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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.

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.

Group B Streptococcus (GBS) is a major cause of neonatal morbidity and mortality. Serbia has not fully implemented preventive measures against GBS neonatal diseases. Therefore, we aimed to assess the maternal GBS colonisation and invasive neonatal disease rate, to reveal the trends of antimicrobial resistance and serotype distribution of GBS from various patient groups. Randomly selected non-invasive (n = 991) and all invasive GBS (n = 80) collected throughout Serbia from 2015 to 2020 were tested for antimicrobial susceptibility, capsular typing, and hvgA detection. Overall, 877/5621 (15.6%) pregnant women were colonised with GBS. Invasive GBS infections incidence in infants (0.18/1000 live births) showed a decreasing trend (0.3 to 0.1/1000 live births). Type III was overrepresented in infants with invasive infections (n = 35, 58.3%), whereas type V predominated among colonised adults (n = 224, 25.5%) and those with noninvasive (n = 37, 32.5%) and invasive infections (n = 8, 40%). The hypervirulent clone III/ST17 was highly associated with invasive infections (n = 28, 35%), particularly late-onset disease (n = 9, 47.4%), showing an increase from 12.3 to 14.8%. The GBS resistance to erythromycin and clindamycin was 26.7% and 22.1%, respectively, with an upward trend. The emergence of the hypervirulent clone III/ST17 and the escalation in GBS resistance highlight an urgent need for continuous monitoring of GBS infections.

Purpose Netupitant is a new highly selective neurokinin-1 receptor antagonist being studied for the prevention of nausea and vomiting in patients undergoing chemotherapy. In vitro studies suggest that netupitant inhibits the cytochrome P-450 isoenzyme 3A4 (CYP3A4). Because netupitant may be used with a variety of drugs, which may be substrates of CYP3A4, two studies were designed to establish the potential risk for drug–drug interaction with three different CYP3A4 substrates: midazolam, erythromycin, and dexamethasone. Methods Both trials were three-period crossover studies performed in healthy subjects. In the first study, 20 subjects received netupitant and either midazolam or erythromycin. In the second study, 25 subjects received netupitant and dexamethasone. Serial blood samples were collected over the course of the two studies and pharmacokinetic parameters were determined for all analytes. Results Netupitant, by inhibiting the CYP3A4, increased the C max and AUC inf of midazolam by 40 and 144 %, respectively, and the C max and AUC inf of erythromycin by 30 %. Netupitant was shown to increase the exposure to dexamethasone in a dose-dependent manner with the mean increase in AUC and C max by 72 and 11 %, respectively, on day 1 and by 138 and 75 %, respectively, on day 4 when co-administered with 300 mg of netupitant. Conclusions The results of these studies suggest that netupitant is a moderate inhibitor of CYP3A4 and therefore, co-administration with drugs that are substrates of CYP3A4 may require dose adjustments. Treatments were well tolerated in both studies.

Context:In type 1 diabetes (T1D), delayed gastric emptying (GE) may predispose to a mismatch between insulin delivery and glucose absorption. Previous studies evaluated, only partly, the relationship between delayed GE and postprandial, but not diurnal, glycemia.Objective:To assess the relationship between GE disturbances and glycemic control in T1D and the effects of accelerating GE on glycemic control.Design, Setting, and Participants:This was a randomized placebo-controlled trial in 30 patients with T1D on an insulin pump at an academic medical center.Intervention(s):GE was evaluated with a [13C]-Spirulina breath test at baseline (GEbaseline), during intravenous saline or erythromycin (2 or 3 mg/kg; GEiv), and after 7 days of oral erythromycin or placebo (GEoral). Weighed meals were provided throughout the study.Main Outcome Measure(s):These were GE and continuous glucose monitoring (CGM).Results:The baseline glycosylated hemoglobin was 7.6% ± 0.8% (60 ± 8.7 mmol/mol); 12 patients (40%) had delayed GE; faster GE was associated with a greater postprandial CGM-based glucose, but slower GE was not associated with postprandial hypoglycemia (<70 mg/dL). Intravenous (3 mg/kg) but not oral erythromycin accelerated GE. The relationship between GE and glycemia differed between the postprandial periods and the entire day. After adjusting for carbohydrate intake and insulin consumption, faster GE was associated with more hyperglycemia during the postprandial period but lower glucose values across the entire study.Conclusions:In T1D, pharmacologically mediated acceleration of GE increases postprandial CGM-based glucose. In contrast, delayed GE is associated with greater CGM-based glucose values over the entire day.In 30 patients with T1D treated with intravenous, then oral, erythromycin or placebo, faster GE was associated with greater postprandial glucose but lower glucose during the entire day.

Aims: Impaired gastric accommodation is a major pathophysiological mechanism in functional dyspepsia. The aim of the present work was to assess a satiety drinking test in the evaluation of accommodation in health and dyspepsia. Methods: Twenty five controls and 37 severely dyspeptic patients seen at a tertiary care centre completed a dyspepsia questionnaire, and gastric emptying and gastric barostat studies. The amount of liquid meal ingested at maximum satiety during a slow satiety drinking test was determined. In controls, we studied the influence of caloric density and of pharmacological agents that influence accommodation. Results: In patients, satiety scores were higher and maximum satiety occurred at lower calories (542 (50) v 1508 (53) kcal; p<0.0001). Six patients had required nutritional support, but excluding these did not alter the correlations. With increasing severity of early satiety, less calories were ingested at maximum satiety. In multivariate analysis, the amount of calories was significantly correlated to accommodation but not to gastric emptying or sensitivity. Sensitivity and specificity of the satiety test in predicting impaired accommodation reached 92% and 86%, respectively. At different caloric densities, ingested volume rather than caloric load determined maximum satiety. Pharmacological agents (sumatriptan, cisapride, erythromycin) affected the satiety test according to their effect on accommodation. Conclusion: A slow caloric drinking test can be used to evaluate accommodation and early satiety. It provides a non-invasive method of predicting impaired accommodation and quantifying pharmacological influences on accommodation.

In a longitudinal study at an elementary school in Pittsburgh, group A streptococci with resistance to erythromycin were unexpectedly identified in surveillance throat cultures in January 2001. Through May 2001, nearly half the isolates were resistant to erythromycin, and 22 of 46 children with resistant isolates had multiple cultures that were positive for this resistant streptococcus. At a school in Pittsburgh, nearly half the isolates were resistant. Group A streptococci are the most frequent and important cause of bacterial pharyngitis in children and adults. 1 , 2 Although many antibiotics are effective for the treatment of streptococcal pharyngitis, penicillin V remains the drug of choice. 3 , 4 Erythromycin is recommended for persons who are allergic to penicillin. 3 , 4 Azithromycin is not recommended as first-line therapy for pharyngitis due to group A streptococci; however, many practitioners find the five-day regimen of one dose of azithromycin per day attractive. Azithromycin and other macrolide antibiotics are also frequently prescribed for nonstreptococcal pharyngitis and other upper respiratory tract infections, and the rates of prescription . . .

Erythromycin Antagonizes the Deceleration of Gastric Emptying by Glucagon-Like Peptide 1 and Unmasks Its Insulinotropic Effect in Healthy Subjects Juris J. Meier 1 2 , Guido Kemmeries 1 , Jens J. Holst 3 and Michael A. Nauck 1 4 1 Department of Medicine, Ruhr University, Bochum, Germany 2 Larry Hillblom Islet Research Center, UCLA School of Medicine, Los Angeles, California 3 Department of Medical Physiology, Panum Institute, University of Copenhagen, Copenhagen, Denmark 4 Diabeteszentrum, Bad Lauterberg im Harz, Germany Address correspondence and reprint requests to Dr. Michael Nauck, Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg im Harz, Germany. E-mail: m.nauck{at}diabeteszentrum.de Abstract Glucagon-like peptide 1 (GLP-1) has been proposed to act as an incretin hormone due to its ability to enhance glucose-stimulated insulin secretion. Because GLP-1 also decelerates gastric emptying, it physiologically reduces rather than augments postprandial insulin secretory responses. Therefore, we aimed to antagonize the deceleration of gastric emptying by GLP-1 to study its effects on insulin secretion after a meal. Nine healthy male volunteers (age 25 ± 4 years, BMI 25.0 ± 4.9 kg/m 2 ) were studied with an infusion of GLP-1 (0.8 pmol · kg −1 · min −1 from −30 to 240 min) or placebo. On separate occasions, the prokinetic drugs metoclopramide (10 mg), domperidone (10 mg), cisapride (10 mg, all at −30 min per oral), or erythromycin (200 mg intravenously from −30 to −15 min) were administered in addition to GLP-1. A liquid test meal (50 g sucrose and 8% mixed amino acids in 400 ml) was administered at 0 min. Capillary and venous blood samples were drawn for the determination of glucose (glucose oxidase), insulin, C-peptide, GLP-1, glucagon, gastric inhibitory polypeptide (GIP), and pancreatic polypeptide (specific immunoassays). Gastric emptying was assessed by the phenol red dilution technique. Statistical analyses were performed using repeated-measures ANOVA and Duncan’s post hoc test. GLP-1 significantly decelerated the velocity of gastric emptying ( P < 0.001). This was completely counterbalanced by erythromycin, whereas the other prokinetic drugs used had no effect. Postprandial glucose concentrations were lowered by GLP-1 ( P < 0.001 vs. placebo), but this effect was partially reversed by erythromycin ( P < 0.05). Insulin secretory responses to the meal were lower during GLP-1 administration ( P < 0.05 vs. placebo). However, when erythromycin was added to GLP-1, insulin concentrations were similar to those in placebo experiments. The suppression of meal-related increments in glucagon secretion by GLP-1 was reversed by erythromycin ( P < 0.001). The time course of GIP secretion was delayed during GLP-1 administration ( P < 0.05), but when erythromycin was added, the pattern was similar to placebo experiments. GLP-1 administration led to a reduction in pancreatic polypeptide plasma concentrations ( P < 0.05). In contrast, pancreatic polypeptide levels were markedly increased by erythromycin ( P < 0.001). Intravenous erythromycin counteracts the deceleration of gastric emptying caused by GLP-1, probably by interacting with the parasympathetic nervous system (pancreatic polypeptide responses). Despite augmented rises in insulin secretion, the glucose-lowering effect of GLP-1 is markedly reduced when the deceleration of gastric emptying is antagonized, illustrating the importance of this facet of the multiple antidiabetic actions of GLP-1. GIP, gastric inhibitory polypeptide GLP-1, glucagon-like peptide 1 Footnotes Accepted March 23, 2005. Received July 13, 2004. DIABETES

Purpose To assess the impacts of erythromycin on the pharmacokinetics of voriconazole and its association with CYP2C19 genotypes in healthy Chinese male subjects. Methods A single-center, open, crossover clinical study with two treatment phases was carried out. Eighteen healthy male volunteers, including 6 CYP2C19 homozygous extensive metabolizers (EMs, *1/*1), 6 heterozygous EMs (HEMs, *1/*2 or *1/*3), and 6 CYP2C19 poor metabolizers (PMs, *2/*2 or *2/*3), were enrolled in this study. A single oral dose of 200 mg voriconazole was administrated to all subjects after 3-day pretreatment with either 500 mg erythromycin or placebo three times daily. Periods were separated by a washout period of 14 days. Serial venous blood samples were collected, and plasma concentrations of voriconazole were determined by HPLC. Results C max , AUC 0–24 , and of voriconazole were increased significantly, while oral clearance of voriconazole was decreased significantly by erythromycin administration ( p  < 0.001, respectively). Compared with individuals with CYP2C19 PM genotypes, individuals with CYP2C19 EM and HEM genotypes showed significantly decreased T ½ , AUC 0–24 , , and increased oral clearance of voriconazole ( p  < 0.05, respectively). In addition, significant increases in AUC 0–24 and and decreases in oral clearance of voriconazole after erythromycin treatment were observed in CYP2C19 HEMs and PMs ( p  < 0.05, respectively), but not in CYP2C19 EMs. Conclusion Both CYP2C19 genotypes and CYP3A4 inhibitor erythromycin can influence the plasma concentration of voriconazole, and erythromycin increases plasma concentration of voriconazole in a CYP2C19 genotype-dependent manner.

Antibiotics are used to fight pathogens but also target commensal bacteria, disturbing the composition of gut microbiota and causing dysbiosis and disease 1 . Despite this well-known collateral damage, the activity spectrum of different antibiotic classes on gut bacteria remains poorly characterized. Here we characterize further 144 antibiotics from a previous screen of more than 1,000 drugs on 38 representative human gut microbiome species 2 . Antibiotic classes exhibited distinct inhibition spectra, including generation dependence for quinolones and phylogeny independence for β-lactams. Macrolides and tetracyclines, both prototypic bacteriostatic protein synthesis inhibitors, inhibited nearly all commensals tested but also killed several species. Killed bacteria were more readily eliminated from in vitro communities than those inhibited. This species-specific killing activity challenges the long-standing distinction between bactericidal and bacteriostatic antibiotic classes and provides a possible explanation for the strong effect of macrolides on animal 3 – 5 and human 6 , 7 gut microbiomes. To mitigate this collateral damage of macrolides and tetracyclines, we screened for drugs that specifically antagonized the antibiotic activity against abundant Bacteroides species but not against relevant pathogens. Such antidotes selectively protected Bacteroides species from erythromycin treatment in human-stool-derived communities and gnotobiotic mice. These findings illluminate the activity spectra of antibiotics in commensal bacteria and suggest strategies to circumvent their adverse effects on the gut microbiota. This study systematically profiles the activity of several classes of antibiotics on gut commensal bacteria and identifies drugs that mitigate their collateral damage on commensal bacteria without compromising their efficacy against pathogens.