Drug-induced nephrotoxicity: pathogenic mechanisms, biomarkers and prevention strategies.

Curr Drug Metab. 2017 Nov 08;:

Authors: Huang J, Wu H

Abstract
Overdosing of the drugs, drug-drug interaction or drug related adverse effects are the risk factors of drug-induced nephrotoxicity. Since the use of some nephrotoxic drugs is still unavoidable in clinic, to understand the pathogenic mechanisms of nephrotoxicity of these drugs is critical to decrease the incidence of kidney injury. Early detection of drug-induced nephrotoxicity and reduce the therapeutic side effects are still accessible approaches to avoid the end stage of renal failure. Therefore, the discovery or development of the early and accurate diagnostic biomarkers is an effective prevention strategy for drug-induced kidney impairment. In the present review, we summarized the mechanisms and prevention strategies for some common used drugs in clinic that induced acute and chronic kidney injury. We discussed the pros and cons of the biomarkers available nowadays. In addition, the in vitro and pre-clinical in vivo models to assess the nephrotoxicity during the drug development stages are also discussed.

PMID: 29119923 [PubMed - as supplied by publisher]

Decreased 5-HT2cR and GHSR1a interaction in antipsychotic drug-induced obesity.

Obes Rev. 2017 Nov 09;:

Authors: Huang XF, Weston-Green K, Yu Y

Abstract
Second generation antipsychotics (SGAs), notably atypical antipsychotics including olanzapine, clozapine and risperidone, can cause weight gain and obesity side effects. Antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling have been identified as a main cause of SGA induced obesity. Here we review the pivotal regulatory role of the 5-HT2cR in ghrelin-mediated appetite signalling. The 5-HT2cR dimerizes with GHSR1a to inhibit orexigenic signalling, while 5-HT2cR antagonism reduces dimerization and increases GHSR1a-induced food intake. Dimerization is specific to the unedited 5-HT2cR isoform. 5-HT2cR antagonism by SGAs may disrupt the normal inhibitory tone on the GHSR1a, increasing orexigenic signalling. The 5-HT2cR and its interaction with the GHSR1a could serve as the basis for discovering novel approaches to preventing and treating SGA-induced obesity.

PMID: 29119689 [PubMed - as supplied by publisher]

Older People's Preferences for Side Effects Associated with Antimuscarinic Treatments of Overactive Bladder: A Discrete-Choice Experiment.

Drugs Aging. 2017 Aug;34(8):615-623

Authors: Decalf VH, Huion AMJ, Benoit DF, Denys MA, Petrovic M, Everaert KCMM

Abstract
INTRODUCTION: Understanding the importance older people attribute to the different side effects associated with oral antimuscarinic treatments for overactive bladder (OAB) could help inform prescribers, healthcare policy makers and the drug industry.
OBJECTIVE: Our objective was to quantify the importance of the most prevalent cognitive and side effects of oral antimuscarinic treatments for OAB in older people.
METHODS: We conducted a discrete-choice experiment (DCE) with the assistance of an interviewer with community-dwelling and hospitalized older people aged >65 years. The DCE involved two hypothetical drugs for imaginary OAB, with three levels of four side effects for each drug, and the International Consultation on Incontinence Questionnaire-Overactive Bladder and EuroQol 5-Dimensions (EQ-5D) questionnaire were also administered. Data were analysed using a conditional logit model.
RESULTS: In total, 276 older people participated in the study. The median age was 75 years (interquartile range [IQR] 69-80), 63% were women and 21% had OAB syndrome. The most unwanted side effect in the choice of antimuscarinics for OAB was severe cognitive effects, followed by severe constipation, severe blurred vision, severe dry mouth, moderate cognitive effects and moderate constipation. Severe cognitive effects were at least 1.7 times as important as severe constipation. Exploratory subgroup analysis showed that none of the attributes was found to be significant in people who scored as anxious or depressed on the EQ-5D, and preferences about cognitive effects, constipation and blurred vision were equal in people with and without OAB.
CONCLUSION: Older people attribute more importance to loss of cognitive function as a possible side effect of antimuscarinic treatment than to the three most prevalent possible side effects of this treatment.

PMID: 28656509 [PubMed - indexed for MEDLINE]

Tolerability, Safety, and Effectiveness of Oxycodone DETERx in Elderly Patients ≥65 Years of Age with Chronic Low Back Pain: A Randomized Controlled Trial.

Drugs Aging. 2017 Aug;34(8):603-613

Authors: Kopecky EA, Vaughn B, Lagasse S, O'Connor M

Abstract
TRIAL DESIGN: This was a phase III, randomized withdrawal, double-blind, placebo-controlled, enriched enrollment, parallel-group, multicenter study intended to demonstrate the safety, tolerability, and analgesic efficacy of oxycodone DETERx(®) (Xtampza™ ER) compared with matching placebo.
METHODS: This post hoc analysis was performed using data from a subpopulation of enrolled patients who were ≥65 years of age. The study enrolled male and female patients with a clinical diagnosis of moderate-to-severe chronic low back pain for a minimum of 6 months prior to screening who required around-the-clock opioid therapy. To be eligible for enrollment, patients were required to have an average 24-h pain intensity score of ≥5 and ≤9 on an 11-point (0-10) Pain Intensity-Numerical Rating Scale at the screening visit. The study enrolled both opioid-experienced and opioid-naïve patients. The study consisted of an open-label titration phase followed by a 12-week double-blind maintenance phase. The dose range was 40-160 mg oxycodone hydrochloride equivalent per day. This post hoc analysis evaluated the safety, tolerability, and effectiveness of oxycodone DETERx among patients ≥65 years of age. The effectiveness of oxycodone DETERx was evaluated based on average pain intensity scores, Patient Global Impression of Change, responder analysis, and Kaplan-Meier survival analysis. The safety and tolerability of oxycodone DETERx were also evaluated. Patients were randomized to either oxycodone DETERx or placebo using a blocked randomization scheme in a 1:1 ratio. Randomization was stratified by previous opioid use (naïve or experienced). The study drug was coded in a manner that maintained the blinding. Study personnel and patients remained blinded to the assigned treatments throughout the study.
RESULTS: For this post-hoc analysis, the intent-to-treat and randomized safety populations included 52 patients ≥65 years old, 26 each in the oxycodone DETERx and placebo groups, who participated in the study during the titration phase and were randomized to the double-blind maintenance phase. Clinically important pain reduction from screening was achieved with oxycodone DETERx, with the median pain intensity score decreasing from 7.50 at screening to 2.69 at Week 12. A clinically meaningful treatment difference of -0.9 in pain score between oxycodone DETERx and placebo was observed. All 18 elderly patients who completed the study reported improvement in pain, with 62% showing ≥30% improvement and 54% showing ≥50% improvement in pain intensity compared with patients on placebo (p = 0.0128 and p = 0.0501, respectively). Patients on oxycodone DETERx remained in the study longer than those on placebo. Of the 26 patients ≥65 years old randomized to continue oxycodone DETERx during the double-blind maintenance phase, 18 (69%) completed the study; only two patients (8%) in the oxycodone DETERx group discontinued due to adverse events. The safety and tolerability profiles showed no new or unexpected safety concerns. The adverse event profiles were similar between the titration and double-blind maintenance phases.
CONCLUSIONS: Oxycodone DETERx was efficacious and generally well tolerated in patients ≥65 years old.
TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (NCT01685684).

PMID: 28600725 [PubMed - indexed for MEDLINE]

[Causality assessment in reports on adverse drug reactions. Algorithm of Spanish pharmacovigilance system].

Med Clin (Barc). 2016 Nov 18;147(10):461-464

Authors: Aguirre C, García M

PMID: 27450163 [PubMed - indexed for MEDLINE]

Long-term safety of long-acting octreotide in patients with diabetic retinopathy: results of pooled data from 2 randomized, double-blind, placebo-controlled phase 3 studies.

Endocrine. 2017 Nov 07;:

Authors: Pivonello R, Muscogiuri G, Holder G, Paul M, Sarp S, Lesogor A, Jordaan P, Eisinger J, Colao A

Abstract
PURPOSE: Octreotide (OCT) has been successfully used for treatment of acromegaly and neuroendocrine tumors for more than 30 years. However, long-term safety of OCT has not been documented in placebo-controlled setting. This present analysis pooled safety data from two similarly-designed, randomized, and placebo-controlled studies to evaluate long-term safety of long-acting OCT (20, 30 mg); targeted post-hoc analyzes focused on cardiac, hepatic, and renal safety.
METHODS: Two studies (NCT00131144, NCT001308450) were conducted in patients with diabetic retinopathy (OCT20 = 191, OCT30 = 348, placebo = 347). In this analysis, patients were stratified based on baseline glomerular filtration rate. Hepatic, cardiac, and renal adverse events (AEs) were identified by standardized MedDRA queries.
RESULTS: Median duration of exposure was >3.5 years. Most common AEs reported with OCT were diarrhea, cholelithiasis, hypoglycemia, nasopharyngitis, and hypertension. Incidence of cardiac events (QT prolongation and arrhythmia) with OCT20 and OCT30 were comparable to placebo (OCT20, RR = 1.11 [95% CI, 0.61-2.03]; OCT30, RR = 1.09 [95% CI, 0.70-1.68]). For ECG findings, changes in QTcF were similar in treatment groups, and outliers did not exceed 480 ms. Incidence of cardiac ischemia was lower with OCT than placebo (OCT20 = 12.6%, OCT30 = 10.6%, placebo = 15.3%). Incidence of liver-related AEs was higher with OCT30 than placebo (RR = 2.04 [95% CI, 1.28-3.26]); incidences were comparable with OCT20 and placebo (RR = 1.50 [95% CI, 0.69-3.25]). Overall incidences of renal AEs were comparable between treatment groups (OCT20 = 5.8%; OCT30 = 6.3%; placebo = 7.2%). Drug-related SAEs were reported more frequently with OCT (OCT20 = 7.9%; OCT30 = 10.1%; placebo = 3.5%); predominantly gallbladder-related, GI-related, and hypoglycemia.
CONCLUSIONS: The results from these long-term placebo-controlled studies confirm the established safety profile of long-acting OCT, in particular low risk of cardiac, hepatic and renal toxicity in a high-risk population.

PMID: 29116540 [PubMed - as supplied by publisher]

Self-administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine Treatment of Latent Tuberculosis Infection: A Randomized Trial.

Ann Intern Med. 2017 Nov 07;:

Authors: Belknap R, Holland D, Feng PJ, Millet JP, Caylà JA, Martinson NA, Wright A, Chen MP, Moro RN, Scott NA, Arevalo B, Miró JM, Villarino ME, Weiner M, Borisov AS, TB Trials Consortium iAdhere Study Team

Abstract
Background: Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation.
Objective: To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self-administration versus direct observation.
Design: An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711).
Setting: Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa.
Participants: 1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection.
Intervention: Participants received once-weekly isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring.
Measurements: The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event-monitoring devices for self-administration. The main secondary outcome was adverse events.
Results: Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration-with-reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met noninferiority criteria. A few drug-related adverse events occurred and were similar across groups.
Limitation: Persons with latent tuberculosis infection enrolled in South Africa would not routinely be treated programmatically.
Conclusion: These results support using self-administered, once-weekly isoniazid and rifapentine to treat latent tuberculosis infection in the United States, and such treatment could be considered in similar settings when direct observation is not feasible.
Primary Funding Source: Centers for Disease Control and Prevention.

PMID: 29114781 [PubMed - as supplied by publisher]

Muscadine Grape Skin Extract in Men with Biochemically Recurrent Prostate Cancer: A Randomized, Multicenter, Placebo-Controlled Clinical Trial.

Clin Cancer Res. 2017 Nov 07;:

Authors: Paller CJ, Zhou XC, Heath EI, Taplin ME, Mayer T, Stein MN, Bubley GJ, Pili R, Hudson T, Kakarla R, Abbas MM, Anders NM, Dowling D, King S, Bruns AB, Wagner WD, Drake CG, Antonarakis ES, Eisenberger MA, Denmeade SR, Rudek MA, Rosner GL, Carducci MA

Abstract
PURPOSE: MPX, a commercial preparation of pulverized muscadine grape skin, was evaluated as a therapeutic option for men with biochemically recurrent (BCR) prostate cancer (PCa) wishing to defer androgen deprivation therapy.
EXPERIMENTAL DESIGN: This was a 12-month, multi-center, placebo-controlled, two-dose, double-blinded trial of MPX in 125 men with BCR PCa, powered to detect a prostate specific antigen doubling time (PSADT) difference of 6 months (low-dose) and 12 months (high-dose) relative to placebo. Participants were stratified (baseline PSADT, Gleason score) and randomly assigned 1:2:2 to receive placebo, 500mg MPX (low), 4000mg MPX (high) daily. Correlates included superoxide dismutase-2 (SOD2) genotype, lipid peroxidation and polyphenol pharmacokinetics.
RESULTS: The evaluable population included 112 patients, all treated for at least 6 months and 62% treated for 12 months. No significant difference was found in PSADT change between control and treatment arms (p=0.81): control 0.9 months (n=20, range -6.7 to 83.1), low-dose 1.5 months (n=52, range: -10.3 to 87.2), high-dose 0.9 months (n=40, range: -27.3 to 88.1). One high-dose patient experienced objective response. No drug-related CTCAE grade 3-4 adverse events were seen. In a preplanned exploratory analysis, PSADT pre-to-post increase was significant in the 27 (26%) genotyped patients with SOD2 Alanine/Alanine genotype (rs4880 T>C polymorphism) on MPX (pooled treatment arms) (6.4 months, p=0.02), but not in control (1.8 months, p=0.25).
CONCLUSIONS: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses. Exploratory analysis revealed a patient population with potential benefit that would require further study.

PMID: 29113986 [PubMed - as supplied by publisher]

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]