Design and rationale of the Edoxaban Treatment in routiNe clinical prActice for patients with Atrial Fibrillation in Europe (ETNA-AF-Europe) study.

J Cardiovasc Med (Hagerstown). 2018 Dec 11;:

Authors: De Caterina R, Kelly P, Monteiro P, Deharo JC, de Asmundis C, López-de-Sá E, Weiss TW, Waltenberger J, Steffel J, de Groot JR, Levy P, Bakhai A, Zierhut W, Laeis P, Reimitz PE, Kirchhof P, ETNA-AF-Europe investigators

Abstract
AIM: Edoxaban, a nonvitamin K antagonist oral anticoagulant, is an oral factor Xa inhibitor approved for the prevention of stroke and systemic embolism in adult patients with atrial fibrillation and for the treatment and secondary prevention in adult patients with venous thromboembolism (VTE). This study details the design of the Edoxaban Treatment in routiNe clinical prActice for patients with Atrial Fibrillation in Europe (ETNA-AF-Europe) study - a postauthorization observational study, which is part of the postapproval plan for edoxaban agreed with the European Medicines Agency.
METHODS: The ETNA-AF-Europe study (Clinicaltrials.gov: NCT02944019) is a multicenter, prospective, observational study that enrolled 13 980 patients with atrial fibrillation treated with edoxaban from 852 sites across 10 European countries (Austria, Belgium, Germany, Ireland, Italy, the Netherlands, Portugal, Spain, Switzerland, and the United Kingdom). Patients treated with edoxaban were prospectively enrolled and will be followed up for 4 years with yearly follow-up visits.
ASSESSMENTS: The primary objective of the ETNA-AF-Europe study is to assess the real-world safety of edoxaban by evaluating bleeding events, including intracranial hemorrhage; drug-related adverse events, such as hepatic events; and cardiovascular and all-cause mortality. In addition, efficacy will be assessed by recording major adverse cardiovascular events including stroke, systemic embolic events, transient ischemic attacks, and also VTE episodes, acute coronary syndromes, and hospitalizations related to cardiovascular condition. Event rates will be compared with event rates reported in the PREvention oF thromboembolic events-European Registry in Atrial Fibrillation in atrial fibrillation (PREFER in AF) and PREFER in AF Prolongation registries, and in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation - Thrombolysis in Myocardial Infarction 48 study datasets.

PMID: 30540648 [PubMed - as supplied by publisher]

Capecitabine monotherapy in advanced breast cancer resistant to anthracycline and taxane: A meta-analysis.

J Cancer Res Ther. 2018 Dec;14(Supplement):S957-S963

Authors: Jiang Z, Yang Y, Li L, Yue Z, Lan L, Pan Z

Abstract
Background: Capecitabine monotherapy is usually used for advanced breast cancer (ABC) resistant to anthracycline and taxane, but there are still many other options too. Our meta-analysis assessed whether capecitabine monotherapy was superior or noninferior to the other regimens in ABC pretreated with anthracycline and taxane.
Materials and Methods: PubMed databases and abstracts from the proceedings of American Society of Clinical Oncology and San Antonio Breast Cancer Symposium were searched for randomized controlled trials that compared capecitabine monotherapy with other regimens for ABC progression after anthracycline- and taxane-treatment. Hazard ratios (HRs) were used for progression-free survival (PFS) and overall survival (OS). Risk ratios (RRs) were used for overall response rate (ORR) and Grade 3-4 drug-related adverse events. All statistical analyses were conducted with RevMan 5.3 software, and statistical significance was defined as P < 0.05.
Results: In total, 4671 patients from eight trials were included. Target therapy as treatment group was involved in four trials, and the other four trials were merely chemotherapy in treatment group. Our study indicated that capecitabine monotherapy was not superior but also noninferior to the other regimens in ORR (RR = 1.32-95% confidence interval [CI] 0.98-1.77, P = 0.07), PFS (HR = 1.03, 95% CI 0.85-1.25, P = 0.76), and OS (HR = 0.96, 95% CI 0.88-1.05, P = 0.40). Subgroup analysis showed that both the other chemotherapy regimens and target drugs failed to improve efficacy compared with capecitabine monotherapy, and target drugs could shorten PFS (HR = 1.22, 95% CI 1.06-1.39, P = 0.004). Incidences of Grade 3-4 hematology toxicity in other regimens group significantly increased compared with capecitabine monotherapy.
Conclusions: Our meta-analysis demonstrated that capecitabine monotherapy could be the first choice for ABC pretreated with anthracycline and taxane due to its efficacy and low toxicity.

PMID: 30539829 [PubMed - in process]

Long-term macrolide treatment for the prevention of acute exacerbations in COPD: a systematic review and meta-analysis.

Int J Chron Obstruct Pulmon Dis. 2018;13:3813-3829

Authors: Cui Y, Luo L, Li C, Chen P, Chen Y

Abstract
Background: Acute exacerbation of COPD (AECOPD) is associated with an increased hospitalization and mortality. Azithromycin and erythromycin are the recommended drugs to reduce the risk of exacerbations. However, the most suitable duration of therapy and drug-related adverse events are still a matter of debate. The aim of this meta-analysis was to assess the current evidence regarding the efficacy and safety of long-term macrolide treatment for COPD.
Materials and methods: We comprehensively searched PubMed, Embase, the Cochrane Library, and the Web of Science and performed a systematic review and cumulative meta-analysis of all randomized controlled trials (RCTs) and retrospective studies.
Results: Eleven RCTs and one retrospective study including a total of 2,151 cases were carried out. Long-term macrolide treatment significantly reduced the total number of cases with one or more exacerbations (OR=0.40; 95% CI=0.24-0.65; P<0.01) and the rate of exacerbations per patient per year (risk ratio [RR]=0.60; 95% CI=0.45-0.78; P<0.01). Subgroup analyses showed that the minimum duration for drug efficacy for both azithromycin and erythromycin therapy was 6 months. In addition, macrolide therapy could improve the St George Respiratory Questionnaire (SGRQ) total score (P<0.01) but did not achieve the level of clinical significance. The frequency of hospitalizations was not significantly different between the treatment and control groups (P=0.50). Moreover, chronic azithromycin treatment was more likely to increase adverse events (P<0.01).
Conclusion: Prophylactic azithromycin or erythromycin treatment has a significant effect in reducing the frequency of AECOPD in a time-dependent manner. However, long-term macrolide treatment could increase the occurrence of adverse events and macrolide resistance. Future large-scale, well-designed RCTs with extensive follow-up are required to identify patients in whom the benefits outweigh risks.

PMID: 30538443 [PubMed - in process]

Mitotane-induced dyspnoea: an unusual side effect.

BMJ Case Rep. 2018 Sep 01;2018:

Authors: Farooq AU, Amjad W, Kochar T, Adhikari S

Abstract
Mitotane is a cytostatic antineoplastic agent that is used in the treatment of adrenocortical carcinoma and Cushing's syndrome. The commonly reported side effects associated with mitotane are anorexia, nausea, vomiting, diarrhoea, decreased memory, rash, gynaecomastia, arthralgias and leucopenia. We present a case of a 68-year-old female who developed gradual dyspnoea concurrent with the use of mitotane for the treatment of adrenocortical carcinoma. To the best of our knowledge and literate review, this is the first reported case of dyspnoea associated with the use of this medication. The purpose of this case report is to raise awareness about this uncommon adverse effect of mitotane that may have gone unrecognised on postmarketing surveillance because of under-reporting, lack of case follow-up or other comorbidities masking shortness of breath.

PMID: 30173131 [PubMed - indexed for MEDLINE]

Efficacy and safety of laxatives for chronic constipation in long-term care settings: A systematic review.

J Clin Pharm Ther. 2018 Oct;43(5):595-605

Authors: Alsalimy N, Madi L, Awaisu A

Abstract
WHAT IS KNOWN AND OBJECTIVE: Constipation is a common disorder among long-term care (LTC) patients due to several factors. However, there are no systematic reviews investigating the use of laxatives for chronic constipation in LTC settings. This study aims to explore the safety and efficacy of laxatives in LTC patients.
METHODS: A systematic review of randomized controlled trials (RCTs) describing the efficacy and safety of laxatives for chronic constipation in LTC patients was conducted using the following databases and search engines: MEDLINE, Cochrane Database of Systematic Reviews, ScienceDirect, ProQuest and Google Scholar. Two of the investigators independently performed the searches, and the data were extracted using a standardized data abstraction tool.
RESULTS AND DISCUSSION: Seven RCTs involving 444 patients were included in the review. These studies included senna (with or without fibre, ie Plantago ovata), lactulose, sodium picosulphate, docusate sodium, docusate calcium, isotonic and hypotonic polyethylene glycol and Chinese herbal medicine. Senna and lactulose were the most studied laxatives in LTC patients, and senna was found to be superior to or as effective as other laxatives. Generally, the frequency and severity of adverse drug reactions (ADRs) were similar between the arms of the studies, and no serious ADRs were reported.
WHAT IS NEW AND CONCLUSION: Considering the short duration of the trials, the lack of trials including newer laxatives and the low quality of some of the included trials, the long-term efficacy and safety of these laxatives are not conclusive. There is a need to conduct more robust RCTs that include newer agents to evaluate long-term outcomes.

PMID: 29885259 [PubMed - indexed for MEDLINE]

Protective effects of tumor necrosis factor alpha inhibitors on methotrexate-induced pancreatic toxicity.

Adv Clin Exp Med. 2018 Jun;27(6):715-720

Authors: Mercantepe T, Kalkan Y, Tumkaya L, Sehitoglu İ, Mercantepe F, Yıldırmıs S

Abstract
BACKGROUND: Methotrexate (MTX), a folate antagonist, is commonly used in the treatment of many different types of cancer and inflammatory diseases, including pancreatic cancer, although its side effects on the pancreas have not yet been researched. The mechanism of MTX-induced toxicity is not well known, and it has been reported in high-dose toxicity studies that the pancreas is sensitive to toxic effects.
OBJECTIVES: The aim of our study was to determine whether adalimumab (ADA) has a preventive effect on MTX-induced pancreas toxicity in rats.
MATERIAL AND METHODS: The rats were equally and randomly divided into 3 groups (Group 1 comprised the healthy controls, Group 2 was the MTX group, and Group 3 was the MTX + ADA group). The rats in Groups 2 and 3 received an intraperitoneal (ip.) single-dose injection of MTX (20 mg/kg). A single dose of 5 mg/kg ADA (REMICADE®) was administered ip. to Group 3. All the rats were sacrificed under anesthesia 5 days after receiving the MTX injection.
RESULTS: Significantly higher mean edema, necrotic cell, and inflammatory scores were recorded in Groups 2 and 3 compared to those recorded in Group 1. Significantly decreased edema, number of necrotic cells, and inflammatory scores were noted in Group 3 than in Group 2. A decrease in islets of Langerhans cell insulin and somatostatin-positive interneurons was demonstrated after the administration of MTX. An increase in insulin and somatostatin-positive cells in islets of Langerhans, as well as a remodeling of the structure of the pancreas, was shown following treatment with ADA.
CONCLUSIONS: Adalimumab was demonstrated to have a protective effect against MTX-induced pancreatic injury in this study.

PMID: 29808967 [PubMed - indexed for MEDLINE]

Guidelines for the management of paediatric cholera infection: a systematic review of the evidence.

Paediatr Int Child Health. 2018 11;38(sup1):S16-S31

Authors: Williams PCM, Berkley JA

Abstract
Background Vibrio cholerae is a highly motile Gram-negative bacterium which is responsible for 3 million cases of diarrhoeal illness and up to 100,000 deaths per year, with an increasing burden documented over the past decade. Current WHO guidelines for the treatment of paediatric cholera infection (tetracycline 12.5 mg/kg four times daily for 3 days) are based on data which are over a decade old. In an era of increasing antimicrobial resistance, updated review of the appropriate empirical therapy for cholera infection in children (taking account of susceptibility patterns, cost and the risk of adverse events) is necessary. Methods A systematic review of the current published literature on the treatment of cholera infection in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was undertaken. International clinical guidelines and studies pertaining to adverse effects associated with treatments available for cholera infection were also reviewed. Results The initial search produced 256 results, of which eight studies met the inclusion criteria. Quality assessment of the studies was performed as per the Grading of Recommendations Assessment, Development and Evaluation guidelines. Conclusions In view of the changing non-susceptibility rates worldwide, empirical therapy for cholera infection in paediatric patients should be changed to single-dose azithromycin (20 mg/kg), a safe and effective medication with ease of administration. Erythromycin (12.5 mg/kg four times daily for 3 days) exhibits similar bacteriological and clinical success and should be listed as a second-line therapy. Fluid resuscitation remains the cornerstone of management of paediatric cholera infection, and prevention of infection by promoting access to clean water and sanitation is paramount.

PMID: 29790841 [PubMed - indexed for MEDLINE]

Guidelines for the treatment of severe acute malnutrition: a systematic review of the evidence for antimicrobial therapy.

Paediatr Int Child Health. 2018 11;38(sup1):S32-S49

Authors: Williams PCM, Berkley JA

Abstract
Background Severe acute malnutrition (SAM) affects nearly 20 million children worldwide and is responsible for up to 1 million deaths per year in children under the age of 5 years. Current WHO guidelines recommend oral amoxicillin for children with uncomplicated malnutrition and parenteral benzylpenicillin and gentamicin for those with complicated malnutrition. Because of cost pressures and increasing antimicrobial resistance, the administration of empirical antibiotics for children with SAM has recently been debated. Methods A systematic review of the current published literature was undertaken to assess the efficacy, safety, cost-effectiveness and pharmacokinetics of antimicrobial treatment of children with SAM in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Results The initial search found 712 papers, eight of which met the inclusion criteria. Quality assessment of the studies was performed as per the Grading of Recommendations Assessment, Development and Evaluation guidelines. International guidelines and clinical data registries were also reviewed which identified inconsistencies in current first- and second-line therapies and dosing regimens. Conclusion Current evidence supports the continued use of broad-spectrum oral amoxicillin for treating children with uncomplicated SAM as outpatients. There is no strong evidence to justify changing the current parenteral therapy guidelines for children admitted with complicated SAM, although they should be clarified to harmonise the dosage regimen of amoxicillin for the treatment of SAM to 40 mg/kg twice daily, and to continue parenteral antimicrobials beyond 2 days if indicated by the clinical condition.

PMID: 29790840 [PubMed - indexed for MEDLINE]

66 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 2018/12/12

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.

Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications.

Sex Med Rev. 2018 Nov 29;:

Authors: Solomon ZJ, Mirabal JR, Mazur DJ, Kohn TP, Lipshultz LI, Pastuszak AW

Abstract
INTRODUCTION: Selective androgen receptor modulators (SARMs) differentially bind to androgen receptors depending on each SARM's chemical structure. As a result, SARMs result in anabolic cellular activity while avoiding many of the side effects of currently available anabolic steroids. SARMs have been studied in the treatment of breast cancer and cachexia and have also been used as performance-enhancing agents. Here, we evaluate and summarize the current literature on SARMs.
AIM: To present the background, mechanisms, current and potential clinical applications, as well as risks and benefits of SARMs.
METHODS: A literature review was performed in MEDLINE using the terms selective androgen receptor modulator, hypogonadism, cachexia, breast cancer, benign prostatic hyperplasia, libido, and lean muscle mass. Both basic research and clinical studies were included.
MAIN OUTCOME MEASURE: To complete a review of peer-reviewed literature.
RESULTS: Although there are currently no U.S. Food and Drug Agency-approved indications for SARMs, investigators are exploring the potential uses for these compounds. Basic research has focused on the pharmacokinetics and pharmacodynamics of these agents, demonstrating good availability with a paucity of drug interactions. Early clinical studies have demonstrated potential uses for SARMs in the treatment of cancer-related cachexia, benign prostatic hyperplasia (BPH), hypogonadism, and breast cancer, with positive results.
CONCLUSION: SARMs have numerous possible clinical applications, with promise for the safe use in the treatment of cachexia, BPH, hypogonadism, breast cancer, and prostate cancer. Solomon ZJ, Mirabal JR, Mazur DJ, et al. Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications. Sex Med Rev 2018;XX:XXX-XXX.

PMID: 30503797 [PubMed - as supplied by publisher]

Inversion and computational maturation of drug response using human stem cell derived cardiomyocytes in microphysiological systems.

Sci Rep. 2018 Dec 04;8(1):17626

Authors: Tveito A, Jæger KH, Huebsch N, Charrez B, Edwards AG, Wall S, Healy KE

Abstract
While cardiomyocytes differentiated from human induced pluripotent stems cells (hiPSCs) hold great promise for drug screening, the electrophysiological properties of these cells can be variable and immature, producing results that are significantly different from their human adult counterparts. Here, we describe a computational framework to address this limitation, and show how in silico methods, applied to measurements on immature cardiomyocytes, can be used to both identify drug action and to predict its effect in mature cells. Our synthetic and experimental results indicate that optically obtained waveforms of voltage and calcium from microphysiological systems can be inverted into information on drug ion channel blockage, and then, through assuming functional invariance of proteins during maturation, this data can be used to predict drug induced changes in mature ventricular cells. Together, this pipeline of measurements and computational analysis could significantly improve the ability of hiPSC derived cardiomycocytes to predict dangerous drug side effects.

PMID: 30514966 [PubMed - in process]

Clozapine-induced myocarditis in Canada: Evidence from spontaneous reports.

Schizophr Res. 2018 Dec 01;:

Authors: Neufeld NH, Remington G

PMID: 30514645 [PubMed - as supplied by publisher]

56 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 2018/12/04

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.

A Rare Case of Levetiracetam and Drug-Induced Idiopathic Aseptic Meningitis in a Pediatric Patient.

Pharmacotherapy. 2018 Nov 29;:

Authors: McDonald D, Sultan R, Viswanathan A, Siu A

Abstract
Levetiracetam (LEV) is a pyrrolidine derivative antiepileptic medication used for treatment of seizures in pediatric and adult patients. We report a case of probable LEV-induced aseptic meningitis in a 13-year-old female. The patient received LEV for a generalized seizure disorder and presented with symptoms 5 days after medication initiation. Ten days after LEV initiation, the patient presented to the hospital for further management. During her hospital course, infectious etiologies were ruled out with clinical and diagnostic testing. Upon discontinuation of LEV, the patient's symptoms resolved. Although select antiepileptic medications have been associated with drug-induced aseptic meningitis (DIAM), to date, there are no published reports of DIAM following administration of LEV. We describe and categorize the probability of DIAM in association with LEV, as observed in a patient case. This article is protected by copyright. All rights reserved.

PMID: 30488976 [PubMed - as supplied by publisher]

Dosimetry, biodistribution, and safety of flurpiridaz F 18 in healthy subjects undergoing rest and exercise or pharmacological stress PET myocardial perfusion imaging.

J Nucl Cardiol. 2018 Nov 28;:

Authors: Maddahi J, Bengel F, Czernin J, Crane P, Dahlbom M, Schelbert H, Sparks R, Phelps M, Lazewatsky J

Abstract
The objectives of this study were to evaluate radiation dosimetry, biodistribution, human safety, and tolerability of 18F-labeled flurpiridaz (Flurpiridaz) in normal subjects undergoing rest and separate-day exercise or adenosine pharmacological stress PET imaging.
METHODS: 12 normal subjects were injected with 58.5 to 121 MBq (1.58 to 3.27 mCi) of Flurpiridaz intravenously at rest on Day 1 and 57 to 171 MBq (1.54 to 4.61 mCi) during stress on Day 2. Sequential whole-body imaging was performed for 5 hours. Blood samples were collected for up to 8 hours.
RESULTS: The heart wall received the largest mean absorbed dose with both exercise and adenosine stresses. The mean effective dose was 0.054 rem/mCi (0.015 mSv/MBq) with exercise and 0.069 rem/mCi (0.019 mSv/MBq) with adenosine pharmacological stress. The maximum dose that may be administered without exceeding 1 rem (10 mSv) effective dose was 19 mCi (685 MBq) for exercise and 15 mCi (539 MBq) for adenosine pharmacological stress. There were no drug-related adverse events, and the tracer was well tolerated in all subjects.
CONCLUSION: Based on radiation dosimetry, biodistribution, and safety observations, 18F-labeled flurpiridaz is found suitable for clinical PET myocardial perfusion imaging in conjunction with either exercise or pharmacological stress testing.

PMID: 30488323 [PubMed - as supplied by publisher]

Risk factors of opioid-induced adverse reactions in elderly male outpatients of Korea Veterans Hospital.

BMC Geriatr. 2018 Nov 29;18(1):293

Authors: Kim JY, Kim JH, Yee J, Song SJ, Gwak HS

Abstract
BACKGROUND: Risk factors associated with opioid-induced adverse reactions (OIARs) in the elderly population have not been well defined. The objective of this study was to determine effects of various risk factors on incidence of OIARs in male elderly patients.
METHODS: A retrospective cohort study in Korea Veterans Hospital was performed. Data were analyzed in male patients aged 65 years and older who received morphine, oxycodone, or codeine. Binomial variables describing patient-related and drug-related characteristics were constructed. Associations between these variables and frequency of OIARs were determined. Odds ratio (OR) and adjusted odds ratio (AOR) were calculated from univariate and multivariable analyses, respectively. Attributable risk was obtained by (1-1/OR)*100%.
RESULTS: Of 316 patients, 28% experienced at least one adverse event. The most common adverse events were gastrointestinal problems (n = 59) and central nerve system adverse effects (n = 20). The odds of OIARs in patients with opioid use ≥12 weeks was increased by 80% compared to those with opioid use < 12 weeks. Attributable risk of GABA analogues was 64~78% in constructed Models. Compared to codeine users, patients using morphine and oxycodone had 653 and 473% increased odds for OIARs, respectively. MME ≥ 60 mg/day had a 317% increased odds for OIARs (95% CI: 1.92-9.04) compared to MME < 60 mg/day. Opioid combination therapy had a 139% increased odds for OIARs compared to monotherapy.
CONCLUSIONS: These findings have significant implications for clinical use of opioid in elderly patients. Our study suggests that low dose short-term use will pose less risk of OIARs for the elderly, whereas concomitant use of GABA analogues, strong opioids and dual-opioid therapy may increase the risk of OIARs. Therefore, clinician should carefully monitor patients when starting opioid therapy in older population.

PMID: 30486785 [PubMed - in process]

Continuing war on pain: a personalized approach to the therapy with nonsteroidal anti-inflammatory drugs and opioids.

Per Med. 2018 Nov 28;:

Authors: Bach-Rojecky L, Vađunec D, Žunić K, Kurija J, Šipicki S, Gregg R, Mikula I, Primorac D

Abstract
Successful pain management requires the delivery of analgesia with minimal risk of adverse drug reactions. Nonsteroidal anti-inflammatory drugs and opioids remain the mainstay of treatment for the majority of patients. Unfortunately, almost 50% of all patients experience inadequate pain relief and serious side effects. Allelic variants in genes coding for target proteins, transporters and enzymes, which govern analgesic drugs action and their fate in the organism, might explain inter-individual variability in pain severity and in drug-induced pain relief and toxicities. Additionally, it seems that epigenetic changes contribute to the highly variable response to pain treatment. Therefore, pharmacogenomic testing might be a valuable tool for personalization of pain treatment, with a multidisciplinary team approach involved.

PMID: 30484741 [PubMed - as supplied by publisher]

11 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 2018/11/28

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.

Mefloquine for preventing malaria in pregnant women.

Cochrane Database Syst Rev. 2018 Nov 14;11:CD011444

Authors: González R, Pons-Duran C, Piqueras M, Aponte JJ, Ter Kuile FO, Menéndez C

Abstract
BACKGROUND: The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for malaria for all women who live in moderate to high malaria transmission areas in Africa. However, parasite resistance to sulfadoxine-pyrimethamine has been increasing steadily in some areas of the region. Moreover, HIV-infected women on cotrimoxazole prophylaxis cannot receive sulfadoxine-pyrimethamine because of potential drug interactions. Thus, there is an urgent need to identify alternative drugs for prevention of malaria in pregnancy. One such candidate is mefloquine.
OBJECTIVES: To assess the effects of mefloquine for preventing malaria in pregnant women, specifically, to evaluate:• the efficacy, safety, and tolerability of mefloquine for preventing malaria in pregnant women; and• the impact of HIV status, gravidity, and use of insecticide-treated nets on the effects of mefloquine.
SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, Latin American Caribbean Health Sciences Literature (LILACS), the Malaria in Pregnancy Library, and two trial registers up to 31 January 2018. In addition, we checked references and contacted study authors to identify additional studies, unpublished data, confidential reports, and raw data from published trials.
SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing mefloquine IPT or mefloquine prophylaxis against placebo, no treatment, or an alternative drug regimen.
DATA COLLECTION AND ANALYSIS: Two review authors independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias, and extracted data. We contacted trial authors to ask for additional information when required. Dichotomous outcomes were compared using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes using mean differences (MDs). We have presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach for the following main outcomes of analysis: maternal peripheral parasitaemia at delivery, clinical malaria episodes during pregnancy, placental malaria, maternal anaemia at delivery, low birth weight, spontaneous abortions and stillbirths, dizziness, and vomiting.
MAIN RESULTS: Six trials conducted between 1987 and 2013 from Thailand (1), Benin (3), Gabon (1), Tanzania (1), Mozambique (2), and Kenya (1) that included 8192 pregnant women met our inclusion criteria.Two trials (with 6350 HIV-uninfected pregnant women) compared two IPTp doses of mefloquine with two IPTp doses of sulfadoxine-pyrimethamine. Two other trials involving 1363 HIV-infected women compared three IPTp doses of mefloquine plus cotrimoxazole with cotrimoxazole. One trial in 140 HIV-infected women compared three doses of IPTp-mefloquine with cotrimoxazole. Finally, one trial enrolling 339 of unknown HIV status compared mefloquine prophylaxis with placebo.Study participants included women of all gravidities and of all ages (four trials) or > 18 years (two trials). Gestational age at recruitment was > 20 weeks (one trial), between 16 and 28 weeks (three trials), or ≤ 28 weeks (two trials). Two of the six trials blinded participants and personnel, and only one had low risk of detection bias for safety outcomes.When compared with sulfadoxine-pyrimethamine, IPTp-mefloquine results in a 35% reduction in maternal peripheral parasitaemia at delivery (RR 0.65, 95% CI 0.48 to 0.86; 5455 participants, 2 studies; high-certainty evidence) but may have little or no effect on placental malaria infections (RR 1.04, 95% CI 0.58 to 1.86; 4668 participants, 2 studies; low-certainty evidence). Mefloquine results in little or no difference in the incidence of clinical malaria episodes during pregnancy (incidence rate ratio (IRR) 0.83, 95% CI 0.65 to 1.05, 2 studies; high-certainty evidence). Mefloquine decreased maternal anaemia at delivery (RR 0.84, 95% CI 0.76 to 0.94; 5469 participants, 2 studies; moderate-certainty evidence). Data show little or no difference in the proportions of low birth weight infants (RR 0.95, 95% CI 0.78 to 1.17; 5641 participants, 2 studies; high-certainty evidence) and in stillbirth and spontaneous abortion rates (RR 1.20, 95% CI 0.91 to 1.58; 6219 participants, 2 studies; I2 statistic = 0%; moderate-certainty evidence). IPTp-mefloquine increased drug-related vomiting (RR 4.76, 95% CI 4.13 to 5.49; 6272 participants, 2 studies; high-certainty evidence) and dizziness (RR 4.21, 95% CI 3.36 to 5.27; participants = 6272, 2 studies; moderate-certainty evidence).When compared with cotrimoxazole, IPTp-mefloquine plus cotrimoxazole probably results in a 48% reduction in maternal peripheral parasitaemia at delivery (RR 0.52, 95% CI 0.30 to 0.93; 989 participants, 2 studies; moderate-certainty evidence) and a 72% reduction in placental malaria (RR 0.28, 95% CI 0.14 to 0.57; 977 participants, 2 studies; moderate-certainty evidence) but has little or no effect on the incidence of clinical malaria episodes during pregnancy (IRR 0.76, 95% CI 0.33 to 1.76, 1 study; high-certainty evidence) and probably no effect on maternal anaemia at delivery (RR 0.94, 95% CI 0.73 to 1.20; 1197 participants, 2 studies; moderate-certainty evidence), low birth weight rates (RR 1.20, 95% CI 0.89 to 1.60; 1220 participants, 2 studies; moderate-certainty evidence), and rates of spontaneous abortion and stillbirth (RR 1.12, 95% CI 0.42 to 2.98; 1347 participants, 2 studies; very low-certainty evidence). Mefloquine was associated with higher risks of drug-related vomiting (RR 7.95, 95% CI 4.79 to 13.18; 1055 participants, one study; high-certainty evidence) and dizziness (RR 3.94, 95% CI 2.85 to 5.46; 1055 participants, 1 study; high-certainty evidence).
AUTHORS' CONCLUSIONS: Mefloquine was more efficacious than sulfadoxine-pyrimethamine in HIV-uninfected women or daily cotrimoxazole prophylaxis in HIV-infected pregnant women for prevention of malaria infection and was associated with lower risk of maternal anaemia, no adverse effects on pregnancy outcomes (such as stillbirths and abortions), and no effects on low birth weight and prematurity. However, the high proportion of mefloquine-related adverse events constitutes an important barrier to its effectiveness for malaria preventive treatment in pregnant women.

PMID: 30480761 [PubMed - as supplied by publisher]

Can we avoid the toxicity of chemotherapy in elderly cancer patients?

Crit Rev Oncol Hematol. 2018 Nov;131:16-23

Authors: Feliu J, Heredia-Soto V, Gironés R, Jiménez-Munarriz B, Saldaña J, Guillén-Ponce C, Molina-Garrido MJ

Abstract
Although approximately 50% of cancer patients are 70 years of age or older, cancer treatment in the elderly remains a therapeutic challenge. The elderly form a very heterogeneous group in relation to their general health state, degree of dependence, comorbidities, performance status, physical reserve and geriatric situation, for which therapeutic decisions must be made in an individualized manner. In addition, changes in pharmacokinetics and pharmacodynamics of the drugs occur with age, as well as the tolerance of the tissues, leading to a narrowing of the therapeutic margin and an increase in toxicity. In the general population, Performace Status (PS) has traditionally been used to estimate tolerance to chemotherapy, but in the elderly population it is not useful. In this review we summarize the current knowledge about the pharmacology of antineoplastic drugs in the elderly and the tools available to help us identify risk of chemotherapy toxicity in these patients.

PMID: 30293701 [PubMed - indexed for MEDLINE]