Randomized trial to assess the efficacy and safety of xyloglucan for the treatment of acute gastroenteritis in children.

Acute gastroenteritis is one of the most common diseases in children and an important cause of morbidity and mortality worldwide. No specific treatment is available; therefore, management is exclusively symptomatic. Xyloglucan has been approved in Europe as a class IIa medical device for restoration of the physiological functions of the intestinal wall. Our objective was to assess efficacy and safety of xyloglucan for the treatment of acute gastroenteritis in children. We performed a triple-blind, randomized placebo-controlled clinical trial in four primary care centers and one continued care hospital center. The study population comprised children with acute gastroenteritis aged >3 months and <5 years. Our primary endpoint was time (in hours) of resolution of diarrhea, defined as the time to resolution of stool consistency (Bristol Stool Form Scale ≤5 or Amsterdam Stool Form Scale B or C) or time until deposition frequency resumes to normality, whichever occurred first. We also recorded intravenous rehydration, hospitalization, stools per day, Vesikari scale, vomiting, relapse, weight loss, drugs prescribed, and adverse events. Eighty children were included in the intention-to-treat population (43 xyloglucan and 37 placebo) and 74 (93%) in the per-protocol population. Time to resolution of diarrhea was similar in both groups with (median, 95% CI) 24, 17-24 h in the xyloglucan group versus 24, 19-24 h in the placebo group, p = .680. Significant differences were observed for patients with moderate-to-severe diarrhea (Vesikari scale ≥9): xyloglucan group (20 [15-24] h) versus placebo group (85 [51-120] h) (p = .04). No other significant differences were found. Xyloglucan can be considered safe and other studies should be performed to confirm the usefulness in patients with moderate-to-severe diarrhea.

Management of Helicobacter pylori infection in paediatric patients in Europe: results from the EuroPedHp Registry.

PURPOSE: The EuroPedHp-registry aims to monitor guideline-conform management, antibiotic resistance, and eradication success of 2-week triple therapy tailored to antibiotic susceptibility (TTT) in Helicobacter pylori-infected children. METHODS: From 2017 to 2020, 30 centres from 17 European countries reported anonymized demographic, clinical, antibiotic susceptibility, treatment, and follow-up data. Multivariable logistic regression identified factors associated with treatment failure. RESULTS: Of 1605 patients, 873 had follow-up data (53.2% female, median age 13.0 years, 7.5% with ulcer), thereof 741 (85%) treatment naïve (group A) and 132 (15%) after failed therapy (group B). Resistance to metronidazole was present in 21% (A: 17.7%, B: 40.2%), clarithromycin in 28.8% (A: 25%, B: 51.4%), and both in 7.1% (A: 3.8%, B: 26.5%). The majority received 2-week tailored triple therapy combining proton pump inhibitor (PPI), amoxicillin with clarithromycin (PAC) or metronidazole (PAM). Dosing was lower than recommended for PPI (A: 49%, B: 41%) and amoxicillin (A: 6%, B: 56%). In treatment naïve patients, eradication reached 90% (n = 503, 95% CI 87-93%) and 93% in compliant children (n = 447, 95% CI 90-95%). Tailored triple therapy cured 59% patients after failed therapy (n = 69, 95% CI 48-71%). Treatment failure was associated with PAM in single clarithromycin resistance (OR = 2.47, 95% CI 1.10-5.53), with PAC in single metronidazole resistance (OR = 3.44, 95% CI 1.47-8.08), and with low compliance (OR = 5.89, 95% CI 2.49-13.95). CONCLUSIONS: Guideline-conform 2-weeks therapy with PPI, amoxicillin, clarithromycin or metronidazole tailored to antibiotic susceptibility achieves primary eradication of ≥ 90%. Higher failure rates in single-resistant strains despite tailored treatment indicate missed resistance by sampling error.

Manejo de la infección por Helicobacter pylori en la edad pediátrica / Management of Helicobacter pylori infection in the pediatric age

El manejo de la infección por Helicobacter pylori en los niños es un dilema permanente en la práctica clínica. A lo largo de los años se han ido creando multitud de interrogantes respecto a los síntomas ligados a la infección, los métodos diagnósticos y los modos de tratamiento, siendo la más controvertida la indicación diagnóstica.En los últimos 10 años el colectivo pediátrico ha dispuesto de una guía elaborada por expertos de las Sociedades de Gastroenterología Pediátrica de Europa (ESPGHAN) y Estados Unidos (NASPGHAN) publicada en 2011 y actualizada en 2017 que nos ha orientado en el manejo de la infección por H.pylori en la edad pediátrica.El presente documento pretende unificar los criterios de indicación de estudio así como las pautas de diagnóstico y tratamiento de la infección por H.pylori en los niños y adolescentes para que puedan ser utilizadas tanto en atención primaria como en la clínica hospitalaria. (AU)

The management of Helicobacter pylori infection in children is a consistent problem in clinical practice. Over the years, many questions have been raised regarding symptoms associated with the infection, the diagnostic methods and type of treatment. What is most controversial is determining the criteria that enable us to initiate and carry out the study in children.In the last 10 years, pediatricians have followed the joint ESPGHAN/NASPGHAN guidelines published in 2011 and updated in 2017 in the management of H.pylori in children.This document aims to unify the study indication criteria as well as the diagnosis and treatment recommendations for H.pylori infection in children and adolescents, so they can be used in both Primary and Hospital care. (AU)

Management of Helicobacter pylori infection in the pediatric age.

The management of Helicobacter pylori infection in children is a consistent problem in clinical practice. Over the years, many questions have been raised regarding symptoms associated with the infection, the diagnostic methods and type of treatment. What is most controversial is determining the criteria that enable us to initiate and carry out the study in children. In the last 10 years, pediatricians have followed the joint ESPGHAN/NASPGHAN guidelines published in 2011 and updated in 2017 in the management of H. pylori in children. This document aims to unify the study indication criteria as well as the diagnosis and treatment recommendations for H. pylori infection in children and adolescents, so they can be used in both Primary and Hospital care.

[Management of Helicobacter pylori infection in the pediatric age]. / Manejo de la infección por Helicobacter pylori en la edad pediátrica.

The management of Helicobacter pylori infection in children is a consistent problem in clinical practice. Over the years, many questions have been raised regarding symptoms associated with the infection, the diagnostic methods and type of treatment. What is most controversial is determining the criteria that enable us to initiate and carry out the study in children. In the last 10 years, pediatricians have followed the joint ESPGHAN/NASPGHAN guidelines published in 2011 and updated in 2017 in the management of H.pylori in children. This document aims to unify the study indication criteria as well as the diagnosis and treatment recommendations for H.pylori infection in children and adolescents, so they can be used in both Primary and Hospital care.

Management of small intestinal bacterial overgrowth by pediatric gastroenterologists in Spain.

BACKGROUND: small intestinal bacterial overgrowth (SIBO) is a heterogeneous condition with nonspecific symptoms. This study aimed to report its management by pediatric gastroenterologists in Spain. METHODS: a descriptive study was performed by means of a survey sent to 184 active members of the Spanish Society of Pediatric Gastroenterology, Hepatology and Nutrition (SEGHNP). RESULTS: one hundred and forty-eight responses (80.4 %) were received. Forty-four patients had no predisposing condition, 31.1 % used antibiotics followed by probiotics, 33.1 % antibiotherapy concomitant with probiotics, 24.3 % only antibiotics and 10.8 % only probiotics. The diagnosis was established via clinical parameters in 73.8 % of participants and the therapeutic response was checked only by clinical data in 90 %. CONCLUSIONS: there is high variability in the management of SIBO among pediatric population in Spain.

Respuesta de los autores: Estandarización, adaptación y validación de pruebas psicométricas: diferencias necesarias / Authors reply: Standardization, adaptation and validation of psychometric tests: Necessary differences

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Helicobacter pylori Infection in Pediatric Patients Living in Europe: Results of the EuroPedHP Registry 2013 to 2016.

OBJECTIVES: The aim of the study was to assess clinical presentation, endoscopic findings, antibiotic susceptibility and treatment success of Helicobacter pylori (H. pylori) infected pediatric patients. METHODS: Between 2013 and 2016, 23 pediatric hospitals from 17 countries prospectively submitted data on consecutive H. pylori-infected (culture positive) patients to the EuroPedHP-Registry. RESULTS: Of 1333 patients recruited (55.1% girls, median age 12.6 years), 1168 (87.6%) were therapy naïve (group A) and 165 (12.4%) had failed treatment (group B). Patients resided in North/Western (29.6%), Southern (34.1%) and Eastern Europe (23.0%), or Israel/Turkey (13.4%). Main indications for endoscopy were abdominal pain or dyspepsia (81.2%, 1078/1328). Antral nodularity was reported in 77.8% (1031/1326) of patients, gastric or duodenal ulcers and erosions in 5.1% and 12.8%, respectively. Primary resistance to clarithromycin (CLA) and metronidazole (MET) occurred in 25% and 21%, respectively, and increased after failed therapy. Bacterial strains were fully susceptible in 60.5% of group A, but in only 27.4% of group B. Primary CLA resistance was higher in Southern and Eastern Europe (adjusted odds ratio [ORadj] = 3.44, 95% confidence interval [CI] 2.22-5.32, P < 0.001 and 2.62, 95% CI: 1.63-4.22, P < 0.001, respectively) compared with Northern/Western Europe. Children born outside Europe showed higher primary MET resistance (ORadj = 3.81, 95% CI: 2.25-6.45, P < 0.001). Treatment success in group A reached only 79.8% (568/712) with 7 to 14 days triple therapy tailored to antibiotic susceptibility. CONCLUSIONS: Peptic ulcers are rare in dyspeptic H. pylori-infected children. Primary resistance to CLA and MET is markedly dependent on geographical regions of birth and residence. The ongoing survey will show whether implementation of the updated ESPGHAN/NASPGHAN guidelines will improve the eradication success.

Discovery of a Series of 2'-α-Fluoro,2'-ß-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.

Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of ß-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 µM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.

Randomized, double-blind, multicenter safety and efficacy study of rifalazil compared with azithromycin for treatment of uncomplicated genital Chlamydia trachomatis infection in women.

A randomized, double-blind study comparing single-dose chlamydia therapies of oral rifalazil (25 mg) and azithromycin (1 g) was conducted in 82 women with uncomplicated genital Chlamydia trachomatis infection. The microbiologic cure rate of C. trachomatis with rifalazil (n = 33) was 84.8% at the visit on day 22 to 26 (test-of-cure visit), versus 92.1% with azithromycin (n = 38), and the number of treatment failures in each group was 5 and 3, respectively. The difference in cure rate was -7.3%, with a lower limit of the 95% confidence interval (95% CI) of -22.5, and thus, noninferiority was not established at the prespecified margin (lower limit of CI of -15%). The overall treatment-emergent adverse event (TEAE) and treatment-related TEAE rates were lower in the rifalazil group (68% and 55%) than in the azithromycin group (71% and 62%), respectively. Subjects classified as treatment failures at day 22 to 26 had a lower mean plasma concentration of rifalazil at the visit on day 8 to 12 than those classified as treatment cures, but this difference was not significant; however, the levels were similar for both groups at the visit on day 22 to 26. A single 25-mg dose of rifalazil was well tolerated and eradicated C. trachomatis in most of these women with uncomplicated genital C. trachomatis infection. (The study was registered at clinicaltrials.gov under registration no. NCT01631201).

Tramadol hydrochloride extended-release once-daily in the treatment of osteoarthritis of the knee and/or hip: a double-blind, randomized, dose-ranging trial.

This 12-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial evaluated tramadol ER (extended-release tramadol) in the management of osteoarthritis pain. Adults with knee and/or hip osteoarthritis and baseline pain intensity of ≥40 on a 100-mm visual analog scale (0 = no pain, 100 = extreme pain) received once-daily tramadol ER 100 mg (n = 201), 200 mg (n = 199), or 300 mg (n = 199), celecoxib 200 mg (n = 202; to test model sensitivity), or placebo (n = 200). Coprimary efficacy variables were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, WOMAC physical function subscale, and patient global assessment of disease activity. Tramadol ER 300 mg significantly improved patient global assessment scores compared with placebo (P ≤ 0.05), but not the other 2 coprimary efficacy variables. Tramadol ER 200 and 100 mg were not significantly different from placebo for the coprimary efficacy variables. Daily diary arthritis pain intensity scores improved significantly for tramadol ER 300 and 200 mg compared with placebo. WOMAC joint stiffness subscale, physician's global assessment, arthritis pain intensity in index and nonindex joints, and overall sleep quality scores improved significantly for tramadol ER 300 mg compared with placebo. Significant differences in efficacy between celecoxib and placebo validated the model sensitivity. Adverse events occurred more frequently with tramadol ER than placebo in the gastrointestinal (nausea, constipation, diarrhea) and central nervous (dizziness, headache) systems. In this study, tramadol ER 300 mg was effective in the management of moderate to severe painful osteoarthritis of the hip or knee. A large, increasing placebo response during the study may have contributed to the lack of statistical separation between tramadol ER 200 or 100 mg and placebo.

Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals.

BACKGROUND: Amdoxovir acts synergistically with zidovudine in vitro and the combination prevents or delays the selection of thymidine analogue and K65R mutations. In silico studies have shown that a reduced dose of zidovudine (200 mg) results in decreased zidovudine-monophosphate levels, associated with toxicity, while maintaining zidovudine-triphosphate levels, which are associated with antiviral effects. Here, we aimed to assess the short-term tolerability and antiviral activity of amdoxovir in combination with reduced and standard doses of zidovudine. METHODS: The study was a double-blind, placebo-controlled study in HIV-1-infected patients not receiving antiretroviral therapy and with plasma HIV-1 RNA > or =5,000 copies/ml. Patients were randomized to 10 days of twice-daily treatment with 200 mg zidovudine, 300 mg zidovudine, 500 mg amdoxovir, 500 mg amdoxovir plus 200 mg zidovudine or 500 mg amdoxovir plus 300 mg zidovudine. The mean change in viral load (VL) log(10) and area under the virus depletion curve (AUC(VL)) from baseline to day 10 were determined. Laboratory and clinical safety monitoring were performed. RESULTS: Twenty-four patients were enrolled. The mean VL log(10) change was 0.10 with placebo, -0.69 with zidovudine 200 mg, -0.55 with zidovudine 300 mg, -1.09 with amdoxovir, -2.00 with amdoxovir plus zidovudine (200 mg) and -1.69 with amdoxovir plus zidovudine (300 mg). Amdoxovir plus zidovudine (200 mg) was significantly more potent than amdoxovir monotherapy in AUC(VL) and mean VL decline (P=0.019 and P=0.021, respectively), suggesting synergy. There was markedly decreased VL variability with the combination compared with amdoxovir alone. All adverse events were mild to moderate. CONCLUSION: The combination of amdoxovir plus zidovudine appeared synergistic with reduced VL variability. This combined therapy, including the use of a lower zidovudine dosage, warrants further development for the therapy of HIV infection.

Low-dose estradiol spray to treat vasomotor symptoms: a randomized controlled trial.

OBJECTIVE: To investigate the safety and efficacy of a transdermal estradiol (E2) spray in women with postmenopausal vasomotor symptoms. METHOD: A randomized, double-blind, placebo-controlled, multicenter, parallel-group clinical trial was conducted. Postmenopausal women (N=454) with at least eight moderate-to-severe hot flushes per day applied daily, one, two, or three E2 (90 microliter spray contains 1.53 mg E2) or matching placebo sprays. The primary efficacy endpoints were mean change from baseline in frequency and severity of moderate-to-severe hot flushes at weeks 4 and 12. RESULTS: All three E2 groups showed a significant decrease in hot flushes at weeks 4 and 12 compared with their placebo groups (P<.010). The mean change in frequency at week 12 was eight fewer flushes per day for women in the E2 groups and between four and six fewer flushes for women in the placebo groups. Women in the three- and two-E2 spray groups demonstrated significant (P<.050) reductions in severity score at weeks 4 and 12; women in the one-spray group showed significant reductions at week 5. At week 12, the majority (74-85%) of women on E2 showed at least a 50% hot flush frequency reduction as compared with 46% in the placebo group. The systemic E2 delivery rates at week 12 were approximately 0.021 mg/d, 0.029 mg/d, and 0.040 mg/d for the one-, two-, and three-spray doses, respectively. Common adverse events were similar to those previously reported with other transdermal products. Treatment-related application site reaction rate was similar to placebo (1.3% compared with 1.8%). CONCLUSION: The three dose levels of E2 spray achieved efficacy at 0.021-0.040 mg/d delivery rates. The spray is a well-tolerated, new, convenient method of delivering low-dose E2 transdermally. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00122200. LEVEL OF EVIDENCE: I.

Extended-release tramadol (tramadol ER) in the treatment of chronic low back pain.

BACKGROUND: This study evaluated the safety and efficacy of tramadol ER 300 mg and 200 mg versus placebo once daily in the treatment of chronic low back pain, using an open-label run-in followed by, without washout, a randomized controlled study design. METHODS: Adults with scores > or = 40 on a pain intensity visual analog scale (VAS; 0 = no pain; 100 = extreme pain) received open-label tramadol ER, initiated at 100 mg once daily and titrated to 300 mg once daily during a three-week open-label run-in. Patients completing run-in were randomized to receive tramadol ER 300 mg, 200 mg, or placebo once daily for 12 weeks. RESULTS: Of 619 patients enrolled, 233 (38 percent) withdrew from the run-in, primarily because of adverse event (n = 128) or lack of efficacy (n = 41). A total of 386 patients were then randomized to receive either 300 mg (n = 128), 200 mg (n = 129), or placebo (n = 129). Following randomization, mean scores for pain intensity VAS since the previous visit, averaged over the 12-week study period, increased more in the placebo group (12.2 mm) than in the tramadol ER 300-mg (5.2 mm, p = 0.009) and 200-mg (7.8 mm, p = 0.052) groups. Secondary efficacy scores for current pain intensity VAS, patient global assessment, Roland Disability Index, and overall sleep quality improved significantly (p < or = 0.029 each) in the tramadol ER groups compared with placebo. The most common adverse events during the double-blind period were nausea, constipation, headache, dizziness, insomnia, and diarrhea. CONCLUSIONS: In patients who tolerated and obtained pain relief from tramadol ER, continuation of tramadol ER treatment for 12 weeks maintained pain relief more effectively than placebo. Adverse events were similar to those previously reported for tramadol ER.

Open-label study of the safety and effectiveness of long-term therapy with extended-release tramadol in the management of chronic nonmalignant pain.

BACKGROUND: Tramadol ER* is a once-daily oral analgesic for management of moderate-to-moderately severe chronic pain in adults who require around-the-clock treatment of pain. This study evaluated long-term safety of tramadol ER and effectiveness outcomes in the management of chronic, nonmalignant pain. METHODS: Patients enrolled directly for approximately 1 year of open-label tramadol ER treatment if they had chronic, nonmalignant pain (n = 919), or 'rolled over' for 38 weeks of open-label tramadol ER treatment if they completed either of two 12-week, placebo-controlled studies of tramadol ER for low back pain (n = 72) or osteoarthritis (n = 61). Tramadol ER was titrated to a dose of 300 mg once daily (patients >or= 75 years) or 300-400 mg once daily (patients < 75 years). RESULTS: A total of 257 (24%) patients completed the study. Common adverse events, regardless of treatment relationship, were nausea, dizziness (excluding vertigo), and constipation. Mean scores for current pain intensity (from 0 = no pain to 100 = extreme pain) and least, worst, and average pain intensity over the past week improved at every post-baseline visit. At each post-baseline visit, > 50% of patients provided a global assessment rating of good, very good, or excellent. Study limitations were mandatory titration to 400 mg in some patients, concomitant analgesic therapy as a confounding variable, and lack of a placebo comparator. CONCLUSIONS: Individualized dose titration and limiting once-daily therapy with tramadol ER to the maximum recommended daily dose of 300 mg may balance tolerability and analgesic effects of tramadol ER in patients with chronic, nonmalignant pain.

Extended-release tramadol in the treatment of osteoarthritis: a multicenter, randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVE: This study evaluated the efficacy and safety of tramadol extended-release (tramadol ER) tablets once daily in subjects with osteoarthritis pain. METHODS: This 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial included 1020 adults with osteoarthritis of the knee or hip and baseline pain intensity >or= 40 on a 100-mm pain visual analog scale (0 = no pain, 100 = extreme pain). Subjects took placebo or were titrated to a target dose of tramadol ER 100, 200, 300, or 400 mg once daily. MAIN OUTCOME MEASURES: The co-primary efficacy variables were pain and physical function subscales of the WOMAC Osteoarthritis Index and subject global assessment of disease activity. RESULTS: Mean changes in WOMAC Osteoarthritis Index pain and physical function subscales were significantly different between tramadol ER and placebo, overall (p