In silico ADME-Tox modeling: progress and prospects.

Expert Opin Drug Metab Toxicol. 2017 Nov;13(11):1147-1158

Authors: Alqahtani S

Abstract
INTRODUCTION: Although significant progress has been made in high-throughput screening of absorption, distribution, metabolism and excretion, and toxicity (ADME-Tox) properties in drug discovery and development, in silico ADME-Tox prediction continues to play an important role in facilitating the appropriate selection of candidate drugs by pharmaceutical companies prior to expensive clinical trials. Areas covered: This review provides an overview of the available in silico models that have been used to predict the ADME-Tox properties of compounds. It also provides a comprehensive overview and summarization of the latest modeling methods and algorithms available for the prediction of physicochemical characteristics, ADME properties, and drug toxicity issues. Expert opinion: The in silico models currently available have greatly contributed to the knowledge of screening approaches in the early stages of drug discovery and the development process. As the definitive goal of in silico molding is to predict the pharmacokinetics and disposition of compounds in vivo by assembling all kinetic processes within one global model, PBPK models can serve this purpose. However, much work remains to be done in this area to generate more data and input parameters to build more reliable and accurate prediction models.

PMID: 28988506 [PubMed - indexed for MEDLINE]

Evaluation of a care transition program with pharmacist-provided home-based medication review for elderly Singaporeans at high risk of readmissions.

Int J Qual Health Care. 2017 Apr 01;29(2):200-205

Authors: Cheen MHH, Goon CP, Ong WC, Lim PS, Wan CN, Leong MY, Khee GY

Abstract
Objective: This study aimed to determine whether pharmacist-provided home-based medication review (HBMR) can reduce readmissions in the elderly.
Design: Retrospective cohort study.
Setting: Patient's home.
Participants: Records of patients referred to a care transition program from March 2011 through March 2015 were reviewed. Patients aged 60 years and older taking more than 5 medications and had at least 2 unplanned admissions within 3 months preceding the first home visit were included.
Intervention: Pharmacist-provided HBMR.
Main outcome measures: Primary outcome was readmission rate over 6 months after the first home visit. Secondary outcomes included emergency department (ED) visits, outpatient visits and mortality. Drug-related problems (DRPs) were reported for the HBMR group. Multivariate incidence rate ratios (IRR) and hazard ratio (HR) were calculated with adjustments for covariates.
Results: The study included 499 patients (97 HBMR, 402 no HBMR). Pharmacist-provided HBMR reduced readmissions by 26% (IRR = 0.74, 95% CI: 0.59-0.92, P = 0.007), reduced ED visits by 20% (IRR = 0.80, 95% CI: 0.66-0.98, P = 0.030) and increased outpatient visits by 16% (IRR = 1.16, 95% CI: 0.95-1.41, P = 0.150). There were 8 and 44 deaths in the HBMR and no HBMR groups respectively (HR = 0.73, 95% CI: 0.29-1.81, P = 0.492). Pharmacists identified 464 DRPs, with 169 (36.4%) resolved within 1 month after the home visit.
Conclusions: The study suggests that pharmacist-provided HBMR is effective in reducing readmissions and ED visits in the elderly. More studies in the Asian population are needed to determine its long term benefits and patient's acceptability.

PMID: 28453819 [PubMed - indexed for MEDLINE]

A prospective study of aromatase inhibitor therapy initiation and self-reported side effects.

Support Care Cancer. 2017 Sep;25(9):2697-2705

Authors: Gallicchio L, Calhoun C, Helzlsouer K

Abstract
PURPOSE: The objective of this study was to examine the associations between aromatase inhibitors (AIs) and side effects less frequently reported in the literature, including difficulty concentrating, forgetfulness, hair loss, and numbness in the extremities.
METHODS: Data were analyzed from a cohort of 146 breast cancer patients initiating AI therapy and followed for 1 year and a cohort of 144 postmenopausal women without a history of cancer followed for 6 months. At baseline (prior to AI therapy for breast cancer patients), and at 3 months, 6 months, and 1 year (for breast cancer patients only), a comprehensive questionnaire was administered that ascertained data on symptoms. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression for new onset of symptoms among the breast cancer patients compared to the women without a history of cancer.
RESULTS: Among the breast cancer patients, 34.2% were treated with chemotherapy prior to AI treatment. Over the first 6 months of AI treatment, breast cancer patients had significantly higher odds of reporting new onset of forgetfulness (OR 4.00; 95% CI 1.67, 9.59), difficulty concentrating (OR 2.73; 95% CI 1.29; 5.78), hair loss (OR 4.12; 95% CI 1.86, 9.17), and numbness/tingling in the extremities (OR 2.47; 95% CI 1.09, 5.62) compared to women without a history of cancer. Similar increases in odds were observed for the subgroup of women not treated with chemotherapy versus the comparison group.
CONCLUSIONS: AI-related symptoms should be monitored and addressed so that adherence to therapy is maintained.

PMID: 28341972 [PubMed - indexed for MEDLINE]

Side Effects of CV Medications Following Hospitalization for ACS Are Associated With More Frequent Health-Care Contacts.

J Cardiovasc Pharmacol Ther. 2017 May;22(3):250-255

Authors: Le RJ, Cullen MW, Lahr BD, Wright RS, Kopecky SL

Abstract
BACKGROUND: Patients hospitalized for first acute coronary syndrome (ACS) are frequently discharged on multiple new medications. The short-term tolerability of these medications is unknown.
METHODS: This single-center cohort study assessed 30-day health-care utilization and how it may be impacted by medication prescribing trends. We included Olmsted County patients presenting with ACS and previously undiagnosed coronary artery disease in 2008 to 2009. All health-care contacts were reviewed 30 days after index hospital discharge for potential adverse medication effects including documented hypotension or bradycardia, or symptoms likely attributed to the medications.
RESULTS: The study included 86 patients; their mean age was 63 (standard deviation: 15.5 years). Antianginal or antihypertensive cardiovascular (CV) medications were prescribed to 98% of patients at discharge; 76% were prescribed 2 or more. There were 233 health-care contacts in 30 days; 90 (39%) of these contacts were unscheduled. More CV medications tended to be prescribed to patients with unscheduled contacts, both pre-ACS ( P = .045) and upon hospital discharge ( P = .051). Hypotension and/or bradycardia at follow-up occurred in 52 patients (60%). Surprisingly, there was no association between hypotension and/or bradycardia at follow-up and increased health-care utilization ( P = .12). Potential adverse drug effects were reported in 34 (40%) patients. These patients had significantly more total health-care contacts ( P < .001) and unscheduled health-care contacts (median 0 vs 1.5; P < .001).
CONCLUSIONS: Symptoms of adverse drug effects were associated with more frequent health-care utilization after ACS. Clinicians need to consider this while striving to increase patient compliance with post-ACS medications and optimize care transitions.

PMID: 27698079 [PubMed - indexed for MEDLINE]

Immunogenicity and safety of inactivated quadrivalent influenza vaccine in adults: A systematic review and meta-analysis of randomised controlled trials.

Vaccine. 2016 Jul 29;34(35):4092-4102

Authors: Moa AM, Chughtai AA, Muscatello DJ, Turner RM, MacIntyre CR

Abstract
BACKGROUND: A quadrivalent influenza vaccine (QIV) includes two A strains (A/H1N1, A/H3N2) and two B lineages (B/Victoria, B/Yamagata). The presence of both B lineages eliminate potential B lineage mismatch of trivalent influenza vaccine (TIV) with the circulating strain.
METHODS: Electronic database searches of Medline, Embase, Cochrane Central Register of Controlled Trials (CCRCT), Scopus and Web of Science were conducted for articles published until June 30, 2015 inclusive. Articles were limited to randomised controlled trials (RCTs) in adults using inactivated intramuscular vaccine and published in English language only. Summary estimates of immunogenicity (by seroprotection and seroconversion rates) and adverse events outcomes were compared between QIV and TIV, using a risk ratio (RR). Studies were pooled using inverse variance weights with a random effect model and the I(2) statistic was used to estimate heterogeneity.
RESULTS: A total of five RCTs were included in the meta-analysis. For immunogenicity outcomes, QIV had similar efficacy for the three common strains; A/H1N1, A/H3N2 and the B lineage included in the TIV. QIV also showed superior efficacy for the B lineage not included in the TIV; pooled seroprotection RR of 1.14 (95%CI: 1.03-1.25, p=0.008) and seroconversion RR of 1.78 (95%CI: 1.24-2.55, p=0.002) for B/Victoria, and pooled seroprotection RR of 1.12 (95%CI: 1.02-1.22, p=0.01) and seroconversion RR of 2.11 (95%CI: 1.51-2.95, p<0.001) for B/Yamagata, respectively. No significant differences were found between QIV and TIV for aggregated local and systemic adverse events within 7days post-vaccination. There were no vaccine-related serious adverse events reported for either QIV or TIV. Compared to TIV, injection-site pain was more common for QIV, with a pooled RR of 1.18 (95%CI: 1.03-1.35, p=0.02).
CONCLUSION: In adults, inactivated QIV was as immunogenic as seasonal TIV, with equivalent efficacy against the shared three strains included in TIV, and a superior immunogenicity against the non-TIV B lineage.

PMID: 27381642 [PubMed - indexed for MEDLINE]

A Randomized Controlled Trial of a Patient-Centered Approach to Improve Screening for the Metabolic Side Effects of Antipsychotic Medications.

Community Ment Health J. 2017 Feb;53(2):163-175

Authors: Kreyenbuhl J, Dixon LB, Brown CH, Medoff DR, Klingaman EA, Fang LJ, Tapscott S, Walsh MB

Abstract
Adherence to recommendations for monitoring of metabolic side effects of antipsychotic medications has been historically low. This randomized controlled trial tested whether a computerized, patient-centered intervention that educated Veterans with serious mental illness about these side effects and encouraged them to advocate for receipt of monitoring would increase rates of monitoring compared to enhanced treatment as usual. The mean proportion of days adherent to monitoring guidelines over the 1-year study was similarly high and did not differ between the intervention (range 0.81-0.98) and comparison (range 0.76-0.96) groups. Many individuals in both groups had persistent abnormal metabolic parameter values despite high rates of monitoring, contact with medical providers, and receipt of cardiometabolic medications. Participants exposed to the intervention were interested in receiving personalized information about their cardiometabolic status, demonstrating the preliminary feasibility of brief interventions for enhancing involvement of individuals with serious mental illness in health care decision making.

PMID: 27061185 [PubMed - indexed for MEDLINE]

Impact of strategies to reduce polypharmacy on clinically relevant endpoints: a systematic review and meta-analysis.

Br J Clin Pharmacol. 2016 Aug;82(2):532-48

Authors: Johansson T, Abuzahra ME, Keller S, Mann E, Faller B, Sommerauer C, Höck J, Löffler C, Köchling A, Schuler J, Flamm M, Sönnichsen A

Abstract
AIM: The aim of the present study was to explore the impact of strategies to reduce polypharmacy on mortality, hospitalization and change in number of drugs.
METHODS: Systematic review and meta-analysis: a systematic literature search targeting patients ≥65 years with polypharmacy (≥4 drugs), focusing on patient-relevant outcome measures, was conducted. We included controlled studies aiming to reduce polypharmacy. Two reviewers independently assessed studies for eligibility, extracted data and evaluated study quality.
RESULTS: Twenty-five studies, including 10 980 participants, were included, comprising 21 randomized controlled trials and four nonrandomized controlled trials. The majority of the included studies aimed at improving quality or the appropriateness of prescribing by eliminating inappropriate and non-evidence-based drugs. These strategies to reduce polypharmacy had no effect on all-cause mortality (odds ratio 1.02; 95% confidence interval 0.84, 1.23). Only single studies found improvements, in terms of reducing the number of hospital admissions, in favour of the intervention group. At baseline, patients were taking, on average, 7.4 drugs in both the intervention and the control groups. At follow-up, the weighted mean number of drugs was reduced (-0.2) in the intervention group but increased (+0.2) in controls.
CONCLUSIONS: There is no convincing evidence that the strategies assessed in the present review are effective in reducing polypharmacy or have an impact on clinically relevant endpoints. Interventions are complex; it is still unclear how best to organize and implement them to achieve a reduction in inappropriate polypharmacy. There is therefore a need to develop more effective strategies to reduce inappropriate polypharmacy and to test them in large, pragmatic randomized controlled trials on effectiveness and feasibility.

PMID: 27059768 [PubMed - indexed for MEDLINE]

Effects of opioid and nonopioid analgesics on canine wheal formation and cultured human mast cell degranulation.

Toxicol Appl Pharmacol. 2017 Oct 27;:

Authors: Schmidt-Rondon E, Wang Z, Malkmus SA, Di Nardo A, Hildebrand K, Page L, Yaksh TL

Abstract
Mast cell (MC) degranulation has been implicated in the side effect profile of a variety of clinically useful agents. Thus, after intrathecal delivery, formation of space-occupying, meningeally-derived masses may be related to local MC degranulation. We systematically characterized degranulating effects of opioid and nonopioid analgesics on cutaneous flares in the dog and in primary human MC (hMC) cultures.
METHODS: Dogs were anesthetized with IV propofol and received intradermal (ID) injections (50μL). Flare diameters were measured at 30min. Drugs showing flare responses were tested after intramuscular (IM) cromolyn (10mg/kg), a MC stabilizer. Human primary MCs (human cord blood CD34(+)/CD45(+) cells) were employed and β-hexosaminidase in cell-free supernatants were measured to assess degranulation.
RESULTS: A significant skin flare for several classes of agents was observed including opioids, ziconotide, ketamine, ST-91, neostigmine, adenosine, bupivacaine, lidocaine, MK-801 and 48/80. Tizanidine, fentanyl, alfentanil, gabapentin and baclofen produced no flare. Flare produced by all ID agents, except adenosine, bupivacaine and lidocaine, was reduced by cromolyn. Naloxone had no effect upon opiate or 48/80 evoked flares. In hMC studies, 48/80 resulted in a concentration-dependent release of β-hexosaminidase. The rank order of drug-induced hMC β-hexosaminidase release was similar to that for flares.
CONCLUSIONS: A variety of therapeutically useful drugs degranulate MCs. This action may account for side effects such as the intrathecal granuloma resulting from spinally-delivered opioids. This degranulating effect may be useful in predicting potential intrathecal toxicity in the development of novel agents.

PMID: 29111148 [PubMed - as supplied by publisher]

Continued use of afatinib with the addition of cetuximab after progression on afatinib in patients with EGFR mutation-positive non-small-cell lung cancer and acquired resistance to gefitinib or erlotinib.

Lung Cancer. 2017 Nov;113:51-58

Authors: Horn L, Gettinger S, Camidge DR, Smit EF, Janjigian YY, Miller VA, Pao W, Freiwald M, Fan J, Wang B, Chand VK, Groen HJM

Abstract
OBJECTIVES: In a phase Ib trial, afatinib plus cetuximab demonstrated promising clinical activity (objective response rate [ORR]: 29%; median progression-free survival [PFS]: 4.7 months) in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with acquired resistance to erlotinib or gefitinib. Here, a separate cohort exploring afatinib plus cetuximab after progression on afatinib is reported.
MATERIALS AND METHODS: Patients with EGFR mutation-positive NSCLC who progressed on erlotinib or gefitinib received afatinib 40mg daily until progression, followed by afatinib daily plus cetuximab 500mg/m(2) every 2 weeks until progression or intolerable adverse events (AEs). Endpoints included safety, ORR, and PFS.
RESULTS: Thirty-seven patients received afatinib monotherapy. Two (5%) patients responded; median PFS was 2.7 months. Thirty-six patients transitioned to afatinib plus cetuximab. Four (11%) patients responded; median PFS was 2.9 months. Median PFS with afatinib plus cetuximab for patients who received afatinib monotherapy for ≥12 versus <12 weeks was 4.9 versus 1.8 months (p=0.0354), and for patients with T790M-positive versus T790M-negative tumors was 4.8 versus 1.8 months (p=0.1306). Fifty percent of patients receiving afatinib plus cetuximab experienced drug-related grade 3/4 AEs. The most frequent drug-related AEs (any grade) were diarrhea (70%), rash (49%), and fatigue (35%) with afatinib monotherapy and rash (69%), paronychia (39%), and dry skin (36%) with afatinib plus cetuximab.
CONCLUSION: Sequential EGFR blockade with afatinib followed by afatinib plus cetuximab had a predictable safety profile and demonstrated modest activity in patients with EGFR mutation-positive NSCLC with resistance to erlotinib or gefitinib. CLINICALTRIALS.
GOV IDENTIFIER: NCT01090011.

PMID: 29110849 [PubMed - in process]

A randomized, placebo-controlled clinical trial evaluating the safety and efficacy of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus inadequately controlled by glimepiride and metformin.

BMC Endocr Disord. 2017 Nov 06;17(1):70

Authors: Lee SH, Gantz I, Round E, Latham M, O'Neill EA, Ceesay P, Suryawanshi S, Kaufman KD, Engel SS, Lai E

Abstract
BACKGROUND: Type 2 diabetes (T2D) is a progressive disease that often requires a patient to use multiple antihyperglycemic agents to achieve glycemic control with disease progression. Omarigliptin is a once-weekly dipeptidyl peptidase-4 inhibitor. The purpose of this trial was to assess the efficacy and safety of adding omarigliptin to the treatment regimen of patients with T2D inadequately controlled by dual therapy with metformin and glimepiride.
METHODS: Patients with T2D and HbA1c ≥7.5% and ≤10.5% while on metformin (≥1500 mg/day) and glimepiride (≥4 mg/day) were randomized to omarigliptin 25 mg once-weekly (N = 154) or placebo (N = 153) for 24 weeks. The primary objective was to assess whether omarigliptin was superior to placebo in reducing HbA1c at Week 24. Secondary objectives were to assess the effects of omarigliptin vs. placebo on FPG and the proportion of subjects attaining HbA1c goals of <7% and <6.5%.
RESULTS: From a mean baseline HbA1c of 8.5% (omarigliptin) and 8.6% (placebo), the least squares (LS) mean change from baseline in HbA1c at Week 24 was -0.67% in the omarigliptin group and -0.06% in the placebo group, with a between-group difference (95% CI) of -0.61% (-0.85, -0.38). Treatment with omarigliptin resulted in a significantly greater reduction in FPG relative to placebo (LS mean difference [95% CI] -0.9 mmol/L [-1.4, -0.4]; p < 0.001). The proportion of patients achieving glycemic goals of <7.0% and <6.5% was higher in the omarigliptin group relative to the placebo group. The overall incidences of adverse events (AEs), serious AEs, drug-related AEs and discontinuations were generally similar between treatment groups. The incidence of symptomatic hypoglycemia was 10.5% in the omarigliptin group and 8.5% in the placebo group. Relative to baseline, omarigliptin and placebo treatments were associated with LS mean changes in body weight of -0.1 kg and -0.9 kg, respectively.
CONCLUSION: In patients with T2D and inadequate glycemic control on dual therapy with metformin and glimepiride, compared with placebo, once-weekly omarigliptin provided greater improvement in glycemic control and was generally well tolerated.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT01704261 , EudraCT Number: 2012-002612-10. Trial Registration Date: October 8, 2012.

PMID: 29110647 [PubMed - in process]

Use of erlotinib and thalidomide in advanced NSCLC patients with acquired resistance to erlotinib: A pilot study.

Pathol Res Pract. 2017 Oct 18;:

Authors: Wang GH, Wu PF, Zhang LH, Fang P, Chen Y, Zuo G, Wu YQ, Wang SH, Sun GP

Abstract
Evidences suggested that combined blockade of the VEGF and EGFR pathways can improve the treatment efficacy of non-small-cell lung cancer (NSCLC). In our previously clinical practice, we observed that thalidomide, a potent VEGF inhibitor, can significantly decrease the tumor size of one EGFR-TKI resistance patient with lung cancer cachexia. In this pilot study, we tried to assess the efficacy and toxicity of the combination therapy of erlotinib and thalidomide in advanced NSCLC patients with acquired resistance to erlotinib. In all, 52 NSCLC patients with drug resistance to erlotinib were recruited and treated with this combination therapy. After treatment, 4 patients presented with partial remission (PR), 16 with stable disease (SD) and 32 with progressive disease (PD). The objective response rate (ORR) and disease control rate (DCR) was 7.7% and 38.5%, respectively. In this study, we firstly confirmed that thalidomide can reversion of erlotinib-acquired resistance with a 7 weeks median progression-free survival (PFS); besides, this combination therapy shows acceptable drug tolerance; the most common drug related adverse events were astriction, numbness and sleeve-like feeling in the limbs, no thrombosis occurred in any patient. Those evidences indicate that thalidomide may be a useful candidate for reversion of erlotinib-acquired resistance.

PMID: 29108922 [PubMed - as supplied by publisher]

Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer.

Oncotarget. 2017 Oct 03;8(45):79546-79555

Authors: Shitara K, Kim TM, Yokota T, Goto M, Satoh T, Ahn JH, Kim HS, Assadourian S, Gomez C, Harnois M, Hamauchi S, Kudo T, Doi T, Bang YJ

Abstract
SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260-570 mg/m(2)) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort (N = 19; unselected population, including three patients with MET-amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m(2). Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade ≥ 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m(2) in the dose-expansion cohort, comprising patients with MET-amplified tumors (N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m(2) has acceptable tolerability and modest antitumor activity in patients with MET-amplified gastric cancer.

PMID: 29108334 [PubMed]

Predictors of adverse drug reaction-related hospitalisation in Southwest Ethiopia: A prospective cross-sectional study.

PLoS One. 2017;12(10):e0186631

Authors: Angamo MT, Curtain CM, Chalmers L, Yilma D, Bereznicki L

Abstract
BACKGROUND: Adverse drug reactions (ADRs) are important causes of morbidity and mortality in the healthcare system; however, there are no studies reporting on the magnitude and risk factors associated with ADR-related hospitalisation in Ethiopia.
OBJECTIVES: To characterise the reaction types and the drugs implicated in admission to Jimma University Specialized Hospital, Southwest Ethiopia, and to identify risk factors associated with ADR-related hospitalisation.
METHODS: A prospective cross-sectional study was conducted from May 2015 to August 2016 among consenting patients aged ≥18 years consecutively admitted to medical wards taking at least one medication prior to admission. ADR-related hospitalisations were determined through expert review of medical records, laboratory tests, patient interviews and physical observation. ADR causality was assessed by the Naranjo algorithm followed by consensus review with internal medicine specialist. ADR preventability was assessed using Schumock and Thornton's criteria. Only definite and probable ADRs that provoked hospitalisation were considered. Binary logistic regression was used to identify independent predictors of ADR-related hospitalisation.
RESULTS: Of 1,001 patients, 103 (10.3%) had ADR-related admissions. Common ADRs responsible for hospitalisation were hepatotoxicity (35, 29.4%) and acute kidney injury (27, 22.7%). The drug classes most frequently implicated were antitubercular agents (45, 25.0%) followed by antivirals (22, 12.2%) and diuretics (19, 10.6%). Independent predictors of ADR-related hospitalisation were body mass index (BMI) <18.5 kg/m2 (adjusted odd ratio [AOR] = 1.69; 95% confidence interval [CI] = 1.10-2.62; p = 0.047), pre-existing renal disease (AOR = 2.84; 95%CI = 1.38-5.85, p = 0.004), pre-existing liver disease (AOR = 2.61; 95%CI = 1.38-4.96; p = 0.003), number of comorbidities ≥4 (AOR = 2.09; 95%CI = 1.27-3.44; p = 0.004), number of drugs ≥6 (AOR = 2.02; 95%CI = 1.26-3.25; p = 0.004) and history of previous ADRs (AOR = 24.27; 95%CI = 11.29-52.17; p<0.001). Most ADRs (106, 89.1%) were preventable.
CONCLUSIONS: ADRs were a common cause of hospitalisation. The majority of ADRs were preventable, highlighting the need for monitoring and review of patients with lower BMI, ADR history, renal and liver diseases, multiple comorbidities and medications. ADR predictors should be integrated into clinical pathways and pharmacovigilance systems.

PMID: 29036230 [PubMed - indexed for MEDLINE]

Off-label use of medicines.

Br Dent J. 2017 04 07;222(7):495-6

Authors: Yeung CA

PMID: 28387299 [PubMed - indexed for MEDLINE]

[Pharmacological and nutritional problems in pregnant patient on chronic dialysis].

G Ital Nefrol. 2017 Jan-Feb;34(1):

Authors: Giannattasio M, Giannattasio F, Gernone G

Abstract
Many of information on the safety of drugs during pregnancy were obtained many years ago, before the pregnant women were excluded from the study protocols for possible fetal risks. Because randomized trials in pregnancy are complex and considered unethical. For the same reasons, there are no randomized controlled trials in pregnant women on dialysis. Moreover Compared to the normal subject, the pharmacokinetics and pharmacodynamics in these patients are influenced or by pregnancy or from dialysis techniques or from chronic uremia. Protein energy wasting PEW- is largely present in dialysis subjects. Nausea and vomiting are present in over 85% of pregnancy and may aggravate PEW. Therefore, it is necessary to adopt specific measures to prevent the PEW as well as periodic inspections of weight gain during pregnancy.

PMID: 28177093 [PubMed - indexed for MEDLINE]

How do researchers determine the difference to be detected in superiority trials? Results of a survey from a panel of researchers.

BMC Med Res Methodol. 2016 Jul 29;16:89

Authors: Gayet-Ageron A, Jannot AS, Agoritsas T, Rudaz S, Combescure C, Perneger T

Abstract
BACKGROUND: There is currently no guidance for selecting a specific difference to be detected in a superiority trial. We explored 3 factors that in our opinion should influence the difference to be detected (type of outcome, patient age group, and presence of treatment side-effects), and 3 that should not (baseline level of risk, logistical difficulties, and cost of treatment).
METHODS: We conducted an experimental survey using a factorial design among 380 corresponding authors of randomized controlled trials indexed in Medline. Two hypothetical vignettes were submitted to participants: one described a trial of a new analgesic in mild trauma injuries, the other described a trial of a new chemotherapy among cancer patients. The first vignette tested the baseline level of risk, patient age-group, patient recruitment difficulties, and treatment side-effects. The second tested the baseline level of risk, patient age-group, type of outcome, and cost of treatment. The respondents were asked to select the smallest gain of effectiveness that should be detected by the trial.
RESULTS: In vignette 1, respondents selected a median difference to be detected corresponding to an improvement of 7.0 % in pain control with the new treatment. In vignette 2, they selected a median difference to be detected corresponding to a reduction of 5.0 % in mortality or cancer recurrence with the new chemotherapy. In both vignettes, the difference to be detected decreased significantly with the baseline risk. The other factor influencing difference to be detected was the age group, but the impact of this factor was smaller. Cost, side-effects, outcome severity, or mention of logistical difficulties did not significantly impact the difference to be detected selected by participants.
CONCLUSIONS: Three of the anticipated effects conformed to our expectations (the effect of patient age, and absence of effect of the cost of treatment and of patient recruitment difficulties) and the other three did not. These findings can guide future research in determining differences to be detected in trials that can translate to meaningful clinical decision-making.

PMID: 27473336 [PubMed - indexed for MEDLINE]

Mortality due to acute adverse drug reactions in Galicia: 1997-2011.

Adicciones. 2016 Mar 02;28(2):80-9

Authors: Miguel-Arias D, Pereiro Gómez C, Bermejo Barrera AM, López de Abajo Rodríguez B, Sobrido Prieto M

Abstract
The aim of this research is to study all people who died in the Autonomous Community of Galicia from acute death after drugconsumption (ADR) in which there was judicial intervention during the period from 1997 to 2011, according to inclusion and exclusión criteria established by the National Drug Plan for the entire national territory. Sociodemographic and clinical characteristics of deceased subjects were studied, in order to identify key risk factors and/or vulnerable populations.A total of 805 deaths were recorded. The distribution by provinces and municipalities corresponds to the areas of greatest population, incidence of consumption and proximity to the coast. The average age of these patients was 34.34 years, with a gradual increase over years. Most of them were male (91.2%) and single (47.7). 43.5% of the deceased habitually used the parenteral route of administration and 36.4% had positive HIV serology. The most frequently-detected substances corresponded to opiates (heroin: 61.3%, methadone: 35.6%), followed by cocaine (53.7%), although the most common pattern was that of poly-consumption. ADR mortality figures remain relatively stable throughout the study period. The predominant pattern is that of males, opiates and a long history of consumption.

PMID: 26990265 [PubMed - indexed for MEDLINE]

A simple Bayesian approach to quantifying confidence level of adverse event incidence proportion in small samples.

J Biopharm Stat. 2016;26(3):499-506

Authors: Liu F

Abstract
In both clinical development and post-marketing of a new therapy or a new treatment, incidence of an adverse event (AE) is always a concern. When sample sizes are small, large sample-based inferential approaches on an AE incidence proportion in a certain time period no longer apply. In this brief discussion, we introduce a simple Bayesian framework to quantify, in small sample studies and the rare AE case, (1) the confidence level that the incidence proportion of a particular AE p is over or below a threshold, (2) the lower or upper bounds on p with a certain level of confidence, and (3) the minimum required number of patients with an AE before we can be certain that p surpasses a specific threshold, or the maximum allowable number of patients with an AE after which we can no longer be certain that p is below a certain threshold, given a certain confidence level. The method is easy to understand and implement; the interpretation of the results is intuitive. This article also demonstrates the usefulness of simple Bayesian concepts when it comes to answering practical questions.

PMID: 26098967 [PubMed - indexed for MEDLINE]

Effect of Novel Allosteric Modulators of Metabotropic Glutamate Receptors on Drug Self-administration and Relapse: A Review of Preclinical Studies and Their Clinical Implications.

Biol Psychiatry. 2017 Sep 05;:

Authors: Caprioli D, Justinova Z, Venniro M, Shaham Y

Abstract
Results from preclinical rodent studies during the last 20 years implicated glutamate neurotransmission in different brain regions in drug self-administration and rodent models of relapse. These results, along with evidence for drug-induced neuroadaptations in glutamatergic neurons and receptors, suggested that addiction might be treatable by medications that inhibit glutamatergic responses to drugs of abuse, drug-associated cues, and stressors. This idea is supported by findings in rodent and primate models that drug self-administration and relapse are reduced by systemic injections of antagonists of ionotropic glutamate receptors or metabotropic glutamate receptors (mGluRs) or orthosteric agonists of mGluR2/3. However, these compounds have not advanced to clinical use because of potential side effects and other factors. This state of affairs has led to the development of positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) of mGluRs. PAMs and NAMs of mGluRs, either of which can inhibit evoked glutamate release, may be suitable for testing in humans. We reviewed results from recent studies of systemically injected PAMs and NAMs of mGluRs in rodents and monkeys, focusing on whether they reduce drug self-administration, reinstatement of drug seeking, and incubation of drug craving. We also review results from rat studies in which PAMs or NAMs of mGluRs were injected intracranially to reduce drug self-administration and reinstatement. We conclude that PAMs and NAMs of mGluRs should be considered for clinical trials.

PMID: 29102027 [PubMed - as supplied by publisher]

Gender-based personalized pharmacotherapy: a systematic review.

Arch Gynecol Obstet. 2017 Jun;295(6):1305-1317

Authors: Islam MM, Iqbal U, Walther BA, Nguyen PA, Li YJ, Dubey NK, Poly TN, Masud JHB, Atique S, Syed-Abdul S

Abstract
PURPOSE: In general, male and female are prescribed the same amount of dosage even if most of the cases female required less dosage than male. Physicians are often facing problem on appropriate drug dosing, efficient treatment, and drug safety for a female in general. To identify and synthesize evidence about the effectiveness of gender-based therapy; provide the information to patients, providers, and health system intervention to ensure safety treatment; and minimize adverse effects.
METHODS: We performed a systematic review to evaluate the effect of gender difference on pharmacotherapy. Published articles from January 1990 to December 2015 were identified using specific term in MEDLINE (PubMed), EMBASE, and the Cochrane library according to search strategies that strengthen the reporting of observational and clinical studies.
RESULTS: Twenty-six studies fulfilled the inclusion criteria for this systematic review, yielding a total of 6309 subjects. We observed that female generally has a lower the gastric emptying time, gastric PH, lean body mass, and higher plasma volume, BMI, body fat, as well as reduce hepatic clearance, difference in activity of Cytochrome P450 enzyme, and metabolize drugs at different rate compared with male. Other significant factors such as conjugation, protein binding, absorption, and the renal elimination could not be ignored. However, these differences can lead to adverse effects in female especially for the pregnant, post-menopausal, and elderly women.
CONCLUSION: This systematic review provides an evidence for the effectiveness of dosage difference to ensure safety and efficient treatment. Future studies on the current topic are, therefore, recommended to reduce the adverse effect of therapy.

PMID: 28378180 [PubMed - indexed for MEDLINE]