Pharmacokinetics of isradipine in patients with chronic liver disease

Summary The pharmacokinetics of the dihydropyridine calcium antagonist isradipine has been examined in 8 healthy volunteers, 7 patients with non-cirrhotic chronic liver disease (CLD), and 8 patients with biopsy-proven cirrhosis (CIR). Isradipine was simultaneously given orally (¹²C 5 mg) and i.v. (¹³C 1 mg).Systemic availability was significantly increased from 17% and 16% in controls and CLD, respectively, to 37% in CIR. The corresponding systemic clearances averaged 1.1, 0.9 and 0.61 · min^–1, the reduction in cirrhotics being significant.Both aminopyrine demethylation capcity, a measure of hepatic microsomal function, and indocyanine green disappearance, a measure of hepatic perfusion, were correlated with the reduction in systemic clearance, and the reduction in oral clearance was correlated with the reciprocal of the serum bile acid concentration.The loss of first-pass extraction should be considered when this calcium antagonist is given perorally in patients with hepatic cirrhosis.     

Pharmacokinetics and biochemical effects of hepapoietin in patients with chronic liver disease

BACKGROUND: Hepapoietin is a naturally occurring cytokine that promotes hepatocyte growth. Animal studies have suggested that hepapoietin and hepatocyte growth factor have a potential role in the prevention and management of liver diseases. However, human studies have been lacking. AIM: To evaluate the safety and pharmacokinetics of single escalating doses of hepapoietin in patients with chronic liver disease. METHODS: An open-label, single escalating dose trial with five different doses of hepapoietin (1, 3, 10, 30 and 100 mg) was performed. Adults with chronic, compensated, non-viral liver disease were included. Liver function tests were obtained before dosing, 24 h after hepapoietin administration and on days 4, 7, 30 and 45. All patients were followed for 45 days. RESULTS: Twenty-five subjects received hepapoietin, with five subjects each at 1, 3, 10, 30 and 100 mg of hepapoietin. Significant decreases occurred in total bilirubin, ammonia, partial thromboplastin time and cholesterol levels overall, and both high-density and low-density lipoprotein cholesterol showed a downward trend. An increase in albumin was observed at the 30 mg dose level. Slight decreases in haemoglobin and red blood cell levels were observed at day 4, but returned to normal levels immediately thereafter. Child-Pugh scores from day 0 to day 7 were improved in 24%, stable in 64% and worse in 12% of patients. Hepatic encephalopathy displayed changes from day 0 to day 45 with improvement in 16%, no change in 80% and worsening in 4%. CONCLUSIONS: Hepapoietin in doses up to 100 mg is safe for use in humans. Potential benefits are suggested by significant decreases in bilirubin, ammonia, partial thromboplastin time and cholesterol levels and an increase in albumin. Further studies with multiple dosing regimens are needed to identify the clinical utility of hepapoietin in the management of chronic liver disease.     

Pharmacokinetics of famotidine in normal subjects and in patients with chronic liver disease

The pharmacokinetics of famotidine were studied in seven healthy control subjects and in 14 patients with cirrhosis, following single oral and intravenous 20-mg dose administration, and after seven daily doses of 40 mg. Following intravenous (i.v.) administration, the mean (range) total plasma clearance values were not significantly different in the patients with compensated cirrhosis (n = 7), 337 (241-576) ml/min or in the patients with decompensated cirrhosis (n = 7), 270 (120-408) ml/min compared with the control group, 370 (154-612) ml/min. The mean half-life in the compensated cirrhotics, 2.86 (1.87-4.98) h, was similar to that in the control group 2.91 (1.86-6.03) h, but it was insignificantly prolonged in the decompensated cirrhotics 3.35 (2.00-5.77) h. The mean, maximum, plasma famotidine concentrations after single oral doses were comparable between the groups but there was considerable inter-subject variability, with individual values ranging from 17 to 139 ng/ml. Peak plasma concentrations were reached within 2-3 h, although more variability was observed among patients with decompensated cirrhosis. The mean systemic availability of the drug, estimated from urinary recovery, was 0.39 (0.15-0.64) in the healthy controls, 0.35 (0.14-0.51) in the patients with compensated cirrhosis and 0.38 (0.13-0.77) in the patients with decompensated cirrhosis. No significant increases were observed in plasma trough famotidine concentrations following multiple oral dosing in any of the subjects, and the kinetic variables after the seventh dose were not significantly different from those following the single oral dose. No significant changes were observed in psychometric performance in control subjects or in patients between the pre-study day and day seven of the multiple oral dose phase.     

Pharmacokinetics of felodipine in patients with liver disease

Summary Nine patients (6 males, 3 females) with biopsy-proven liver cirrhosis participated in an open, cross-over, three centre study of the effect of impaired liver function on the pharmacokinetics of felodipine. Two of the nine patients had undergone porto-caval anastomosis. Each patient was given 0.75 mg i.v. and 10 mg p.o. on separate occasions. The results of this study have been compared with published data from younger subjects and elderly hypertensive patients.The mean peak plasma concentration normalized to a dose of 10 mg (C_max 46 nmol/l) was twice as high in the cirrhotic patients as in the healthy subjects, but the bioavailability, f, (17.0%) was comparable. Subjects with a porto-caval shunt did not have higher f than the mean for the group. The volume of distribution at steady-state, V_ss, was significantly lower than in the healthy subjects. Protein binding was significantly lower in the patients with cirrhosis: 99.46% compared to 99.64% in the healthy subjects. The weight-corrected clearance was 1/3 of the value in healthy subjects.No correlation between systemic availability and oral clearance was found, so it is proposed that felodipine is metabolized both in the liver and also in the gut wall. The results suggest that at least the starting dose should be reduced in patients with severe liver disease.     

Pharmacokinetics of quinine in chronic liver disease.

The pharmacokinetics of quinine were investigated in a) six healthy male Thai subjects, and b) nine male Thai patients with a moderate degree of chronic liver disease, after a single oral dose of 600 mg quinine sulphate. tmax and t1/2.2 were significantly prolonged in patients (median [range] tmax 2 [1-5] vs 1.6 [0.8-2] h; t1/2,z 23.4 [17.4-41.7] vs 9.7 [7.8-17.2] h), and Vz/F was significantly larger (median [range] 4.21 [2.33-15.87] vs 2.78 [1.49-3.38] 1 kg-1). Median (range) concentration of the plasma unbound Qn fraction collected from the patients at 4 h after drug administration was 17 (8.4-17.8)% of total drug concentration.     

Eltrombopag in patients with chronic liver disease

Objective: To compare change in low-density lipoprotein cholesterol (LDL-C) levels and National Cholesterol Education Program (NCEP) Adult Treatment Panel III LDL-C goal attainment in diabetic patients treated with rosuvastatin versus other statins in a large, managed care health plan. Research Design and Methods: This retrospective cohort analysis used medical and pharmacy claims linked to laboratory results from a commercial/MedicareAdvantage health plan. Study participants were ≥ 18 years of age, had a diagnosis of diabetes, were newly treated with statins from 8/1/03 to 2/28/05, and were considered at high risk for cardiovascular events as defined by NCEP guidelines. Subjects were continuously enrolled for 12 months pre-index and ≥ 30 days post-index, with variable follow-up until therapy discontinuation or end of health plan eligibility. Main Outcome Measures: Change in LDL-C from baseline, and attainment of NCEP LDL-C goal among patients not at goal before starting therapy. Results: A total of 3337 adult patients with diabetes were identified with new use of statin therapy during the identification period. A total of 9% (n = 301) started on rosuvastatin, 49.4% (n = 1,649) on atorvastatin, 20.7% (n = 690) on simvastatin, 7.0% (n = 234) on pravastatin, 11.7% (n = 391) on lovastatin and 2.2% (n = 72) on fluvastatin. After controlling for covariates, rosuvastatin patients experienced a significantly greater decrease in LDL-C from baseline (38.7%) than patients taking atorvastatin (34.2%) (p = 0.05), simvastatin (31.5%), pravastatin (24.2%), fluvastatin (26.3%) or lovastatin (24.9%) (p < 0.0001). Rosuvastatin users were significantly more likely to attain LDL-C goal than those taking the other statins (odds ratio: 0.44, 0.28, 0.14, 0.14, 0.19, respectively; p < 0.001). Predicted percent attaining goal was significantly greater for those taking rosuvastatin (87.3%) than for those taking atorvastatin (76.9%), simvastatin (68.7%), pravastatin (55.0%), lovastatin (55.3%) or fluvastatin (61.3%) (p < 0.001). Conclusion: For diabetic patients, rosuvastatin is more effective at reducing LDL-C levels and attaining NCEP ATP III LDL-C goal than other statins in real-world clinical practice.     

Low serum retinol levels are associated with hepatocellular carcinoma in patients with chronic liver disease

BACKGROUND: Retinol and other vitamin A derivatives affect the differentiation and growth of many tissues and have anti-tumour properties. AIM: To investigate serum retinol levels in patients with liver disease and hepatocellular carcinoma (HCC) and to assess its importance as a risk factor for the development of HCC. METHODS: Serum retinol levels were measured in healthy volunteers and 175 patients (34 with chronic hepatitis C, 117 with cirrhosis, and 24 with HCC. RESULTS: The serum retinol levels (mean +/- s.e.) in ng/mL, were 972.1 +/- 37.7 in the control group and 647 +/- 41.1 in patients with chronic hepatitis C. Serum retinol levels in patients with cirrhosis and HCC were lower than in patients with cirrhosis alone (365.8 +/- 43.1 vs. 438.9 +/- 22.1, P < 0.04). In particular, there was a more significant difference in serum retinol levels between Child-Pugh grade A patients with cirrhosis and Child-Pugh grade A patients with cirrhosis/HCC (serum retinol levels 532.4 +/- 26.7 vs. 366.1 +/- 86.4, P < 0.03). There was a significant difference in serum retinol levels between normal controls and all patients' groups (P < 0.001). There were significantly lower serum retinol levels in cholestatic Child-Pugh grade A patients with cirrhosis compared with noncholestatic Child-Pugh grade A patients with cirrhosis/HCC (411.5 +/- 30.3 vs. 579.7 +/- 32.7, P < 0.0004). Sixty percent of patients with Child-Pugh grade A cirrhosis/HCC had serum retinol levels below 350 ng/mL compared with only 18.4% of cirrhotics without HCC (chi 2-test, P=0.01). No correlation was found between serum retinol levels and alpha FP or any other liver function tests, apart from serum albumin, which showed a positive correlation (r=0.61 P < 0.018). CONCLUSIONS: There was a progressive reduction in serum retinol levels from controls to patients with liver cirrhosis. Those patients with cirrhosis and HCC had significantly lower values than patients with cirrhosis alone. Serum retinol levels may be a risk factor for the development of HCC.     

Pharmacokinetics of morphine are not altered in subjects with Gilbert's syndrome

AIMS: To verify that Gilbert's syndrome, which is caused by decreased glucuronidation capacity of the UDP-glucuronosyl transferase (UGT)1A1, does not account for impaired morphine clearance. METHODS: Noncompartmental pharmacokinetic parameters for morphine and its glucuronide metabolites were compared between five carriers of Gilbert's syndrome and six noncarriers after a 7.5 mg (19.8 micro mol) intravenous injection of morphine sulphate pentahydrate. To estimate the amount of morphine-6-glucuronide (M6G) formed from morphine, 1 mg of deuterized M6G was injected intravenously at the same time. RESULTS: No differences were detected between carriers and noncarriers of Gilbert's syndrome in the clearance of morphine (80.1 +/- 12 l h(-1) vs 87.9 +/- 22 l h(-1)) and in the percentage of morphine that was metabolized to M6G (10.9 +/- 1.4 vs 13 +/- 2). The areas under the plasma concentration vs time curves of morphine, M6G and morphine-3-glucuronide also did not differ between carriers and noncarriers of Gilbert's syndrome. CONCLUSIONS: Gilbert's syndrome is not a factor to be considered when prescribing morphine.     

Pharmacokinetics and safety of propiverine in patients with fatty liver disease

Objective: The present study was designed to assess the pharmacokinetics of propiverine after single and multiple dosing in patients with and without fatty liver disease. Methods: The serum concentration-time curves of propiverine and its main metabolite propiverine-N-oxide were investigated in 12 patients with mild to moderate impairment of liver function (mean antipyrine clearance 26.0?ml?·?min^?1) and in 12 controls (antipyrine clearance 42.8?ml?·?min^?1). Subjects were treated orally with propiverine hydrochloride (Mictonorm) for 5 days (15?mg t. i. d.) to reach steady state. Results: No significant differences were observed for propiverine and its main metabolite with regard to peak serum concentration (C_max), area under the serum concentration-time curve (AUC) and elimination half-life (t_1/2). Adverse events were reported by 12 patients. Five patients with fatty liver disease and seven patients with normal liver function complained of dry mouth and/or blurred vision. All adverse events reported were transient and mild. Conclusion: No pharmacokinetic differences relevant for safety were observed, comparing patients with and without fatty liver disease following repeated oral administration of propiverine. Thus there seems to be no need to adjust the dose in patients with mild to moderate impairment of liver function.     

Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects

To study the effects of cirrhosis of the liver on the pharmacokinetics of midazolam single IV (7.5 mg as base) and p.o. (15.0 mg as base) doses of midazolam were administered to seven patients with cirrhosis of the liver and to seven healthy control subjects. One cirrhotic patient did not receive the oral dose. The distribution of midazolam in both study groups was alike as indicated by similar values of t1/2 alpha, V1 and Vss. Also the plasma protein binding of midazolam was unchanged in the patients with cirrhosis. The elimination of midazolam was significantly retarded in the patients as indicated by its lower total clearance (3.34 vs. 5.63 ml/min/kg), lower total elimination rate constant (0.400 vs. 0.721 h-1), and longer elimination half-life (7.36 vs. 3.80 h). The bioavailability of oral midazolam was significantly (P less than 0.05) higher in patients than controls (76% vs. 38%). The antipyrine-half-life was 32.4 h in the patients and 11.8 h in the controls. There were statistically significant (P less than 0.01) correlations between the clearances of the two drugs (r = 0.680) and between their half-lives (r = 0.755). The hypnotic effects of midazolam were similar in both groups. However, on a pharmacokinetic basis a reduced dosage of midazolam to patients with advanced cirrhosis of the liver is recommended.     

Pharmacokinetics of irbesartan are not altered in special populations

Studies were conducted to determine whether pharmacokinetics of irbesartan (IRBE), a potent, long-acting angiotensin (AT)-II receptor antagonist selective for AT-II type 1 receptor subtype, are altered in patients with renal impairment (RI), hepatic impairment (HI), or heart failure (HF) or by patient gender, age, or race. IRBE pharmacokinetics and blood pressure (BP) response in hypertensive (HT) children and adolescents were also studied. HI or RI (including end-stage renal disease requiring hemodialysis) had no effect on IRBE pharmacokinetics after single or repeated dosing. IRBE was not removed by hemodialysis. In patients with New York Heart Association class II or III HF, IRBE single-dose pharmacokinetics were not altered following either oral or IV administration. There were no clinically significant differences in IRBE pharmacokinetics between men and women, elderly and young, or black and white patients. No accumulation of IRBE occurred with repeated dosing in RI or HI patients or in HT men or women. In a pediatric study, IRBE pharmacokinetics were comparable between 6- to 12-year and 13- to 16-year age groups and to that previously determined for adult subjects receiving the same dose; accumulation of IRBE was minimal during multiple dosing. IRBE lowered BP in the pediatric population. Adverse event profile with IRBE was similar in all patient groups. Based on these pharmacokinetic and safety data, no dosage adjustments of IRBE are necessary for patients with RI, HI, or HF, or based on patient age, gender, or race. IRBE may be a treatment option for pediatric HT patients. The pharmacokinetic profile of IRBE and lack of necessary dosage adjustments in special populations suggest that IRBE is an excellent choice for management of hypertension across all patient groups.     

Pharmacokinetics in liver disease

Some general pharmacokinetic principles, relevant to understand and predict altered disposition of drugs in liver disease, are reviewed. It is appropriate to differentiate between high- and low-clearance drugs as to the influence of hepatic dysfunction. On intravenous administration highclearance drugs generally show reduced systemic clearance predominantly caused by decreased liver blood flow, whereas on oral administration a considerable increase in systemic availability may occur caused by reduced enzyme activity and (in cirrhosis) bij portacaval shunting. Low-clearance drugs are sensitive to reduced enzyme activity and reduced protein binding. It seems that oxidative reactions are far more affected than conjugation reactions in liver disease. Large inter-patient variability exists in the kinetics of a drug in any type of hepatic disease. The conventional liver-function tests are of no value in predicting altered drug disposition.     

Metabolism of amylobarbitone in patients with chronic liver disease

1. A single dose of amylobarbitone (3.23 mg/kg) was given by intravenous injection to each of ten healthy controls and two groups of five patients with chronic liver disease. A curve of serum amylobarbitone concentration against time was prepared for each subject and the proportion of the serum amylobarbitone bound to protein determined. The urinary excretion of the metabolite hydroxyamylobarbitone, ethyl (3 hydroxyisoamyl) barbituric acid was measured.2. The degree of protein binding of serum amylobarbitone was reduced in the five patients (group I) with abnormally low concentrations of albumin in serum (<3.5 g/100 ml) but was normal in the five patients (group II) with normal serum albumin concentrations (>3.5 g/100 ml).3. The equation for a double exponential decay was fitted to the concentration/time curves for amylobarbitone free in the serum water. The mean intercepts and rate constants were used to calculate the dimensions of mathematical models based on a two compartment open system.4. The five patients (group I) who had abnormally low concentrations of albumin in serum showed impairment of amylobarbitone metabolism; the rate constant beta(h(-1)) for the second exponential decay of serum amylobarbitone concentration was reduced (P<0.01), the urinary excretion of hydroxyamylobarbitone was reduced (P<0.001) and the mean serum water clearance (C, ml/min) representing amylobarbitone elimination by metabolism was reduced.5. The five patients (group II) who had normal concentrations of albumin in serum showed no impairment of amylobarbitone metabolism. Within the total patient group there were strong and significant positive correlations between the serum albumin concentration and each of the indices of the rate of amylobarbitone metabolism.6. Both patient groups showed an increase in the first dispositional rate constant alpha(h(-1)) and in the clearance (C(t) ml/min) representing transfer between central and peripheral compartments. The physiological basis for this observation is uncertain.7. The clinical response to the single intravenous dose of amylobarbitone was not significantly greater (P=0.11) in the patient group (I) with slow amylobarbitone metabolism than in the patient group (II) with a normal rate of amylobarbitone metabolism.     

Pharmacokinetics of N-acetylcysteine in man

Summary N-Acetylcysteine was given intravenously and as three fast dissolving and one slow-release formulation, on separate occasions, as a single dose of 600 mg to 10 fasting (5 men and 5 women) healthy volunteers. Blood and urine were sampled for the following 12 h.Renal clearance constituted around 30% of total body clearance, which was 0.21 l/h/kg. Volume of distribution was 0.33 l/kg, consistent with distribution mainly to extracellular water. The late elimination half-life was 2.27 h and the mean residence time 1.62 h.The slow-release tablet resulted in a flattened plasma concentration-time curve typical of slow release formulations, while the other three oral formulations were rapidly absorbed.The oral availability of N-acetylcysteine varied between 6 and 10%, with the slow-release tablet having the lowest and the fast dissolving tablet the highest availability.     

Pharmacokinetics of lansoprazole in patients with renal or liver disease of varying severity

Summary The pharmacokinetics of lansoprazole (L) after a single oral dose of 30 mg was determined in 18 healthy volunteers, 17 renal failure patients and 24 hepatic failure patients; 8 hepatitis and 16 with compensated (CC) or uncompensated (UCC) cirrhosis.In renal failure, the absorption of L was unchanged, its half-life being similar to that in healthy subjects; a small change seen in mild renal failure patients (creatinine clearance between 40 and 60 ml/min) was attributed to the age of the patients. Urinary elimination, essentially as metabolites of lansoprazole, was decreased, in relation to the degree of renal impairment.In hepatitis patients, the AUC and t_1/2 of L were doubled, without any change in C_max. In cirrhotics t_max was prolonged, the AUC was increased (P<0.001) and there was prolongation of t_1/2 (6.1 h in CC and 7.2 h in UCC compared to 1.4 h in healthy subjects). These changes resulted from a decrease in the clearance of L. There was also an increase in its sulphone metabolite (C_max, R_m) and a decrease in the hydroxylated metabolite (C_max, R_m) in relation to the degree of liver disease, and reflecting a decrease in hydroxylation and biliary elimination.Thus, renal failure had no effect on the pharmacokinetics of L, but severe hepatic failure caused marked changes. A repeated dosing study would be necessary to evaluate the repercussions of the possible accumulation in cirrhotic patients.     

Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients

Objective N-acetylcysteine (NAC) is a mucolytic agent with anti-oxidant properties. It might have potential positive effects in renal patients and, therefore, its pharmacokinetics and safety in haemodialysis was investigated.Methods Twelve dialysis patients received 2 g NAC (10 ml NAC 20% solution i.v.) mixed with 500 ml saline during the first 3 h of the session for six dialysis sessions. A bolus of heparin was injected intravenously as LWH-heparin. In six patients, one session was repeated with NAC mixed with heparin and infused through the heparin pump.Results Baseline NAC was on average 454 ng ml^–1; its concentration increased to 9,253 ng ml^–1 at the second infusion and attained a steady state between 14,000 ng ml^–1 and 17,000 ng ml^–1 at the fourth dose. We observed a C _max of 53,458 ng ml^–1 with a t _max of 3.0 h. Plasma clearance was 1.25 l h^–1 and dialytic clearance 5.52 l h^–1. No side effects were observed.Conclusion In the case of repeated doses, the NAC pre-dose concentration after repeated infusion of 2 g of the drug during the first 3 h of a dialysis session reached the steady state at the fourth infusion, without further accumulation. The dialytic clearance is effective, the total body clearance being reduced to 1.25 l h^–1. In dialysis patients, 2 g NAC given intravenously over 3 h is a safe dosage, with no short-term side effects.The study was conducted in accordance with the guidelines for Good Clinical Practice and all current Swiss laws concerning clinical research. The protocol was approved by the Ethics Committee of the Canton Ticino, Switzerland.     

Pharmacokinetics of a microcrystalline theophylline preparation in patients with chronic obstructive airways disease

Summary Plasma theophylline concentrations have been measured in 9 patients with chronic obstructive airways disease following the oral administration of a microcrystalline theophylline preparation. Some measurements of FEV₁ were also made. Four patients were given 375 mg as a single dose and then subsequently 375 mg stat and 125 mg 4 times daily for 3 days, (Group I). A further 5 patients took 250 mg as a single dose and then 250 mg 4 times daily for 3 days, (Group II). In both groups, following the single dose and again after the last dose of chronic administration, blood samples were obtained at frequent intervals up to 24 h for plasma drug estimation. During the 3-day course, blood samples were drawn before and 2 h after each morning dose. In Group I patients, substantial plasma theophylline concentrations were seen only after the loading dose. Thereafter, the mean concentrations before or 2 h after the morning doese were always less than 4.0 µg/ml. Trough concentrations were usually below 2.0 µg/ml. In contrast patients in Group II achieved substantially higher plasma theophylline concentrations, with mean peak concentrations always 10 µg/ml or greater, and trough concentrations greater than 5 µg/ml on at least one occasion in every subject. The elimination half-lives after chronic administration in both groups were not significantly different from those obtained after single doses. Mean drug accumulation, measured as AUC_ss/AUC₁, was 0.87±0.07 in Group I and 0.72±0.14 in Group II, indicating that accumulation had not occurred with either regimen. The mean increase in FEV₁ 2 h after the administration of a single dose was 19.2% after 375 mg and 16.7% after 250 mg. These results indicate that the recommended dosage regimen for microcrystalline theophylline preparation (375 mg stat and 125 mg 4 times daily) produces inadequate plasma theophylline concentrations: 250 mg 4 times daily would appear to be likely to result in satisfactory theophylline levels in more patients.     

Clinical predictors of fibrosis in patients with chronic liver disease

Aliment Pharmacol Ther 31 , 1085–1094

Summary

Background Patients with chronic liver disease and components of metabolic syndrome may be at higher risk for fibrosis. Aim To assess the impact of clinicodemographic factors on hepatic fibrosis in CLD. Methods Of 1028 chronic liver disease patients, 964 were included in the analysis. Extensive clinico‐demographic and histological data were available. Significant baseline fibrosis (METAVIR stage ≥2) and fibrosis progression (increase of ≥1 stage in subsequent biopsy) were compared between groups using univariate and multivariate analyses. Results Compared with HCV and HBV, NAFLD patients were more obese (higher BMI and waist circumference), diabetic, hypertensive and hyperlipidaemic. Significant fibrosis occurred in 55%, 43% and 20% of HCV, HBV and NAFLD, respectively. Factors independently associated with fibrosis in NAFLD included DM, elevated AST and ALT. For viral hepatitis, independent predictors of fibrosis were low platelet count (HBV and HCV), age (HBV) and elevated AST and ALT (HCV). A second biopsy was available for 96 patients with follow‐up of about 4 years. Factors independently associated with progression of fibrosis were HCV infection, higher ALT and lower platelet count. Conclusions Diabetes mellitus is an independent risk factor for fibrosis only in NAFLD. Elevated aminotransferases and/or low platelet counts are independently associated with significant baseline fibrosis or progression of fibrosis, in patients with chronic liver disease.     

Pharmacokinetics of theophylline in hyperthyroid and hypothyroid patients with chronic obstructive pulmonary disease

Summary The pharmacokinetics of theophylline was investigated in five hyperthyroid, five hypothyroid, and five euthyroid patients, all with chronic obstructive pulmonary disease. Wide individual variability was found in theophylline kinetics, but the rate of elimination of theophylline was significantly higher in hyperthyroid, and lower in hypothyroid patients than in the euthyroid patients (k_el=0.155, 0.060 and 0.107 h^–1, respectively). The values for clearance and volume of distribution were not consistently changed compared with those in the euthyroid group, although all the parameters except AUC were significantly different in hyperthyroid and hypothyroid patients. There was a positive correlation between both thyroxine and triiodothyronine serum concentrations and total body clearance of theophylline (r=0.795 and r=0.791, respectively). It is concluded that in spite of the wide interindividual variability and the relatively small differences in the pharmacokinetics of theophylline in thyroid dysfunction compared with the euthyroid status, these differences have to be considered in certain clinical situations, as they may require changes in the therapeutic regimen for administration of theophylline in hyperthyroid or hypothyroid patients.