The influence of food on the pharmacokinetics of the triazole antimycotics fluconazole and itraconazole was investigated in a randomised, parallel group, single dose study in 24 healthy subjects. Each group took either a 100 mg capsule of fluconazole or a 100 mg capsule of itraconazole, pre-prandially or after a light meal or a full meal, in a three-way crossover design. Gastric and intestinal pH were measured with a co-administered radiotelemetric pH capsule, and gastric emptying time of the capsule (GET) was taken as the maximum gastric residence time of drug and food. The plasma AUC and Cmax of itraconazole were significantly different under the various conditions and the mean AUC was greatest after the full meal. The bioavailability (90% confidence intervals) of itraconazole relative to that after the full meal, was 54% (41-77%) on an empty stomach and 86% (65-102%) after a light meal. The criteria for bioequivalence were not attained. In contrast, the bioavailability (90% CI) of fluconazole relative to the full meal was 110% pre-prandially (100-115%) and 102% after the light meal (88-103%), and the criteria for bioequivalence were attained. Itraconazole absorption was promoted by low stomach pH, long gastric retention time and a high fat content of the coadministered meal, whereas the pharmacokinetics of fluconazole was relatively insensitive to physiological changes in the gastrointestinal tract.

The distribution in the skin of orally active antifungals and other drugs claimed to be active in the treatment of skin diseases is of major importance, but to date has been studied only rarely. In the present study the distribution of fluconazole in stratum corneum, epidermis-dermis (without stratum corneum), eccrine sweat and serum was studied in human male volunteers after dosages of 50 mg daily for 12 days and 150 mg once weekly for 2 weeks. In the present study high levels of fluconazole were found especially in the stratum corneum. At a dose of 50 mg once daily the concentration of fluconazole after 12 days was 73.0 micrograms/g and 7 days after cessation of treatment the concentration was still 5.8 micrograms/g. At the 150 mg once a week dose the concentration 7 days after the second dose was still 7.1 micrograms/g in stratum corneum indicating that medication once a week may be effective in the treatment of dermatomycoses. High concentrations, all above the serum concentrations, were also seen in sweat and epidermis/dermis. These results indicate that fluconazole is delivered to the stratum corneum, where it is accumulated, through sweat and by direct diffusion through the dermis-epidermis. These pharmacokinetic results indicate that the drug should be very effective in the treatment of dermatomycoses. An extremely high concentration of the drug in the stratum corneum combined with concentrations from 2.93 to 4.62 micrograms/g in the rest of the epidermis and dermis is important in the treatment of these diseases.

The concentrations of azithromycin in polymorphonuclear leukocytes (PMNLs), monocytes, erythrocytes, and plasma were measured in six healthy volunteers after the last treatment of a 3-day regimen of 500 mg once daily. Marked enrichment of azithromycin was found in PMNLs and monocytes. The drug concentrations after the last dose amounted to 114 +/- 43 (mean +/- standard deviation) mg/liter at 12 h in PMNLs and 34 +/- 17 mg/liter at 6 h in monocytes. Fourteen days thereafter, azithromycin was still detectable in the PMNLs at 53 +/- 34 mg/liter and in the monocytes at 1 +/- 2 mg/liter, although the drug was no longer detectable in plasma (< 0.02 mg/liter). Maximum drug concentrations for azithromycin in plasma (0.40 +/- 0.30 mg/liter) and erythrocytes (0.15 +/- 0.05 mg/liter) at 3 h after the last administration were much lower and occurred earlier than those observed in the phagocytic cells. The mean enrichment factors (cellular/extracellular ratios) of azithromycin in phagocytes relative to plasma came to 231 +/- 150 and 3,924 +/- 584 at 3 and 120 h, respectively, for PMNLs and 83 +/- 55 and 523 +/- 285 at 3 and 120 h for monocytes, respectively, after the last dose. The phagocytosis tests with PMNLs separated from the blood of volunteers at various times after the last treatment confirmed the enhanced intracellular activity of these cells against staphylococci.

Summary. Fluconazole is an antimycotic drug which until now has been used mostly in the systemic therapy of yeast infections. We have now demonstrated the presence of this drug in various skin structures. After administration of 50 mg of fluconazole per day for 12 days to healthy volunteers, the following mean drug concentrations were measured: serum 1.81 μg ml‐1, sweat 4.58 μg ml‐1, dermis‐epidermis (without stratum corneum) 2.77 μg g‐1 and stratum corneum 73 μg g‐1. Thus, 4 h after the last dose the antimycotic attains a 40‐fold higher concentration in the stratum corneum than in serum. One week after ending the oral treatment, 5.8 μg g‐1 fluconazole was present in stratum corneum. After daily ingestion of 200 mg of fluconazole for 5 days there was a further increase in the mean concentration of fluconazole in stratum corneum, to 127 μg g‐1. Even 4–5 months after completing the oral treatment, fluconazole was detectable in the head hair and toenails of healthy volunteers. Fluconazole is eliminated from the stratum corneum about 2–3 times more slowly than from serum or plasma. After oral administration fluconazole evidently accumulated rapidly and intensively into the stratum corneum. The concentrations then attained or exceeded the in vitro minimal inhibitory concentrations of fluconazole for most of the dermatophytes and yeasts which are involved in cutaneous mycoses. Zusammenfassung. Fluconazol, ein bisher vor allem in der systemischen Therapie von Sproßpilzinfektionen etabliertes Antimykotikum, wird in verschiedenen Strukturen der Haut nachgewiesen. Nach oraler Einnahme von 50 mg Fluconazol einmal täglich über 12 Tage konnten an gesunden Probanden folgende mittlere Wirkstoffkonzentrationen gemessen werden: Serum 1.81 μg ml‐1. Schweiß 4.58 μg ml‐1. Dermis‐Epidermis (ohne Stratum corneum) 2.77 μg g‐1 und Stratum corneum 73 μg g‐1. Damit erreicht das Antimykotikum vier Stunden nach der letzten Einnahme im Stratum corneum eine etwa 40fach höhere Konzentration als im Serum. Eine Woche nach Ende der oralen Behandlung werden noch 5.8 μg g‐1 Fluconazol im Stratum corneum gefunden. Die tägliche Einnahme von 200 mg Fluconazol über fünt Tage zeigt zwei Stunden nach der letzten Applikation einen weiteren Anstieg der mittleren Fluconazol‐Konzentration im Stratum corneum auf 127 μg g‐1. Das Antimykotikum ist in Kopfhaaren und Zehennägeln gesunder Probanden noch vier bzw. fünf Monate nach Beendigung der oralen Therapie nachweisbar. Aus Stratum corneum wird Fluconazol zwei‐ bis dreimal langsamer als aus Serum oder Plasma eliminiert. Fluconazol akkumuliert nach oraler Einnahme schnell und intensiv im Stratum corneum. Die dabei gemessenen Konzentrationen überschreiten die in vitro ermittelten Minimalen Hemmkonzentrationen von Fluconazol gegenüber den meisten an kutanen Mykosen beteiligten Dermatophyten und Sproßpilzen.

In a prospective clinical investigation of 20 patients with primary Sjögren's syndrome (SS), neurological complications, not attributable to other diseases were detected in 14 patients (= 70%). Dysfunction of the peripheral nervous system (PNS) was nearly twice as frequent as central nervous system (CNS) complications. PNS involvement was dominated by symmetric sensory neuropathies, carpal tunnel syndromes, cranial nerve palsies (above all trigeminal sensory neuropathy) and pupillary dysfunction. CNS impairment was represented by cortical atrophy (n = 4), hemiparesis (n = 1) and aseptic meningitis (n = 1). Though CNS complications were rare, psychometric testing revealed diminished cognitive capacity in 14 patients. In addition to the characteristic sicca syndrome patients suffered from musculoskeletal pain and recurring abnormal sensation which frequently lead to the misdiagnosis of functional disorders. Additionally the frequent occurrence of psychiatric symptoms such as nervosity and depression support the impression of a psychosomatic pattern with no organic basis.