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Biomedical subjects

R Farinotti

Publications and source records attributed to R Farinotti.

At least 73 records · Page 4Linked to original sources
PubMed1996

Effect on gastric secretion, gastrin and histamine release during and after long-term treatment by pirenzepine in dogs.

We assessed the effects of pirenzepine (2 mg/kg per os) on gastric secretion and gastrin and histamine release in response to food and histamine dihydrochloride infusion in four dogs during 24 weeks of treatment and for 15 weeks after the end of treatment. The results were compared to those obtained in the same animals in control experiments, before treatment, and in four untreated dogs. Pirenzepine absorption was checked by measuring plasma concentrations. Pirenzepine led to a significant reduction in acid and pepsin secretion in response to histamine. In response to food, the reduction in secretion was concomitant with a reduction in gastrin and histamine release. Baseline concentrations of gastrin were reduced, while those of histamine were unchanged. No side effects were observed. After treatment, a long time lapse (about 15 weeks) was required for acid and pepsin secretion and gastrinemia to return to control levels, while histamine release in response to food normalized rapidly. Pirenzepine fixes selectively to M1 muscarinic receptors of the synaptic ganglion, thus inhibiting the effect of vagal stimulation, especially on pepsin secretion. Our data suggest that it might also fix to M1 receptors located on ECL cells, thereby reducing histamine release. In addition, pirenzepine probably fixes to other muscarinic receptors inhibiting gastrin release and resulting in a G and secretory cell mass reduction, probably by increasing somatostatin release.

Animals↗
PubMed1996

Comparison of fluconazole and amphotericin B for treatment of experimental Candida albicans endocarditis in rabbits.

Amphotericin B (AmB) and fluconazole, administered intraperitoneally for 7 days, were compared in a rabbit model for Candida albicans endocarditis. When given early, AmB was more effective than fluconazole for reducing CFU counts in vegetations (P < 0.01) and kidneys. Forty-eight hours after the last dose, AmB was still detected in all vegetations whereas fluconazole was detected in only one case.

Amphotericin B↗
PubMed1996

Effects of nifedipine and diltiazem on pharmacokinetics of cefpodoxime following its oral administration.

We compared the effects of nifedipine and diltiazem on the uptake of cefpodoxime proxetil (CP). The study was aimed at establishing the impact of increased mesenteric blood flow due to calcium channel blockers on passive transport. Twelve volunteers were given CP (200 mg) orally in a crossover design. The absorption, disposition, and elimination parameters of cefpodoxime were compared among the following three treatment groups: CP alone, CP following oral administration of diltiazem (60 mg), or CP following oral administration of nifedipine (20 mg). No statistically significant difference in pharmacokinetic parameters was observed between the three treatment groups.

Administration, Oral↗
PubMed1996

Therapy of visceral leishmaniasis due to Leishmania infantum: experimental assessment of efficacy of AmBisome.

The tolerance and efficacy of amphotericin B (AmB) deoxycholate (Fungizone) were compared with those of liposomal AmB (AmBisome) in a murine model of visceral leishmaniasis induced by Leishmania infantum. Control groups consisted of untreated mice and mice treated with a pentavalent antimonial (Glucantime). BALB/c mice were infected intravenously on day 0 with 10(7) promastigotes of L. infantum and then treated from day 7 to 17 (early treatment group) or from day 60 to 70 (delayed treatment group). The pentavalent antimonial was administered daily by intraperitoneal injection, whereas AmB formulations were administered intravenously on alternate days. On days 20, 60, and 120 (early treatment group) and on days 72 and 125 (delayed treatment group), parasite burdens in the liver, spleen, and lungs were determined by subculturings using a microtitration method. A dose range study showed that administration of AmBisome at the well-tolerated doses of 5 or 50 mg/kg of body weight completely eradicated the parasites from the tissues. At 0.8 mg/kg, AmBisome proved more efficacious than AmB deoxycholate administered at the same dose. We also compared the levels of AmB deoxycholate and AmBisome in plasma and tissue. Mice treated with AmBisome had levels of AmB in tissue much higher than did AmB deoxycholate-treated mice with persistent detectable levels 14 weeks after treatment. These results seem to account for the remarkable efficacy of the liposomal formulation of AmB in the treatment of visceral leishmaniasis due to L. infantum.

Amphotericin B↗
PubMed1996

Importance of penicillinase production for activity of penicillin alone or in combination with sulbactam in experimental endocarditis due to methicillin-resistant Staphylococcus aureus.

The activity of penicillin, alone and in combination with sulbactam, against a heterogeneously methicillin-resistant, penicillinase-producing clinical isolate of Staphylococcus aureus and its penicillinase-negative derivative was investigated in vitro and in a rabbit experimental endocarditis model. Penicillin was significantly more effective than vancomycin against the penicillinase-negative derivative in vivo (P < 0.001), and it sterilized 25% of the vegetations. The combination of penicillin and sulbactam exhibited an in vivo synergistic effect on the penicillinase-producing strain (P < 0.01) but did not produce any advantage over treatment with vancomycin, even when a high dose of sulbactam was used (100 mg/kg of body weight every 6 h). This combination was significantly less effective against the penicillinase-producing strain than was penicillin alone against the penicillinase-negative derivative (P < 0.03). In addition, the most resistant subpopulation of the surviving bacteria, which grew on agar containing 16 micrograms of methicillin per ml, was detected in 5 of 6 animals treated with penicillin and a high dose of sulbactam against the penicillinase-producing strain compared with only 1 of 12 animals treated with penicillin alone against the penicillinase-negative derivative (P < 0.01). We conclude that penicillin is highly effective against penicillinase-negative methicillin-resistant S. aureus and that penicillinase production, rather than methicillin resistance, appears to be the limiting factor for the activity of the penicillin-sulbactam combination against penicillinase-producing, methicillin-resistant S. aureus.

Animals↗
PubMed1996

In vitro and in vivo effects of rifabutin alone or combined with atovaquone against Toxoplasma gondii.

The efficacy of rifabutin (RIFA) alone or in combination with atovaquone (ATO) was examined in vitro and in a murine model of acute toxoplasmosis. In vitro studies were performed with MRC5 fibroblast tissue cultures, with quantification of Toxoplasma growth by enzyme-linked immunosorbent assay. For in vivo studies, mice were acutely infected with 10(4) tachyzoites of the virulent RH strain and were then treated perorally for 10 days from day 1 or day 4 postinfection. The efficacy of each drug regimen was assessed by determination of survival rates and sequential titration of parasites in blood, brain, and lungs by a tissue culture method. In vitro, RIFA was inhibitory for Toxoplasma growth at concentrations between 0.5 and 20 micrograms/ml; the 50% inhibitory concentration was estimated to be 1.68 micrograms/ml. When RIFA and ATO were combined, synergistic effects were noted for RIFA at 20 micrograms/ml combined with ATO at 0.01 or 0.02 microgram/ml and RIFA at 1, 2, or 5 micrograms/ml combined with ATO at 0.02 microgram/ml. In vivo, administration of RIFA at 200 mg/kg of body weight per day from day 1 to day 10 resulted in a 100% protection during treatment, with clearance of parasites from the blood, brain, and lungs. After the cessation of therapy, relapses occurred in the brain and lungs; the mortality was 46% at the end of the experiment (day 30). Among the mice treated with RIFA at 200 mg/kg/day from day 4 to day 14, no death was recorded during the treatment period and a marked reduction in parasite burdens was observed in blood and tissues; however, relapses occurred and 10% of mice survived until day 30. Administration of RIFA at 200 mg/kg/day in combination with ATO at 100 mg/kg/day resulted in a marked prolongation of survival compared with that for mice that received ATO or RIFA alone. However, in mice receiving the combination, parasite burdens in blood and organs were similar to those in mice treated with RIFA alone. These results confirmed the activity of RIFA in the treatment of acute toxoplasmosis and the potential of the combination of RIFA-ATO since the two drugs act synergistically against Toxoplasma gondii.

Animals↗
PubMed1996

Intestinal elimination of ofloxacin enantiomers in the rat: evidence of a carrier-mediated process.

The aim of this work was to examine the mechanism involved in intestinal elimination of the two optical isomers of ofloxacin in the rat. An intestinal segment was isolated in situ and perfused with saline, while drug solution was administered via the carotid artery. Blood samples and intestinal effluents were collected and analyzed by a high-performance liquid chromatography method. We observed saturable and stereoselective intestinal elimination of the ofloxacin enantiomers. The elimination process favored the R-(+) form of the molecule. After a parenteral dose of 20 mg of racemic ofloxacin per kg of body weight, intestinal clearances were 0.23 +/- 0.03 versus 0.30 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively. Ciprofloxacin and pefloxacin interfered with ofloxacin elimination and significantly reduced the intestinal clearance of S-(-)- and R-(+)-ofloxacin. With concomitant ciprofloxacin, intestinal clearances became 0.13 +/- 0.02 versus 0.17 +/- 0.03 ml/min and 0.14 +/- 0.01 versus 0.19 +/- 0.05 ml/min with pefloxacin for S-(-)- and R-(+)-ofloxacin, respectively. Those findings argue for the presence of a common transport system in the rat intestine with variable affinities for fluoroquinolones. In addition, verapamil and quinidine, two P-glycoprotein blockers, significantly reduced the intestinal elimination of both ofloxacin isomers (with concomitant verapamil, intestinal clearances were 0.12 +/- 0.02 versus 0.18 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively, while with concomitant quinidine, values were 0.18 +/- 0.01 versus 0.23 +/- 0.01 ml/min without modifying their areas under the concentration-time curve in serum. Similar results were found with another fluoroquinolone, ciprofloxacin, in previous work. P-glycoprotein appears to be involved in the intestinal elimination of fluoroquinolones in rats. The characterization of fluoroquinolone intestinal elimination has significant clinical relevance for the better evaluation of the influence of this secretory pathway on antibiotic efficacy and selection of resistant bacteria within the intestinal flora.

Animals↗
PubMed1996

Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements.

This paper presents the current state of knowledge on chloroquine disposition, with special emphasis on stereoselectivity and microsomal metabolism. In addition, the impact of the patient's physiopathological status and ethnic origin on chloroquine pharmacokinetics is discussed. In humans, chloroquine concentrations decline multiexponentially. The drug is extensively distributed, with a volume of distribution of 200 to 800 L/kg when calculated from plasma concentrations and 200 L/kg when estimated from whole blood data (concentrations being 5 to 10 times higher). Chloroquine is 60% bound to plasma proteins and equally cleared by the kidney and liver. Following administration chloroquine is rapidly dealkylated via cytochrome P450 enzymes (CYP) into the pharmacologically active desethylchloroquine and bisdesethylchloroquine. Desethylchloroquine and bisdesethylchloroquine concentrations reach 40 and 10% of chloroquine concentrations, respectively; both chloroquine and desethylchloroquine concentrations decline slowly, with elimination half-lives of 20 to 60 days. Both parent drug and metabolite can be detected in urine months after a single dose. In vitro and in vivo, chloroquine and desethylchloroquine competitively inhibit CYP2D1/6-mediated reactions. Limited in vitro studies and preliminary data from clinical experiments and observations point to CYP3A and CYP2D6 as the 2 major isoforms affected by or involved in chloroquine metabolism. In vitro efficacy studies did not detect any difference in potency between chloroquine enantiomers but, in vivo in rats, S(+)-chloroquine had a lower dose that elicited 50% of the maximal effect (ED950) than that of R(-)-chloroquine. Stereoselectivity in chloroquine body disposition could be responsible for this discrepancy. Chloroquine binding to plasma proteins is stereoselective, favouring S(+)-chloroquine (67% vs 35% for the R-enantiomer). Hence, unbound plasma concentrations are higher for R(-)-chloroquine. Following separate administration of the individual enantiomers, R(-)-chloroquine reached higher and more sustained blood concentrations. The shorter half-life of S(+)-chloroquine appears secondary to its faster clearance. Blood concentrations of the S(+)-forms of desethylchloroquine always exceeded those of the R(-)-forms, pointing to a preferential metabolism of S(+)-chloroquine.

Animals↗
PubMed1996

[Comparative study of the performance and ergonomics of nebulizers in cystic fibrosis].

This study had, as its aim, to test twelve nebulizers (6 jet, 6 ultrasonic) which are used in the treatment of cystic fibrosis. Devices were connected to a respirator in order to mimic the ventilation of a child and of an adult suffering from cystis fibrosis. Three medications: tobramycine, colistine and amiloride were nebulised. The volume of the recommended solution varied between 1.5 and 13 ml according to the manufacturer. During a session of ten minutes the ultrasonic nebulizer delivered an inhaled volume which was significantly greater than the jet (2.72 +/- 0.98 ml vs 1.22 +/- 0.59 ml, p < 0.0001) for the three drugs. Regarding granulometry, the fraction of particles between 0.5 and 5 microns, was higher with ultrasonic than with pneumatic nebulizer for tobramycine (67.1 +/- 10.7 vs 55.5 +/- 11.5%, p < 0.001) and amiloride (66.4 +/- 9.2% vs 58.1 +/- 15%, p < 0.05%). The variation of concentration due to nebulisation were independent of the type of apparatus but influenced by the drug since concentration was increased for tobramycine (+10.5 +/- 18.6%) and amiloride (+13.4 +/- 8/9%). In summary the effective fraction resulting from the inhalable fraction, from granulometry and from changes in concentration was significantly greater for ultrasonic than for jet nebrulizer (17.3 +/- 6.7% vs 9.7 +/- 9.6%, p < 0.001). This study underlines the great variability of the performance of aerosols generators and therefore the need for an accurate evaluation of nebulizer performances in order to prescribe the best nebulizer/drug association in clinical practice.

Administration, Inhalation↗
PubMed1995

High-performance liquid chromatographic assay for 3'-amino-3'-deoxythymidine in plasma, with 9-fluorenyl methyl chloroformate as the derivatization agent.

We have developed a sensitive high-performance liquid chromatographic assay for the determination of the zidovudine metabolite 3'-amino-3'-deoxythimidine (AMT) using fluorescence and sensitivity in the picomolar range. Plasma was diluted with 0.05 M sodium phosphate buffer pH 7.2 and subsequently prepared for analysis using solid-phase extraction. AMT was derivatized with 9-fluorenyl methylchloroformate and chromatographed using a reversed-phase system. The mobile phase consisted of acetonitrile-0.01 M potassium phosphate buffer (pH 7) (32.68, v/v). The fluorescence of the column effluent was monitored at 262 nm (excitation) and 306 nm (emission). Good resolution of AMT from endogenous plasma components was obtained. Within- and between-day variability was less than 10%. The limit of quantitation was 0.9 microgram/l. The assay was successfully applied to the determination of AMT in human plasma and in plasma of mice treated with zidovudine.

Animals↗
PubMed1995

Nebulizer performance: AFLM study. Association Française de Lutte contre la Mucoviscidose.

This study was conducted by the AFLM order to determine the performance characteristics of 12 commercially available nebulizers (6 ultrasonic and 6 jet) used in the treatment of cystic fibrosis (CF). The nebulizers were connected to a circuit which simulated the ventilation of a CF child and CF adult, and were tested using three drug solutions: tobramycin (T), colistin (C), and amiloride (A). Nebulizer performance was evaluated according to the volume of drug solution delivered in 10 min during the simulated inspiratory phase (VI), drug granulometry (G%), drug concentration modification in the nebulizer reservoir (delta C), and percentage of efficiently aerosolized drug EA%). The ultrasonic devices delivered a significantly higher VI than the jet nebulizers (p < 0.0001) for all three study drug. Ventilation rate did not influence VI. Regarding granulometry, higher percentages of T and A were found to be contained in droplets ranging from 0.5 to 5.0 micron following ultrasonic nebulization. Drug concentration modifications were independent of the nebulizer used but were influenced by drug type; overconcentrations of T and A were observed (delta C = +10.5 +/- 18.6 and +13.4 +/- 8.9%, respectively). On average, the ultrasonic devices achieved a higher EA% than the jet nebulizers (17.3 +/- 6.7 and 9.7 +/- 9.6%, respectively). This study highlights the significant variability in performance of different nebulizer types and empahsizes the importance of accurately testing nebulizers prior to clinical use so that the most efficacious nebulizer/drug combinations may be prescribed.

Administration, Inhalation↗
PubMed1995

Clinical pharmacokinetics of zopiclone.

Zopiclone is a cyclopyrrolone hypnotic agent. It possesses a chiral centre and is commercially available as a racemic mixture. Methods involving high performance liquid chromatography (HPLC), gas chromatography, capillary electrophoresis (CE) and high performance thin layer chromatography have been developed for the quantitation of zopiclone and its 2 main metabolites in biological samples. For the chiral determination of the enantiomers of zopiclone and its metabolites, HPLC and CE methods are available. After oral administration, zopiclone is rapidly absorbed, with a bioavailability of approximately 80%. The plasma protein binding of zopiclone has been reported to be between 45 and 80%. Zopiclone is rapidly and widely distributed to body tissues including the brain, and is excreted in urine, saliva and breast milk. Zopiclone is partly metabolised in the liver to form an inactive N-demethylated derivative and an active N-oxide metabolite. In addition, approximately 50% of the administered dose is decarboxylated and excreted via the lungs. Less than 7% of the administered dose is renally excreted as unchanged zopiclone. In urine, the N-demethyl and N-oxide metabolites account for 30% of the initial dose. The terminal elimination half-life (t1/2z) of zopiclone ranges from 3.5 to 6.5 hours. The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixture, Cmax (time to maximum plasma concentration), AUC (area under the plasma time-concentration curve) and t1/2z values are higher for the dextrorotatory enantiomer owing to the slower total clearance and smaller volume of distribution (corrected by the bioavailability), compared with the levorotatory enantiomer. In urine, the concentrations of the dextrorotatory enantiomers of the N-demethyl and N-oxide metabolites are higher than those of the respective antipodes. The pharmacokinetics of zopiclone are altered by aging and are influenced by renal and hepatic functions. Drug interactions have been observed with erythromycin, trimipramine and carbamazepine.

Azabicyclo Compounds↗
PubMed1994

High-performance liquid chromatographic method for the determination of cefpodoxime levels in plasma and sinus mucosa.

A selective HPLC method is described for the determination of cefpodoxime levels in plasma and sinus mucosa. Sample preparation included solid-phase extraction with a C8 cartridge. Cefpodoxime and cefaclor (internal standard) were eluted with methanol and analyzed on an optimised system consisting of a C18 stationary phase and a ternary mobile phase (0.05 M acetate buffer pH 3.8-methanol-acetonitrile, 87:103, v/v) monitored at 235 nm. Linearity and both between- and within-day reproducibility were assessed for plasma and sinus mucosa samples. Inter-assay coefficients of variation were lower than 13.6% (n = 10) for plasma (0.2 micrograms/ml) and lower than 12.4% (n = 5) for sinus mucosa (0.25 micrograms/g). The quantification limit was 0.05 micrograms/ml for plasma and 0.13 micrograms/g for tissue. The method was used to study the diffusion of cefpodoxime in sinus mucosa.

Ceftizoxime↗
PubMed1994

Stereoselective pharmacokinetics of mefloquine in healthy Caucasians after multiple doses.

Mefloquine (MQ) is a chiral antimalarial agent effective against chloroquine-resistant Plasmodium falciparum. It is commercially available as a racemic mixture of the (+) and (-) enantiomers for oral administration. The pharmacokinetics of the (+) and (-) enantiomers of MQ were studied in eight healthy volunteers after administration of a first oral dose of 250 mg of racemic MQ and at steady state after 13 repeated doses of 250 mg given at 1-week intervals. Plasma samples were collected, and concentrations of each enantiomer were determined using a previously described achiral-chiral double column-switching liquid chromatographic method. At each time point, higher plasma concentrations values were found for the (-) enantiomer (p < 0.001). At steady state, Cmax values of (-)-MQ were higher than those of (+)-MQ (1.42 +/- 0.19 versus 0.26 +/- 0.05 mg/L; p < 0.001). Similarly, the plasma concentrations 7 days after the final dose were higher for (-)-MQ (1.01 +/- 0.26 versus 0.11 +/- 0.04 mg/L; p < 0.001). AUC values at steady state were also higher for (-)-MQ (197.3 +/- 36.7 versus 30.1 +/- 8.9 mg/L x h; p < 0.001). The terminal half-life values (T1/2beta) were longer for (-)-MQ (430.4 +/- 225.2 versus 172.8 +/- 56.5 h; p < 0.001). This study shows that the pharmacokinetics of MQ is highly stereoselective.

Adult↗