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Biomedical subjects

E Frigerio

Publications and source records attributed to E Frigerio.

At least 37 records · Page 2Linked to original sources
PubMed1997

Pharmacokinetics of reboxetine enantiomers in the dog.

Reboxetine, (RS)-2-[(RS)-alpha-(2-ethoxyphenoxy)benzyl]morpholine methanesulphonate, is a racemic compound and consists of a mixture of the (R,R)- and (S,S)-enantiomers. The pharmacokinetics of reboxetine enantiomers were determined in a crossover study in three male beagle dogs. Each animal received the following oral treatments, separated by 1-week washout period: 10 mg/kg reboxetine, 5 mg/kg (R,R)- and 5 mg/kg (S,S)-. Plasma and urinary levels of the reboxetine enantiomers were monitored up to 48 h post-dosing using an enantiospecific HPLC method with fluorimetric detection (LOQ: 1.1 ng/ml in plasma and 5 ng/ml in urine for each enantiomer). After reboxetine administration mean tmax was about 1 h for both enantiomers. Cmax and AUC were about 1.5 times higher for the (R,R)- than for the (S,S)-enantiomer, mean values +/- SD being 704 +/- 330 and 427 +/- 175 ng/ml for Cmax and 2,876 +/- 1,354 and 1,998 +/- 848 ng.h/ml for AUC, respectively. No differences between the (R,R)- and (S,S)-enantiomers were observed in t1/2 (3.9 h). Total recovery of the two enantiomers in urine was similar, the Ae (0-48 h) being 1.3 +/- 0.7 and 1.1 +/- 0.7% of the enantiomer dose for the (R,R)- and the (S,S)-enantiomers, respectively. No marked differences in the main plasma pharmacokinetic parameters were found for either enantiomer on administration of the single enantiomers or reboxetine. No chiral inversion was observed after administration of the separate enantiomers, as already observed in humans.

Animals↗
PubMed1997

A study of the pharmacokinetics and tolerability of ritipenem acoxil in healthy volunteers following multiple oral dosing.

The pharmacokinetics of ritipenem acoxil, the oral prodrug of the antibiotic ritipenem, were studied in volunteers after single and repeated dosing (500 mg, three times daily for 10 days). Concentrations of ritipenem and open beta-lactam ring metabolites were measured using HPLC/UV. Ritipenem did not accumulate significantly in plasma, owing to its half-life of about 0.7 h; the area under the curve for 0-8 h was on average about 10 mg x h/L. Plasma pharmacokinetics of ritipenem and metabolites were time-independent. A decrease of ritipenem renal clearance (87 versus 132 mL/min) and a slight increase in the amount of metabolites excreted in urine were observed following repeated dosing.

Administration, Oral↗
PubMed1996

Determination of FCE 26644, a new polysulphonated derivative of distamycin A, in monkey plasma by reversed-phase ion-pair high-performance liquid chromatography with ultraviolet detection.

A sensitive and selective ion-pair high-performance liquid chromatographic method for the determination of 7,7'-carbonylbis[imino-N-methyl-4, 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino]¿- bis(1,3-naphthalenedisulphonic acid), tetrasodium salt in monkey plasma has been developed. The compound and internal standard (bromphenol blue) were extracted from plasma samples were methylene chloride (twice) after deproteination with acetonitrile and addition of the ion-pairing agent (tetrabutylammonium hydroxide). The combined organic phases were dried, the residue dissolved in the mobile phase and then analysed by reversed-phase ion-pair liquid chromatography under isocratic conditions. The HPLC analysis time was about 20 min. Quantitation was achieved by UV detection at 323 nm. The linearity, precision and accuracy of the method were evaluated. The limit of quantitation was 0.3 microgram/ml plasma. No interference from blank monkey, mouse, rat, dog and human plasma was observed. The suitability of the method for in vivo samples was checked by analysis of plasma samples drawn from three male cynomolgus monkeys that had received a 20 mg/kg single i.v. dose of the test compound.

Animals↗
PubMed1995

Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding.

The pharmacokinetics of reboxetine, a new antidepressant agent, were found to be close to linear in a crossover study comparing administration of single 2, 3, 4, and 5 mg capsule doses in 15 healthy male volunteers, and in the same study the capsules were bioequivalent to the proposed therapeutic tablet formulation (4 mg). Kinetic analysis was based on HPLC assay of reboxetine in plasma and urine collected up to 72 h after each administration. Plasma levels indicated a rapid absorption (tmax approximately equal to 2 h) and an elimination half-life of about 13 h. Clearance and volume of distribution were modest (ratios to bioavailability: CL/F approximately equal to 29 mL min-1; Vz/F approximately equal to 32 L); urinary excretion was approximately 9% of dose, corresponding to a renal clearance of only 3 mL min-1 (a value consistent with the rate of glomerular filtration of unbound drug). In vitro, binding to plasma proteins, estimated from radioactivity levels following dialysis of 14C-labelled reboxetine, appeared to be dominated by alpha 1-acid glycoprotein without marked saturation up to plasma concentrations of over 500 ng mL-1 (2.8-3.1% unbound with human plasma from three additional volunteers; 1.8-2.0% for 2 gL-1 orosomucoid alpha 1-acid glycoprotein, and 46.4-47.4% for 40 g L-1 albumin), whilst the mean Cmax in the current study was much lower (164 ng mL-1 after a 5mg dose).

Adult↗
PubMed1995

Stereoselective and species-dependent kinetics of reboxetine in mouse and rat.

Reboxetine, (RS)-2-[(RS)-alpha-(2-ethoxyphenoxy)benzyl]morpholine methanesulphonate, is a racemic compound and consists of a mixture of the (R,R)- and (S,S)-enantiomers. In this study, brain and plasma levels of both enantiomers were determined in mice and rats after oral administration of reboxetine at doses (1.1 mg/kg, mouse; 20 mg/kg, rat) twice the respective ED50 values in the antireserpine test. Plasma and brain concentrations of each enantiomer were measured up to 6 h postdosing using an HPLC method with fluorimetric detection after derivatization with a chiral agent (FLEC). In mice and rats, brain and plasma levels of the (R,R)-enantiomer were always higher than those of the (S,S)-enantiomer. After normalization for dose, the mean AUC0-tz values of both the (R,R)- and (S,S)-enantiomers in mouse brain were about 23 and 32 times higher than in rat brain, respectively. In plasma, the corrected mean AUC0-tz values were about 5 (R,R) and 10 (S,S) times higher in mice than in rats. These results provide evidence for the higher bioavailability and/or lower clearance of both enantiomers in mice than in rats, and for a higher penetration of both enantiomers into mouse brain compared to rat brain.

Animals↗
PubMed1995

A sensitive procedure for the quantitation of free and N-(2-hydroxypropyl) methacrylamide polymer-bound doxorubicin (PK1) and some of its metabolites, 13-dihydrodoxorubicin, 13-dihydrodoxorubicinone and doxorubicinone, in human plasma and urine by reversed-phase HPLC with fluorimetric detection.

A high-performance liquid chromatographic assay has been developed and validated for the determination in plasma and urine of doxorubicin (DXR) and some of its metabolites released in vivo from an N-(2-hydroxypropyl)methacrylamide (HPMA) polymer containing DXR linked through its aminosugar moiety to the polymer via an oligopeptide spacer (PK1). The method also allows measurement of the DXR still bound to the polymer. Following addition of two internal standards, the free compounds were extracted twice with isopropanol-chloroform (25:75, v/v). The first extraction was performed at physiological pH and the second after buffering at pH 8.4, in order to extract the aglycones and the glycosides, respectively. Determination of total DXR (polymer-bound plus free DXR) was performed, after quantitative acid hydrolysis to release doxorubicinone from free or polymer-bound DXR, by extraction with the same solvent mixture at pH 7.4. In both cases the organic phase was evaporated to dryness; the compounds were then separated by reversed-phase high-performance liquid chromatography (HPLC) under isocratic conditions and quantitated by fluorimetric detection. In the chromatograms all the analytes appeared to be separated at the baseline and no interference from blank human plasma and urine was observed. The suitability of the method for in vivo samples was checked by the analysis of plasma and urine samples obtained from a cancer patient who had received a single intravenous dose of the test compound.

Blood↗
PubMed1995

Sarcoidosis presenting as erythema annulare centrifugum.

Erythema annulare centrifugum (EAC), a disease belonging to the poorly characterized category of 'figurate erythemas', has been associated with a variety of conditions, such as connective tissue diseases, infections, neoplasms and drug reactions. Here we report a case of EAC associated with sarcoidosis, the first case in the literature to our knowledge. EAC was the sole sign of the granulomatous disease process, which was diagnosed by means of appropriate investigations only after the patient reported the sudden resolution of a long-standing sensitization to perfumes and parabens. Steroid treatment for sarcoidosis improved the patient's condition, and restored the allergic response to these substances.

Erythema↗
PubMed1994

Sensitive procedure for the determination of reboxetine enantiomers in human plasma by reversed-phase high-performance liquid chromatography with fluorimetric detection after chiral derivatization with (+)-1-(9-fluorenyl)ethyl chloroformate.

A sensitive and selective high-performance liquid chromatographic method for the determination of reboxetine enantiomers in human plasma was developed. Although two chiral centres are present in reboxetine, its stereospecific synthesis leads to two rather than four possible enantiomers. After extraction from plasma and reaction with (+)-1-(9-fluorenyl)ethyl chloroformate, reboxetine enantiomers were separated as diastereoisomeric derivatives by reversed-phase high-performance liquid chromatography (HPLC) and determined by fluorimetric detection. The HPLC analysis time was about 90 min. The linearity, precision, accuracy and limit of quantification of the method were evaluated. No interference from blank plasma sample was observed. The suitability of the method for in vivo samples was assessed by the analysis of plasma samples obtained from a healthy male volunteer who had received a single oral dose of 4 mg of reboxetine in tablet form.

Antidepressive Agents↗
PubMed1992

Random mutagenesis of the human immunodeficiency virus type-1 trans-activator of transcription (HIV-1 Tat).

A new method is described for the direct construction of randomly mutagenized genes by applying the polymerase chain reaction (PCR) to an oligonucleotide synthesized using doped nucleotide reservoirs. We have demonstrated the utility of this method by generating a library of mutant HIV-1 tat genes. Several arbitrarily selected, inactive tat clones were sequenced to evaluate the extent of the mutagenesis. Moreover, fourteen recombinants encoding varying levels of transcriptional trans-activator activity were isolated by transient transfection of sub-library pools into a HeLa cell line bearing an HIV-LTR-chloramphenicol acetyltransferase (CAT) reporter gene. Sequence data revealed a spectrum of alterations including nucleotide substitutions, insertions, and deletions, suggesting that mutations arose from both the doped DNA synthesis and the subsequent PCR 'rescue' of full-length product. Sequence comparison between inactive and active Tat clones revealed a selection pressure against amino-acid substitutions within the N-terminal domains of Tat, indicating the importance of this region to trans-activation competence. In addition, single and double missense mutations within the basic-rich, TAR RNA-binding domain were seen to be tolerated within active Tat clones.

Amino Acid Sequence↗
PubMed1992

The dispositional enantioselectivity of indobufen in man.

The plasma pharmacokinetics and urinary elimination of the enantiomers of indobufen (2-[p-(1-oxo-2-isoindolinyl)-phenyl]butyric acid), a novel platelet aggregation inhibitor, have been studied in male healthy volunteers given either the racemic compound or the S-enantiomer (200 mg racemate, 100 mg S-enantiomer). Enantiospecific analysis of indobufen in plasma and urine was achieved by HPLC of its L-leucinamide diastereoisomers. After administration of the racemate, the pharmacokinetic behaviour of the R- and S-enantiomers differed, the plasma levels of the S form declining more rapidly [half-lives = 6.2 hr (S), 8.7 hr (R)]. No substantial differences were observed in terms of plasma level profile of S-indobufen when administered alone and in the racemic mixture. A statistically significant difference between the two enantiomers after administration of the racemate was found in the area under the curve (AUC), peak plasma levels (Cmax) and elimination half-life (t1/2 beta) whereas no statistically significant difference was detected in the time of peak (tmax). When the pharmacokinetic parameters Cmax, AUC, t1/2 beta and tmax of S-indobufen administered alone or as racemate were compared, there were no statistically significant differences between treatments as well as between periods and sequences. The urinary excretion of total S-indobufen (free + glucuronide) and of total R-indobufen after administration of the racemate was essentially the same. No difference was observed either in the urinary excretion of total S-indobufen after administration of the racemate or of the S-enantiomer.

Adult↗
PubMed1991

Effect of L-dopa, oxyferriscorbone and ferrous iron on in vivo lipid peroxidation.

We report here on an in vivo model of lipid peroxidation, which consists in measuring the amount of ethane present in the exhaled air after the oral administration of linolenic acid to rats. This model was used to study the effect of L-dopa, oxyferriscorbone (OFS), a ferri-ferro-complex, and ferrous iron, this latter alone or associated with ascorbic acid, on lipid peroxidation. Intravenous or oral administration of L-dopa did not influence the amount of ethane produced by an oral dose of 1.25 ml/kg of linolenic acid. Intravenous injection of OFS (50 mg/kg) as well as the co-injection of FeSO4, 7H2O (15 mg/kg) and ascorbic acid (15 mg/kg) were found to decrease the amount of ethane produced by 1.25 ml/kg of linolenic acid given orally, whereas the same dose of ferrous sulfate alone was ineffective. The possible causes which might underlie the absence of effects of L-dopa and ferrous iron and the partial inhibition of lipid peroxidation by OFS and ferrous ions associated with ascorbic acid are discussed.

2,3-Diketogulonic Acid↗
PubMed1990

The dispositional enantioselectivity of indobufen in rat and mouse.

The plasma pharmacokinetics and urinary elimination of the enantiomers of indobufen, a novel platelet aggregation inhibitor, have been studied in rats and mice given either the racemic compound or the individual enantiomers (rat 8 mg/kg racemate, 4 mg/kg enantiomers; mouse 25 mg/kg racemate, 12.5 mg/kg enantiomers). Enantiospecific analysis of indobufen in plasma and urine was achieved by HPLC of its L-leucinamide diastereoisomers. In rat, the two enantiomers have very different plasma elimination half lives (S, 3.9 hr; R, 12.2 hr), irrespective of the optical form administered. The plasma concentration-time curves of S-indobufen were identical after racemic or S-indobufen, but the plasma levels of R-indobufen were lower after the R-enantiomer than after the racemate. Urinary recovery of free and conjugated indobufen was less than 3% of the dose, independent of the optical form administered. In the mouse, R-indobufen was cleared from plasma more rapidly than its S-antipode (elimination T1/2 R, 2.5 hr; S, 3.8 hr) but differences were smaller than those seen in the rat. The plasma concentration-time curves of the S-enantiomer were the same after racemic or S-indobufen, but levels of its R-antipode were much lower when it was given alone than after administration of the racemate. The urinary recovery of free and conjugated indobufen also exhibited enantioselectivity, with preferential elimination of the S-enantiomer.

Animals↗
PubMed1990

The disposition and urinary metabolism of 14C-labelled FCE 22891, a pro-drug of FCE 22101, in animals.

[2-14C]FCE 22891 was given orally and intravenously to the rat, orally to the dog and monkey. Radioactivity was eliminated by both the renal and faecal route after oral administration, but mainly in the urine after the iv route in the rat. Radioactivity as expired 14CO2 was detected in the rat and accounted for less than 1% of the dose after iv and 3.2% after oral dosage within 72 h. After oral FCE 22891 labelled by 14C in the acetoxymethyl moiety, radioactivity recovered as expired 14CO2 accounted for over 55% of the dose at 72 h in the rat. No FCE 22891 was detected in plasma, whereas consistent amounts of FCE 22101 were detected. The metabolism was studied by radio-HPLC in the urine of the animals treated with [2-14C]FCE 22891. No unchanged drug was detected at any time interval. FCE 22101 was the main urinary metabolite with the exception of the dog and accounted for about one-half of the radioactivity excreted in 0-24 h urine. Significant amounts of metabolite P1, an open beta-lactam ring derivative obtained by action of dehydropeptidase, were found in the urine of rat and monkey but not in the dog. The remaining urinary radioactivity was due to other metabolites, named P, X and LP, which might originate from P1, as stability of P1 is pH-dependent.

Administration, Oral↗
PubMed1982

Bioavailability study on a new slow-release formulation of ketoprofen.

Four healthy subjects volunteered for a crossover bioavailability study to compare the rate and extent of absorption of plain capsules and new slow-release capsules of ketoprofen. The formulations were administered in two consecutive 4-day periods at the following dose schedules: 2 x 50 mg plain capsules t.i.d. and 150 mg slow-release capsules b.i.d. The plasma levels profile of unchanged ketoprofen was assessed by GLC during the 4th day of treatment with each formulation. The absorption from slow-release capsules was slower and more sustained than from plain capsules but almost complete. The bioavailability properties of new slow-release capsules of ketoprofen appear suitable for clinical use with reduced frequency of daily dosing.

Adult↗
PubMedDate not supplied

Association of cyclosporine and 311 nM UVB in the treatment of moderate to severe forms of psoriasis: a new strategic approach.

Psoriasis is a T-lymphocyte mediated autoimmune disease. The response to therapies targeting T-lymphocytes suggest that the latter is a key cell in the pathogenesis of the disease. Cyclosporine (CsA) inhibits the proliferation and the IL-2 dependent expansion of T-lymphocytes. Ultraviolet radiation is an effective treatment for psoriasis. Several studies have demonstrated a significant improvement of the therapeutic response when narrow-band radiation is issued by TL-01 fluorescent lamp compared to broad- band UVB issued by other fluorescent sources. The effects of UVB on the immune system appear to be limited to the cell-mediated compartment of the immune response. In order to reduce the cumulative dose of UVB and limit the toxicity of drugs in the therapy of psoriasis, phototherapy with UVB has been used as treatment in association with other standard therapies. The purpose of the study is to evaluate, in patients with moderate to severe psoriasis a combined therapy with Cyclosporine A and 311 nm UVB phototherapy.

Adult↗