Therapeutic efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria from three highly malarious states in India.

Malar J. 2016 Oct 13;15(1):498

Authors: Bharti PK, Shukla MM, Ringwald P, Krishna S, Singh PP, Yadav A, Mishra S, Gahlot U, Malaiya JP, Kumar A, Prasad S, Baghel P, Singh M, Vadadi J, Singh MP, Bustos MD, Ortega LI, Christophel EM, Kashyotia SS, Sonal GS, Singh N

Abstract
BACKGROUND: Anti-malarial drug resistance continues to be a leading threat to malaria control efforts and calls for continued monitoring of waning efficacy of artemisinin-based combination therapy (ACT). Artesunate + sulfadoxine/pyrimethamine (AS + SP) is used for the treatment of uncomplicated Plasmodium falciparum malaria in India. However, resistance against AS + SP is emerged in northeastern states. Therefore, artemether-lumefantrine (AL) is the recommended first line treatment for falciparum malaria in north eastern states. This study investigates the therapeutic efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in three malaria-endemic states in India. The data generated through this study will benefit the immediate implementation of second-line ACT as and when required.
METHODS: This was a one-arm prospective evaluation of clinical and parasitological responses for uncomplicated falciparum malaria using WHO protocol. Patients diagnosed with uncomplicated mono P. falciparum infection were administered six-dose regimen of AL over 3 days and subsequent follow-up was carried out up to 28 days. Molecular markers msp-1 and msp-2 were used to differentiate recrudescence and re-infection and K13 propeller gene was amplified and sequenced covering the codon 450-680.
RESULTS: A total of 402 eligible patients were enrolled in the study from all four sites. Overall, adequate clinical and parasitological response (ACPR) was 98 % without PCR correction and 99 % with PCR correction. At three study sites, ACPR rates were 100 %, while at Bastar, cure rate was 92.5 % on day 28. No early treatment failure was found. The PCR-corrected endpoint finding confirmed that one late clinical failure (LCF) and two late parasitological failures (LPF) were recrudescences. The PCR corrected cure rate was 96.5 %. The mean fever clearance time was 27.2 h ± 8.2 (24-48 h) and the mean parasite clearance time was 30.1 h ± 11.0 (24-72 h). Additionally, no adverse event was recorded. Analysis of total 186 samples revealed a mutation in the k13 gene along with non-synonymous mutation at codon M579T in three (1.6 %) samples.
CONCLUSION: AL is an efficacious drug for the treatment of uncomplicated falciparum malaria. However, regular monitoring of AL is required in view of malaria elimination initiatives, which will be largely dependent on therapeutic interventions, regular surveillance and targeted vector control.

PMID: 27737665 [PubMed - indexed for MEDLINE]

Metamizole (Dipyrone) as an Alternative Agent in Postoperative Analgesia in Patients with Contraindications for Nonsteroidal Anti-Inflammatory Drugs.

Pain Pract. 2017 Mar;17(3):402-408

Authors: Konijnenbelt-Peters J, van der Heijden C, Ekhart C, Bos J, Bruhn J, Kramers C

Abstract
PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) play an important role in multimodal pain management. In patients with a contraindication for NSAIDs, pain management is challenging. A recent Dutch anesthesiology guideline propagates the use of metamizole (dipyrone) in these patients. Metamizole is a controversial drug, its use being previously discouraged because of the risk for agranulocytosis. We discuss whether metamizole could be an alternative to classical NSAIDs and opioids in postoperative pain management despite this drawback.
METHOD: Literature review and pharmacovigilance research based on World Health Organization adverse effect registrations.
RESULTS: Metamizole causes fewer gastric and duodenal ulcers than other nonselective NSAIDs, and the risk for bleeding is limited. It is unknown whether it is safer than a nonselective NSAID combined with a proton pump inhibitor. Although the drug appears to be safe for renal function in healthy volunteers, data in high-risk patients (eg, those with heart or renal failure) are lacking. The incidence of metamizole-induced agranulocytosis is controversial, but the risk is likely to be limited with short-term postoperative use in this selected group of patients.
CONCLUSION: Although firm evidence is lacking, metamizole may be safer for the upper intestinal tract and kidneys than other NSAIDs, and could alternatively be used in patients with an increased risk for stomach or renal problems. Hereby, improved postoperative pain relief can potentially be achieved. The risk for metamizole-induced agranulocytosis is judged to be acceptable.

PMID: 27346584 [PubMed - indexed for MEDLINE]

Pharmacological Treatment of Pain in Cancer Patients: The Role of Adjuvant Analgesics, a Systematic Review.

Pain Pract. 2017 Mar;17(3):409-419

Authors: van den Beuken-van Everdingen MH, de Graeff A, Jongen JL, Dijkstra D, Mostovaya I, Vissers KC, national guideline working group “Diagnosis treatment of cancer pain”

Abstract
CONTEXT: In patients with cancer, pain is one of the most feared and burdensome symptoms. Adjuvant analgesics are an important cornerstone on which treatment of pain in patients with cancer is based.
OBJECTIVES: To update our guidelines for the treatment of pain in patients with cancer, we performed a systematic review on the use of adjuvant analgesics in pain in cancer.
METHODS: A systematic search of the literature was performed searching for articles that studied the effect of (1) antidepressants, (2) anti-epileptics, (3) N-methyl-d-aspartate (NMDA) receptor antagonists, and (4) other adjuvant analgesics in patients with cancer pain and described their effects on pain intensity and/or side effects.
RESULTS: Based on the keywords and after reading the full papers, we could include 12 papers on anticonvulsants, 10 papers on antidepressants, four on NMDA receptor antagonists, and 10 papers on other adjuvant analgesics. The methodological quality of the included papers was graded as low to very low. Overall, there was a low quality of evidence that gabapentin, pregabalin, amitriptyline, and venlafaxine were effective in reducing pain intensity in patients with cancer pain. There was insufficient evidence on the effectiveness of lamotrigine, levetiracetam, NMDA antagonists, cannabinoids, corticosteroids, and local anesthetics on reducing pain intensity in patients with cancer pain.
CONCLUSION: The quality of currently available evidence on the effectiveness of adjuvant analgesics in the treatment of cancer pain is low. The treatment of pain associated with cancer should be tailored to the patient's personal preferences.

PMID: 27207115 [PubMed - indexed for MEDLINE]

Ertapenem-Induced Thrombocytosis.

Cureus. 2017 May 19;9(5):e1263

Authors: Docobo RA, Bukhari S, Qutrio Baloch Z

Abstract
Ertapenem is a β-lactam antibiotic that has a broad spectrum of anti-microbial coverage. Hematological adverse events like thrombocytosis, neutropenia, and neutropenia are infrequent. Here we report a rare case of drug-induced thrombocytosis in a 68-year-old female, who was treated with ertapenem for the diagnosis of complicated abdominal infection. This case emphasizes that any patient with thrombocytosis should be assessed with a careful and detailed history with consideration for possible drug side effects.

PMID: 28652947 [PubMed - in process]

Age-related trends in injection site reaction incidence induced by the tumor necrosis factor-α (TNF-α) inhibitors etanercept and adalimumab: the Food and Drug Administration adverse event reporting system, 2004-2015.

Int J Med Sci. 2017;14(2):102-109

Authors: Matsui T, Umetsu R, Kato Y, Hane Y, Sasaoka S, Motooka Y, Hatahira H, Abe J, Fukuda A, Naganuma M, Kinosada Y, Nakamura M

Abstract
Tumor necrosis factor-α (TNF-α) inhibitors are increasingly being used as treatment for rheumatoid arthritis (RA). However, the administration of these drugs carries the risk of inducing injection site reaction (ISR). ISR gives rise to patient stress, nervousness, and a decrease in quality of life (QoL). In order to alleviate pain and other symptoms, early countermeasures must be taken against this adverse event. In order to improve understanding of the risk factors contributing to the induction of ISR, we evaluated the association between TNF-α inhibitors and ISR by applying a logistic regression model to age-stratified data obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The FAERS database contains 7,561,254 reports from January 2004 to December 2015. Adjusted reporting odds ratios (RORs) (95% Confidence Intervals) were obtained for interaction terms for age-stratified groups treated with etanercept (ETN) and adalimumab (ADA). The adjusted RORs for ETN* ≥ 70 and ADA* ≥ 70 groups were the lowest among the age-stratified groups undergoing the respective monotherapies. Furthermore, we found that crude RORs for ETN + methotrexate (MTX) combination therapy and ADA + MTX combination therapy were lower than those for the respective monotherapies. This study was the first to evaluate the relationship between aging and ISR using the FAERS database.

PMID: 28260984 [PubMed - indexed for MEDLINE]

India's changing clinical trials scene.

Lancet. 2016 12 03;388(10061):2727-2728

Authors: Bahri C

PMID: 27924767 [PubMed - indexed for MEDLINE]

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Efficacy and safety of tenofovir disoproxil fumarate in preventing vertical transmission of hepatitis B in pregnancies with high viral load.

Sci Rep. 2017 Jun 23;7(1):4132

Authors: Chen JZ, Liao ZW, Huang FL, Su RK, Wang WB, Cheng XY, Chen JQ, Liu JQ, Huang Z

Abstract
This study was a meta-analysis of the literature on the efficacy and safety of tenofovir disoproxil fumarate (TDF) in preventing vertical transmission of hepatitis B in pregnancies with high viral load. Four observational studies and one randomized controlled trial involving 585 pregnant women and 595 newborns were included in the meta-analysis. TDF was more effective than the placebo in reducing vertical transmission in HBeAg-positive chronic hepatitis B (CHB) pregnancies with high serum HBV-DNA levels (OR = 0.21, 95% CI = 0.07-0.61) at 4-12 months, infant HBV DNA seropositivity at delivery (OR = 0.16, 95% CI = 0.07-0.37), and a severe flair in maternal alanine aminotransferase (ALT) levels (OR = 0.43, 95% CI = 0.19-0.95) during pregnancy. In addition, TDF showed more improvement in HBV DNA suppression at delivery (OR = 254.46, 95% CI = 28.39-2280.79). No significant differences were found in HBeAg seroconversion or ALT normalization; or in rates of cesarean section, emergent cesarean section, postpartum hemorrhage, prematurity, congenital malformations, or infant death. However, TDF induced more drug-related adverse events (OR = 2.33, 95% CI = 1.39-3.89) and elevated creatine kinase (CK) (OR = 9.56, 95% CI = 1.17-78.09) than in controls. The available evidence suggests that TDF is effective and safe in preventing vertical transmission of hepatitis B in pregnancies exhibiting a high viral load.

PMID: 28646142 [PubMed - in process]

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]

[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]

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]

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]

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]

[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]

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]

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]

Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer.

Oncotarget. 2017 Jun 16;:

Authors: Shitara K, Kim TM, Yokota T, Goto M, Satoh T, Ahn JH, Kim HS, Assadourian S, Gomez C, Harnois M, Hamauchi S, Kudo T, Doi T, Bang YJ

Abstract
SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260-570 mg/m2) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort (N = 19; unselected population, including three patients with MET-amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m2. Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade ≥ 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m2 in the dose-expansion cohort, comprising patients with MET-amplified tumors (N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m2 has acceptable tolerability and modest antitumor activity in patients with MET-amplified gastric cancer.

PMID: 28636538 [PubMed - as supplied by publisher]

Sorafenib in Japanese Patients With Locally Advanced or Metastatic Medullary Thyroid Carcinoma and Anaplastic Thyroid Carcinoma.

Thyroid. 2017 Jun 21;:

Authors: Ito Y, Onoda N, Ito KI, Sugitani I, Takahashi S, Yamaguchi I, Kabu K, Tsukada K

Abstract
BACKGROUND: Therapeutic options for treating advanced or metastatic medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma (ATC) are still limited in Japan even though vandetanib for MTC, and lenvatinib for MTC and ATC have been approved. Sorafenib is an oral multikinase inhibitor approved for the treatment of patients with radioactive iodine-refractory (RAI-R) differentiated thyroid cancer (DTC). We conducted an uncontrolled, open-label, multicenter, single-arm, phase 2 clinical study to evaluate the safety and efficacy of sorafenib in Japanese patients with MTC and ATC.
METHODS: Japanese patients with histologically confirmed ATC and locally advanced or metastatic MTC were enrolled from April to September 2014. The primary endpoint was to evaluate the safety of sorafenib. Treatment efficacy variables including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and maximum reduction in tumor size were evaluated as secondary endpoints. Patients received sorafenib 400 mg orally twice daily on a continuous basis and then continued treatment until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent.
RESULTS: A total of 20 patients were screened and 18, including 8 with MTC and 10 with ATC, were enrolled. The most common drug-related adverse events were palmar-plantar erythrodysesthesia (72%), alopecia (56%), hypertension (56%), and diarrhea (44%). In the ATC patients, median PFS was 2.8 months (95% CI, 0.7-5.6), and median OS was 5.0 months (95% CI, 0.7-5.7); ORR and DCR were 0% and 40%, respectively. In the MTC population, neither median PFS nor OS had been reached at the time of this analysis; ORR was 25% and DCR was 75%.
CONCLUSIONS: The toxicities reported in this study were consistent with the known safety profile of sorafenib. Sorafenib seems to be effective in the treatment of advanced MTC but not ATC and could be a new treatment option for locally advanced or metastatic MTC and RAI-R DTC.

PMID: 28635560 [PubMed - as supplied by publisher]

No blank slates: Pre-existing schemas about pharmaceuticals predict memory for side effects.

Psychol Health. 2017 Apr;32(4):402-421

Authors: Heller MK, Chapman SC, Horne R

Abstract
OBJECTIVES: Attribution of symptoms as medication side effects is informed by pre-existing beliefs about medicines and perceptions of personal sensitivity to their effects (pharmaceutical schemas). We tested whether (1) pharmaceutical schemas were associated with memory (recall/recognition) for side effect information (2) memory explained the attribution of a common unrelated symptom as a side effect.
DESIGN: In this analogue study participants saw the patient leaflet of a fictitious asthma drug listing eight side effects.
MAIN OUTCOME MEASURES: We measured recall and recognition memory for side effects and used a vignette to test whether participants attributed an unlisted common symptom (headache) as a side effect.
RESULTS: Participants who perceived pharmaceuticals as more harmful in general recalled fewer side effects correctly (rCorrect Recall = -.273), were less able to differentiate between listed and unlisted side effects (rRecognition Sensitivity = -.256) and were more likely to attribute the unlisted headache symptom as a side effect (rside effect attribution = .381, ps < .01). The effect of harm beliefs on side effect attribution was partially mediated by correct recall of side effects.
CONCLUSION: Pharmaceutical schemas are associated with memory for side effect information. Memory may explain part of the association between pharmaceutical schemas and the attribution of unrelated symptoms as side effects.

PMID: 28219295 [PubMed - indexed for MEDLINE]