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Biomedical subjects

G Cauwenbergh

Publications and source records attributed to G Cauwenbergh.

At least 37 records · Page 2Linked to original sources
PubMed1992

Itraconazole compared with griseofulvin in the treatment of tinea corporis/cruris and tinea pedis/manus: an interpretation of the clinical results of all completed double-blind studies with respect to the pharmacokinetic profile.

Itraconazole is an orally active triazole antifungal which has been compared to griseofulvin in a number of double-blind trials. In dermatophytosis with a non-fixed treatment regimen for a maximum of 3 months, itraconazole 100 mg o.d. has produced a 100% mycological cure rate as compared with a 67% rate with griseofulvin 500 mg o.d. (p less than 0.01). Based on the pharmacokinetic profile, 100 mg itraconazole daily was then compared with 500 mg ultramicronized griseofulvin daily using a fixed treatment schedule of 15 days in tinea corporis and/or cruris and 30 days in tinea pedis and/or manus. In all studies in tinea corporis/cruris (n = 277), the superiority of itraconazole was shown for the clinical outcome at the last follow-up visit 2 weeks post-therapy (88 vs. 69%, p less than 0.01) and in the mycological outcome at the last follow-up visit (81 vs. 65%, p less than 0.05). In tinea pedis/manus (n = 210), the clinical response was virtually the same for the two treatment groups, but the most important finding was the mycological outcome with a significantly better result in favor of itraconazole at the end of treatment (77 vs. 61%, p less than 0.05) even more pronounced at the follow-up visit (85 vs. 48%, p less than 0.01). We conclude that itraconazole 100 mg daily in the treatment of tinea corporis/cruris and in tinea pedis/manus is significantly more effective than 500 mg griseofulvin daily when fixed treatment regimens are used. Furthermore, the best results are obtained with itraconazole 2-3 weeks after the end of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Phase II trial: an evaluation of oral saperconazole in acute vaginal candidosis: a comparison of three dosage schedules.

In an open, randomized phase II comparative study, 256 patients with acute vaginal candidosis (less than two episodes of vaginal candidosis in the 6 months preceding study entry) were treated with saperconazole according to one of the following treatment schedules: 2 x 100 mg o.d. for 1 day (87 patients), 2 x 100 mg b.i.d. for 1 day (83 patients), or 2 x 100 mg o.d. for 2 days (86 patients). A total of 236 patients were included in the efficacy analysis. Diagnosis of vaginal candidosis was made at the start by a direct microscopic examination of a vaginal smear and was confirmed by culture. The majority of isolated yeasts were Candida albicans (97.6%). All three dose regimens resulted in clinical cure rates of over 75%, and these were maintained for at least 1 month after the end of treatment. There was a difference in mycological cure rates between the three dose schedules (71, 85 and 92%) 1 week after the end of therapy. In view of the clinical and mycological results both 1 week and 1 month after the end of treatment, it can be concluded that a total dose of 400 mg of saperconazole given in a single day is the optimum treatment schedule. All treatment regimens were well tolerated (adverse experiences occurred in 1.6% of the patients) and the results 1 month after termination of therapy suggest a low relapse rate.

Acute Disease↗
PubMed1991

Itraconazole penetrates the nail via the nail matrix and the nail bed--an investigation in onychomycosis.

Nail-matrix kinetics were studied in 21 patients (19 with onychomycosis, two with tinea corporis) as soon as taking itraconazole (Sporanox) 100 mg daily for up to 7 months. Itraconazole was detected in the distal nail as soon as 1 month after the start of therapy (42 ng/g in fingernails and 16 ng/g in toenails). During the course of treatment, this concentration rose and reached a mean of 160 ng/g in fingernail clippings and 197 ng/g in toenail clippings. Moreover, in fingernails of 12 out of 21 patients and in toenails of six out of 20 patients, itraconazole was detected in the distal nail clippings before full outgrowth of the fastest-growing nail. In most patients, itraconazole was detected in the distal nail clippings earlier than would be expected if the drug were incorporated only via the nail matrix, indicating that in addition to the nail matrix, a second route of penetration into the nail exists, i.e. the nail bed.

Adult↗
PubMed1991

The antiinflammatory effects of ketoconazole. A comparative study with hydrocortisone acetate in a model using living and killed Staphylococcus aureus on the skin of guinea-pigs.

Several reports have demonstrated the efficacy of topical ketoconazole in dermatologic conditions that are not exclusively related to fungi. Some basic pharmacologic studies have indicated effects of ketoconazole on cholesterol production in keratinocytes, on the 5-lipoxygenase enzyme, and on the metabolism of all-trans-retinoic acid in the skin. These observations have led to the hypothesis that topically applied ketoconazole may possess antiinflammatory properties. This hypothesis was tested in an animal model in which living and killed Staphylococcus aureus applied to the backs of guinea pigs resulted in inflammation with erythema and hyperkeratosis. Ketoconazole 0.5% or 2% was applied topically once daily in an ointment base, either as monotherapy or in combination with hydrocortisone acetate 1%. In addition, untreated, excipient-treated, and hydrocortisone acetate-treated animals were included in the study design. All groups consisted of 10 animals that were observed and scored daily up to 3 days after the experimental therapy was stopped. In the animal model involving killed bacteria (i.e., no infection), topical ketoconazole had antiinflammatory activity comparable to that of hydrocortisone acetate. The activity of ketoconazole on the skin of animals infected with living bacteria (i.e., active bacterial infection) was superior to that of steroid therapy, which suggests some antibacterial effect of topically applied ketoconazole. The combination therapy was highly active under both conditions. These results suggest that, apart from the known antimycotic effects of ketoconazole, this molecule might also have effects against gram-positive bacteria at the high concentrations obtained after local application.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1990

A double-blind vehicle-controlled study of R 68 151 in psoriasis: a topical 5-lipoxygenase inhibitor.

Recently the pharmacologic role of leukotrienes (LTs), especially that of LTB4, has been intensively investigated in psoriasis. In vitro, R 68 151 is a potent 5-lipoxygenase inhibitor and consequently reduces LTB4 formation. Therefore the role of an in vitro 5-lipoxygenase inhibitor and its clinical use in psoriasis were evaluated with topical R 68 151 in a double-blind vehicle-controlled study. Eighty-eight patients with localized psoriatic lesions were treated twice daily with R 68 151 2% ointment (n = 44) or vehicle ointment (n = 44) during 4 weeks. Most patients (n = 73) had psoriasis vulgaris (n = 37, R 68 151; n = 36, vehicle). In 27% of the R 68 151-treated patients with psoriasis vulgaris, the lesions disappeared or showed marked improvement, compared with 8% in the vehicle group (X2, p = 0.06). The scores in global evaluation, however, were significantly different between both treatment groups (p less than 0.05, Mann-Whitney U test). The improvement of the mean symptom score with R 68 151 was 46% for scaling and 34% for erythema at the end of the study compared with an improvement of 6% and a deterioration of 3%, respectively, in the control group (p less than 0.05, p less than 0.01; Mann-Whitney U test). The global evaluation in the total group of patients with psoriasis (all different subtypes) was consistent with the response rate in the group of patients with psoriasis vulgaris: 30% in the test group versus 11% in the control group (X2, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1990

Management of fungal skin infections with 15 days itraconazole treatment: a worldwide review.

Initial dose-finding and placebo-controlled studies in skin dermatophytoses demonstrated that itraconazole was more effective than placebo and that short-term treatment with itraconazole 100 mg daily gave better results than 50 mg daily. Subsequently, an approach has been followed which is quite different from the classical attitude in treating fungal infections. Indeed, it is usual policy to continue antifungal therapy for some days after complete disappearance of clinical signs and symptoms. With itraconazole, the opposite approach has been followed. Kinetic studies have shown that (a) tissue levels are higher (up to ten times in skin areas with a high density of sebaceous glands) than corresponding plasma levels, and (b) therapeutic concentrations of itraconazole remain present in the epidermis for up to four weeks after discontinuation of therapy, plasma levels being undetectable after one week. These findings confirm the exceptional affinity of itraconazole for the epidermis without re-uptake into the blood circulation. Based on these findings, fixed treatment schedules were initiated with a 15-day treatment course of 100 mg itraconazole once daily in patients with tinea cruris, tinea corporis or tinea pedis, with a 30-day treatment of 100 mg itraconazole once daily in patients with palmoplantar infections. With these short and fixed treatment regimens it became evident that an 80% mycological cure and a 90% clinical response could be obtained 3-4 weeks after discontinuation of therapy in tinea corporis/cruris infections when itraconazole was given at a daily dose of 100 mg for 15 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Antifungal Agents↗
PubMed1990

Pharmacokinetics of oral antifungals and their clinical implications.

Orally active antifungals have different physicochemical and pharmacokinetic properties. Itraconazole is a broad-spectrum triazole antifungal with pronounced lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic bistriazole antifungal, fluconazole. The pharmacokinetics of itraconazole in man are characterised by good oral absorption (when taken with a meal), an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination half-life of about one day, and biotransformation into a large number of metabolites. Distribution studies have shown that therapeutically active levels of intraconazole are maintained much longer in some infected tissues than in plasma. For instance, active levels persist for four days in the vaginal epithelium after a one-day treatment and for four weeks in the stratum corneum of the skin after treatment has been stopped. These unique distribution characteristics may explain why itraconazole with relatively low plasma concentrations (but with high tissue concentrations) is as effective as fluconazole. Fluconazole interacts with cytochrome P450-dependent enzyme activities in hepatic microsomes of rats and mice. These effects in rodents are seen at plasma and liver concentrations of fluconazole comparable to those obtained in man at therapeutic dose levels. Unlike fluconazole, itraconazole does not interfere with mammalian drug-metabolising enzymes, minimising the risk of interaction with concomitantly administered drugs. These pharmacokinetic properties may contribute to the high efficacy and safety of itraconazole in patients with various mycotic infections.

Absorption↗
PubMed1989

Use of topical ketanserin in the treatment of skin ulcers: a double-blind study.

The use of a 2% ointment formulation of ketanserin, an S2-serotoninergic blocking agent, was investigated in a randomized double-blind clinical trial for its effect on the healing of wounds of patients with decubitus, venous, and ischemic skin ulcers. The result demonstrates a significant difference in favor of the ketanserin-treated group (35 patients) versus the placebo-treated group (37 patients) on the basis of two factors: formation of granulation tissue and epithelialization. In addition, a significant difference of 150% in the initial velocity of wound closure was observed in favor of the patients treated with ketanserin. This effect was persistent during the entire study period.

Administration, Cutaneous↗
PubMed1989

The clinical pharmacokinetics of itraconazole: an overview.

Itraconazole (R 51211) is the prototype of a class of triazole antifungals characterized by a high lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic triazole antifungal fluconazole. The pharmacokinetics of itraconazole in man are characterized by a good oral absorption, an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination half-life of about one day and a biotransformation into a large number of metabolites. One of them, hydroxy-itraconazole, is antifungally active and explains why antifungal plasma levels, when measured by bioassay, are about three times the itraconazole levels measured by a specific HPLC-method. Distribution studies have shown that therapeutically active levels of itraconazole are maintained much longer in some infected tissues than in plasma. For instance, active levels persist for four days in the vaginal epithelium after a one-day treatment and for 3 weeks in the stratum corneum of the skin after treatment has been stopped. Unlike fluconazole, itraconazole does not interfere with mammalian drug metabolizing enzymes, minimizing the risk of interaction with concomitantly administered drugs. These pharmacokinetic properties may contribute to the high efficacy and safety of itraconazole in patients with various mycotic infections. New pharmaceutical formulations are being explored in order to broaden the application field of itraconazole to intravenous and oral therapy of patients with malabsorption.

Absorption↗
PubMed1989

Safety aspects of ketoconazole, the most commonly used systemic antifungal.

Ketoconazole was first considered as a more or less safe drug. When used on a very large scale, however, it became obvious that this drug, as others mainly metabolized in the liver, can cause liver damage, i.e. chemical hepatitis sometimes even leading to death. Such very rare events seem to be linked to the protracted use of ketoconazole. Taking into account what is now known on the rational use of ketoconazole it still is a drug with a favourable benefit risk ratio.

Androgen Antagonists↗
PubMed1989

Itraconazole versus ketoconazole for the prophylaxis of fungal infection in neutropenic children: results of two consecutive nonrandomized studies.

Two consecutive nonrandomized studies were conducted in children with prolonged granulocytopenia to evaluate the prophylactic antifungal activity of ketoconazole and the new triazole itraconazole. The conditions were equivalent in both studies. The incidence of colonization was 10% in the ketoconazole group and 19% in the itraconazole group (this difference is not significant). For suspected and proven infections, the incidence was 5% for ketoconazole and 10% for itraconazole, but the incidences were too low for statistical comparison. Although the colonization rate was higher for itraconazole, there was no sign of Aspergillus, whereas in the ketoconazole group an autopsy, proven aspergillosis has been reported.

Adolescent↗
PubMed1989

Terconazole. Pharmacology of a new antimycotic agent.

Terconazole belongs to a new chemical class of antifungal agents, the triazoles. It was designed and synthesized to be more active than the imidazoles. The basic mechanism of action of terconazole, inhibition of fungal cytochrome P-450, is similar to that of the imidazoles. However, because of the additional nitrogen atom in the triazole ring and the lipophilic tail, terconazole establishes a firmer and longer-lasting link with the membrane-bound fungal cytochrome P-450. In addition, terconazole is more metabolically stable and less vulnerable to oxidation and conjugation than are the imidazoles. Terconazole has far greater selectively for yeast cytochrome P-450 than for mammalian microsomal cytochrome P-450. The spectrum of terconazole's in vitro activity includes a wide range of pathogenic fungi; in Eagle's Minimum Essential Medium, fungicidal activity against all strains of Candida albicans occurred at less than or equal to 100 ng/mL. In a rat model of severe vaginal candidiasis, terconazole was more potent than all the imidazoles tested. The high affinity and selectivity of terconazole for fungal cytochrome P-450 and its potent in vitro and in vivo activity indicate that the drug may well become a significant agent for the treatment of fungal disease.

Antifungal Agents↗
PubMed1988

Pharmacokinetic profile of orally administered itraconazole in human skin.

Itraconazole is an orally effective antifungal agent with a high affinity for tissues. The skin kinetics in human volunteers have been studied after administration of 100 and 200 mg of itraconazole daily. From day 7 onward, tissue levels in the beard region and on the back were consistently higher than the corresponding plasma levels. The levels in the palmar stratum corneum were lower than the corresponding plasma levels but persisted for 3 weeks after discontinuation of therapy. Stratum corneum levels in the beard area were still measurable 4 weeks after the end of therapy. With the 200-mg dose, sweat levels became detectable 24 hours after the first drug intake. The sweat levels were usually lower than the corresponding plasma levels and followed the same curve as the plasma levels. Sebum levels of itraconazole were 10 times as high as the corresponding peak plasma levels. Sebum levels were undetectable 14 days after discontinuation of therapy. The results indicate that oral intake of itraconazole will result in therapeutic levels in the skin and these levels vary, depending on the region of skin tested. There are at least three routes of delivery of itraconazole to the skin: (1) passive uptake by keratinocytes in the basal layer (as shown by the continued presence of the drug in the palmar stratum corneum at a moment when plasma, sebum, and sweat levels are again undetectable); (2) a less significant excretion through the sweat glands (as shown by the lower drug levels compared with the plasma levels); and (3) a massive excretion through the sebaceous glands (as shown by the sebum levels compared with the plasma levels).

Administration, Oral↗
PubMed1988

Role of animal and human pharmacology in antifungal drug design.

Since the late sixties, several new antifungal drugs have become available. Initially, they were all intended for topical use, and, consequently, animal and human pharmacology always primarily aimed at confirming therapeutic efficacy. With the new tendency for the development of orally active antifungal drugs, human and animal pharmacology have significantly gained in importance. Indeed, not only is it now necessary to demonstrate the presence of adequate antifungal concentrations at the site of infection, but the systemic availability of the antifungal drug also necessitates an in-depth study of the effects of the drug on the function of several organs. As a result, human and animal pharmacology have become the cornerstones in the selection of orally active antifungal drugs. The development of ketoconazole has been an example of the need for optimized pharmacological screening. The choice of itraconazole--with its improved tissue affinity, its lower therapeutic dose requirements, and its increased selectivity for fungal cytochrome P-450--demonstrates very well that the use of animal and human pharmacology helps in the design of an antifungal drug with as much effect as possible on the fungus and as little effect as possible on the host.

Animals↗
PubMed1987

Pityriasis versicolor and Pityrosporum ovale. Morphogenetic and ultrastructural considerations.

Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) have been performed on skin material of patients with pityriasis versicolor who were orally treated with itraconazole. Before as well as after therapy, variously sized spherical structures were observed on the surface of the keratinocytes with SEM. TEM examination revealed Pityrosporum ovale, predominantly in its mycelial phase, inside keratinocytes. The spherules as observed by SEM appeared to be amorphous, lipid-like droplets originating from the inside of the keratinocytes. The cytoplasm of the keratinocytes was at least partly occupied by the same amorphous material. It is therefore suggested that P. ovale penetrates the keratinocyte where degradation of the normal keratinous content to amorphous material takes place. This newly formed lipidic substrate may be an essential nutritive factor. The lipidified state of the stratum corneum persisted for at least 3 weeks after eradication of the fungus by itraconazole. It is speculated that the presence of large quantities of this lipid-like material might be the cause of hypopigmentation because it may constitute an ultraviolet light block.

Humans↗