Incidence of paradoxical reactions in patients treated with tocilizumab for rheumatoid arthritis: Data from the French registry REGATE.

Joint Bone Spine. 2018 01;85(1):53-57

Authors: Terreaux W, Masson C, Eschard JP, Bardin T, Constantin A, Le Dantec L, Marcelli C, Perdriger A, Scotto Di Fazano C, Wendling D, Sibilia J, Morel J, Salmon JH

Abstract
OBJECTIVES: Assess the frequency of paradoxical reactions encountered in daily practice under tocilizumab, using the REGATE (Registry-RoActemra) registry. The secondary objectives were to determine the type of paradoxical reaction and the consequences of these reactions.
METHODS: The REGATE registry is an independent prospective registry, promoted by the French Society of Rheumatology, consisting of patients treated with tocilizumab for rheumatoid arthritis. The paradoxical reaction was retained if it was a paradoxical precipitation of a condition for which tocilizumab was indicated, if tocilizumab was being used for an alternative indication, and if it appeared after at least one tocilizumab infusion.
RESULTS: Among the 1491 patients included with at least one follow-up visit (3429 patient-years), a paradoxical reaction occurred in 9 patients (0.60% of patients; 2.62/1000 patient-years). These were 7 de novo pathologies (3 vasculitis, 3 uveitis, 1 lupus) and 2 exacerbations of pre-existing conditions (1 vasculitis, 1 lupus). Permanent discontinuation of tocilizumab was chosen for 5 patients.
CONCLUSIONS: In the REGATE registry, the occurrence of paradoxical reactions in patients treated with tocilizumab was rare.

PMID: 28115268 [PubMed - indexed for MEDLINE]

Hepatotoxicity associated with Garcinia cambogia: A case report.

World J Hepatol. 2019 Nov 27;11(11):735-742

Authors: Yousaf MN, Chaudhary FS, Hodanazari SM, Sittambalam CD

Abstract
BACKGROUND: Herbal supplements (HS) for weight loss are perceived to be "safe" and "natural", as advertised in ads, however, hepatotoxicity can be associated with consumption of some HS. Use of HS may be missed, as the patient may not report these unless specifically asked about these products, since they are often not thought of as medications with potential side effects or interaction potential.
CASE SUMMARY: We reported a case of a 21-year-old female with morbid obesity who presented with abdominal pain for 1 wk associated with nausea, vomiting, anorexia and myalgias. She denied smoking tobacco, drinking alcohol, usage of illicit drugs, hormonal contraceptives, or energy drinks. There was no significant past medical or family illnesses. Her laboratory workup revealed acute liver failure. The workup for possible etiologies of acute liver failure was unremarkable. She was using a weight loss herbal supplement "Garcinia cambogia" for 4 wks. This case demonstrates the association of acute liver failure with Garcinia cambogia.
CONCLUSION: Medical reconciliation of HS should be performed in patients with suspected acute liver failure and early discontinuation of HS can prevent further progression of drug induced hepatoxicity.

PMID: 31772720 [PubMed]

Abdominal visceral adipose tissue is associated with unsuspected pulmonary embolism on routine CT scans in patients with gastrointestinal cancer.

Br J Radiol. 2019 Dec;92(1104):20190526

Authors: Xiao X, Wang Y, Gao Y, Xie Q, Zhou X, Lin L, Dekkers IA, Lamb HJ

Abstract
OBJECTIVE: Unsuspected pulmonary embolism (UPE) has been increasingly diagnosed as an incidental finding on CT scans for routine staging in cancer patients. Previous studies suggest that obesity is an independent risk factor for venous thromboembolism in patients with malignant tumors. In this study, we aimed to investigate the association between abdominal adipose tissue, especially visceral adipose tissue (VAT) and the occurrence of UPE in hospitalized patients with gastrointestinal cancer.
METHODS: Routine contrast-enhanced chest and abdominal CT scans of 1974 patients were retrospectively assessed for the presence of UPE, of which 58 patients were identified with UPE and 108 non-UPE patients were selected as the non-UPE control group based on several matching criteria. Abdominal adipose tissue was measured by volumes of VAT and subcutaneous adipose tissue (SAT) at the navel level.
RESULTS: VAT, SAT, indwelling venous catheters, surgery, chemotherapy, and bed rest or immobilization were associated with the occurrence of UPE. Higher VAT volumes were associated with increased risk of UPE (odds ratio: 1.96; 95% confidence interval: 1.25, 3.06; p = 0.003) adjusting body mass index (BMI), bed rest or immobilization, surgery, chemotherapy and smoking, while SAT was not associated with UPE adjusting the same confounders (p = 0.117). No statistical association was found between BMI and UPE (p = 0.102).
CONCLUSION: Higher VAT rather than SAT is associated with an increased risk of unsuspected pulmonary embolism on routine CT scans in hospitalized gastrointestinal cancer patients.
ADVANCES IN KNOWLEDGE: Our findings indicate that VAT is a stronger risk factor for unsuspected pulmonary embolism than BMI and SAT in hospitalized patients with gastrointestinal cancer.

PMID: 31595778 [PubMed - indexed for MEDLINE]

Classifying adverse drug reactions from imbalanced twitter data.

Int J Med Inform. 2019 09;129:122-132

Authors: Dai HJ, Wang CK

Abstract
BACKGROUND: Nowadays, social media are often being used by general public to create and share public messages related to their health. With the global increase in social media usage, there is a trend of posting information related to adverse drug reactions (ADR). Mining the social media data for this type of information will be helpful for pharmacological post-marketing surveillance and monitoring. Although the concept of using social media to facilitate pharmacovigilance is convincing, construction of automatic ADR detection systems remains a challenge because the corpora compiled from social media tend to be highly imbalanced, posing a major obstacle to the development of classifiers with reliable performance.
METHODS: Several methods have been proposed to address the challenge of imbalanced corpora. However, we are not aware of any studies that investigated the effectiveness of the strategies of dealing with the problem of imbalanced data in the context of ADR detection from social media. In light of this, we evaluated a variety of imbalanced techniques and proposed a novel word embedding-based synthetic minority over-sampling technique (WESMOTE), which synthesizes new training examples from the sentence representation based on word embeddings. We compared the performance of all methods on two large imbalanced datasets released for the purpose of detecting ADR posts.
RESULTS: In comparison with the state-of-the-art approaches, the classifiers that incorporated imbalanced classification techniques achieved comparable or better F-scores. All of our best performing configurations combined random under-sampling with techniques including the proposed WESMOTE, boosting and ensemble, implying that an integration of these approaches with under-sampling provides a reliable solution for large imbalanced social media datasets. Furthermore, ensemble-based methods like vote-based under-sampling (VUE) and random under-sampling boosting can be alternatives for the hybrid synthetic methods because both methods increase the diversity of the created weak classifiers, leading to better recall and overall F-scores for the minority classes.
CONCLUSIONS: Data collected from the social media are usually very large and highly imbalanced. In order to maximize the performance of a classifier trained on such data, applications of imbalanced strategies are required. We considered several practical methods for handling imbalanced Twitter data along with their performance on the binary classification task with respect to ADRs. In conclusion, the following practical insights are gained: 1) When dealing with text classification, the proposed word embedding-based synthetic minority over-sampling technique is more effective than traditional synthetic-based over-sampling methods. 2) In cases where large amounts of training data are available, the imbalanced strategies combined with under-sampling techniques are preferred. 3) Finally, employment of advanced methods does not guarantee better performance than simpler ones such as VUE, which achieved high performance with advantages like faster building time and ease of development.

PMID: 31445246 [PubMed - indexed for MEDLINE]

The European Medicines Agency's scientific opinion on oral fexinidazole for human African trypanosomiasis.

PLoS Negl Trop Dis. 2019 06;13(6):e0007381

Authors: Pelfrene E, Harvey Allchurch M, Ntamabyaliro N, Nambasa V, Ventura FV, Nagercoil N, Cavaleri M

PMID: 31246956 [PubMed - indexed for MEDLINE]

Herb-Drug Interactions and Hepatotoxicity.

Curr Drug Metab. 2019;20(4):275-282

Authors: Parvez MK, Rishi V

Abstract
BACKGROUND: In recent times, herbals or phytomedicines have become very popular due to their global acceptance as a complementary and alternative remedy. While modern drugs are commercially available only after laboratory validations, clinical trials, as well as approval from drug regulatory authorities, majority of the marketed herbal products lack such scientific evidence of efficacy and safety. This results in herb or herb-drug interaction induced unfavorable clinical outcomes without crucial documentation on their temporal relations and concomitant use.
METHODS: An online literature search for peer-reviewed articles was conducted on the PubMed, Europe PMC, Medline and Google Scholar portals, using the phrases: complementary & alternative medicine, traditional Chinese medicine, herb-drug interaction, mechanisms of herb-drug interaction, herb-induced toxicity, herbal hepatotoxicity and causality, traditional medicine, viral hepatitis, etc.
Results: The retrieved data showed that globally, patients are attracted to herbal remedies with the misconception that these are completely safe and therefore, use them simultaneously with prescription drugs. Notably, there exists a potential risk of herb-drug interactions leading to some adverse side effects, including hepatotoxicity. The toxicological effect of a drug or herb is due to the inhibition of drug metabolizing enzymes (e.g., cytochrome P450), including interactions with certain prescription drugs through various mechanisms. Several cases of hepatotoxicity due to use of herbals in viral hepatitis-related liver diseases have been recently reported. However, limited experimental data and clinical evidence on herbal pharmacokinetics hamper the evaluation and reporting of adverse reactions and the underlying mechanisms.
CONCLUSION: Herb-drug interaction related morbidity is thus an emerging serious public health issue with broad implications for clinicians, pharmaceutical industries and health authorities. Nonetheless, despite increasing recognition of herb-drug interaction, a standard system for interaction prediction and evaluation is still nonexistent. This review article discusses the herb-drug interactions related hepatotoxicity and underlying mechanisms, including drug metabolizing enzymes and their regulation.

PMID: 30914020 [PubMed - indexed for MEDLINE]

A Metabonomics Approach to Drug Toxicology in Liver Disease and its Application in Traditional Chinese Medicine.

Curr Drug Metab. 2019;20(4):292-300

Authors: Su G, Wang H, Bai J, Chen G, Pei Y

Abstract
BACKGROUND: The progression of liver disease causes metabolic transformation in vivo and thus affects corresponding endogenous small molecular compounds. Metabonomics is a powerful technology which is able to assess global low-molecular-weight endogenous metabolites in a biological system. This review is intended to provide an overview of a metabonomics approach to the drug toxicology of diseases of the liver.
METHODS: The regulation of, and relationship between, endogenous metabolites and diseases of the liver is discussed in detail. Furthermore, the metabolic pathways involved in drug interventions of liver diseases are reviewed. Evaluation of the protective mechanisms of traditional Chinese medicine in liver diseases using metabonomics is also reviewed. Examples of applications of metabolite profiling concerning biomarker discovery are highlighted. In addition, new developments and future prospects are described.
RESULTS: Metabonomics can measure changes in metabolism relating to different stages of liver disease, so metabolic differences can provide a basis for the diagnosis, treatment and prognosis of various diseases.
CONCLUSION: Metabonomics has great advantages in all aspects of the therapy of liver diseases, with good prospects for clinical application.

PMID: 30599107 [PubMed - indexed for MEDLINE]

A retrospective study evaluating the tolerability and effectiveness of adjunctive antihypertensive drugs in patients with inadequate response to initial treatment.

J Clin Hypertens (Greenwich). 2018 06;20(6):1058-1066

Authors: Ayyagari R, Xie J, Cheng D, Wu EQ, Huang XY, Chen S

Abstract
Real-world tolerability and effectiveness of nebivolol as first add-on therapy were compared with hydrochlorothiazide, metoprolol, and amlodipine. Medical records of hypertensive adults initiating nebivolol, hydrochlorothiazide, metoprolol, or amlodipine as first add-on therapy between December 16, 2010 and July 21, 2011 were retrospectively abstracted (N = 1600; 400/treatment). Outcomes included medication-related side-effect rates and blood pressure (BP) reduction and control. Compared with nebivolol, metoprolol and amlodipine had significantly higher side-effect rates (incidence rate ratio [95% CI]: 1.82 [1.14-2.92] and 2.67 [1.69-4.21]), respectively); the hydrochlorothiazide-nebivolol rate ratio was not significant (1.61 [0.95-2.71]). All treatments reduced BP at 2 months. Metoprolol, amlodipine, and hydrochlorothiazide were associated with significantly lower odds of achieving 2-month BP control than nebivolol (odds ratios [95% CI]: 0.34 [0.23-0.51], 0.51 [0.35-0.75] and 0.66 [0.44-0.99], respectively). In a real-world setting, nebivolol as first add-on therapy was associated with fewer side effects than metoprolol or amlodipine and with a higher BP control rate than hydrochlorothiazide, metoprolol, or amlodipine.

PMID: 29902367 [PubMed - indexed for MEDLINE]

National Trends in Emergency Room Visits of Dialysis Patients for Adverse Drug Reactions.

Am J Nephrol. 2018;47(6):441-449

Authors: Chan L, Saha A, Poojary P, Chauhan K, Naik N, Coca S, Garimella PS, Nadkarni GN

Abstract
BACKGROUND: Various medications are cleared by the kidneys, therefore patients with impaired renal function, especially dialysis patients are at risk for adverse drug events (ADEs). There are limited studies on ADEs in maintenance dialysis patients.
METHODS: We utilized a nationally representative database, the Nationwide Emergency Department Sample, from 2008 to 2013, to compare emergency department (ED) visits for dialysis and propensity matched non-dialysis patients. Log binomial regression was used to calculate relative risk of hospital admission and logistic regression to calculate ORs for in-hospital mortality while adjusting for patient and hospital characteristics.
RESULTS: While ED visits for ADEs decreased in both groups, they were over 10-fold higher in dialysis patients than non-dialysis patients (65.8-88.5 per 1,000 patients vs. 4.6-5.4 per 1,000 patients respectively, p < 0.001). The top medication category associated with ED visits for ADEs in dialysis patients is agents primarily affecting blood constituents, which has increased. After propensity matching, patient admission was higher in dialysis patients than non-dialysis patients, (88 vs. 76%, p < 0.001). Dialysis was associated with a 3% increase in risk of admission and 3 times the odds of in-hospital mortality (adjusted OR 3, 95% CI 2.7-2.3.3).
CONCLUSIONS: ED visits for ADEs are substantially higher in dialysis patients than non-dialysis patients. In dialysis patients, ADEs associated with agents primarily affecting blood constituents are on the rise. ED visits for ADEs in dialysis patients have higher inpatient admissions and in-hospital mortality. Further studies are needed to identify and implement measures aimed at reducing ADEs in dialysis patients.

PMID: 29895030 [PubMed - indexed for MEDLINE]

[Cancer patients in operative intensive care medicine].

Anaesthesist. 2018 02;67(2):83-92

Authors: Annecke T, Hohn A, Böll B, Kochanek M

Abstract
Cancer is one of the leading causes of death worldwide. New targeted and individualized therapies and drugs provide a survival benefit for an increasing number of patients, but can also cause severe side effects. An increasing number of oncology patients are admitted to intensive care units (ICU) because of cancer-related complications or treatment-associated side effects. Postoperative care, respiratory distress and sepsis are the leading causes for admission. Tumor mass syndromes and tumor lysis may require urgent treatment. Traditional anticancer chemotherapy is associated with infections and immunosuppression. Newer agents are generally well-tolerated and side effects are mild or moderate, but overwhelming inflammation and autoimmunity can also occur. Cellular treatment, such as with chimeric antigen receptor modified T‑cells, monoclonal and bispecific antibodies targeting immune effectors and tumor cells are associated with cytokine release syndrome (CRS) with hypotension, skin reactions and fever. It is related to excessively high levels of inflammatory cytokines. Immune checkpoint inhibitors can lead to immune-related adverse events (IRAEs), such as colitis and endocrine disorders. Noninfectious respiratory complications, such as pneumonitis can also occur. Recent studies revealed that short-term and medium-term survival of cancer patients is better than previously expected. In this review article we summarize diagnostic and treatment strategies for common life-threatening complications and emergencies requiring ICU admission. Furthermore, strategies for rational admission policies are presented.

PMID: 29368008 [PubMed - indexed for MEDLINE]

A 2018 Approach to Combating Methotrexate Toxicity Folic Acid and Beyond.

Bull Hosp Jt Dis (2013). 2018 Sep;76(3):151-155

Authors: Labadie JG, Hashim R, Raheel S, Awad L, Jain M

Abstract
Methotrexate (MTX) is the cornerstone to management across a variety of rheumatic diseases. Effective use and adherence to MTX treatment is dependent on toxicity prevention and management. The major deterrents to patient tolerability and adherence can include GI upset, hepatic transaminase elevation, stomatitis, hair loss, and CNS toxicity. Many rheumatologists are familiar with employing supplementation of folic acid and folinic acid, as well as a change from oral to subcutaneous (SC) MTX, to help combat MTX toxicity. There are, however, more potential strategies in a rheumatologist's armamentarium to ameliorate side effects and improve adherence, including vitamin A supplementation and dextromethorphan. Herein, we will provide a review of the literature (both rheumatologic and oncologic) and expert opinion in terms of managing methotrexate toxicity and improving adherence in rheumatic diseases.

PMID: 31513516 [PubMed - indexed for MEDLINE]

Antibiotic prophylaxis for the prevention of infective endocarditis for dental procedures is not associated with fatal adverse drug reactions in France.

Med Oral Patol Oral Cir Bucal. 2019 May 01;24(3):e296-e304

Authors: Cloitre A, Duval X, Tubiana S, Giraud P, Veyrac G, Nosbaum A, Gouraud A, Mahé J, Lesclous P

Abstract
BACKGROUND: One of the major reasons to stop antibiotic prophylaxis (AP) to prevent infective endocarditis (IE) in the United Kingdom but not in the rest of the world was that it would result in more deaths from fatal adverse drug reactions (ADRs) than the number of IE deaths. The main aim of this study was to quantify and describe the ADRs with amoxicillin or clindamycin for IE AP. The second aim was to infer a crude incidence of anaphylaxis associated with amoxicillin for IE AP.
STUDY DESIGN: The Medical Dictionary for Regulatory Activities (MedDRA) was used to group ADRs for IE AP using the broad Standardized MedDRA Queries "Anaphylactic reaction, Amoxicillin, Clindamycin, Clostridium Difficile infection" to the French Pharmacovigilance Database System. From this first-line collection, we selected all cases occurring for IE AP and ultimately, the cases for IE AP for a dental procedure. Then, each case was analyzed.
RESULTS: Of 11639 first-line recorded ADRs, 100 were for IE AP but no fatal anaphylaxis to amoxicillin or clindamycin and no C. difficile infection associated with clindamycin were identified. Only 17 cases of anaphylaxis to amoxicillin related to dental procedures were highlighted. The estimation of the crude incidence rate of anaphylaxis associated with amoxicillin for IE AP for invasive dental procedure was 1/57 000 (95% CI 0.2-0.6).
CONCLUSIONS: Fatal or severe ADRs with amoxicillin or clindamycin is not a rational argument to stop IE AP before invasive dental procedures.

PMID: 31011140 [PubMed - indexed for MEDLINE]

Magnetic extraction of toxin binding liposomes; a method to ameliorate drug toxicity? Preliminary in vitro/ in vivo study.

Nanomedicine (Lond). 2018 12;13(24):3083-3089

Authors: Cave G, Harvey M, Sleigh J, Kanamala M, Wu Z

Abstract
AIM: Removal of a toxin from the body once absorbed is usually not possible. We describe the use of magnetite containing pH gradient 'MagnepH' liposomes to overcome limitations preventing removal.
METHODS: MagnepH liposomes were added to albumin solution containing amitriptyline and dosed intravenously in rats prior to amitriptyline injection. Albumin solution or drawn blood was exposed to a magnet and sampled.
RESULTS: One third of amitriptyline was extracted in vitro. In vivo amitriptyline concentrations were 1830 nmol/l (controls) and 10870 nmol/l (MagnepH; n = 2). Amitriptyline extraction increased from 0.6% (control) to 10.4% (MagnepH; 95% CI for difference 2.0-17.6%).
CONCLUSION: MagnepH liposomes sequestered amitriptyline and could then be extracted. This method has potential to ameliorate limitations to extracorporeal removal of toxins in poisoning.

PMID: 30457425 [PubMed - indexed for MEDLINE]

Human tissue-engineered skeletal muscle: a novel 3D in vitro model for drug disposition and toxicity after intramuscular injection.

Sci Rep. 2018 08 15;8(1):12206

Authors: Gholobova D, Gerard M, Decroix L, Desender L, Callewaert N, Annaert P, Thorrez L

Abstract
The development of laboratory-grown tissues, referred to as organoids, bio-artificial tissue or tissue-engineered constructs, is clearly expanding. We describe for the first time how engineered human muscles can be applied as a pre- or non-clinical model for intramuscular drug injection to further decrease and complement the use of in vivo animal studies. The human bio-artificial muscle (BAM) is formed in a seven day tissue engineering procedure during which human myoblasts fuse and differentiate to aligned myofibers in an extracellular matrix. The dimensions of the BAM constructs allow for injection and follow-up during several days after injection. A stereotactic setup allows controllable injection at multiple sites in the BAM. We injected several compounds; a dye, a hydrolysable compound, a reducible substrate and a wasp venom toxin. Afterwards, direct reflux, release and metabolism were assessed in the BAM constructs in comparison to 2D cell culture and isolated human muscle strips. Spectrophotometry and luminescence allowed to measure the release of the injected compounds and their metabolites over time. A release profile over 40 hours was observed in the BAM model in contrast to 2D cell culture, showing the capacity of the BAM model to function as a drug depot. We also determined compound toxicity on the BAMs by measuring creatine kinase release in the medium, which increased with increasing toxic insult. Taken together, we show that the BAM is an injectable human 3D cell culture model that can be used to measure release and metabolism of injected compounds in vitro.

PMID: 30111779 [PubMed - indexed for MEDLINE]

Population Pharmacokinetics and Exposure-Response Analyses of Eslicarbazepine Acetate Efficacy and Safety in Monotherapy of Partial-Onset Seizures.

J Clin Pharmacol. 2018 07;58(7):927-938

Authors: Sunkaraneni S, Ludwig EA, Passarell JA, Blum D, Grinnell T, Fiedler-Kelly J

Abstract
Eslicarbazepine acetate (ESL) is a once-daily oral antiepileptic drug (AED) indicated for partial-onset seizures (POS). ESL pharmacokinetics (PK) and exposure-response analyses were supported by 2 phase 3 conversion to ESL (1200, 1600 mg) monotherapy studies. The PK model development included 10 phase 1-2 studies (ESL 600-1200 mg daily). Seizure diaries were completed daily; subjects exited if seizures worsened. Exposure-response models were developed for time to study exit, probability of seizure freedom, time to first occurrence of dizziness, headache, and nausea; serum sodium levels were explored. A 1-compartment model with first-order absorption/elimination described ESL PK. Clearance and distribution volume were significantly related to body weight and sex. Higher eslicarbazepine minimum concentration (Cmin ) and use of 1 baseline AED were associated with significantly lower risk of study exit, whereas eslicarbazepine Cmin was a significant predictor of seizure freedom during the last 4 weeks of monotherapy. Eslicarbazepine exposure and the time to first occurrence of adverse events were not related. A shallow negative relationship described the relationship between change from baseline in serum sodium level and eslicarbazepine exposure. Eslicarbazepine apparent clearance and distribution volume estimates were similar to those reported for ESL adjunctive therapy. Dose adjustment based on body weight was not required. The time to study exit and probability of seizure freedom during the last 4 weeks of monotherapy were weakly related to eslicarbazepine exposure. Because the first occurrence of adverse events or hyponatremia were also not significantly related to eslicarbazepine exposure, dose adjustment using plasma eslicarbazepine concentrations is not supported.

PMID: 29528499 [PubMed - indexed for MEDLINE]

Design of a tripartite network for the prediction of drug targets.

J Comput Aided Mol Des. 2018 02;32(2):321-330

Authors: Kunimoto R, Bajorath J

Abstract
Drug-target networks have aided in many target prediction studies aiming at drug repurposing or the analysis of side effects. Conventional drug-target networks are bipartite. They contain two different types of nodes representing drugs and targets, respectively, and edges indicating pairwise drug-target interactions. In this work, we introduce a tripartite network consisting of drugs, other bioactive compounds, and targets from different sources. On the basis of analog relationships captured in the network and so-called neighbor targets of drugs, new drug targets can be inferred. The tripartite network was found to have a stable structure and simulated network growth was accompanied by a steady increase in assortativity, reflecting increasing correlation between degrees of connected nodes leading to even network connectivity. Local drug environments in the tripartite network typically contained neighbor targets and revealed interesting drug-compound-target relationships for further analysis. Candidate targets were prioritized. The tripartite network design extends standard drug-target networks and provides additional opportunities for drug target prediction.

PMID: 29340865 [PubMed - indexed for MEDLINE]

Efficacy and safety of elbasvir/grazoprevir for 8 or 12 weeks for hepatitis C virus: genotype 4 infection: a randomized study.

Liver Int. 2019 Nov 25;:

Authors: Asselah T, Pol S, Hezode C, Loustaud-Ratti V, Leroy V, Ahmed SNS, Ozenne V, Bronowicki JP, Larrey D, Tran A, Alric L, Nguyen-Khac E, Robertson MN, Hanna GJ, Brown D, Asante-Appiah E, Su FH, Hwang P, Hall JD, Guidoum A, Hagen K, Haber BA, Talwani R, Serfaty L

Abstract
BACKGROUND & AIMS: Hepatitis C virus (HCV) genotype (GT) 4 infection is prevalent in North Africa and the Middle East, particularly in Egypt. This study evaluated the safety and efficacy of elbasvir/grazoprevir administered for 8 and 12 weeks in participants with HCV genotype (GT)4 infection.
METHODS: In this partially randomized, open-label multicenter study conducted in France (NCT03111108; Protocol MK5172-096), treatment-naive participants with GT4 infection and F0-F2 fibrosis were randomized 2:1 to elbasvir (50 mg)/grazoprevir (100 mg) for 8 or 12 weeks. Treatment-naive participants with F3-F4 fibrosis and all treatment-experienced participants (F0-F4) were assigned to elbasvir/grazoprevir for 12 weeks. The primary endpoint was sustained virologic response (SVR) 12 weeks after the end of therapy.
RESULTS: 117 participants were enrolled. Among treatment-naive participants with F0-F2 fibrosis, SVR was achieved by 94% (50/53) and 96% (26/27) of those receiving elbasvir/grazoprevir for 8 or 12 weeks, respectively and 4 participants relapsed. In the 12-week arm, 95% (35/37) achieved SVR and 2 participants relapsed. NS5A resistance-associated substitutions were present at baseline and virologic failure in 5 of the participants with relapse. Drug-related adverse events occurred in 42% (n=22) and 50% (n=32) of participants receiving 8 and 12 weeks of treatment, respectively. No participant discontinued treatment owing to an adverse event.
CONCLUSION: These data confirm the efficacy of elbasvir/grazoprevir 12 weeks in treatment-experienced individuals with HCV GT4 infection and those with advanced fibrosis. Treatment-naive individuals with mild fibrosis can be treated effectively with an 8-week regimen.

PMID: 31765046 [PubMed - as supplied by publisher]

Efficacy and safety of bifid triple viable plus aminosalicylic acid for the treatment of ulcerative colitis: A systematic review and meta-analysis.

Medicine (Baltimore). 2019 Nov;98(47):e17955

Authors: Chen MY, Qiu ZW, Tang HM, Zhuang KH, Cai QQ, Chen XL, Li HB

Abstract
OBJECTIVE: Ulcerative colitis (UC), one of the most stubborn diseases, is mainly treated by aminosalicylic acid (ASA). However, the side effects of ASA include vomiting, nausea, rash, diarrhea, headache, etc, which seriously affect life-quality of UC patients. Probiotics such as bifid triple viable (BTV) could reduce drug-induced adverse reactions and has a good clinical effect on UC. Therefore, we aimed to evaluate the clinical efficacy and safety of BTV plus ASA in treating UC.
METHODS: PubMed, Cochrane Library, Embase, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, Chinese National Knowledge Infrastructure, and Wanfang databases were searched from the inception dates to October 12, 2018. Randomized controlled trials (RCTs) were included by comparing BTV plus ASA programs with ASA alone in patients with UC. Methodological quality was assessed by 2 independent researchers according to the inclusion criteria and exclusion criteria. Meta-analysis was performed by using the Review Manager 5.3 Software. Risk ratios (RRs), 95% confidence interval (CI), and standardized mean difference were calculated.
RESULTS: Sixty RCTs involving 4954 participants were selected for final review. Compared with ASA, BTV plus ASA significantly improved the clinical effect rate [RR = 1.23, 95% CI (1.20, 1.26), P < .00001]; reduced the relapse rate [RR = 0.34, 95% CI (0.18, 0.62), P = .0005]; and adverse effect rate [RR = 0.66, 95% CI (0.53, 0.82), P = .0002]. Compared with the controls, levels of tumor necrosis factor-α, interleukin-6 (IL-6), IL-8, C-reactive protein (CRP), hypersensitive CRP, erythrocyte sedimentation rate, and malondialdehyde were reduced; levels of IL-10, CD3+, CD4+, and superoxide dismutase were increased in BTV plus ASA group.
CONCLUSIONS: BTV plus ASA has positive therapeutic effects on UC, and it might be a safe way to treat UC. However, comprehensive clinical trials are needed to obtain high level of clinical evidence.

PMID: 31764796 [PubMed - in process]

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

J Pediatr Gastroenterol Nutr. 2019 Nov 19;:

Authors: Atia O, Ledder O, Ben-Moshe T, Abitbol G, Tzion RL, Rachmen Y, Meyer EO, Beeri R, Renbaum P, Algur N, Shemasna I, Shteyer E, Turner D

Abstract
BACKGROUND AND OBJECTIVES: Use of thiopurines for inflammatory bowel diseases (IBD) 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 TPMT-activity at baseline and by clinical response and toxicity at 4 months; one year into the study, therapeutic-drug-monitoring (TDM) at 4 months was also considered in the decision making. The primary outcome was steroid-free remission without treatment escalation by 12 month (SFR), utilizing the intention-to-treat approach.
RESULTS: A total of 129 children were included (74% Crohn's disease (CD) and 26% ulcerative colitis (UC)). SFR was achieved in 37 (39%) CD and 13 (39%) UC patients, and SFR with normal ESR/CRP in 20 (21%) and 9 (27%), respectively. At 4 months, MCV/WBC ratio and ΔANC 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 wPCDAI (2.5 (IQR 0-7.5) in responders vs 5 in non-responders (0-12.5), p = 0.048) and ΔANC (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.
CONCLUSION: In this real-life prospective cohort utilizing dose optimization, thiopurines were safe and effective in 21% of CD and 27% of UC patients, including normalization of CRP and ESR. Thiopurines remain a viable option in the treatment algorithm of mild-moderate paediatric IBD, especially in females whose risk for lymphoma is lower.

PMID: 31764416 [PubMed - as supplied by publisher]

An evaluation of adherence to anti-diabetic medications among type 2 diabetic patients in a Sudanese outpatient clinic.

Pan Afr Med J. 2019;34:34

Authors: Mirghani HO

Abstract
Introduction: Adherence to anti-diabetic medication is a known cornerstone in the management of type 2 diabetic patients. We sought to assess the factors associated with adherence to medication s among type 2 diabetic patients being followed up in a Sudanese outpatient clinic.
Methods: This cross-sectional study conducted among 102 patients with type 2 diabetes attending an outpatient clinic in Omdurman, Sudan during the period from June to December 2017. Participants were interviewed using a structured questionnaire to collect demographic data, number, and type of medications, polypharmacy, medications side effects, financial problems and education regarding drug used. The study of participants' adherence to anti-diabetic medications was assessed using a validated questionnaire asking the patients about the percent and self-rating of adherence (Excellent, very good, good, fair and poor). The Statistical Package for Social Sciences (SPSS) was used to compare the adherent patients and their counterparts. A P-value < 0.05 was considered significant.
Results: The study results summarized the following: participants (70.6% women), their mean age was (59.62±9.91) years and nearly 60.8% were housewives, their glycated hemoglobin (mean± SD) was about 10.16±3.14, 37.3%, it implies that the patients were non-adherent to medications. In addition, other groups of patients with medication but non-adherence were younger ones (55.94±9.94 vs. 61.81±9.36, P=0.04) and had shown inadequate glycemic control (11.33±3.05vs. 9.47±3.04, P=0.04), however, this group of patients has reported more drug-related side effects (57.8% vs. 28.1%) because they were taking more drugs compared to their counterparts( F=4.115, P=0.047). The present study found no statistically significant differences in the following factors such as sex, occupation, education level, financial problems and insulin use.
Conclusion: In conclusion, the study revealed that adherence to anti-diabetic medications was sub-optimal among Sudanese type 2 diabetic patients and was associated with higher glycated hemoglobin seen among younger age groups. Besides the above, overdosing of medications and their side effects were evident.

PMID: 31762902 [PubMed - in process]