Oral Cholic Acid is Efficacious and well Tolerated in Patients with Bile Acid Synthesis and Zellweger Spectrum Disorders.

J Pediatr Gastroenterol Nutr. 2017 Jun 21;:

Authors: Heubi JE, Bove KE, Setchell KDR

Abstract
BACKGROUND/AIMS: Patients with bile acid synthesis disorders (BASD) due to single enzyme defects (SED) or Zellweger spectrum disorders (ZSD) accumulate hepatotoxic atypical bile acids resulting in potentially fatal progressive liver disease. We evaluated the efficacy and safety of oral cholic acid in patients with BASD.
METHODS: In this phase 3, open-label, single-arm, nonrandomized, noncomparative study conducted over 18 years, patients were administered cholic acid orally 10 to 15 mg/kg/day. The primary efficacy variables were changes from pre- to post-treatment in atypical urinary bile acids, liver chemistries (serum aspartate aminotransferase [AST], alanine aminotransferase [ALT]), and height and weight. Additional efficacy variables included changes in serum bilirubin and liver histology.
RESULTS: Of 85 enrolled patients (63 with SED and 22 with ZSD), 79 received at least 1 dose of study medication; 70 patients (50 with SED and 20 with ZSD) were included in the modified intent-to-treat dataset. Cholic acid significantly improved urine bile acid metabolite scores (P < 0.0001) and serum AST and ALT (P < 0.0001) in patients with SED and ZSD. Cholic acid also improved height and weight percentiles in both groups, but only the change in weight was significant (P < 0.05). Serum direct bilirubin decreased significantly post-treatment (P < 0.001) in the ITT population, and liver biopsies showed either stable findings or histologic improvement in all parameters except bridging fibrosis. The overall safety profile of cholic acid was favorable, with no study drug-related serious adverse events or drug-related deaths reported.
CONCLUSION: Oral cholic acid is a safe, efficacious, and well-tolerated treatment for BASD due to SED and ZSD.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.

PMID: 28644367 [PubMed - as supplied by publisher]

Dexmedetomidine and general anesthesia: a narrative literature review of its major indications for use in adults undergoing non-cardiac surgery.

Minerva Anestesiol. 2017 Jun 22;:

Authors: Davy A, Fessler J, Fischler M, le Guen M

Abstract
BACKGROUND: In Europe, dexmedetomidine has marketing approval only for sedation in intensive care units. However, its use during general anesthesia has been widely reported. The aim of this narrative review is to draw a picture of potential indications in anesthesia.
METHODS: We searched in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials using the keywords "Dexmedetomidine, Dexdor, Precedex and Dexdomitor". The research ended in December 2016. Studies were eligible for inclusion they reported the use of dexmedetomidine in adults receiving general anesthesia. We excluded studies related to cardiac surgery and studies reporting the use of dexmedetomidine as an adjuvant of locoregional anesthesia.
RESULTS: Several potential uses for dexmedetomidine during general anesthesia are described, especially: awake fiber optic intubation, the sparing effect of dexmedetomidine on hypnotic and opioid drugs, prevention of postoperative pain, nausea and vomiting and shivering, improvement of postoperative sleep and postoperative recovery, opioid-free anesthesia, use in craniotomy, endovascular stroke treatment and drug-induced sleep endoscopy. A protective effect against cardiac complications, an anti-inflammatory effect, and side effects, particularly bradycardia, are also described.
CONCLUSIONS: The properties of dexmedetomidine lead to its use for elective indications such as awake fiberoptic intubation and neurosurgical anesthesia. New topics are under debate. These subjects must be studied thoroughly because of their implication in the patients' surgical course. These advantages must be weighed against the major drawback of dexmedetomidine administration which is the potential for hemodynamic abnormalities.

PMID: 28643999 [PubMed - as supplied by publisher]

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[Clinical aspects of treatment with amiodarone].

Herzschrittmacherther Elektrophysiol. 2017 Jun 22;:

Authors: Haverkamp W, Israel C, Parwani A

Abstract
Amiodarone has multiple and complex electrophysiological effects that render it a very effective antiarrhythmic drug for the treatment of both, supraventricular and ventricular arrhythmias. Proarrhythmic effects of amiodarone in patients with structural heart disease are rare. However, extracardiac adverse effects occurring in association with amiodarone treatment are frequent and feared. These adverse effects have usually been related to total amiodarone exposure (i. e., dose and duration of treatment). Parallel to a more frequent use of lower amiodarone maintenance doses (100-200 mg/day), the incidence of severe unwanted extracardiac side effects has decreased. High-dose maintenance regiments (daily dose ≥300 mg) are usually obsolete. This paper discusses recommendations regarding the monitoring of cardiac and extracardiac side effects of amiodarone. They need to be regarded by physicians using amiodarone to ensure long-term safety of amiodarone therapy.

PMID: 28643175 [PubMed - as supplied by publisher]

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Combined data of intravaginal prasterone against vulvovaginal atrophy of menopause.

Menopause. 2017 Jun 19;:

Authors: Labrie F, Archer DF, Martel C, Vaillancourt M, Montesino M

Abstract
OBJECTIVE: To analyze the effects of intravaginal prasterone obtained in the three randomized clinical studies performed in postmenopausal women suffering from moderate to severe (MS) dyspareunia due to vulvovaginal atrophy (VVA).
METHODS: In three independent 12-week prospective, randomized, double-blind, and placebo-controlled clinical studies, the effect of daily intravaginal 0.50% (6.5 mg) prasterone was examined on four co-primary objectives in women having MS pain during sexual activity (dyspareunia), identified as their most bothersome symptom (MBS) of VVA at baseline.
RESULTS: In 436 women treated with 0.50% prasterone and 260 women who received placebo, an average 35.1% decrease over placebo in the percentage of parabasal cells (P < 0.0001), an average 7.7% increase in the percentage of superficial cells (P < 0.0001), and a mean 0.72 pH unit decrease in vaginal pH (P < 0.0001) were observed. The severity score of most bothersome symptom dyspareunia was decreased by a 0.46 unit (49%) (P < 0.0001 over placebo), whereas the severity score of MS vaginal dryness decreased by 0.31 unit (P < 0.0001 over placebo). A very positive evaluation was obtained on the acceptability of the technique of administration of the insert, whereas the male partners reported a very positive evaluation of the changes observed in their sexual partner.
CONCLUSION: The efficacy data demonstrate highly positive effects on all the symptoms and signs of vulvovaginal atrophy with no significant drug-related side effects in line with the physiology of menopause and intracrinology.

PMID: 28640161 [PubMed - as supplied by publisher]

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Safety of a fixed-dose combination of artesunate and amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in real-life conditions of use in Côte d'Ivoire.

Malar J. 2017 Jan 03;16(1):8

Authors: Assi SB, Aba YT, Yavo JC, Nguessan AF, Tchiekoi NB, San KM, Bissagnéné E, Duparc S, Lameyre V, Tanoh MA

Abstract
BACKGROUND: In many malaria-endemic, sub-Saharan African countries, existing pharmacovigilance systems are not sufficiently operational to document reliably the safety profile of anti-malarial drugs. This study describes the implantation of a community-based pharmacovigilance system in Côte d'Ivoire and its use to document the safety of ASAQ Winthrop(®) (artesunate-amodiaquine).
METHODS: This prospective, longitudinal, descriptive, non-comparative, non-interventional study on the use of artesunate-amodiaquine in real-life conditions of use was conducted in seven Community Health Centres of the Agboville district in Côte d'Ivoire. Twenty trained Health Centre employees and 70 trained community health workers were involved in data collection in the field. All patients with suspected uncomplicated falciparum malaria, seeking treatment at one of the participating Health Centres, and treated with artesunate-amodiaquine could be enrolled. Two visits were planned, one for inclusion at the Health Centre and a second at home, performed by a community health worker 3-10 days after the inclusion visit. Administration of artesunate-amodiaquine was unsupervised. Adverse events (AEs) were documented at the home visit or during any unexpected visit to the Health Centre or to the hospital and coded and adjudicated by a local pharmacovigilance committee. Symptoms suggestive of hepatic failure, severe neutropaenia, extrapyramidal disorders and retinopathy were considered a priori as AEs of special interest.
RESULTS: Some 15,228 malaria episodes in 12,198 patients were evaluated; 2545 AEs were documented during 1978 malaria episodes (13.0%). The most frequently observed events were asthenia (682 cases), vomiting (482 cases) and somnolence (174 cases). Most reported AEs were of mild or moderate intensity and resolved without corrective treatment. One-hundred and five (105) AEs reported during 100 episodes (0.7%) were considered as serious. Three serious cases of transient extrapyramidal disorders, identified as AEs of special interest were reported in three patients.
CONCLUSION: The fixed dose artesunate-amodiaquine combination ASAQ Winthrop(®) for the unsupervised treatment of uncomplicated falciparum malaria under real-life conditions of care in Côte d'Ivoire is well tolerated. The study emphasizes the interest of involving properly trained community health workers to collect pharmacovigilance data in the field in order to document rare AEs.

PMID: 28049523 [PubMed - indexed for MEDLINE]

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Lot-to-lot Consistency, Safety, Tolerability and Immunogenicity of an Investigational Hexavalent Vaccine in US Infants.

Pediatr Infect Dis J. 2017 Feb;36(2):202-208

Authors: Block SL, Klein NP, Sarpong K, Russell S, Fling J, Petrecz M, Flores S, Xu J, Liu G, Stek JE, Foglia G, Lee AW

Abstract
BACKGROUND: This multicenter phase III study (NCT01340937) evaluated the consistency of immune responses to 3 separate lots of diphtheria-tetanus toxoids-acellular pertussis 5, inactivated poliovirus vaccine, Haemophilus influenzae type b, and hepatitis B (DTaP5-IPV-Hib-HepB), an investigational hexavalent vaccine (HV).
METHODS: Healthy infants were randomized (2:2:2:1) to receive HV or Pentacel (Control). Groups 1, 2 and 3 received HV at 2, 4 and 6 months, and Control at 15 months. Group 4 received Control at 2, 4, 6 and 15 months, plus Recombivax HB (HepB) at 2 and 6 months. Concomitant Prevnar 13 was given to all groups at 2, 4, 6 and 15 months; pentavalent rotavirus vaccine (RV5) was given to all groups at 2, 4 and 6 months. Blood specimens (3-5 mL) were collected immediately before administration of dose 1, postdose 3, immediately before toddler dose, and after toddler dose. Adverse events were recorded after each vaccination.
RESULTS: The 3 manufacturing lots of HV induced consistent antibody responses to all antigens. Immunogenicity of HV was noninferior to Control for all antibodies, except for pertussis filamentous hemagglutinin geometric mean concentration postdose 3, and pertussis pertactin (PRN) geometric mean concentration after toddler dose. Postdose 3 immunogenicity of concomitantly administered Prevnar 13 was generally similar (except for serotype 6B) when given with HV or Control. Adverse events of HV were similar to Control, except for a higher rate of fever ≥38.0°C [49.2% vs. 35.4%, estimated difference 13.7% (8.4, 18.8)].
CONCLUSIONS: HV demonstrated lot-to-lot manufacturing consistency; safety and immunogenicity were comparable with the licensed vaccines. HV provides a new combination vaccine option within the US 2-month, 4-month and 6-month vaccine series.

PMID: 27846058 [PubMed - indexed for MEDLINE]

Related Articles

[Polypharmacy viewed not only through the prism of multi-morbidity, but also as an independent geriatric syndrome].

Vnitr Lek. Fall 2016;62(9 Suppl 3):135-139

Authors: Weber P, Meluzínová H, Prudius D, Bielaková K

Abstract
Polypharmacy is common in the elderly, especially in the late age (over 75 years). Usually it is closely related to the geriatric multi-morbidity. The authors highlight the medication used in the anticipated positive and potential negative potential. While physicians often must make difficult trade-offs between the guidelines on one hand and complicated multi-morbidity, on the other hand, while trying to avoid polypharmacy ( 5 drugs), especially excessive polypharmacy ( 10 drugs). Multimorbid elderly patients who are treated in accordance with guidelines typically use large amounts of medicaments. This polypharmacy increases the risk of adverse drug reactions and drug interactions. The authors point out the pitfalls of performance of large clinical studies and EBM on one side and the daily clinical practice at the risk of their indiscriminate application, albeit with good intentions to improve the health of seniors.Key words: evidence based medicine - geriatrisation of medicine - multi-morbidity - old age - polypharmacy - prescription - randomized clinical trials.

PMID: 27734707 [PubMed - indexed for MEDLINE]

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Incidence and Clinical Associations of Childhood Acute Pancreatitis.

Pediatrics. 2016 Sep;138(3):

Authors: Majbar AA, Cusick E, Johnson P, Lynn RM, Hunt LP, Shield JP

Abstract
OBJECTIVES: To establish the UK incidence and clinical associations of acute pancreatitis (AP) in children aged 0 to 14 years.
METHODS: Monthly surveillance of new cases of AP in children under 15 years of age through the British Pediatric Surveillance Unit conducted from April 2013 to April 2014 (inclusive) followed by 1-year administrative follow-up for all valid cases.
RESULTS: Ninety-four cases (48 boys) fulfilled the diagnostic criteria. The median age at diagnosis was 11.2 years (range 1.3-14.9). White children accounted for 61% of the cases compared with 28% from Asian and 5% from African ethnicities. Pakistani children accounted for 18 of 26 (69%) Asian patients and 19% of the total cohort. The incidence of AP in children in the United Kingdom was 0.78 per 100 000/year (95% confidence interval [CI] 0.62-0.96). The incidence in Pakistani children (4.55; 95% CI 2.60-7.39) was sevenfold greater than white children (0.63; 95% CI 0.47-0.83). Of the 94 cases, 35 (37%) were idiopathic; other associations were: drug therapy, 18 (19%); gallstones, 12 (13%); hereditary, 7 (7%); organic acidemias, 7 (7%); anatomic anomalies, 5 (5%); viral infections, 3 (3%); systemic diseases, 2 (2%); and trauma 1 (1%). The most common drug associations were asparaginase (28%), azathioprine (17%), and sodium valproate (17%).
CONCLUSIONS: Although still relatively uncommon in the United Kingdom, on average there is >1 case of childhood AP diagnosed every week. The associations of AP have changed significantly since the 1970-80s. Overrepresentation of Pakistani children is worthy of further investigation.

PMID: 27535145 [PubMed - indexed for MEDLINE]

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Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine.

Neuropharmacology. 2016 Jun;105:215-27

Authors: Zadina JE, Nilges MR, Morgenweck J, Zhang X, Hackler L, Fasold MB

Abstract
Opioids acting at the mu opioid receptor (MOR) are the most effective analgesics, however adverse side effects severely limit their use. Of particular importance, abuse liability results in major medical, societal, and economic problems, respiratory depression is the cause of fatal overdoses, and tolerance complicates treatment and increases the risk of side effects. Motor and cognitive impairment are especially problematic for older adults. Despite the host of negative side effects, opioids such as morphine are commonly used for acute and chronic pain conditions. Separation of analgesia from unwanted effects has long been an unmet goal of opioid research. Novel MOR agonist structures may prove critical for greater success. Here we tested metabolically stable analogs of the endomorphins, endogenous opioids highly selective for the MOR. Compared to morphine, the analogs showed dramatically improved analgesia-to-side-effect ratios. At doses providing equal or greater antinociception than morphine in the rat, the analogs showed reduced a) respiratory depression, b) impairment of motor coordination, c) tolerance and hyperalgesia, d) glial p38/CGRP/P2X7 receptor signaling, and e) reward/abuse potential in both conditioned place preference and self-administration tests. Differential effects on glial activation indicate a mechanism for the relative lack of side effects by the analogs compared to morphine. The results suggest that endomorphin analogs described here could provide gold standard pain relief mediated by selective MOR activation, but with remarkably safer side effect profiles compared to opioids like morphine.

PMID: 26748051 [PubMed - indexed for MEDLINE]

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