Metabolic effects of low-dose fluconazole in healthy female users and non-users of oral contraceptives.

1. Azole antifungal agents such as ketoconazole act by inhibiting cytochrome P-450 mediated sterol synthesis in the fungal cell membrane and thus have the potential to interfere with mammalian steroidogenesis. Fluconazole is a novel orally-effective antifungal triazole which has been reported to have more specific effects on the cytochrome P-450 enzymes involved in fungal sterol synthesis. 2. Due to the potential value of systemic antifungal agents in the treatment of infections commonly occurring in women, we assessed the effect of oral fluconazole on the metabolic profile of 18 healthy premenopausal women, 10 of whom were taking combined oral contraceptives (OC). Each woman acted as her own control, being studied both before and 21-28 days after fluconazole therapy (50 mg daily), in the luteal phase of consecutive menstrual cycles. 3. The endocrinological profile included measurement of serum oestradiol, progesterone, testosterone and sex hormone binding globulin (SHBG) concentrations, short tetracosactrin adrenal stimulation test and thyroid function tests. Carbohydrate metabolism was investigated by means of an oral glucose tolerance test with measurement of plasma glucose, insulin and C-peptide concentrations. Serum lipids, lipoproteins and apolipoproteins were analysed on samples taken after an overnight fast. 4. Minor biochemical changes associated with fluconazole treatment included increases in serum thyroxine and testosterone concentrations (but not in women taking OC as well as fluconazole) and in insulin and apolipoprotein B levels (but only in women taking OC as well as fluconazole). In general, these changes were small and of no clinical significance with the values remaining within the laboratory normal range. There were no adverse side-effects.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: The metabolic effects of the anti-fungal drug fluconazole were investigated in 18 women, 10 of whom were taking oral contraceptives, to examine whether this steroid antagonist has any effects primarily on hormone systems. The women, aged 29-40, took 50 mg fluconazole orally from Day 1 of their menstrual cycle for 21-28 days. Subjects kept a symptom diary, were tested weekly for hematological and liver function, and were checked for compliance by analyzing blood for drug by GLC. 5 women reported side effects: somnolence, dizziness, fatigue, increased appetite, headache (1) and nausea (1). No effects on liver function or menses were noted. The only significant findings were increases in serum thyroxine and testosterone in fluconazole-only subjects, and increases in insulin and apo-lipoprotein B in fluconazole-oral contraceptive subjects. Pills containing levonorgestrel were used by 9 women, desogestrel by 1. No significant differences were seen in estradiol, progesterone, sex-hormone-binding globulin, thyroid function, cortisol, glucose, C-peptide, cholesterol, triglycerides, lipoproteins. Thus it is unlikely that the short-term use of fluconazole for treatment of superficial mycoses, such as vulvovaginal candidiasis, will adversely affect steroid metabolism in women.

Pharmacokinetics of sulbactam and ampicillin following oral administration of sultamicillin with probenecid.

Eight volunteers each received lg of probenecid followed immediately by 1.5 g sultamicillin, both given by the oral route. Plasma concentrations of ampicillin and sulbactam were measured using a differential bioassay method. An ampicillin mean peak plasma concentration of 23.1 mg/l was found typically 1.5 h after dosing; the mean peak plasma concentration of sulbactam (10.0 mg/l) occurred at the same time. The mean plasma half-life of ampicillin was 1.45 h and that of sulbactam 1.3 h. The mean urinary recovery of ampicillin was 65% and that of sulbactam 62%. Five of the volunteers reported minor changes in bowel habits.

Pharmacokinetics and bioavailability of sultamicillin estimated by high performance liquid chromatography.

Sultamicillin is an orally absorbed double ester of sulbactam (penicillanic acid sulphone, a semisynthetic inhibitor of the beta-lactamases of many Gram-positive and Gram-negative species) and ampicillin. First-pass hydrolysis of this prodrug liberates equimolar proportions of sulbactam in plasma, saliva and urine is described and was used to determine the absolute bioavailability of sulbactam and ampicillin from sultamicillin in six normal male volunteers who each received a single 750 mg oral dose of sultamicillin or an iv dose of the equivalent amounts of ampicillin (441 mg) and sulbactam (294 mg). Treatments were given in random order with not less than four days intervening. The mean peak plasma concentrations and time to peak of sulbactam and ampicillin following the 750 mg oral half lives, systemic and renal clearances for sulbactam and ampicillin were similar. The bioavailability for both drugs from sultamicillin as estimated from both plasma and urine pharmacokinetics was better than 80%. We conclude that sultamicillin is an extremely efficient prodrug for ampicillin and sulbactam and that the HPLC assay method is accurate, rapid and easier to perform than the differential microbiological assay.

Biliary excretion of amoxycillin and ceftriaxone after intravenous administration in man.

1 Plasma and biliary concentrations of amoxycillin and ceftriaxone were measured after bolus intravenous administration (500 mg) in four subjects with normal hepato-biliary and renal function. 2 The mean plasma elimination half-life for ceftriaxone (t 1/2 = 330 +/- 30 min) was considerably longer than that for amoxycillin (t 1/2 = 60 +/- 9 min). 3 The biliary concentration of ceftriaxone was above plasma concentration of the drug throughout the study period, whereas amoxycillin concentration in the bile was lower than that in plasma. 4 Both plasma and biliary concentrations of ceftriaxone were substantially higher than previously determined minimum inhibitory concentration (MIC) values for E. coli (and several other common biliary tract pathogens) for over 6 h following drug administration. Amoxycillin concentration in plasma fell below MIC by 2 h, and did not reach inhibitory concentrations in bile.

Pharmacokinetics of alafosfalin, alone and in combination with cephalexin, in humans.

Alafosfalin is a phosphonodipeptide with significant activity as an antibacterial agent and as a potentiator of beta-lactam antibiotics. Studies in humans showed that oral doses of 50 to 2,500 mg were well absorbed, but some metabolic hydrolysis occurred before the drug reached the general circulation. Oral bioavailability was approximately 50% and was largely independent of dose. Alafosfalin has an elimination half-life of about 60 min and does not accumulate during chronic administration. Healthy volunteers excreted intact phosphonodipeptide in the urine. The recovery was dose dependent and increase from 6 +/- 1% after 50-mg doses to 17 +/- 1% after 2,500-mg doses. This change with dose occurred because the human kidney has a small, saturable capacity for reabsorbing the phosphonopeptide. Less alafosfalin was excreted in the urine of subjects with impaired glomerular function. When alafosfalin was coadministered with cephalexin, both compounds wer absorbed, distributed, and eliminated at virtually identical rates. Oral administration of 500 mg of the phosphonodipeptide plus 250 mg of the beta-lactam antibiotic gave approximately equal concentrations of the drugs in plasma, with a fourfold excess of cephalexin in the urine. This 2:1 combination is being tested in the clinic.

Effect of a polynucleotide interferon inducer of fungal origin on experimental rhinovirus infection in humans.

A double-stranded RNA of fungal origin (BRL 5907) was given intranasally to volunteers. Apart from mild local irritancy of the higher dosage, the compound was well tolerated. A double-blind placebo-controlled trial of a three-day course (5 mg per day) of BRL 5907 against challenge with rhinovirus type 4 showed that treatment was associated with a delay in onset of symptoms and a reduction in shedding of virus, but the differences were not statistically significant. Low titers of interferon were found in nasal washings.

Bioavailability and metabolism of talampicillin.

Talampicillin is an ester of ampicillin which is readily hydrolysed on absorption to release ampicillin. It is well absorbed from the gastro-intestinal tract resulting in a greater bioavailiability of ampicillin than can be achieved with equivalent doses of ampicillin itself. Dose response studies have confirmed a direct relationship between the dose of talampicillin administered and peak serum ampicillin concentration and urinary excretion of ampicillin. Dosing of ampicillin after food has been shown to adversely affect the total bioavailability of ampicillin. This is not so after dosing with talampicillin. The bioavailability of ampicillin from a 250-mg Talpen tablet dosed after a large meal was significantly greater than that from 250 mg ampicillin dosed in the fasting state. Studies in volunteer subjects at multiples of the proposed therapeutic dose for periods of up to 28 days have indicated its acceptability, bioavailability and lack of side effects on repeated dosing. The fate of the phthalidyl moiety of talampicillin has been investigated in repeated dose studies and in a single dose studies and in a single dose study in which radiolabelled talampicillin was administered. The principal metabolite of the phthalidyl moiety in man has been shown to be 2-hydroxymethylbenzoic acid, which is identical to that in experimental animals used for toxicological investigations.