In closely monitored patients, adherence in the first month predicts completion of therapy for latent tuberculosis infection.

BACKGROUND: Current therapy for latent TB infection (LTBI) is long, and requires close follow-up. This results in sub-optimal adherence-the major reason for failure of therapy. METHODS: In an open label randomised trial comparing 4 months of rifampicin with 9 months of isoniazid, the proportion and regularity of doses taken, measured with an electronic monitoring system (MEMS), and provider estimates of adherence in the first month of therapy, were assessed as predictors of treatment completion. RESULTS: Of 104 patients analysed, 86 took more than 80% of doses within the expected interval, 11 took more than 80% of doses but over a longer time interval than usually allowed, and seven did not complete treatment. Treatment completion was associated with the number of doses taken, and the variability of intervals between doses during the first month of treatment. CONCLUSIONS: Adherence in the first month, based on the number of doses and variability of times when taken, could be useful to predict completion of LTBI therapy. Interventions could be targeted to patients with suboptimal adherence in the first month.

Binding of indapamide to serum proteins and erythrocytes.

The binding of indapamide to isolated serum proteins and erythrocytes was studied in order to understand its blood distribution. In serum, indapamide was mainly bound to alpha 1-acid glycoprotein with a high affinity (K = 73.4/mM), and to albumin and lipoproteins. Indapamide was bound to erythrocytes via a saturable process with a high affinity (K = 385/mM and N = 57 microM for an hematocrit value of 0.48), and erythrocytes were the main binding component in blood (more than 80% of indapamide was associated to erythrocytes in blood). The binding to serum proteins affected indapamide distribution in blood, and alpha 1-acid glycoprotein was shown to be the more effective protein in decreasing the amount of indapamide associated to erythrocytes.

Structure-activity relationships as a response to the pharmacological differences in beta-receptor ligands.

With a few notable exceptions, beta-receptor ligands (agonists and antagonists) belong to the aryl- or heteroaryl-ethanolamine series and to the aryl- or heteroaryl-oxypropanolamine series. Structure-activity relationships for beta-adrenergic agonists show that a secondary amine in the phenylethanolamine side chain ending is essential for receptor stimulation. The 3,4-dihydroxyphenyl groups may be replaced by "phenol equivalents" (-CH2OH, -NHCONH2, -CHOH, -NHSO2CH3). In contrast, substitution at carbon alpha of the phenyl-ethanolamine side chain decreases or suppresses beta-adrenergic activity. The general requirements for beta-adrenergic blocking activity in the aryl- or heteroaryl-oxypropanolamine are as follows: (1) the potency of beta-blockade is conferred by a branched alkyl group (isopropyl or tert-butyl) grafted on the terminal amino N, and by the nature and position of a substituent on the aromatic ring: ortho-substituted compounds (especially when they have an hetero-atom in alpha) are the most potent ones. (2) The cardioselectivity is improved by the attachment of 3,4-dimethoxyphenylethyl,4-amide-substituted phenoxyethyl or acylamino-alkyl moieties to the terminal amino N of the side chain. Para substitution on the aromatic ring (particularly 4-acylamido substitution) has also yielded cardioselective drugs. Finally, the beta 1-selectivity is strongly and negatively correlated with lipophilicity. (3) Intrinsic sympathomimetic activity can be modulated by aromatic nucleus variations, particularly by hydroxyl-equivalents (electron withdrawing groups) on meta- and para-positions (3,4-substitutions).

Tertatolol in chronic renal failure. A pharmacokinetic study.

Pharmacokinetics of tertatolol were investigated in 22 hypertensive patients (12 men and 10 women; mean age +/- SD: 52.6 +/- 12.3 years) with chronic renal failure defined by a mean creatinine clearance (Clcr) of 24.6 +/- 15.9 mL/min/1.73 m2 (range: 6.2 to 68.7). A daily single dose of 5 mg tertatolol was administered orally for 4 weeks, except in the 72 h following the first administration. Plasma samples and urine collections were carried out over 72 h after the first (D0) and the last dose (D27). After the first administration, tertatolol was rapidly absorbed (time to peak concentration: 1.2 +/- 0.7 h) and peak concentration was 160 +/- 80 ng/mL. Plasma concentrations decreased following a biphasic curve, with two half-lives of 2.5 +/- 1.1 and 17.0 +/- 8.5 h, respectively. These parameters were not modified by repeated administration of tertatolol and did not significantly correlate with Clcr either at D0 or at D27. Plasma levels were stable along the study with similar areas under plasma curves following the first and the last dose (P = NS). In addition, plasma levels extrapolated from first dose data did not significantly differ from those observed during repeated dosage. Plasma levels of the 4-OH metabolite which possesses a beta-blocking activity were low, inconstantly detectable, not related to the degree of renal impairment, and no accumulation occurred after chronic dosage. Renal excretion of tertatolol and 4-OH tertatolol was significantly increased by repeated administration (P less than .01) and correlated well with Clcr either at D0 or at D27. Four week treatment was well tolerated and significantly improved Clcr (+6.5%, P less than .02). In conclusion, tertatolol was well tolerated and did not accumulate in patients with renal failure of various degrees. The usual daily single dose of 5 mg may be kept unchanged whatever the degree of renal impairment.

Stereoselective binding of tertatolol and of 4-hydroxytertatolol to human plasma proteins.

The binding of racemic tertatolol and 4-hydroxytertatolol and of their enantiomers was compared in alpha 1-acid glycoprotein and albumin solutions. The binding rate of S(-)tertatolol to alpha 1-acid glycoprotein was much greater than that of R(+)tertatolol, the binding of the racemate being intermediate. It was the reverse for the binding to albumin, although the differences were slight. The binding of 4-hydroxytertatolol racemate and enantiomers was very low as compared to the binding of tertatolol, and there were no statistically significant differences in the binding of the 4-hydroxytertatolol enantiomers to either alpha 1-acid glycoprotein or albumin.

Factors associated with compliance in treatment of tuberculosis.

The most important cause of failure of antituberculosis therapy is that the patient does not take the medication as prescribed. To assess this problem, a retrospective review was conducted, using medical and nursing records, of adult patients treated at the tuberculosis clinic of the Montreal Chest Hospital in 1987-1988. In all, 352 patients were identified, of whom 59% were judged to have completed therapy. Completion of therapy was recorded in 92% of those with culture-positive disease, 76% of those with active but culture-negative disease and 54% among the 300 prescribed preventive therapy (P < 0.001). Compliance with preventive therapy was highest among those who had been in contact with an active case, and lowest among those identified through a workforce screening survey (P < 0.01). At the time of the first follow-up visit, patients identified to have suboptimal compliance were more likely to fail to complete therapy (P < 0.001). Compliance was higher among those initially hospitalized, those assessed to have better understanding (P < 0.05), those prescribed 6-9 rather than 12 months of therapy (P < 0.01), and those who returned for follow-up within 4 weeks of initiation of therapy (P < 0.01). Compliance could be improved by enhancing patient understanding, closer follow-up, and shorter therapy, particularly for those at lower risk of reactivation. As well, additional compliance enhancing interventions can be targeted to those patients with suboptimal compliance who can be accurately identified early in the course of therapy.

The effect of antacid and aspirin on the bioavailability of isofezolac in man.

Bioavailability of isofezolac, a new non-steroid anti-inflammatory drug, with or without antacid and aspirin coadministration was investigated in 6 healthy volunteer. Each subject received, in random order, isofezolac (50 mg) alone or associated with aspirin (1 g) or phosphalugel (11 g aluminum phosphate). Isofezolac plasma concentrations were salicylic acid by spectrofluorimetric method. Plasma protein binding of drugs was studied by dialysis equilibrium method. During the absorption phase isofezolac plasma levels were slightly decreased in association with isofezolac-aspirin, but bioavailability of isofezolac was not modified. Time to peak of isofezolac was comparable in the three treatments, as was the case with plasma half-lives. Aluminum phosphate did not modify isofezolac availability. Plasma protein binding of isofezolac was very high (99%) and did not influence salicylic acid binding.

The booster effect in two-step tuberculin testing among young adults in Montreal.

OBJECTIVES: No consensus exists regarding the definition and interpretation of a significant boosting reaction after sequential tuberculin testing. The booster phenomenon is thought to represent remote tuberculous infection where tuberculin reactivity has waned, but it has also been described among persons with previous exposure to other mycobacteria or Bacille Calmette-Guérin (BCG) vaccine. We studied the factors affecting the booster phenomenon among Canadian-born young adults to determine the definition that would maximize sensitivity and specificity of a positive booster reaction in these persons. DESIGN: Point-prevalence survey of initial tuberculin reactions and response to repeated tuberculin testing after 1 to 4 weeks. SETTING: Community-based study of all students entering health professional training programs at six post-secondary institutions. MEASUREMENTS: In 1989, 1990, and 1991, students completed self-administered questionnaires, underwent two-step tuberculin testing with purified protein derivative-tuberculin (PPD-T), and had their childhood BCG vaccination status verified. In 1991, students were also tested with purified protein derivative-Battey (PPD-B) (for Mycobacterium intracellulare). RESULTS: Overall, 74 students (5.2%) had positive booster reactions, which were significantly associated with older age (P < 0.001), larger initial tuberculin reactions (P < 0.001), previous BCG vaccination (P < 0.001), older age when vaccinated (P < 0.02), longer interval from vaccination to testing (P < 0.01), and sensitivity to PPD-B (P < 0.001). Boosting was not associated with the number of BCG vaccinations, sex, or risk factors for tuberculous infection. The pattern, mean, and mode of the frequency distributions of booster reactions among those with BCG vaccination and sensitivity to PPD-B were similar to those with assumed tuberculous infection. CONCLUSIONS: In young adults, booster reactions due to previous tuberculous infection are uncommon and cannot be distinguished from false-positive reactions due to past exposure to other mycobacteria.

Interaction of tertatolol with rifampicin and ranitidine pharmacokinetics and antihypertensive activity.

The interaction of the new beta-receptor antagonist tertatolol with rifampicin and ranitidine was investigated in ten patients with arterial hypertension (WHO stages I-II). They were treated orally with a single dose of tertatolol 5 mg alone and, after randomized allocation, with ranitidine 150 mg twice daily or rifampicin 600 mg once daily for 1 week each (tertatolol 5 mg was concurrently administered on the seventh day of the treatment phases). Following each therapeutic phase, circadian blood pressure values as well as kinetic parameters were obtained. On treatment with tertatolol alone, maximum plasma concentrations were 123.7 +/- 32.4 ng/ml (mean +/- SD) and were reached after 1.95 +/- 1.77 hours. The tertatolol elimination half-life was 9.0 +/- 7.1 hours. Coadministration of ranitidine did not significantly alter the kinetic parameters and antihypertensive effect of tertatolol. Rifampicin, however, decreased the maximum plasma levels of tertatolol to 80.6 +/- 18.5 ng/ml and markedly shortened the elimination half-life to 3.4 +/- 2.6 hours (p less than 0.01 compared with tertatolol alone). Urinary excretion of parent tertatolol and unchanged 4-hydroxy tertatolol was decreased under rifampicin, and a tendency to a reduction in the effect of tertatolol on circadian blood pressure values was observed. Twenty-four hours after administration, the heart rate in those patients on tertatolol alone (68 +/- 6 beats/min) was lower than in those on tertatolol plus rifampicin (74 +/- 7 beats/min). In conclusion, a pronounced pharmacokinetic interaction, with a limited consequence in terms of pharmacodynamic effects, was found in the present study when tertatolol was administered with rifampicin, but not with ranitidine.

Hemodynamic and pharmacokinetic study of propranolol and atenolol in cirrhosis patients.

The pharmacokinetic properties of propranolol and atenolol were evaluated both in 9 patients with cirrhosis and in 12 healthy subjects. The hemodynamic effects of the drugs were evaluated separately in the cirrhotic patients. Propranolol and atenolol significantly decreased wedged hepatic venous pressure and cardiac output in cirrhotic patients. Propranolol Cmax, tmax and AUC were significantly increased and plasma half-life was significantly prolonged in cirrhotic patients. In contrast, the corresponding pharmacokinetic values of atenolol were not significantly different in cirrhotic patients and in healthy subjects.

Variation in serum binding of tertatolol mediated by disease-induced modification of alpha-acid glycoprotein concentration.

The serum concentrations of alpha 1-acid glycoprotein (AAG), albumin (HSA) and non-esterified fatty acids, and the serum binding of tertatolol were measured in four groups of individuals: healthy control subjects (n = 24), and patients with inflammation (n = 28), and hepatic (n = 20) and renal (n = 27) insufficiency. Serum binding of tertatolol was increased in patients with inflammation (94.6%), decreased in patients with hepatic insufficiency (88.8%) and it was unchanged in patients with renal insufficiency (92.8%) as compared to controls (92.7%). Multivariate analysis indicated that the changes were mainly related to concomitant changes in AAG concentration, which could account for 57% of intersubject variability in the bound/free ratio, and to a lesser extent in HSA, which accounted for only 4% of the variability in the binding. The data show that the free fraction of the basic drug tertatolol in serum is affected by pathological conditions that cause changes in AAG concentration.

Clinical pharmacology and pharmacokinetics of prizidilol in hypertensive patients.

We evaluated the clinical pharmacology of prizidilol, a compound with vasodilator and beta-blocking properties, in 12 hypertensive patients with normal renal function. A single dose of 600 mg prizidilol was given orally and blood samples were withdrawn at intervals for high-performance liquid chromatography assay. Blood pressure and heart rate were recorded every hour in supine and standing positions. A nitroglycerin test was performed at the 2nd, 4th, and 6th h for evaluation of cardiac beta-adrenoceptor activity. Results were compared with those after placebo intake the day before. Prizidilol produced a significant decrease in supine systolic and diastolic blood pressures (-22 and -24%, respectively), with a maximum effect 5 h after intake. Blood pressure changes were not different in slow and fast acetylators, suggesting that the acetylated metabolites were active. Heart rate decreased slightly but significantly during the first 2 h, but was similar to control levels thereafter. However, the nitroglycerin test data suggested a prolonged blockade of beta-adrenoceptor activity. Pharmacokinetics showed large variations among patients; several peaks were observed on the curves, indicating irregular absorption. The apparent plasma elimination half-life was 4.4 +/- 0.4 h. Total body clearance was high despite a very low renal clearance, indicating that the drug was eliminated mainly by the metabolic or intestinal route. No significant correlations were found among plasma concentration, blood pressure, and heart rate. In conclusion, prizidilol is a potent antihypertensive drug having equilibrated vasodilator and beta-blocking effects. The pharmacokinetic data suggest a first-pass effect and elimination by extra-renal routes.

Hemodynamic and pharmacokinetic study of tertatolol in patients with alcoholic cirrhosis and portal hypertension.

Tertatolol, a recently developed beta 1-beta 2-blocker has two advantages: it does not induce withdrawal syndrome after abrupt cessation, and it preserves renal function. It has been suggested that the kinetics of tertatolol in patients with hepatic dysfunction are altered. Therefore, the hemodynamic effects and pharmacokinetics following the acute administration of tertatolol were studied in cirrhotic patients with portal hypertension. Systemic, splanchnic and renal hemodynamics were evaluated before and 30 min after the simultaneous administration of 2.5 mg tertatolol p.o. and 1.25 mg deuterated tertatolol i.v. in 10 cirrhotic patients with esophageal varices. The pharmacokinetics of tertatolol were evaluated over a 4-day period. Tertatolol significantly decreased heart rate (-22 +/- 10%), cardiac output (-26 +/- 8%), and hepatic blood flow (-27 +/- 23%). The hepatic venous pressure gradient decreased from 15.7 +/- 5.0 to 12.9 +/- 4.0 mmHg (-17 +/- 13%, P < 0.01). Three out of 10 patients were non-responders to tertatolol. Renal blood flow (-9 +/- 28%) and intrinsic hepatic clearance of indocyanin green (-9 +/- 25%) were not significantly modified. The duration of effective beta-blockade was far less than 12 h. Tertatolol was rapidly absorbed with a Cmax of 70 +/- 51 micrograms/l at a peak time of 0.75 +/- 0.26 h. In comparison with healthy volunteers referred to in literature sources, plasma clearance was reduced to 49 +/- 28 ml/min, bioavailability was increased to 72 +/- 20%, and the volume of distribution was increased to 50 +/- 34 l, probably due, in part, to a weaker protein binding -85%--effect.(ABSTRACT TRUNCATED AT 250 WORDS)