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]

A PHASE IIA STUDY REPOSITIONING DESIPRAMINE IN SMALL CELL LUNG CANCER AND OTHER HIGH-GRADE NEUROENDOCRINE TUMORS.

Cancer Treat Res Commun. 2020 Apr 20;23:100174

Authors: Riess JW, Jahchan NS, Das M, Zach Koontz M, Kunz PL, Wakelee HA, Schatzberg A, Sage J, Neal JW

Abstract
BACKGROUND: A bioinformatics approach identified antitumor effects of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinomas) (G3NEC) that was subsequently validated in preclinical models with a putative mechanism of action via inhibition of neuroendocrine signaling pathways. This study was undertaken to reposition the candidate TCA desipramine in a clinical trial in SCLC and G3NEC.
METHODS: In this prospective, phase IIa intrapatient dose escalation clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC. Treatment with desipramine began at 75 mg nightly with escalation in increments of 75 mg weekly to a maximum of 450 mg daily.
RESULTS: Six patients were enrolled, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreas). Tolerability of desipramine was worse than predicted. Of the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 neurocognitive adverse events. Median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6).
CONCLUSIONS: No clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated. Intolerable low and medium grade neurocognitive side effects led to intermittent treatment and early discontinuation in most patients; given this limitation, doses achieved may be inadequate compared to the preclinical studies.
MICROABSTRACT: A bioinformatics approach previously identified a potential antitumor effect of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinoma) (G3NEC), which was validated in preclinical models. In this prospective, phase IIa clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC (Ki-67 ≥ 20% or ≥ 20 mitoses/10 HPF). Treatment with desipramine began at 75 mg nightly with escalation by 75 mg weekly to a maximum dose of 450 mg daily. Six patients were enrolled on this clinical trial, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreatic). Tolerability of desipramine was worse than predicted. In the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 drug related dizziness, confusion, and somnolence. Though numbers are small, median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6). Although preclinical evidence was promising, no clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated.

PMID: 32413603 [PubMed - as supplied by publisher]

A phase 1b study of the MET inhibitor capmatinib combined with cetuximab in patients with MET-positive colorectal cancer who had progressed following anti-EGFR monoclonal antibody treatment.

Invest New Drugs. 2020 May 14;:

Authors: Delord JP, Argilés G, Fayette J, Wirth L, Kasper S, Siena S, Mesia R, Berardi R, Cervantes A, Dekervel J, Zhao S, Sun Y, Hao HX, Tiedt R, Vicente S, Myers A, Siu LL

Abstract
Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positive mCRC who had progressed following anti-EGFR mAb treatment received escalating oral doses of capmatinib (150, 300, and 400 mg) twice daily plus weekly intravenous cetuximab (at the approved dose). The primary objective was to establish a recommended dose for expansion (RDE) of capmatinib in combination with cetuximab. Safety, preliminary activity, pharmacokinetics, and pharmacodynamics were also explored. Results Thirteen patients were enrolled. No patients experienced a dose-limiting toxicity at investigated doses; the RDE was established as capmatinib 400 mg twice daily plus cetuximab. All patients experienced adverse events (AEs) suspected to be related to the study treatment. Five patients (38.5%) reported study-drug-related AEs of grade 3/4 in severity. No patients achieved a complete or partial response according to RECIST v1.1; however, tumor shrinkage of 29-44% was observed in 4 patients. Conclusions Capmatinib plus cetuximab was well tolerated. Preliminary signs of activity were observed. Further investigation is warranted to obtain efficacy data and refine predictive biomarkers of response. Clinical trial registration NCT02205398.

PMID: 32410080 [PubMed - as supplied by publisher]

Real-life study of safety of thiopurine-allopurinol combination therapy in inflammatory bowel disease: myelotoxicity and hepatotoxicity rarely affect maintenance treatment.

Aliment Pharmacol Ther. 2019 08;50(4):407-415

Authors: Kreijne JE, de Veer RC, de Boer NK, Dijkstra G, West R, Moorsel SAW, de Jong DJ, van der Woude CJ, de Vries AC, of the Dutch Initiative on Crohn, Colitis (ICC)

Abstract
BACKGROUND: Low-dose thiopurine-allopurinol (LDTA) combination therapy is a commonly applied optimisation strategy in IBD patients with a skewed thiopurine metabolism.
AIM: To assess continued LDTA maintenance treatment at annual intervals and explore risk factors for treatment cessation METHODS: Adult IBD patients treated with LDTA between 2009 and 2016 were retrospectively included. Data on the incidence of clinical and laboratory adverse events (AEs), including hepatotoxicity and myelotoxicity resulting in imposing LDTA therapy cessation and associated risk factors were collected.
RESULTS: In total, 221 IBD patients (46% male, median age 42 years) were included. Maintenance LDTA treatment was continued in 78% of patients at 1 year (n = 145), 66% at 2 years (n = 83), 57% at 3 years (n = 52) and 52% at 4 years (n = 33). Treatment in patients receiving LDTA therapy for AEs during thiopurine monotherapy was more often continued than in patients initiating LDTA for other indications (eg, ineffectiveness of thiopurine monotherapy, routinely discovered skewed metabolism) (P = 0.016). Myelotoxicity during thiopurine monotherapy resolved in 87% and hepatotoxicity in 86% after median of 1.2 and 1.4 months after LDTA initiation. Cumulative incidence of AEs during LDTA resulting in therapy cessation within total follow-up of 449 treatment-years was 7% for clinical AEs, 4% for myelotoxicity and 1% for hepatotoxicity.
CONCLUSION: LDTA therapy is a safe and beneficial optimisation strategy in IBD patients. Continued maintenance LDTA treatment is 52% after 4 years of treatment and most commonly affected by ineffectiveness of LDTA rather than LDTA-attributed toxicity. LDTA optimisation strategy is most advantageous in patients failing thiopurine monotherapy due to AEs.

PMID: 31359480 [PubMed - indexed for MEDLINE]