A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Biapenem in Healthy Adult Subjects

The pharmacokinetics and safety of biapenem were studied in 36 healthy adult subjects in a randomized, placebo-controlled, double blind, sequential single and multiple-ascending dose study using doses from 250 to 1250 mg administered three times a day using 3-hour infusions. Maximum concentrations for biapenem were achieved at the end of the 3-hour infusion. Biapenem exposure (AUC) increased in a slightly greater than dose-proportional manner following single and multiple doses with no evidence of accumulation with multiple doses. Plasma AUCs increased from 18 mg*h/L at 250 mg to 150 mg*h/L at 1250 mg. Urinary recovery ranged from 14.2% at 250 mg to 42.3% at 1250 mg. Biapenem was well tolerated up to 1000 mg administered every 8 hours by 3-hour infusion for 7 days; however, a higher incidence of nausea, vomiting, and rash was reported at 1250 mg. There were no serious adverse events (SAEs) reported following either single or multiple doses of biapenem and all AEs were mild or moderate in severity.

Direct Implementation of Intestinal Permeability Test in NMR Metabolomics for Simultaneous Biomarker Discovery—A Feasibility Study in a Preterm Piglet Model

Measurement of intestinal permeability (IP) is often used in the examination of inflammatory gastrointestinal disorders. IP can be assessed by measurement of urinary recovery of ingested non-metabolizable lactulose (L) and mannitol (M). The present study aimed to examine how measurements of IP can be integrated in a NMR-based metabolomics approach for a simultaneous quantification of L/M ratio and biomarker exploration. For this purpose, plasma and urine samples were collected from five-day-old preterm piglets (n = 20) with gastrointestinal disorders (subjected to intra-amniotic lipopolysaccharide (LPS, 1 mg/fetus)) after they had been administrated a 5% lactulose and 5% mannitol solution (15 mL/kg). The collected plasma and urine samples were analyzed by 1H NMR-based metabolomics. Urine L/M ratio measured by 1H NMR spectroscopy showed high correlation with the standard measurement of the urinary recoveries by enzymatic assays (r = 0.93, p < 0.05). Partial least squares (PLS) regressions and correlation analyses between L/M ratio and NMR metabolomics data revealed that L/M ratio was positively correlated with plasma lactate, acetate and succinate levels and negatively correlated with urinary hippuric acid and glycine. In conclusion, the present study demonstrated that NMR metabolomics enables simultaneous IP testing and discovery of biomarkers associated with an impaired intestinal permeability.

Changes in plasma concentration of flavonoids after ingestion of a flavonoid-rich meal prepared with basic foodstuffs

Background: As flavonoids have a variety of functions, such as antioxidant activity, there is growing interest in the development of flavonoid supplements. However, there have been reports of DNA damage due to exposure to flavonoids at high concentrations in rats, which could suggest that a habitual intake of flavonoid supplements may cause toxicity. Therefore, we considered that ingesting flavonoids from a typical meal combined basic foodstuffs are safe because of unlikely to result high concentrations like supplements, and focused on the intake of flavonoids from a typical meal. Thus, this study investigated the absorption of flavonoids in humans after the consumption of a typical meal. Methods: On the first 2 days of the study, seven healthy volunteers were provided with low-flavonoid meals (flavonoid content below the detection limit by HPLC: less than 0.24 mg/meal) three times a day as a washout. A flavonoid-rich meal (40.44 ± 1.49 mg/meal) was then provided for breakfast on the third day. Blood was collected from all volunteers 0, 2, 3, 7, 8, and 9 h after the flavonoid-rich meal was consumed. After enzyme hydrolysis of the plasma, the plasma concentrations of flavonoids aglycone of quercetin, daidzein and genistein were measured using LC-MS. Urine was also collected and pooled 24 h after the flavonoid-rich meal was consumed. Thereafter, the urine was treated with enzyme hydrolysis, and the measurement of urinary flavonoids was performed. Results: Plasma flavonoid peaks were observed 8 h after consumption of the flavonoid-rich meal (quercetin: 4.29 ± 1.46 μM, daidzein: 0.51 ± 0.41 μM, genistein: 0.91 ± 0.73 μM). Furthermore, flavonoids were confirmed to be present in plasma even at 9 h after the intake meal. The urinary recovery of flavonoids was 3.43 ± 1.50% for quercetin, 13.87 ± 6.68% for daidzein, and 16.89 ± 11.40% for genistein. Conclusion: These results suggest that consuming a typical meal that combines a variety of basic foodstuffs delays attainment of the plasma flavonoid peak compared with consuming a single type of food or supplements as previously reported. In addition, the flavonoid urinary recovery were also reduced compared with those previously reported.

Wine and Olive Oil Phenolic Compounds Interaction in Humans

Extra virgin olive oil (EVOO) and red wine (RW) are two basic elements that form part of the so-called Mediterranean diet. Both stand out because of their high phenolic compound content and their potential related health benefits. The present study is focused on the metabolic disposition of resveratrol (RESV), tyrosol (TYR), and hydroxytyrosol (HT) following the consumption of EVOO, RW, and a combination of both. In this study, 12 healthy volunteers consumed a single dose of 25 mL of EVOO, 150 mL of RW, and a combination of both in a crossover randomized clinical trial. Urinary recovery of RESV, TYR, and HT was analysed in urine samples collected over a 6-h period following the intake of each treatment. Higher HT levels were observed following EVOO compared to RW (3788 ± 1751 nmols and 2308 ± 847 nmols respectively). After the combination of EVOO and RW, the recovery of TYR and HT metabolites increased statistically compared to their separate consumption (4925 ± 1751 nmols of TYR and 6286 ± 3198 nmols of HT). EVOO triggered an increase in glucuronide conjugates, while RW intake raised sulfate metabolites. Marginal effects were observed in RESV increased bioavailability after the combination of RW with the fat matrix provided by EVOO.

Urinary Concentrations of Colistimethate and Formed Colistin after Intravenous Administration in Patients with Multidrug-Resistant Gram-Negative Bacterial Infections

ABSTRACT Limited information is available on the urinary excretion of colistin in infected patients. This study aimed to investigate the pharmacokinetics of colistimethate sodium (CMS) and formed colistin in urine in patients with multidrug-resistant (MDR) Gram-negative bacterial infections. A pharmacokinetic study was conducted on 12 patients diagnosed with an infection caused by an extremely drug-resistant (XDR) P. aeruginosa strain and treated with intravenous CMS. Fresh urine samples were collected at 2-h intervals, and blood samples were collected predose (C min ss) and at the end of the CMS infusion (C max ss) for measurement of concentrations of CMS and formed colistin using high-performance liquid chromatography (HPLC). CMS urinary recovery was determined as the summed amount of CMS and formed colistin recovered in urine for each 2-h interval divided by the CMS dose. There were 12 enrolled patients, 9 of whom were male (75%). Data [median (range)] were as follows: age, 65.5 (37 to 86) years; colistimethate urinary recovery 0 to 6 h, 42.6% (2.9% to 72.8%); range of concentrations of colistin in urine, <0.1 to 95.4 mg/liter; C min ss and C max ss of colistin in plasma, 0.9 (<0.2 to 1.4) and 0.9 (<0.2 to 1.4) mg/liter, respectively. In 6/12 (50%) patients, more than 40% of the CMS dose was recovered in the urine within the first 6 h after CMS administration. This study demonstrated rapid urinary excretion of CMS in patients within the first 6 h after intravenous administration. In all but one patient, the concentrations of formed colistin in urine were above the MIC for the most predominant isolate of P. aeruginosa in our hospital. Future studies are warranted for optimizing CMS dosage regimens in urinary tract infection (UTI) patients.

Pharmacokinetics of metformin in the rat: assessment of the effect of hyperlipidemia and evidence for its metabolism to guanylurea

Metformin pharmacokinetics are highly dependent upon organic cationic transporters. There is evidence of a change in its renal clearance in hyperlipidemic obese patients, and no information on its metabolic fate. To study some of these aspects, the influence of poloxamer 407 (P407)-induced hyperlipidemia on metformin pharmacokinetics was assessed. Control and P407-treated adult male rats were administered 30 mg/kg metformin intravenously (i.v.). The pharmacokinetic assessments were performed at 2 time points, 36 and 108 h, following the intraperitoneal dose of P407 (1 g/kg). mRNA and protein expressions of cationic drug transporters were also measured. There was no evidence of a change in metformin pharmacokinetics after i.v. doses as a consequence of short-term hyperlipidemia, and a change in transporter mRNA but not protein expression was observed in the P407- treated rats 108 h after P407 injection. Urinary recovery of unchanged drug was high (>90%) but incomplete. Presumed metabolite peaks were detected in chromatograms of hepatocytes and microsomal protein spiked with metformin. Comparative chromatographic elution times and mass spectra suggested that one of the predominant metabolites was guanylurea. Hyperlipidemia by itself did not affect the pharmacokinetics of metformin. Guanylurea is a putative metabolite of metformin in rats.

A national FFQ for the Netherlands (the FFQ-NL 1.0): validation of a comprehensive FFQ for adults

A standardised, national, 160-item FFQ, the FFQ-NL 1.0, was recently developed for Dutch epidemiological studies. The objective was to validate the FFQ-NL 1.0 against multiple 24-h recalls (24hR) and recovery and concentration biomarkers. The FFQ-NL 1.0 was filled out by 383 participants (25–69 years) from the Nutrition Questionnaires plus study. For each participant, one to two urinary and blood samples and one to five (mean 2·7) telephone-based 24hR were available. Group-level bias, correlation coefficients, attenuation factors, de-attenuated correlation coefficients and ranking agreement were assessed. Compared with the 24hR, the FFQ-NL 1.0 estimated the intake of energy and macronutrients well. However, it underestimated intakes of SFA andtrans-fatty acids and alcohol and overestimated intakes of most vitamins by >5 %. The median correlation coefficient was 0·39 for energy and macronutrients, 0·30 for micronutrients and 0·30 for food groups. The FFQ underestimated protein intake by an average of 16 % and K by 5 %, relative to their urinary recovery biomarkers. Attenuation factors were 0·44 and 0·46 for protein and K, respectively. Correlation coefficients were 0·43–0·47 between (fatty) fish intake and plasma EPA and DHA and 0·24–0·43 between fruit and vegetable intakes and plasma carotenoids. In conclusion, the overall validity of the newly developed FFQ-NL 1.0 was acceptable to good. The FFQ-NL 1.0 is well suited for future use within Dutch cohort studies among adults.