The penetration of topically applied ointment containing hyaluronic acid in rabbit tissues.

The properties of hyaluronic acid used for treatment of acute and chronic joint disease are known for many years and this compound is widely used both in humans and animals. To obtain a therapeutic effect of a certain drug, the appropriate concentration in the target organ or tissue is important. The application of labeled compounds is one of the frequently applied techniques to estimate drug penetration into the skin and other body tissues or organs. The aim of the study was to evaluate the penetration of hyaluronic acid labeled with I-131 through the skin and its distribution within the knee joint and other internal organs in rabbits after a topical application of an ointment containing hyaluronic acid. The experiment was performed on 22 albino rabbits divided into control and examined groups. Fifteen rabbits were exposed to the multicomponent ointment containing hyaluronic acid labeled with I-131. Time of exposure was 48 hours. Hyaluronate penetrated to a high degree into the examined tissues. No significant differences in terms of leg tissue activity were observed between a leg tissue exposed to labeled ointment and that unexposed, suggesting that after topical administration, the active component of the ointment is delivered to the joint via the blood stream. Hyaluronate applied topically penetrates through the skin into the rabbit tissues and organs and into the joint fluid of both legs (exposed and not exposed). This route of administration seems to be useful for this drug delivery and allows to avoid unnecessary side effects.

Rowell's syndrome in the course of treatment with sodium valproate: a case report and review of the literature data.

Rowell's syndrome (RS) is a rare type of coexistence of one of the lupus erythematosus (LE) types (systemic, subacute cutaneous or discoid) and erythema multiforme (EM) (including toxic epidermal necrolysis). We present the case of a 51-year-old patient with a diagnosis of RS, most probably caused by drugs given as psychiatric treatment. After cessation of sodium valproate and initiation of treatment with prednisolone, a spectacular clinical remission was achieved. The likely role of psychiatric drugs, namely sodium valproate and sertraline, as triggering factors, is discussed.

Evaluation of skin penetration of topically applied drugs in humans by cutaneous microdialysis: acyclovir vs. salicylic acid.

BACKGROUND AND OBJECTIVE: Cutaneous drug application is used for both local drug therapy and systemic treatment. For both types of treatment, the drug concentration profile in, and transport across, the skin is important. To evaluate skin penetration of topically-applied drugs we recently used cutaneous microdialysis. The aim of this study was the use of this method for studying acyclovir and salicylic acid. METHOD: Five per cent acyclovir cream was applied on intact and tape-stripped skin of healthy volunteers and 5% salicylic acid ointment-onto intact skin of other volunteers. Microdialysis probes with 2 kDa molecular weight cut-off were inserted intradermally and were perfused with Ringer solution. Drug concentrations were measured by high-performance liquid chromatography. RESULTS: Following topical application of 5% acyclovir cream onto intact skin of eight healthy volunteers, no drug was determinable in the skin (cutaneous microdialysate) in any of the subjects studied. After partial removal of the stratum corneum the penetration of this drug into skin increased markedly. The mean maximum skin concentration was about 2 x 5 micromol/L after 2 x 4 +/- 0 x 7 h. Topically applied salicylic acid penetrated intact skin with a maximum concentration in the cutaneous microdialysate of 7 x 57 +/- 3 x 90 micromol/L after 5 x 3 +/- 0 x 4 h. CONCLUSION: Cutaneous microdialysis is a valuable method for estimating skin concentration of topically-applied drug. It allows evaluation after application to a small skin area, of about 2 cm(2), thereby reducing the risk of systemic toxicity. The method may be helpful for evaluating the influence of skin condition on the transport process.

Penetration of ciprofloxacin and its desethylenemetabolite into skin in humans after a single oral dose of the parent drug assessed by cutaneous microdialysis.

OBJECTIVE: To measure the concentration of ciprofloxacin and its desethylenemetabolite in plasma and cutaneous microdialysates and to compare ciprofloxacin penetration into cutaneous microdialysates against theoretically predicted penetration in a peripheral compartment. METHOD: A single oral dose of 0.5 g of the parent drug was administered to 10 healthy male volunteers. Microdialysis probes with 2 kDa molecular weight cut-off were inserted intradermally and were perfused with Ringer solution up to 8 h after drug ingestion. Drug and metabolite concentrations were measured by high performance liquid chromatography. RESULTS: Mean maximum concentrations of ciprofloxacin in plasma, cutaneous microdialysates and theoretical peripheral compartment were 7.01+/-1.69, 2.95+/-0.64 and 3.37+/-0.60 micromol/L, respectively, and were achieved after about 2.0+/-0.6, 2.4+/-0.9 and 4.8+/-0.9 h. The extent of penetration into cutaneous microdialysates and theoretical peripheral compartment relative to plasma were 0.550+/-0.150 and 0.788+/-0.131, respectively, and differed significantly. Similarly, time to maximum concentration as well as area under the concentration-time curve in these compartments also differed significantly unlike the maximum concentration. CONCLUSION: Microdialysis permits the evaluation of the penetration of drug and its metabolites into target tissues. Such evaluation is helpful to optimize treatment strategies. After a single 0.5 g oral dose, ciprofloxacin penetrated into skin and achieved concentrations above the minimum inhibitory concentrations for susceptible pathogens, recommended by the National Committee for Clinical Laboratory Standards (NCCLS).

Application of cutaneous microdialysis to evaluate metronidazole and its main metabolite concentrations in the skin after a single oral dose.

OBJECTIVE: To measure the concentration of metronidazole and its hydroxymetabolite in plasma and cutaneous microdialysates and to compare metronidazole penetration into cutaneous microdialysates against theoretical predicted penetration in a peripheral compartment. METHOD: A single oral dose of 2 g of the parent drug was administered to 10 healthy male volunteers. Microdialysis probes with 2 kDa molecular weight cut-off were inserted intradermally and were perfused with Ringer solution up to 8 h after drug ingestion. Drug and metabolite concentrations were measured by high performance liquid chromatography. RESULTS: Mean maximum concentration in plasma, cutaneous microdialysates and theoretical peripheral compartment were 214 +/- 49, 151 +/- 52 and 146 +/- 38 micromol/L, respectively, and were achieved after about 2.1 +/- 0.8, 2.8 +/- 1.0 and 6.0 +/- 2.9 h. The extent of penetration into cutaneous microdialysates and theoretical peripheral compartment relative to plasma were 0.672 +/- 0.196 and 0.675 +/-0.207, respectively, and did not differ significantly. Moreover, maximum concentration as well as area under concentration-time curve in these compartments also did not differ significantly. CONCLUSION: Use of cutaneous microdialysis technique permits the characterization of true systemic drug disposition, for optimizing drug treatment strategies.

Plasma and skin blister fluid concentrations of metronidazole and its hydroxy metabolite after oral administration.

Plasma and cantharidin-induced skin blister fluid concentrations of metronidazole and its main metabolite-hydroxymetronidazole were determined after a single and multiple oral doses. Metronidazole is nitroimidazole compound applied for the treatment of Protozoa infections. It is also active against anaerobic bacteria. The maximum concentrations of unchanged drug and its metabolite following a single oral dose of 2 g were observed after 1 +/- 1 and 11 +/- 2 h in plasma, whereas in blister fluid after 6 +/- 2 and 16 +/- 5 h, respectively. The average ratio of area under concentration time curve (AUC) in blister fluid to that of plasma was 1.02 +/- 0.12 for parent drug and 1.02 +/- 0.02 for the metabolite. After multiple doses of metronidazole (0.25 g every 8 h) the concentrations of unchanged drug in plasma and blister fluid, collected before the morning dose and 2 h after its administration, exceeded the minimal inhibitory concentrations for majority of susceptible pathogens. Hydroxymetronidazole concentrations in body fluids at steady-state amounted to about 30-50% of the parent drug and they could contribute to the overall activity against susceptible microorganisms since antibacterial activity of the metabolite is about 30-65% that of the metronidazole.

Penetration of tinidazole into skin blister fluid following its oral administration.

Plasma and skin blister fluid concentrations of tinidazole following a single oral dose of 2 g drug, and after multiple doses of 0.25 g every 12 h, were determined. Skin blisters were produced by direct application of 0.25% cantharidin ointment to the skin. The maximum concentration in plasma of about 36 mg.l-1 was observed after about 2 h, whereas in skin blister fluid the peak occurred after about 6 h and was 30 mg.l-1. The half-life in plasma was slightly shorter than in blister fluid at 17 and 19 h, respectively, but the difference was not significant. The penetration of tinidazole into cantharidin-induced skin blister fluid, defined according to Wise as the ratio of the AUCs in blister fluid and plasma was 1.00. During routine treatment with tinidazole (0.25 g every 12 h), the concentrations in plasma and blister fluid collected before and 3 h after the morning dose exceeded the minimal inhibitory concentrations for susceptible pathogens. The results provide a pharmacokinetic basis for the proven efficacy of tinidazole in the treatment of protozoal and anaerobic infections.