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]

Related Articles

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]

Related Articles

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]

Related Articles

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]

Related Articles

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]

Related Articles

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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PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Funding Opportunity PA-18-773 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages collaborative research applications on drug abuse and addiction that: 1. Take advantage of unusual opportunities that exist outside the United States to access talent, resources, populations, or environmental conditions in other countries that will speed scientific discovery 2. Describe how the research will significantly advance U.S. health sciences 3. Demonstrate specific relevance to the NIDA mission and objectives. To determine whether your research plan is relevant to the NIDA mission and objectives, review the NIDA Strategic Plan (https://www.drugabuse.gov/about-nida/2016-2020-nida-strategic-plan). Where feasible, applications should address NIDAs international scientific priority areas (https://www.drugabuse.gov/international/research-priorities) 4. Include an investigator from a U.S. institution and a non-U.S. citizen partner living and working in another country.

Funding Opportunity PAR-18-777 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) seeks grant applications to develop major advances in genomic technologies. Advances in genomics and more broadly in biomedical research have been greatly facilitated by significant and sustained genomics technology throughput increases, cost decreases, and improvements in ease of use. The proposed technology development work should allow comprehensive genomic analysis of features not assayable today, or an increase of no less than an order of magnitude improvement in an existing technology in terms of data quality, throughput, efficiency or comprehensiveness (individually or in combination). This FOA explicitly excludes the development of novel technologies for DNA sequencing and for direct RNA sequencing; those projects should respond to a parallel set of FOAs (RFA-HG-18-001, RFA-HG-18-002, and RFA-HG-18-003).

Funding Opportunity PAR-18-779 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages SBIR grant applications from small businesses to catalyze major advances in genomics through technology development (beyond developing nucleic acid sequencing technologies). The goal is to provide a mechanism for support of very novel and high impact work from across this gamut of genomics technology development. This initiative seeks to support technologies that will have a major impact in the next three to five years.

Funding Opportunity PAR-18-778 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) seeks grant applications to develop major advances in genomic technologies. Advances in genomics and more broadly in biomedical research have been greatly facilitated by significant and sustained genomics technology throughput increases, cost decreases, and improvements in ease of use. The proposed technology development work should allow comprehensive genomic analysis of features not assayable today, or an increase of no less than an order of magnitude improvement in an existing technology in terms of data quality, throughput, efficiency or comprehensiveness (individually or in combination). This FOA explicitly excludes the development of novel technologies for DNA sequencing and for direct RNA sequencing; those projects should respond to a parallel set of FOAs (RFA-HG-18-001, RFA-HG-18-002, and RFA-HG-18-003).

Funding Opportunity PA-18-776 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages applications to improve health outcomes for women, infants and children, by stimulating interdisciplinary research focused on maternal nutrition and pre-pregnancy obesity. Maternal health significantly impacts not only the mother but also the intrauterine environment, and subsequently fetal development and the health of the newborn.

Funding Opportunity PA-18-775 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) for R34 applications seeks to support: (a) pilot and/or feasibility testing of innovative new, revised, or adapted prevention intervention approaches to prevent or delay the initiation and onset of drug and alcohol use, the progression to misuse or problem use or alcohol and other substance use disorder, reduce drinking and driving and deaths related to impaired driving, and the drug- or alcohol-related acquisition or transmission of HIV infection and viral hepatitis among diverse populations and settings; and, (b) pre-trial feasibility and acceptability testing for prevention services and systems research. It is expected that research conducted via this R34 mechanism will consist of studies that are a pre-requisite for preparing and submitting subsequent applications for larger scale drug or alcohol abuse prevention and/or drug- or alcohol-related HIV prevention intervention studies. This R34 FOA does not support applications for which the sole focus is development of intervention protocols, manuals, or the standardization of protocols. Any intervention development work must be imbedded within a pilot/feasibility study. Of particular interest is prevention research that addresses current public health priorities and priority settings and systems.

Notice NOT-TR-18-025 from the NIH Guide for Grants and Contracts

Notice NOT-NR-18-010 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-18-774 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages pilot and preliminary research in preparation for larger-scale services research effectiveness trials. Relevant trials may test a wide range of approaches, including interventions, practices, and policies designed to optimize access to, and the quality, effectiveness, affordability and utilization of drug, tobacco, or alcohol use disorder treatments and related services, as well as services for comorbid medical and mental disorder conditions. Relevant approaches may include both those that are novel, and those that are commonly used in practice but lack an evidence base. This FOA provides resources for assessing the feasibility, acceptability, and utility of these approaches, in addition to usual trial preparation activities.

Notice NOT-DA-18-013 from the NIH Guide for Grants and Contracts

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