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Biomedical subjects

J Forn

Publications and source records attributed to J Forn.

At least 55 records · Page 3Linked to original sources
PubMed1992

Pharmacokinetic study of [14C]flutrimazole after oral and intravenous administration in dogs. Comparison with clotrimazole.

This trial involved a comparative study using 6 Beagle dogs on the pharmacokinetics of 14C-labelled 1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H-imidazole (flutrimazole, CAS 119006-77-8) and [14C]clotrimazole labelled in the imidazole ring. On the basis of a cross-over trial, each animal received a dose of 5 mg/kg (approx. 100 microCi) [14C]flutrimazole and [14C]clotrimazole, both intravenously and orally. The levels in plasma, urine and faeces of the total radioactivity, unchanged drug and the [14C]imidazole formed by metabolization of the unchanged drug were determined. Flutrimazole presented a biological half-life (t1/2) of 14.4 +/- 3.8 h and a clearance (Cl) of 6.7 +/- 0.8 l/h, while the values for clotrimazole were very different: t1/2 4.6 +/- 0.8 h and Cl: 13.6 +/- 1.0 l/h. After oral administration a fraction of absorbed dose (f) of 78 +/- 21% and bioavailability of 8.9 +/- 6.1% were calculated for flutrimazole. For clotrimazole, these were: 52 +/- 10% and 4.9 +/- 1.9%, respectively. Both drugs showed a significant first-pass effect, with 90% of the absorbed dose being metabolized before reaching the systemic circulation. The total recovery of radioactivity in faeces and urine 5 days after i.v. and oral administration was 58% and 68%, respectively, for [14C]flutrimazole, and 81% and 79% for [14C]clotrimazole. In both cases, most of the radioactivity was recovered in the faeces. The high radioactivity obtained in faeces after i.v. administration of both drugs confirms biliary elimination. For both flutrimazole and clotrimazole, less than 1% of the total recovered in the urine after i.v. administration was recovered as unchanged drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Local and systemic tolerance of flutrimazole skin creams following single and repeated topical application in healthy volunteers.

A double-blind, randomized phase I study was performed in 21 healthy volunteers to evaluate the dermal tolerance of skin creams containing 1% and 2% 1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H-imidazole (flutrimazole, UR-4056, CAS 119006-77-8) or only the excipient, versus a commercial skin cream containing 1% clotrimazole. The study was carried out using the patch-test procedure performed in three stages: 1. single application in the back skin; 2. induction period (usage test) using three skin areas on the volar side of the forearm of each subject, where skin cream samples were applied once a day for a period of three weeks; and 3. after a wash-out period of two weeks, challenge applications in the back and forearm skin. The systemic tolerance of the formulations was also tested. There was no evidence of allergic sensitization after the application of flutrimazole creams, or their excipients, with signs of mild and doubtful skin reactions being observed in few subjects with all formulations. Furthermore, no systemic side effects after topical administration were detected throughout the study.

Administration, Topical↗
PubMed1991

Chronic treatment of guinea pigs with lithium chloride: effects on myenteric plexus preparations and on cyclic AMP levels.

We studied the effects of lithium chloride, given i.p. in doses of 0.05, 1, 2, 4 and 8 mEq/kg twice daily for 14 days, on preparations of guinea pig myenteric plexus. The effects of lithium added to isolated myenteric plexus preparations derived from chronically treated animals showed that relatively low lithium concentrations produced a statistically significant decrease in the force of contraction, this effect being concentration-dependent. 3-Isobutyl-1-methylxanthine (IBMX) induced a statistically significant inhibition, between 30 and 50%, of the lithium effects. cAMP levels in animals treated chronically with lithium were studied, using an isotopic displacement technique. Our results show that only the highest dose of lithium (8 mEq/kg per day) significantly decreased basal levels of cAMP. In the presence of IBMX, low doses of lithium (1 mEq/kg per day) induced a very significant decrease in cAMP levels, but the inhibition remained constant, approximately 30-35%, at doses from 2 mEq/kg per day. In guinea pig myenteric plexus preparations from acutely treated animals, our results show a direct relationship between lithium concentration and inhibition of the cAMP accumulation induced by IBMX.

Animals↗
PubMed1991

Disubstituted tetrahydrofurans and dioxolanes and PAF antagonists.

A new series of disubstituted tetrahydrofuran and dioxolane derivatives were prepared and evaluated for their PAF antagonist activity in the PAF-induced in vitro platelet-aggregation and in vivo hypotension tests. Several of these compounds exhibited more potent activity than the structurally related 2-[N-acetyl-N-[[[[2-methoxy-3-[(octadecylcarbamoyl) oxy]propoxy]carbonyl]amino]methyl]-1-ethylpyridinium chloride (CV-6209, 3) in the in vitro assay, whereas all showed less potency in the in vivo test. The role of both the substituent nature and the placement and number of oxygen atoms in the ring are discussed. A quantitative SAR study carried out on these nuclei.

Animals↗
PubMed1991

Effects of PAF-antagonists in mouse ear oedema induced by several inflammatory agents.

1. Several platelet activating factor (PAF)-antagonists of different chemical structures were tested in the arachidonic acid-, tetradecanoylphorbol acetate-, dithranol-, and benzoic acid-induced mouse ear oedema models. 2. Topical application of UR-10324, UR-11353, CV-6209 and WEB-2086 markedly inhibited ear oedema induced by the four irritants tested, mimicking the profile obtained with dexamethasone. YM-461 was highly effective only in the dithranol-induced ear oedema, while BN-52021 failed to inhibit ear oedema in all models tested. 3. Leukocyte recruitment into the inflamed ears was prevented by PAF-antagonists, as measured by myeloperoxidase activity in the supernatants of ear homogenates. 4. A relationship between PAF-antagonist and anti-inflammatory activities was found in some cases, but other mechanisms cannot be excluded to explain the topical anti-inflammatory effect of these compounds. 5. Our results suggest that topical formulations containing PAF-antagonists could be useful in the treatment of some inflammatory skin diseases and provide evidence on the involvement of PAF in these inflammatory processes.

Administration, Topical↗
PubMed1990

Comparative study of the effect of CV-6209, a specific PAF-antagonist, on rat paw edema caused by different phlogogen agents.

Comparative effects of CV-6209, a potent and specific platelet activating factor (PAF) antagonist, on PAF-acether-, carrageenin-, histamine-, serotonin-, compound 48/80-, dextran-, zymosan A- and arachidonic acid-induced rat paw edema were investigated. CV-6209 has proven to be effective in PAF-induced edema, but it also showed a significant activity in other models of paw edema, except those induced by zymosan A and arachidonic acid. Other drugs tested, namely indometacin, mepyramine, methysergide and nordihydroguaiaretic acid showed a more selective inhibitory profile. These results suggest an important role of PAF in the inflammatory process caused by intraplantar injection of different phlogogenes in the rat paw.

Animals↗
PubMed1990

Pharmacokinetics of triflusal after single and repeated doses in man.

Triflusal pharmacokinetics were evaluated in 8 healthy subjects after a single 300 mg dose and after repeated doses of 300 mg every 8 h and 600 mg every 24 h during 13 days, with the aim of establishing a relationship between plasma levels and dosage patterns. Plasma concentrations of triflusal and its main metabolite, 2-hydroxi-4-trifluoromethylbenzoic acid (HTB), were determined by HPLC. Triflusal (t1/2 = 29-35 min) metabolized rapidly into HTB. Four h after the first or last repeated dose administration, triflusal levels could not be detected. After the administration of 300 mg every 8 h, the parameters obtained for HTB were: Cmax-ss = 178 +/- 42 micrograms/ml, tmax-ss = 1.9 +/- 0.7 h, Cmin-ss = 155.6 +/- 41.2 micrograms/ml, Cavg-ss = 168.0 +/- 41.8 micrograms/ml and a t1/2 of 48 +/- 15 h. The parameters obtained for the dosage of 600 mg every 24 h were: Cmax-ss = 153 +/- 40 micrograms/ml, tmax-ss = 2.7 +/- 0.9 h, and a t1/2 of 50 +/- 16 h. No significant differences were observed between the elimination half-life obtained after the single dose and after the two repeated dose regimens studied. This finding suggests that HTB displays a linear pharmacokinetic behaviour.

Adult↗
PubMed1989

Pharmacokinetics of fosfosal in rats and dogs.

Fosfosal (Disdolen) is a non acetyl derivative of salicylic acid with antiinflammatory and analgesic properties and a greater tolerance than acetylsalicylic acid and lysine acetylsalicylate. In the present work the pharmacokinetics of fosfosal have been studied after oral and intravenous administrations of 100 and 80 mg/kg in rats and dogs, respectively. Plasma concentrations of fosfosal and salicylic acid were determined by an HPLC method. After intravenous administration fosfosal plasma levels decreased rapidly showing a half-life of 2.7 min in rats and 6.7 min in dogs. Fosfosal in plasma is quickly hydrolyzed into salicylic acid producing high concentrations in few minutes after administration. The half-life of salicylic acid was 13.8 and 7.1 h for rats and dogs, respectively. After oral administration only salicylic acid was detected in plasma, indicating that fosfosal, when orally administered, behaves as a prodrug. From the comparison of the AUC for salicylic acid obtained after oral and intravenous administrations it can be deduced that fosfosal it totally absorbed in the two species studied.

Administration, Oral↗
PubMed1989

Bioavailability study of fosfosal and codeine administered alone or in combination.

Fosfosal (2-phosphonoxybenzoic acid) is a new salicylic acid derivative which is used for treating inflammatory disease as well as in analgesic therapy. On the other hand, codeine together with acetylsalicylic acid is widely used in patients who require analgesic treatment for mild to moderate pain. The present study was carried out in ten healthy subjects to assess the pharmacokinetic profiles of single oral doses of fosfosal (1,200 mg) and codeine (30 mg) when administered alone or in combination. Blood samples were drawn on each study day and salicylic acid and codeine plasma concentrations were determined by HPLC and enzyme immunoassay methods, respectively. Individual pharmacokinetic parameters were calculated according to standard procedures and the magnitude and rate of bioavailability were tested using a 95% confidence internal approach. Results indicated no statistical differences in any of the kinetic parameters studied except for tmax values which were higher for fosfosal combined with codeine (2 +/- 0.39 h) when compared to fosfosal alone (1.55 +/- 0.35 h). Regarding codeine compared in combination with fosfosal, no significant differences were observed in Cmax and AUC values, while tmax showed a higher value for the combination (1.75 +/- 0.6 vs 0.85 +/- 0.32 h). Although statistical differences in the elimination constant rate and MRT were found between both codeine administrations, these cannot be considered significant in clinical terms. The changes in bioavailability rate observed for both drugs when administered together provide support for the use of this combination in a single formulation.

Adult↗
PubMed1988

The effect of fosfosal and acetylsalicylic acid on leukocyte migration and PGE2 concentration in experimentally induced acute inflammation.

The effect of fosfosal, a non-acetylated salicylic acid derivative, on the content of prostaglandin E2 (PGE2) and the migration of polymorphonuclear leukocytes in inflammatory exudates induced by s.c. implantation of 0.5% carrageenan soaked sponges in rats has been determined. Fosfosal, which does not inhibit PG synthesis in vitro, is capable of reducing, in a dose-dependent manner, the PGE2 content of the exudates, with a maximum reduction of 50-60% at a total dose of 100 mg/kg i.p. Acetylsalicylic acid was slightly more potent (68% reduction, 2 x 50 mg/kg i.p.). Six hours after fosfosal administration, salicylic acid, the principal metabolite of fosfosal, accumulated in the exudates at concentrations of about 100 micrograms/ml. These concentrations were sufficient to inhibit PG synthetase activity in vitro. Neither fosfosal nor acetylsalicyclic acid affected polymorphonuclear leukocyte migration at doses which significantly reduced the concentrations of PGE2. Indomethacin, used as reference, reduced leukocyte migration by 28 and 45% at a dose of 1 and 10 mg/kg i.p. respectively. The results indicate that fosfosal, in spite of its lack of effect on PG biosynthesis in vitro, exerts an effect on the inflammatory locus in vivo which may account, at least in part, for its anti-inflammatory activity. Moreover, our results confirm that the inhibition of PG synthesis and leukocyte migration are mediated by different mechanisms.

Animals↗
PubMed1988

Pharmacokinetics of fosfosal after single and multiple oral doses in man.

Fosfosal is a new salicylic acid derivative used in analgesic and anti-inflammatory therapy. In this study, pharmacokinetic evaluation of fosfosal after a single 2,400 mg and three different oral dose schedules (1,200 mg t.i.d., 2,400 mg b.i.d. and 2,400 mg t.i.d.) was carried out, in six healthy male volunteers, to assess which doses provide steady state plasma concentrations within the therapeutic range (150-300 micrograms/ml). Plasma concentrations of both fosfosal and its active metabolite, salicylic acid, were determined by means of an HPLC method. For the 2,400 mg t.i.d., Cmin-ss and Cmax-ss values were 184 micrograms/ml and 276 micrograms/ml, respectively, being significantly higher (p less than 0.02) than with the other regimes and, unlike the latter, falling within the anti-inflammatory therapeutic range. In addition, the 2,400 mg t.i.d. showed a significant prolongation (p less than 0.005) of salicylic acid t1/2, as well as a higher AUC-ss 0-8 h dosing interval compared to the other multidose schedules and to the AUC0-infinity for the single dose. As expected, both facts reflect that the highest daily dose of fosfosal has a nonlinear concentration-dependent elimination rate.

Administration, Oral↗
PubMed1987

Protective effect of triflusal and acetylsalicylic acid against arachidonic acid induced cerebrovascular occlusion in anesthetized rats.

Within 60 sec after intracarotid injection of 0.33 mg/kg arachidonic acid, a pronounced attenuation of electrocortical activity, approaching electrocerebral silence, was induced in the ipsilateral hemisphere of anesthetized and heparinized rats. This effect was a consequence of the cerebrovascular occlusion due to platelet aggregates induced by arachidonic acid. This model has been used to evaluate the protective effect of acetylsalicylic acid (ASA) and of triflusal 2 hr after a single oral dose of 50 mg/kg or after 50 mg/kg, for 5 days. Pentylenetetrazol at 10 mg/kg, i.v. exerts a stimulant effect on CNS, and was used as a positive control. ASA and triflusal exhibit a protective effect in about 35% of animals when acutely administered. After chronic treatments (5 days), the effect of triflusal (60% protection) was superior to that of ASA (27% protection) (p less than 0.01).

Animals↗
PubMed1986

Effect of triflusal and other salicylic acid derivatives on cyclic AMP levels in rat platelets.

The effect of triflusal, acetylsalicylic acid (ASA), and of their principal metabolites 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and salicylic acid (SA), alone or combined with dypiridamole (DIP) and/or PGE1 on cyclic AMP levels in washed rat platelets (37 degrees C, 4 min), has been determined. DIP at 0.1 mM increased cyclic AMP levels by 25%. The effect of triflusal and HTB was significant at therapeutic concentrations of triflusal (1 mM: 36% increase) and HTB (0.5 mM: 37% increase). The effect of HTB was always greater than that of triflusal. ASA, at 1 mM and 5 mM, alone or combined with PGE1 was without effect. When 1 mM triflusal was combined with 0.1 mM DIP an increased effect was obtained (95%). ASA, at the highest concentration tested (5 mM), did not modify the DIP-induced increase of cyclic AMP levels.

Alprostadil↗
PubMed1985

Effects of triflusal in patients with prosthetic heart valves.

The biological effects of a new antiplatelet agent, triflusal, were evaluated in patients with cardiac valvular prostheses. Each patient received 900 mg/day of oral triflusal for 30 days. Triflusal significantly inhibited platelet aggregation induced by adenosine diphosphate (1 to 5 mumol) or epinephrine (12.5 mumol), showing a slight effect on bleeding time (basal: 6 +/- 1.7 min; 30 days of treatment: 8.0 +/- 2.7 min). Serum levels of thromboxane B2 were significantly reduced during treatment, but changes in serum levels of 6-keto-prostaglandin F1 alpha were not observed, suggesting that triflusal does not affect prostacyclin biosynthesis by the vascular wall. The results show that triflusal has a marked inhibitory and selective effect on platelet function in patients with cardiac valvular prostheses.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Intravenous arachidonate-induced respiratory distress: comparative study of three in vivo models for the measurement of antithrombotic activity.

Three different in vivo methods for the study of antithrombotic drugs have been compared. A syndrome of acute respiratory distress has been induced by intravenous injection of arachidonate in three different animal species: mouse, rabbit, and hamster. The intensity of the induced stress was quantified by different procedures: visual observation in the mouse, death or survival in the rabbit, and mechanical recording of the respiration in the hamster. The protective effect of a new antithrombotic agent, triflusal, a salicylic acid derivative, was studied. At the doses used, triflusal has no effect on the respiratory center activity of control animals. The results show that a new method using a mechanical device to record the intensity and duration of the respiratory distress in hamsters is the most suitable of the three methods studied.

Animals↗