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Background Cariprazine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Aim This study aimed to evaluate the effects of erythromycin, a moderate cytochrome P450 (CYP)3A4 inhibitor, on the pharmacokinetics of cariprazine in male patients with schizophrenia, and to assess the influence of CYP2D6 phenotypes on cariprazine metabolism. Methods Forty-two patients received oral doses of 1.5 mg cariprazine alone for 28 days (to reach steady state), followed by a co-administration of cariprazine 1.5 mg daily with erythromycin 500 mg twice daily (BID) and Enterol 250 mg BID for 21 days, followed by a 14-day post-treatment period. Blood samples were collected at predefined time points and analysed for cariprazine, its two active metabolites: desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), and erythromycin using validated high performance liquid chromatography-tandem mass spectrometry methods. CYP2D6 phenotypes were determined by genotyping. The pharmacokinetic parameters were calculated using non-compartmental analysis. Results Erythromycin increased the area under the curve (AUC τ ) and peak concentration ( C max ) of Total cariprazine (cariprazine + DCAR + DDCAR) by about 40–50% but did not affect the time to peak concentration ( T max ). The CYP2D6 phenotypes had no substantial effect on the pharmacokinetics of cariprazine and its metabolites, either alone or in combination with erythromycin. Cariprazine was well tolerated and safe. Conclusion The findings suggest that co-administration of cariprazine with moderate CYP3A4 inhibitors may require dose adjustment or monitoring; however, pharmacogenetic testing for CYP2D6 is not necessary for optimising cariprazine therapy. Trial Registration Trial registration number (EudraCT Number): 2018-003721-28. Date of registration: 21-SEP-2018.

This is a protocol for PPROM-AZM Study, phase II, nonblinded, randomized controlled trial. Bronchopulmonary dysplasia (BPD) at a postmenstrual age of 36 weeks (BPD 36 ) is often observed in infants with preterm premature rupture of the membranes (pPROM). A regimen of ampicillin (ABPC) intravenous infusion for 2 days and subsequent amoxicillin (AMPC) oral administration for 5 days plus erythromycin (EM) intravenous infusion for 2 days followed by EM oral administration for 5 days is standard treatment for pPROM. However, the effect on the prevention of moderate/severe BPD 36 using the standard treatment has not been confirmed. Recently, it is reported that ampicillin/sulbactam (ABPC/SBT) plus azithromycin (AZM) was effective for the prevention of moderate/severe BPD 36 in pPROM patients with amniotic infection of Ureaplasma species. Therefore, our aim is to evaluate the occurrence rate of the composite outcome of “incidence rate of either moderate/severe BPD 36 or intrauterine fetal death, and infantile death at or less than 36 weeks 0 days” comparing subjects to receive ABPC/SBT for 14 days plus AZM for 14 days (intervention group) and those to receive ABPC/SBT for 14 days plus EM for 14 days (control group), in a total of 100 subjects (women with pPROM occurring at 22–27 weeks of gestation) in Japan. The recruit of subjects was started on April 2022, and collection in on-going. We also investigate the association between the detection of Ureaplasma species and occurrence of BPD 36 . In addition, information on any adverse events for the mother and fetus and serious adverse events for infants are collected during the observation period. We allocate patients at a rate of 1:1 considering two stratification factors: onset of pPROM (22–23 or 24–27 weeks) and presence/absence of a hospital policy for early neonatal administration of caffeine. Trial registration: The trial number in the Japan Registry of Clinical Trials is jRCTs031210631 .

Introduction: Although long-term macrolide antibiotics could reduce the recurrent exacerbation of chronic obstructive pulmonary disease (COPD), the side effect of bacterial resistance and the impact on the microbiota remain concerning. We investigated the influence of long-term erythromycin treatment on the airway and gut microbiota in mice with emphysema and patients with COPD. Methods: We conducted 16S rRNA gene sequencing to explore the effect of erythromycin treatment on the lung and gut microbiota in mice with emphysema. Liquid chromatography-mass spectrometry was used for lung metabolomics. A randomized controlled trial was performed to investigate the effect of 48-week erythromycin treatment on the airway and gut microbiota in COPD patients. Results: The mouse lung and gut microbiota were disrupted after cigarette smoke exposure. Erythromycin treatment depleted harmful bacteria and altered lung metabolism. Erythromycin treatment did not alter airway or gut microbial diversity in COPD patients. It reduced the abundance of pathogens, such as Burkholderia, in the airway of COPD patients and increased levels of symbiotic bacteria, such as Prevotella and Veillonella. The proportions of Blautia, Ruminococcus, and Lachnospiraceae in the gut were increased in COPD patients after erythromycin treatment. The time to the first exacerbation following treatment was significantly longer in the erythromycin treatment group than in the COPD group. Conclusion: Long-term erythromycin treatment reduces airway and gut microbe abundance in COPD patients but does not affect microbial diversity and restores microbiota balance in COPD patients by reducing the abundance of pathogenic bacteria.

Abstract Rationale The mechanism by which low-dose macrolide therapy reduces exacerbations in non–cystic fibrosis bronchiectasis is not known. Pseudomonas aeruginosa quorum sensing controls the expression of a range of pathogenicity traits and is inhibited by macrolide in vitro. Quorum sensing inhibition renders P. aeruginosa less pathogenic, potentially reducing its contribution to airway damage. Objectives The aim of this study was to determine whether long-term low-dose erythromycin inhibits P. aeruginosa quorum sensing within the airways of patients with non–cystic fibrosis bronchiectasis. Methods Analysis was performed on induced sputum from P. aeruginosa–positive subjects at recruitment to the BLESS (Bronchiectasis and Low-Dose Erythromycin Study) trial and after 48 weeks of treatment with erythromycin or placebo. To avoid changes in gene expression during culture, bacterial mRNA was extracted directly from sputum, and the relative expression of functionally critical quorum sensing genes was determined by quantitative polymerase chain reaction. Measurements and Main Results: In keeping with the BLESS study, a significant reduction in total exacerbations was seen in this subgroup (placebo: 6, [interquartile range (IQR), 4–8]; erythromycin: 3, [IQR, 3–4]; P = 0.008; Mann-Whitney test). Erythromycin therapy did not change P. aeruginosa bacterial load determined by polymerase chain reaction. A significant reduction was observed in the expression of the quorum sensing genes, lasR (erythromycin: fold change, 0.065 [IQR, 0.01–0.85], n = 11; placebo: fold change, 1.000 [IQR, 0.05–3.05]; P = 0.047, Mann-Whitney U test) and pqsA (erythromycin: fold change, 0.07 [IQR, 0.02–0.25]; placebo: fold change, 1.000 [IQR, 0.21–4.31], P = 0.017, Mann-Whitney U test), after 48 weeks of erythromycin, compared with placebo. Conclusions We demonstrate inhibition of P. aeruginosa quorum sensing within the airways of patients with non–cystic fibrosis bronchiectasis receiving long-term, low-dose erythromycin, without a reduction in bacterial load, representing a potential mechanism of therapeutic impact beyond a classical antimicrobial or antiinflammatory pathway.

We investigated the efficacy and cost-effectiveness of five antimicrobial regimens for mild to moderate facial acne and whether propionibacterial antibiotic resistance affects treatment response. In this randomised, observer-masked trial, 649 community participants were allocated one of five antibacterial regimens. Primary outcomes were patients' self-assessed improvement and reduction in inflamed lesions at 18 weeks. Analyses were by intention to treat. Moderate or greater improvement at 18 weeks was reported in 72 (55%) of 131 participants assigned oral oxytetracycline plus topical placebo, 70 (54%) of 130 assigned oral minocycline plus topical placebo, 78 (60%) of 130 assigned topical benzoyl peroxide plus oral placebo, 84 (66%) of 127 assigned topical erythromycin and benzoyl peroxide in a combined formulation plus oral placebo, and 82 (63%) of 131 assigned topical erythromycin and benzoyl peroxide separately plus oral placebo. Most improvement occurred in the first 6 weeks. Treatment differences for the proportion of people with at least moderate improvement were: minocycline versus oxytetracycline –1·2% (unadjusted 95% CI –13·3 to 10·9); combined erythromycin and benzoyl peroxide versus oxytetracycline 11·1% (–0·7 to 22·9) and versus minocycline 12·3% (0·4 to 24·2); erythromycin and benzoyl peroxide separately versus combined formulation –3·5% (–15·2 to 8·2); benzoyl peroxide versus oxytetracycline 5·0% (–7·0 to 17·0), versus minocycline 6·2% (–5·8 to 18·2), and versus combined formulation –6·1% (–17·9 to 5·7). Benzoyl peroxide was the most cost-effective treatment. Efficacy of both tetracyclines was reduced by pre-existing tetracycline resistance. Topical benzoyl peroxide and benzoyl peroxide/erythromycin combinations are similar in efficacy to oral oxytetracycline and minocycline and are not affected by propionibacterial antibiotic resistance.

AimsUnexplained chronic cough is a common condition with no satisfactory treatments. Previous work has suggested that cough may be linked to neutrophilic airway inflammation. This study tested the hypothesis that long-term low-dose erythromycin reduces the induced sputum neutrophil count and 24 h cough frequency in patients with unexplained chronic cough.Methods30 patients with an unexplained chronic cough lasting more than 8 weeks were randomly assigned to take 250 mg erythromycin once daily (n=15) or placebo (n=15) for 12 weeks in a double-blind parallel group study. Cough frequency, cough reflex sensitivity and cough severity were assessed at baseline, 6, 12 and 24 weeks. The primary outcome measure was change in 24 h cough frequency at 12 weeks.ResultsThere was no difference in the change in cough frequency between the erythromycin and placebo groups at 12 weeks (mean difference in fold change 1.1; 95% CI 0.7 to 1.5; p=0.585) or at other times. There was a statistically significant between-treatment difference in the change in sputum neutrophils at 12 weeks (−10.2% vs +6.6% with erythromycin and placebo; mean difference 16.8%; 95% CI 1.6 to 32.1; p=0.03) but not at other times. There was no difference in the change in other measures of cough between treatments.ConclusionsTreatment with low-dose erythromycin for 12 weeks reduces the induced sputum neutrophil count but not cough frequency or severity in patients with unexplained chronic cough.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation and is associated with acute exacerbations. Macrolide antibiotics have been shown to exhibit anti-inflammatory effects in some chronic airway inflammatory diseases. Objective: The aim of this study was to assess the effect of treatment with erythromycin on airway inflammation and health outcome in COPD patients. Methods: We conducted a randomized, placebo-controlled, double-blind trial of erythromycin for a period of 6 months. Thirty-six COPD patients were randomized to treatment with oral erythromycin (125 mg, three times/day) or placebo. The primary outcomes were neutrophil number in sputum and exacerbations. Results: Thirty-one patients completed the study. At the end of treatment, neutrophil counts in the sputum were significantly decreased in the group treated with erythromycin compared with placebo-treated patients (p = 0.005). Total cells in the sputum and neutrophil elastase in sputum supernatant were also significantly decreased in those treated with erythromycin compared with the placebo group (p = 0.021 and p = 0.024, respectively). The mean exacerbation rate was lower in the erythromycin group than in the placebo group (relative risk = 0.554, p = 0.042). Kaplan-Meier survival analysis showed that erythromycin significantly delayed the time to the first COPD exacerbation compared with placebo (p = 0.032). Conclusions: Erythromycin treatment in COPD patients can reduce airway inflammation and decrease exacerbations and may therefore be useful in the management of COPD.

Objective To investigate the impact of zinc supplementation in children with cholera.Design Double blind, randomised, placebo controlled trial.Setting Dhaka Hospital, Bangladesh.Participants 179 children aged 3-14 years with watery diarrhoea and stool dark field examination positive for Vibrio cholerae and confirmed by stool culture.Intervention Children were randomised to receive 30 mg elemental zinc per day (n=90) or placebo (n=89) until recovery. All children received erythromycin suspension orally in a dose of 12.5 mg/kg every six hours for three days.Main outcome measures Duration of diarrhoea and stool output.Results 82 children in each group completed the study. More patients in the zinc group than in the control group recovered by two days (49% v 32%, P=0.032) and by three days (81% v 68%, P=0.03). Zinc supplemented patients had 12% shorter duration of diarrhoea than control patients (64.1 v 72.8 h, P=0.028) and 11% less stool output (1.6 v 1.8 kg/day, P=0.039).Conclusion Zinc supplementation significantly reduced the duration of diarrhoea and stool output in children with cholera. Children with cholera should be supplemented with zinc to reduce its duration and severity.Trial registration Clinical trials NCT00226616.

Background. Although third-generation cephalosporins, such as ceftriaxone (CTRX), and pneumococcal fluoroquinolones, such as moxifloxacin (MXF), are currently recommended first-line antibiotics for empirical treatment of inpatients with community-acquired pneumonia, CTRX and MXF have never undergone a head-to-head comparison. We therefore compared the efficacy, safety, and speed and quality of defervescence of sequential intravenous or oral MXF and high-dose CTRX with or without erythromycin (CTRX ± ERY) for patients with community-acquired pneumonia requiring parenteral therapy. Methods. In this prospective, multicenter, randomized, controlled, nonblinded study, 397 patients were randomly assigned to receive either MXF (400 mg once daily intravenously, possibly followed by oral tablets) or CTRX (2 g intravenously once daily) with or without ERY (1 g intravenously every 6–8 h) for 7–14 days. Results. Among 317 patients evaluable for efficacy and safety, 138 (85.7%) of 161 MXF-treated patients and 135 (86.5%) of 156 CTRX ± ERY—treated patients (59 [37.8%] of whom received CTRX and ERY) achieved continued clinical resolution. Defervescence and relief of symptoms, such as chest pain, occurred significantly earlier in the MXF-treated group than in the CTRX ± ERY-treated group. Both regimens were generally well tolerated. Conclusions. For adult patients hospitalized with community-acquired pneumonia, sequential MXF therapy was clinically equivalent to high-dose CTRX ± ERY therapy but led to a faster clinical improvement.

Background Food residue in the remnant stomach after subtotal gastrectomy (STG) interferes with endoscopic observation. We investigated whether intravenous erythromycin improves gastric mucosa visualization in patients with STG. Methods This study was conducted from April 2012 to October 2012 as a double-blinded, placebo-controlled, randomized trial. Patients who received STG with complete resection (stage T1–2N0M0) were included. Exclusion criteria were diabetes mellitus, neurologic disease, myopathy, recent viral enteritis history, concomitant therapy influencing gastrointestinal motility and severe comorbidity. Patients were instructed to consume a soft diet for dinner between 1800 and 2000 h, and endoscopies were performed between 0900 and 1200 h. Patients were assigned randomly to receive either erythromycin (125 mg in normal saline 50 cc) or placebo saline. The endoscopy was performed 15 min after infusion. Grade of residual food was rated as follows: G0, no residual food; G1, a small amount of residual food; G2, a moderate amount of residual food; G3, a moderate amount of residual food that hinders observation of the entire surface, even with body rolling; G4, a great amount of residual food such that endoscopic observation is impossible. Results When good visibility was defined as G0+G1, visibility was significantly better in the erythromycin group (61 + 19 %) than in the placebo group (38 + 12 %, p  < 0.001). However, this effect was not seen in patients within 6 months after gastrectomy. The risk factor for food stasis in the placebo group ( n  = 58) was food stasis at last endoscopy. The only factor predicting erythromycin response in the erythromycin group ( n  = 56) was elapsed time since surgery. Adverse effects included nausea [11 (19.7 %)] and vomiting [1 (1.8 %)] in the erythromycin group and vomiting [3 (5.2 %)] in the placebo group. However, they were transient and tolerable. Conclusions Premedication with erythromycin improves mucosal visualization during endoscopy in patients with STG. (Clinical Trials registration number: NCT01659619).