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Biomedical subjects

R Farinotti

Publications and source records attributed to R Farinotti.

At least 55 records · Page 3Linked to original sources
PubMed1998

Determination of ethambutol in plasma by high-performance liquid chromatography after pre-column derivatization.

A new HPLC assay using UV detection (200 nm) was developed to determine ethambutol (EMB) concentrations in plasma. Following extraction (0.1 ml plasma) with chloroform, EMB and octylamine (used as internal standard) were derivatized with phenylethylisocyanate. Quantitation in plasma was achieved at 200 nm. There were no interferences from endogenous compounds. Intra- and inter-day variabilities were lower than 5.2 and 7.6%, respectively. The limit of quantitation of the method was 0.2 microg/ml. In plasma, ethambutol was found to be stable for at least one month when samples were stored at -20 degrees C. This assay was applied to the therapeutic monitoring of EMB concentrations in 19 patients suffering from tuberculosis.

Adult↗
PubMed1998

Interests of the 'artificial stomach' techniques to study antacid formulations: comparison with in vivo evaluation.

In this overview, the methods for assessing antacid activity in vitro are surveyed, and the problems of their comparison with in vivo methods of evaluation are discussed. In vitro assessment is based on two types of method: static and dynamic. The static method of titration, with end-of-titration pH values ranging between 3.0 and 1.0, has been used to quantify the number of sites capable of binding H+ ions at each end-of-titration pH, and to identify certain chemical mechanisms involved in this binding; in other words, this approach provides the pharmacological characteristics of the drugs tested. In contrast, it does not take into account physiological factors modulating antacid activity, such as gastroduodenal fluxes (including gastric emptying), drug adherence to the mucosa, and acid secretion. The dynamic method was initially based on an artificial stomach model, which has gradually been upgraded to a computer-controlled artificial stomach-duodenum model. This model overcomes certain weaknesses of the static method by simulating flux and pH conditions in the gastroduodenal tract, by taking into account interactions with the gastric mucosa and thereby reproducing the in vivo medium encountered by antacids. It is therefore capable of reflecting the characteristics of antacids, namely their effect on gastric pH and resistance to acidification, at the same time helping to identify the underlying chemicophysical mechanisms. In vivo, the antacid effect can be assessed qualitatively by means of pH-meter studies in healthy volunteers, both in baseline conditions and during secretory stimulation, and also quantitatively by methods based on intragastric titration in response to a liquid meal (IGT). pH-meter studies in baseline conditions come up against the variability of the basal pH and antacid homogenization with gastric contents, which results in a wide range of individual values. This variability is found in pH-meter studies during pentagastrin infusion and, to a lesser degree, in response to a meal. Close correlations have, however, been established between results obtained with the artificial stomach model and in healthy volunteers submitted to pH-metric or IGT studies, with several antacids. It seems that the artificial stomach method is sufficiently reproducible to make it the method of choice for investigating the antacid activity of all drugs aimed at treating acid hypersecretion disorders. In contrast, in vivo studies may be warranted for precise therapeutic indications, such as treatment of duodenal ulcer or gastro-esophageal reflux, in which the therapeutic effect is judged on the basis of an improvement in symptoms and endoscopic criteria, without the need to demonstrate the antacid effect itself.

Antacids↗
PubMed1998

Effects of Salmonella typhimurium infection and ofloxacin treatment on glucose and glutamine metabolism in Caco-2/TC-7 cells.

The effects of both Salmonella typhimurium infection and 5 mM ofloxacin treatment on 2 mM glutamine and 5 mM glucose metabolism in the enterocyte-like Caco-2/TC-7 cell line were studied. These cells utilized glutamine (212.07 +/- 16.75 [mean +/- standard deviation] nmol per h per 10(6) viable cells) and, to a lesser extent, glucose (139.63 +/- 11.52 nmol per h per 10(6) viable cells). Metabolism of these substrates in Caco-2/TC-7 cells resembled that in rat, pig, or human enterocytes. Infection by S. typhimurium C53-enhanced glucose and glutamine substrate utilization by 32 and 22%, respectively and enhanced glucose and glutamine substrate oxidation by eight- and twofold, respectively. These increases in glucose and glutamine metabolism (especially glucose metabolism) were due in part to the metabolism of intracellular bacteria and/or to the activation of cellular metabolism. Substrate metabolism (especially glucose metabolism) in C53-infected cells was partially reduced by treatment with ofloxacin. It was concluded that cellular fuel metabolism is stimulated at the earliest stage of infection (3 to 4 h) and that treatment with 5 mM ofloxacin does not completely restore substrate metabolism to the levels observed in uninfected cells, possibly because this treatment does not eradicate intracellular S. typhimurium completely.

Anti-Infective Agents↗
PubMed1998

Influence of renal failure on ciprofloxacin pharmacokinetics in rats.

Ciprofloxacin pharmacokinetics have been shown to be modified in patients with renal failure (e.g., the intestinal secretion of ciprofloxacin is increased). This study investigated the influence of renal failure on the pharmacokinetics of ciprofloxacin following oral and parenteral administration to rats of a dose of 50 mg/kg of body weight. After parenteral administration, only renal clearance (CLR) was reduced in nephrectomized rats (5.3+/-1.4 versus 17.8+/-4.7 ml/min/kg, P < 0.01, nephrectomized versus control rats). However, nonrenal clearance was increased in nephrectomized rats (32+/-4 versus 15+/-5 ml/min/kg, P < 0.01, nephrectomized versus control rats), suggesting compensatory mechanisms for reduced renal function. After oral administration, apparent total clearance and CLR were reduced (P < 0.01) in nephrectomized rats (117+/-25 and 6.8+/-4.4 ml/min/kg, respectively) compared with the values for control rats (185+/-9 and 22.6+/-5.3 ml/min/kg, respectively) and the area under the concentration-time curve was higher (P < 0.01) for nephrectomized rats (436.3+/-90.5 mg. min/liter) than for control rats (271.3+/-14.3 mg.min/liter). Terminal elimination half lives in the two groups remained constant after oral and parenteral administration. These results suggest an increased bioavailability of ciprofloxacin in nephrectomized rats, which was confirmed by a nonlinear mixed-effect model.

Administration, Oral↗
PubMed1998

Critical importance of in vivo amoxicillin and cefotaxime concentrations for synergy in treatment of experimental Enterococcus faecalis endocarditis.

The synergy between amoxicillin and cefotaxime against two strains of Enterococcus faecalis (JH2-2 and 6370) in vitro and in rabbit endocarditis was investigated. In vitro synergy was obtained only when amoxicillin concentrations were below the MBC and when cefotaxime concentrations were above 1 microg/ml. No synergy was observed in vivo, because of the short period of time during which these pharmacologic requirements were achieved.

Amoxicillin↗
PubMed1997

Cefpodoxime-proxetil hydrolysis and food effects in the intestinal lumen before absorption: in vitro comparison of rabbit and human material.

The luminal and mucosal deesterification of the prodrug ester cefpodoxime-proxetil was studied in human duodenal washings in vitro. Enzymatic hydrolysis of the ester, releasing the active third generation cephalosporin, was observed in luminal washing in the same way as it had previously been observed in the rabbit. Eserine and PMSF and HgCl(2) were potent inhibitors of cefpodoxime-proxetil hydrolysis in luminal washing, suggesting the participation of a cholinesterase in the hydrolysis of cefpodoxime-proxetil. These results are in agreement with our previous findings performed in the rabbit. Moreover, cefpodoxime-proxetil directly decreases the acetylcholinesterase activity when tested by a specific enzymatic method. These observations support the hypothesis that the partial oral bioavailability of cefpodoxime-proxetil results from hydrolysis by luminal cholinesterases. In vitro experiments run with rabbit duodenal washing with food components were compared with the pharmacokinetics of cefpodoxime-proxetil in humans. Amino acids, trace elements and vitamins were potent inhibitors for cefpodoxime-proxetil hydrolysis in duodenal washings. Otherwise, lipids (LTC and mixed LCT/MCT) did not interact. In the human, cefpodoxime-proxetil bioavailability is significantly enhanced when tablets are administered with food. The correlation found between animal results and human results in vitro for prospective investigation of a new prodrug ester could be very useful. An in vitro hydrolysis in intestinal animal washings could allow the potentially degraded condition and the food effect of the luminal tract to be assessed before absorption.

Journal Article↗
PubMed1997

Rapid and simple method to determine chloroquine and its desethylated metabolites in human microsomes by high-performance liquid chromatography with fluorescence detection.

A sensitive and selective method was developed for the simultaneous determination of chloroquine (CQ) and its desethylated metabolites monodesethylchloroquine (DCQ) and bisdesethylchloroquine (BDCQ) in human liver microsomes. Analytes were separated on a C1 column using methanol-water (70:30, v/v) and triethylamine (0.1% v/v) as the mobile phase. The fluorescence detector was set at 250 (excitation) and 380 nm (emission). Following protein precipitation with ice-cold acetonitrile, microsomal incubation supernatants were directly injected into the HPLC system. Typically, 200 microl of incubate were diluted with 200 microl of acetonitrile and 15 microl were injected. The limit of quantitation was 78 nM of CQ or metabolite. Intra-day variability averaged 2.9% for CQ, 1.5% for DCQ and 2.5% for BDCQ. Inter-day variability was 3.1% for CQ, 3.5% for DCQ and 3.7% for BDCQ. Mean accuracies were 100% for CQ and BDCQ and 102% for DCQ.

Antimalarials↗
PubMed1997

Acute effects of propylthiouracil on hemodynamics and oxygen content in patients with alcoholic cirrhosis.

BACKGROUND/AIMS: The antithyroid drug propylthiouracil has been suggested for the treatment of alcoholic liver disease. Its beneficial effects could be due to either a decrease in hepatic oxygen consumption or an increase in hepatic blood flow. The aim of this study was to test these two hypotheses in patients with proven alcoholic cirrhosis. METHODS: The pharmacokinetic parameters after intravenous administration of 300 mg of propylthiouracyl were first determined in four patients. Then, the effects on systemic and splanchnic hemodynamics, and oxygen content were measured 45 and 90 min after the intravenous administration of 300 mg (n=6) or 600 mg (n=6) of propylthiouracil. RESULTS: Systemic hemodynamics (heart rate, arterial pressure, cardiac output and systemic vascular resistance) and splanchnic hemodynamics (hepatic venous pressure gradient, hepatic and azygos blood flows) were not modified 45 and 90 min after the administration of 300 mg or 600 mg of propylthiouracil. Moreover, neither oxygen content in the radial artery, pulmonary artery or hepatic vein, nor systemic oxygen uptake was modified after propylthiouracyl administration. The absence of effect of propylthiouracyl administration was also confirmed in patients with cirrhosis with proven acute alcoholic hepatitis (n=7). CONCLUSIONS: In patients with alcoholic cirrhosis, acute administration of propylthiouracyl has no effect on systemic and splanchnic hemodynamics or on oxygen contents. The presence of acute alcoholic hepatitis does not modify these results.

Adult↗
PubMed1997

Stereoselective passage of mefloquine through the blood-brain barrier in the rat.

The pharmacokinetics of the enantiomers of mefloquine were studied in the rat after administration of a racemic mixture and of the separate enantiomers (+)-mefloquine and (-)-mefloquine. When 50 mg kg-1 racemic mixture was administered orally for 22 days, plasma concentrations of the (+) enantiomer were 2-3 times higher than those of the (-) enantiomer whereas the opposite was true in every part of the brain (cerebellum, cortex, hippocampus, hypothalamus and striatum). Different concentrations of mefloquine were found in the different regions of the brain; the lowest concentrations of (+/-)-mefloquine (27.0 nmol g-1) were in the cerebellum and the highest (110.0 nmol g-1) in the hippocampus. The main metabolite, carboxymefloquine, was detected in plasma but not in the brain. The results indicate the mefloquine crosses the blood-brain barrier stereoselectively.

Animals↗
PubMed1997

Absorption of ofloxacin isomers in the rat small intestine.

Ofloxacin, a chiral fluoroquinolone, possesses two optical isomers. The antibacterial activity of S-(-)-ofloxacin is 8 to 128 times higher than that of R-(+)-ofloxacin. In the rat, a saturable absorption process has been described for racemic ofloxacin. In the present study we investigated the mechanism underlying the in vivo intestinal absorption of ofloxacin enantiomers in the rat. Blood samples were collected from the portal vein. Our results show that the intestinal absorption of ofloxacin isomers is pH dependent, both enantiomers being best absorbed at neutral pH. S-(-)-Ofloxacin seems to have a greater affinity for the intestinal transporter (initial concentrations at 5 min [C(init)] are 0.17 +/- 0.04 and 0.12 +/- 0.03 microg/ml for S-(-)- and R-(+)-ofloxacin, respectively). Dipeptides fail to modify ofloxacin absorption, but amino acids reduce both isomers' absorption (C(init) is reduced by 53 and 33% with glycine for S-(-)- and R-(+)-ofloxacin, respectively, and by 59 and 42% with L-leucine). Gamma amino butyric acid interferes with the absorption of ofloxacin isomers, but less seriously than do amino acids. Furthermore, ofloxacin competes with other fluoroquinolones or P-glycoprotein substrates for a common secretory pathway, resulting in an increased rate of absorption for both ofloxacin isomers; this is probably an indirect result of their reduced efflux from the apical side of intestinal cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Physiology of chemotherapy-induced emesis and antiemetic therapy. Predictive models for evaluation of new compounds.

The physiology of emesis has been studied for several hundred years, focusing on the different centres involved and the mechanics of expulsion. The vomiting centre receives inputs from various emetic detectors such as the gut, the vestibular labyrinths and the chemoreceptor trigger zone. Emesis is a common disabling effect in motion sickness, postoperative conditions and in radio- and chemotherapy. Our current understanding of the mechanisms has been provided mainly by the recent introduction of serotonin 5-HT3 receptor antagonists into therapeutic use. Nevertheless, despite the considerable advances made in the understanding of the different pathways involved in emesis, there are number of areas that still require experimental investigation. Different animal and human models are available to study the physiology of emesis and to evaluate the antiemetic activity of new compounds, but they need to be predictors of clinical situations.

Animals↗
PubMed1997

Increased intestinal absorption of cefixime by nifedipine in the rat intestinal perfusion model: evidence for a neural regulation.

In healthy volunteers, the simultaneous administration of nifedipine and cefixime has been shown to increase the oral absorption of the antibiotic. To investigate the pharmacological basis of this interaction, we used an in situ intestinal perfusion technique in the rat. pH 5.5 yielded optimum cefixime absorption, which was greater in segments from the duodenojejunum than in those from the jejunoileum. Cefixime absorption was similar when perfused at 0.5 and 1.0 mg/ml, suggesting transport saturation at the lower concentration. Cefixime arterial and portal blood concentrations after an intestinal perfusion of 0.5 mg/ml cefixime were significantly increased by a previous 15-min intestinal perfusion of 0.05 mg/ml nifedipine. Nifedipine did not significantly alter intestinal blood flow. At the end of the cefixime perfusion, intestinal blood flow was higher in the nifedipine group than in the control group (0.44 +/- 0.12 vs. 0.26 +/- 0.09 ml.min-1.g of intestine wt-1, respectively), although the difference did not reach statistical significance. The absorption kinetics of salicylic acid, which is strictly absorbed by passive diffusion, were unaffected by nifedipine. After 15 and 50 min of recirculation, residual salicylate levels fell from 85.1 +/- 5.6% to 57.1 +/- 2.8% with nifedipine compared with 87.4 +/- 1.4% to 52.8 +/- 1.6% without nifedipine. Thus, the improvement in cefixime absorption by nifedipine was not secondary to increased local blood flows or to induced passive diffusion mechanisms. Nifedipine did not affect intestinal motility. The action of nifedipine appears to indirect, involving a neural regulation, because any increase in cefixime absorption was prevented by tetrodotoxin and hexamethonium administration.

Animals↗
PubMed1996

Critical issues in chiral drug analysis in biological fluids by high-performance liquid chromatography.

This review article focuses on the specificities of chiral liquid chromatography, with particular emphasis on stability, stereoconversion, enantiomeric separation, recovery and drug concentration determinations. In addition, the paper presents an overview of the different steps which have to be followed for a chiral method to be validated. Sensitivity, selectivity, linearity, precision and accuracy all have to be ensured for three chemical entities, the two enantiomers and the racemate. Only accurate and precise concentrations of the parent drug and its metabolites will lead to the reliable description of their in vitro stability and in vivo body disposition.

Chromatography, High Pressure Liquid↗
PubMed1996

Altered trimethoprim-sulfamethoxazole ratios for prophylaxis and treatment of Toxoplasma gondii and Pneumocystis carinii dual infections in rat model.

Trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line drug for prophylaxis and treatment of Pneumocystis carinii pneumonia (PCP) and for prophylaxis of toxoplasmosis in HIV-infected patients. Evidence indicating intolerance related to the dose of SMX led us to examine the efficacy of altered TMP-SMX ratios in a corticosteroid-treated rat model. Infections were assessed by counting P. carinii cysts in lung and by titration of Toxoplasma gondii burdens in tissue culture. For prophylaxis, the reference regimen of 20 mg/kg TMP plus 100 mg/kg SMX was effective. Reduced doses of SMX (5 and 20 mg/kg) effective against PCP were effective against toxoplasmosis, provided the TMP dose was increased to 100 mg/kg. For curative treatment, the reversed ratio of 100 mg/kg TMP plus 20 mg/kg SMX was not effective. These results may provide a basis for altering the TMP-SMX ratios in setting of prophylaxis for both infections, especially in HIV infected patients who often poorly tolerate sulfonamides.

Animals↗
PubMed1996

Stereoselective pharmacokinetics of mefloquine in young children.

OBJECTIVE: the stereospecificity of mefloquine pharmacokinetics in children has been investigated. PATIENTS: Twelve children aged 6 to 24 months were treated for uncomplicated falciparum malaria with a single oral dose of 25 mg.kg-1 racemic mefloquine in combination with sulfadoxine and pyrimethamine. METHODS: concentrations of mefloquine enantiomers were determined using a coupled achiral-chiral chromatographic system. Pharmacokinetic parameters were calculated using model-independent analysis. RESULTS: Maximum plasma concentrations, areas under the curve and apparent plasma elimination half-lives were higher for the (-) enantiomer than its antipode. In contrast, the apparent volume of distribution (V/f) and total clearance (Cl/f) values were higher for the (+) enantiomer. CONCLUSION: the stereoselectivity of mefloquine pharmacokinetics is similar to that observed in adults.

Antimalarials↗
PubMed1996

Role of prostaglandins and nitric oxide on halothane-induced arteriolar dilatation in rat diaphragm.

The effects of anaesthetics on the microcirculation of the diaphragm are incompletely understood. Therefore, we assessed by in vivo intravital microscopy in rats the action of halothane on diaphragmatic arteriolar diameter and the role of nitric oxide and prostaglandins on halothane-induced diaphragmatic arteriolar diameter. We studied 54 rats anaesthetized with thiopentone. Dose-response curves to topically applied Krebs' solution saturated with halothane at increasing concentrations of 0%, 1%, 3% and 5% were carried out in the presence of an inhibitor of nitric oxide synthesis (N omega-nitro-L-arginine (LNA), 300 mumol litre-1) or inhibitors of prostaglandin synthesis (mefenamic acid 20 mumol litre-1 or indomethacin 20 mol litre-1) or in the absence of any inhibitor. We found dose-dependent arteriolar dilatation which was abolished by mefenamic acid and indomethacin. In contrast, the effect of halothane was not modified by LNA. These data demonstrated that halothane-induced arteriolar dilatation in the diaphragm of the rat was mediated by prostaglandins but not by nitric oxide.

Anesthetics, Inhalation↗
PubMed1996

Pharmacokinetics of propofol after a single dose in children aged 1-3 years with minor burns. Comparison of three data analysis approaches.

BACKGROUND: No complete pharmacokinetic profile of propofol is yet available in children younger than 3 yr, whereas clinical studies have demonstrated that both induction and maintenance doses of propofol are increased with respect to body weight in this age group compared to older children and adults. This study was therefore undertaken to determine the pharmacokinetics of propofol after administration of a single dose in aged children 1-3 yr requiring anesthesia for dressing change. METHODS: This study was performed in 12 children admitted to the burn unit and in whom burn surface area was less than or equal to 12% of total body surface area. Exclusion criteria were: unstable hemodynamic condition, inappropriate fluid loading, associated pulmonary injury, or burn injury older than 2 days. Propofol (4 mg.kg(-1))plus fentanyl (2.5 microg.kg(-1)) was administered while the children were bathed and the burn area cleaned during which the children breathed spontaneously a mixture of oxygen and nitrous oxide (50:50). Venous blood samples of 300 microl were obtained at 5, 15, 30, 60, 90, and 120 min, and 3, 4, 8, and 12 thereafter injection; an earlier sample was obtained from 8 of 12 children. The blood concentration curves obtained for individual children were analyzed by three different methods: noncompartmental analysis, mixed effects population model, and standard two-stage analysis. RESULTS: Using noncompartmental analysis, total clearance of propofol (+/-SD) was 0.053+/-0.013l.kg(-1).min(-1), volume of distribution at steady state9.5 +/- 3.7l.kg(-1),and residence time 188 +/- 85 min. Propofol pharmacokinetics were best described by a weight-proportional three-compartmental model in both population and two-stage analysis. Estimated and derived pharmacokinetic parameters were similar using these two pharmacokinetic approaches. Results of population versus two-stage analysis are as follow: systemic clearance 0.049 versus 0.048 l.kg(-).min(-1), volume of central compartment 1.03 versus 0.95 l.kg(-1), volume of steady state 8.09 versus 8.17 l.kg(-1). CONCLUSIONS: The volume of the central compartment and the systemic clearance were both greater than all values reported in older children and adults. This is consistent with the increased propofol requirements for both induction and maintenance of anesthesia in children 1-3 yr. (Key words: Anesthesia: pediatric. Pharmacokinetics: propofol.)

Age Factors↗