Fluconazole and testosterone: in vivo and in vitro studies.

Fluconazole (UK-49,858), a novel bis-triazole antifungal agent, was given orally to groups of 10 male volunteers at doses of 25 and 50 mg/day for 28 days. Blood samples for testosterone estimation were taken from these and from a placebo group at several time points on days 1, 14, and 28 of the study, and the assay results demonstrated that the compound had no significant effect on circulating testosterone levels. Similarly, in studies with rat Leydig cells in vitro, fluconazole at concentrations up to 10 micrograms/ml was found to be only a weak inhibitor of testosterone production, whereas ketoconazole caused more than 50% inhibition at 0.1 microgram/ml. It is concluded that fluconazole, in contrast to ketoconazole, has little effect on the biosynthesis of testosterone by mammalian cells.

Effects of haemodialysis on taste for salt in relation to changes in blood constituents.

Taste sensitivity and preference for sodium chloride in bread and pea soup were assessed before and after haemodialysis in 12 female chronic renal failure patients. Blood samples were also taken pre- and post-dialysis and analysed for zinc, sodium and renin. The patients demonstrated an increased sensitivity to, and decreased preference for, sodium chloride in both bread and pea soup following dialysis. These taste changes were found to correlate with pre- to post-dialysis changes in the zinc levels in the blood. Patients receiving a more severely sodium-restricted diet showed a greater sensitivity to the taste of sodium chloride in the foods tested. Renin levels dropped in all patients following dialysis, the size of the change correlating with the size of the change in body weight.

Comparative and non-comparative studies of the efficacy and tolerance of tioconazole cream 1% versus another imidazole and/or placebo in neonates and infants with candidal diaper rash and/or impetigo.

Eleven open multicentre studies were conducted to evaluate the efficacy of tioconazole cream 1% as a treatment for diaper rash with or without fungal (Candida) involvement, or impetigo in neonates and infants. In the dermal candidiasis/diaper rash group, 320 patients had either tioconazole (n = 220), a comparative imidazole (n = 43), or vehicle cream (n = 57) applied to the affected area twice daily. Twenty-one impetigo patients had only tioconazole cream 1% applied three times daily to lesions. The overall cure rate (patients with both clinical and mycological cure) at the end of treatment for tioconazole treated patients was 78%, for the comparative imidazole group it was 76% and for vehicle cream it was 39%. At the long-term follow-up evaluation approximately 6 weeks after treatment for patients with diaper rash, the overall cure rate was about the same in both tioconazole- and comparative imidazole-treated patients (87% and 90%, respectively), and 14% in patients using vehicle cream. Side-effects were coincident with disease symptoms and consisted primarily of erythema localized to the treatment area; they occurred in 5.4% (13/241) of the patients who received tioconazole and in 21% (9/43) of the patients who received comparative imidazole (econazole or miconazole). No side-effects were reported in this open study for the 57 patients who used vehicle cream. The results of these studies show that tioconazole cream 1% is safe and effective for the treatment of neonates and infants with dermal candidiasis, diaper rash and impetigo.

Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans.

The pharmacokinetic profile of UK-49,858 (fluconazole), a novel triazole antifungal agent which is being developed for oral and intravenous use, was determined in mice, rats, dogs, and humans. Comparative data following oral and intravenous administration showed that bioavailability was essentially complete in all four species. Peak concentrations in plasma of drug normalized to a 1-mg/kg dose level following oral administration, were relatively high: 0.7, 0.6, 1.1, and 1.4 micrograms/ml in mice, rats, dogs, and humans, respectively. The volumes of distribution ranged between 1.1 liter/kg in mice and 0.7 liter/kg in humans, which are approximate to the values for total body water. Whole body autoradiography studies in mice following intravenous administration of [14C]UK-49,858 demonstrated that the drug was evenly distributed throughout the tissues, including the central nervous system and the gastrointestinal tract. Plasma protein binding was low (11 to 12%) in all species. Marked species differences were observed in elimination half-lives, with mean values of 4.8, 4.0, 14, and 22 h in mice, rats, dogs, and humans, respectively. The major route of elimination of the drug was renal clearance, with about 70% of the dose being excreted unchanged in the urine in each species. Studies with [14C]UK-49,858 on metabolism and excretion (intravenous and oral) in mice and dogs showed that about 90% of the dose was recovered as unchanged drug in urine and feces, confirming the metabolic stability of the drug. This pharmacokinetic profile is markedly different from that of imidazole antifungal drugs and undoubtedly contributes to the excellent efficacy of UK-49,858 in vivo.

Tioconazole, a new imidazole-antifungal agent for the treatment of dermatomycoses. Antifungal and pharmacologic properties.

Tioconazole is a new imidazole antifungal agent with broad-spectrum activity. Its in vitro activity against common dermal pathogens is generally better than miconazole by a factor of 2-8. This activity is paralleled by good topical efficacy in a guinea pig dermatomycosis model. Pharmacokinetic studies in animals have demonstrated minimal systemic exposure following dermal application. Acute general pharmacology studies have shown that the compound is well tolerated in animals and unlikely to produce side-effects in man.

Tioconazole in the treatment of fungal infections of the skin. An international clinical research program.

In 32 studies involving 1,304 patients tioconazole 1% dermal cream has been shown to be effective and safe in the treatment of a wide variety of superficial fungal infections of the skin and erythrasma. Tioconazole cream is more effective than miconazole nitrate 2% cream in the treatment of pityriasis versicolor and in infections with Trichophyton rubrum and Trichophyton mentagrophytes which cause 70% of dermatophyte infections in man. Data from comparisons with econazole and clotrimazole are too few to allow conclusions to be drawn on relative efficacy. All the creams were easy to apply and there were no serious adverse reactions, local or systemic.

Synthesis and antibacterial activity of 1-N-(1,3-dihydroxy-2-propyl)kanamycin B (UK-31,214).

1-N-(1,3-Dihydroxy-2-propyl)kanamycin B was prepared and its in vitro activity against aminoglycoside-sensitive and aminoglycoside-resistant organisms was compared with that of kanamycin B and gentamicin. This kanamycin B derivative (code No. UK-31,214) demonstrated potent activity in all of these tests and gave good protection in experimental infections in mice.

Inhibition of transpeptidase activity in Escherichia coli by thienamycin.

Thienamycin was shown to be a more potent inhibitor than ampicillin of the enzyme peptidoglycan transpeptidase from Escherichia coli.

Antifungal activity of tioconazole (UK-20,349), a new imidazole derivative.

Tioconazole (UK-20,349), a new antifungal imidazole derivative, was compared with miconazole for activity in vitro against Candida spp., Torulopsis glabrata, Cryptococcus neoformans, Aspergillus spp., and dermatophyte fungi (Trichophyton spp. and Microsporum spp.). Tioconazole was more active than miconazole against all the fungal species examined except Aspergillus, against which both agents showed similar activity. Both tioconazole and miconazole inhibited the growth of all fungi examined at concentrations well below their quoted minimum inhibitory concentrations. Their activity against fungi in vivo was investigated in mice infected systemically with Candida albicans. Both agents significantly reduced the numbers of viable Candida cells recoverable from the kidneys of infected animals, with tioconazole producing a generally more marked reduction. After administration of a single oral dose (25 mg/kg) to beagle dogs or white mice, higher and more sustained circulating levels of bioactive drug were detectable of tioconazole than of miconazole. These observations suggest that tioconazole may have potential in the treatment of both superficial and systemic mycoses in humans.

Peptidoglycan transpeptidase inhibition in Pseudomonas aeruginosa and Escherichia coli by Penicillins and Cephalosporins.

Peptidoglycan transpeptidase activity has been studied in cells of Escherichia coli 146 and Pseudomonas aeruginosa 56 made permeable to exogenous, nucleotide-sugar peptidoglycan precursors by ether treatment. Transpeptidase activity was inhibited, in both organisms, by a range of penicillins and cephalosporins, the Pseudomonas enzyme being more sensitive to inhibition in each case. Conversely, growth of E. coli 146 was more susceptible to these antibiotics than growth of P. aeruginosa 56. Furthermore, similar transpeptidase inhibition values were ob-obtained for the four penicillins examined against the Pseudomonas enzyme, although only two of these (carbenicillin and pirbenicillin) inhibited the growth of this organism. We therefore conclude that the high resistance of P. aeruginosa 56 to growth inhibition by most beta-lactam antibiotics cannot be due to an insensitive peptidoglycan transpeptidase.

UK-18,892: resistance to modification by aminoglycoside-inactivating enzymes.

UK-18,892, a new semisynthetic aminoglycoside, was active against bacteria possessing aminoglycoside-inactivating enzymes, with the exception of some known to possess AAC(6') or AAD(4') enzymes. This activity has been rationalized by using cell-free extracts of bacteria containing known inactivating enzymes, where it was shown that UK-18,892 was not a substrate for the APH(3'), AAD(2''), AAC(3), and AAC(2') enzymes. It was also demonstrated that UK-18,892 protected mice against lethal infections caused by organisms possessing aminoglycoside-inactivating enzymes.

In vitro studies with UK-18,892, a new aminoglycoside antibiotic.

The antibacterial activity of UK-18,892, a new semisynthetic aminoglycoside, was examined against aminoglycoside-susceptible and aminoglycoside-resistant clinical isolates of gram-negative bacilli and Staphylococcus aureus. UK-18,892 had a similar degree of activity to those of amikacin and kanamycin A against aminoglycoside-susceptible bacteria but was less potent than gentamicin against all isolates except Providencia spp. UK-18,892 was highly active against aminoglycoside-resistant bacteria, inhibiting 93% of the 268 isolates examined at 12.5 mug/ml. Amikacin was similarly active, whereas gentamicin inhibited only 14% of these isolates at 12.5 mug/ml.

Synthesis and antibacterial activities of 1-N [(S)-omega-amino-2-hydroxyalkyl] kanamycin A derivatives.

Four 1-N-aminohydroxy-alkyl derivatives of kanamycin A were prepared and their in vitro activities against aminoglycoside-sensitive and aminoglycoside-resistant organisms were compared with amikacin. 1-N-[(S)-4-Amino-2-hydroxybutyl] kanamycin A (Fig. 1, compound 2, code no. UK-18,892) was equipotent to amikacin in all these tests and in mouse protection studies.