Short-term effects of withdrawing angiotensin converting enzyme inhibitor therapy on home self-measured blood pressure in hypertensive patients.

The aim of this study was to compare blood pressure rise after interruption of two angiotensin converting enzyme (ACE) inhibitors in hypertensive patients. After a 2-week placebo run-in period, hypertensive patients were treated with either trandolapril 2 mg once daily or perindopril 4 mg once daily for 4 weeks in a double-blind design. A placebo was then administered for 1 week. Three periods of 1-week home self-measured blood pressure (SMBP) were programmed: end of placebo run-in period, end of treatment period, and final withdrawal placebo period. Every day, three consecutive measurements were requested both in the evening and in the morning. Individual reversion to baseline BP level was studied in the subgroup of patients responding to therapy (evening diastolic SMBP decrease > or =6 mm Hg). The ratio (R) of mean post-drug DBP lowering (residual effect) over evening on-drug DBP lowering (full effect) was used to study reversion to baseline. Patients exhibiting a lower value than the median of this ratio were called Reverters, whereas others were called Nonreverters. One hundred-nineteen patients entered the analysis. During the treatment period, mean SMBP decreased significantly, from 150 +/- 14/97 +/- 7 mm Hg to 139 +/- 15/91 +/- 9 mm Hg (all P < .001). The on-drug BP level was similar in the evening in the two treatment groups. However, both systolic and diastolic morning SMBP levels were significantly lower in the trandolapril group. After drug discontinuation, the mean BP level significantly rose to 144 +/- 14/94 +/- 9 mm Hg (all P = .01) but remained lower than the baseline BP values (P = .003 for SBP and P = .002 for DBP). The post-drug BP level was significantly lower in the trandolapril group than in the perindopril group. Seventy-four patients were responders to therapy. In this subgroup, the median of the R ratio used to analyze reversion to baseline after drug discontinuation was 44%. Nonreverters were characterized by a sustained on-drug BP decrease, compared to Reverters. We therefore conclude that ACE inhibitor treatment withdrawal is accompanied by a rapid rise in BP (within 48 h), followed by a 5-day BP plateau that is lower than the initial level. Reverters to baseline after drug discontinuation were more likely to be insufficiently controlled during therapy, particularly in the morning. The longer duration of action of trandolapril was associated with a lower BP level during both the morning during the active treatment phase and the 1-week posttreatment phase.

Lysosomal alterations induced in cultured rat fibroblasts by long-term exposure to low concentrations of azithromycin.

Computer-aided simulations suggest that the doses and schedules of administration of azithromycin proposed in treatment and prophylaxis of Mycobacterium avium complex (MAC) in AIDS patients will result in drug concentrations in serum and extracellular fluids remaining for sustained periods of time in the 0.03-0.1 mg/L range. We exposed cultured rat embryo fibroblasts to these concentrations (and multiples up to 20 mg/L) for up to 16 days. Electron microscopy showed that after 7 days' incubation in 0.03 mg/L azithromycin, there was conspicuous accumulation of osmiophilic, lamellar structures (myeloid bodies) in lysosomes, suggesting the onset of a phospholipidosis. Assay of total cell phospholipids and cholesterol showed significant increases in cells exposed to > or = 1 to 5 mg/L of azithromycin in association with hyperactivity of the lysosomal enzyme cathepsin B. The data suggest that azithromycin, at extracellular concentrations pertinent to its use for MAC treatment, and perhaps also prophylaxis, causes limited morphological alterations of the lysosomes in cultured cells which are of the same nature as those developing rapidly and extensively at higher concentrations.

Prednisolone concentrations in cerebrospinal fluid after oral prednisone. Preliminary data.

Penetration of prednisolone across the blood-brain barrier was studied in 17 patients (ten women and seven men) with a mean age of 64 +/- 17 years admitted for nerve root pain warranting a lumbar puncture. One blood sample and one cerebrospinal fluid sample were obtained concomitantly from each patient, two hours (n = 7), four hours (n = 5) or six hours (n = 5) after an oral dose of 40 mg of prednisone. Prednisolone was assayed in all samples using high performance liquid chromatography and its binding to plasma proteins was determined using ultrafiltration. Total plasma prednisolone levels declined over time from 597 +/- 174 ng/ml two hours post-dose to 422 +/- 106 ng/ml four hours post-dose and 250 +/- 85 ng/ml six hours post-dose. Plasma levels of free prednisolone were 95 +/- 21 ng/ml, 59 +/- 17 ng/ml, and 18 +/- 14 ng/ml, respectively, at the same time points. Prednisolone was detectable in all cerebrospinal fluid samples, in levels of 14 +/- 2 ng/ml after two hours, 29 +/- 9 ng/ml after four hours and 17 +/- 7 ng/ml after six hours. These data demonstrate that equilibration of plasma and cerebrospinal fluid levels is achieved after six hours.

Pharmacokinetics of tiaprofenic acid in infants after a single oral dose.

Ten healthy infants (15.2 +/- 10.6 months old, range 6-35) anesthetized for minor surgery were given a single oral dose (3 mg x kg-1) of tiaprofenic acid (TA). Seven venous blood samples and 0-12 h urine were collected. TA concentrations in plasma and urine were measured by HPLC. Within the whole group the mean +/- SD kinetic parameters were: Cmax: 10.55 +/- 3.31 mg x l-1, Tmax: 1.73 +/- 0.87 h, AUC0-1 32.53 +/- 4.42 mg x l-1 x h, AUC0-infinity 35.33 +/- 4.73 mg x l-1 x h, t1/2 1.82 +/- 0.48 h, Cl/F: 0.09 +/- 0.01 l x h-1 x kg-1, VZ/F: 0.23 +/- 0.08 l x kg-1. Renal clearance was 0.030 +/- 0.009 l x h-1 x kg-1. 32% of the TA dose was recovered in urine, 60% of which was conjugated. AUC0-8h increased significantly with age. The TA kinetic parameters were close to those in 3 to 11-year-old children. The present study suggests slight differences in the TA kinetics between infants and adults. However, the lack of an evidenced direct relationship between plasma TA concentration and either efficacy or tolerance suggests that the TA dose regimen in infants may not have to be different from that in adults.

Pharmacokinetics of thiocolchicoside in humans using a specific radioimmunoassay.

The myorelaxant thiocolchicoside (TC), an analogue of colchicine (COL), was assayed in plasma and urine by a radioimmunoassay (RIA) using a cross-reacting COL-specific polyclonal antibody. Cross-reactivity was 56% for TC, giving a limit of quantification of 0.5 ng/ml and a linear response from 0.5 to 100 ng/ml. Specificity was checked by cross-reactivity studies with COL analogues and by using liquid chromatography and RIA in tandem on urine samples. Two immunoreactive peaks were detected, but the nonspecific peak represented < 2% of the total urine concentration of TC. Pharmacokinetics of TC following infusion of 4 mg in two subjects revealed a moderate distribution (Vss from 31 to 35 L) and mainly extrarenal elimination (75% of the total body clearance). Terminal half-lives ranged from 2.4 to 2.7 h in plasma and from 3.2 to 3.7 h in urine.