Large-scale computational drug repositioning to find treatments for rare diseases.

NPJ Syst Biol Appl. 2018;4:13

Authors: Govindaraj RG, Naderi M, Singha M, Lemoine J, Brylinski M

Abstract
Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning. In order to find new targets for known drugs ultimately leading to drug repositioning, we recently developed eMatchSite, a new computer program to compare drug-binding sites. In this study, eMatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases. The effectiveness of this integrated approach is demonstrated for a kinase inhibitor, which is a confirmed candidate for repositioning to synapsin Ia. The resulting dataset comprises 31,142 putative drug-target complexes linked to 980 orphan diseases. The modeling accuracy is evaluated against the structural data recently released for tyrosine-protein kinase HCK. To illustrate how potential therapeutics for rare diseases can be identified, we discuss a possibility to repurpose a steroidal aromatase inhibitor to treat Niemann-Pick disease type C. Overall, the exhaustive exploration of the drug repositioning space exposes new opportunities to combat orphan diseases with existing drugs. DrugBank/Orphanet repositioning data are freely available to research community at https://osf.io/qdjup/.

PMID: 29560273 [PubMed]

Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome.

Ann Clin Transl Neurol. 2018 Mar;5(3):323-332

Authors: O'Leary HM, Kaufmann WE, Barnes KV, Rakesh K, Kapur K, Tarquinio DC, Cantwell NG, Roche KJ, Rose SA, Walco AC, Bruck NM, Bazin GA, Holm IA, Alexander ME, Swanson LC, Baczewski LM, Mayor Torres JM, Nelson CA, Sahin M

Abstract
Objective: To measure the efficacy of mecasermin (recombinant human insulin-like growth factor 1, rhIGF-1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double-blind crossover study design.
Methods: Thirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF-1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28-week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory- and electroencephalography (EEG)-based biomarkers were also analyzed.
Results: There were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication.
Interpretation: As in the phase 1 trial, rhIGF-1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

PMID: 29560377 [PubMed]

Deciding on cystic fibrosis carrier screening: three citizens' juries and an online survey.

Eur J Public Health. 2018 Mar 19;:

Authors: Mosconi P, Colombo C, Roberto A, Candiani G, Greco MT, Satolli R, Castellani C

Abstract
Background: Health technology assessment and ethical issues have to be dealt with in deciding on national carrier screening for cystic fibrosis (CF)-the most frequent severe autosomal recessive disease in Caucasian populations and several stakeholders need to be involved. A citizens' jury is one way to ask citizens to deliberate on controversial topics in the interests of a society. The aims of this project were to gather opinions about CF carrier screening through citizens' jury deliberations and to match them with the findings of a large online consultation survey open to the general population, people with CF and families and health professionals.
Methods: Three citizens' juries and an online survey were asked: 'Should the Health Service organize screening of the population with the aim of identifying healthy people who may have children with CF?' The jurors had no medical background and no personal or family CF history. The survey was open to people with CF, families, and healthcare professionals.
Results: Jurors and survey respondents were in favour of CF carrier screening, mainly considering the severity of CF, the value of informed reproductive choices and the equality of the screening. All the citizens' juries felt positively about the health service actively offer CF carrier screening to provide women and couples of reproductive age equal access and standardized information on the pros and cons.
Conclusion: Considering the favourable attitude towards CF screening, the feasibility of CF screening, in terms of best setting, target age and healthcare professionals providing it, should be tested in a clinical trial.

PMID: 29562330 [PubMed - as supplied by publisher]

Meconium Ileus in a Neonate with Cystic Fibrosis.

N Engl J Med. 2018 Mar 22;378(12):1142

Authors: Wood KE

PMID: 29562160 [PubMed - in process]

The presence of Interleukin-13 in nasal lavage may be a predictor of nasal polyposis in pediatric patients with cystic fibrosis.

Rhinology. 2018 Mar 21;:

Authors: Manji J, Thamboo A, Tacey M, Garnis C, Chadha NK

Abstract
BACKGROUND: Sinonasal disease is a common feature of cystic fibrosis (CF) and can cause significant morbidity in these patients. Our objective was to determine if CF individuals with concomitant nasal polyposis (NP) express a unique profile of inflammation and if so, whether these inflammatory cytokine mediators have predictive value in identifying these individuals for prompt management by an Otolaryngologist.
METHODOLOGY: Nasal lavage samples and clinical outcomes of disease severity were obtained from thirty-eight pediatric CF individuals. Participants were subdivided based on the presence or absence of NP. Nasal lavage samples were analyzed on a panel of seventeen cytokine targets using a Bio-Plex Luminex assay. A Perl Permutation test with correction for multiple hypotheses was performed to identify uniquely expressed cytokines between CF individuals with NP (CFwNP) and those without (CFsNP).
RESULTS: Thirty-five patients were included in the analysis. Cytokines IL-13 and GM-CSF were uniquely expressed in the CFwNP group when compared to the CFsNP group. Logistic regression analysis demonstrated a significant association of IL-13 with NP.
CONCLUSION: In children diagnosed with CF, the level of IL-13 in nasal lavage samples could potentially serve as a non-invasive clinical tool in predicting NP in this population, and a target for future immunotherapy.

PMID: 29561922 [PubMed - as supplied by publisher]

Dextran Sulfate Sodium (DSS)-induced Chronic Colitis Attenuates Ca2+-activated Cl- Secretion in Murine Colon by Down-regulating TMEM16A.

Am J Physiol Cell Physiol. 2018 Mar 21;:

Authors: Rottgen TS, Nickerson AJ, Minor EA, Stewart AB, Harold AD, Rajendran VM

Abstract
Attenuated Ca2+-activated Cl- secretion has previously been observed in the model of dextran-sulfate-sodium (DSS)-induced colitis. Prior studies have implicated dysfunctional muscarinic signaling from basolateral membranes as the potential perpetrator leading to decreased Ca2+-activated Cl- secretion. However, in our chronic model of DSS-colitis, Chrm3 transcript (1.028 {plus minus} 0.12 vs. 1.029 {plus minus} 0.27, p > 0.05) and CHRM3 protein expression (1.021 {plus minus} .24 vs. .928 {plus minus} .09, p > 0.05) were unchanged. Therefore, we hypothesized that decreased CCH-stimulated Cl- secretion in DSS-induced colitis can be attributed to a loss of Ca2+-activated Cl- channels (CaCC) in apical membranes of colonic epithelium. To establish this chemically-induced colitis, Balb/C mice were exposed to 4% DSS for 5 alternating weeks to stimulate a more moderate, chronic colitis. Upon completion of the 10-week protocol, whole thickness sections of colon were mounted in the Ussing chamber under voltage-clamp conditions. DSS-induced colitis demonstrated a complete inhibition of basolateral administration of CCH-stimulated Cl- secretion that actually displayed a reversal in polarity (15.40 {plus minus} 2.22 μA/cm2 vs. -2.47{plus minus}0.25 μA/cm2). Western blot of potential CaCCs, quantified by densitometric analysis, demonstrated no change in bestrophin-2 (BEST2) and cystic fibrosis transmembrane regulator (CFTR), while Anoctamin-1 (ANO1, TMEM16A) was significantly down-regulated (1.001 {plus minus} 0.13 vs. 0.510 {plus minus} 0.12, p < 0.05). Our findings indicate that decreased expression of TMEM16A in DSS-induced colitis contributes to the decreased Ca2+-activated Cl- secretion in murine colon.

PMID: 29561662 [PubMed - as supplied by publisher]

Intrapulmonary percussive ventilation improves lung function in cystic fibrosis patients chronically colonized with Pseudomonas aeruginosa: a pilot cross-over study.

Eur J Clin Microbiol Infect Dis. 2018 Mar 20;:

Authors: Dingemans J, Eyns H, Willekens J, Monsieurs P, Van Houdt R, Cornelis P, Malfroot A, Crabbé A

Abstract
High levels of shear stress can prevent and disrupt Pseudomonas aeruginosa biofilm formation in vitro. Intrapulmonary percussive ventilation (IPV) could be used to introduce shear stress into the lungs of cystic fibrosis (CF) patients to disrupt biofilms in vivo. We performed a first-of-its-kind pilot clinical study to evaluate short-term IPV therapy at medium (200 bursts per minute, bpm) and high frequency (400 bpm) as compared to autogenic drainage (AD) on lung function and the behavior of P. aeruginosa in the CF lung in four patients who are chronically colonized by P. aeruginosa. A significant difference between the three treatment groups was observed for both the forced expiratory volume in 1 s (FEV1) and the forced vital capacity (FVC) (p < 0.05). More specifically, IPV at high frequency significantly increased FEV1 and FVC compared to AD (p < 0.05) and IPV at medium frequency (p < 0.001). IPV at high frequency enhanced the expression levels of P. aeruginosa planktonic marker genes, which was less pronounced with IPV at medium frequency or AD. In conclusion, IPV at high frequency could potentially alter the behavior of P. aeruginosa in the CF lung and improve lung function.
TRIAL REGISTRATION: The trail was retrospectively registered at the ISRCTN registry on 6 June 2013, under trial registration number ISRCTN75391385.

PMID: 29560543 [PubMed - as supplied by publisher]

Combination antibiotics against Pseudomonas aeruginosa, representing common and rare cystic fibrosis strains from different Irish clinics.

Heliyon. 2018 Mar;4(3):e00562

Authors: Kapoor P, Murphy P

Abstract
Objectives: To evaluate the effect of antibiotic combination therapy versus single therapy against cystic fibrosis strains of Pseudomonas aeruginosa identified as common and rare among patient groups in different Irish hospitals.
Methods: This study compares the susceptibility profiles of P. aeruginosa isolates from different cystic fibrosis (CF) clinics in Ireland, collected from 2004-2005. Strains were recovered in small numbers and typed by pulsed-field gel electrophoresis. Five common clonal variants were identified in five different hospitals, described as 'common strains'. A number of 'rare strains' associated with any single patient were also included in the study. Certain virulence factors were determined and in vitro assays such as minimum inhibitory concentrations (MIC) and biofilm inhibitory concentrations (BIC) were employed to assess potential synergistic effects of antipseudomonal antibiotic combination therapy.
Results: There was no distinct virulence factors associated with clinical strains that were common in comparison to those that were rare. Antibiotic combination testing revealed the majority of combinations were similar to the activity of either antibiotic used as single agents. Tobramycin-ceftazidime was the most effective combination exhibiting synergistic interactions (FIC ≤ 0.5) against certain clinical isolates of P. aeruginosa.
Conclusion: The efficacy of single antibiotics and synergistic interactions of antibiotic combinations were strain specific, irrespective of virulence characteristics of P. aeruginosa. Common clonal P. aeruginosa strains do not have distinct characteristics that possibly influence persistence in the chronic CF lung. Tobramycin-ceftazidime may be successful for controlling specific P. aeruginosa strains. Further studies on representative isolates are needed to support these results.

PMID: 29560472 [PubMed]

The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites.

ERJ Open Res. 2018 Jan;4(1):

Authors: Schneider EK, McQuade RM, Carbone VC, Reyes-Ortega F, Wilson JW, Button B, Saito A, Poole DP, Hoyer D, Li J, Velkov T

Abstract
Ivacaftor-lumacaftor and ivacaftor are two new breakthrough cystic fibrosis transmembrane conductance modulators. The interactions of ivacaftor and its two metabolites hydroxymethylivacaftor (iva-M1) and ivacaftorcarboxylate (iva-M6) with neurotransmitter receptors were investigated in radioligand binding assays. Ivacaftor displayed significant affinity to the 5-hydroxytryptamine (5-HT; serotonin) 5-HT2C receptor (pKi=6.06±0.03), β3-adrenergic receptor (pKi=5.71±0.07), δ-opioid receptor (pKi=5.59±0.06) and the dopamine transporter (pKi=5.50±0.20); iva-M1 displayed significant affinity to the 5-HT2C receptor (pKi=5.81±0.04) and the muscarinic M3 receptor (pKi=5.70±0.10); iva-M6 displayed significant affinity to the 5-HT2A receptor (pKi=7.33±0.05). The in vivo central nervous system activity of ivacaftor (40 mg·kg-1 intraperitoneally for 21 days) was assessed in a chronic mouse model of depression. In the forced swim test, the ivacaftor-treated group displayed decreased immobility (52.8±7.6 s), similarly to fluoxetine (33.8±11.0 s), and increased climbing/swimming activity (181.5±9.2 s). In the open field test, ivacaftor produced higher locomotor activity than the fluoxetine group, measured both as mean number of paw touches (ivacaftor 81.1±9.6 versus fluoxetine 57.9±9.5) and total distance travelled (ivacaftor 120.6±16.8 cm versus fluoxetine 84.5±16.0 cm) in 600 s. Treatment of 23 cystic fibrosis patients with ivacaftor-lumacaftor resulted in significant improvements in quality of life (including anxiety) in all five domains of the AweScoreCF questionnaire (p=0.092-0.096). Our findings suggest ivacaftor displays potential clinical anxiolytic and stimulating properties, and may have beneficial effects on mood.

PMID: 29560360 [PubMed]

Case Report: Dual nebulised antibiotics among adults with cystic fibrosis and chronic Pseudomonas infection.

F1000Res. 2017;6:2079

Authors: Mann N, Murray S, Hoo ZH, Curley R, Wildman MJ

Abstract
Pulmonary exacerbations in adults with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa (Psae) infection are usually treated with dual intravenous antibiotics for 14 days, despite the lack of evidence for best practice. Intravenous antibiotics are commonly associated with various systemic adverse effects, including renal failure and ototoxicity. Inhaled antibiotics are less likely to cause systematic adverse effects, yet can achieve airway concentrations well above conventional minimum inhibitory concentrations. Typically one inhaled antibiotic is used at a time, but dual inhaled antibiotics (i.e. concomitant use of two different inhaled antibiotics) may have synergistic effect and achieve better results in the treatment of exacerbations. We presented anecdotal evidence for the use of dual inhaled antibiotics as an acute treatment for exacerbations, in the form of a case report. A female in her early thirties with CF and chronic Psae infection improved her FEV 1 by 5% and 2% with two courses of dual inhaled antibiotics to treat exacerbations in 2016. In contrast, her FEV 1 changed by 2%, -2%, 0% and 2%, respectively, with four courses of dual intravenous antibiotics in 2016. Baseline FEV 1 was similar prior to all six courses of treatments. The greater FEV 1 improvements with dual inhaled antibiotics compared to dual intravenous antibiotics suggest the potential role of using dual inhaled antibiotics to treat exacerbations among adults with CF and chronic Psae infection, especially since a greater choice of inhaled anti-pseudomonal antibiotics is now available. A previous study in 1985 has looked at the concomitant administration of inhaled tobramycin and carbenicillin, by reconstituting antibiotics designed for parenteral administration. To our knowledge, this is the first literature to describe the concomitant use of two different antibiotics specifically developed for delivery via the inhaled route.

PMID: 29560254 [PubMed]

A fuzzy rule-based expert system for diagnosing cystic fibrosis.

Electron Physician. 2017 Dec;9(12):5974-5984

Authors: Hassanzad M, Orooji A, Valinejadi A, Velayati A

Abstract
Background: Finding a valid diagnosis is mostly a prolonged process. Current advances in the sector of artificial intelligence have led to the appearance of expert systems that enrich the experiences and capabilities of doctors for making decisions for their patients.
Objective: The objective of this research was developing a fuzzy expert system for diagnosing Cystic Fibrosis (CF).
Methods: Defining the risk factors and then, designing the fuzzy expert system for diagnosis of CF were carried out in this cross-sectional study. To evaluate the performance of the proposed system, a dataset that corresponded to 70 patients with respiratory disease who were serially admitted to the CF Clinic in the Pediatric Respiratory Diseases Center, Masih Daneshvari Hospital in Tehran, Iran during August 2016 to January 2017 was considered. Whole procedures of system construction were implemented in a MATLAB environment.
Results: Results showed that the suggested system can be used as a strong diagnostic tool with 93.02% precision, 89.29% specificity, 95.24% sensitivity and 92.86% accuracy for diagnosing CF. There was also a good relationship between the user and the system through the appealing user interface.
Conclusion: The system is equipped with information, knowledge, and expertise from certified specialists; hence, as a training tool it can be useful for new physicians. It is worth mentioning that the accomplishment of this project depends on advocacy of decision making in CF diagnosis. Nevertheless, it is expected that the system will reduce the number of false positives and false negatives in unusual cases.

PMID: 29560150 [PubMed]

Comparative Genomics of Environmental and Clinical Burkholderia cenocepacia Strains Closely Related to the Highly Transmissible Epidemic ET12 Lineage.

Front Microbiol. 2018;9:383

Authors: Bodilis J, Denet E, Brothier E, Graindorge A, Favre-Bonté S, Nazaret S

Abstract
The Burkholderia cenocepacia epidemic ET12 lineage belongs to the genomovar IIIA including the reference strain J2315, a highly transmissible epidemic B. cenocepacia lineage. Members of this lineage are able to cause lung infections in immunocompromised and cystic fibrosis patients. In this study, we describe the genome of F01, an environmental B. cenocepacia strain isolated from soil in Burkina Faso that is, to our knowledge, the most closely related strain to this epidemic lineage. A comparative genomic analysis was performed on this new isolate, in association with five clinical and one environmental B. cenocepacia strains whose genomes were previously sequenced. Antibiotic resistances, virulence phenotype, and genomic contents were compared and discussed with an emphasis on virulent and antibiotic determinants. Surprisingly, no significant differences in antibiotic resistance and virulence were found between clinical and environmental strains, while the most important genomic differences were related to the number of prophages identified in their genomes. The ET12 lineage strains showed a noticeable greater number of prophages (partial or full-length), especially compared to the phylogenetically related environmental F01 strain (i.e., 5-6 and 3 prophages, respectively). Data obtained suggest possible involvements of prophages in the clinical success of opportunistic pathogens.

PMID: 29559964 [PubMed]

IN VITRO ANTIMICROBIAL ACTIVITY OF CEFTOLOZANE/TAZOBACTAM AGAINST P. AERUGINOSA AND OTHER NON-FERMENTING GRAM-NEGATIVE ORGANISMS IN ADULTS WITH CYSTIC FIBROSIS.

J Glob Antimicrob Resist. 2018 Mar 17;:

Authors: Gramegna A, Millar BC, Blasi F, Elborn JS, Downey DG, Moore JE

Abstract
INTRODUCTION: Pulmonary exacerbations in people with Cystic Fibrosis (CF), with chronic Gram-negative pathogens, are associated with reduced survival. These pathogens are usually treated with repeated courses of systemic antibiotics. However there is a linked emergence of multidrug resistant (MDR) pathogens. Ceftolozane/tazobactam is a new cephalosporin/beta-lactamase inhibitor combination that has been demonstrated to have good activity against MDR Pseudomonas aeruginosa.
MATERIAL & METHODS: In this study ceftolozane/tazobactam was compared to other commonly used intravenous antibiotics against 193 non-fermenting Gram-negative bacteria isolated from CF sputum specimens, including P. aeruginosa, Achromobacter xylosoxidans, Stenotrophomonas maltophilia and Burkholderia. MICs to ceftolozane/tazobactam were determined by standard E-test assay and interpreted according to current EUCAST guidelines.
RESULTS: Ceftolozane/tazobactam had good in vitro antimicrobial activity against CF clinical isolates of P. aeruginosa in comparison to other antimicrobials with the exception of colistin. Ceftolozane/tazobactam also had activity against S. maltophilia, but was not active against B. cenocepacia and A. xylosoxidans.
DISCUSSION: ceftolozane/tazobactam showed excellent in vitro activity against P. aeruginosa from CF clinical isolates. This antibiotic is a potential therapeutic option when presented with challenging MDR P. aeruginosa and S. maltophilia exacerbations. Further clinical experience and trials in CF are required to determine the place of this antimicrobial in clinical practice.

PMID: 29559421 [PubMed - as supplied by publisher]

Cystic fibrosis sputum rheology correlates with both acute and longitudinal changes in lung function.

Chest. 2018 Mar 17;:

Authors: Ma JT, Tang C, Kang L, Voynow JA, Rubin BK

Abstract
BACKGROUND: Cystic fibrosis (CF) airway secretions are abnormal, contributing to decreased clearance and a cycle of infection and inflammation. CF sputum properties may predict disease progression. We hypothesized that sputum viscoelasticity and clearance abnormalities would inversely correlate with pulmonary function during exacerbation and that sputum properties would return to baseline after therapy.
METHODS: We collected sputa longitudinally from 13 CF subjects with moderate to severe lung disease during both clinical stability and exacerbation. Dynamic rheology was analyzed using cone and plate rheometer. Mucociliary clearability was measured on mucus depleted frog palate, cough clearability in a simulated cough machine, and sputum hydration as percent solids was measured following lyophilization.
RESULTS: Elastic modulus G' and viscous modulus G" increased during exacerbation and returned to baseline levels with recovery (p<0.05 for both). Solid content did not change. Sputum mucociliary clearability decreased during exacerbations (p<0.01) but not cough clearance. FEV1% predicted was inversely correlated with G' and G" (p< 0.01 for both). The regression slope of the natural log transformed of G' and G" vs FEV1% predicted was statistically homogenous among subjects (estimated common slope m = -3.84, p<0.001 and m = -8.53, p<0.0001, respectively).
CONCLUSIONS: Among these subjects with CF, there is a striking identity of the slope defining the relationship between ln Gꞌ or ln G" and FEV1. There are dramatic increases in dynamic viscosity and elasticity during a pulmonary exacerbation with return to baseline at recovery. This suggests that sputum viscoelastic properties are tightly associated with lung function and disease status.

PMID: 29559310 [PubMed - as supplied by publisher]

Sweat chloride testing: controversies and issues.

Lancet Respir Med. 2016 08;4(8):605-607

Authors: Kharrazi M, Milla C, Wine J

PMID: 27511631 [PubMed - indexed for MEDLINE]

Pilot evaluation of ivacaftor for chronic bronchitis.

Lancet Respir Med. 2016 06;4(6):e32-3

Authors: Solomon GM, Hathorne H, Liu B, Raju SV, Reeves G, Acosta EP, Dransfield MT, Rowe SM

PMID: 27185048 [PubMed - indexed for MEDLINE]

Mefloquine for preventing malaria in pregnant women.

Cochrane Database Syst Rev. 2018 Mar 21;3: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%; high-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; high-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; high-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: 29561063 [PubMed - as supplied by publisher]

A Chinese medicine warm compress (Wen Jing Zhi Tong Fang), combined with WHO 3-step analgesic ladder treatment for cancer pain relief: A comparative randomized trial.

Medicine (Baltimore). 2018 Mar;97(11):e9965

Authors: Cai P, Li L, Hong H, Zhang L, He C, Chai X, Liu B, Chen Z

Abstract
INTRODUCTION: This study aimed to assess the effectiveness of Chinese medicine warm compress (CMWC) on back meridians in relieving cancer pain, reducing adjuvant analgesic doses and adverse reactions, and improving the quality of life (QOL).
METHODS: A total of 62 patients (age range 39-82 years) diagnosed with a malignant tumor and suffering from cancer-related pain were randomly divided into a treatment group (group A) and a control group (group B) (n = 31 for each). The patients in both groups were administered appropriate drugs for 2 cycles of 7-day treatments according to the World Health Organization (WHO) 3-step ladder for cancer pain relief in adults. In addition, a CMWC was given to patients in group A. Pain relief was assessed using the visual analogue scale (VAS) at various time points before and after interventions in each group. Alteration of analgesic doses, adverse reactions, performance status (PS), and QOL were evaluated and any differences between groups A and B evaluated.
RESULTS: VAS scores at various time points after treatment were significantly decreased compared with the baseline level in group A. Overall response rate was significantly improved in group A compared with group B (70.97% vs 29.03%, P < .001). Significant differences in clinical pain relief efficacy in various locations were found in group A after treatment vs before treatment (P < .05). Adjuvant analgesic doses were significantly changed in the control group compared to the treatment group after 1 cycle of 7-day treatment (22.58% vs 12.90%, P = .023). QOL were improved more in group A than in group B (3.00 ± 4.23 vs -2.06 ± 2.38, P < .001). Significantly reduced adverse reactions were observed after treatment of group A compared with group B in terms of the overall incidence (3.23% vs 80.65%, P < .05) or incidence of constipation (3.23% vs 77.42%, P < .05).
CONCLUSIONS: The application of CMWC on back meridians combined with WHO 3-step analgesic ladder treatment was effective in relieving cancer-related pain with reduced doses, less adverse reactions, and improved QOL.

PMID: 29538220 [PubMed - indexed for MEDLINE]

Improving multiple sclerosis management and collecting safety information in the real world: the MSDS3D software approach.

Expert Opin Drug Saf. 2018 Apr;17(4):369-378

Authors: Haase R, Wunderlich M, Dillenseger A, Kern R, Akgün K, Ziemssen T

Abstract
INTRODUCTION: For safety evaluation, randomized controlled trials (RCTs) are not fully able to identify rare adverse events. The richest source of safety data lies in the post-marketing phase. Real-world evidence (RWE) and observational studies are becoming increasingly popular because they reflect usefulness of drugs in real life and have the ability to discover uncommon or rare adverse drug reactions. Areas covered: Adding the documentation of psychological symptoms and other medical disciplines, the necessity for a complex documentation becomes apparent. The collection of high-quality data sets in clinical practice requires the use of special documentation software as the quality of data in RWE studies can be an issue in contrast to the data obtained from RCTs. The MSDS3D software combines documentation of patient data with patient management of patients with multiple sclerosis. Following a continuous development over several treatment-specific modules, we improved and expanded the realization of safety management in MSDS3D with regard to the characteristics of different treatments and populations. Expert opinion: eHealth-enhanced post-authorisation safety study may complete the fundamental quest of RWE for individually improved treatment decisions and balanced therapeutic risk assessment. MSDS3D is carefully designed to contribute to every single objective in this process.

PMID: 29436244 [PubMed - indexed for MEDLINE]

The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis.

BMC Psychiatry. 2017 Aug 24;17(1):305

Authors: Nasrallah HA, Earley W, Cutler AJ, Wang Y, Lu K, Laszlovszky I, Németh G, Durgam S

Abstract
BACKGROUND: Schizophrenia is a chronic and debilitating neuropsychiatric disorder that often requires long-term pharmacotherapy to manage symptoms and prevent relapse. Cariprazine is a potent dopamine D3 and D2 receptor partial agonist that is FDA-approved in the US for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults; the recommended dose range is 1.5-6 mg/d.
METHODS: To further characterize the long-term safety of cariprazine, data from two 48-week open-label, flexible-dose extension studies were pooled for post hoc analyses. Outcomes were evaluated in the pooled safety population (patients who received ≥1 dose of cariprazine during an open-label extension period); findings were summarized using descriptive statistics for the overall cariprazine group and in modal daily dose groups (1.5-3, 4.5-6, and 9 mg/d).
RESULTS: Of the 679 patients in the overall cariprazine safety population, 40.1% completed the study. The only adverse events (AEs) leading to discontinuation of ≥2% of patients in any dose group were akathisia, worsening of schizophrenia, and psychotic disorder. Treatment-emergent AEs (TEAEs) of akathisia, insomnia, weight increased, and headache were reported in ≥10% of the overall population. Mean prolactin levels decreased in all dose groups (overall, -15.4 ng/mL). Clinically insignificant changes in aminotransferase levels and alkaline phosphatase were observed; no dose-response relationship was observed across groups. Mean total (-5.3 mg/dL), low-density lipoprotein (-3.5 mg/dL), and high-density lipoprotein (-0.8 mg/dL) cholesterol levels decreased; no dose-response relationship was observed for metabolic parameters. Mean change in body weight was 1.58 kg; body weight increase and decrease ≥7% occurred in 27% and 11% of patients, respectively. Mean changes in cardiovascular parameters, including blood pressure and pulse, were generally not considered clinically significant. EPS-related TEAEs that occurred in ≥5% of patients were akathisia, tremor, restlessness, and extrapyramidal disorder.
CONCLUSION: In these post hoc pooled analyses of data from 2 long-term open-label studies, treatment with cariprazine was generally safe and well tolerated. Results support the safety and tolerability of cariprazine within the FDA-recommended dose range of 1.5-6 mg/d for schizophrenia.
CLINICAL TRIALS REGISTRATION: NCT01104792, NCT00839852.

PMID: 28836957 [PubMed - indexed for MEDLINE]