George Foulds

Fluconazole Penetration into Cerebrospinal Fluid in Humans

One hour after intravenous doses of 50 mg/d fluconazole for 6 days or 100 mg/d for seven days to healthy subjects, the cerebrospinal fluid concentrations of fluconazole were 1.26 mg/L and 2.74 mg/L, respectively. These values were approximately 52% and 62% those of serum. Four patients with an initial clinical diagnosis of meningitis also had significant concentrations of fluconazole in the cerebrospinal fluid.

Azithromycin prophylaxis against a chloroquine-resistant strain of Plasmodium falciparum

Azithromycin has antimalarial activity and favourable pharmacokinetic properties for a prophylactic antimalarial agent. We investigated the ability of azithromycin to prevent malaria in volunteers infected with a chloroquine-resistant strain of Plasmodium falciparum. 4 volunteers received oral azithromycin 500 mg followed by 250 mg daily for 7 further days. Subjects were infected on the third day of azithromycin. 3 subjects were protected compared with none of 15 controls. The volunteer not protected by azithromycin had unquantifiable plasma levels of azithromycin, probably because of poor absorption. Azithromycin could be a promising prophylactic agent for P falciparum malaria.

Determination of trovafloxacin, a new quinolone antibiotic, in biological samples by reversed-phase high-performance liquid chromatography.

A simple, accurate and precise high-performance liquid chromatographic method was developed and validated for the determination of trovafloxacin, a new quinolone antibiotic, in serum and urine. Following solid-phase extraction, chromatographic separation was accomplished using a C18 column with a mobile phase consisting of 0.04 M H3PO4-acetonitrile-tetrabutylammonium hydroxide-0.005 M dibutyl amine phosphate (D-4) reagent (83:16.85:0.05:0.1, v/v), pH 3. Trovafloxacin and the internal standard (a methyl derivative of trovafloxacin) were detected by ultraviolet absorbance at 275 nm. The lower limit of quantification for trovafloxacin was 0.1 microgram/ml and the calibration curves were linear over a concentration range of 0.1 to 20.0 micrograms/ml (r2 = 0.9997). The average recoveries were greater than 70% for both trovafloxacin and internal standard. The intra-day and inter-day coefficients of variation were generally less than 5% in urine and serum over the concentration range of 0.1 to 20.0 micrograms/ml. Human serum samples could be stored for up to 12 months at -20 degrees C and urine samples could be stored up to 18 months at -80 degrees C.

Disposition of oral azithromycin in humans

The oral bioavailability of azithromycin is approximately 37% in healthy subjects; little is known about the disposition of the remaining 63% of the dose. This study attempted to describe the fate of azithromycin before absorption.

Assay of fluconazole by megabore capillary gas-liquid chromatography with nitrogen-selective detection.

A megabore column gas-liquid chromatographic method which uses nitrogen-phosphorus detection was developed for the analysis of fluconazole in plasma, serum, cerebrospinal fluid, or urine. The assay was linear from 0.2 to 200 micrograms/ml and had an average coefficient of variation of 7%. The suitability of the assay for pharmacokinetic studies was demonstrated.

A Study of the Pharmacokinetics of Azithromycin and Nelfinavir When Coadministered in Healthy Volunteers

A two‐way, open‐label, crossover study in 12 subjects was undertaken to study the potential for azithromycin to alter the pharmacokinetics of nelfinavir and/or its active metabolite, M8. A secondary objective was to characterize any potential interaction that nelfinavir may have with azithromycin. During one dosing arm, subjects received a single 1200 mg oral dose of azithromycin. During the other, subjects received 11 days of nelfinavir 750 mg q8h with a single 1200 mg oral dose of azithromycin given concurrently with the Day 9 morning nelfinavir dose. Serum samples were collected after each azithromycin dose for 168 hours and after the Day 8 and 9 morning nelfinavir doses for 8 hours to characterize azithromycin, nelfinavir, and M8 pharmacokinetic parameters during both control and test periods. Both dosing regimens were well tolerated, with only mild to moderate GI side effects being the most frequently reported. Azithromycin was found to cause a statistically, though not clinically, significant decrease in nelfinavir and M8 exposures. In contrast, nelfinavir caused azithromycin Cmax and exposure (AUC) values to increase by > 100%. Inhibition of p‐glycoprotein by nelfinavir may be responsible for this significant interaction. This increase in azithromycin exposure has the potential to increase clinical antibacterial efficacy without significantly increasing gastrointestinal side effects, though the impact on other systemic sites needs to be studied.

Assay of fluconazole by high-performance liquid chromatography with a mixed-phase column.

A mixed-phase liquid chromatographic column was used to assay fluconazole in plasma, serum, and cerebrospinal fluid. The assay was linear from 0.2 to 20 micrograms/ml, with an average coefficient of variation of less than 5%. The partitioning of the drug between serum and cerebrospinal fluid was determined for 34 patients. The method was demonstrated to be suitable for both pharmacokinetic studies and monitoring of patients receiving treatment with this antifungal agent.

THE EFFECTS OF AN ANTACID OR CIMETIDINE ON THE SERUM CONCENTRATIONS OF AZITHROMYCIN

The effects of an antacid and of cimetidine on the serum concentrations of azithromycin were examined in volunteers. Ten subjects were given 500 mg azithromycin alone and immediately after being given 30 mL Maalox (Rorer, Fort Washington, PA) in a crossover design. There were no statistically significant differences in Tmax or AUC0–48 after administration of azithromycin alone or with antacid, but mean values of Cmax were reduced by 24% (P = .015). Thus, although Cmax was decreased, the extent of absorption of azithromycin was not affected by coadministration with an antacid. Two groups of six volunteers were given 500 mg azithromycin on day 1. On day 8, one group was given 800 mg cimetidine 2 hours before a dose of azithromycin; the remaining group received placebo before azithromycin. There were no differences in the pharmacokinetic parameters produced by administration with cimetidine or placebo, relative to those on day 1. Thus, cimetidine administered 2 hours before a dose of azithromycin had no apparent effect on the serum concentrations of azithromycin.

Severe neutropenia caused by recommended prophylactic doses of rifabutin

important distal problem. Both these alternatives ring true. However, if the centrifugal theory is accepted its apologists are left explaining why it is that technically competent vascular surgeons still have recurrences despite perfect high ties. Are the centrifugalists seriously arguing that the often minute neovascular networks reported in the groin cause the sometimes gross recurrences we all see in the calf? The haemodynamics involved in this latter scenario stretch credulity.

Concentration of azithromycin in human prostatic tissue

Prostatic tissue was obtained from 36 patients at two study locations and assayed for azithromycin by HPLC or bioassay. The mean concentration of azithromycin in human prostatic tissue (2.54 µg/ml) 14 h after 500 mg oral dosing (two 250 mg doses 12 h apart) was much greater than plasma concentrations (≤ 0.1 µg/ml). Azithromycin was slowly eliminated from prostatic tissue (half-life 60 h) and a mean concentration of 0.62 µg/ml remained 137 h after dosing.