Short-chain fatty acids in the saliva of patients with gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is a condition characterized by persistent symptoms and complications resulting from reflux of gastric contents into the esophagus. Short-chain fatty acids (SCFAs) are fermentation products of dietary fibres by the gut microbiota and are often studied for their anti-inflammatory and anticancer effects. The presence of SCFAs in the upper gastrointestinal tract, including in patients with GERD, has not been previously studied. The aim of this study was to investigate the relationship between the concentrations of SCFAs in the saliva of different age groups of patients with GERD. The study included 86 patients diagnosed with GERD, divided into two groups according to age: under and over 60 years of age, treated in the Gastroenterology and Hepatology Outpatient Clinic of the University Hospital in Cracow and 39 patients without gastrointestinal tract diseases. After clinical examination, blood was drawn to determine complete blood count, haemoglobin, and CRP. The oral cavity was examined, and unstimulated mixed saliva was collected. The SCFAs analysis was made by liquid chromatography-tandem mass spectrometry after facile derivatization coupled with liquid-liquid extraction. Of the six SCAFs studied, the highest median concentrations of acetic acid and propionic acid were observed in the saliva of patients with GERD and in the control group, in both the younger and older groups of patients. The concentrations of acetic acid and propionic acid were also higher compared with the four other fatty acids in the saliva of patients with GERD and in the control subjects. There were no correlations between salivary SCFAs levels and selected clinical and endoscopic parameters, including chronic inflammatory changes of the esophagus and stomach. In conclusions: SCFAs are present in the saliva of patients with GERD and in the control healthy persons. With the exception of valeric and isovaleric acids, salivary levels of SCFAs were significantly higher in patients with GERD compared to the control group. The highest concentrations of acetic acid and propionic acid were observed in patients with GERD and in both the younger and older patient groups. There were no differences in the concentrations of SCFAs in the saliva of female and male groups. We found no correlations between salivary SCFAs levels and selected clinical, laboratory and endoscopic changes of the oesophagus and stomach.

Tyramine kinetics and pressor sensitivity during monoamine oxidase inhibition by selegiline.

The effect of the monoamine oxidase inhibitor selegiline on tyramine metabolism and intravenous and oral tyramine pressor sensitivity was studied in healthy subjects. After oral doses of tyramine, which caused systolic blood pressure to increase by 30 mm Hg, we determined plasma concentrations of p-hydroxyphenylacetic acid (HPAA) and of conjugated and unconjugated tyramine. When 20 mg/day of selegiline was administered, the AUCspec of HPAA decreased from 86% to 64% and the AUCspec of conjugated tyramine increased from 13% to 35% of the sum of total tyramine and HPAA. Pressor sensitivity was enhanced more with oral administration of tyramine than with intravenous administration of tyramine. After the drug was discontinued, initial values were reached within 4 days (one subject) and 2 weeks (two subjects). Fifty-five percent of the selegiline dose was eliminated in urine as amphetamine and methamphetamine. The findings support the assumption that selegiline does not selectively inhibit monoamine oxidase-B (MAO-B) when administered in doses of 20 mg/day and higher.

High-performance liquid chromatographic determination of a new pyrazoloquinoline type benzodiazepine receptor antagonist and its hydroxy metabolite.

A rapid high-performance liquid chromatographic (HPLC) method for the determination of the novel benzodiazepine receptor antagonist 2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one (CGS 8216) and its hydroxy metabolite is described. The method involves a solid-phase extraction with C18 disposable columns and quantification by HPLC with UV-detection. In plasma 20 ng/ml of the antagonist and 10 ng/ml of metabolite can be measured with a coefficient of variation of about 10%. The high sensitivity and selectivity of the assay makes it suitable for use in pharmacokinetic studies.

Oxprenolol absorption in man after single bolus dosing into two segments of the colon compared with that after oral dosing.

The systemic availability of oxprenolol after colonic and oral administration has been compared in a crossover study involving six healthy male volunteers. Drug administration into two regions of the colon (caecum and left flexure) was achieved by means of a colonoscopic technique. There were no obvious differences in plasma concentrations after drug administration to the caecum and left flexure, although in one subject it was necessary to repeat colonic administration because of unexpectedly high plasma drug levels on the first occasion. The possible reasons for this abnormal response are discussed. The mean systemic availability of oxprenolol was 82% after colonic compared with oral dosing, although marked differences were observed in individual plasma levels following drug administration by the two routes. The results of this study support the concept of extending the duration of oxprenolol release from a rate-controlled dosage form to permit once-daily administration with this short elimination half-life drug.

Pharmacokinetic and pharmacodynamic effects of the novel benzodiazepine antagonist 2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one in humans.

2-Phenylpyrazolo[4,3-c]quinolin-3(5H)-one (CGS 8216) is pharmacologically characterized as benzodiazepine antagonist with low inverse agonistic effects. Single oral doses up to 650 mg and subchronic doses up to 100 mg daily for seven days are well tolerated by young healthy volunteers. Plasma concentrations of CGS 8216 are variable, not dose-related and relatively low considering the doses administered. A high plasma concentration ratio of metabolite vs. parent compound (3:1) points to an extensive gastrointestinal first-pass metabolism. CGS 8216 influences the human electroencephalogram similar to anxiolytic and vigilance enhancing drugs in doses which do not change performance of psychometric tests. CGS 8216 antagonizes the diazepam-induced impairment of alertness.

Role of cytochrome P4502D6 in the metabolism of brofaromine. A new selective MAO-A inhibitor.

The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0-infinity) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0-72 h) (40%) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.