Hepatotoxicity associated to synthetic cannabinoids use.

Eur Rev Med Pharmacol Sci. 2017 Mar;21(1 Suppl):1-6

Authors: Solimini R, Busardò FP, Rotolo MC, Ricci S, Mastrobattista L, Mortali C, Graziano S, Pellegrini M, di Luca NM, Palmi I

Abstract
Synthetic cannabinoids (SCs) are psychotropic compounds, chemically created in laboratory to mimic cannabinergic brain activity of delta-9 tetrahydrocannabinol. The consumption of these compounds for recreational purposes can lead to a variety of adverse effects on health including overdose and deaths. Increasingly popular as substances of abuse since the 2000s, SCs were produced initially to bind and study cannabinoid receptors (they also can be called synthetic cannabimimetics) failing in eliminating the psychoactive effects. Currently, SCs are misused by students and young adults as "natural products" because of their herbal aspect. Actually, these apparently innocuous recreational substances hide toxic effects to health. Reported side effects are cardiovascular, gastrointestinal, neurological, renal, metabolic, ophthalmologic, pulmonary and psychoactive including dependence and withdrawal. A few cases of SCs ingestion have also been associated with liver failure. We herein review the recent literature on the SCs toxicity with particular attention to liver damage aspects.

PMID: 28379600 [PubMed - indexed for MEDLINE]

Sildenafil-associated hepatoxicity: a review of the literature.

Eur Rev Med Pharmacol Sci. 2017 Mar;21(1 Suppl):17-22

Authors: Graziano S, Montana A, Zaami S, Rotolo MC, Minutillo A, Busardò FP, Marinelli E

Abstract
Sildenafil citrate (Viagra®) is a vasoactive agent available worldwide since 1998 for the treatment of male erectile dysfunction. It is a selective phosphodiesterase type 5-enzyme inhibitor able to potentiate the downstream effects of nitric oxide on smooth muscle relaxation and vasodilation through its effects on the cyclic guanosine monophosphate (c-GMP) pathway in the erectile tissue of the penis. When sildenafil is orally administered, it is rapidly absorbed with a maximum plasma concentration achieved within 1 h and has a terminal half-life of between 3 to 6 h. The drug is extensively and rapidly metabolized by the liver, primarily by the CYP3A4 enzyme. Although the drug is well tolerated, specific adverse events have been observed, like flushing, headaches, dyspepsia, and visual disturbances. Liver toxicity related to sildenafil consumption has been considered a very rare event. However, in the last decade, some cases of sildenafil-associated hepatotoxicity have been reported. Furthermore, some hepatic intoxications have been reported after the intake of "natural" or "herbal" aphrodisiac supplements sold through Internet, sex shops, social media, and by word-of-mouth found to contain sildenafil and other phosphodiesterase type 5 (PDE-5) inhibitors. Studies investigating a possible link between sildenafil use and liver damage are limited, and the underlying mechanism responsible for hepatotoxicity is still missing. Studies in animals evidence that the hematopoietic function of the liver may have severely been affected as a result of a probable toxic effect of sildenafil. Here, the studies reporting liver toxicity by sildenafil in humans and in animals are reported and discussed.

PMID: 28379598 [PubMed - indexed for MEDLINE]

Flutamide-induced hepatotoxicity: ethical and scientific issues.

Eur Rev Med Pharmacol Sci. 2017 Mar;21(1 Suppl):69-77

Authors: Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A

Abstract
OBJECTIVE: Flutamide (FLU) is a non-steroidal antiandrogen drug approved for the treatment of advanced prostate cancer. While this indication limits the use to male patients, FLU is widely prescribed to women, off-label, for the treatment of polycystic ovary syndrome (POCS) related hirsutism and acne. According to the literature, its assumption is associated with a higher incidence of adverse events in women than in male patients.
MATERIALS AND METHODS: A literature search was conducted in main databases targeting unwilling FLU effects in hepatic and reproductive function. References in the selected paper were also considered as an additional source of data. Human- and animal-based studies were separately considered.
RESULTS: Twenty-three human-based studies were evaluated: ten were case reports, six were retrospective studies, four were prospective, two were surveillance studies, while the last was an observational study. Nine animal-based studies were also evaluated.
CONCLUSIONS: Scientific contributions highlight that FLU is responsible for specific hepatotoxic profiles in the female gender. From the ethical point of view, off-label prescribing of FLU in women is not only substantially unlawful, but also, without major safeguards being granted, a potential source of liability for prescribers.

PMID: 28379593 [PubMed - indexed for MEDLINE]

Systolic Blood Pressure Intervention Trial (SPRINT) and Target Systolic Blood Pressure in Future Hypertension Guidelines.

Hypertension. 2016 Aug;68(2):318-23

Authors: Egan BM, Li J, Wagner CS

Abstract
The Systolic Blood Pressure (SBP, mm Hg) Intervention Trial (SPRINT) showed that targeting SBP <120 mm Hg (intensive treatment, mean SBP: 121.5 mm Hg) versus <140 (standard treatment, mean SBP: 134.6 mm Hg) reduced cardiovascular events 25%. SPRINT has 2 implicit assumptions that could impact future US hypertension guidelines: (1) standard therapy controlled SBP similarly to that in adults with treated hypertension and (2) intensive therapy produced a lower mean SBP than in adults with treated hypertension and SBP <140 mm Hg. To examine these assumptions, US National Health and Nutrition Examination Survey 2009 to 2012 data were analyzed on 3 groups of adults with treated hypertension: group 1 consisted of SPRINT-like participants aged ≥50 years; group 2 consisted of participants all aged ≥18 years; and group 3 consisted of participants aged ≥18 years excluding group 1 but otherwise similar to SPRINT-like participants except high cardiovascular risk. Mean SBPs in groups 1, 2, and 3 were 133.0, 130.1, and 124.6, with 66.2%, 72.2%, and 81.9%, respectively, controlled to SBP <140; 68.3%, 74.8%, and 83.4% of the controlled subset had SBP <130. Mean SBPs in those controlled to <140 were 123.3, 120.9, and 118.9, respectively. Among US adults with treated hypertension, (1) the SPRINT-like group had higher mean SBP than comparison groups, yet lower than SPRINT standard treatment group and (2) among groups 1 to 3 with SBP <140, SBP values were within <3 mm Hg of SPRINT intensive treatment. SPRINT results suggest that treatment should be continued and not reduced when treated SBP is <130, especially for the SPRINT-like subset. Furthermore, increasing the percentage of treated adults with SBP <140 could approximate SPRINT intensive treatment SBP without lowering treatment goals.

PMID: 27354422 [PubMed - indexed for MEDLINE]

Medication Regimen Complexity and Number of Medications as Factors Associated With Unplanned Hospitalizations in Older People: A Population-based Cohort Study.

J Gerontol A Biol Sci Med Sci. 2016 Jun;71(6):831-7

Authors: Wimmer BC, Bell JS, Fastbom J, Wiese MD, Johnell K

Abstract
BACKGROUND: Adverse drug events are a leading cause of hospitalization among older people. Up to half of all medication-related hospitalizations are potentially preventable. The objective of this study was to investigate and compare the association between medication regimen complexity and number of medications with unplanned hospitalizations over a 3-year period.
METHODS: Data were analyzed for 3,348 participants aged 60 years or older in Sweden. Regimen complexity was assessed using the 65-item Medication Regimen Complexity Index (MRCI) and number of medications was assessed as a continuous variable. Cox proportional hazard models were used to compute unadjusted and adjusted hazard ratios with 95% confidence intervals (CIs) for associations between regimen complexity and number of medications with unplanned hospitalizations over a 3-year period. Receiver operating characteristics curves with corresponding areas under the curve were calculated for regimen complexity and number of medications in relation to unplanned hospitalizations. The population attributable fraction of unplanned hospitalizations was calculated for MRCI and number of medications.
RESULTS: In total, 1,125 participants (33.6%) had one or more unplanned hospitalizations. Regimen complexity (hazard ratio 1.22; 95% CI 1.14-1.34) and number of medications (hazard ratio 1.07; 95% CI 1.04-1.09) were both associated with unplanned hospitalizations and had similar sensitivity and specificity (area under the curve 0.641 for regimen complexity and area under the curve 0.644 for number of medications). The population attributable fraction was 14.08% (95% CI 9.62-18.33) for MRCI and 17.61% (95% CI 12.59-22.35) for number of medications.
CONCLUSIONS: There was no evidence that using a complex tool to assess regimen complexity was better at predicting unplanned hospitalization than number of medications.

PMID: 26707381 [PubMed - indexed for MEDLINE]

No Effect of Levothyroxine and Levothyroxine-induced Subclinical Thyrotoxicosis on the Pharmacokinetics of Sorafenib in Healthy Male Subjects.

Thyroid. 2017 Jul 25;:

Authors: Huang F, Ajavon-Hartmann A, Huang E, Lettieri J, Liu R, Pena C, Berse M

Abstract
<b>Background</b>: Patients receiving the multikinase inhibitor sorafenib for locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine often receive concomitant levothyroxine for thyroid-stimulating hormone (TSH) suppression. In the phase 3 DTC trial (DECISION), sorafenib exposure was ~2-fold higher than that observed in other cancers. We assessed sorafenib pharmacokinetics without and with concomitant levothyroxine to examine whether a levothyroxine interaction or levothyroxine-induced subclinical thyrotoxicosis results in increased sorafenib exposure in DTC patients. <b>Methods</b>: This was an open-label, 2-period sequential treatment study in healthy males. Period 1, day 1: subjects received a single oral dose of sorafenib 400 mg, followed by a minimal 10-day washout. Period 2, day 1: levothyroxine 300μg was administered orally once daily (QD) for 14 days; after 10 days, a single oral concomitant dose of sorafenib 400mg was given. Blood samples for sorafenib pharmacokinetic analyses were obtained predose and at time points up to 96 hours after sorafenib dosing. Samples for thyroid tests were collected before and after levothyroxine dosing. <b>Results</b>: Twenty-five subjects completed the study and were evaluable for pharmacokinetic analysis. Levothyroxine 300 µg QD was well tolerated and induced subclinical thyrotoxicosis, producing full suppression of TSH (mean±SD, 0.032±0.027 mU/L) and increased free thyroxine (0.94±0.09 to 1.77±0.33 ng/dL) and free tri-iodothyronine (2.87±0.28 to 4.24±0.66 pg/mL) levels by day 11 of period 2. The geometric mean (%CV) sorafenib maximum concentration (C_max) without and with levothyroxine was 2.09 (68.1) and 1.78 (63.9) mg/L, respectively, with a corresponding geometric mean area under the curve of 68.1 (68.2) and 64.3 (66.3) mg·h/L. Median (range) time to C_max was 4.00 (2.98-16.0) and 4.02 (1.98-36.0) hours, respectively; mean (%CV) half-life was 24.0 (25.3) and 25.7 (21.0) hours. All study drug-related adverse events were mild and included headache and fatigue for sorafenib, and headache, increased alanine aminotransferase and glutamate dehydrogenase, fatigue, and nervousness for levothyroxine. <b>Conclusions</b>: Levothyroxine 300 µg QD for 14 days was well tolerated, induced subclinical thyrotoxicosis, and did not affect sorafenib pharmacokinetics. The findings suggest that concomitant use of levothyroxine with sorafenib is not likely responsible for the previously reported increase in sorafenib exposure in DTC patients; however, the effects of long-term levothyroxine dosing were not assessed.

PMID: 28741453 [PubMed - as supplied by publisher]

Ovarian cancer survivors' acceptance of treatment side effects evolves as goals of care change over the cancer continuum.

Gynecol Oncol. 2017 Aug;146(2):386-391

Authors: Frey MK, Ellis AE, Koontz LM, Shyne S, Klingenberg B, Fields JC, Chern JY, Blank SV

Abstract
OBJECTIVES: Women with ovarian cancer can have long overall survival and goals of treatment change over time from cure to remission to stable disease. We sought to determine whether survivors' acceptance of treatment side effects also changes over the disease continuum.
METHODS: Women with ovarian cancer completed an online survey focusing on survivors' goals and priorities. The survey was distributed through survivor networks and social media.
RESULTS: Four hundred and thirty-four women visited the survey website and 328 (76%) completed the survey. Among participants, 141 (43%) identified themselves as having ever recurred, 119 (36%) were undergoing treatment at the time of survey completion and 86 (26%) had received four or more chemotherapy regimens. Respondents' goals of care were cure for 115 women (35%), remission for 156 (48%) and stable disease for 56 (17%). When asked what was most meaningful, 148 women (45%) reported overall survival, 135 (41%) reported quality of life and 40 (12%) reported progression-free survival. >50% of survivors were willing to tolerate the following symptoms for the goal of cure: fatigue (283, 86%), alopecia (281, 86%), diarrhea (232, 71%), constipation (227, 69%), neuropathy (218, 66%), arthralgia (210, 64%), sexual side effects (201, 61%), reflux symptoms (188, 57%), memory loss (180, 55%), nausea/vomiting (180, 55%), hospitalization for treatment side effects (179, 55%) and pain (169, 52%). The rates of tolerance for most symptoms decreased significantly as the goal of treatment changed from cure to remission to stable disease.
CONCLUSIONS: Women with ovarian cancer willingly accept many treatment side effects when the goal of treatment is cure, however become less accepting when the goal is remission and even less so when the goal is stable disease. Physicians and survivors must carefully consider treatment toxicities and quality of life effects when selecting drugs for patients with incurable disease.

PMID: 28602549 [PubMed - indexed for MEDLINE]

A systematic review of patient values, preferences and expectations for the treatment of recurrent ovarian cancer.

Gynecol Oncol. 2017 Aug;146(2):392-398

Authors: PEBC’s Ovarian Oncology Guidelines Group

Abstract
BACKGROUND AND OBJECTIVES: It is our belief that patient preference should play a significant role in disease management of recurrent ovarian cancer. Since cure is seldom an endpoint in this circumstance, patients' attitudes toward the risks and benefits of chemotherapy versus palliation are relevant.
METHODS: Medline, Embase, CINAHL and PsycINFO from were searched from January 1, 2000 to December 13, 2016 for studies of values, preferences or expectations of women with platinum-sensitive recurrent or refractory ovarian cancer.
RESULTS: Ten studies representing five countries met inclusion criteria. Although there was regional variation in preference for palliation over treatment, certain themes emerged. 1) Patients, even in the context of counselling overestimated the curative capability of chemotherapy. In one study 92% of patients had high expectations of healing after completing an expectation of treatment checklist. Another study observed that patients are often overwhelmed by information provided at diagnosis and there can be a discrepancy between what patients report to have heard and what the clinicians said. 2) Patients who had previously tolerated chemotherapy well were more likely to be accepting of the side-effects of chemotherapy. 3) Patients were more willing to accept chemotherapy and the related side effects when treatment was of curative intent or when overall survival was increased. 4) Patients valued both overall and progression free survival. 5) A significant minority (24%) consistently chose treatment over palliation. 6) Patients were more willing to accept the side effects of chemotherapy than were their health care providers.
CONCLUSIONS: These findings, in aggregate, highlight the importance of communication with patients regarding prognosis, adverse effects and symptom management to help negotiate the decision making process. Chemotherapy in the recurrent setting should be managed on a case by case basis, combining both medical constraints and consideration to patient preferences.

PMID: 28601379 [PubMed - indexed for MEDLINE]

ZeGlobalTox: An Innovative Approach to Address Organ Drug Toxicity Using Zebrafish.

Int J Mol Sci. 2017 Apr 19;18(4):

Authors: Cornet C, Calzolari S, Miñana-Prieto R, Dyballa S, van Doornmalen E, Rutjes H, Savy T, D'Amico D, Terriente J

Abstract
Toxicity is one of the major attrition causes during the drug development process. In that line, cardio-, neuro-, and hepatotoxicities are among the main reasons behind the retirement of drugs in clinical phases and post market withdrawal. Zebrafish exploitation in high-throughput drug screening is becoming an important tool to assess the toxicity and efficacy of novel drugs. This animal model has, from early developmental stages, fully functional organs from a physiological point of view. Thus, drug-induced organ-toxicity can be detected in larval stages, allowing a high predictive power on possible human drug-induced liabilities. Hence, zebrafish can bridge the gap between preclinical in vitro safety assays and rodent models in a fast and cost-effective manner. ZeGlobalTox is an innovative assay that sequentially integrates in vivo cardio-, neuro-, and hepatotoxicity assessment in the same animal, thus impacting strongly in the 3Rs principles. It Reduces, by up to a third, the number of animals required to assess toxicity in those organs. It Refines the drug toxicity evaluation through novel physiological parameters. Finally, it might allow the Replacement of classical species, such as rodents and larger mammals, thanks to its high predictivity (Specificity: 89%, Sensitivity: 68% and Accuracy: 78%).

PMID: 28422076 [PubMed - indexed for MEDLINE]

Guided Imagery And Progressive Muscle Relaxation as a Cluster of Symptoms Management Intervention in Patients Receiving Chemotherapy: A Randomized Control Trial.

PLoS One. 2016;11(6):e0156911

Authors: Charalambous A, Giannakopoulou M, Bozas E, Marcou Y, Kitsios P, Paikousis L

Abstract
OBJECTIVE: Patients receiving chemotherapy often experience many different symptoms that can be difficult to alleviate and ultimately negatively influence their quality of life. Such symptoms include pain, fatigue, nausea, vomiting and retching, anxiety and depression. There is a gap in the relevant literature on the effectiveness of cognitive-behavioural and relaxation techniques in symptom clusters. The study reflects this gap in the literature and aimed to test the effectiveness of Guided Imagery (GI) and Progressive Muscle Relaxation (PMR) on a cluster of symptoms experienced by patients undergoing chemotherapy.
METHODS: This was a randomized control trial with 208 patients equally assigned either in the intervention or the control group. Measurements in both groups were collected at baseline and at completion of intervention (4 weeks). Patients were assessed for pain, fatigue, nausea, vomiting and retching, anxiety and depression. The overall management of the cluster was also assessed based on the patients' self-reported health related quality of life-HRQoL. Chi-square tests (X2), independent T-tests and Linear Mixed Models were calculated.
RESULTS: Patients in the intervention group experienced lower levels of Fatigue (p<0.0.0225), and Pain (p = 0.0003) compared to those in the control group and experienced better HRQoL (p<0.0001) [PRE-POST:
INTERVENTION: Pain 4.2(2.5) - 2.5(1.6), Fatigue 27.6(4.1) - 19.3(4.1), HRQoL 54.9(22.7) - 64.5(23), CONTROL: Pain 3.5(1.7) - 4.8(1.5), Fatigue 28.7(4.1) - 32.5(3.8), HRQoL 51.9(22.3)- 41.2(24.1)]. Nausea, vomiting and retching occurred significantly less often in the intervention group [pre-post: 25.4(5.9)- 20.6(5.6) compared to the control group (17.8(6.5)- 22.7(5.3) (F = 58.50 p<0.0001). More patients in the control group (pre:n = 33-post:n = 47) were found to be moderately depressed compared to those in the intervention group (pre:n = 35-post:n = 15) (X2 = 5.93; p = 0.02).
CONCLUSION: This study provided evidence that the combination of GI and PMR can be effective in the management of a cluster of symptoms in cancer patients receiving chemotherapy. These techniques can complement existing management measures to achieve a comprehensive management of this symptom cluster and increase patients HRQoL.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01275872.

PMID: 27341675 [PubMed - indexed for MEDLINE]

Co-Prescription of QT-Interval Prolonging Drugs: An Analysis in a Large Cohort of Geriatric Patients.

PLoS One. 2016;11(5):e0155649

Authors: Schächtele S, Tümena T, Gaßmann KG, Fromm MF, Maas R

Abstract
BACKGROUND: Drug-induced QT-interval prolongation is associated with occurrence of potentially fatal Torsades de Pointes arrhythmias (TdP). So far, data regarding the overall burden of QT-interval prolonging drugs (QT-drugs) in geriatric patients are limited.
OBJECTIVE: This study was performed to assess the individual burden of QT-interval prolonging drugs (QT-drugs) in geriatric polymedicated patients and to identify the most frequent and risky combinations of QT-drugs.
METHODS: In the discharge medication of geriatric patients between July 2009 and June 2013 from the Geriatrics in Bavaria-Database (GiB-DAT) (co)-prescriptions of QT-drugs were investigated. QT-drugs were classified according to a publicly available reference site (CredibleMeds®) as ALL-QT-drugs (associated with any QT-risk) or High-risk-QT-drugs (corresponding to QT-drugs with known risk of Torsades de Pointes according to CredibleMeds®) and in addition as SmPC-high-risk-QT-drugs (according to the German prescribing information (SmPC) contraindicated co-prescription with other QT-drugs).
RESULTS: Of a cohort of 130,434 geriatric patients (mean age 81 years, 67% women), prescribed a median of 8 drugs, 76,594 patients (58.7%) received at least one ALL-QT-drug. Co-prescriptions of two or more ALL-QT-drugs were observed in 28,768 (22.1%) patients. Particularly risky co-prescriptions of High-risk-QT-drugs or SmPC-high-risk-QT-drugs with at least on further QT-drug occurred in 55.9% (N = 12,633) and 54.2% (N = 12,429) of these patients, respectively. Consideration of SmPCs (SmPC-high-risk-QT-drugs) allowed the identification of an additional 15% (N = 3,999) patients taking a risky combination that was not covered by the commonly used CredibleMeds® classification. Only 20 drug-drug combinations accounted for more than 90% of these potentially most dangerous co-prescriptions.
CONCLUSION: In a geriatric study population co-prescriptions of two and more QT-drugs were common. A considerable proportion of QT-drugs with higher risk only could be detected by using more than one classification-system. Local adaption of international classifications can improve identification of patients at risk.

PMID: 27192430 [PubMed - indexed for MEDLINE]

Predictive Factors of Spontaneous Reporting of Adverse Drug Reactions among Community Pharmacists.

PLoS One. 2016;11(5):e0155517

Authors: Yu YM, Lee E, Koo BS, Jeong KH, Choi KH, Kang LK, Lee MS, Choi KH, Oh JM, Shin WG

Abstract
PURPOSE: To evaluate the association between spontaneous reporting (SR) and the knowledge, attitude, and needs of community pharmacists (CPs), using a questionnaire following a conceptual model known as the mixed model of knowledge-attitude-practices and the satisfaction of needs.
METHODS: Self-administered questionnaires were used with a nationwide convenience sample of CPs between September 1, 2014 and November 25, 2014 in Korea. The association between SR and the predictive factors was evaluated using multivariate logistic regression analysis.
RESULTS: In total, 1,001 questionnaires were analyzed. The mean age of the respondents and the number of years spent in community pharmacy practice were 45.6 years and 15.3 years, respectively. CPs with experience of SR was 29.4%. Being older than 60 (ORadj, 0.16; 95% CI, 0.06-0.42), having prior experience with adverse drug reactions (ADR) (ORadj, 6.46; 95% CI, 2.46-16.98), having higher specific knowledge of SR (ORadj, 3.58; 95% CI, 1.96-6.56), and having less concern about the obstacles to SR (ORadj, 0.36; 95% CI, 0.23-0.57) were significant contributing factors to SR. The main obstacles to SR included perception of ADRs as 'not serious ADR' (77.9%), 'already well known ADR' (81.5%), and 'uncertain about causality' (73.3%). CPs without reporting experience had greater concerns related to the reporting method and the liability of the pharmacy than those with reporting experience (p<0.05).
CONCLUSIONS: Findings from our study showed around one in three CPs had ADR reporting experience in Korea, while 87.1% had prior experience with ADR cases. The knowledge of SR, prior experience of ADR, and less concern about the obstacles to SR were contributing factors for reporting levels.

PMID: 27192159 [PubMed - indexed for MEDLINE]

Patterns of adverse drug reaction signals in NAFDAC Pharmacovigilance activities from September to November, 2014.

Int J Risk Saf Med. 2016 Mar 16;28(1):13-23

Authors: Awodele O, Ibrahim A, Orhii P

Abstract
BACKGROUND: Adverse drug reaction signals are reported information on possible causal relationships between an adverse event and a drug. The National Pharmacovigilance Centre (NPC) in Nigeria has over 3,000 reported adverse drug reaction cases which have been adequately entered into the ADR data bank.
OBJECTIVE: Data mining of ADR reports from September to November, 2014 were carried out in this present study with the intention to describe the pattern of ADRs and generate possible signals.
METHODS: A total of about 100 reported cases with arrays of adverse drug reactions were reported between September and November, 2014 and the data were analyzed using SPSS version 17.
RESULTS: Efavirenz/Tenofovir/Lamivudine combination was the highest reported drugs (24.2%) while efavirenz alone was reported in 8 times (8.8%) and HIV (63.3%) was the highest reported indication of drug use. Efavirenz caused central nervous system adverse reactions as revealed in the ADRs analyses. Zidovudine/Lamivudine/Nevirapine combination in concomitant use with Cotrimoxazole were reported 8 times with generalized maculopapular rashes on the trunk with some area of hyper pigmentation with intense itching documented twice and big/swollen rashes all over the faces. Zidovudine was also reported four times to cause severe anaemia.
CONCLUSION: More surveillance is advocated so as to ascertain the consistency of the observed ADRs and thereafter establish appropriate signals.

PMID: 27176753 [PubMed - indexed for MEDLINE]

Illuminating drug action by network integration of disease genes: a case study of myocardial infarction.

Mol Biosyst. 2016 Apr 26;12(5):1653-66

Authors: Wang RS, Loscalzo J

Abstract
Drug discovery has produced many successful therapeutic agents; however, most of these drugs were developed without a deep understanding of the system-wide mechanisms of action responsible for their indications. Gene-disease associations produced by molecular and genetic studies of complex diseases provide great opportunities for a system-level understanding of drug activity. In this study, we focused on acute myocardial infarction (MI) and conducted an integrative network analysis to illuminate drug actions. We integrated MI drugs, MI drug interactors, drug targets, and MI disease genes into the human interactome and showed that MI drug targets are significantly proximate to MI disease proteins. We then constructed a bipartite network of MI-related drug targets and MI disease proteins and derived 12 drug-target-disease (DTD) modules. We assessed the biological relevance of these modules and demonstrated the benefits of incorporating disease genes. The results indicate that DTD modules provide insights into the mechanisms of action of MI drugs and the cardiovascular (side) effects of non-MI drugs.

PMID: 27004607 [PubMed - indexed for MEDLINE]

Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.

Lancet Oncol. 2017 Jul 19;:

Authors: Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz S, André T

Abstract
BACKGROUND: Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer.
METHODS: In this ongoing, multicentre, open-label, phase 2 trial, we enrolled adults (aged ≥18 years) with histologically confirmed recurrent or metastatic colorectal cancer locally assessed as dMMR/MSI-H from 31 sites (academic centres and hospitals) in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the USA). Eligible patients had progressed on or after, or been intolerant of, at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. Patients were given 3 mg/kg nivolumab every 2 weeks until disease progression, death, unacceptable toxic effects, or withdrawal from study. The primary endpoint was investigator-assessed objective response as per Response Evaluation Criteria in Solid Tumors (version 1.1). All patients who received at least one dose of study drug were included in all analyses. This trial is registered with ClinicalTrials.gov, number NCT02060188.
FINDINGS: Of the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, 40 (54%) had received three or more previous treatments. At a median follow-up of 12·0 months (IQR 8·6-18·0), 23 (31·1%, 95% CI 20·8-42·9) of 74 patients achieved an investigator-assessed objective response and 51 (69%, 57-79) patients had disease control for 12 weeks or longer. Median duration of response was not yet reached; all responders were alive, and eight had responses lasting 12 months or longer (event rate 86%, 95% CI 62-95). The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (six [8%]) and amylase (two [3%]). 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator.
INTERPRETATION: Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a new treatment option for these patients.
FUNDING: Bristol-Myers Squibb.

PMID: 28734759 [PubMed - as supplied by publisher]

Large-Scale Analysis of Drug Side Effects via Complex Regulatory Modules Composed of microRNAs, Transcription Factors and Gene Sets.

Sci Rep. 2017 Jul 20;7(1):5962

Authors: Jia X, Jin Q, Liu X, Bian X, Wang Y, Liu L, Ma H, Tan F, Gu M, Chen X

Abstract
Identifying the occurrence mechanism of drug-induced side effects (SEs) is critical for design of drug target and new drug development. The expression of genes in biological processes is regulated by transcription factors(TFs) and/or microRNAs. Most of previous studies were focused on a single level of gene or gene sets, while studies about regulatory relationships of TFs, miRNAs and biological processes are very rare. Discovering the complex regulating relations among TFs, gene sets and miRNAs will be helpful for researchers to get a more comprehensive understanding about the mechanism of side reaction. In this study, a framework was proposed to construct the relationship network of gene sets, miRNAs and TFs involved in side effects. Through the construction of this network, the potential complex regulatory relationship in the occurrence process of the side effects was reproduced. The SE-gene set network was employed to characterize the significant regulatory SE-gene set interaction and molecular basis of accompanied side effects. A total of 117 side effects complex modules including four types of regulating patterns were obtained from the SE-gene sets-miRNA/TF complex regulatory network. In addition, two cases were used to validate the complex regulatory modules which could more comprehensively interpret occurrence mechanism of side effects.

PMID: 28729650 [PubMed - in process]

Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study.

Lancet HIV. 2017 Jul 17;:

Authors: Orrell C, Hagins DP, Belonosova E, Porteiro N, Walmsley S, Falcó V, Man CY, Aylott A, Buchanan AM, Wynne B, Vavro C, Aboud M, Smith KY, ARIA study team

Abstract
BACKGROUND: Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV-1.
METHODS: The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA-B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single-tablet regimen of dolutegravir plus abacavir and lamivudine once a day (dolutegravir group) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention-to-treat exposed population). We used a non-inferiority margin of -12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402.
FINDINGS: Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive study medication. At week 48, 203 (82%) of 248 participants in the dolutegravir group compared with 176 (71%) of 247 in the atazanavir group had HIV-1 RNA viral loads of less than 50 copies per mL (mean difference 10·5%, 95% CI 3·1-17·8, p=0·005). One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor-associated resistance that led to reduced emtricitabine susceptibility. Adverse events were similar between the dolutegravir and atazanavir groups; the most common were nausea (46 [19%] of 248 in the dolutegravir group vs 49 [20%] of 247 in the atazanavir group) and headache (28 [11%] vs 32 [13%]). Fewer participants in the dolutegravir group than the atazanavir group reported drug-related adverse events (83 [33%] vs 121 [49%]) or adverse events that led to discontinuation (ten [4%] vs 17 [7%]). One death was reported in each treatment group, but neither was considered related to the study medications.
INTERPRETATION: The non-inferior efficacy and similar safety profile of the dolutegravir combined regimen compared with the atazanavir regimen support the use of dolutegravir for HIV-1 infection in treatment-naive women.
FUNDING: ViiV Healthcare.

PMID: 28729158 [PubMed - as supplied by publisher]

Using QR codes to enable quick access to information in acute cancer care.

Br J Nurs. 2017 May 25;26(10):S4-S12

Authors: Upton J, Olsson-Brown A, Marshall E, Sacco J

Abstract
Quick access to toxicity management information ensures timely access to steroids/immunosuppressive treatment for cancer patients experiencing immune-related adverse events, thus reducing length of hospital stays or avoiding hospital admission entirely. This article discusses a project to add a QR (quick response) code to a patient-held immunotherapy alert card. As QR code generation is free and the immunotherapy clinical management algorithms were already publicly available through the trust's clinical network website, the costs of integrating a QR code into the alert card, after printing, were low, while the potential benefits are numerous. Patient-held alert cards are widely used for patients receiving anti-cancer treatment, and this established standard of care has been modified to enable rapid access of information through the incorporation of a QR code.

PMID: 28541108 [PubMed - indexed for MEDLINE]

Pharmacy Educators' Knowledge of Medication Safety and Their Perception Toward Its Integration into the Doctor of Pharmacy Curriculum in Saudi Arabia.

Am J Pharm Educ. 2017 Mar 25;81(2):30

Authors: Alkatheri AM, Bustami R, Albekairy AM, Almodaimegh H, Alghamdi S, Alharbi S, Khalidi N, Murphy JE, Qandil AM

Abstract
Objective. To assess pharmacy educators' knowledge of medication safety and their perception toward its integration into the PharmD curriculum in Saudi Arabia. Methods. A survey was administered to pharmacy educators at a college of pharmacy and its affiliate hospital. Knowledge, training, and perception toward integrating medication safety into the PharmD curriculum were evaluated. Results. More than 50% of respondents indicated that medication safety should be covered within selected courses, and 65% indicated that such courses should be mandatory. Pharmacy practice educators had significantly higher levels of knowledge about medication safety than their nonpractice counterparts. Perceptions toward medication safety integration into the curriculum varied significantly by general discipline, academic degree, years of experience, and gender. Conclusion. Pharmacy educators in Saudi Arabia understand the importance of medication safety and its integration into the curriculum. Further studies are needed to guide curricular change to achieve this integration.

PMID: 28381890 [PubMed - indexed for MEDLINE]

Pioglitazone utilization, efficacy & safety in Indian type 2 diabetic patients: A systematic review & comparison with European Medicines Agency Assessment Report.

Indian J Med Res. 2016 Nov;144(5):672-681

Authors: Pai SA, Kshirsagar NA

Abstract
BACKGROUND & OBJECTIVES: With pioglitazone ban and subsequent revoking in India along with varying regulatory decisions in other countries, it was decided to carry out a systematic review on its safety, efficacy and drug utilization in patients with type 2 diabetes mellitus (T2DM) in India and compare with the data from the European Medicines Agency Assessment Report (EMA-AR).
METHODS: Systematic review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching Medline/PubMed, Google Scholar and Science Direct databases using 'pioglitazone AND India AND human' and 'pioglitazone AND India AND human AND patient' and compared with EMA-AR. Spontaneous reports in World Health Organization VigiBase from India were compared with VigiBase data from other countries.
RESULTS: Sixty six publications, 26 (efficacy), 32 (drug utilization) and eight (safety), were retrieved. In India, pioglitazone was used at 15-30 mg/day mostly with metformin and sulphonylurea, being prescribed to 26.7 and 8.4 per cent patients in north and south, respectively. The efficacy in clinical trials (CTs) was similar to those in EMA-AR. Incidence of bladder cancer in pioglitazone exposed and non-exposed patients was not significantly different in an Indian retrospective cohort study. There were two cases and a series of eight cases of bladder cancer published but none reported in VigiBase.
INTERPRETATION & CONCLUSIONS: In India, probably due to lower dose, lower background incidence of bladder cancer and smaller sample size in epidemiological studies, association of bladder cancer with pioglitazone was not found to be significant. Reporting of CTs and adverse drug reactions to Clinical Trials Registry of India and Pharmacovigilance Programme of India, respectively, along with compliance studies with warning given in package insert and epidemiological studies with larger sample size are needed.

PMID: 28361819 [PubMed - indexed for MEDLINE]