Different methods are available for rapid assessment of renal function using the patient's serum creatinine concentration and body weight without obtaining urine collection over 24 hr. However, the reliability of these methods in patients with liver diseases has not been established. The purpose of this study was to determine the accuracy and precision of the estimated creatinine clearances obtained by the methods of Cockcroft-Gault, Jelliffe, Mawer, and Siersbaek-Nielsen in patients with liver diseases who have different degrees of renal function. Creatinine clearances obtained from 24-hr urine collection were used as the standard. The different methods for rapid renal function estimation had limited accuracy and reliability in patients with severe liver dysfunction (Child-Pugh class C) and also in those with creatinine clearances of less than 60 ml/min. Creatinine clearances were overestimated by about 40-100%. Using lean body weights, instead of total body weights, reduced the prediction errors. In patients with mild liver dysfunction (Child-Pugh class A), all four estimation methods provided reasonable estimation of the creatinine clearances.

It is apparent that the sooner the virus is cleared from the serum following IFN monotherapy, the better the sustained virologic response rates. It is also clear that in patients infected with HCV genotype 1a and 1b, standard dosages of IFN-alpha 2b (3 MU) administered three times a week are inadequate for a substantial and sustained lowering of HCV RNA serum levels. Understanding the kinetics and dynamics of HIV and HBV has greatly improved the understanding of the life cycle of these viruses and their response to therapy. Studies of the kinetics of HCV following initiation of IFN monotherapy have revealed that IFN-alpha 2b causes a rapid dose-dependent (3 < 5 < 10 = 15 MU) reduction in HCV RNA levels within 24 to 48 hours. This rapid exponential decline in RNA levels is best explained by an effect of IFN on viral production or release. The dose of other IFN products that maximally suppresses viral levels needs to be determined. Mathematical calculations reveal that HCV has a serum half-life of 3 hours and a viral production rate of 1.0 x 10(12) virions/d. After this rapid decline, there is a slower phase of viral decline that varies widely among patients and is attributed to the death rate of infected liver cells. The rate of decline of the second phase, which is probably mediated by immune clearance of infected liver cells, is the best viral kinetic predictor of early viral clearance. This kinetic information indicates that in patients infected with HCV genotype 1a or 1b, initial therapy with IFN should be daily and initial doses should be sufficient to reduce viral levels by more than 95% within 48 hours. Whether higher doses of IFN will alter or enhance the second phase of viral decline needs to be investigated. Also, the effect of ribavirin on IFN-mediated changes in HCV RNA levels needs to be investigated in carefully performed kinetics studies to better determine its mechanism of action. Defining the viral kinetics in patients infected with HCV genotype 2 or 3 and in patients who do not respond to IFN therapy will also improve the approach to therapy.

Chronic viral hepatitis is a worldwide health problem. Complications associated with chronic viral hepatitis include liver failure, cirrhosis and hepatocellular carcinoma. The disease often is asymptomatic, but malaise, weakness and fatigue can occur. Alfa-inter-feron (α-IFN) is the only treatment with proven benefit in chronic viral hepatitis. Common adverse physical and psychiatric effects of therapy are described. The efficacy, however, varies widely. In chronic hepatitis B, α-IFN improves liver aminotransferases and histology, and leads to loss of viral replication in 25–40% of patients. Nucleoside analogues are being evaluated as an alternative treatment. In chronic hepatitis C, α-IFN leads to improvement in liver aminotransferases and histology, and clearance of HCV RNA in 10–25% of patients. The new treatment under investigation is a combination of α-IFN and ribavirin. In chronic hepatitis D, prolonged treatment using similar dosing regimens of α-IFN in chronic hepatitis B result in clearance of HDV RNA in 50% of patients. Relapses are common after treatment discontinuation. Future treatment approaches for chronic viral hepatitis will most likely utilize combination therapies.

The aim of this study is to determine inpatients infected with hepatitis C virus (HCV) whetherearly HCV RNA measurements at 48 hr following standarddoses of interferon-α (IFN-α) (3 million IU) would predict response during six months oftherapy. Twenty-three patients with HCV were treatedwith IFN-α 3 million IU three times a week and HCVRNA levels were quantified by branched-chain (b-)DNA analysis at baseline and 24 and 48 hr followingIFN-α and at one, three, and six months. Meanbaseline HCV RNA levels significantly declined from 6.0± 1.6 Meq/ml at baseline to 2.4 ± 0.7Meq/ml 24 hr after IFN-α. However, HCV RNAvalues increased to 4.3 ± 1.1 Meq/ml by 48 hr.Mean HCV RNA values at one and six months were notsignificantly lower than 48-hr values. In six patientsin whom HCV RNA was negative by bDNA at 48 hr, threewere negative by polymerase chain reaction at sixmonths. Of the 17 patients who were positive by bDNA at48 hr, all were positive at one and three months; and in the nine of nine who continued therapy forsix months, there was no further decrease in HCV RNAlevels. In patients receiving standard doses ofIFN-α (3 million IU), serum RNA values 48 hr after the first injection predict long-termresponse.

Summary: Purpose: To evaluate the pharmacokinetics and safety of multiple oral doses of tiagabine HC1 in subjects with different degrees of hepatic impairment.Methods: Four subjects with mild hepatic impairment, three subjects with moderate hepatic impairment, and six matched normal subjects received twice daily oral tiagabine HCl for 5.5 days. Serial blood specimens were obtained for 48 h after the final dose. Total and unbound tiagabine plasma concentrations were determined by high‐performance liquid chromatography (HPLC) and ultrafiltration, respectively. Pharmacokinetic parameters were compared between the groups by analysis of covariance.Results: For total tiagabine concentrations in normal subjects and subjects with mild and moderate hepatic impairment, Cmax values (mean i SD) were 117 ± 54, 172 ± 40, and 172 ± 28 ng/ml; Cmin values were 13 ± 4,27 ± 4, and 28 ± 6 ng/ml; areas under the plasma concentration‐time curve were 396 ± 59, 633 ± 16, and 675 ± 32 ng Wml, and elimination half‐lives (harmonic means) were 7, 12, and 16 h, respectively. Unbound tiagabine coricentrations, area under the unbound plasma concentration‐time curve, and the free fractions were increased in the hepatically impaired subjects. Reduced serum albumin and α1‐acid glycoprotein concentrations may have contributed to increases in the unbound fraction. Adverse events observed included dizziness, tremor, nausea, somnolence, incoordination, and unsteady gait. The frequency of these events was increased in the subjects with liver impairment.Conclusions: Because of the decreased drug elimination caused by liver function impairment, reduced doses or increased dosing interval or both may be needed to attain therapeutic plasma drug concentrations. Time to reach steady state also may be prolonged. The patients should be monitored closely for potential neurologic adverse events.

The objective of this study was to evaluate the economic outcomes of drug options for stress ulcer prophylaxis in critically ill and/or intensive care unit patients. Decision analytic modelling was used to compare the costs of stress ulcer prophylaxis and possible clinical outcomes [acute upper gastrointestinal bleeding (AUGB) and nosocomial pneumonia].The regimens evaluated were: antacids, histamine H-2 receptor antagonists (H(2)RAs), sucralfate and no prophylaxis. The results of published studies were pooled to determine the expected probability of AUGB and nosocomial pneumonia following stress ulcer prophylaxis with each of the agents under study. The costs of stress ulcer prophylaxis, treatment of AUGB and treatment of nosocomial pneumonia were identified from various sources.Sucralfate was the least costly agent for stress ulcer prophylaxis. The average net costs per patient for sucralfate, antacids, no prophylaxis and H(2)RAs were $US1457, $US1737, $US2268, and $US2638 to $US2712, respectively (1994 dollars). No prophylaxis was found to be less costly than giving H(2)RAs. Sucralfate and antacids, which induced net savings of $US7373 and $US4321 per case of AUGB averted, respectively, were more cost effective than H(2)RAs.Sensitivity and threshold analyses revealed that the results were constant over a wide range of cost and probability values. Break-even analysis suggested that sucralfate was the optimal agent for stress ulcer prophylaxis unless the acquisition cost of a prophylactic course of sucralfate was >$US304.05 per patient. At that point, antacids become the optimal agent. Based on this analysis, sucralfate may be the most cost-effective agent for stress ulcer prophylaxis in critically ill or intensive care patients.

To evaluate if any pretreatment characteristics of patients with chronic hepatitis C (HCV) can be used to predict response to the current recommended dose (3 million units three times a week) and higher doses of interferon-alpha (IFN), we retrospectively assessed the response of 37 patients with HCV who were treated with IFN. Sixteen patients (43%) responded to the standard dose of IFN with normalization of ALT. Weight and liver histology were found to be significant factors for response. The responders weighed significantly less than nonresponders (161.8 +/- 35.5 lb versus 200.3 +/- 45.4 lb, P = 0.008). Seventy-five percent of patients with chronic lobular or persistent hepatitis were responders, whereas only 28% of patients with more advanced hepatitis responded (P = 0.01). There was no correlation between the degree of bile duct damage or steatosis and response rate. This study suggests that obesity and severe histologic injury are negative predictive factors of response to the current recommended dose of IFN. The adequacy of the current recommended dose of IFN in overweight patients needs to be investigated.

Metronidazole was first introduced for the treatment of trichomoniasis. Its therapeutic use has subsequently been expanded to include amoebiasis, giardiasis and, more recently, anaerobic infections. Most of the early pharmacokinetic studies employed nonspecific assays such as microbiological and chemical assays. These assays were not able to differentiate the parent drug from the metabolites or other interfering substances. Pharmacokinetic data obtained through the use of specific Chromatographic techniques provide the basis for this review of recent pharmacokinetic findings concerning metronidazole and other nitroimidazole antibiotics.