Colchicine clearance is impaired in alcoholic cirrhosis

Colchicine may have benefit in primary biliary cirrhosis and alcoholic liver disease. It is currently used in patients with impaired liver function, yet little is known about its elimination in such patients. Colchicine clearance in the rat is significantly impaired in various models of liver disease. To study this in human beings, colchicine pharmacokinetics were compared in normal subjects and patients with alcoholic cirrhosis. Colchicine clearance was impaired in the cirrhotic patients. Normal subjects had a mean clearance of 10.65 +/- 1.82 ml/min.kg, whereas cirrhotic patients had a mean clearance of 4.22 +/- 0.45 ml/min.kg (p less than 0.01). The half-life was 57.4 +/- 14.2 min in control subjects vs. 114.4 +/- 19.7 min in cirrhotic patients (p = 0.054). Volume of distribution was not different in the two groups (0.718 +/- 0.1 L/kg in control subjects; 0.716 +/- 0.158 L/kg in cirrhotic patients, p greater than 0.99). No correlation was seen between colchicine clearance and bilirubin, albumin, prothrombin time or Child-Pugh classification, but this may be the result of the small number of patients studied. Based on the values measured, it is estimated that colchicine steady state would change from an average 1.12 ng/ml in normal individuals to 2.82 ng/ml in the cirrhotic patients if 0.6 mg were taken every 12 hr. It is unknown whether this change would be clinically significant. These data show that cirrhosis impairs colchicine clearance and demonstrates that the liver is a major route of colchicine elimination.     

Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis

Hepatic insulin extraction is difficult to measure in humans; as a result, the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001), which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose, the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min), suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients, both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However, with oral glucose the rise in serum C-peptide concentration was relatively delayed, and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Theophylline metabolism in patients with hepatosplenic mansoniasis and cirrhosis.

The pharmacokinetics of theophylline were studied in 12 patients with hepatosplenic mansoniasis, 14 patients with cirrhosis and 16 normal controls. Following a single intravenous dose of aminophylline volumes of distribution, serum half-lives and body clearances were determined. Volumes of distribution of theophylline in patients with schistosomiasis (mean 0.624 l/kg) did not differ from cirrhotic patients (mean 0.616 l/kg) or normal controls (mean 0.593 l/kg). Cirrhotic patients had a prolonged half-life compared to normal subjects (mean 22.1 vs. 9.9 h), while patients with schistosomiasis did not substantially differ from normal controls (15.8 vs. 9.9 h). Body clearance in patients with schistosomiasis was similar to controls (34.02 vs. 49.20 ml/h per kg) but decreased (29.24 ml/h per kg) in patients with cirrhosis. Individual analysis of the group with schistosomiasis disclosed three patients with reduced theophylline elimination. No relationship was found between laboratory tests of liver function and the pharmacokinetics of theophylline in any group. The administration of theophylline to patients with hepatosplenic schistosomiasis, although less dangerous than in cirrhosis, must be closely followed.     

Kinetics of theophylline; variability and effect of arterial pH in chronic obstructive lung disease.

The pharmacokinetic behavior of theophylline was determined in 12 patients during an acute exacerbation of their chronic obstructive pulmonary disease. A 5.6 mg/kg loading dose of aminophylilne was administered, followed three hours later by a 0.9 mg/kg/hr continuous infusion. The loading dose increased the serum theophylline level an average of only 5.77 microgram/ml. After the loading dose, only five patients had levels greater than 10 microgram/ml. Mean initial drug clearance was 0.77 L/kg/hr, half-life 9.1 hr, and apparent volume of drug distribution .887 L/kg. Wide inter- and intrapatient pharmacokinetic variability was observed. The variability of drug distribution was inversely correlated with the arterial pH. These patients with chronic obstructive pulmonary disease appeared to require more theophylline when acidemic than when alkalemic to achieve similar serum theophylline concentrations.     

Serum levels and bronchodilatation after intravenous administration of theophylline in asthmatic patients

Forced expiratory volume in the first second (FEV1) and serum theophylline levels were measured comparatively in 26 patients with stable bronchial asthma after a 240 mg theophylline infusion. The mean (+/- s.e.m.) elimination half-life and clearance of theophylline were 6.37 +/- 2.03 hours and 0.78 +/- 0.31 ml/min/kg respectively. A bronchodilator response (more than 20% increase in FEV1) was obtained in 17 patients whose pretreatment FEV1 was less than 30% of predicted normal values. No significant bronchodilator response was obtained in the other patients. There was no relationship in responders between changes in FEV1 and simultaneous serum theophylline levels. Maximal ventilatory response was apparent 1 to 2 hours only after the theophylline peak concentration.     

A comparison between antipyrine and aminopyrine blood clearances.

The purpose of this study was to investigate the relationship between two quantitative liver functions, that is, antipyrine blood clearance and aminopyrine blood clearance, in normal subjects and in patients with liver cirrhosis. The mean blood clearances of antipyrine and aminopyrine in cirrhotic patients (0.220 +/- 0.085 ml/min/kg and 1.13 +/- 0.56 ml/min/kg; n = 64) was 50% and 38% of that of normal subjects (0.440 +/- 0.110 ml/min/kg and 2.95 +/- 0.59 ml/min/kg; n = 11). While no significant correlation was demonstrated between these two values in normal subjects (n = 11, r = -0.107, p greater than 0.10), a strong positive correlation was observed between antipyrine and aminopyrine blood clearances in cirrhotic patients (n = 64, r = 0.846, p less than 0.001). These results suggest that both antipyrine and aminopyrine blood clearances may be valuable indicators for assessing the total hepatic functioning mass in cirrhotics.     

Parathyroid hormone status and renal responsiveness in familial hypophosphatemic rickets.

Basal serum and urinary biochemical parameters and their response to PTH or calcium infusion were examined in 14 untreated patients with familial hypophosphatemic rickets (FHR) from 5 kindreds and 9 normal control subjects after a period of dietary equilibration. FHR subjects exhibited significantly elevated basal serum iPTH levels (FHR: 11.4 +/- 0.8, controls: 5.1 +/- 0.5 ng/ml, P less than 0.001) and urinary cAMP excretion (FHR: 7.83 +/- 0.81, controls: 3.78 +/- 0.46 nmol/mg creatinine P less than 0.001). In response to PTH infusion (6 units/kg over 4 hours) FHR subjects exhibited a mean 34% decrease in TRP and a 22-fold increase in cAMP excretion, both comparable to the control response. Calcium infusion (10 mg/kg over 1 h) rapidly suppressed serum iPTH and urinary cAMP values in FHR subjects. However, TRP remained inappropriately low for the level of serum phosphate. Basal and post-calcium infusion serum iPTH levels correlated positively with urinary cAMP in FHR subjects and controls. Pre- and post-calcium infusion iPTH levels correlated with serum calcium in FHR subjects. Mean Salivary phosphate concentration was significantly reduced in FHR subjects (FHR: 12.68 +/- 0.87, controls: 22.47 +/- 2.16 mg/100 ml, P less than 0.001). However, calculated salivary phosphate clearance rates were similar in FHR and control subjects. PTH or calcium infusion did not significantly alter salivary phosphate concentration or clearance rates in either patients or controls. We concluded that untreated FHR patients exhibit a state of mild secondary hyperparathyroidism and an at least normal renal phosphaturic response to PTH. In addition, there is no evidence for increased salivary phosphate excretion in FHR.     

Bronchodilation from intravenous theophylline in patients with cystic fibrosis: results of a blinded placebo-controlled crossover clinical trial

Most patients with cystic fibrosis (CF) eventually develop chronic obstructive pulmonary disease and theoretically could benefit from theophylline therapy. The purpose of this study was to investigate the pharmacologic response to intravenous theophylline by pulmonary function tests (PFT) and the theophylline pharmacokinetics in patients with CF. A randomized, double-blind, placebo-controlled, crossover trial was conducted in 10 ambulant patients with CF (5 females, 5 males), aged 11 to 21 years. Each patient received an intravenous dose of theophylline and normal saline over 1/2 hour on consecutive days. Spirometry and whole-body plethysmography were performed at baseline, 1, 3, 5, and 7 h after the theophylline dose, and 10 blood samples were collected over 9 h on both study days. The percent change of PFT from the baseline was recorded. Analysis of variance for balanced two-period crossover design was used to evaluate the effectiveness of theophylline therapy. The serum concentration (Conc.) vs. time data were fitted using nonlinear least-squares regression analysis. The theophylline dose administered was 7.9 +/- 0.4 (mean +/- SD) mg/kg, which produced a maximal Conc. (Cmax) of 14.6 +/- 2.7 microgram/ml. The half-life (T1/2), volume of distribution (Vd), and total body clearance (TBC) were 4.9 +/- 1.9 h, 537 +/- 124 mL/kg, and 80 +/- 16 ml/h/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of repirinast, an anti-allergic drug, on theophylline pharmacokinetics in patients with bronchial asthma]

In order to clarify whether repirinast, an inhibitor of chemical mediator release, could influence the pharmacokinetics of theophylline, a loading test using intravenous injection of aminophylline was performed in 10 subjects with bronchial asthma before and after treatment with 300 mg/day of repirinast. There was no significant difference in theophylline half-life before treatment (7.25 +/- 2.43 hr) and after treatment (7.82 +/- 3.35 hr). There was no significant difference in theophylline clearance before treatment (0.047 +/- 0.018 L/kg/hr) and after treatment (0.047 +/- 0.020 L/kg/hr). These results demonstrated that repirinast does not modify theophylline pharmacokinetics significantly.     

Enhancement of theophylline clearance by oral albuterol.

The possible effect of albuterol on theophylline clearance was studied in ten adult volunteers. Subjects received intravenous aminophylline loading dose (5.6 mg/kg), with oral albuterol (4 mg every 6 h), or inhaled albuterol (200 micrograms every 6 h), or alone (control). Theophylline levels were determined for 12-h periods. Theophylline clearance and elimination t 1/2 were calculated. Theophylline clearance was significantly higher when given with oral albuterol, in comparison with control (0.83 +/- 0.05 vs 0.73 +/- 0.06 ml/kg/min, p less than 0.02). Theophylline elimination t 1/2 was shorter with the coadministration of oral albuterol, compared with control (7.1 +/- 0.3 vs. 8.1 +/- 0.6 h, p less than 0.02). These alterations in theophylline clearance and elimination were greater in subjects who had lower control theophylline clearance. Theophylline clearance and elimination t 1/2 recorded with inhaled albuterol were not significantly different from control values. Coadministration of oral albuterol and theophylline resulted in enhancement of theophylline clearance, particularly in subjects with initially slow theophylline elimination. Such patients may require theophylline dosage adjustment as a result of this interaction.     

Theophylline toxicity in a patient with status asthmaticus]

A 70-year-old woman was hospitalized for status asthmaticus. The level of CRP was high and chest roentgenogram showed infiltrative shadows in the left middle lung field. Artificial respiration and continuous infusion of methylprednisolone and aminophylline 750 mg/24 hr were performed. Eight hours after admission, seizures suddenly occurred. At this time, brain CT showed no abnormal findings. The seizures were thought to be induced by theophylline toxicity, since serum theophylline concentration was high at 69.9 micrograms/ml. Because theophylline clearance of the patient in a clinically stable condition was normal, it was speculated that theophylline clearance was reduced during status asthmaticus. It is thought that this rare case of theophylline toxicity occurred due to reduction of theophylline clearance during status asthmaticus associated with pneumonia.     

Bioavailability and elimination of digitoxin in patients with hepatorenal insufficiency

Following administration of digitoxin, 1 mg intravenously, the pharmacokinetics of this glycoside were studied in eight healthy volunteers and in eight patients with hepatorenal insufficiency (mean creatinine clearance 19.6 +/- 2.9 ml/min; antipyrine clearance 25.6 +/- 3.2 ml/min; means +/- SEM). Liver cirrhosis of the patients was confirmed by liver biopsy. Plasma protein binding of digitoxin (means +/- SEM) was 95.1 +/- 0.7% in the patients and 95.6 +/- 1.2% in the volunteers (NS). Total body clearance of digitoxin was 0.0530 +/- 0.0040 ml/min/kg of body weight in the patients and 0.0547 +/- 0.0043 ml/min/kg of body weight in the healthy subjects (NS). When elimination half-lives of the patients and the volunteers were compared, there was also no significant difference (7.0 +/- 0.77 days in the patient group and 7.8 +/- 0.8 days in the volunteers). Our data concerning digitoxin kinetics in patients with hepatorenal insufficiency do not indicate an accumulation of the drug in these patients.     

Bioavailability and pharmacological effects of two slow-release theophylline preparations: intrasubject tablet-to-tablet variability

The bioavailability and pharmacological effects of slow-release preparations oxtriphylline (Choledyl SA) and anhydrous theophylline (Theo-Dur) were compared in a single-blind, randomized, crossover study in 10 normal men. Subjects were administered three doses from the same lot of each preparation at weekly intervals. Plasma concentration of theophylline was measured at timed intervals for 33 hr by high-pressure liquid chromatography. Pharmacokinetic analysis showed that Choledyl SA peaked earlier (4.7 +/- 1.0 hr) than did Theo-Dur (9.6 +/- 8.2 hr), with higher peak concentrations, 6.4 +/- 0.7 micrograms/ml versus 4.1 +/- 0.5 micrograms/ml for Theo-Dur, and greater are under the curve, 102.4 +/- 15.7 micrograms/ml X hr versus 75.3 +/- 9.1 micrograms/ml X hr for Theo-Dur. 88% absorption was achieved in 6 hr with Choledyl SA versus 10 hr with Theo-Dur. Wide intra- and intersubject variations were observed with both preparations. Likewise, variable effects on systolic and diastolic blood pressure and pulse were observed with both preparations. The effects of both theophylline preparations on urine flow, osmolar clearance, and glomerular filtration rate were compared. Osmotic diuresis without detectable changes in the glomerular filtration rate was observed in subjects who received Choledyl SA versus Theo-Dur. Differences in the bioavailability and renal effects were observed between Choledyl SA and Theo-Dur. Wide intra- and intersubject tablet-to-tablet variability were observed with both preparations.     

Glucagon metabolism in normal subjects and in cirrhotic patients before and after portasystemic venous shunt surgery

The effect of portasystemic shunt surgery on basal immunoreactive glucagon (IRG) levels, metabolic clearance rate (MCR) and t 1/2 for glucagon decay, and basal systemic delivery rate (BSDR) of glucagon was investigated in paired studies in ten cirrhotic subjects. The degree of hepatocellular dysfunction and extent of portasystemic venous shunting was also recorded. Basal IRG levels were highest in the post-shunt (mean +/- SEM, 382 +/- 73 pg/ml) as compared to the pre-shunt (213 +/- 27 pg/ml; P less than 0.05) cirrhotic and control (53 +/- 13 pg/ml; P less than 0.005) groups. The MCR of glucagon was similar in control (13.0 +/- 1.3 ml/kg/min) and pre-shunt cirrhotic patients (13.3 +/- 1.7 ml/kg/min) but was significantly (P less than 0.02) decreased in the post-shunt cirrhotics (7.6 +/- 1.3 ml/kg/min). The t 1/2 for glucagon decay was similar in the control and cirrhotic groups. The BSDR, an estimate of pancreatic A cell secretion, was increased four-fold (P less than 0.01) in the pre-shunt (3042 +/- 454 pg/kg/min) and post-shunt (2518 +/- 535 pg/kg/min) cirrhotic groups, as compared to controls (750 +/- 244 pg/kg/min). It is concluded that (a) in the presence of cirrhosis, the magnitude of portasystemic shunting is important in determining the degree of hyperglucagonaemia; (b) in preshunt cirrhotics raised basal IRG levels are principally due to A cell hypersecretion of glucagon whereas in post-shunt cirrhotics riased IRG levels reflect both A cell hypersecretion and delayed clearance of glucagon; and (c) acute shunting of splanchnic venous blood away from the liver reduces the clearance of glucagon, suggesting that, in man, the liver contributes to the clearance of circulating glucagon.     

Amiodarone-digoxin interaction: clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications

Administration of amiodarone (600 to 1,600 mg/day) to 28 patients during long-term digoxin therapy (0.25 +/- 0.05 mg/day) increased serum digoxin level from 0.97 +/- 0.45 to 1.98 +/- 0.84 ng/ml (p less than 0.001). Gastrointestinal side effects occurred in nine patients, central nervous system reactions occurred in five and cardiovascular reactions occurred in four. Pharmacokinetic studies in six patients with a 1 mg intravenous digoxin dose before and during amiodarone therapy increased serum digoxin level at 30 minutes from 8.59 +/- 1.68 to 10.07 +/- 1.70 ng/ml (p less than 0.05). Amiodarone caused a 31% prolongation of digoxin elimination half-life from 49.5 +/- 8.8 to 65.0 +/- 28.8 hours, but the increase in half-life was not statistically significant. Total body clearance was reduced significantly (29%, p less than 0.05) from 2.05 +/- 0.76 to 1.46 +/- 0.64 ml/min per kg. Nonrenal clearance also showed a significant decrease (33%, p less than 0.05) from 1.20 +/- 0.46 to 0.80 +/- 0.30 ml/min per kg. The renal clearance decreased by 22% and the volume of distribution decreased by 11% after amiodarone therapy, but these changes were not significant. The data show that the mechanism of digoxin-amiodarone interaction is multifactorial and emphasize the need for close monitoring of serum digoxin levels and clinical features during concurrent digoxin-amiodarone therapy.     

Utilisation de la théophylline dans les états bronchospastiques graves

The aim of this study was to assess the variations in plasma theophylline in 40 patients with chronic obstructive airways disease (COAD) presenting with acute respiratory failure and treated with continuous intravenous theophylline infusion. High performance liquid chromatography was used to measure the theophyllic levels.The results show a wide variation in theophyllic clearance (mean 41,34 ml/kg/hr). No correlations were found between plasma levels and smoking, obesity, pH, pa CO2, pa 02, HC03, serum albumin, serum bilirubin or hepatic enzyme levels. This variability was observed not only between different patients but also in the same patient at different stages of acute respiratory failure. The theophylline clearance levels were significantly lower than in a control population — 80 to 100 ml/kg/hr) and suggest that theophylline dosage should be reduced in patients with chest disease in severe, acute respiratory failure.     

Pharmacokinetics of benzodiazepine antagonist Ro 15-1788 in cirrhotic patients with moderate or severe liver dysfunction

Ro 15-1788, a benzodiazepine antagonist, has been advocated as a new treatment for hepatic encephalopathy. This drug is extensively metabolized by the liver in normal subjects. In the present study, we examined Ro 15-1788 disposition in eight healthy controls (Group I), eight cirrhotic patients with moderately impaired liver function (Pugh score less than 10, Group II) and eight patients with severe liver dysfunction (Pugh score greater than 10, Group III). The subjects of each group were age and sex matched. After an intravenous infusion of 2 mg Ro 15-1788 over 5 min, blood samples were taken at fixed intervals up to 7 hr after the infusion. Plasma levels of the drug were determined by capillary gas chromatography. In controls, Ro 15-1788 had a high plasma clearance [16.3 +/- 2.6 ml per min per kg (mean +/- S.D.)], a short half-life (45.7 +/- 8.5 min), a large volume of distribution (0.62 +/- 0.09 liter per kg) and a low plasma protein binding (45 +/- 6%). Plasma clearance was reduced markedly in both groups of cirrhotic patients (-57 and -74%, respectively); the volume of distribution was unchanged in Group II and moderately increased in Group III (+37%). The elimination half-life was markedly prolonged in Groups II and III (+66 and +210%, respectively). Plasma clearance and Pugh score were highly correlated in cirrhotic patients (r = 0.830, p less than 0.001). The plasma protein binding of Ro 15-1788 was lower in cirrhotics, resulting in a significant increase in the free fraction of the drug (+16% in Group II; +44% in Group III).(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical pharmacology of tobramycin in children

The pharmacokinetics of tobramycin were evaluated in 50 pediatric patients (two to 18 years of age) with malignancies and normal renal function. Patients receiving either 240 or 300 mg/m2 per 24 hr (8 or 10 mg/kg per 24 hr) divided into doses given every 4 hr had peak serum concentrations (mean +/- standard error) of 3.10 +/- 0.23 microgram/ml and 4.23 +/- 0.25 microgram/ml, respectively, at the end of a 1-hr infusion. Serum concentrations at 4 hr were 0.82 +/- 0.15 and 1.05 +/- 0.15 microgram/ml, respectively. The half-life of the drug was 96.6 min and was inversely correlated with age of the patients. The total clearance rate of tobramycin was 164 +/- 15 mg/min per 1.73 m2 and was directly correlated with age. The mean volume of distribution was 0.42 +/- 0.038 liter/kg and was inversely correlated with age. No accumulation of tobramycin was noted, and no side effects occurred. If therapeutic serum concentrations of tobramycin are to be achieved and maintained in children, the currently recommended dose and frequency of administration should be changed to 300 mg/m2 per 24 hr given in divided doses every 4 hr.     

Assessment of hepatic function. Comparison of caffeine clearance in serum and saliva during the day and at night

Hepatic microsomal function was assessed by a caffeine clearance test at night and during the day using saliva and serum samples obtained simultaneously. In 26 patients with cirrhosis, 21 patients with noncirrhotic liver disease and 15 control subjects caffeine elimination correlated well during the day and at night (r = 0.915 for serum and 0.917 for saliva). The correlation coefficients for caffeine clearance in saliva and serum were 0.940 during the day and 0.963 overnight. In the cirrhotic patients, clearance differed significantly from noncirrhotic liver disease and controls in saliva samples overnight: 0.51 +/- 0.45 ml/min per kg versus 0.91 +/- 0.44 and 1.41 +/- 0.56, respectively. Comparable results were obtained for serum clearance overnight and clearances during the day. Serum and saliva clearances at night correlated well with the aminopyrine breath test (rs = 0.884 and 0.907, respectively). Overnight caffeine clearance in saliva might be a simple useful method for assessing progression and prognosis of liver disease.     

Intravenous theophylline: adaptation of dosage to blood theophylline levels at admission and to clearance

Intravenous infusions of aminophylline expose the patient to the risk of overdosage related to the narrow safety margin of the therapeutic concentrations and to the great individual variability of its excretion. The aim of this study was to evaluate a simplified protocol designed to determine the optimal dose of theophylline based on total body clearance. Forty-four patients (average age: 63 years) admitted with decompensation of chronic respiratory failure (N = 33) or with status asthmaticus (N = 11) were studied. Theophylline was administered initially at a constant rate R0 (mg/kg/h) depending on serum theophylline concentrations on admission T0 (mg/l): R0 = 0.75 - 0.75 T0/20. Serum theophylline concentrations were measured at the 6th and 12th hours (T6 and T12) for calculation of clearance (Chiou et al. J. Pharmacokinet. Biopharm., 1978, 6, 135-151) and for adjusting dosage R. After 48 hours of treatment at this infusion rate, serum theophylline was again measured (T48) to check the adjustment of the dosage and recalculate clearance. In 11 patients T0 was greater than 15 mg/l (max = 44) and T12 was 10.5 +/- 6.4 mg/l. Theophylline was withdrawn in 6 patients with initial clearances less than 5 ml/kg/h (zero in 5 cases). T48 was within therapeutic values (10-20 mg/l) in 55 p. 100 of cases (21/38). Twelve patients had T48 less than 10 mg/l due to an increase in theophylline clearance (+ 80 p. 100 on average) related to improved right ventricular function in 7 cases. In 5 patients T48 was greater than 20 mg/l (max = 27.5) due to a fall in clearance (average -47 p. 100) which could have been caused by administration of erythromycin in 1 case and by dose-dependent kinetics in 2 cases. This protocol which is simple to carry out in practice allows early adjustment of dosage to give effective serum theophylline concentrations in over 50 p. 100 of cases. No serious cases of overdosage were observed, even in patients with high T0 and/or low initial clearances. Under-dosage and overdosage are related to large individual variations in theophylline clearance.