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Biomedical subjects

Robert Farinotti

Publications and source records attributed to Robert Farinotti.

29 records · Page 2Linked to original sources
PubMed2003

Improvement of cefpodoxime proxetil oral absorption in rats by an oil-in-water submicron emulsion.

Absolute bioavailability of cefpodoxime proxetil is both limited by its low solubility in aqueous solution and its intraluminal hydrolysis. The oil-in-water submicron emulsion was proven to be effective in protecting the prodrug from the enzymatic attack in rabbit intestinal washings. The aim of the study was to perform a pharmacokinetic study in conscious rats to confirm o/w submicron superiority in comparison to other oral formulations (hydro-alcoholic solution, suspension and coarse emulsion). The pharmacokinetic study was performed in conscious rats implanted with permanent aortic catheters. A parenteral solution of cefpodoxime was injected via this catheter, and oral formulations were administered orally. The cefpodoxime plasma level was performed by a HPLC validated method. The pharmacokinetic parameters, t1/2, Cmax, tmax, AUC and absolute bioavailability (F) were determined with a non-compartmental analysis. The results show a significant increase of F for submicron emulsion (97.4%) between the other oral formulations. No significant difference of F was found between the other oral formulations, even with the coarse o/w emulsion. The o/w submicron emulsion made the enhancement of the absolute bioavailability of cefpodoxime proxetil possible. This benefit could be explained by the low droplet size of the submicron emulsion which improve the absorption process of the prodrug.

Absorption↗
PubMed2003

Influence of tumor necrosis factor-alpha on the expression and function of P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT.

Drug cerebral pharmacokinetics may be altered in the case of inflammatory diseases. This may be due to a modification of drug transport through the blood-brain barrier, in particular through drug interaction with the membrane efflux transporter, P-glycoprotein. The objective of this study was to investigate the influence of the inflammatory cytokine, tumor necrosis factor (TNF)-alpha, on the functionality and expression of P-glycoprotein, and on mdr1a and mdr1b mRNA expression in immortalised rat brain endothelial cells, GPNT. Cells were treated with TNF-alpha for 4 days. Levels of mdr1a and mdr1b mRNAs were quantitated using real-time RT-PCR analysis and expression of P-glycoprotein was analyzed by Western blot. The functionality of P-glycoprotein was studied by following the accumulation of [3H]vinblastine in the cells without and with a pre-treatment with a P-glycoprotein inhibitor, GF120918. TNF-alpha increased the levels of mdr1a and mdr1b mRNAs while no effect was observed on protein expression. TNF-alpha increased [3H]vinblastine accumulation indicating a time and concentration-dependent decrease of P-glycoprotein activity. This effect was eliminated when the cells were pre-treated with GF120918. Our observation of a decrease in P-glycoprotein activity could suggest that in the case of inflammatory diseases, brain delivery of P-glycoprotein-dependent drugs can be enhanced.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

[Computerized physician order entry, a tool for added safety in the hospital].

DRUG-RELATED IATROGENIC NOSOCOMIAL ILLNESS: Remains a matter of concern in the public health area. Responsibility of hospitals is challenged by the ever increasing number of patients' claims. Dysfunction in the drug-prescribing and delivery system account, to a large extent, for medication errors, some of them resulting in adverse drug events. Most generally, medication ordering by the physician is handwritten, without nominative recapitulating prescriptions, and followed by nurse transcriptions and a global medication order is transmitted to the pharmacy. This system does not integrate the pharmaceutical analysis of the prescription, before distribution of the drugs. THE COMPUTERIZED DRUG ORDER ENTRY PROCESS: The prescription is entered directly and is displayed on the computer screen, together with the previous prescriptions for the same patient. Transcription is hence eliminated. Depending on the sophistication of the software, the prescription undergoes a series of tests; warnings and reminders can be displayed online before the physician validates the prescription. Moreover, various guidelines in some aspects of drug therapy may be presented online before the prescription is completed. POSSIBILITIES: The pharmacist's access to the complete prescriptions permits analysis of the quality and safety of the prescriptions and the adequation with eventual current applicable recommendations. Prospective drug utilization review, with immediate feedback to the prescribing physician in case of concern, may be undertaken, further improving the quality of drug therapy. Moreover, a work sheet is printed out for the nurses, further enhancing the safety of drug administration and validation. The computerized drug network also permits the development of other functions. A TOOL FOR SAFETY: Currently available reports in the literature suggest that computerized drug prescription reduces the incidence of prescribing errors, improves the appropriateness of drug choices, optimises therapeutic follow-up, and reduces the incidence adverse drug events and leads to substantial reduction in drug expenditures.

Computers↗
PubMed2003

Potentiation of mivacurium blockade by low dose of pancuronium: a pharmacokinetic study.

BACKGROUND: Mivacurium is potentiated by pancuronium to a much greater extent than other relaxants. In a previous investigation we suggested that this potentiation could be due to the ability of pancuronium to inhibit plasma cholinesterase activity, but we did not measure plasma concentrations of mivacurium. In the current study we performed a pharmacokinetic analysis by measuring the plasma concentration of mivacurium when preceded by administration of a low dose of pancuronium. METHODS: After induction of general anesthesia with propofol and fentanyl and orotracheal intubation, 10 patients (pancuronium-mivacurium group) received 15 microg/kg pancuronium followed 3 min later by 0.1 mg/kg mivacurium, whereas 10 other patients (mivacurium group) received saline followed by 0.13 mg/kg mivacurium 3 min later. Plasma cholinesterase activity was measured before and 3 and 30 min after pancuronium dosing in the pancuronium-mivacurium group and was measured before and after administration of saline in the mivacurium group. Arterial plasma concentrations of mivacurium and its metabolites were measured at 0.5, 1, 1.5, 2, 4, 10, 20, and 30 min after injection. Neuromuscular blockade was assessed by mechanomyography. RESULTS: Plasma cholinesterase activity decreased by 26% in the pancuronium-mivacurium group 3 min after injection of pancuronium (P < 0.01) and returned to baseline values 30 min later; however, no significant variation was observed in the mivacurium group. The clearances of the two most active isomers (Cis-Trans and Trans-Trans) were lower in the pancuronium-mivacurium group (17.6 +/- 5.1, 14.7 +/- 5.3 ml. min-1. kg-1, respectively) than in the mivacurium group (32.4 +/- 20.2, 24.8 +/- 13.5 ml. min-1. kg-1; P < 0.05). CONCLUSIONS: A subparalyzing dose of pancuronium decreased plasma cholinesterase activity and the clearance of the two most active isomers of mivacurium. Pancuronium potentiates mivacurium more than other neuromuscular blocking agents because, in addition to its occupancy of postsynaptic acetylcholine receptors, it slows down the hydrolysis of mivacurium.

Adolescent↗
PubMed2003

Pharmacokinetics of propofol administered by target-controlled infusion to alcoholic patients.

BACKGROUND: Chronic alcoholic patients are frequently presented for anesthesia and surgery. These patients require higher doses of propofol than control patients for induction of anesthesia, but whether this is because of changes in pharmacokinetics or pharmacodynamics is not known. This study was designed to investigate the influence of chronic ethanol intake on propofol pharmacokinetics. METHODS: Fifteen chronic alcoholic and 15 control patients, receiving propofol by target-controlled infusion for otolaryngologic surgery, were studied. Blood propofol concentrations were measured at regular intervals during and after the propofol infusion. Nonlinear mixed-effects population models (NONMEM) examining the influence of alcoholism were constructed. The influence of recovery on propofol pharmacokinetic parameters was also addressed. RESULTS: The total amount of propofol and the predicted and measured concentrations during all phases of anesthesia did not differ between the two groups. The fact that the measured concentrations at the time of opening eyes were similar further confirmed that the potency of propofol was not modified by the alcoholic status of the patients. Chronic alcoholism was associated with only mild changes in propofol pharmacokinetics (increase in rapid intercompartmental clearance and greater interindividual variability in the central volume of distribution). The rebound in concentration frequently observed during the recovery phase could be related to decreased propofol peripheral volumes of distribution despite an increase in elimination clearance. CONCLUSIONS: Chronic alcoholism induces only mild changes in the pharmacokinetics of propofol. Conversely, propofol pharmacokinetics are markedly different during anesthesia and surgery or after opening eyes in the recovery period.

Adolescent↗
PubMed2003

In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4, and CYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation.

In humans, the antimalarial drug chloroquine (CQ) is metabolized into one major metabolite, N-desethylchloroquine (DCQ). Using human liver microsomes (HLM) and recombinant human cytochrome P450 (P450), we performed studies to identify the P450 isoform(s) involved in the N-desethylation of CQ. In HLM incubated with CQ, only DCQ could be detected. Apparent Km and Vmax values (mean +/- S.D.) for metabolite formation were 444 +/- 121 microM and 617 +/- 128 pmol/min/mg protein, respectively. In microsomes from a panel of 16 human livers phenotyped for 10 different P450 isoforms, DCQ formation was highly correlated with testosterone 6beta-hydroxylation (r = 0.80; p < 0.001), a CYP3A-mediated reaction, and CYP2C8-mediated paclitaxel alpha-hydroxylation (r = 0.82; p < 0.001). CQ N-desethylation was diminished when coincubated with quercetin (20-40% inhibition), ketoconazole, or troleandomycin (20-30% inhibition) and was strongly inhibited (80% inhibition) by a combination of ketoconazole and quercetin, which further corroborates the contribution of CYP2C8 and CYP3As. Of 10 cDNA-expressed human P450s examined, only CYP1A1, CYP2D6, CYP3A4, and CYP2C8 produced DCQ. CYP2C8 and CYP3A4 constituted low-affinity/high-capacity systems, whereas CYP2D6 was associated with higher affinity but a significantly lower capacity. This property may explain the ability of CQ to inhibit CYP2D6-mediated metabolism in vitro and in vivo. At therapeutically relevant concentrations ( approximately 100 microM CQ in the liver), CYP2C8, CYP3A4, and, to a much lesser extent, CYP2D6 are expected to account for most of the CQ N-desethylation.

Animals↗
PubMed2002

Recombinant interleukin-2 treatment decreases P-glycoprotein activity and paclitaxel metabolism in mice.

Recombinant rIL-2 was reported to be able to decrease P-glycoprotein (P-gp) expression in cultured cells from human colon carcinoma. P-gp is considered an important factor in the control of Taxol efflux from tumor cells. Based on the premise that Taxol pharmacokinetic parameters could be modified as a result of diminished P-gp expression induced by recombinant interleukin (rIL)-2 and that this might elicit an interaction between the two drugs, we evaluated the pharmacokinetics of a novel strategy combining i.p. immunotherapy with rIL-2 and a cytotoxic agent, Taxol. Mice were allocated to two groups treated with rIL-2 (15 microg x 2/day from day 1 to 4) then Taxol (10 mg/kg i.p. day 5) or Taxol (10 mg/kg i.p.) alone (control group). The Taxol + rIL-2 combination provoked the development of ascites, presumably due to the presence of Cremophor EL in the Taxol preparation. Paclitaxel was measured in plasma and ascites by HPLC with UV detection. Paclitaxel pharmacokinetics were strongly modified by rIL-2 pretreatment. Compared to that observed in control mice, the apparent volume of distribution increased dramatically (Vd/F = 18.2 versus 4.1 l/kg) and the apparent plasma clearance decreased (Cl/F = 1.12 versus 1.66 l/h/kg). P-gp expression was determined in the liver, lung, intestine, brain and kidney in the two groups by immunodetection with the C219 anti-P-gp monoclonal antibody. A significant decrease in P-gp expression was observed in the intestine and in the brain in the rIL-2-pretreated mice as compared to controls. To study the functionality of P-gp, we compared digoxin (a model P-gp substrate) pharmacokinetics before and after pretreatment with rIL-2 (10 microg x 2/day from day 1 to 4), after a single 1 microg oral dose of digoxin used to quantify P-gp activity. Results showed a decrease in oral digoxin clearance after rIL-2 pretreatment indicating modified P-gp activity. We conclude that rIL-2 pretreatment is able to decrease P-gp activity and paclitaxel metabolism in vivo. This is the first study to demonstrate a decrease in P-gp activity and expression in organs such as the brain in vivo. A novel strategy combining immunotherapy with rIL-2 and a cytotoxic agent could potentially improve clinical results, particularly in brain cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Effect of interleukin-2 on intestinal P-glycoprotein expression and functionality in mice.

P-glycoprotein (Pgp), an active drug transporter expressed in enterocytes, can reduce intestinal absorption of drugs. Until now, interleukin-2 (IL2) has been reported as a Pgp modulator only in vitro. The present study examines the effects in vivo of IL2 after chronic treatment on intestinal Pgp protein expression and activity. This work also describes the effects of IL2 on the oral bioavailability of a Pgp substrate (digoxin) and of a Pgp/CYP3A cosubstrate (saquinavir). Human recombinant interleukin-2 (rIL2), administered to mice at 9 million international units/kg by intraperitoneal route twice daily for 4 days, led to a decrease in intestinal Pgp protein expression evaluated by Western blot with C219 antibody. In an in vitro everted gut sac model, rIL2 pretreatment decreased the Pgp-mediated transport of rhodamine 123 across mouse intestine by 37%. Moreover, rIL2 pretreatment markedly raised the area under the curve of orally administered digoxin from 3.5 +/- 0.5 to 9.7 +/- 1.5 mg min l(-1) as a consequence of the reduction in intestinal Pgp activity. rIL2 treatment increased saquinavir bioavailability from 2.5 to 4.5%, showing that first-pass metabolism is not affected and that Pgp by itself has only a moderate effect on saquinavir oral bioavailability. In conclusion, rIL2 pretreatment reduces intestinal Pgp protein expression and activity in mice. However, the effect of such a treatment on drug bioavailability depends on the extent of their metabolism by CYP3A.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Stereoselective distribution and stereoconversion of zopiclone enantiomers in plasma and brain tissues in rats.

Concentrations of (-)-zopiclone and (+)-zopiclone were determined in plasma and brain after oral administration, to investigate the stereoselectivity of distribution in rats. Zopiclone enantiomers were administered separately to rats and concentrations were determined by chiral HPLC in plasma and brain. In initial experiments, rats were treated with urethane before cannulation for blood sampling but as this drug modified zopiclone pharmacokinetics, it was not used in subsequent studies. This study showed that zopiclone pharmacokinetics after oral gavage in rats are stereoselective. After oral administration of (+)-zopiclone, no stereoconversion was observed in plasma. Conversely, after administration of (-)-zopiclone, both enantiomers were found in plasma and brain with (+)-zopiclone/(-)-zopiclone ratios of 1 and 8.4 in plasma and brain, respectively. Our findings suggest that zopiclone undergoes stereoconversion and that it is stereospecifically distributed to the brain.

Administration, Oral↗
PubMed2002

Effect of hr-IL2 treatment on intestinal P-glycoprotein expression and activity in Caco-2 cells.

Caco-2 cells were used to investigate the effect of human recombinant interleukin-2 (IL2) on intestinal P-glycoprotein (P-gp) transporter activity in-vitro. More specifically the efflux function of P-gp was studied by measuring the transepithelial transport of rhodamine-123, a fluorescent substrate of P-gp. Its transport was completely inhibited by two specific P-gp inhibitors, ciclosporin A and GG918, in our experiments. Conversely, these two specific P-gp inhibitors inhibited only 50% of transepithelial transport when [3H]vincristine was used as substrate. After Caco-2 cells were treated with 100 IU mL-1 (6.1 ng mL-1) IL2 for 24 h, a significant diminution (21%) of P-gp transporter function was observed with rhodamine-123 substrate. This effect was also confirmed after 48 and 72 h of exposure to IL2. However, for higher concentrations of IL2 (1000 and 5000 IU mL-1), diminution of P-gp function only occurred after a longer treatment period (48 h and more). The inhibitory effect of IL2 on P-gp activity was found to be independent of tight junction function as demonstrated by constant transepithelial electrical resistance (TEER) measurements for all experimental conditions encountered in this study (time and concentration of IL2 exposure). Furthermore, the MDR1 mRNA level was found to be strongly repressed in Caco-2 cells exposed with 1000 IU mL-1 IL2 for 72 h while the amount of MRP1 mRNA remained unchanged. In conclusion, acute incubation of Caco-2 cells with IL2 induced a decrease of P-gp transporter expression and activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗