Nancy P. Lam

Differences in Viral Dynamics between Genotypes 1 and 2 of Hepatitis C Virus

Many studies have shown that patients infected with hepatitis C virus (HCV) of genotype 2 have better response to interferon (IFN)-alpha treatment than genotype 1 patients; however, the mechanisms responsible for this difference are not understood. In this study, viral dynamics during high-dose IFN induction treatment were compared between the genotypes. Patients in each group received 10 MU of IFN-alpha2b for 14 days, and HCV RNA levels were frequently determined. Nonlinear fitting, both individually for each patient and using a mixed-effects approach, of the viral kinetic data to a mathematical model of the IFN effect on HCV infection was performed. The antiviral effectiveness of IFN in blocking virus production, the free virion clearance rate, and the HCV-infected cell death rate were all significantly higher for genotype 2 patients than for genotype 1 patients. Thus, the better response rate of patients infected with HCV genotype 2 is multifactorial. This is the first finding of a difference in viral dynamics between subtypes of the same virus and demonstrates the importance of subtype-specific virus-host-drug interactions.

Clinical Pharmacokinetics of Metronidazole and Other Nitroimidazole Anti-Infectives

SummaryMetronidazole 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.When given intravenously or orally at usual recommended doses, metronidazole attains concentrations well above the minimum inhibitory concentrations for most susceptible micro-organisms. The drug has an oral bioavailability approaching 100%. Rectal and vaginal administration results in a smaller amount of drug absorption and lower serum concentrations. Metronidazole has limited plasma protein binding but can attain very favourable tissue distribution, including into the central nervous system. The drug is extensively metabolised by the liver to form 2 primary oxidative metabolites: the hydroxy and acetic acid metabolites. The kidney is responsible for the elimination of only a small amount of the parent drug; however, normal excretion of the 2 metabolites is dependent on the integrity of kidney function.The metabolism of metronidazole was found to vary among patient groups. Preterm and term infants have lower total body clearance (CL) and prolonged elimination half-lives. However, children older than 4 years old were observed to have pharmacokinetic parameters similar to those in adults. Reduced CL was also observed in children who are malnourished. Elderly patients have reduced renal excretion of both the parent drug and hydroxy metabolite. Pharmacokinetic parameters in pregnant patients were not significantly different from those in nonpregnant women; however, the drug is distributed into breastmilk and the infant will be exposed to the drug through the nursing mother. Patients undergoing gastrointestinal surgery or having enteric diseases and those who are hospitalised or critically ill also have altered pharmacokinetics. Metabolism of the drug is reduced in patients with liver dysfunction, giving delayed production of metabolites. In contrast, renal failure has little effect on the elimination of the parent drug, but affects the excretion of the metabolites more significantly. Haemodialysis was found to remove a substantial amount of the metronidazole while the effect of peritoneal dialysis was more limited. Energy and protein deficient diets as well as occupational exposure to gasoline did not alter metronidazole pharmacokinetics. However, the effect of alcohol consumption on metronidazole CL requires further study.Drug interactions with warfarin, alcohol, disulfiram, phenytoin, lithium, phenobarbital, phenazone (antipyrine), prednisone, rifampicin, antacids and cholestyramine have been reported. No significant change in pharmacokinetics was observed with concurrent administration of theophylline, alprazolam, lorazepam, diazepam, ciprofloxacin or sulfasalazine. Studies conducted with cimetidine revealed varied findings.Metronidazole is generally well tolerated when administered in dosages of <2g per day. Some adverse reactions, such as gastrointestinal effects, neutropenia, neuropathies and certain central nervous system effects, appear to be related to the dosage and treatment duration.On the basis of the available data on metronidazole pharmacokinetics and microbiology, the traditional dosage recommendation of 500mg every 6h is more than adequate to treat most anaerobic infections. In fact, a regimen of 500mg every 8h can be expected to maintain serum concentrations above the minimum inhibitory concentrations of susceptible anaerobic organisms. Alternatively, once-daily administration has also been suggested. There is also some recent evidence to support a postantibiotic effect of metronidazole on certain anaerobic bacteria.The pharmacokinetics of other nitroimidazole derivatives are similar to those of metronidazole. They all have good oral absorption, and extensive hepatic metabolism and tissue distribution. The elimination half-lives of most of the derivatives are longer than that of metronidazole with the exception of nimorazole. Side effects of the derivatives are generally mild and they are usually well tolerated by patients. One notable exception is misonidazole; its use is often limited by frequent peripheral neuropathy.

Pharmacokinetics and Safety of Tiagabine in Subjects with Various Degrees of Hepatic Function

Summary: Purpose: To evaluate the pharmacokinetics and safety of multiple oral doses of tiagabine HC1 in subjects with different degrees of hepatic impairment.

Effect of Obesity on Pharmacokinetics and Biologic Effect of Interferon-alpha in Hepatitis C

To examine potential adverse effects of obesityin reducing the response to interferon-alpha (IFN-alpha)in chronic hepatitis C (HCV), IFN-alpha and HCV RNAlevels in serum and the 2′,5′-oligoadenylatesynthetase (2-5 OAS) levels in peripheral bloodmononuclear cells (PBMC) were compared between six obeseand five nonobese patients before and after a single, 10mIU dose of IFN-alpha2b. There were nodifferences in the mean histologic activity index between thetwo groups. The maximal IFN concentration and the areaunder the serum IFN concentration-time curve were higherin nonobese patients. These two parameters were inversely correlated with body weight andbody surface area. No differences were found in the meanreduction in HCV RNA levels between the two groupsfollowing IFN-alpha. The maximal 2-5 OAS level after treatment divided by the pretreatment 2-5OAS level (2-5 OAS response ratio) was greater in thenonobese patients, suggesting stronger biologic responseupon exposure to exogenous IFN-alpha in nonobese patients.

Efficacy of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in the treatment of patients with hypercholesterolemia : A meta-analysis of clinical trials

Recent studies have documented the long-term impact of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on mortality and morbidity related to coronary heart disease, establishing the link between lowering cholesterol levels and reducing cardiac events. Our study was a comparative literature review and meta-analysis of the efficacy of four HMG-CoA reductase inhibitors-fluvastatin, lovastatin, pravastatin, and simvastatin-used in the treatment of patients with hypercholesterolemia. The data sources for our meta-analysis of the efficacy of these cholesterol-lowering agents were 52 randomized, double-masked clinical trials with at least 25 patients per treatment arm. The results showed all four agents to be effective in reducing blood cholesterol levels. We computed summary efficacy estimates for all published dose strengths for the four agents. Fluvastatin 20 mg/d reduced low-density lipoprotein cholesterol (LDL-C) levels by 21.0% and total cholesterol (total-C) levels by 16.4%; fluvastatin 40 mg/d reduced these levels by 23.1% and 17.7%, respectively. Lovastatin 20 mg/d reduced LDL-C levels by 24.9% and total-C levels by 17.7%; lovastatin 80 mg/d reduced these levels by 39.8% and 29.2%, respectively. Pravastatin 10 mg/d reduced LDL-C levels by 19.3% and total-C levels by 14.0%; pravastatin 80 mg/d reduced these levels by 37.7% and 28.7%, respectively. Simvastatin 2.5 mg/d reduced LDL-C levels by 22.9% and total-C levels by 15.7%; simvastatin 40 mg/d reduced these levels by 40.7% and 29.7%, respectively. The results of our meta-analysis can be used in conjunction with treatment objectives and comparative cost-effectiveness data for these agents to decide appropriate therapeutic alternatives for individual patients.

Clinical and histologic predictors of response to interferon-α in patients with chronic hepatitis C viral infection

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-α (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.

Early HCV RNA Values After Interferon Predict Response

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.

Effect of diuretic drugs on creatinine clearance determination.

Diuretic drugs have been reported to alter the glomerular filtration rate and possibly the creatinine excretion by the kidneys. We evaluated the effects of single doses of diuretic drugs on creatinine clearance determination. Ten healthy volunteers were randomized to receive either oral hydrochloro-thiazide, oral furosemide, intravenous furosemide, or no treatment in a crossover fashion during four separate test days with 6-day washout periods. Urine and blood specimens were collected during 24 h after the treatments. Specimens were assayed for creatinine, and the creatinine clearance corresponding to the 4-, 6-, 12-, and 24-h urine collections were calculated. Analysis of variance did not show a statistically significant effect of the diuretic regimens on creatinine clearance over these periods. This study demonstrates that single doses of diuretic drugs do not have significant effect on creatinine clearance determination using urine collected during 4–24-h periods.

Pharmacokinetics of Dexmedetomidine (DEX) in Patients with Hepatic Failure (HF)

Clinical Pharmacology & Therapeutics (1999) 65, 128–128; doi:

Pharmacoeconomic analysis of stress ulcer prophylaxis for critically ill patients.

SummaryThe 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 H2 receptor antagonists (H2RAS), 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 H2RAS were