Preparation and antitumor evaluation of quercetin nanosuspensions with synergistic efficacy and regulating immunity.

Int J Pharm. 2020 Aug 30;:119830

Authors: Qiao Y, Cao Y, Yu K, Zong L, Pu X

Abstract
To study the effect of quercetin (QUR) on modulating immune effects, enhancing anti-tumor activity, and reducing drug related side effects, three QUR nanosuspensions (QUR-NPs) with different particle sizes were prepared by a microprecipitation-high pressure homogenization method using mPEG-DCA as a stabilizer. Dynamic light scattering was used to analyze the particle sizes of the three QUR-NPs. The results of stability tests showed that the three QUR-NPs had good storage and plasma stability. It was confirmed that plasma protein adsorption occurred for all three QUR-NPs. The results of DSC, DTG, XRPD, and Raman spectroscopy showed that there was no significant change in the crystal form of QUR for any of the three QUR-NPs compared with the commercial QUR. The in vitro dissolution rate of the three QUR-NPs was significantly faster than that of the micronized QUR, with the dissolution rate increasing as particle size decreased. All three QUR-NPs showed stronger in vitro inhibitory activity on MCF-7 cells than the pure QUR solution, with the largest NPs having the strongest inhibitory effect. The pharmacokinetic parameters in rats showed that the MRT and t1/2 of the QUR-NPs increased as particle size increased. QUR-NPs and the pure QUR solution showed obvious anti-tumor effects against murine hepatic carcinoma H22 model in vivo, although they were not as effective as cyclophosphamide (CTX). However, the anti-tumor effect of the large QUR-NPs combined with CTX was the strongest among all the tested groups. From the results of the thymus and spleen index, it was found that the QUR-NPs could not only regulate the immunity of tumor-bearing mice, but also alleviate the immunosuppression caused by CTX and protect normal tissues, all while enhancing the anti-tumor effect. The immunomodulatory effect of the QUR-NPs on tumor-bearing mice was significantly better than that of the pure QUR solution. Therefore, nanosuspensions can be used as a new drug delivery system for QUR to assist tumor therapy and regulate immunity.

PMID: 32877732 [PubMed - as supplied by publisher]

The assessment of drug safety for the fetus.

Int J Clin Pharm. 2020 Sep 02;:

Authors: Hecht EM

Abstract
Long standing concerns regarding the use of medications during pregnancy and their unknown effects on fetal development and child health suggests the need for modified study methods regarding the establishment of drug safety for the fetus. This Current Commentary highlights several pharmacological study method limitations and offers suggestions for the establishment of drug safety for the fetus. For example, extensive phase 1 pharmacology studies are needed to assess the complex pharmacokinetic relationships between mother and fetus in order to determine injurious doses to the fetus throughout pregnancy. In addition, long term randomized clinical trials are needed to assess the effects medications may have on children following exposure during gestation.

PMID: 32876828 [PubMed - as supplied by publisher]

Long-term safety of vedolizumab for inflammatory bowel disease.

Aliment Pharmacol Ther. 2020 Sep 02;:

Authors: Loftus EV, Feagan BG, Panaccione R, Colombel JF, Sandborn WJ, Sands BE, Danese S, D'Haens G, Rubin DT, Shafran I, Parfionovas A, Rogers R, Lirio RA, Vermeire S

Abstract
BACKGROUND: Vedolizumab, a gut-selective α4 β7 integrin antibody, is approved for moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD).
AIM: To report the final results from the vedolizumab GEMINI long-term safety (LTS) study.
METHODS: The phase 3, open-label GEMINI LTS study (initiated May 2009) enrolled patients with UC or CD from four prior clinical trials and vedolizumab-naïve patients. Vedolizumab LTS was evaluated; efficacy and patient-reported outcomes were exploratory endpoints.
RESULTS: Enrolled patients (UC, n = 894; CD, n = 1349) received vedolizumab 300 mg IV every 4 weeks; median cumulative exposure was 42.4 months (range: 0.03-112.2) for UC and 31.5 months (range: 0.03-100.3) for CD. Over 8 years, adverse events (AEs) occurred in 93% (UC) and 96% (CD) of patients, with UC (36%) and CD (35%) exacerbations most frequent. Serious AEs were reported for 31% (UC) and 41% (CD) of patients. Vedolizumab discontinuation due to AEs occurred in 15% (UC) and 17% (CD) of patients. There were no new trends for infections, malignancies, infusion-related reactions, or hepatic events, and no cases of progressive multifocal leukoencephalopathy. Of the ten deaths (UC, n = 4; CD, n = 6), two were considered drug-related by local investigators (West Nile virus infection-related encephalitis and hepatocellular carcinoma). Continuous vedolizumab maintained clinical response long-term, with 33% (UC) and 28% (CD) of patients in clinical remission at 400 treatment weeks.
CONCLUSIONS: The safety profile of vedolizumab remains favourable with no unexpected or new safety concerns. These results further establish the safety of vedolizumab and support its long-term use (NCT00790933/EudraCT 2008-002784-14).

PMID: 32876349 [PubMed - as supplied by publisher]

Long-term vemurafenib therapy in advanced melanoma patients: cutaneous toxicity and prognostic implications.

J Dermatolog Treat. 2020 Sep 02;:1-19

Authors: Mandel VD, Medri M, Manganoni AM, Pavoni L, De Rosa F, Ribero S, Foca F, Andreis D, Mazzoni L, Magi S, Farnetani F, Palla M, Ulivi P, Stanganelli I

Abstract
Background: The introduction of targeted therapies for the treatment of BRAF-mutated metastatic melanoma was associated with different cutaneous adverse events (AEs).Objectives: To describe the type, frequency and severity of cutaneous AEs related to vemurafenib; to understand the association between AEs and vemurafenib efficacy in terms of median overall survival (OS) and median progression-free survival (PFS); to identify molecular characteristics of long-term responders.Methods: This observational, retrospective, monocentric study included all consecutive patients with unresectable stage III or stage IV melanoma and BRAF V600E mutation that started treatment with vemurafenib between May 2012 and May 2014.Results: 62 patients with a median age of 56 years (range 26-82) were enrolled and received vemurafenib for a median period of 7.9 months (range 0.8-63.7). Among them, 45 patients presented at least one skin AE, 12 reduced the dosage due to cutaneous toxicity, and only one firstly reduced and after stopped the therapy. No specific molecular biomarkers were detected in long-term survivors.Conclusions: Among long-term survivors, skin AEs seem to be less frequent and less severe. Results on multivariable analysis revealed that the presence of at least one G2 toxicity is a protective factor considering PFS, but not in terms of OS.

PMID: 32875931 [PubMed - as supplied by publisher]

A phase 0 analysis of ixazomib in patients with glioblastoma.

Mol Clin Oncol. 2020 Nov;13(5):43

Authors: Quillin J, Patel R, Herzberg E, Alton D, Bikzhanova G, Geisler L, Olson J

Abstract
Improving overall survival in recurrent glioblastoma remains a challenge, and drugs acting by unique mechanisms are urgently required. Ixazomib is an orally-administered proteasome inhibitor used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy. However, ixazomib's ability to reach brain tumors has not been studied during its development. The aim of the present study (ClinicalTrials.gov, NCT02630030) was to establish and quantify ixazomib's presence in glioblastoma. The present study investigated 3 patients with recurrent glioblastoma after administration of oral ixazomib citrate (MLN 9708) at a fixed 4.0 mg dose within a 3-hpreoperative window. A total of 2 blood samples were taken from each patient at the time of incision, tumor sampling and closure. Brain tumor samples were collected during tumor resection. These samples were then used to measure the plasma and brain tumor tissue concentration of the biologically-active form of ixazomib (MLN 2238). Patient 1 had plasma concentrations of ixazomib averaging 26.2, 21.8 and 15.3 ng/ml at incision, tumor sampling and closure, respectively. The brain tumor tissue concentration was 7.88 ng/g. Patient 2 had the same interval and brain tumor tissue measurements of 19.0, 18.0 and 8.93 ng/ml, and 2.03 ng/g. Patient 3 had plasma concentration interval measurements of 25.6, 36.2 and 28.7 ng/ml. Multiple brain tumor tissue samples were taken in patient 3, with an average tissue ixazomib concentration of 3.37 ng/g. Ixazomib was found at plasma concentrations commensurate with its previously established pharmacokinetic profile without clinically relevant drug-related adverse events. Ixazomib reaches glioblastoma tissues at measurable concentrations at the time of tumor resection, confirming target tissue delivery. This justifies the phase I study of ixazomib in recurrent glioblastoma currently in development.

PMID: 32874573 [PubMed]

In silico systems for predicting chemical-induced side effects using known and potential chemical protein interactions, enabling mechanism estimation.

J Toxicol Sci. 2020;45(3):137-149

Authors: Amano Y, Honda H, Sawada R, Nukada Y, Yamane M, Ikeda N, Morita O, Yamanishi Y

Abstract
In silico models for predicting chemical-induced side effects have become increasingly important for the development of pharmaceuticals and functional food products. However, existing predictive models have difficulty in estimating the mechanisms of side effects in terms of molecular targets or they do not cover the wide range of pharmacological targets. In the present study, we constructed novel in silico models to predict chemical-induced side effects and estimate the underlying mechanisms with high general versatility by integrating the comprehensive prediction of potential chemical-protein interactions (CPIs) with machine learning. First, the potential CPIs were comprehensively estimated by chemometrics based on the known CPI data (1,179,848 interactions involving 3,905 proteins and 824,143 chemicals). Second, the predictive models for 61 side effects in the cardiovascular system (CVS), gastrointestinal system (GIS), and central nervous system (CNS) were constructed by sparsity-induced classifiers based on the known and potential CPI data. The cross validation experiments showed that the proposed CPI-based models had a higher or comparable performance than the traditional chemical structure-based models. Moreover, our enrichment analysis indicated that the highly weighted proteins derived from predictive models could be involved in the corresponding functions of the side effects. For example, in CVS, the carcinogenesis-related pathways (e.g., prostate cancer, PI3K-Akt signal pathway), which were recently reported to be involved in cardiovascular side effects, were enriched. Therefore, our predictive models are biologically valid and would be useful for predicting side effects and novel potential underlying mechanisms of chemical-induced side effects.

PMID: 32147637 [PubMed - indexed for MEDLINE]

Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis.

Clin Pharmacokinet. 2019 09;58(9):1103-1129

Authors: Abulfathi AA, Decloedt EH, Svensson EM, Diacon AH, Donald P, Reuter H

Abstract
The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8-12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of ≥ 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg. Rifampicin maximum (peak) concentration (Cmax) > 8.2 μg/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of ≥ 8 µg/mL. A higher rifampicin Cmax is required for severe forms TB such as TB meningitis, with Cmax ≥ 22 μg/mL and area under the concentration-time curve (AUC) from time zero to 6 h (AUC6) ≥ 70 μg·h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were found to be safe and well-tolerated over a period of 12 weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as Cmax/MIC (minimum inhibitory concentration) and AUC/MIC.

PMID: 31049868 [PubMed - indexed for MEDLINE]

Adverse publicity of serious side effects to healthy volunteers has limited effect on willingness-to-participate in clinical trials.

Clin Trials. 2019 08;16(4):440-442

Authors: Molinari N, Suehs C, Vachier I, Pahus L, Halimi L, Gamez AS, Chanez P, Bourdin A

PMID: 30922104 [PubMed - indexed for MEDLINE]

Plasma and red blood cell membrane accretion and pharmacokinetics of RT001 (bis-allylic 11,11-D2-linoleic acid ethyl ester) during long term dosing in patients.

J Pharm Sci. 2020 Aug 29;:

Authors: Brenna JT, James G, Midei M, Heerinckx F, Atwal P, Milner P, Schmidt K, van der Ploeg L, Fielding R, Shchepinov MS

Abstract
RT001 is the di-deutero isotopologue of linoleic acid ethyl ester (D2-LA). Resistance to oxidative damage at the carbon-deuterium bond depends upon the concentration of D2-LA as a percentage of total LA. We report here on the plasma and red cell (RBC) pharmacokinetics (PK) of D2-LA, and its metabolite 13,13-D2-arachidonic acid (D2-AA), in patients with multiple neurodegenerative diseases (total of 59 participants). In Friedreich's ataxia patients, D2-LA was absorbed and transported similarly to dietary LA, peaking at about 6 h after oral dosing. Plasma D2-LA concentrations approached steady state after 28 days of dosing. After 6 months of daily dosing in subjects with other disorders, D2-LA and D2-AA levels were at or above the 20% of total (D2-LA/ total LA, or D2-AA/ total AA) therapeutic targets for most subjects. We conclude that chronic dosing of RT001 and associated dietary guidance can be maintained over many months to achieve target plasma and RBC levels, forming a basis for therapeutic dosing across a broad range of conditions. RT001 has been safe and well-tolerated in 59 different participants treated across 10 different neurodegenerative diseases in multiple clinical trials for up to 36 months with no significant drug related adverse events limiting use.

PMID: 32871154 [PubMed - as supplied by publisher]

Efavirenz-Associated Retinal Toxicity Presenting with Night Vision Defects in Patients with Human Immunodeficiency Virus.

Ocul Immunol Inflamm. 2020 Sep 01;:1-9

Authors: Sudharshan S, Kumar KD, Bhende M, Biswas J, Selvamuthu P

Abstract
Ocular lesions in patients with human immunodeficiency virus (HIV) are commonly due to underlying opportunistic infections. With highly active antiretroviral therapy (HAART), infectious lesions have reduced and noninfectious ocular manifestations including drug-related side effects have been noted. While retinal toxicity has been noted with few other HAART drugs, there are not many on the same with Efavirenz usage. We report a series of five patients with possible efavirenz-related retinal toxicity, visual function abnormalities, and its management. Efavirenz was replaced with alternate anti-retroviral drug. Reversal of ocular side effects were noted subjectively in the form of symptom amelioration of the patients. Objectively, it could be documented with electroretinogram changes and other visual function tests reverting back to normal after change in HAART regime. Early identification of this uncommon side effect in select patients can prevent irreversible vision loss due to efavirenz-associated retinal toxicity.

PMID: 32870052 [PubMed - as supplied by publisher]

Lithium in pregnancy.

Drug Ther Bull. 2020 Aug 31;:

Authors:

Abstract
Every month, DTB scans sources of information on treatments, disease management and other healthcare topics for key items to bring to our readers' attention and help them keep up to date. To do this, we produce succinct, contextualised summaries of the information concerned.

PMID: 32868385 [PubMed - as supplied by publisher]

Cardiac changes in pediatric cancer survivors.

J Investig Med. 2020 Aug 31;:

Authors: Mokshagundam D, Olivieri LJ, McCarter R, Kim A, Sable CA, Spurney CF, Dham N

Abstract
Cardiac damage from chemotherapy is a known phenomenon leading to significant morbidity and mortality in the cancer surviving population, and identifying high-risk pediatric patients early is challenging. The purpose of this pilot study was to evaluate whether echo strain, cardiac MRI (CMR), and serum biomarkers are more sensitive methods for detecting cardiac toxicity than standard echo and to examine the relationship between biomarkers in patients without decreased systolic function as determined by standard echo. In this pilot study, we prospectively enrolled pediatric subjects after completion of anthracycline inclusive chemotherapy. Each subject underwent a post-treatment echocardiogram (standard with strain), serum biomarkers (N-terminal brain natriuretic peptide (NT-pro-BNP) and interleukin 1 receptor-like 1 protein (ST2)), and CMR (standard and extracellular volumes (ECVs)). We correlated the markers using Pearson correlation. We enrolled 30 subjects, 11F/19M, aged 8-21 years. Cumulative anthracycline dose (CAD) correlated with BNP (p=0.06), CMR ECV 4-chamber (p=0.05) and sagittal (p=0.01), and mitral valve E/A (p=0.02). BNP correlated with CMR ECV 4-chamber (p=0.001) and sagittal (p=0.001) and with echo average longitudinal strain (ALS) (p=0.05). This study demonstrated a significant correlation of CAD with BNP and CMR ECV. There was also a significant correlation of NT-pro-BNP with CMR ECV and ALS. Combining these parameters with standard echo has the potential to identify high-risk patients early. Further studies are needed for long-term follow-up and management in this vulnerable population.

PMID: 32868378 [PubMed - as supplied by publisher]

Supporting Active Pharmacovigilance via IT Tools in the Clinical Setting and Beyond: Regulatory and Management Aspects.

Stud Health Technol Inform. 2020 Jun 26;272:342-345

Authors: Natsiavas P, Gavriilidis GI, Linardaki Z, Kolangi G, Gkaliagkousi E, Zamboulis C, Jaulent MC

Abstract
Information Technology (IT) could have a prominent role towards the "Active Pharmacovigilance" (AP) paradigm by facilitating the analysis of potential Adverse Drug Reactions (ADRs). PVClinical project aims to build an IT platform enabling the investigation of potential ADRs in the clinical environment and beyond. In this paper, we outline the respective EU regulatory framework and the related Business Processes (BPs), elaborated based on input from clinicians and PV experts as part of the project's "user requirements analysis" phase, highlighting their potential pivotal role in the design of IT tools aiming to support AP.

PMID: 32604672 [PubMed - indexed for MEDLINE]

New Evidence to Help to Prevent Lethal Outcomes in Intentional Overdoses.

JAMA Netw Open. 2020 03 02;3(3):e201131

Authors: Barber C

PMID: 32202639 [PubMed - indexed for MEDLINE]

Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents.

Leukemia. 2020 04;34(4):1182-1186

Authors: Kubasch AS, Schulze F, Giagounidis A, Götze KS, Krönke J, Sockel K, Middeke JM, Chermat F, Gloaguen S, Puttrich M, Weigt C, William D, Fenaux P, Schlenk RF, Thiede C, Stasik S, Mies A, Adès L, Oelschlägel U, Platzbecker U

PMID: 31796915 [PubMed - indexed for MEDLINE]

The rate of occurrence, healthcare resource use and costs of adverse events among metastatic non-small cell lung cancer patients treated with first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors.

Lung Cancer. 2019 12;138:131-138

Authors: Subramanian J, Fernandes AW, Laliberté F, Pavilack M, DerSarkissian M, Duh MS

Abstract
OBJECTIVES: Clinical trials with first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) reported severe adverse events (SAEs) in 6%-49% of patients with EGFR-mutated non-small cell lung cancer. This study describes incremental healthcare resource utilization (HRU) and costs associated with real-world management of AEs in this population, with a focus on SAEs.
MATERIALS AND METHODS: Patients receiving erlotinib, gefitinib, or afatinib as first-line (1L) monotherapy were identified from IQVIA™ Real-World Data Adjudicated Claims-US database (04/01/2012-03/31/2017). Relevant AEs were selected from corresponding prescribing information; SAEs were identified from hospitalization claims. HRU and cost per-patient-per-month (PPPM) were assessed during 1L treatment and compared for patients with and without each AE using multivariate Poisson and linear regression, respectively, adjusting for baseline characteristics.
RESULTS: Of 1646 patients, 86.9% were treated with erlotinib, 12.1% with afatinib, and 1.0% with gefitinib. In 1L, 12.2% of patients had ≥1 acute SAE (220.1/1000 patient-years). Patients with any SAE had higher PPPM costs than patients without SAEs (cost difference = $4700, p < 0.001). Incremental costs ranged from $2604 PPPM for diarrhea to $10,143 PPPM for microangiopathic hemolytic anemia (MAHA), and were statistically significant for all SAEs (all p < 0.001) except MAHA (p < 0.0528). Patients with any SAEs had higher rates of HRU relative to patients without SAEs (hospitalization rate ratio = 6.15; outpatient visits rate ratio = 1.21; all p < 0.001).
CONCLUSION: More than one-tenth of patients experienced SAEs, resulting in sizeable economic burden with respect to HRU and costs. EGFR-TKIs with more favorable safety profiles may reduce the burden of managing this population.

PMID: 31733614 [PubMed - indexed for MEDLINE]

Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomised controlled trial (D-LIFT trial).

Diabetologia. 2020 Aug 31;:

Authors: Kuchay MS, Krishan S, Mishra SK, Choudhary NS, Singh MK, Wasir JS, Kaur P, Gill HK, Bano T, Farooqui KJ, Mithal A

Abstract
AIMS/HYPOTHESIS: Liraglutide, a daily injectable glucagon-like peptide-1 receptor (GLP-1r) agonist, has been shown to reduce liver fat content (LFC) in humans. Data regarding the effect of dulaglutide, a once-weekly GLP-1r agonist, on human LFC are scarce. This study examined the effect of dulaglutide on LFC in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).
METHODS: Effect of dulaglutide on liver fat (D-LIFT) was a 24 week, open-label, parallel-group, randomised controlled trial to determine the effect of dulaglutide on liver fat at a tertiary care centre in India. Adults (n = 64), who had type 2 diabetes and MRI-derived proton density fat fraction-assessed LFC of ≥6.0% at baseline, were randomly assigned to receive dulaglutide weekly for 24 weeks (add-on to usual care) or usual care, based on a predefined computer-generated number with a 1:1 allocation that was concealed using serially numbered, opaque, sealed envelopes. The primary endpoint was the difference of the change in LFC from 0 (baseline) to 24 weeks between groups. The secondary outcome measures included the difference of the change in pancreatic fat content (PFC), change in liver stiffness measurement (LSM in kPa) measured by vibration-controlled transient elastography, and change in liver enzymes.
RESULTS: Eighty-eight patients were screened; 32 were randomly assigned to the dulaglutide group and 32 to the control group. Overall, 52 participants were included for per-protocol analysis: those who had MRI-PDFF data at baseline and week 24. Dulaglutide treatment resulted in a control-corrected absolute change in LFC of -3.5% (95% CI -6.6, -0.4; p = 0.025) and relative change of -26.4% (-44.2, -8.6; p = 0.004), corresponding to a 2.6-fold greater reduction. Dulaglutide-treated participants also showed a significant reduction in γ-glutamyl transpeptidase (GGT) levels (mean between-group difference -13.1 U/l [95% CI -24.4, -1.8]; p = 0.025) and non-significant reductions in aspartate aminotransferase (AST) (-9.3 U/l [-19.5, 1.0]; p = 0.075) and alanine aminotransferase (ALT) levels (-13.1 U/l [-24.4, 2.5]; p = 0.10). Absolute changes in PFC (-1.4% [-3.2, 0.3]; p = 0.106) and LSM (-1.31 kPa [-2.99, 0.37]; p = 0.123) were not significant when comparing the two groups. There were no serious drug-related adverse events.
CONCLUSIONS/INTERPRETATION: When included in the standard treatment for type 2 diabetes, dulaglutide significantly reduces LFC and improves GGT levels in participants with NAFLD. There were non-significant reductions in PFC, liver stiffness, serum AST and serum ALT levels. Dulaglutide could be considered for the early treatment of NAFLD in patients with type 2 diabetes.
TRIAL REGISTRATION: ClinicalTrials.gov NCT03590626 FUNDING: The current study was supported by an investigator-initiated study grant from Medanta-The Medicity's departmental research fund and a grant from the Endocrine and Diabetes Foundation (EDF), India. Graphical abstract.

PMID: 32865597 [PubMed - as supplied by publisher]

Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis.

Lancet Respir Med. 2020 04;8(4):383-394

Authors: Lan Z, Ahmad N, Baghaei P, Barkane L, Benedetti A, Brode SK, Brust JCM, Campbell JR, Chang VWL, Falzon D, Guglielmetti L, Isaakidis P, Kempker RR, Kipiani M, Kuksa L, Lange C, Laniado-Laborín R, Nahid P, Rodrigues D, Singla R, Udwadia ZF, Menzies D, Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment 2017

Abstract
BACKGROUND: Treatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens.
METHODS: We did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug.
FINDINGS: 58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]), and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2% [6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1% [9·9-19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed.
INTERPRETATION: Fluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis.
FUNDING: Canadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.

PMID: 32192585 [PubMed - indexed for MEDLINE]

A qualitative study on reasons for early removal of Implanon among users in Arba Minch town, Gamo Goffa zone, South Ethiopia: a phenomenological approach.

BMC Womens Health. 2020 01 02;20(1):2

Authors: Utaile MM, Debere MK, Nida ET, Boneya DJ, Ergano AT

Abstract
BACKGROUND: Implanon is one of the cost - effective long acting reversible contraceptive methods used for spacing and limiting births in Ethiopia. Despite the scaling up initiative undertaken by the Ethiopian Government, Implanon uptake is very low compared to short acting contraceptive methods. There is low utilization of Implanon with high level of discontinuation in Ethiopia. Therefore, this study was conducted to explore the reasons for early removal of Implanon among users in Arba Minch town, South Ethiopia.
METHODS: A community-based qualitative exploratory study using phenomenological approach was conducted. In-depth and key informant interviews were used to collect data from April 20-27, 2018 in Arba Minch town. Convenient sampling was employed to recruit participants from the households of targeted villages. A total of 10 in-depth interviews with women who recently removed Implanon and 5 key informant interviews with health extension workers were conducted. The sample size was determined based on the concept of saturation. The collected data were analyzed using thematic content analysis technique. Data coding and analysis were facilitated by using Open code version 4.0 software.
RESULTS: This study revealed that majority of participants were able to mention at least three types of contraceptive methods available in the nearby health facilities. The study underlined that side effect of the method, husband opposition, seeking more children, and method failure were the common reasons for early removal of Implanon, in which side effect of the method was the main reason. Among various forms of side effects of Implanon identified by users, heavy and irregular bleeding was mentioned as the most frequently occurring side effect.
CONCLUSION: Our result indicated that heavy and irregular bleeding was the main reason for early removal of Implanon. Therefore it suggests improvement in the service delivery system. Improving client's education and counseling service program could contribute much to avoid unreasonable and untimely removal of Implanon.

PMID: 31896349 [PubMed - indexed for MEDLINE]

New horizons in deprescribing for older people.

Age Ageing. 2019 11 01;48(6):768-775

Authors: Woodford HJ, Fisher J

Abstract
Deprescribing has gained interest recently, driven by an ageing population seeing an increasing number living with multiple long-term conditions. This, coupled with disease-specific guidelines derived from clinical trials in younger people, has led to an increase in exposure to polypharmacy and the associated therapeutic burden. Older people, especially those living with frailty, tend to experience lower efficacy of these medications along with a higher risk of drug adverse effects. Explanations for these differences include the physiological effects of frailty, drug-drug interactions, drug-disease interactions and reduced medication adherence. Adverse drug reactions often go unnoticed and can trigger further prescribing. Certain medications have been recognised as potentially inappropriate for people with frailty, yet their use remains common. Evidence suggests that many older people are open to the concept of reducing medications. Deprescribing should be based around a shared decision-making approach. Trials to date have suggested that it can often be achieved without harm. To date, there are few data to support improvements in hospitalisation or mortality rates. However, there is some evidence that it may reduce polypharmacy, improve medication adherence, reduce financial costs and improve quality of life. In the future, it will be necessary to grow the evidence base and improve public and clinician awareness of the potential benefits of deprescribing. It will require excellent team working and communication between all of those involved in the prescribing and administration of medications, also supported by improved healthcare informatics. Non-pharmacological approaches will need to be promoted. Fewer drugs is not less care.

PMID: 31595290 [PubMed - indexed for MEDLINE]