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]

Successful oral desensitization with osimertinib following osimertinib-induced fever and hepatotoxicity: a case report.

Invest New Drugs. 2018 May 02;:

Authors: Hirabayashi R, Fujimoto D, Satsuma Y, Hirabatake M, Tomii K

Abstract
Osimertinib is a standard second-line therapy for patients who develop EGFR Thr790Met resistance mutation after treatment with first-line epidermal growth factor receptor tyrosine kinase inhibitors. Although no other effective targeted treatment option exists for these patients, osimertinib might be permanently discontinued owing to the onset of severe drug-induced toxicities like hepatotoxicity. Herein, we report a case of successful oral desensitization with osimertinib after the patient developed osimertinib-induced fever and hepatotoxicity. In the present case report, a 62-year-old Japanese woman received osimertinib as the sixth-line therapy for non-small cell lung carcinoma harboring EGFR Thr790Met-mutation. After 15 days of treatment, she developed general malaise. Although we reduced the drug at a lower dose, she again presented with high fever and elevated serum AST/ALT levels three days after re-initiating treatment. We then attempted oral desensitization with osimertinib over a two-week period. Thereafter, the patient continued osimertinib treatment for 6 months without the recurrence of side effects. In conclusion, oral desensitization may be a useful method in treating hepatotoxicity and drug fever caused by osimertinib.

PMID: 29721756 [PubMed - as supplied by publisher]

Comprehensive genomic transcriptomic tumor-normal gene panel analysis for enhanced precision in patients with lung cancer.

Oncotarget. 2018 Apr 10;9(27):19223-19232

Authors: Rabizadeh S, Garner C, Sanborn JZ, Benz SC, Reddy S, Soon-Shiong P

Abstract
A CMS approved test for lung cancer is based on tumor-only analysis of a targeted 35 gene panel, specifically excluding the use of the patient's normal germline tissue. However, this tumor-only approach increases the risk of mistakenly identifying germline single nucleotide polymorphisms (SNPs) as somatically-derived cancer driver mutations (false positives). 621 patients with 30 different cancer types, including lung cancer, were studied to compare the precision of tumor somatic variant calling in 35 genes using tumor-only DNA sequencing versus tumor-normal DNA plus RNA sequencing. When sequencing of lung cancer was performed using tumor genomes alone without normal germline controls, 94% of variants identified were SNPs and thus false positives. Filtering for common SNPs still resulted in as high as 48% false positive variant calling. With tumor-only sequencing, 29% of lung cancer patients had a false positive variant call in at least one of twelve genes with directly targetable drugs. RNA analysis showed 18% of true somatic variants were not expressed. Thus, sequencing and analysis of both normal germline and tumor genomes is necessary for accurate identification of molecular targets. Treatment decisions based on tumor-only analysis may result in the administration of ineffective therapies while also increasing the risk of negative drug-related side effects.

PMID: 29721196 [PubMed]

Brain's compensatory response to drug-induced cognitive impairment.

J Clin Exp Neuropsychol. 2018 May 02;:1-13

Authors: Babu Henry Samuel I, Barkley C, Marino SE, Wang C, Han SM, Birnbaum AK, Cibula JE, Ding M

Abstract
INTRODUCTION: Topiramate (TPM), a frequently prescribed antiseizure medication, can cause severe cognitive side-effects. Though these side-effects have been studied behaviorally, the underlying neural mechanisms are unknown. In a double-blind, randomized, placebo-controlled, crossover study of TPM's impact on cognition, nine healthy volunteers completed three study sessions: a no-drug baseline session and two sessions during which they received either TPM or placebo. Electroencephalogram was recorded during each session while subjects performed a working-memory task with three memory-loads.
RESULTS: Comparing TPM with baseline we found the following results. (a) TPM administration led to declines in behavioral performance. (b) Fronto-central event-related potentials (ERP) elicited by probe stimuli, representing the primary task network activity, showed strong memory-load modulations at baseline, but the magnitude of these load-dependent modulations was significantly reduced during TPM session, suggesting drug-induced impairments of the primary task network. (c) ERP responses over bilateral fronto-temporal electrodes, which were not load sensitive at baseline, showed significant memory-load modulations after TPM administration, suggesting the drug-related recruitment of additional neural resources. (d) At fronto-central scalp sites, there was significant increase in response amplitude for low memory-load during TPM session compared to baseline, and the amplitude increase was dependent on TPM plasma concentration, suggesting that the primary task network became less efficient under TPM impact. (e) At bilateral fronto-temporal electrodes, there were no ERP differences when comparing low memory-load trials, but TPM administration led to an increase in ERP responses to high load, the magnitude of which was positively correlated with task performance, suggesting that the recruited neural resources were beneficial for task performance. Placebo-TPM comparison yielded similar effects albeit with generally reduced significance and effect sizes.
CONCLUSION: Our findings support the hypothesis that TPM impairs the primary task network by reducing its efficiency, which triggers compensatory recruitment of additional resources to maintain task performance.

PMID: 29720037 [PubMed - as supplied by publisher]

Barriers and facilitators to adherence to secondary stroke prevention medications after stroke: analysis of survivors and caregivers views from an online stroke forum.

BMJ Open. 2017 07 16;7(7):e016814

Authors: Jamison J, Sutton S, Mant J, De Simoni A

Abstract
OBJECTIVE: To identify barriers and facilitators of medication adherence in patients with stroke along with their caregivers.
DESIGN: Qualitative thematic analysis of posts about secondary prevention medications, informed by Perceptions and Practicalities Approach.
SETTING: Posts written by the UK stroke survivors and their family members taking part in the online forum of the Stroke Association, between 2004 and 2011.
PARTICIPANTS: 84 participants: 49 stroke survivors, 33 caregivers, 2 not stated, identified using the keywords 'taking medication', 'pills', 'size', 'side-effects', 'routine', 'blister' as well as secondary prevention medication terms.
RESULTS: Perceptions reducing the motivation to adhere included dealing with medication side effects, questioning doctors' prescribing practices and negative publicity about medications, especially in regard to statins. Caregivers faced difficulties with ensuring medications were taken while respecting the patient's decisions not to take tablets. They struggled in their role as advocates of patient's needs with healthcare professionals. Not experiencing side effects, attributing importance to medications, positive personal experiences of taking tablets and obtaining modification of treatment to manage side effects were facilitators of adherence. Key practical barriers included difficulties with swallowing tablets, dealing with the burden of treatment and drug cost. Using medication storage devices, following routines and getting help with medications from caregivers were important facilitators of adherence.
CONCLUSIONS: An online stroke forum is a novel and valuable resource to investigate use of secondary prevention medications. Analysis of this forum highlighted significant barriers and facilitators of medication adherence faced by stroke survivors and their caregivers. Addressing perceptual and practical barriers highlighted here can inform the development of future interventions aimed at improving adherence to secondary prevention medication after stroke.

PMID: 28713074 [PubMed - indexed for MEDLINE]

First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies.

Clin Cancer Res. 2017 Jul 01;23(13):3269-3276

Authors: Beatty GL, O'Dwyer PJ, Clark J, Shi JG, Bowman KJ, Scherle PA, Newton RC, Schaub R, Maleski J, Leopold L, Gajewski TF

Abstract
Purpose: Indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the degradation of tryptophan to N-formyl-kynurenine. Overexpressed in many solid malignancies, IDO1 can promote tumor escape from host immunosurveillance. This first-in-human phase I study investigated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent and selective inhibitor of IDO1.Experimental Design: Fifty-two patients with advanced solid malignancies were treated with epacadostat [50 mg once daily or 50, 100, 300, 400, 500, 600, or 700 mg twice daily (BID)] in a dose-escalation 3 + 3 design and evaluated in 28-day cycles. Treatment was continued until disease progression or unacceptable toxicity.Results: One dose-limiting toxicity (DLT) occurred at the dose of 300 mg BID (grade 3, radiation pneumonitis); another DLT occurred at 400 mg BID (grade 3, fatigue). The most common adverse events in >20% of patients overall were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. Treatment produced significant dose-dependent reductions in plasma kynurenine levels and in the plasma kynurenine/tryptophan ratio at all doses and in all patients. Near maximal changes were observed at doses of ≥100 mg BID with >80% to 90% inhibition of IDO1 achieved throughout the dosing period. Although no objective responses were detected, stable disease lasting ≥16 weeks was observed in 7 of 52 patients.Conclusions: Epacadostat was generally well tolerated, effectively normalized kynurenine levels, and produced maximal inhibition of IDO1 activity at doses of ≥100 mg BID. Studies investigating epacadostat in combination with other immunomodulatory drugs are ongoing. Clin Cancer Res; 23(13); 3269-76. ©2017 AACR.

PMID: 28053021 [PubMed - indexed for MEDLINE]

Retrospective case series analysis of characteristics and trends in unintentional pharmaceutical drug poisoning by methadone, opioid analgesics, antidepressants and benzodiazepines in Clark County, NV 2009-13.

J Public Health (Oxf). 2017 Jun 01;39(2):304-311

Authors: Bruno T, Pharr JR

Abstract
Background: Poisoning has become the leading cause of injury death in the USA-with opioid analgesic involved in more fatal poisonings than any other drug, including cocaine and heroin. The epidemic of prescription drug poisonings is a public health concern. This study aimed to define potential high-risk groups for unintentional prescription drug poisoning by methadone, opioid analgesics, antidepressants or benzodiazepines.
Methods: A hospital-based retrospective case series analysis of admissions related to prescription drug poisonings associated with methadone, opioid analgesics, antidepressants or benzodiazepines for hospitals in Clark County, Nevada between 2009 and 2013 was employed.
Results: There were 7414 admissions with a primary diagnosis of an unintentional poisoning due to methadone, opioid analgesics, antidepressants or benzodiazepines. Women had the highest rate of admissions particularly in the 45-54 age group. Higher rates of admissions were also found among non-Hispanic whites, single and uninsured populations. There were concerning increases in admissions among 65+ and Native American/Alaskan Native subgroups in 2013. Benzodiazepines and opioid analgesics were the most prevalent drug categories for prescription drug poisoning admissions.
Conclusion: Public health professionals can utilize hospital data to identify populations at risk and in need of targeted interventions.

PMID: 27222239 [PubMed - indexed for MEDLINE]

Higher versus Lower Dose of Cefotetan or Cefoxitin for Surgical Prophylaxis in Patients Weighing One Hundred Twenty Kilograms or More.

Surg Infect (Larchmt). 2018 May 02;:

Authors: Banoub M, Curless MS, Smith JM, Jarrell AS, Cosgrove SE, Rock C, Avdic E

Abstract
BACKGROUND: Clinical practice guidelines recommend a 2-g dose of cefotetan and cefoxitin for surgical prophylaxis. Pharmacokinetic data suggest benefit from higher cefotetan and cefoxitin dosing in obese patients. However, clinical studies examining higher dosing strategies in this at-risk population are lacking. The purpose of this study was to determine whether 3 g of cefotetan or cefoxitin administered pre-operatively for patients who weigh 120 kg or more is associated with a lower proportion of surgical site infection (SSI) compared with 2 g.
PATIENTS AND METHODS: Medical records of patients weighing 120 kg or more who had received cefotetan or cefoxitin (2 or 3 g) as surgical prophylaxis for intra-abdominal procedures between July 2012 and August 2015 were reviewed for the development of an SSI (primary outcome), study drug-related adverse events, and re-admissions attributed to SSIs (secondary outcomes). Relative risk calculations were performed for analysis of the primary and secondary outcomes.
RESULTS: One-hundred seventy-five procedures in 169 patients were included in the study. Cefotetan was used in 81% (141/175) of procedures. Three grams of cefotetan or cefoxitin was used in 20% (35/175) of procedures. The median body mass index (BMI) in both dosing groups was 42 kg/m2 and patients who received 3 g more often weighed more than 130 kg (relative risk [RR] 1.36, 1.01-1.76; p = 0.04). Surgical site infections occurred in 20.7% within the 2-g group and 22.9% in the 3-g group (RR 1.10, 0.55-2.20; p = 0.78). There was no difference in the number of study drug-related adverse effects in the 3-g compared with the 2-g group. Thirty-day re-admissions because of SSI also did not differ between the 2-g and 3-g groups (7.9% vs. 17.1%, respectively; p = 0.11).
CONCLUSION: This small retrospective study did not find a difference in SSI rates between 3-g and 2-g surgical prophylaxis dosing for patients 120 kg or more with a median BMI >40 kg/m2.

PMID: 29717917 [PubMed - as supplied by publisher]

Anabolic Steroid Effect on the Liver.

Curr Sports Med Rep. 2018 Mar;17(3):97-102

Authors: Niedfeldt MW

Abstract
Anabolic steroids are synthetic derivatives of testosterone shown to increase muscle size and strength. Chemical substitutions on the testosterone molecule cause increased potency and duration of action. The 17-α-alkylation modification allows steroids to be taken orally, but the slower clearance in the liver makes them more hepatotoxic. The frequency and severity of side effects depends on several factors including the formulation of the drug, route of administration, dosage, duration of use, and individual sensitivity and response. Anabolic steroid users tend to take supraphysiologic doses or multiple steroids and other drugs simultaneously which increases risk of adverse effects. Hepatotoxicity can be seen as elevated liver transaminases, acute cholestatic syndrome, chronic vascular injury, hepatic tumors, and toxicant-associated fatty liver disease, as well as significant changes in lipoproteins. Many of these changes will stabilize or reverse with cessation of steroid use, but some can be life-threatening. Over-the-counter supplements can be contaminated with anabolic steroids, causing hepatotoxicity in unsuspecting consumers.

PMID: 29521706 [PubMed - indexed for MEDLINE]

Pulmonary toxicity following bleomycin use: A single-center experience.

J Cancer Res Ther. 2017 Jul-Sep;13(3):466-470

Authors: Madabhavi I, Modi G, Patel A, Anand A, Panchal H, Parikh S

Abstract
BACKGROUND: Bleomycin-induced pulmonary (BIP) toxicity is a notorious entity and cropped up in roughly 10% of cases. The aim of the study is to evaluate BIP at our tertiary care cancer center.
PATIENTS AND METHODS: This is a retrospective, analytical study conducted at a tertiary care center from January 1998 to December 2012. Records of all the patients who were offered bleomycin chemotherapy as an integral part of adriamycin, bleomycin, vinblastine, and dacarbazine or bleomycin, etoposide, and cisplatin regimen in Hodgkin disease (HD) or germ cell tumor (GCT) were studied for the study inclusion criteria. Twenty-two patients treated with bleomycin who had respiratory symptoms and/or abnormal high-resolution computed tomography (HRCT) findings, suggestive of bleomycin-induced lung injury were included in this study. Results and Statistical Analysis: A total of 22 patients met the inclusion criteria for the study cohort. Of 22 patients, 8 were of HD and 14 were of GCT (nonseminomatous GCT [NSGCT] = 10 and seminomatous GCT = 4). Of 22 patients, 14 had symptoms of nonproductive cough, dyspnea and showed HRCT findings of ground glass opacities, diffuse alveolar damage, extensive reticular markings, traction bronchiectasis, and/or nodular densities. Two patients had fever and pleuritic pain. Eight patients were asymptomatic. Symptomatic patients were treated with prednisone at the dose of 0.75-1 mg/kg 4-8 weeks then gradually tapered. Four patients required noninvasive ventilatory support and managed with oxygen, nebulization, and antibiotics. Two patients required mechanical ventilatory support (HD = 1 and NSGCT = 1) and developed multiorgan failure subsequently succumbed to death.
CONCLUSION: BIP is noteworthy lung toxicity as subsequent mortality ranges from 10% to 20% and shrinks survival rate in patients with highly curable malignant conditions. Physicians should be vigilant concerning this impending side effect.

PMID: 28862210 [PubMed - indexed for MEDLINE]