Adverse reactions associated with first-line regimens in patient initiating antiretroviral therapy.

Eur J Clin Pharmacol. 2018 May 08;:

Authors: Mendes JC, Bonolo PF, Ceccato MDGB, Costa JO, Reis AMM, Dos Santos H, Silveira MR

Abstract
OBJECTIVE: To evaluate the prevalence of adverse drug reactions (ADR) and associated factors during the use of Highly Active Antiretroviral Therapy (HAART) in patients initiating treatment.
METHODS: This is a cross-sectional analysis of a prospective study conducted in three public referral services specialized in HIV/AIDS care in Belo Horizonte, Brazil. Self-reported ADR and explanatory variables were obtained from face-to-face interview and from Information Systems. Associated factors with ADR were evaluated by logistic regression in SPSS software v.22.
RESULTS: We included 399 patients, of which 85.5% reported at least one and 72.7% up to 5 ADRs after HAART initiation. Neurological reactions were the most frequent, with self-reported ADRs being distinct according to HAART regimen used. The global model showed higher chance of ADRs among females (OR = 3.52) and illicit drug users (OR = 2.28). Lower chance of ADRs was found for patients aged > 33 years (OR = 0.37), DTG/TDF/3TC users (OR = 0.41), and higher physical domain of quality of life (OR = 0.78). The model restricted to patients using the single-tablet regimen EFV/TDF/3TC showed lower ADRs among patients with CD4+ T lymphocyte count > 200 cells/mm3 (OR = 0.23) and higher independence domain of quality of life (OR = 0.74). The model restricted to DTG/TDF/3TC and to other regimens showed lower ADRs with higher physical domain of quality of life (OR = 0.74 and OR = 0.55, respectively).
CONCLUSIONS: The prevalence of self-reported ADRs to first-line antiretroviral regimens was high and patients using DTG/TDF/3TC had a smaller number of ADRs. In addition to HAART regimen, sociodemographic, clinical, and quality of life characteristics were associated with ADRs.

PMID: 29740676 [PubMed - as supplied by publisher]

Optimal nonvitamin K antagonist oral anticoagulant therapy in a warfarin-sensitive patient after left atrial appendage closure: A case report.

Medicine (Baltimore). 2018 May;97(18):e0683

Authors: Shen L, Fang SS, Ge H, Qiao ZQ, Gu ZC

Abstract
RATIONALE: Developing an optimal medication strategy poses a challenging task in fragile patients after left atrial appendage closure (LAAC). We report an optimal nonvitamin K antagonist oral anticoagulant (NOAC) therapy in a warfarin-sensitive patient after LAAC.
PATIENT CONCERNS: A 77-year-old nonvalvular atrial fibrillation (NVAF) male carrying 2 warfarin-sensitive alleles experienced 2 gum-bleeding with the international normalized ratio (INR) around 3.
DIAGNOSES: Persistent NVAF with a history of subtotal gastrectomy and moderate renal insufficiency.
INTERVENTIONS: Warfarin was discontinued and vitamin K1 was immediately administrated via intravenous infusion. LAAC was regarded as a preferable option, and rivaroxaban 15 mg daily was managed after LACC.
OUTCOMES: Complete endothelialization on the surface of device was detected via transoesophageal echocardiography (TEE), and no peridevice spillage and adverse event occurred.
LESSONS: A post-LAAC treatment with NOAC may be a viable regimen in patients intolerant to warfarin.

PMID: 29718897 [PubMed - indexed for MEDLINE]

Visual field defects following different resective procedures for mesiotemporal lobe epilepsy.

Epilepsy Behav. 2017 Nov;76:39-45

Authors: Schmeiser B, Daniel M, Kogias E, Böhringer D, Egger K, Yang S, Foit NA, Schulze-Bonhage A, Steinhoff BJ, Zentner J, Lagrèze WA, Gross NJ

Abstract
INTRODUCTION: One of the most common side effects of mesiotemporal lobe resection in patients with medically intractable epilepsy are visual field defects (VFD). While peripheral defects usually remain unnoticed by patients, extended VFD influence daily life activities and can, in particular, affect driving regulations. This study had been designed to evaluate frequency and extent of VFD following different surgical approaches to the mesiotemporal area with respect to the ability to drive.
MATERIALS AND METHODS: This study comprises a consecutive series of 366 patients operated at the Epilepsy Center in Freiburg for intractable mesiotemporal lobe epilepsy from 1998 to 2016. The following procedures were performed: standard anterior temporal lobectomy (ATL: n=134; 37%), anterior temporal or keyhole resection (KH: n=53; 15%), and selective amygdalohippocampectomy via the transsylvian (tsAHE: n=145; 40%) and the subtemporal (ssAHE: n=34; 9%) approach. Frequency and extent of postoperative VFD were evaluated in relation to different surgical procedures. According to the German driving guidelines, postoperative VFD were classified as driving-relevant VFD with the involvement of absolute, homonymous central scotoma within 20° and driving-irrelevant VFD with either none or exclusively minor VFD sparing the center.
RESULTS: Postoperative visual field examinations were available in 276 of 366 cases. Postoperative VFD were observed in 202 of 276 patients (73%) and were found to be driving-relevant in 133 of 276 patients (48%), whereas 69 patients (25%) showed VFD irrelevant for driving. Visual field defects were significantly less likely following ssAHE compared with other temporal resections, and if present, they were less frequently driving-relevant (p<0.05), irrespective of the side of surgery.
CONCLUSION: Subtemporal sAHE (ssAHE) caused significantly less frequently and less severely driving-relevant VFD compared with all other approaches to the temporal lobe, irrespective of the side of surgery.

PMID: 28954709 [PubMed - indexed for MEDLINE]

Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy.

Epilepsy Behav. 2017 Nov;76:24-31

Authors: Chen B, Choi H, Hirsch LJ, Katz A, Legge A, Buchsbaum R, Detyniecki K

Abstract
PURPOSE: Psychiatric and behavioral side effects (PBSEs) are common, undesirable effects associated with antiepileptic drug (AED) use. The objective of the study was to compare the PBSE profiles of older and newer AEDs in a large specialty practice-based sample of patients diagnosed with epilepsy.
METHODS: As part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 4085 adult patients (age: 18 years) newly started on an AED regimen. Psychiatric and behavioral side effects were determined by patient or physician report in the medical record, which included depressive mood, psychosis, anxiety, suicidal thoughts, irritability, aggression, and tantrum. Significant non-AED predictors of PBSE rate were first determined from 83 variables using logistic regression. Predictors were then controlled for in the comparison analysis of the rate of PBSEs and intolerable PBSEs (PBSEs that led to dosage reduction or discontinuation) between 18 AEDs.
RESULTS: Psychiatric and behavioral side effects occurred in 17.2% of patients and led to intolerability in 13.8% of patients. History of psychiatric condition(s), secondary generalized seizures, absence seizures, and intractable epilepsy were associated with increased incidence of PBSE. Levetiracetam (LEV) had the greatest PBSE rate (22.1%). This was statistically significant when compared with the aggregate of the other AEDs (P<0.001, OR=6.87). Levetiracetam was also significantly (P<0.001) associated with higher intolerability rate (17.7%), dose decreased rate (9.4%), and complete cessation rate (8.3%), when compared with the aggregate of the other AEDs. Zonisamide (ZNS) was also significantly associated with a higher rate of PBSE (9.7%) and IPBSE (7.9%, all P<0.001). On the other hand, carbamazepine (CBZ), clobazam (CLB), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), phenytoin (PHT), and valproate (VPA) were significantly associated with a decreased PBSE rates (P<0.001). Carbamazepine, GBP, LTG, PHT, and VPA were also associated with lower IPBSE rates when compared individually with the aggregate of other AEDs. All other AEDs were found to have intermediate rates that were not either increased or decreased compared with other AEDs. When each AED was compared to LTG, only CBZ had a significantly lower PBSE rate. The main limitations of this study were that the study design was retrospective and not blinded, and the AEDs were not randomly assigned to patients.
CONCLUSIONS: Psychiatric and behavioral side effects occur more frequently in patients taking LEV and ZNS than any other AED and led to higher rates of intolerability. Lower PBSE rates were seen in patients taking CBZ, CLB, GBP, LTG, OXC, PHT, and VPA. Our findings may help facilitate the AED selection process.

PMID: 28931473 [PubMed - indexed for MEDLINE]

Factors contributing to antiretroviral drug adherence among adults living with HIV or AIDS in a Kenyan rural community.

Afr J Prim Health Care Fam Med. 2017 Jul 31;9(1):e1-e7

Authors: Kioko MT, Pertet AM

Abstract
BACKGROUND: Antiretroviral (ARV) adherence of ≥ 95% is recommended for suppressing HIV. However, studies have shown that the ≥ 95% recommended level is rarely achieved.
OBJECTIVE: This cross-sectional community-based study sought to assess factors contributing to ARV drug adherence among adults living with HIV or AIDS.
SETTING: The study was conducted in a rural community in Machakos County, Kenya.
METHODS: The questions used for the study were adapted from the Patient Medicine Adherence Questionnaire (PMAQ), a tool grounded in the Health Belief Model. Adherence to ARV was measured using self-reports and pill counts. The perception social support was measured with a 5-point Likert scale, whereas the type and the number of side effects experienced were recorded using 'yes' and 'no' questions. We used the chi-square test to test associations and binary logistic regression to assess factors explaining dose adherence to ARV.
RESULTS: The levels of adherence of 86% using self-reports were significantly higher (p &lt; 0.001) than the pill count of 58.6%. The immediate family was rated high in providing social support (3.7 ± 0.6) followed by social support groups (3.1 ± 0.8). A binary logistic regression analysis was conducted to predict ARV adherence (adherent, non-adherent) using social support, side effects and marital status as explanatory variables. The Wald criterion demonstrated that marital status (p = 0.019) and burden of side effects (p ≤ 0.001) made a significant contribution to the prediction of ARV adherence.
CONCLUSION: The burden of side effects and being a divorcee are primary predictors of ARV adherence.

PMID: 28828875 [PubMed - indexed for MEDLINE]

Pharmacogenomics of off-target adverse drug reactions.

Br J Clin Pharmacol. 2017 Sep;83(9):1896-1911

Authors: Garon SL, Pavlos RK, White KD, Brown NJ, Stone CA, Phillips EJ

Abstract
Off-target adverse drug reactions (ADRs) are associated with significant morbidity and costs to the healthcare system, and their occurrence is not predictable based on the known pharmacological action of the drug's therapeutic effect. Off-target ADRs may or may not be associated with immunological memory, although they can manifest with a variety of shared clinical features, including maculopapular exanthema, severe cutaneous adverse reactions (SCARs), angioedema, pruritus and bronchospasm. Discovery of specific genes associated with a particular ADR phenotype is a foundational component of clinical translation into screening programmes for their prevention. In this review, genetic associations of off-target drug-induced ADRs that have a clinical phenotype suggestive of an immunologically mediated process and their mechanisms are highlighted. A significant proportion of these reactions lack immunological memory and current data are informative for these ADRs with regard to disease pathophysiology, therapeutic targets and biomarkers which may identify patients at greatest risk. Although many serious delayed immune-mediated (IM)-ADRs show strong human leukocyte antigen associations, only a small subset have successfully been implemented in screening programmes. More recently, other factors, such as drug metabolism, have been shown to contribute to the risk of the IM-ADR. In the future, pharmacogenomic targets and an understanding of how they interact with drugs to cause ADRs will be applied to drug design and preclinical testing, and this will allow selection of optimal therapy to improve patient safety.

PMID: 28345177 [PubMed - indexed for MEDLINE]

Hydralazine-associated adverse events: a report of two cases of hydralazine-induced ANCA vasculitis.

J Bras Nefrol. 2018 May 07;:

Authors: Zuckerman R, Patel M, Costanzo EJ, Dounis H, Haj RA, Seyedali S, Asif A

Abstract
Hydralazine is a direct-acting vasodilator, which has been used in treatment for hypertension (HTN) since the 1950s. While it is well known to cause drug-induced lupus (DIL), recent reports are indicating the emergence of the drug-induced anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (DIV). Herein, we describe two patients (aged 57 and 87 years) who presented with severe acute kidney injury (AKI), proteinuria, and hematuria. Both were receiving hydralazine for the treatment of hypertension. ANCA serology was positive in both patients along with anti-histone antibodies (commonly seen in drug-induced vasculitis). Renal biopsy revealed classic crescentic (pauci-immune) glomerulonephritis in these patients and hydralazine was discontinued. During the hospital course, the 57-year-old patient required dialysis therapy and was treated with steroids and rituximab for the ANCA disease. Renal function improved and the patient was discharged (off dialysis) with a serum creatinine of 3.6 mg/dL (baseline = 0.9 mg/dL). At a follow-up of 2 years, the patient remained off dialysis with advanced chronic kidney disease (CKD) (stage IIIb). The 87-year-old patient had severe AKI with serum creatinine at 10.41 mg/dL (baseline = 2.27 mg/dL). The patient required hemodialysis and was treated with steroids, rituximab, and plasmapheresis. Unfortunately, the patient developed catheter-induced bacteremia and subsequently died of sepsis. Hydralazine can cause severe AKI resulting in CKD or death. Given this extremely unfavorable adverse-event profile and the widespread availability of alternative anti-hypertensive agents, the use of hydralazine should be carefully considered.

PMID: 29738027 [PubMed - as supplied by publisher]

Expression Profile of Markers of Oxidative Stress, Injury and Apoptosis in anti-tuberculosis drugs induced nephrotoxicity.

Nephrology (Carlton). 2018 May 08;:

Authors: Sharma R, Battu P, Singla M, Goyal N, Sharma VL

Abstract
AIM: Isoniazid (INH), Rifampicin (RIF) and Pyrazinamide (PZA) are part of first-line anti-tuberculosis therapy used against infection caused by Mycobacterium tuberculosis. However these drugs are known to be potentially harmful as these are associated with numerous side effects and when taken together their harmful outcomes are elevated in a synergistic manner. Identification of possible mechanism underlying RIF+INH+PZA induced nephrotoxicity may be advantageous in developing strategies to prevent their toxic implications.
METHODS: In this study rats were distributed in 2 groups of 6 each: Control (tap water) and Toxicant (INH + RIF + PZA) in dosage derived through extrapolation from human dosage for 28 days once in a day. Antioxidant activity and histology of kidney were examined. In addition apoptosis was also studied using pro and anti-apoptotic markers and TUNEL staining to check nephrotoxicity.
RESULTS: Findings indicated that combined (INH, RIF and PZA) 28 day exposure in wistar rats caused increase in number of free radicals/ reactive oxygen species which further cause changes in levels of enzymatic antioxidants such as glutathione, Superoxide dismutase, Catalase, and Glutathione-s-transferase. Altered content of pro (BAD&BAX) and anti-apoptotic genes (BCL-2&BCL2L1) genes, TUNEL positive cells and DNA fragmentation emphasized involvement of apoptosis.
CONCLUSION: This study concluded that nephrotoxicity is accompanied during combinational anti-tuberculosis drug therapy.

PMID: 29737591 [PubMed - as supplied by publisher]

Subcutaneous administration of paracetamol-Good local tolerability in palliative care patients: An observational study.

Palliat Med. 2018 May 01;:269216318772472

Authors: Leheup BF, Ducousso S, Picard S, Alluin R, Goetz C

Abstract
BACKGROUND: The subcutaneous route is widely used in both palliative care and geriatrics. Numerous compounds are administered by this route, including paracetamol. However, there is no recommendation on which to base this latter practice and, in the absence of published evidence, nothing is known regarding its local tolerability in palliative care patients.
AIM: The main objective of this study was to assess the local tolerability of paracetamol when administered subcutaneously for analgesic or antipyretic purposes in patients hospitalized in the palliative care unit. The secondary objective was to identify the factors favoring the occurrence of local adverse events.
DESIGN: This is a prospective multicenter observational study (NCT02884609).
PARTICIPANTS: Study conducted in 160 patients hospitalized in the palliative care units of three hospitals in metropolitan France from 2014 to 2017.
RESULTS: Of the 160 patients, 44 (28%) presented at least one non-serious local adverse event (edema in 29, erythema in 5, pain in 15, hematoma in 2, pruritus in 1, and local heat in 2). No serious adverse events were observed. Factors associated with the occurrence of local adverse events were younger age, administration in the arm and thorax, and a high number of daily administrations.
CONCLUSION: This first ever study carried out on this subject reveals that subcutaneous administration of paracetamol in palliative care patients was well tolerated locally.

PMID: 29737243 [PubMed - as supplied by publisher]

Risk factors of early adverse drug reactions with phenytoin: A prospective inpatient cohort.

Epilepsy Behav. 2017 Nov;76:139-144

Authors: Uribe-San-Martín R, Ciampi E, Uslar W, Villagra S, Plaza J, Godoy J, Mellado P

Abstract
INTRODUCTION: Phenytoin (PHT) is an effective and inexpensive antiepileptic drug (AED). However, its use has been limited for fear of adverse drug reactions (ADRs) and is being replaced by newer AED, increasing the costs and causing major budget problems, particularly for developing countries.
OBJECTIVE: The objective of this study was to determine ADR frequency, explore, and establish related risk factors.
METHODS: Prospective data were collected from a cohort of inpatients using PHT for the first time. Pharmacovigilance was performed during hospitalization and after one month from the discharge. Clinical variables, plasma levels, and concomitant medications were collected and their association with the occurrence of different ADRs was explored.
RESULTS: One hundred patients were included: 59 were women, and mean age was 59±21years. Thirty-three patients presented ADR, all moderate and idiosyncratic. The most frequent were rash (17%), fever (10%), and elevated transaminases (10%). Female gender (85% vs 52%, p=0.029), younger age (mean age: 49 vs 62years, p=0.032), and higher PHT plasmatic levels after IV-PO load (mean plasmatic levels: 18.6 vs 13.9μg/mL, p=0.040) were found to be associated with rash. A higher number of concomitant medications were also found to be associated with the risk for developing any ADR. The multivariate analysis revealed an association between rash and younger age (cut-off: 35years old; relative risk (RR)=11.7; p=0.026), and higher PHT plasmatic levels (cut-off: 16μg/mL; RR=12.5; p=0.021); and increased risk of elevated transaminases with use of PHT inductors (RR=18; p=0.006). A longer hospital stay was found in patients who developed fever (mean: 43days, p<0.0001) and elevated transaminases (mean: 26days, p=0.041) compared with patients without ADR (mean: 17days).
CONCLUSIONS: Phenytoin is a widely used AED associated with easily detectable ADR through structured pharmacovigilance. The development of ADR is associated with longer hospital stays. Recognition of local risk factors may lead to ADR prevention in a near future. Larger studies are needed to better define PHT-related ADR risk profile and to individualize treatment regimens.

PMID: 28927713 [PubMed - indexed for MEDLINE]

A decade of drug metabolite safety testing: industry and regulatory shared learning.

Expert Opin Drug Metab Toxicol. 2017 09;13(9):897-900

Authors: Luffer-Atlas D, Atrakchi A

PMID: 28797172 [PubMed - indexed for MEDLINE]

Comparing the safety and efficacy of voriconazole versus posaconazole in the prevention of invasive fungal infections in high-risk patients with hematological malignancies.

Int J Antimicrob Agents. 2017 Sep;50(3):384-388

Authors: Hachem R, Assaf A, Numan Y, Shah P, Jiang Y, Chaftari AM, Raad II

Abstract
Invasive fungal infection (IFI) is a leading cause of morbidity and mortality in immunocompromised cancer patients. New triazole-based antifungal agents have been recommended for IFI prophylaxis in these patients. This retrospective study compared the safety and efficacy of voriconazole and posaconazole as prophylaxis in patients with hematological malignancies (HM), who were admitted to The University of Texas MD Anderson Cancer Center between January 2014 and August 2015, and who were started on single antifungal prophylaxis consisting of either voriconazole or posaconazole. A total of 200 patients with hematological malignancy were evaluated, the majority of whom had acute myeloid leukemia (AML) (67%). Baseline characteristics, including malignancy status and neutropenia status, were comparable in the two groups. The duration of prophylaxis was similar in the two groups, with medians of 46 days for voriconazole and 48 days for posaconazole. There was no significant difference in breakthrough IFIs between the two groups (3% vs. 0%, P = 0.25). Adverse events occurred in 65% of the voriconazole group vs. 78% of the posaconazole group (P = 0.08). Symptomatic adverse events were more common for voriconazole than for posaconazole (6% vs. 0%, P = 0.03). Eleven patients discontinued voriconazole and seven patients discontinued posaconazole due to adverse events. All-cause mortality was similar in the two groups. Both agents were effective in preventing IFI in hematological malignancy, with comparable all-cause mortality rates. Symptomatic adverse events were significantly more common in the voriconazole group, whereas liver function test abnormality was more common in the posaconazole group.

PMID: 28694233 [PubMed - indexed for MEDLINE]

Recently approved antibacterials for methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive pathogens: the shock of the new.

Int J Antimicrob Agents. 2017 Sep;50(3):303-307

Authors: David MZ, Dryden M, Gottlieb T, Tattevin P, Gould IM

Abstract
A number of novel antimicrobial drugs with activity against Gram-positive bacterial pathogens have been licensed in the past 4 years. These drugs have the potential to enrich the group of intravenous drugs already available that are in common use against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci and other antibiotic-resistant Gram-positive pathogens. The advantages and disadvantages of these drugs are not yet fully appreciated. Here we review the five most promising newly approved compounds, namely ceftaroline, ceftobiprole, oritavancin, dalbavancin and tedizolid. The advantages of their dosing regimens, mechanisms of action and adverse effect profiles as well as evidence for their clinical usefulness and the unique characteristics that distinguish them from one another and from older drugs are reviewed.

PMID: 28666751 [PubMed - indexed for MEDLINE]

Prediction and management of drug reaction with eosinophilia and systemic symptoms (DRESS).

Expert Opin Drug Metab Toxicol. 2017 07;13(7):701-704

Authors: Shiohara T, Kano Y, Hirahara K, Aoyama Y

PMID: 28633581 [PubMed - indexed for MEDLINE]

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Management and grading of EGFR inhibitor-induced cutaneous toxicity.

Future Oncol. 2018 May 04;:

Authors: Beech J, Germetaki T, Judge M, Paton N, Collins J, Garbutt A, Braun M, Fenwick J, Saunders MP

Abstract
Cutaneous toxicities associated with EGFR inhibitors (EGFRIs) have a significant impact on patient treatment continuation, quality of life and healthcare resource utilization. This paper reviews the current prophylaxis and management of EGFRI-induced cutaneous toxicities in patients with colorectal cancer, and combines these findings with the authors' clinical expertise to define a novel algorithm for healthcare professionals managing patients receiving EGFRIs. This tool includes a grading system based on the location, severity and psychological impact, and provides a standard prescription pack, advice on prophylaxis/self-management of cutaneous symptoms for patients initiating EGFRIs, and essential guidance on subsequent review and treatment escalation. It aims to optimize treatment of metastatic colorectal cancer by minimizing cutaneous toxicities to maintain dose intensity and efficacy of EGFRI-based chemotherapy.

PMID: 29727211 [PubMed - as supplied by publisher]

A Phase 1 dose-escalation and dose-expansion study of brontictuzumab in subjects with selected solid tumors.

Ann Oncol. 2018 May 03;:

Authors: Ferrarotto R, Eckhardt G, Patnaik A, LoRusso P, Faoro L, Heymach JV, Kapoun AM, Xu L, Munster P

Abstract
Background: Brontictuzumab is a monoclonal antibody that targets Notch1 and inhibits pathway activation. The purpose of this first-in-human study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, immunogenicity and preliminary efficacy of brontictuzumab in patients with solid tumors.
Patients ans Methods: Subjects with selected refractory solid tumors were elegible. Brontictuzumab was administered intravenously at various dose levels and schedule during dose escalation, and at 1.5mg/kg every three weeks (Q3W) during expansion. Evidence of Notch1 pathway activation as determined by an immunohistochemistry assay was required for entry in the expansion cohort. Adverse events were graded according to the NCI-CTCAE v 4.03. Efficacy was assessed by RECIST 1.1.
Results: Forty-eight subjects enrolled (33 in dose escalation and 15 in the expansion phase). The MTD was 1.5 mg/kg Q3W. Dose-limiting toxicities were grade 3 diarrhea in two subjects and grade 3 fatigue in one subject. The most common drug-related adverse events of any grade were diarrhea (71%), fatigue (44%), nausea (40%), vomiting (21%), and AST increase (21%). Brontictuzumab exhibited nonlinear PK with dose-dependent terminal half-life ranging 1-4 days. Clinical benefit was seen in six out of 36 (17%) evaluable subjects: two had unconfirmed partial response (PR) and four subjects had prolonged (≥ 6 months) disease stabilization (SD). Both PRs and three prolonged SD occurred in adenoid cystic carcinoma (ACC) subjects with evidence of Notch1 pathway activation. Pharmacodynamic effects of brontictuzumab was seen in patients' blood and tumor.
Conclusion: Brontictuzumab was well tolerated at the MTD. The main toxicity was diarrhea, an on-target effect of Notch1 inhibition. An efficacy signal was noted in subjects with ACC and Notch1 pathway activation.
ClinicalTrials.gov Identifier: NCT01778439.

PMID: 29726923 [PubMed - as supplied by publisher]

Systematic Evaluation of Corticosteroid Use in Obese and Non-obese Individuals: A Multi-cohort Study.

Int J Med Sci. 2017;14(7):615-621

Authors: Savas M, Wester VL, Staufenbiel SM, Koper JW, van den Akker ELT, Visser JA, van der Lely AJ, Penninx BWJH, van Rossum EFC

Abstract
Background: Although the use of corticosteroids has been linked to high incidence of weight gain, no data are available concerning the differences in corticosteroid use between a diverse obese population and non-obese individuals. The main purpose of this study was to systematically explore the use of corticosteroids in obese subjects compared to non-obese controls. In addition, we also explored self-reported marked weight gain within obese subjects. Methods: Two hundred seventy-four obese outpatients (median [range] BMI: 40.1 kg/m2 [30.5-67.0]), and 526 non-obese controls (BMI: 24.1 kg/m2 [18.6-29.9]) from two different Dutch cohort studies were included. Corticosteroid use at the time of clinic or research site visit for up to the preceding three months was recorded in detail. Medical records and clinical data were evaluated with regard to age and body mass index in relation to corticosteroid use, single or multiple type use, and administration forms. Results: Recent corticosteroid use was nearly twice as high for obese subjects than for non-obese controls (27.0% vs. 11.9% and 14.8%, both P<.001). Largest differences were found for use of local corticosteroids, in particular inhaled forms, and simultaneous use of multiple types. Marked weight gain was self-reported during corticosteroid use in 10.5% of the obese users. Conclusion: Corticosteroid use, especially the inhaled agents, is higher in obese than in non-obese individuals. Considering the potential systemic effects of also local corticosteroids, caution is warranted on the increasing use in the general population and on its associations with weight gain.

PMID: 28824292 [PubMed - indexed for MEDLINE]

Statin myopathy: over-rated and under-treated?

Curr Opin Cardiol. 2016 Jul;31(4):417-25

Authors: Maghsoodi N, Wierzbicki AS

Abstract
PURPOSE OF REVIEW: Statins are recommended as first-line therapy for cardiovascular disease. Unfortunately, a proportion of patients cannot tolerate these drugs because of muscle-related side-effects. This review summarizes the definition of statin-related muscle disorders, aetiological factors, and recommended management strategies.
RECENT FINDINGS: A number of consensus groups have defined and classified statin-related muscle disorders, whereas others have suggested diagnostic and management strategies. Mechanisms behind statin-related muscle toxicity have been identified. Therapeutic and clinical investigation pathways have been reviewed and algorithms defined. New drugs have become available to reduce low-density lipoprotein cholesterol levels that are not associated with causing muscle side-effects.
SUMMARY: Statin-related muscle side-effects are common. Secondary causes of muscle disease unmasked by statin therapy should be identified. Most patients can be managed by adjustment of standard treatment protocols.

PMID: 27258372 [PubMed - indexed for MEDLINE]

Sunitinib does not acutely alter left ventricular systolic function, but induces diastolic dysfunction.

Cancer Chemother Pharmacol. 2018 May 02;:

Authors: Wada T, Ando K, Naito AT, Nakamura Y, Goto A, Chiba K, Lubna NJ, Cao X, Hagiwara-Nagasawa M, Izumi-Nakaseko H, Nakazato Y, Sugiyama A

Abstract
PURPOSE: Cancer chemotherapies have improved the prognosis of cancer patients in recent years; however, their side effects on the cardiovascular systems have emerged as a major concern in the field of both cardiology and oncology. In particular, multi-targeted tyrosine kinase inhibitors are known to induce various types of cardiovascular adverse events including hypertension, QT-interval prolongation and heart failure, but their underlying mechanisms remain elusive. To explore how to better predict such drug-induced cardiovascular adverse events, we assessed the electropharmacological effects of sunitinib using the halothane-anesthetized dogs (n = 5), while plasma concentrations of cardiac enzymes including aspartate aminotransferase, lactate dehydrogenase, creatinine kinase and cardiac troponin I  were measured.
METHODS: Sunitinib was intravenously administered at 0.01 and 0.1 mg/kg for 10 min with 20 min interval.
RESULTS: Sunitinib decreased the amplitude of maximum downstroke velocity of the left ventricular pressure, prolonged the isovolumic relaxation time and increased the left ventricular end-diastolic pressure in a dose-related manner without affecting the other cardiohemodynamic and electrophysiological variables. More importantly, sunitinib significantly elevated cardiac troponin I level for 30-60 min after the high dose without altering the other biomarkers.
CONCLUSIONS: Monitoring of the cardiac diastolic function together with cardiac troponin I after the start of sunitinib administration may become a reliable measure to predict the onset of sunitinib-induced cardiovascular adverse events.

PMID: 29721849 [PubMed - as supplied by publisher]