Design, synthesis and biological evaluation of AZD9291 derivatives as selective and potent EGFRL858R/T790M inhibitors.

Eur J Med Chem. 2019 Feb 01;163:367-380

Authors: Zhao B, Xiao Z, Qi J, Luo R, Lan Z, Zhang Y, Hu X, Tang Q, Zheng P, Xu S, Zhu W

Abstract
Third-generation epidermal growth factor receptor (EGFR)L858R/T790M inhibitors are still the main drugs for the treatment of advanced non-small cell lung cancer (NSCLC), and these drugs have achieved remarkable clinical efficacy. However, there are still many patients suffering from drug-resistant mutations and drug side effects caused by NSCLC. In this study, guided by the molecular simulation, we applied a structure-based drug design strategy (SBDD) and optimized the structure to obtain a series of potent and selective EGFRL858R/T790M inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFRL858R/T790M double mutants and the IC50 value reached nanomolar level. The selectivity of 18e against wild-type EGFR was near to 200-fold. In addition, compound 18e also inhibited H1975 cells proliferation at G2/M phase and induced apoptosis at a concentration of 0.25 μM, which makes it more valuable for potential lung cancer research.

PMID: 30530173 [PubMed - indexed for MEDLINE]

Pharmacologic Renal Therapy.

Nurs Clin North Am. 2018 12;53(4):491-497

Authors: Ruffin T

Abstract
This article discusses some of the recommended pharmacologic treatments for patients with renal drug toxicity, acute kidney injury (AKI), and chronic kidney injury (CKI). The treatment of AKI often consists of treating patients in emergency departments. Renal pharmacologic management in an acute care setting consists of identifying the cause of AKI, reviewing serum creatinine levels, administration of crystalloids, and the elimination of nephrotoxic agents.

PMID: 30388975 [PubMed - indexed for MEDLINE]

Data Mining for Adverse Drug Events With a Propensity Score-matched Tree-based Scan Statistic.

Epidemiology. 2018 11;29(6):895-903

Authors: Wang SV, Maro JC, Baro E, Izem R, Dashevsky I, Rogers JR, Nguyen M, Gagne JJ, Patorno E, Huybrechts KF, Major JM, Zhou E, Reidy M, Cosgrove A, Schneeweiss S, Kulldorff M

Abstract
The tree-based scan statistic is a statistical data mining tool that has been used for signal detection with a self-controlled design in vaccine safety studies. This disproportionality statistic adjusts for multiple testing in evaluation of thousands of potential adverse events. However, many drug safety questions are not well suited for self-controlled analysis. We propose a method that combines tree-based scan statistics with propensity score-matched analysis of new initiator cohorts, a robust design for investigations of drug safety. We conducted plasmode simulations to evaluate performance. In multiple realistic scenarios, tree-based scan statistics in cohorts that were propensity score matched to adjust for confounding outperformed tree-based scan statistics in unmatched cohorts. In scenarios where confounding moved point estimates away from the null, adjusted analyses recovered the prespecified type 1 error while unadjusted analyses inflated type 1 error. In scenarios where confounding moved point estimates toward the null, adjusted analyses preserved power, whereas unadjusted analyses greatly reduced power. Although complete adjustment of true confounders had the best performance, matching on a moderately mis-specified propensity score substantially improved type 1 error and power compared with no adjustment. When there was true elevation in risk of an adverse event, there were often co-occurring signals for clinically related concepts. TreeScan with propensity score matching shows promise as a method for screening and prioritization of potential adverse events. It should be followed by clinical review and safety studies specifically designed to quantify the magnitude of effect, with confounding control targeted to the outcome of interest.

PMID: 30074538 [PubMed - indexed for MEDLINE]

The use of mechanistic evidence in drug approval.

J Eval Clin Pract. 2018 10;24(5):1166-1176

Authors: Aronson JK, La Caze A, Kelly MP, Parkkinen VP, Williamson J

Abstract
The role of mechanistic evidence tends to be under-appreciated in current evidence-based medicine (EBM), which focusses on clinical studies, tending to restrict attention to randomized controlled studies (RCTs) when they are available. The EBM+ programme seeks to redress this imbalance, by suggesting methods for evaluating mechanistic studies alongside clinical studies. Drug approval is a problematic case for the view that mechanistic evidence should be taken into account, because RCTs are almost always available. Nevertheless, we argue that mechanistic evidence is central to all the key tasks in the drug approval process: in drug discovery and development; assessing pharmaceutical quality; devising dosage regimens; assessing efficacy, harms, external validity, and cost-effectiveness; evaluating adherence; and extending product licences. We recommend that, when preparing for meetings in which any aspect of drug approval is to be discussed, mechanistic evidence should be systematically analysed and presented to the committee members alongside analyses of clinical studies.

PMID: 29888417 [PubMed - indexed for MEDLINE]

Longitudinal assessment of chemotherapy-induced changes in brain and cognitive functioning: A systematic review.

Neurosci Biobehav Rev. 2018 09;92:304-317

Authors: Li M, Caeyenberghs K

Abstract
In addition to the burden of a life-threatening diagnosis, cancer patients are struggling with adverse side-effects from cancer treatment. Chemotherapy has been linked to an array of cognitive impairments and alterations in brain structure and function ("chemobrain"). In this review, we summarized the existing evidence that evaluate the changes in cognitive functioning and brain with chemotherapy, as assessed using structural and functional MRI-based techniques in a longitudinal design. This review followed the latest PRISMA guidelines using Embase, Medline, PsychINFO, Scopus, and Web of Science databases with date restrictions from 2012 to 2017. Fourteen research articles met the key inclusion criteria: (i) the studies involved adult cancer patients (mean age ≥ 18); (ii) the use of chemotherapy in the treatment of cancer; (iii) pre-post assessment of behavioral and brain-based outcomes; and (iv) abstracts written in English. Effect sizes of subjective and objective cognitive impairments from the reviewed studies were estimated using Cohen's d or z-scores. We calculated percentage of mean change or effect sizes for main neuroimaging findings when data were available. Strength of the correlations between brain alterations and cognitive changes was obtained using squared correlation coefficients. Small to medium effect sizes were shown? on individual tests of attention, processing speed, verbal memory, and executive control; and medium effect sizes on self-report questionnaires. Neuroimaging data showed reduced grey matter density in cancer patients in frontal, parietal, and temporal regions. Changes in brain function (brain activation and cerebral blood flow) were observed with cancer across functional networks involving (pre)frontal, parietal, occipital, temporal, and cerebellar regions. Data from diffusion-weighted MRI suggested reduced white matter integrity involving the superior longitudinal fasciculus, corpus callosum, forceps major, and corona radiate, and altered structural connectivity across the whole brain network. Finally, we observed moderate-to-strong correlations between worsening cognitive function and morphological changes in frontal brain regions. While MRI is a powerful tool for detection of longitudinal brain changes in the 'chemobrain', the underlying biological mechanisms are still unclear. Continued work in this field will hopefully detect MRI metrics to be used as biomarkers to help guide cognitive treatment at the individual cancer patient level.

PMID: 29791867 [PubMed - indexed for MEDLINE]

A new outlook on cholinergic interneurons in Parkinson's disease and L-DOPA-induced dyskinesia.

Neurosci Biobehav Rev. 2018 09;92:67-82

Authors: Conti MM, Chambers N, Bishop C

Abstract
Traditionally, dopamine (DA) and acetylcholine (ACh) striatal systems were considered antagonistic and imbalances or aberrant signaling between these neurotransmitter systems could be detrimental to basal ganglia activity and pursuant motor function, such as in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). Herein, we discuss the involvement of cholinergic interneurons (ChIs) in striatally-mediated movement in a healthy, parkinsonian, and dyskinetic state. ChIs integrate numerous neurotransmitter signals using intrinsic glutamate, serotonin, and DA receptors and convey the appropriate transmission onto nearby muscarinic and nicotinic ACh receptors to produce movement. In PD, severe DA depletion causes abnormal rises in ChI activity which promote striatal signaling to attenuate normal movement. When treating PD with L-DOPA, hyperkinetic side effects, or LID, develop due to increased striatal DA; however, the role of ChIs and ACh transmission, until recently has been unclear. Fortunately, new technology and pharmacological agents have facilitated understanding of ChI function and ACh signaling in the context of LID, thus offering new opportunities to modify existing and discover future therapeutic strategies in movement disorders.

PMID: 29782883 [PubMed - indexed for MEDLINE]

Feasibility and implementation of CYP2C19 genotyping in patients using antiplatelet therapy.

Pharmacogenomics. 2018 05;19(7):621-628

Authors: Bergmeijer TO, Vos GJ, Claassens DM, Janssen PW, Harms R, der Heide RV, Asselbergs FW, Ten Berg JM, Deneer VH

Abstract
AIM: A tailored antiplatelet strategy based on CYP2C19 genotype may reduce atherothrombotic and bleeding events. We describe our experience with CYP2C19 genotyping, using on-site TaqMan or Spartan genotyping or shipment to a central laboratory.
METHODOLOGY: Data from two ongoing projects were used: Popular Risk Score project (non-urgent percutaneous coronary intervention patients) and the Popular Genetics study (ST-segment elevation myocardial infarction patients). For both projects, the time to genotyping result was calculated.
RESULTS: In the Popular Risk Score project (n = 2556), median time from blood collection to genotyping result was 4:04 h. In the Popular Genetics study (n = 1038), median time from randomization to genotyping result was 2:24 h.
CONCLUSION: CYP2C19 genotyping is feasible in everyday clinical practice, both in the acute and non-acute settings.

PMID: 29701129 [PubMed - indexed for MEDLINE]

Application of in Vitro T Cell Assay Using Human Leukocyte Antigen-Typed Healthy Donors for the Assessment of Drug Immunogenicity.

Chem Res Toxicol. 2018 03 19;31(3):165-167

Authors: Usui T, Faulkner L, Farrell J, French NS, Alfirevic A, Pirmohamed M, Park BK, Naisbitt DJ

Abstract
It is unclear whether priming of naïve T cells to drugs is detectable in healthy human donors expressing different human leukocyte antigen (HLA) alleles. Thus, we examined T cell priming with drugs associated with HLA risk alleles and control compounds in 14 HLA-typed donors. Nitroso sulfamethoxazole and piperacillin activated T cells from all donors, whereas responses to carbamazepine and oxypurinol were only seen in donors expressing HLA-B*15:02 and HLA-B*58:01, respectively. Weak flucloxacillin-specific T cell responses were detected in donors expressing HLA-B*57:01 and HLA-B*58:01. These data show that the priming of T cells with certain drugs is skewed toward donors expressing specific HLA alleles.

PMID: 29436218 [PubMed - indexed for MEDLINE]

Modification of cardiovascular pharmacotherapy in palliative care patients with cancer: a narrative review.

Pol Arch Intern Med. 2017 10 31;127(10):687-693

Authors: Pasierski T

Abstract
Palliative care patients with cancer are treated with many drugs, especially at the end of life. Limiting polypharmacy decreases the risk of associated adverse effects, medical errors, and harmful drug interactions. The time lag to benefit from the use of many medications used for cardiovascular diseases or their risk factors, such as hypertension and hypercholesterolemia, is frequently longer than the life expectancy of palliative care patients with cancer. It is ethically appropriate to modify, and even to discontinue, cardiovascular pharmacotherapy when there is no prospect of benefit. The decision to discontinue lipid‑lowering drugs and antihypertensive drugs is rather straightforward. Antithrombotic therapy may be stopped in low‑risk primary prevention but not in high‑risk group. Discontinuation of drugs for heart failure may provoke exacerbation of symptoms and should be considered only in the last weeks of life.

PMID: 28918428 [PubMed - indexed for MEDLINE]

Efficacy and Safety of Ruzasvir 60 mg and Uprifosbuvir 450 mg for 12 Weeks in Adults With Chronic Hepatitis C Virus Genotype 1, 2, 3, 4, or 6 Infection.

J Viral Hepat. 2019 Feb 09;:

Authors: Lawitz E, Poordad F, Anderson LJ, Vesay M, Kelly MM, Liu H, Gao W, Fernsler D, Asante-Appiah E, Robertson MN, Hanna GJ, Barr E, Butterton J, Kowdley KV, Hassanein T, Sahota A, Gordon SC, Yeh WW

Abstract
In clinical trials, the three-drug regimen of ruzasvir (RZR) 60 mg, uprifosbuvir (UPR) 450 mg, and grazoprevir 100 mg, with or without ribavirin has demonstrated promising efficacy and excellent tolerability across a wide range of hepatitis C virus (HCV)-infected individuals. The present study assessed the efficacy and safety of the two-drug combination of RZR 60 mg plus UPR 450 mg administered for 12 weeks in participants with HCV genotype (GT) 1-6 infection. In this open-label clinical trial, treatment-naive or -experienced and cirrhotic or noncirrhotic participants with chronic HCV GT1-6 infection received RZR 60 mg plus UPR 450 mg orally once daily for 12 weeks (NCT02759315/protocol PN035). The primary efficacy endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). One hundred and sixty participants were enrolled. SVR12 rates were 96% (52/54) in participants with GT1a infection; 100% (15/15) in those with GT1b infection; 97% (28/29) in those with GT2 infection; 77% (30/39) in those with GT3 infection; 90% (18/20) in those with GT4 infection; and 67% (2/3) in those with GT6 infection. Drug-related adverse events (AEs) reported by >5% of participants were fatigue (n=10, 6.3%) and diarrhea (n=9, 5.6%). Five participants reported a total of 11 serious AEs, none considered drug-related. One participant experienced on-treatment alanine aminotransferase/aspartate aminotransferase elevations that resolved without intervention. Data from the present study indicate that the combination of RZR 60 mg plus UPR 450 mg once daily for 12 weeks was well-tolerated overall but was effective only for certain genotypes. This article is protected by copyright. All rights reserved.

PMID: 30739366 [PubMed - as supplied by publisher]

Acute tubulointerstitial nephritis caused by rifampicin: An increasing and often overlooked side effect in elderly patients
.

Int J Clin Pharmacol Ther. 2019 Feb 10;:

Authors: Nagata M, Ohji G, Iwata K

Abstract
BACKGROUND: There are many side effects of antituberculous drugs, however, renal failure is relatively rare. Therefore, this side effect is thought to be unrecognized by most physicians. We experienced one case of acute renal failure caused by antituberculous therapy (rifampicin).
CASE REPORT: A 64-year-old Japanese male developed tuberculous pleuritis. Six weeks after starting isoniazid (INH), rifampicin (RFP), and ethambutol (EB), his renal function worsened. We temporarily stopped antituberculous therapy, but the patient's renal failure did not improve, and he was admitted to our hospital for renal biopsy. Renal pathology indicated a diagnosis of acute interstitial nephritis. After starting prednisolone, his renal function slowly improved while INH was continued. A drug-induced lymphocyte stimulation test (DLST) of the antituberculous drugs did not reveal the causative agent. However, we consider RFP to be the most likely culprit.
CONCLUSION: In recent reports, renal failure is not a rare complication during antituberculous treatment in the elderly population. Physicians who are involved with the administration of antituberculous therapy have to be aware of this side effect. DLST is not useful for identifying the causative agent of antituberculous drug side effects. Leukocyte migration test may be more useful than DLST for this purpose, but further clinical studies are necessary to verify effectiveness.
.

PMID: 30738495 [PubMed - as supplied by publisher]

Safety and efficacy of glecaprevir/pibrentasvir in patients with chronic hepatitis C genotypes 1-6 receiving opioid substitution therapy.

Int J Drug Policy. 2019 Feb 05;66:73-79

Authors: Grebely J, Dore GJ, Alami NN, Conway B, Dillon JF, Gschwantler M, Felizarta F, Hézode C, Tomasiewicz K, Fredrick LM, Dumas EO, Mensa FJ

Abstract
BACKGROUND: International guidelines recommend treatment of hepatitis C virus (HCV) infection in people who inject drugs (PWID), including those on opioid substitution therapy (OST). The pangenotypic combination of glecaprevir and pibrentasvir has shown high sustained virologic response at post-treatment Week 12 (SVR12) in clinical trials. Herein, we evaluate the safety and efficacy of glecaprevir/pibrentasvir in patients receiving OST.
METHODS: Pooled data from patients with HCV genotypes 1-6 who were treated with glecaprevir/pibrentasvir for 8, 12, or 16 weeks in eight Phase 2 and 3 trials were categorized by use of OST. Treatment completion, treatment adherence, SVR12, adverse events (AEs), and laboratory abnormalities were evaluated for patients receiving and not receiving OST.
RESULTS: Among 2256 patients, 157 (7%) were receiving OST. Compared with patients not receiving OST, OST patients were younger (mean age, 46.8 vs 52.8 years), male (69% vs 54%), white (93% vs 80%), HCV treatment-naïve (86% vs 72%), had HCV genotype 3 (60% vs 26%), and had a history of depression or bipolar disorder (43% vs 19%). Most patients completed (OST: 98% [n/N = 154/157]; non-OST: 99% [n/N = 2070/2099]) and were adherent (received ≥90% of study drug doses) to glecaprevir/pibrentasvir treatment (OST: 98% [n/N = 121/123]; non-OST: 99% [n/N = 1884/1905] among patients with available data). In the intention-to-treat population, SVR12 rates in OST and non-OST patients were 96.2% (n/N = 151/157; 95% CI 93.2-99.2) and 97.9% (n/N = 2055/2099; 95% CI 97.3-98.5), respectively. For OST patients, reasons for nonresponse included virologic relapse (<1%; n = 1), premature study drug discontinuation (<1%; n = 1), and loss to follow-up (3%; n = 4). AEs occurring in ≥10% of OST patients were headache, fatigue, and nausea. Drug-related serious AEs, AEs leading to study drug discontinuation, and Grade 3 or higher laboratory abnormalities were infrequent in both groups (<1%). No HCV reinfections occurred through post-treatment Week 12.
CONCLUSION: Glecaprevir/pibrentasvir is highly efficacious and well tolerated in HCV-infected patients receiving OST.

PMID: 30735896 [PubMed - as supplied by publisher]

Safety of eribulin as third-line chemotherapy in HER2-negative, advanced breast cancer pre-treated with taxanes and anthracycline: OnSITE study.

Breast J. 2019 Feb 08;:

Authors: Manso L, Moreno Antón F, Izarzugaza Perón Y, Delgado Mingorance JI, Borrega García P, Echarri González MJ, Martínez-Jañez N, López-González A, Olier Garate C, Ballesteros García A, Chacón López-Muñíz I, Ciruelos Gil E, García-Sáenz JA, Paz-Ares L

Abstract
Eribulin is active and safe in heavily pre-treated metastatic breast cancer patients. Few safety data have been published in third line. We aimed to report the specific safety profile on third line beyond taxanes and anthracyclines in advanced breast cancer (ABC). A multicenter phase II, prospective study was conducted in anthracyclines and taxanes pre-treated HER2-negative ABC, programmed to receive eribulin as third-line chemotherapy. Adverse events (AEs) were assessed and classified according to CTCAE. In addition, efficacy, in terms of overall survival (OS) and progression-free survival (PFS), and the dynamics of circulating tumor cells (CTCs) during treatment were assessed. 59 patients fulfilled the criteria. All but one showed AEs with a cumulative number of 598 AEs. The most frequent grade 3/4 drug-related AEs were neutropenia (1.7%), febrile neutropenia (0.5%), leukopenia (0.5%), alopecia (0.5%), asthenia (0.3%), elevated gamma glutamyl transferase levels (0.2%), and respiratory tract infection (0.2%). Median PFS was 4 months (95% CI 3.1-5.9) and median OS was 13.6 months (11.8-not reached). The mean number of CTCs in peripheral blood was significantly reduced from baseline to cycle 2 (16.8 vs 5.4 CTCs; P < 0.001). Median OS was significantly longer in <5 baseline CTC patients compared to ≥5 baseline CTC patients (13.1 months [95% CI: 11.8-not reached] vs 12.5 months [95% CI: 7.6-not reached]; P = 0.045). A significant correlation (P = 0.0129) was observed between CTC levels at cycle 2 and death when CTCs were analyzed using cox regression. Eribulin chemotherapy is effective and safe as third line in advanced HER2-negative breast cancer. CTC levels correlate with overall survival.

PMID: 30734437 [PubMed - as supplied by publisher]

Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial.

Lancet Infect Dis. 2019 Feb 04;:

Authors: Aboud M, Kaplan R, Lombaard J, Zhang F, Hidalgo JA, Mamedova E, Losso MH, Chetchotisakd P, Brites C, Sievers J, Brown D, Hopking J, Underwood M, Nascimento MC, Punekar Y, Gartland M, Smith K

Abstract
BACKGROUND: Doubts exist regarding optimal second-line treatment options for HIV-1-infected patients in resource-limited settings. We assessed safety and efficacy of dolutegravir compared with ritonavir-boosted lopinavir, plus two nucleoside reverse transcriptase inhibitors (NRTIs) in adults in whom previous first-line antiretroviral therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two NRTIs has failed.
METHODS: DAWNING is a phase 3b, open-label, parallel-group, non-inferiority, active-controlled trial done at 58 sites in 13 countries. Eligible adults were aged at least 18 years and, during at least 6 months of treatment with a first-line treatment containing an NNRTI and two NRTIs, had virological failure (confirmed HIV-1 RNA ≥400 copies per mL). Participants were randomly assigned by a central randomisation system to receive oral dolutegravir (50 mg once daily) or ritonavir-boosted lopinavir (800 mg lopinavir plus 200 mg ritonavir once daily or 400 mg plus 100 mg twice daily), plus two investigator-selected NRTIs (at least one fully active based on resistance testing at screening). The primary outcome was the proportion of participants achieving viral suppression (defined as plasma HIV-1 RNA <50 copies per mL) at week 48 using the snapshot algorithm and a non-inferiority margin of -12%. The primary analysis was done in an intention-to-treat-exposed (ITT-E) population of participants who received at least one dose of study medication, according to original group assignment. Safety was analysed in all participants who received at least one dose of study drug, according to which drug was received. The study was registered at ClinicalTrials.gov, number NCT02227238, and viiv-studyregister.com, number 200304.
FINDINGS: Between Dec 11, 2014, and June 27, 2016, 968 adults were screened and 627 were randomly assigned to the dolutegravir group (n=312) or the ritonavir-boosted lopinavir group (n=315). Three patients in the ritonavir-boosted lopinavir group did not receive study medication and so 624 were included in the ITT-E population. At week 48, 261 (84%) of 312 participants in the dolutegravir group achieved viral suppression compared with 219 (70%) of 312 in the ritonavir-boosted lopinavir group (adjusted difference 13·8%; 95% CI 7·3-20·3). Non-inferiority was achieved on the basis of the 95% CI of the adjusted treatment difference having a lower bound greater than -12% (prespecified non-inferiority margin). Because the lower bound of the 95% CI is greater than zero (7·3%), superiority of dolutegravir was also concluded (p<0·0001). The safety profile for dolutegravir was favourable compared with that of ritonavir-boosted lopinavir. More grade 2-4 drug-related adverse events occurred with ritonavir-boosted lopinavir than dolutegravir (44 [14%] of 310 with ritonavir-boosted lopinavir vs 11 [4%] of 314 with dolutegravir), mainly driven by gastrointestinal disorders.
INTERPRETATION: When administered with two NRTIs, dolutegravir was superior to ritonavir-boosted lopinavir at 48 weeks and can be considered a suitable option for second-line treatment.
FUNDING: ViiV Healthcare.

PMID: 30732940 [PubMed - as supplied by publisher]

Roles of Moringa oleifera Leaf Extract in Improving the Impact of High Dietary Intake of Monosodium Glutamate-Induced Liver Toxicity, Oxidative Stress, Genotoxicity, DNA Damage, and PCNA Alterations in Male Rats.

Oxid Med Cell Longev. 2018;2018:4501097

Authors: Albrahim T, Binobead MA

Abstract
It is common for food to be made more palatable through the use of the flavour enhancer monosodium glutamate, also known as vetsin powder. The purpose of the study described in this paper was to explore how vetsin-induced hepatic toxicity, DNA fragmentation, damage, and oxidative stress modifications could be mitigated with moringa leaf extract (MLE). To that end, 40 male rats were separated into four groups: normal control, positive control or MLE, vetsin, and vetsin combined with MLE. Results indicated that, compared to the control group, the levels of serum alanine aminotransferase (ALT), aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), liver malondialdehyde (MDA), DNA damage, injury, PCNA, and P53 expressions were significantly enhanced by the administration of vetsin (P < 0.05). However, the vetsin group had significantly reduced levels of albumin, globulin, total protein, liver glutathione (GSH), superoxide dismutase enzyme (SOD), catalase, and glutathione S-transferase (GST) enzyme activities (P < 0.05) by comparison to control. Meanwhile, modifications in liver functions, oxidative stress, DNA damage, liver injury, and PCNA expression were alleviated when vetsin was administered alongside MLE. The authors conclude that vetsin may have many side effects and that MLE can ameliorate biochemical changes, oxidative stress, hepatic injury, PCNA, and P53 alterations induced by vetsin administration.

PMID: 30647808 [PubMed - indexed for MEDLINE]

Effects of Shengmai injection add-on therapy to chemotherapy in patients with non-small cell lung cancer: a meta-analysis.

Support Care Cancer. 2018 Jul;26(7):2103-2111

Authors: Duan B, Xie J, Rui Q, Zhang W, Xi Z

Abstract
PURPOSE: Shengmai injection (SMI) has shown promising outcomes in the management of non-small cell lung cancer (NSCLC). This meta-analysis aimed to investigate the add-on effects of SMI to chemotherapy in NSCLC patients.
METHODS: A comprehensive literature search was performed in the Cochrane Library, PubMed, Embase, CNKI, VIP, and Wanfang up to December 2017. Only randomized controlled trials (RCTs) evaluating SMI in combination with chemotherapy versus chemotherapy alone in NSCLC patients were eligible. The outcome measures were quality of life, chemotherapy-induced grade 3/4 myelosuppression or gastrointestinal reactions, and objective tumor response (equals complete response plus partial response). Pooled risk ratio (RR) with 95% confidence interval (CI) was used to evaluate dichotomous and continuous outcome, respectively.
RESULTS: A total of 15 RCTs were included and analyzed. Meta-analysis showed that SMI combined with chemotherapy was associated with a significant improvement in Karnofsky Performance Status (RR 2.36; 95% CI 1.50-3.96) compared with the chemotherapy alone. Moreover, adjunctive treatment with SMI significantly reduced grade 3/4 myelosuppression (RR 0.61; 95% CI 0.46-0.81) and gastrointestinal reactions (RR 0.64; 95% CI 0.46-0.90). However, there was no significant difference in objective tumor response (RR 1.17; 95% CI 0.99-1.37) between two groups.
CONCLUSIONS: SMI add-on therapy appeared to be more effective in improving quality of life and reducing chemotherapy-induced adverse effects. However, more well-designed RCTs are warranted to confirm the findings of this meta-analysis because of the suboptimal methodological quality of the included trials.

PMID: 29594484 [PubMed - indexed for MEDLINE]

Antiarrhythmic drugs-clinical use and clinical decision making: a consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and International Society of Cardiovascular Pharmacotherapy (ISCP).

Europace. 2018 05 01;20(5):731-732an

Authors: Dan GA, Martinez-Rubio A, Agewall S, Boriani G, Borggrefe M, Gaita F, van Gelder I, Gorenek B, Kaski JC, Kjeldsen K, Lip GYH, Merkely B, Okumura K, Piccini JP, Potpara T, Poulsen BK, Saba M, Savelieva I, Tamargo JL, Wolpert C, ESC Scientific Document Group

PMID: 29438514 [PubMed - indexed for MEDLINE]

Sociodemographic Information, Aversive and Traumatic Events, Offence-Related Characteristics, and Mental Health of Delinquent Women in Forensic-Psychiatric Care in Switzerland.

Int J Offender Ther Comp Criminol. 2018 09;62(12):3815-3833

Authors: Krammer S, Eisenbarth H, Fallegger C, Liebrenz M, Klecha D

Abstract
The present study describes a much understudied group-namely, female prisoners under forensic-psychiatric care in the German-speaking part of Switzerland-to improve understanding of their risks and their needs. Data were derived from internal databases of a Forensic-Psychiatric Service. Data were collected in the form of their sociodemographic characteristics, prevalence of aversive and traumatic events, type of offence committed, and mental health conditions. Based on a full-sample approach, a total of 1,571 files were analysed. Results reveal that two thirds of the participants were not in a stable relationship, more than half did not complete a school degree, and three quarters were without stable employment prior to their incarceration. Two thirds were mothers and about one third did not grow up with their parents. Almost half grew up with an alcohol abusing parent, about half experienced violence and/or neglect in childhood, and about a quarter of the cases sexual abuse. About 95% had a mental health diagnosis according to International Classification of Diseases-Version 10 (ICD-10), and the most prevalent mental and behavioural disorder was due to psychoactive substance abuse. The most frequent offence type was drug-related crimes. Women convicted for drug-related crimes were more likely to have an ICD-10 F1 disorder compared with those convicted for other crimes. Conversely, women with violent offences were less likely to suffer from ICD-10 F1 disorder than those who had committed nonviolent offences. Findings have implications for practitioners and policy makers, and contribute to the cycle of violence theory discussion. In conclusion, future research areas are suggested.

PMID: 29284379 [PubMed - indexed for MEDLINE]

Protective effects of agomelatine on testicular damage caused by bortezomib.

Biotech Histochem. 2017;92(8):552-559

Authors: Akaras N, Bal T, Atilay H, Selli J, Halici MB

Abstract
Bortezomib is a chemotherapeutic agent used to treat several cancers; however, it exhibits severe side effects in testicular tissue. We investigated the use of agomelatine to prevent testicular tissue damage caused by bortezomib. We used 36 male Sprague-Dawley rats divided randomly into six equal groups: group 1, no treatment control; group 2, agomelatine treatment only; group 3, bortezomib treatment only for 48 h; group 4, bortezomib + agomelatine treatment for 48 h; group 5, bortezomib treatment only for 72 h; and group 6, bortezomib + agomelatine treatment for 72 h. After treatments, the rats were sacrificed and testicular tissue was harvested. Lipid oxidation (LPO) and superoxide dismutase (SOD) levels in the tissues were determined using biochemical methods. Tissue samples also were examined using histopathological and immunohistochemical techniques. The LPO level was increased, while the SOD level was decreased in the bortezomib treated groups. We found that agomelatine treatment normalized LPO and SOD activities in the bortezomib treated groups. In the spermatogonia and Sertoli cells, the staining density of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and caspase 3 were decreased in the bortezomib + agomelatine groups at both 48 and 72 h compared to bortezomib only treated groups. We observed maturation arrest, basal membrane thickening, increase in inflammatory cells and connective tissue, and edema between germ cells in the bortezomib only treated groups. By contrast, normal basal membrane, less edema and more normal maturation were observed in the bortezomib + agomelatine groups at 48 and 72 h. We found that agomelatine reduced the damaging effects of bortezomib. The use of agomelatine to prevent bortezomib induced testicular tissue damage in human patients should be investigated further.

PMID: 29161153 [PubMed - indexed for MEDLINE]

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