Dose related pharmacokinetics of ofloxacin in healthy volunteers.

OBJECTIVE: To evaluate the pharmacokinetic profile of ofloxacin in healthy volunteers after single oral doses of 600 and 800 mg. DESIGN: Seven healthy volunteers were administered 600 and 800 mg of ofloxacin on two occasions with an interval of one week. Paired samples of blood and saliva were collected after 1, 2, 3, 6, 9, 12, 24, 32 and 48 hours post-dose. Urine samples were collected over a period of 0-6, 6-12 and 12-24 hours. Concentrations of ofloxacin in plasma, saliva and urine were assayed by high performance liquid chromatography. RESULTS: Increases of 22% in peak plasma concentration (Cmax) and 40% in area under the concentration-time curve (AUC0-24) were observed with the 800 mg dose. The other parameters, namely time to attain Cmax, half-life, the apparent volume of distribution, plasma and renal clearance and percentage of dose excreted in urine over 24 hours were independent of doses. The mean ratios of the concentration in saliva to the concentration in plasma ranged from 0.4-0.6, and the correlation coefficient was 0.94. CONCLUSIONS: Dose proportionality was observed in Cmax and AUC0-24 when 600 and 800 mg doses of ofloxacin were given. Ofloxacin determined in saliva seems to be suitable for therapeutic drug monitoring.

Simple and rapid high-performance liquid chromatography method for the determination of ofloxacin concentrations in plasma and urine.

A high-performance liquid chromatographic method for the determination of ofloxacin in human plasma and urine was developed. The method involved deproteinisation of the sample with perchloric acid and analysis of the supernatant using a reversed-phase C18 column and fluorescence detection at an excitation wavelength of 290 nm and an emission wavelength of 460 nm. The assay was linear from 0.5 to 10.0 microg/ml. The relative standard deviation of intra- and inter-day assays was lower than 5%. The average recovery of ofloxacin from plasma was 93%. The method was evaluated in samples from healthy subjects whose drug levels were already measured by microbiological assay.

Serial evaluation of serum neopterin in HIV seronegative patients treated for tuberculosis.

OBJECTIVE: To delineate the course of serum neopterin (s-neo) concentrations in patients with pulmonary tuberculosis who are on anti-tuberculosis therapy. DESIGN: S-neo concentrations were measured by high performance liquid chromatography (HPLC) in 39 patients treated for pulmonary tuberculosis at pretreatment, at one month and at end of treatment. It was also measured in 11 relapse cases and their matched controls at the above time points and at the time of relapse. The results were correlated with bacteriological and radiological findings. RESULTS: All patients had elevated levels of s-neo at pretreatment which had declined at 1 month and were near normal at the end of treatment. The decline was more significant in patients with moderate lesions, suggesting that immune activation is maximum in this group of patients. The mean decrease was 37% at one month and 66% at the end of treatment. The corresponding decreases were 11% and 56% in patients with limited lesions and 11% and 45% in those with extensive lesions. It continued to fall after completion of therapy in patients who did not relapse, whereas an increase after completion of therapy was associated with bacteriologically proven relapse. CONCLUSIONS: The measurement of s-neo concentration could be of help in evaluating response to therapy. This study provides a rational basis for the association between s-neo concentration and relapse.

Neopterin as a marker for cell-mediated immunity in patients with pulmonary tuberculosis.

SETTING: Cell-mediated immunity (CMI) involves macrophage activation and T cell proliferation. These two parameters are compared in this study. OBJECTIVE: To ascertain the role of neopterin as a biochemical marker for CMI in patients with pulmonary tuberculosis. DESIGN: We measured neopterin levels in serum and the culture supernatants of peripheral blood mononuclear cells (MNC) after stimulation with purified protein derivative (PPD) in 11 patients with pulmonary tuberculosis and 10 healthy individuals. Lymphocyte proliferative response to PPD was carried out in these two groups. RESULTS: The mean concentration of serum neopterin was significantly higher in patients than in controls (P < 0.01). The spontaneous release of neopterin was significantly higher in culture supernatants of MNC from patients when compared with those of healthy controls (P < 0.05). Release of neopterin from MNC stimulated with PPD, however, was similar in both groups. The neopterin release and the stimulation index (SI) in lymphocyte proliferation assay were not comparable, suggesting that these two parameters do not run in parallel for measuring the status of CMI. However, serum concentration of neopterin was inversely related to the SI in a large proportion of subjects (66%). CONCLUSION: Measurement of neopterin, a soluble product of immune cells (macrophage), may provide information on the state of CMI.

Salivary cortisol in the assessment of adrenocortical function in patients with pulmonary tuberculosis.

Adrenocortical function was assessed on the basis of changes in salivary cortisol in patients with pulmonary tuberculosis and the findings compared with those in healthy subjects. A method of direct radioimmunoassay of salivary cortisol was standardized and the sensitivity was 0.8 nmol/l. Cortisol levels in saliva were significantly higher in the patients than in the healthy subjects (P less than 0.001). The diurnal rhythm of cortisol secretion was disturbed in the patients with a significant increase in salivary cortisol beyond 1800 h. While dexamethasone caused an appreciable suppression (87%), stimulation with ACTH (tetracosactrin) resulted in a marked increase in salivary cortisol, the increase being significantly higher in the healthy subjects than in the patients (P less than 0.001). Attempts to classify subjects as positive or negative responders to tetracosactrin based on increases in salivary cortisol in relation to plasma cortisol changes were however not successful, as the agreement between the two methods ranged from 73 to 80 per cent with various criteria used.

Adrenocortical function in patients with pulmonary tuberculosis.

Adrenocortical function was studied in patients with pulmonary tuberculosis and the findings compared with those in healthy subjects. Plasma cortisol levels in newly diagnosed patients were appreciably higher than in the healthy subjects (P less than 0.001). A normal (positive) response to ACTH (tetracosactrin) stimulation was observed in 35 (97%) of 36 healthy subjects, 15 (56%) of 27 newly diagnosed patients with tuberculosis and 5 (42%) of 12 chronic cases (i.e. those who had had the disease for more than 3 years); the difference between the healthy subjects and the two groups of tuberculosis patients was highly significant (P less than 0.001). Dexamethasone caused an appreciable decrease in the plasma cortisol levels of tuberculosis patients. Considering the diurnal variation of cortisol secretion, there was a steady decline in the cortisol levels between 08:00 and 20:00 in the healthy subjects (P = 0.02); in the tuberculosis patients, however, there was a decrease up to 16:00 followed by a significant increase (P = 0.05), and the mean value at 20:00 was similar to that at 08:00.

Acute phase proteins in tuberculous patients.

The serum concentrations of some acute phase proteins were determined on admission, during treatment, at the end of treatment and at 12 months after stopping treatment in 20 patients with pulmonary tuberculosis. Measurements were also made, on admission and at the end of treatment, in 19 patients with abdominal tuberculosis, and 11 children with tuberculous meningitis. All 20 patients with pulmonary TB had quiescent disease by the end of treatment and none had a bacteriological relapse during the follow-up period of 12 months. The response to treatment was considered favourable in 18 of the 19 patients with abdominal TB, and the CSF findings had returned to normal in 9 of 11 patients with TB meningitis. There was a significant decrease with treatment in the concentrations of C-reactive protein, ceruloplasmin, haptoglobin and alpha-1-acid glycoprotein in all 3 groups of patients. While there was an increase in the concentrations of transferrin in patients with pulmonary and abdominal TB, there was a significant decrease in those with TB meningitis; alpha 2-macroglobulin did not appear to function as an acute phase reactant in any of the 3 groups. Amalgamating the findings in all 3 groups of tuberculous patients, the proportions of patients with abnormal values on admission and at the end of treatment were 62% and 14% for C-reactive protein, 78% and 50% for ceruloplasmin, 86% and 26% for haptoglobin and 92% and 6% for alpha 1-acid glycoprotein, respectively.

Induction of rifampicin metabolism during treatment of tuberculous patients with daily and fully intermittent regimens containing the drug.

Self-induction of rifampicin metabolism during daily and intermittent chemotherapy was studied by monitoring the changes in the serum half-life of the drug over a 4-week period in patients with pulmonary tuberculosis. Rifampicin 450 mg was administered to 8 patients who received treatment daily, 7 on thrice-weekly and 7 others on twice-weekly treatment. Serum half-life was computed from concentrations of the drug determined at 3, 4 1/2 and 6 hours after drug administration, on admission and at 1, 2 and 4 weeks after start of treatment. In the daily series, the mean serum half-life decreased from 4.9 hours on admission to 3.6 hours at 1 week (P = 0.02), and treatment beyond this had no further effect. In the thrice-weekly series, maximal induction was observed at the 2nd week, the mean values on admission and at 2 weeks being 5.8 and 3.7 hours, respectively (P less than 0.01). In the twice-weekly series, maximal induction was observed only at the 4th week, the mean values on admission and at 4 weeks being 4.9 and 3.7 hours, respectively (P less than 0.01). Serum activity of gamma glutamyl transferase was not found to be a suitable in vivo marker to monitor induction of the hepatic microsomal enzymes as no significant changes were observed in the activity of this enzyme in any of the 3 series during the 4-week period.

Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin.

The effect of daily administration of rifampin on the direct conversion of isoniazid to isonicotinic acid and hydrazine by isoniazid hydrolase was investigated in 6 slow and 8 rapid acetylators of isoniazid. The proportion of isoniazid metabolized through this direct pathway during the first 6 h was estimated from the ratio of total isonicotinic acid formed to acetylisoniazid in urine after administration of isoniazid or acetylisoniazid. In slow acetylators, this proportion was approximately 3% when isoniazid alone was administered and approximately 6% during the maximal phase of induction caused by the daily administration of rifampin in addition to isoniazid (p less than 0.001); in rapid acetylators, the proportions were considerably less (less than 1 and 2.5%, respectively), suggesting that isoniazid hydrolase was induced by rifampin. The increased formation of hydrazine, a known hepatotoxic agent in animals, could explain the substantially higher frequency of the occurrence of hepatitis in slow than in rapid acetylators among tuberculous patients treated with daily rifampin and isoniazid.