Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing's syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial.

Lancet Diabetes Endocrinol. 2019 11;7(11):855-865

Authors: Fleseriu M, Pivonello R, Elenkova A, Salvatori R, Auchus RJ, Feelders RA, Geer EB, Greenman Y, Witek P, Cohen F, Biller BMK

Abstract
BACKGROUND: Levoketoconazole is a ketoconazole stereoisomer in development for treatment of Cushing's syndrome and has not been assessed previously in a clinical trial in patients with Cushing's syndrome. We aimed to investigate the efficacy and safety of levoketoconazole in patients with endogenous Cushing's syndrome.
METHODS: SONICS is a phase 3, multicentre, open-label, non-randomised, single-arm study in which we recruited adults (≥18 years) with confirmed Cushing's syndrome and a mean 24-h urinary free cortisol (mUFC) of at least 1·5 times the upper limit of normal from 60 hospital and community sites in 19 countries (15 countries in Europe, and Canada, Israel, Turkey, and the USA). Patients were treated with oral levoketoconazole in a 2-21 week incremental dose-titration phase starting at 150 mg twice daily (150 mg increments until mUFC normalisation, maximum 600 mg twice daily) and a 6-month maintenance phase. The primary outcome was the proportion of patients with mUFC normalisation at end of maintenance, without dose increase during the maintenance phase (in the intention-to-treat population). Prespecified adverse events of special interest were potential liver toxicity, corrected QT prolongation, and adrenal insufficiency. This trial is registered with ClinicalTrials.gov, NCT01838551.
FINDINGS: Between July 30, 2014, and June 30, 2017, 201 individuals were screened and 94 patients were enrolled and received at least one dose of study medication. Of the 94 patients, 80 (85%) had pituitary Cushing's syndrome. Mean mUFC at baseline was 671·4 nmol/24 h (243·3 μg/24 h), which is 4·9 times the upper limit of normal. Of the 77 patients who advanced to the maintenance phase, 62 (81%) had mUFC normalisation by end-of-dose titration. At the end of the 6-month maintenance phase, 29 (31%) of 94 patients were responders; the least-squares mean estimate of the proportion of responders was 0·30 (95% CI 0·21-0·40; p=0·0154 vs null hypothesis of ≤0·20). The most common adverse events in the 94 patients were nausea (30 [32%]) and headache (26 [28%]). Adverse events led to study discontinuation in 12 (13%) of 94 patients. Two patients had a QT interval (Fridericia corrected) of more than 500 ms, and three patients had suspected adrenal insufficiency. Alanine aminotransferase reversibly increased to more than three times the upper limit of normal in ten (11%) patients. Four patients had serious adverse events that were considered probably or definitely related to the study drug: abnormal liver function test results (n=1), prolonged QT interval (n=2), and adrenal insufficiency (n=1). One person died from colon carcinoma unrelated to study medication.
INTERPRETATION: Twice-daily oral levoketoconazole treatment led to sustained improvements in urinary free cortisol, with an acceptable safety and tolerability profile. Levoketoconazole might represent a useful therapeutic option for the medical treatment of Cushing's syndrome.
FUNDING: Strongbridge Biopharma.

PMID: 31542384 [PubMed - indexed for MEDLINE]

17 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")

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Role of Thiopurines in Pediatric Inflammatory Bowel Diseases: A Real-Life Prospective Cohort Study.

J Pediatr Gastroenterol Nutr. 2020 Jun;70(6):825-832

Authors: Atia O, Ledder O, Ben-Moshe T, Lev-Tzion R, Rachmen Y, Meyer EO, Beeri R, Renbaum P, Shamasneh I, Shteyer E, Turner D

Abstract
OBJECTIVES: Use of thiopurines for inflammatory bowel diseases (IBDs) is declining in some parts of the world. We aimed to explore outcomes of thiopurines and predictors of response in a real-world prospective cohort of children with dose optimization.
METHODS: Children with IBD treated with thiopurines without biologics were enrolled. Dosing was guided by thiopurine S-methyltransferase-activity at baseline and by clinical response and toxicity at 4 months; 1 year into the study, therapeutic drug monitoring at 4 months was also considered in the decision making. The primary outcome was steroid-free remission without treatment escalation by 12 months (SFR), using the intention-to-treat approach.
RESULTS: A total of 129 children were included (74% Crohn disease [CD] and 26% ulcerative colitis [UC]). SFR was achieved in 37 (39%) CD and 13 (39%) UC patients, and SFR with normal erythrocyte sedimentation rate/C-reactive protein in 20 (21%) and 9 (27%), respectively. At 4 months, mean corpuscular volume/white blood cell ratio and Δ absolute neutrophil count weakly correlated with 6-thioguanine (r = 0.33, P = 0.02 and r = 0.32, P = 0.02, respectively). In CD, SFR was associated with 4-month median weighted Pediatric Crohn Disease Activity Index (2.5 [IQR 0-7.5] in responders vs 5 in nonresponders [0-12.5], P = 0.048) and Δabsolute neutrophil count (1.7 [IQR 0.7-4.1] vs 0.05 [-2.3-0.9]; P = 0.03). Mild drug-related adverse events were recorded in 30 children (22%), 3 required stopping the drug.
CONCLUSIONS: In this real-life prospective cohort using dose optimization, thiopurines were safe and effective in 21% of CD and 27% of UC patients, including normalization of C-reactive protein and erythrocyte sedimentation rate. Thiopurines remain a viable option in the treatment algorithm of mild-moderate pediatric IBD, especially in girls whose risk for lymphoma is lower.

PMID: 32443042 [PubMed - as supplied by publisher]

Drug-Related Hypertension Associated with the Efficacy of Apatinib on Hepatocellular Carcinoma.

Cancer Manag Res. 2020;12:3163-3173

Authors: Yang X, Hou Z, Zhu K, Zhang S, Gu X, Wang Z, Mu H, Zhou H, Chen P, Zhu X, Cui Y, Li Q, Li H, Zhang T

Abstract
Purpose: We retrospectively evaluated the efficacy and safety of apatinib as a first-line treatment for advanced hepatocellular carcinoma (HCC) and explored whether drug-related hypertension (HTN) could predict its efficacy.
Patients and Methods: This retrospective analysis included patients with advanced HCC who received oral treatment with apatinib. We evaluated the effectiveness by overall survival (OS), progression-free survival (PFS), time to progression (TTP), and disease control rate (DCR), and assessed the safety of the drug based on the occurrence of adverse events. In order to explore whether apatinib-related HTN can be used as a predictor of therapeutic effect, patients were divided into an HTN group and a non-HTN group and adjusted for propensity score-matched (PSM) to reduce mixed deviation. Subgroup analyses of negative prognostic factors for advanced HCC were also performed, including alpha-fetoprotein (AFP), Child-Pugh Score, macrovascular invasion, and extrahepatic metastasis.
Results: A total of 208 patients were analyzed, of which 40.9% (n =85) developed drug-related HTN. For all patients, the OS was 13.4 months (95% CI, 12.2-14.6), the PFS was 5.7 months (95% CI, 5.1-6.3), and the TTP was 6.9 months (95% CI, 6.0-7.8). The OS of the HTN group and the non-HTN group was 17.4 months (m) and 12.5m (p=0.001), and the PFS was 7.4m and 4.7m (p=0.000), respectively. After PSM, the OS (p=0.001) and PFS (p=0.003) of the HTN group were still significantly better than the non-HTN group. Subgroup analysis suggested that overall survival was significantly longer in patients with HTN when serum AFP ≤400 μg/L or extrahepatic metastases. Moreover, OS in the HTN group increased significantly with or without macrovascular invasion. In addition, through the analysis of two groups of patients with PFS>6m and PFS≤6m, we know that the patients with drug-related HTN may develop resistance later, so they have longer survival time.
Conclusion: Apatinib demonstrates compelling anti-cancer activity and acceptable safety in advanced HCC. Apatinib-related HTN can potentially predict prolonged survival in patients with advanced HCC.

PMID: 32440214 [PubMed]

How Did Research on Medication Safety in Pregnancy Define, Develop and Advance the Field of Pharmacoepidemiology?

Clin Ther. 2019 12;41(12):2464-2466

Authors: Willey C, Calip GS

PMID: 31810581 [PubMed - indexed for MEDLINE]

Lack of adverse effects in subchronic and chronic toxicity/carcinogenicity studies on the glyphosate-resistant genetically modified maize NK603 in Wistar Han RCC rats.

Arch Toxicol. 2019 04;93(4):1095-1139

Authors: Steinberg P, van der Voet H, Goedhart PW, Kleter G, Kok EJ, Pla M, Nadal A, Zeljenková D, Aláčová R, Babincová J, Rollerová E, Jaďuďová S, Kebis A, Szabova E, Tulinská J, Líšková A, Takácsová M, Mikušová ML, Krivošíková Z, Spök A, Racovita M, de Vriend H, Alison R, Alison C, Baumgärtner W, Becker K, Lempp C, Schmicke M, Schrenk D, Pöting A, Schiemann J, Wilhelm R

Abstract
In 2012, a controversial study on the long-term toxicity of a Roundup herbicide and the glyphosate-tolerant genetically modified (GM) maize NK603 was published. The EC-funded G-TwYST research consortium tested the potential subchronic and chronic toxicity as well as the carcinogenicity of the glyphosate-resistant genetically modified maize NK603 by performing two 90-day feeding trials, one with GM maize inclusion rates of 11 and 33% and one with inclusion rates of up to 50%, as well as a 2-year feeding trial with inclusion rates of 11 and 33% in male and female Wistar Han RCC rats by taking into account OECD Guidelines for the testing of chemicals and EFSA recommendations on the safety testing of whole-food/feed in laboratory animals. In all three trials, the NK603 maize, untreated and treated once with Roundup during its cultivation, and the conventional counterpart were tested. Differences between each test group and the control group were evaluated. Equivalence was assessed by comparing the observed difference to differences between non-GM reference groups in previous studies. In case of significant differences, whether the effects were dose-related and/or accompanied by changes in related parameters including histopathological findings was evaluated. It is concluded that no adverse effects related to the feeding of the NK603 maize cultivated with or without Roundup for up to 2 years were observed. Based on the outcome of the subchronic and combined chronic toxicity/carcinogenicity studies, recommendations on the scientific justification and added value of long-term feeding trials in the GM plant risk assessment process are presented.

PMID: 30756133 [PubMed - indexed for MEDLINE]

Effect of Selective IK,ACh Inhibition by XAF-1407 in an Equine Model of Tachypacing-induced Persistent Atrial Fibrillation (AF).

Br J Pharmacol. 2020 May 20;:

Authors: Fenner MF, Carstensen H, Nissen SD, Hesselkilde EZ, Lunddahl C, Jensen MA, Loft-Andersen AV, Sattler SM, Platonov PG, El-Haou S, Jackson C, Tang R, Kirby R, Ford JW, Schotten U, Milnes JT, Sørensen US, Jespersen T, Buhl R

Abstract
BACKGROUND AND PURPOSE: Inhibition of the G-protein gated acetylcholine-activated inward rectifier potassium (K+ ) current, IK,ACh , may be an effective atrial selective treatment strategy for atrial fibrillation. Therefore, the anti-arrhythmic and electrophysiological properties of a novel putatively potent and highly specific IK,ACh inhibitor, XAF-1407 (3-methyl-1-[5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]azetidin-3-ol), were characterised for the first time in vitro and investigated in an in vivo equine, atrial-tachypacing-induced model of persistent AF in the following.
EXPERIMENTAL APPROACH: The in vitro ion channel pharmacological profile of XAF-1407, was investigated using cell lines stably expressing Kir 3.1/3.4, Kir 3.4/3.4, Kir 2.1, Kir 6.2/SUR2A, hERG, Kv 1.5, Kv 4.3 and Nav 1.5. A tachypacing induced model of persistent AF in the horse, a large animal model suited to pre-clinical investigations of longer duration AF, was employed to study the in vivo electrophysiological and anti-arrhythmic profile of XAF-1407. Eleven horses were implanted with implantable cardioverter defibrillators (ICD) enabling atrial-tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 were investigated at different time points over a period of one month. Cardioversion success, drug induced changes of atrial tissue refractoriness and ventricular electrophysiology were assessed at baseline (day 0) and at day 3, 5, 11, 17 and 29 after AF induction.
KEY RESULTS: XAF-1407 potently and selectively inhibited Kir 3.1/3.4 hetero- and Kir 3.4 homotetramers, underlying the IK,ACh current. XAF-1407 treatment in horses prolonged atrial effective refractory period (aERP) as well as decreased atrial fibrillatory rate (AFR) significantly by approximately 20% and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened AV-nodal refractoriness, without effect on the QRS duration. A QTc prolongation of 4% within 15 minutes of drug infusion was observed, however, without any evidence of ventricular arrhythmia.
CONCLUSION AND IMPLICATIONS: XAF-1407 efficiently cardioverted sustained tachypacing induced AF of short duration in horses without notable side effects. The study supports IK,ACh inhibition as a potentially safe treatment modality of paroxysmal AF in horses and suggests potential clinical value for other species including humans.

PMID: 32436234 [PubMed - as supplied by publisher]

Transgenic LQT2, LQT5 and LQT2-5 rabbit models with decreased repolarisation reserve for prediction of drug-induced ventricular arrhythmias.

Br J Pharmacol. 2020 May 20;:

Authors: Hornyik T, Castiglione A, Franke G, Perez-Feliz S, Major P, Hiripi L, Koren G, Bősze Z, Varró A, Zehender M, Brunner M, Bode C, Baczkó I, Odening KE

Abstract
BACKGROUND AND PURPOSE: The reliable prediction of pro-arrhythmic side-effects of novel drug candidates represents a major but unsolved challenge. Although drug-induced pro-arrhythmia occurs primarily in patients harbouring repolarisation disturbances, mostly healthy animal models are employed for pro-arrhythmia testing. To improve current safety screening, transgenic long-QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss-of-function mutations of human HERG (HERG-G628S, loss of IKr ; LQT2), KCNE1 (KCNE1-G52R, decreased IKs ; LQT5), or both transgenes (LQT2-5) in the heart.
EXPERIMENTAL APPROACH: The effects of K+ -channel-blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild-type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff-perfused hearts.
KEY RESULTS: LQTS models reflect patients with clinically 'silent' (LQT5) or 'manifest' (LQT2 and LQT2-5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr - (LQT5) or IK1 /IKs - (LQT2 and LQT2-5) blocking properties of drugs compared to healthy WT animals. Impaired QT-shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2-5. Importantly, LQTS models exhibited higher incidence, longer duration and more malignant type of ex vivo arrhythmias than WT.
CONCLUSION AND IMPLICATIONS: LQTS models represent patients with reduced repolarisation reserve due to different patho-mechanisms. As they demonstrate increased sensitivity to different specific ion channel-blockers (IKr -blockade in LQT5, IK1 - and IKs -blockade in LQT2 and LQT2-5), their combined use could provide more reliable, and more thorough prediction of (multi-channel-based) pro-arrhythmic potential of novel drug candidates.

PMID: 32436214 [PubMed - as supplied by publisher]

Impact of DARC, GSDMA and CXCL2 polymorphisms on induction toxicity in children with acute lymphoblastic leukemia: A complementary study.

Leuk Res. 2019 11;86:106228

Authors: Gatineau-Sailliant S, Glisovic S, Gagné V, Laverdière C, Leclerc JM, Silverman LB, Sinnett D, Krajinovic M, Pastore Y

PMID: 31590117 [PubMed - indexed for MEDLINE]

Evaluating dose-limiting toxicities of MDM2 inhibitors in patients with solid organ and hematologic malignancies: A systematic review of the literature.

Leuk Res. 2019 11;86:106222

Authors: Pi L, Rooprai J, Allan DS, Atkins H, Bredeson C, Fulcher AJ, Ito C, Ramsay T, Shorr, Stanford WL, Sabloff M, Christou G

Abstract
INTRODUCTION: Mouse double minute 2 protein (MDM2), a negative regulator of the p53 tumour suppressor gene, is frequently amplified in malignancies. MDM2 antagonists have shown efficacy in treating malignancies with MDM2 overexpression and can overcome chemoresistance in acute myeloid leukemia. We systematically evaluated the safety profile of MDM2 inhibitors in the treatment of solid organ and hematologic malignancies.
MATERIALS AND METHODS: We searched Medline and EMBASE from January 1947 to November 2018 for prospective clinical studies, in English or French, investigating any MDM2 inhibitor in pediatric or adult cancers, and reporting dose and toxicity outcomes. Primary outcome was dose-limiting toxicity (DLT) and secondary outcome was death.
RESULTS: The search yielded 493 non-duplicate citations. Eighteen studies of 10 inhibitors met inclusion criteria (total N = 1005 patients). Two-thirds of included studies did not define DLTs and the reporting of toxicities was highly variable. The most commonly reported DLTs were cytopenias, gastrointestinal toxicity, metabolic disturbances, fatigue and cardiovascular toxicity; there was one death attributed to treatment toxicity.
CONCLUSION: MDM2 antagonists have been studied in a variety of malignancies with toxicities similar to other commonly used chemotherapy agents and may represent a safe adjuvant treatment for further study in in acute leukemia.

PMID: 31522038 [PubMed - indexed for MEDLINE]

Capecitabine in advanced hepatocellular carcinoma: A multicenter experience.

Dig Liver Dis. 2019 12;51(12):1713-1719

Authors: Pelizzaro F, Sammarco A, Dadduzio V, Pastorelli D, Giovanis P, Soldà C, Rizzato MD, Lombardi G, Lonardi S, Peserico G, Imondi A, Sartori A, Maddalo G, Farinati F

Abstract
BACKGROUND: Recent data suggest a potential activity and a good tolerability of capecitabine in advanced hepatocellular carcinoma (HCC).
AIMS: To evaluate capecitabine activity and safety in a wide cohort of advanced HCC patients.
METHODS: Retrospective analysis of 143 capecitabine-treated patients (January 2010 to December 2017) in three centers of the Veneto Oncology Network.
RESULTS: Capecitabine was administered in second and third line, but also in first line instead of sorafenib in Child-Pugh B patients (70%), compromised clinical conditions (14%) or contraindications to antiangiogenetics (16%). Median overall survival (OS) and time to progression (TTP) were 6.9 and 2.8 months, respectively. There were no differences in OS and TTP between the 32 patients treated with non-metronomic scheme (2000 mg/day for 14 days) and the 111 patients treated with metronomic scheme (1000 mg/day) after correction for prognostic factors at baseline with a propensity score analysis. Capecitabine was more active in patients intolerant to sorafenib than in those progressing during treatment (p = 0.024). At least one adverse event (mainly hematological) was experienced by 73% of patients but discontinuation was necessary only in 11 (8%).
CONCLUSIONS: Capecitabine can be considered an active and safe option in advanced HCC, especially for patients unfit for other treatments.

PMID: 31320302 [PubMed - indexed for MEDLINE]

MicroRNA-128-3p aggravates doxorubicin-induced liver injury by promoting oxidative stress via targeting Sirtuin-1.

Pharmacol Res. 2019 08;146:104276

Authors: Zhao X, Jin Y, Li L, Xu L, Tang Z, Qi Y, Yin L, Peng J

Abstract
As one classic anticancer drug, clinical application of Doxorubicin (Dox) is limited due to its side effects. In our previous work, we have investigated the drug targets to treat Dox-induced cardiotoxicity, hepatotoxicity and nephrotoxicity. In this paper, the mechanisms and new drug-target associated with Dox-induced hepatotoxicity were explored. The results showed that Dox markedly inhibited cell viability and cellular respiration, induced cell morphologic change and increased ROS level. Moreover, Dox increased ALT and AST levels, caused pathological damage, increased MDA level and decreased SOD level in mice. Mechanism investigation showed that Dox markedly up-regulated the expression level of miR-128-3p, down-regulated Sirt1 expression level and affected the protein levels of Nrf2, Keap1, Sirt3, NQO1 and HO-1 to cause oxidative stress in liver. Furthermore, double-luciferase reporter assay, and co-transfection test showed that miR-128-3p directly targeted Sirt1. In addition, miR-128-3p mimics in AML-12 cells enhanced Dox-induced oxidative damage via inhibiting cellular respiration, increasing ROS level and mitochondrial superoxide formation. The protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1 in miR-128-3p mimic + Dox group were decreased compared with Dox group. Transfection of miR-128-3p inhibitor weakened Dox-induced oxidative damage via increasing cellular respiration, suppressing cellular ROS level and mitochondrial superoxide formation. The protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1 in miR-128-3p inhibitor + Dox group were increased compared with Dox group. In mice, Dox-induced liver damage was deteriorated by miR-128-3p agomir via increasing the levels of ALT, AST, MDA, and down-regulating the protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1. While, miR-128-3p antagomir alleviated liver injury via decreasing the levels of ALT, AST, MDA, and up-regulating the protein levels of Sirt1, Nrf2, Sirt3, NQO1 and HO-1. Our data showed that miRNA-128-3p aggravated Dox-induced liver injury by promoting oxidative stress via targeting Sirt1, which should be considered as one new drug target to treat Dox-induced liver injury.

PMID: 31112750 [PubMed - indexed for MEDLINE]

Immune-related adverse events predict the therapeutic efficacy of anti-PD-1 antibodies in cancer patients.

Eur J Cancer. 2019 03;109:21-27

Authors: Rogado J, Sánchez-Torres JM, Romero-Laorden N, Ballesteros AI, Pacheco-Barcia V, Ramos-Leví A, Arranz R, Lorenzo A, Gullón P, Donnay O, Adrados M, Costas P, Aspa J, Alfranca A, Mondéjar R, Colomer R

Abstract
BACKGROUND: Cancer immune therapy has shown remarkable benefit in the treatment of a range of cancer types, although it may initiate autoimmune-related disorders in some patients. We have attempted to establish whether the incidence of irAEs after the use of anti-PD-1 antibodies nivolumab or pembrolizumab in advanced malignancies is associated with anti-PD-1 treatment efficacy.
PATIENTS AND METHODS: We studied patients treated with single-agent nivolumab or pembrolizumab for advanced cancer. irAEs (immune-related adverse events) were identified clinically and graded as per the Common Terminology Criteria for Adverse Events version 4.0. Efficacy was evaluated with objective response rate (ORR, immune-Response Evaluation Criteria in Solid Tumours [RECIST] criteria) progression-free survival (PFS) and overall survival (OS). Tests were performed to determine the association between irAEs and ORR, PFS or OS.
RESULTS: We identified 106 patients. Primary diagnoses were lung cancer (n = 77), melanoma (n = 8), head and neck carcinoma (n = 7), renal carcinoma (n = 5), Hodgkin's lymphoma (n = 3), urothelial carcinoma (n = 3) and gallbladder adenocarcinoma, hepatocellular carcinoma and Merkel cell carcinoma (n = 1 each). IrAEs were observed in 40 patients (37.7%). The most frequent irAEs were hypothyroidism (n = 15), nephritis (n = 5) and hyperthyroidism (n = 4). Objective response was observed in 44 patients (41.5%), and median PFS was 5.5 months (0.5-31 months). Thirty-three of the 40 patients with irAEs had objective response (82.5%) in contrast with 11 of the 66 cases without irAEs (16.6%) (OR 23.5, P < 0.000001). PFS in patients with irAEs was 10 months and 3 months in those without irAEs (HR 2.2, P = 0.016). OS in patients with irAEs was 32 months and 22 in those without irAEs, without statistically significant differences.
CONCLUSION: In advanced cancer treated with single-agent anti-PD-1 antibodies, patients with irAEs showed a markedly improved efficacy over patients without irAEs (ORR of 82.5% and PFS of 10 months vs ORR of 16.6% and PFS of 3 months). Future studies of anti-PD-1 immune-therapy should address this association to explore the underlying biological mechanisms of efficacy.

PMID: 30682533 [PubMed - indexed for MEDLINE]

16 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 2020/05/21

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.

15 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 2020/05/21

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.

15 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 2020/05/20

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.

19 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 2020/05/19

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.

Transient dose-dependent effects of ketamine on neural oscillatory activity in Wistar-Kyoto rats.

Neuroscience. 2020 May 14;:

Authors: Manduca JD, Thériault RK, Williams OOF, Rasmussen DJ, Perreault ML

Abstract
Ketamine is a promising therapeutic for treatment-resistant depression (TRD) but is associated with an array of short-term psychomimetic side-effects. These disparate drug effects may be elicited through the modulation of neural circuit activity. The purpose of this study was to therefore delineate dose- and time-dependent changes in ketamine-induced neural oscillatory patterns in regions of the brain implicated in depression. Wistar Kyoto (WKY) rats were used as a model system to study these aspects of TRD neuropathology whereas Wistar rats were used as a control strain. Animals received a low (10 mg/kg) or high (30 mg/kg) dose of ketamine and temporal changes in neural oscillatory activity recorded from the prefrontal cortex (PFC), cingulate cortex (Cg), and nucleus accumbens (NAc) for ninety minutes. Effects of each dose of ketamine on immobility in the forced swim test were also evaluated. High dose ketamine induced a transient increase in theta power in the PFC and Cg, as well as a dose-dependent increase in gamma power in these regions 10-minutes, but not 90-minutes, post-administration. In contrast, only low dose ketamine normalized innate deficits in fast gamma coherence between the NAc-Cg and PFC-Cg, an effect that persisted at 90-minutes post-injection. These low dose ketamine-induced oscillatory alterations were accompanied by a reduction in immobility time in the forced swim test. These results show that ketamine induces time-dependent effects on neural oscillations at specific frequencies. These drug-induced changes may differentially contribute to the psychomimetic and therapeutic effects of the drug.

PMID: 32417341 [PubMed - as supplied by publisher]

A Comparative Study of Rat Urine 1H-NMR Metabolome Changes Presumably Arising from Isoproterenol-Induced Heart Necrosis Versus Clarithromycin-Induced QT Interval Prolongation.

Biology (Basel). 2020 May 13;9(5):

Authors: Dallons M, Delcourt M, Schepkens C, Podrecca M, Colet JM

Abstract
Cardiotoxicity remains a challenging concern both in drug development and in the management of various clinical situations. There are a lot of examples of drugs withdrawn from the market or stopped during clinical trials due to unpredicted cardiac adverse events. Obviously, current conventional methods for cardiotoxicity assessment suffer from a lack of predictivity and sensitivity. Therefore, there is a need for developing new tools to better identify and characterize any cardiotoxicity that can occur during the pre-clinical and clinical phases of drug development as well as after marketing in exposed patients. In this study, isoproterenol and clarithromycin were used as prototypical cardiotoxic agents in rats in order to evaluate potential biomarkers of heart toxicity at very early stages using 1H-NMR-based metabonomics. While isoproterenol is known to cause heart necrosis, clarithromycin may induce QT interval prolongation. Heart necrosis and QT prolongation were validated by histological analysis, serum measurement of lactate dehydrogenase/creatine phosphate kinase and QTc measurement by electrocardiogram (ECG). Urine samples were collected before and repeatedly during daily exposure to the drugs for 1H-NMR based-metabonomics investigations. Specific metabolic signatures, characteristic of each tested drug, were obtained from which potential predictive biomarkers for drug-induced heart necrosis and drug-induced QT prolongation were retrieved. Isoproterenol-induced heart necrosis was characterized by higher levels of taurine, creatine, glucose and by lower levels of Krebs cycle intermediates, creatinine, betaine/trimethylamine N-oxide (TMAO), dimethylamine (DMA)/sarcosine. Clarithromycin-induced QT prolongation was characterized by higher levels of creatinine, taurine, betaine/TMAO and DMA/sarcosine and by lower levels of Krebs cycle intermediates, glucose and hippurate.

PMID: 32414184 [PubMed - as supplied by publisher]

N-Acetyl Cysteine as an Adjunct in the Treatment of Tuberculosis.

Tuberc Res Treat. 2020;2020:5907839

Authors: Ejigu DA, Abay SM

Abstract
Oxidative stress is a common feature of tuberculosis (TB), and persons with reduced antioxidants are at more risk of TB. TB patients with relatively severe oxidative stress had also more advanced disease as measured by the Karnofsky performance index. Since adverse effects from anti-TB drugs are also mediated by free radicals, TB patients are prone to side effects, such as hearing loss. In previous articles, researchers appealed for clinical trials aiming at evaluating N-acetyl cysteine (NAC) in attenuating the dreaded hearing loss during multidrug-resistant TB (MDR-TB) treatment. However, before embarking on such trials, considerations of NAC's overall impact on TB treatment are crucial. Unfortunately, such a comprehensive report on NAC is missing in the literature and this manuscript reviews the broader effect of NAC on TB treatment. This paper discusses NAC's effect on mycobacterial clearance, hearing loss, drug-induced liver injury, and its interaction with anti-TB drugs. Based on the evidence accrued to date, NAC appears to have various beneficial effects on TB treatment. However, despite the favorable interaction between NAC and first-line anti-TB drugs, the interaction between the antioxidant and some of the second-line anti-TB drugs needs further investigations.

PMID: 32411461 [PubMed]