Pharmacokinetics and tissue penetration of fluconazole in humans.

The pharmacokinetics and tissue/fluid penetration of fluconazole have been studied in more than 400 healthy individuals and various subsets of patients. The pharmacokinetics of fluconazole are similar following intravenous and oral dosing. Oral bioavailability is greater than 90%, and concentrations peak approximately 2 hours after dosing. The apparent volume of distribution is 0.7 L/kg, and plasma protein binding is low (12%). The drug is metabolically stable, with renal excretion accounting for approximately 80% of the elimination as unchanged drug. Repeated once-daily dosing results in an increase in plasma levels of approximately 2.5-fold, with steady state achieved by day 7. Plasma levels are dose-proportional, and the elimination rate remains constant across the dosage range and over time. The plasma half-life of fluconazole is approximately 30 hours. The pharmacokinetics are similar in healthy young adults and in the elderly, but dose modification is required in patients with renal impairment. Fluconazole diffuses readily into the cerebrospinal fluid, sputum, and saliva and is concentrated in the urine and skin.

Effects of alpha-interferon on theophylline pharmacokinetics and metabolism.

1. The influence of alpha-interferon (Roferon-A) on the pharmacokinetics and metabolism of theophylline was studied in healthy adults. Roferon-A was administered as an intra-muscular injection (3 x 10(6) iu) once-a-day over 3 days. One week prior to and immediately after this course a single 20 min aminophylline infusion (4 mg kg-1) was given. 2. Blood samples for theophylline analysis were taken over 48 h. Urine was collected up to 72 h and assayed for theophylline and its major metabolites 3-methylxanthine, 1,3-dimethyluric acid and 1-methyluric acid. 3. Pharmacokinetic parameters for theophylline in plasma were calculated. From urinary excretion data the overall metabolic clearance of theophylline and clearances for formation of the metabolites were calculated. 4. After interferon administration, there was a significant increase of approximately 15% in the mean values of the terminal elimination half-life, area under the curve and mean residence time of theophylline in association with a similar decrease in plasma clearance (P less than 0.05). Formation clearances of the metabolites tended to be smaller after treatment, but only the change in the overall clearance of theophylline was significantly different (P less than 0.05). There was no systematic shift in the metabolic pattern of theophylline. 5. Additional investigations of the influence of the duration of alpha-interferon treatment are necessary before definite conclusions can be drawn about the mechanism and the clinical relevance of the described interaction.

Sputum levels of fluconazole in humans.

We measured fluconazole levels in sputum samples obtained from 11 bronchiectatic volunteers at 4 and 24 h after a single oral dose of 150 mg of fluconazole. Levels in sputum were similar to levels in plasma at both times.

Effects of food on the bioavailability of sustained-release pinacidil in humans.

The effects of a standard breakfast meal on the bioavailability of a sustained-release tablet formulation of pinacidil [(+/-)-2-cyano-1- (4-pyridyl)-3-(1,2,2-trimethylpropyl)guanidine monohydrate) were investigated in eight healthy volunteers. Concomitant food intake resulted in significantly increased maximum measured serum pinacidil concentrations, Cmax, (172 +/- 21 versus 102 +/- 49 ng/mL, p less than 0.05), and relative bioavailability, measured as AUCo-infinity (904 +/- 189 versus 697 +/- 279 ng.h/mL, p less than 0.05). The time to maximum serum concentration (tmax) was not affected by food (2.3 +/- 1.3 versus 3.3 +/- 1.2 h, p greater than 0.05), and the terminal elimination half-life, (t1/2z) was significantly decreased (4.7 +/- 2.2 versus 2.3 +/- 0.4 h, p less than 0.05).

Effects of formulation on the pharmacokinetics of orally administered pinacidil in humans.

Serum concentrations, relative bioavailability, and urinary excretion of pinacidil [(+/-)-2-cyano-1-(4-pyridyl)-3-(1,2,2-trimethylpropyl) guanidine monohydrate] from two sustained-release oral formulations (tablet and capsule) were compared in 12 healthy volunteers. Maximum measured serum concentrations (Cmax) from the sustained-release tablet and capsule did not differ significantly (75 +/- 17 versus 70 +/- 14 ng/mL, p greater than 0.05), but the time to achieve maximum concentration (tmax), was longer for the capsule (2.4 +/- 1.8 versus 0.98 +/- 0.5 h, p less than 0.05). There was no significant difference in bioavailability between the formulations, as measured by the area under the concentration-time curve (AUC0-8 h; 279 +/- 99 versus 311 +/- 85 ng.h/mL, p greater than 0.05). Twenty-four hour urinary excretion of both pinacidil and its major metabolite, pinacidil pyridine-N-oxide, was similar for both tablet and capsule preparations (3.9 +/- 1.2 and 55 +/- 19% versus 4.4 +/- 1.0 and 55 +/- 14%, respectively, of the administered dose, p greater than 0.05).

Pre-exposure studies with purified chick embryo cell culture rabies vaccine and human diploid cell vaccine: serological and clinical responses in man.

Clinical reactions and neutralizing antibody responses to six pre-exposure regimens of purified chick embryo cell culture rabies vaccine (PCECV) and human diploid cell strain rabies vaccine (HDCSV) were studied in 177 volunteers. Antibody kinetics, height of the response and persistence of antibody over two years were virtually identical after PCECV and HDCSV. An antibody response was detected in all subjects on day 14 when the highest titres were found after two intramuscular (i.m.) 1.0 ml doses of a schedule of immunization on days 0, 7 and 21. In comparison, a schedule of immunization on days 0, 28 and 56 ultimately evoked the highest titres 21 days after the final injection, but antibody persisted equally well over two years with either schedule. Neutralizing antibody titres were lower after intradermal (i.d.) vaccination with 0.1 ml compared to 1.0 ml i.m. on days 0, 7 and 21, but when given on days 0, 28 and 56 the responses were comparable. Three subjects with a personal or family history of atopy developed urticarial lesions after PCECV. Both vaccines were otherwise well tolerated.

Does ipratropium bromide by nebulizer and face-mask have local ocular effects?

No acute ocular atropinic effect of nebulized ipratropium bromide administered by carefully applied or deliberately misplaced face-mask has been demonstrated.

Thoracic lymphadenopathy in Asians resident in the United Kingdom: role of mediastinoscopy in initial diagnosis.

Although the incidence of superficial glandular tuberculosis is high in Asian immigrants, a clinical diagnosis without biopsy has previously been shown to be inaccurate in 22% of cases. The role of diagnostic mediastinoscopy and biopsy in thoracic lymphadenopathy was therefore evaluated in 41 consecutive Asian patients. Tuberculosis was diagnosed by histological examination or culture (or both) of gland biopsy material in 24 (59%). A further 12 patients, however, also received antituberculous chemotherapy, with a response in 10 cases. If these are included, 34 (83%) were finally considered to have tuberculosis. The symptoms and ages of the patients with tuberculosis were similar to those typically seen in caucasians with sarcoidosis. Six had tuberculous bilateral hilar lymphadenopathy. In only four cases (10%) was a positive diagnosis other than tuberculosis established; in two (lymphoma and thymoma) mediastinoscopy confirmed preoperative suspicions, and saved only two more (with sarcoidosis and vascular anomaly) from unnecessary antituberculous treatment. Complications included severe haemorrhage (1) and chronic tuberculous sinus in the endoscopy tract (2). Mediastinoscopy is unlikely to change management in most patients, produces an appreciable amount of morbidity, and should be reserved for cases in which there is additional clinical doubt. Any future decline in the prevalence of tuberculosis in Asians may, however, require its further evaluation.

Serum concentrations and urinary excretion of pinacidil and its major metabolite, pinacidil pyridine-N-oxide following i.v. and oral administration in healthy volunteers.

Serum concentrations of pinacidil and its major metabolite pinacidil pyridine-N-oxide were determined following administration of both an intravenous solution and a sustained release oral preparation to healthy volunteers. Mean bioavailability of pinacidil was 57.1 +/- 13.7%. Following intravenous administration, the mean AUC0-8 h metabolite/AUC 0-8 h pinacidil ratio was 0.559 +/- 0.272 and after oral administration, 0.825 +/- 0.656. Only one subject had serum metabolite concentrations in excess of pinacidil during the intravenous study whereas three subjects achieved metabolite concentrations in excess of pinacidil during the oral study. The mean serum elimination half-life of metabolite was significantly longer than parent drug following intravenous administration (P less than 0.01) but not after oral administration. No significant difference was found in the maximum measured metabolite concentration (Cmax.m) between the studies. The time to Cmax.m was significantly delayed (P less than 0.001) following oral dosage. Twenty four hour urinary excretion of metabolite was significantly increased (P less than 0.001) following oral administration whilst that of pinacidil was decreased (P less than 0.02). These results suggest that pinacidil pyridine-N-oxide may be a 'first-pass' metabolite of pinacidil. In most patients pinacidil pyridine-N-oxide is unlikely to contribute significantly to the hypotensive effect of pinacidil.

Lack of effect of influenza and pneumococcal vaccines on anticoagulation by warfarin.

The effects on anticoagulation of a purified trivalent sub-unit influenza vaccine and a 14-valent pneumococcal vaccine were investigated in a single-blind controlled study involving 69 well-stabilised warfarin recipients. There were no clinically or statistically significant alterations of anticoagulant control in vaccine recipients as compared with controls at 2, 7 and 21 days after vaccination. On the basis of these data, concern about warfarin-vaccine interaction should not deter practitioners from immunising warfarin recipients against influenza or infection with Streptococcus pneumoniae.

Pharmacokinetics and hypotensive effect in healthy volunteers of pinacidil, a new potent vasodilator.

Preliminary investigation in 3 healthy volunteers suggested that intravenous pinacidil in a dose of 0.2 mg/kg had a potent but well-tolerated hypotensive action in the supine position. Facial flushing, uncomfortable chest sensation and distressing postural hypotension occurred at serum concentrations above 300 ng/ml. Pinacidil, 0.2 mg/kg, was given intravenously over 4 min to 15 healthy volunteers in the supine position. Maximum fall in mean arterial pressure (MAP) was 15.7 +/- 6.0 mmHg. Maximum rise in heart rate was 23.8 +/- 6.6 beats/min. Pinacidil serum distribution half-life (T1/2 alpha) was 13.4 +/- 8.5 min and elimination half-life (T1/2 beta) was 2.13 +/- 0.49 h. The apparent volume of distribution (Vd beta) was 90.3 +/- 13.21 and total body clearance was 31.1 +/- 9.61/h. Pinacidil was approximately 40% bound to plasma protein over the concentration range 40-400 ng/ml. Urinary excretion of unchanged pinacidil accounted for 5.7 +/- 1.3% of the administered dose over 24 hours and urinary excretion of the major metabolite, pinacidil pyridine-N-oxide, was 31.6 +/- 9.2% of the administered dose. It was concluded that intravenous pinacidil is a potent vasodilator hypotensive compound, with a duration of action between 1.5 and 2 h.