhibitor) will prolong the QT interval. In the EHR, we found that patients taking both ceftriaxone and lansoprazole had significantly longer QTc intervals (up to 12 ms in white men) and were 1.4 times more likely to have a QTc interval above 500 ms. In the laboratory, we found that, in combination and at clinically relevant concentrations, these drugs blocked the hERG channel. As a negative control, we evaluated the combination of lansoprazole and cefuroxime (another cephalosporin), which lacked evidence of an interaction in the adverse event reports. We found no significant effect of this pair in either the EHR or in the electrophysiology experiments. Class effect analyses suggested this interaction was specific to lansoprazole combined with ceftriaxone but not with other cephalosporins.
CONCLUSIONS: Coupling data mining and laboratory experiments is an efficient method for identifying QT-DDIs. Combination therapy of ceftriaxone and lansoprazole is associated with increased risk of acquired long QT syndrome.

PMID: 27737742 [PubMed - indexed for MEDLINE]