Search

In order to improve the effectiveness of treatment of vaginal yeast infections, flutrimazole, (CAS 119006-77-8), a broad spectrum local imidazolic fungicide, has been formulated in an advanced delivery system (Site Release, here in after briefly referred to as SR) designed to improve vaginal retention of the drug. To determine the extent of absorption of 14C-flutrimazole from this formulation, the absorption and excretion of total radioactivity have been studied in healthy postmenopausal female volunteers after intravaginal administration of approximately 5 g of SR Vaginal Cream containing 2% 14C-flutrimazole. Concentrations of unchanged flutrimazole have also been measured in plasma and urine, using a validated gas chromatography-mass spectrometry method. The rate of absorption was slow, with a mean peak plasma radioactivity concentration, Cmax, of 56 ng equivalents/ml, achieved at a mean Tmax of 28 h. Corresponding parameters for flutrimazole were 1.94 ng/ml at 24 h. At 24 h post-dose, unchanged flutrimazole represented only 3% of plasma total radioactivity which indicates that flutrimazole is extensively metabolised in man. Total radioactivity and unchanged flutrimazole were eliminated from plasma with terminal half-lives of 37 and 22 h, respectively. From the proportion of the radioactive dose excreted in urine and faeces, the maximal extent of absorption indicated for the intravaginal dose was about 8%, which is similar to that observed with other imidazolic compounds administered by this route. Thus, the formulation achieves the aim of prolonged drug action through the maintenance of therapeutic concentrations of the drug at the site of infection without notably increased absorption.

Flutrimazole (1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1 H-imidazole, CAS 119006-77-8, UR-4056) is a new wide spectrum local imidazolic antifungal agent that has already been formulated as a dermal cream (FDC). A comparative study was carried out of the release of flutrimazole from two emulsions in which the drug has been incorporated differently: one dissolved in the oily phase (E24) and the other dispersed in the aqueous formulation phase (E25). Based on the E25 formulation, two more dermal creams were prepared, E27 with benzyl alcohol and E28 with diazolidinyl urea as preservative agents. A comparative study of transdermal penetration including E27, E28, FDC (reference 1% flutrimazole dermal cream) and 1% flutrimazole hydroalcoholic solution was also performed. An amount of the sample dosage form containing 10 mg of flutrimazole was applied to a Franz type cell. The penetration membrane used was cellulose acetate in the release studies and human skin provided by a plastic surgery clinic in the transdermal penetration study. The amount released after 7 h was 36.3 +/- 4.9 micrograms when flutrimazole was dissolved (E24) and 35.9 +/- 5.3 micrograms when flutrimazole was dispersed (E25). Although the differences were not significant, the cream with dispersed flutrimazole was selected for further penetration studies due to its better stability observed in previous studies. The amounts of drug penetrated after 44 h were 31.3, 41.5, 38.3 and 186.5 micrograms for E27, E28, FDC dermal creams and topical hydroalcoholic solution, respectively. The solution showed a statistically significant difference (p < 0.05) from the other formulations, however, no differences were observed between the dermal cream formulations. No differences were neither obtained between the different dermal creams when the amount of drug retained in the skin was compared. This allows to assert that the excipients used do not have different influences on transdermal penetration. In all cases, the mean quantity penetrated in relation to the dose applied was at most 0.5%. These results allow to infer that flutrimazole shows scarce transdermal penetration. Further, the amount of flutrimazole retained per gram of skin is more than 100 times the MIC per gram obtained in previous in vitro studies. It may be assumed that the topical application of the new formulations assayed would allow to obtain a good therapeutic response.

The percutaneous absorption and skin distribution of a skin cream containing 1% 14C-labelled 1-[(fluorophenyl) (4-fluorophenyl) phenylmethyl]-1H-imidazole (flutrimazole, UR-4056, CAS 119006-77-8) was studied in minipigs. The same dose of flutrimazole was administered i.v. and topically (as a cream) on scarified skin according to a crossover protocol. Samples of urine and faeces were taken at various intervals after administration, and radioactivity was measured. The percentage of radioactivity accumulated in urine after topical and intravenous administration were 1.46% and 41.7%, respectively. In faeces, the percentage of radioactivity observed was 6.0% after intravenous administration, and none was detected after topical application. In order to study the distribution and penetration of [14C]flutrimazole, the cream was applied to intact and scarified skin. At various intervals after administration, skin samples were taken. The samples for the autoradiographic studies were cut transversely, and for the measurement of the levels of radioactivity at different skin depths, slices were cut parallel to the cutaneous layers. The results obtained indicate that [14C]flutrimazole penetrates quickly into the different epidermic layers and is retained mainly in the strata spinosum, granulosum and basale. The stratum basale possibly acts as a selective barrier preventing the penetration of the compound into the dermis. The percentage of radioactivity in the stratum corneum is lower than that detected in all the other epidermic layers taken together. The stratum corneum offers low resistance to penetration by the flutrimazole, which very probably crosses the epidermic strata by a transcellular route.

Studies with 1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H- imidazole (flutrimazole, CAS 119006-77-8), a new topical imidazole antifungal agent, have been carried out to investigate the acute toxicity of the active substance in mice and rats, as well as the acute ocular and dermal irritation in rabbits, the dermal tolerance after repeated dose (21 days) applications in rabbits, and the sensitising, photoallergic and phototoxic potential in guinea pigs using 1% flutrimazole cream. LD50 values after oral or intraperitoneal administration were greater than or equal to 1000 mg/kg in both mice and rats, which reveal a very low acute toxicity of flutrimazole. No differences were found between the excipient and 1% flutrimazole cream in the acute ocular and dermal irritation studies in rabbits, the irritation indexes being indicative of no lesions due to flutrimazole. Cumulative dermal irritation studies in rabbits showed an improved local tolerance of a skin cream containing 1% flutrimazole as compared to a commercial skin cream containing 1% clotrimazole. The irritation indexes were 1.2 and 3.7, respectively (p less than 0.01). The corresponding histophatological findings confirmed the better local tolerance of 1% flutrimazole cream. Furthermore, it has been found that flutrimazole cream lacks sensitising potential (Magnusson and Kligman test), is also devoid of phototoxic potential and does not induce photoallergic reactions in guinea pigs, these data being confirmed by histopathological studies. These results, together with the very slight systemic absorption rate of flutrimazole from the 1% topical drug form, clearly show that no restrictions should be taken in the use of the cream for reasons of systemic toxicity or dermal tolerance.

1-[(2-Fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H-imidazole (flutrimazole, UR-4056, CAS 119006-77-8) is a new topical imidazole antifungal agent which displays potent broad-spectrum in vitro activity against dermatophytes, filamentous fungi and yeasts, saprophytic and pathogenic to animals and humans (MIC = 0.025-5.0 micrograms/ml). In most of these studies the activity of flutrimazole was comparable to that of clotrimazole and markedly higher than that of bifonazole (MIC differences of greater than or equal to 1 order of magnitude). Tested against Scopulariopsis brevicaulis (8 strains), both flutrimazole and clotrimazole exhibited fungistatic and fungicidal activity, and clotrimazole appeared something less active (MIC = 0.3-2.5 micrograms/ml) than flutrimazole (MIC = 0.15-0.6 micrograms/ml). In animal experiments, topical application of 1% and 2% flutrimazole, as a cream or solution, was highly effective in models of rat vaginal candidiasis and guinea-pig trichophytosis, giving a rate of cured or cured plus markedly improved animals higher than 80%. Flutrimazole shares the mode of action of other imidazole or triazole-containing antifungals, i.e. inhibition of fungal lanosterol 14 alpha-demethylase, as it strongly inhibits ergosterol biosynthesis in a cell-free homogenate of Candida albicans, with an IC50 value of 0.071 mumol/l.

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)

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.

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.

The effect of several non-steroidal antiinflammatory agents (some of them original from our laboratory) on prostaglandin biosynthesis in guinea pig lung (biological method) and in bovine seminal vesicles (spectrophotometric method) has been studied. When this effect is compared with the in vivo antiinflammatory activity determined in the rat carragenin foot edema and with the recommended clinical daily dose in rheumatoid arthritis, a good correlation between these properties was observed. Only mefenamic acid showed a clear discordance. The experience shows that inhibitory effect of antiinflammatory drugs on prostaglandin synthetase in vitro may be used to predict, in most cases, their antiinflammatory activity in vivo in the pharmacological screening of the new compounds. Structure-activity relationship in the UR-series is also discussed.

Acute, subacute and chronic toxicity studies of 2-phosphonoxy benzoic acid (fofosal) were carried out in several animal species. LD50 values in mice and rats were determined at two pH values; an additional toxic effect of acidity was found at the lowest pH tested (pH = 1.0), specially so by i.p. route. Differences in LD5- values between mice and rats of either sex were not significant; however, acute toxicity of male rabbits was higher than that of rats and mice. Long-term toxicity studies revealed a slight growth retardation and a significant mortality at the highest dose tested (500 mg/kg). These studies showed that fosfosal produced no hematological, blood chemical or pathological changes.