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]

Computational approaches to understand the adverse drug effect on potassium, sodium and calcium channels for predicting TdP cardiac arrhythmias.

J Mol Graph Model. 2017 Sep;76:152-160

Authors: Sharifi M

Abstract
Ion channels play a crucial role in the cardiovascular system. Our understanding of cardiac ion channel function has improved since their first discoveries. The flow of potassium, sodium and calcium ions across cardiomyocytes is vital for regular cardiac rhythm. Blockage of these channels, delays cardiac repolarization or tend to shorten repolarization and may induce arrhythmia. Detection of drug risk by channel blockade is considered essential for drug regulators. Advanced computational models can be used as an early screen for torsadogenic potential in drug candidates. New drug candidates that are determined to not cause blockage are more likely to pass successfully through preclinical trials and not be withdrawn later from the marketplace by manufacturer. Several different approved drugs, however, can cause a distinctive polymorphic ventricular arrhythmia known as torsade de pointes (TdP), which may lead to sudden death. The objective of the present study is to review the mechanisms and computational models used to assess the risk that a drug may TdP.
KEY POINTS: There is strong evidence from multiple studies that blockage of the L-type calcium current reduces risk of TdP. Blockage of sodium channels slows cardiac action potential conduction, however, not all sodium channel blocking antiarrhythmic drugs produce a significant effect, while late sodium channel block reduces TdP. Interestingly, there are some drugs that block the hERG potassium channel and therefore cause QT prolongation, but they are not associated with TdP. Recent studies confirmed the necessity of studying multiple distinctionic ion channels which are responsible for cardiac related diseases or TdP, to obtain an improved clinical TdP risk prediction of compound interactions and also for designing drugs.

PMID: 28756335 [PubMed - indexed for MEDLINE]

Adverse event management in patients with relapsed and refractory multiple myeloma taking pomalidomide plus low-dose dexamethasone: A pooled analysis.

Eur J Haematol. 2017 Sep;99(3):199-206

Authors: Moreau P, Dimopoulos MA, Richardson PG, Siegel DS, Cavo M, Corradini P, Weisel K, Delforge M, O'Gorman P, Song K, Chen C, Bahlis N, Oriol A, Hansson M, Kaiser M, Anttila P, Raymakers R, Joao C, Cook G, Sternas L, Biyukov T, Slaughter A, Hong K, Herring J, Yu X, Zaki M, San-Miguel J

Abstract
OBJECTIVES: Heavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment-related adverse events (AEs). Managing AEs are important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM-002, MM-003, and MM-010 trials were pooled to further characterize the safety profile of pomalidomide plus low-dose dexamethasone and AE management.
METHODS: This analysis included 1088 patients who received ≥ 2 prior therapies, including lenalidomide and bortezomib, and progressed ≤ 60 days of last therapy. Patients received 28-day cycles of pomalidomide 4 mg/day on days 1-21 and low-dose dexamethasone 40 mg (20 mg if aged > 75 years) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required.
RESULTS: The most common grade 3/4 AEs were neutropenia (56.2%), anemia (32.3%), and thrombocytopenia (25.8%), which occurred within the first few cycles of treatment. Grade 3/4 infections occurred in 33.7% patients, of whom 13.9% had pneumonia, and 40.3% had neutropenia. Pomalidomide dose reductions or interruptions were reported in 24.2% and 66.0% of patients, respectively. AEs were managed by dose modifications and/or supportive care.
CONCLUSIONS: Pomalidomide plus low-dose dexamethasone showed an acceptable safety profile, and AEs were well managed according to study protocols and established guidelines.

PMID: 28504846 [PubMed - indexed for MEDLINE]

Compact Magnetic Resonance Imaging Systems-Novel Cost-Effective Tools for Preclinical Drug Safety and Efficacy Evaluation.

Toxicol Sci. 2017 05 01;157(1):3-7

Authors: Ramot Y, Schiffenbauer YS, Maronpot R, Nyska A

Abstract
Practical magnetic resonance imaging for use in investigative and preclinical toxicology studies is now feasible. Newly developed, self-containing imaging systems provide an efficient and cost-effective means to rapidly obtain in vivo and ex vivo magnetic resonance imaging images to improve how we perform toxicology and toxicologic pathology.

PMID: 28329801 [PubMed - indexed for MEDLINE]

NMDA receptor signaling is important for neural tube formation and for preventing antiepileptic drug-induced neural tube defects.

J Neurosci. 2018 Apr 30;:

Authors: Sequerra EB, Goyal R, Castro PA, Levin JB, Borodinsky LN

Abstract
Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that during Xenopus laevis neural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that N-methyl-D-aspartate (NMDA) receptors are important for the formation of the neural tube and loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation.SIGNIFICANCE STATEMENTNeural tube defects are one of the most common birth defects. Clinical investigations have determined that use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that are the side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy.

PMID: 29712790 [PubMed - as supplied by publisher]

Pharmacokinetics, pharmacodynamics, and tolerability of single-dose oral LCB01-0371, a novel oxazolidinone with broad-spectrum activity, in healthy volunteers.

Antimicrob Agents Chemother. 2018 Apr 30;:

Authors: Cho YS, Lim HS, Lee SH, Cho YL, Nam HS, Bae KS

Abstract
LCB01-0371 is a novel oxazolidinone with broad-spectrum activity against Gram-positive pathogens in both in vitro studies and animal infection models. The objectives of this study were to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics following single ascending doses (NCT01554995). Single oral doses of 600 mg Linezolid, a placebo, or LCB01-0371 between 50 mg and 3200 mg were tested in 69 healthy male subjects. Blood and urine were sampled, and LCB01-0371 concentrations were measured, and the serum inhibitory and bactericidal titers of LCB01-0371 and Linezolid were determined. LCB01-0371 was well tolerated up to 2400 mg. The most common drug-related clinical and laboratory adverse events were nausea with or without vomiting, decreased neutrophil count, and increased total bilirubin. The frequency of adverse events and drug-related adverse events was similar among the treatment groups. The systemic exposure was approximately dose-proportional over the range of 50mg--800 mg, which includes the anticipated clinical dose. The mean clearance, renal clearance, and volume of distribution were significantly decreased at higher doses (above 800 mg). LCB01-0371 exhibited early bacteriostatic activity against all tested strains except for S. pneumonia, and the potency of LCB01-0371 at 800 mg was similar to that of Linezolid at the therapeutic dose (600 mg). However, LCB01-0371 had less bactericidal activity than Linezolid. Taken together, LCB01-0371 was well tolerated and exhibited approximate dose proportionality within the anticipated clinically relevant dose range, and showed bacteriostatic and bactericidal activity comparable to that of Linezolid. These results support the further clinical development of LCB01-0371.

PMID: 29712654 [PubMed - as supplied by publisher]

Centaurea albonitens extract enhances the therapeutic effects of Vincristine in leukemic cells by inducing apoptosis.

Biomed Pharmacother. 2018 Mar;99:598-607

Authors: Bahmani F, Esmaeili S, Bashash D, Dehghan-Nayeri N, Mashati P, Gharehbaghian A

Abstract
Drug-induced toxicities and dose-related side effects are the major challenges in the conventional cancer therapy by the chemo drugs. On the other hand, herbal derivatives have obtained a great research interest in the field of therapeutic applications because of their more favorable specifications including less toxicity, cost-effective and more physiologically compatible than the chemical drugs. For this purpose, we evaluated methanolic extract prepared from Centaurea albonitens Turrill alone and in combination with Vincristine (VCR) for its potential cytotoxic effects in NALM-6, REH, NB4 and KMM-1 cell lines by using the various approaches. Centaurea genus is one of the current medicinal plants, which has used in traditional medicine, However, there are rare studies to examine its anticancer properties against hematologic malignant cells. In this study, we demonstrated Centaurea albonitens extract (CAE) induces cytotoxicity through G0/G1 phase arrest followed by apoptosis in a dose- and time- dependent manner, although with varying efficiency. Interestingly, normal cells didn't exhibit significant cytotoxicity after CAE treatment. Moreover, we found that low dose of CAE enhances anti-cancer effects of VCR in pre-B ALL cell lines (NALM-6 and REH). Further investigations validated synergistic anticancer activities of VCR and CAE through inducing apoptosis without significant cell cycle arrest. Taken together, our results demonstrated for the first time that the methanolic extract of Centaurea albonitens can be considered as a potential anticancer agent and/or an enhancer of chemotherapeutic sensitivity of VCR.

PMID: 29710458 [PubMed - in process]

PhID: An Open-Access Integrated Pharmacology Interactions Database for Drugs, Targets, Diseases, Genes, Side-Effects, and Pathways.

J Chem Inf Model. 2017 Oct 23;57(10):2395-2400

Authors: Deng Z, Tu W, Deng Z, Hu QN

Abstract
The current network pharmacology study encountered a bottleneck with a lot of public data scattered in different databases. There is a lack of an open-access and consolidated platform that integrates this information for systemic research. To address this issue, we have developed PhID, an integrated pharmacology database which integrates >400 000 pharmacology elements (drug, target, disease, gene, side-effect, and pathway) and >200 000 element interactions in branches of public databases. PhID has three major applications: (1) assisting scientists searching through the overwhelming amount of pharmacology element interaction data by names, public IDs, molecule structures, or molecular substructures; (2) helping visualizing pharmacology elements and their interactions with a web-based network graph; and (3) providing prediction of drug-target interactions through two modules: PreDPI-ki and FIM, by which users can predict drug-target interactions of PhID entities or some drug-target pairs of their own interest. To get a systems-level understanding of drug action and disease complexity, PhID as a network pharmacology tool was established from the perspective of data layer, visualization layer, and prediction model layer to present information untapped by current databases.

PMID: 28906116 [PubMed - indexed for MEDLINE]

Influence of knowledge and beliefs on consumption of performance enhancing agents in north-western Saudi Arabia.

Ann Saudi Med. 2017 Jul-Aug;37(4):317-325

Authors: Al OM, Elshatarat RA

Abstract
BACKGROUND: Consumption of performance enhancing agents (PEAs) has a wide range of negative health consequences, but knowledge of these consequences among gym users of PEAs in Saudi Arabia is not well understood.
OBJECTIVES: Identify the knowledge, awareness, beliefs and attitudes of gym users about negative health consequences of using PEAs, and the relationship between these factors and use of these agents.
DESIGN: Cross-sectional study.
SETTING: Five gyms in Madinah city, Saudi Arabia.
SUBJECTS AND METHODS: Convenience sampling was used to recruit gym users. An electronic self-administered questionnaire was used to collect data.
MAIN OUTCOME MEASURE(S): Level of knowledge about the negative health consequences of PEAs among gym users.
RESULTS: About 70% of 316 participants had used one or more of PEAs over the last six months. Of those, about 68.4% used protein powder supplements and 48.1% used energy drinks. Participants who believed that protein powder supplements (c2=52.3, P < .01) and energy drinks (c2=35.2, P < .01) had health hazards used these agents less often than others during the six months preceding data collection. Participants who had less knowledge about the negative health consequences were more likely to use protein powder supplement (t=2.38, P=.018). On the other hand, those who were more knowledgeable about the negative health consequences of insulin, were more likely to use insulin (t=2.45, P=.015).
CONCLUSION: Misuse of PEAs is widespread among gym users in Saudi Arabia. Improving the level of knowledge and awareness of possible serious health consequences would hopefully lead to reduced PEA consumption.
LIMITATIONS: The temporal sequence of cause and effect could not be determined in a cross sectional study. Convenience sampling in a single city limited the generalizability of the findings to all regions of Saudi Arabia.

PMID: 28761032 [PubMed - indexed for MEDLINE]

Indirect comparison between pembrolizumab and nivolumab for the treatment of non-small cell lung cancer: A meta-analysis of randomized clinical trials.

Int Immunopharmacol. 2017 Aug;49:85-94

Authors: Peng TR, Tsai FP, Wu TW

Abstract
OBJECTIVE: The purpose of this study is to evaluate the efficacy and adverse effects of nivolumab and pembrolizumab for the treatment of advanced non-small-cell lung cancer (NSCLC) by meta-analysis.
MATERIALS AND METHODS: This meta-analysis of randomized controlled trials (RCTs) was performed after searching PubMed, EMBASE, and American Society of Clinical Oncology meeting abstracts, clinicaltrial gov, and Cochrane library databases. Two reviewers independently assessed the quality of the trials. Outcomes analysis was overall response rates (ORR), overall survival (OS), progression- free survival (PFS) and major adverse effects with odds ratio (OR) or hazard ratio (HR) and 95% confidence intervals (CI).
RESULTS: Results reported from three RCTs involving 1,887 patients are included in this analysis. Indirect comparison between pembrolizumab and nivolumab in advanced NSCLC shows no statistically significant difference in ORR (OR: 1.14, 95% CI, 0.60-2.01), OS (HR: 0.98, 95% CI, 0.35-2.74) and PFS (HR: 1.12, 95% CI, 0.70-1.77). The incidence of grades≥3 adverse effects is higher with pembrolizumab as compared with nivolumab (OR: 3.44, 95% CI, 1.87-6.32). There are no significant statistical differences between severe adverse effects, such as pneumonitis and hypothyroidism, of the two drugs.
CONCLUSIONS: This study has demonstrated that pembrolizumab and nivolumab have similar survival outcomes in patients with advanced NSCLC, but pembrolizumab has a higher incidence of grades≥3 adverse effects than nivolumab.

PMID: 28554108 [PubMed - indexed for MEDLINE]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/05/01

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.

Hypersensitivity reactions to intravenous antibiotics in cystic fibrosis.

Paediatr Respir Rev. 2018 Apr 05;:

Authors: Wright MFA, Bush A, Carr SB

Abstract
Hypersensitivity reactions to intravenous antibiotics are common in cystic fibrosis (CF). As well as causing immediate morbidity, the need for future avoidance of the causative antibiotic can have a long-term negative impact on CF management. This paper reviews the epidemiology and clinical presentation of hypersensitivity reactions in CF patients, and using an illustrative case describes a rare but severe form of delayed drug reaction for which a high index of suspicion is required.

PMID: 29703693 [PubMed - as supplied by publisher]