Age-dependent increase of discoidin domain receptor 2 and matrix metalloproteinase 13 expression in temporomandibular joint cartilage of type IX and type XI collagen-deficient mice.

Our previous studies demonstrated that mutations in type IX and type XI collagens in mice caused osteoarthritis (OA)-like changes in knee and temporomandibular (TM) joints. We also found that the overexpression of matrix metalloproteinase 13 (Mmp-13) was probably due to the up-regulation of a collagen receptor, discoidin domain receptor 2 (Ddr2), which was responsible for knee cartilage degeneration in mutant mice. The objective of our study was to determine whether the expression of Mmp-3, Mmp-13 and Ddr2 was increased in OA-like TM joints in mutant mice using immunohistochemistry. We found that the staining for Ddr2, Mmp-13 and Mmp-derived type II collagen fragments in tissue sections from 6-month-old mice was increased in TM joints of the mutant mice. In contrast, we found no difference in the staining for Mmp-3 amongst the two mutant mice and their wild-type littermates. We conclude that, similar to previous observations in knee joints, the overexpression of Ddr2 and Mmp-13 may be responsible for the OA-like change in TM joints in mutant mice.

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.

Rapid estimation of creatinine clearances in patients with liver dysfunction.

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.

Hepatitis C: natural history, diagnosis, and management.

The virology, epidemiology, clinical spectrum, diagnosis, and management of hepatitis C are reviewed. Hepatitis C infection is responsible for most cases of chronic viral hepatitis in the United States and is the major reason for liver transplantation. Hepatitis C virus (HCV) is divided into six major genotypes, with type 1 being the most prevalent in the United States. Direct percutaneous exposure is the main route of HCV transmission. Diagnosis of the infection is made by HCV antibody testing or direct detection of HCV RNA in serum. Liver biopsy is recommended for evaluating disease severity before treatment is started. The currently approved treatment for patients with chronic hepatitis C who have elevated liver transaminases and compensated liver disease consists of interferon alfa alone or in combination with ribavirin. Rates of sustained biochemical and virological responses in the range of 20-40% have been reported for a 12-month regimen of interferon alfa. Combination therapy with ribavirin improves these rates. Response rates are lower in patients with HCV genotype 1, a serum HCV RNA concentration higher than 1 million copies/mL, and cirrhosis. In patients who relapse after an initial response to interferon alfa, retreatment with interferon alfa plus ribavirin or with a higher dosage of interferon alfa is recommended. New agents under development for use against hepatitis C include viral enzyme inhibitors, ribozymes and antisense oligonucleotides, and immunomodulators. Further research is needed to optimize existing strategies for treating hepatitis C and to develop new, more effective therapies. Ultimately, combination therapies may hold the key.

National survey of stress ulcer prophylaxis.

OBJECTIVE: To determine the rationale for using stress ulcer prophylaxis (SUP) among clinicians; to assess criteria used to define failure of SUP; and to evaluate the decision-making process in the selection of a prophylactic agent. DESIGN: A cross-sectional national mail survey. SETTING: Random sample of the members of the Society of Critical Care Medicine who identified anesthesiology, surgery, or internal medicine as their primary specialty area. PATIENTS: None. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Questionnaires consisting of multiple-choice and short-answer questions were sent to a simple random sample of 1,268 physicians to assess the current practice of SUP. A total of 328 usable questions were returned, resulting in a response rate of 26%. All percentages reported in the results are based on the total number of responses. The risk factors for SUP that were most commonly identified were burns (91%), shock (90%), and sepsis (88%). These were also risk factors for which the respondents most commonly started SUP. Histamine-2-receptor (H2)-antagonists as a class, were the most commonly used prophylactic agents (67%). The most commonly used agents for SUP were ranitidine (31%), famotidine (24%), sucralfate (24%), and cimetidine (12%). Most respondents selected ranitidine for ease of administration, famotidine because of formulary availability, sucralfate for a better side effects profile, and cimetidine for cost-effectiveness. Eighty-two percent of respondents considered the presence of bright red blood in the nasogastric tube as failure of SUP. In cases where SUP failed, most respondents would add a second agent from a different therapeutic class. Of those respondents who used an H2-antagonist initially, 48% would add sucralfate, 36% would add antacid, and 13% would add omeprazole. Of those respondents who used sucralfate, 77% would add an H2-antagonist when SUP failed. For those respondents who would switch to another agent when the H2-antagonist failed, 52% would change to omeprazole, whereas 67% would change to an H2-antagonist when sucralfate failed. Only eight respondents would discontinue SUP when risk factors were resolved. Most respondents would discontinue SUP when the patient was no longer in the "nothing by mouth" status (28%), started on enteral feeding (23%), or discharged from the intensive care unit (21%). The mean duration of SUP was 6.3+/-4.5 (SD) days. CONCLUSIONS: This survey highlighted the lack of consensus in the use of SUP. Many patients receive SUP for an extended period, without clear-cut indications or documented benefit. The cost of unwarranted SUP in patients with low risk of stress ulcer gastrointestinal bleeding is prohibitive. Treatment algorithms or protocols for SUP based on prescribing patterns, hospital formulary restrictions, and cost-analysis should be considered for each institution to guide critical care physicians on the proper use of SUP therapies.

Hepatitis C viral dynamics.

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.

Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.

To better understand the dynamics of hepatitis C virus and the antiviral effect of interferon-alpha-2b (IFN), viral decline in 23 patients during therapy was analyzed with a mathematical model. The analysis indicates that the major initial effect of IFN is to block virion production or release, with blocking efficacies of 81, 95, and 96% for daily doses of 5, 10, and 15 million international units, respectively. The estimated virion half-life (t1/2) was, on average, 2.7 hours, with pretreatment production and clearance of 10(12) virions per day. The estimated infected cell death rate exhibited large interpatient variation (corresponding t1/2 = 1.7 to 70 days), was inversely correlated with baseline viral load, and was positively correlated with alanine aminotransferase levels. Fast death rates were predictive of virus being undetectable by polymerase chain reaction at 3 months. These findings show that infection with hepatitis C virus is highly dynamic and that early monitoring of viral load can help guide therapy.

Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa.

To determine if the clearance of hepatitis C genotype 1 virus (HCV) is dependent on the dose of interferon alfa-2b (IFN-alpha2b), the acute clearance of HCV after a single dose of either 3, 5, or 10 mIU of IFN-alpha was compared in patients with chronic hepatitis C. HCV-RNA levels following IFN-alpha administration were measured. At 24 hours, mean percentage serum viral reduction was 41.4%, 63.7%, and 85.5% for 3, 5, and 10 mIU, respectively (P < .001). At 48 hours, the mean viral reduction was consistently less than the reduction at 24 hours, averaging 22.9%, 61.9%, and 74.3%, respectively (P < .001), indicating that the drug effect diminishes before 48 hours. Regression analysis showed a positive correlation between dose and percent reduction of HCV-RNA levels (r = .6; P < .001). A mathematical model showed that such dose dependence is expected if IFN-alpha partially blocks viral production. Minimum clearance and production rates of HCV were estimated from measurements of HCV-RNA levels after the 10-mIU dose. HCV decay followed an exponential decline with a minimum estimate of the viral clearance rate constant of 2.8 per day, corresponding to a virion half-life of 0.3 days or less. A minimal estimate of the daily HCV production and clearance is 3.7 x 10(11) virions per day, indicating a high rate of replication and turnover. These results indicate that there is a dose-dependent effect of IFN-alpha in clearance of HCV genotype 1. Because the virion production rate is very rapid and because the current recommended dose of IFN-alpha (3 mIU) is often ineffective, larger doses should be considered to treat genotype 1-infected 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.

Pharmacokinetics and safety of tiagabine in subjects with various degrees of hepatic function.

PURPOSE: To evaluate the pharmacokinetics and safety of multiple oral doses of tiagabine HCl 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, C(max) values (mean +/- SD) were 117 +/- 54, 172 +/- 40, and 172 +/- 28 ng/ml; C(min) 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 x h/ml, and elimination half-lives (harmonic means) were 7, 12, and 16 h, respectively. Unbound tiagabine concentrations, area under the unbound plasma concentration-time curve, and the free fractions were increased in the hepatically impaired subjects. Reduced serum albumin and alpha1-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.

Effect of obesity on pharmacokinetics and biologic effect of interferon-alpha in hepatitis C.

To examine potential adverse effects of obesity in reducing the response to interferon-alpha (IFN-alpha) in chronic hepatitis C (HCV), IFN-alpha and HCV RNA levels in serum and the 2',5'-oligoadenylate synthetase (2-5 OAS) levels in peripheral blood mononuclear cells (PBMC) were compared between six obese and five nonobese patients before and after a single, 10 mIU dose of IFN-alpha2b. There were no differences in the mean histologic activity index between the two groups. The maximal IFN concentration and the area under the serum IFN concentration-time curve were higher in nonobese patients. These two parameters were inversely correlated with body weight and body surface area. No differences were found in the mean reduction in HCV RNA levels between the two groups following IFN-alpha. The maximal 2-5 OAS level after treatment divided by the pretreatment 2-5 OAS level (2-5 OAS response ratio) was greater in the nonobese patients, suggesting stronger biologic response upon exposure to exogenous IFN-alpha in nonobese patients.

Pharmacoeconomic analysis of stress ulcer prophylaxis for critically ill patients.

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 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 $US1457, $US1737, $US2268, and $US2638 to $US2712, respectively (1994 dollars). No prophylaxis was found to be less costly than giving H2RAs. Sucralfate and antacids, which induced net savings of $US7373 and $US4321 per case of AUGB averted, respectively, were more cost effective than H2RAs. 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.

Gender effect on diuretic response to hydrochlorothiazide and furosemide.

Gender has been shown to elicit differences in drug disposition and response to therapeutic agents. We measured the diuretic response to oral hydrochlorothiazide, oral and intravenous furosemide in 6 male and 6 female normal volunteers. After fasting overnight, each subject received single doses of the individual diuretics or no treatment on 4 separate days. Total urine output was collected over the next 24 hours for volume measurement and determination of sodium and potassium concentrations. There was no statistically significant difference found between male and female subjects with respect to urine flow rate, sodium, and potassium excretion rates among the treatments. However, when natriuretic response was adjusted for mg/kg of the intravenous furosemide dose received, male subjects had a higher peak sodium excretion rate than the female subjects. Results of this study reveal a gender-related difference on the natriuretic response to diuretics. Further studies are necessary to identify if this gender-related difference is caused by differences in drug metabolism, disposition, or intrinsic diuretic responsiveness at the site of action.

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 hydrochlorothiazide, oral furosemide, intravenous furosemide, or no treatment in a cross-over 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.

Clinical and histologic predictors of response to interferon-alpha 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-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.

Helicobacter pylori and peptic ulcer disease.

The role played by Helicobacter pylori in the pathogenesis of peptic ulcer disease (PUD) is discussed, and the epidemiology, identification, diagnosis, eradication, and treatment of H. pylori infection are reviewed. Isolation of H. pylori from up to 100% of patients with duodenal ulcer and 80% of patients with gastric ulcer establishes a strong association between H. pylori and idiopathic PUD, although other factors also may be essential for the development of PUD. Invasive procedures for diagnosis of H. pylori infection include upper endoscopy and biopsy of gastroduodenal tissues followed by culture or the rapid urea test; noninvasive tests include the urea breath tests and serology. Although H. pylori is susceptible to a number of antimicrobials, eradication (as opposed to suppression) of this organism has been a major challenge. The most important predictive factor for clinical and microbiological efficacy is the pretreatment susceptibility of H. pylori to nitroimidazoles. Triple therapy with bismuth, metronidazole, and either amoxicillin or tetracycline has resulted in better clinical and microbiological outcomes than either monotherapy or dual therapy. Possible adverse effects of this regimen include nausea, vomiting, taste disturbance, and diarrhea. Anti-H. pylori therapy should be reserved for those patients who have recurrent symptomatic or intractable PUD. Currently, the regimen of choice includes bismuth, metronidazole, and either amoxicillin or tetracycline given for at least two weeks.

Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives.

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. 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.(ABSTRACT TRUNCATED AT 400 WORDS)

Stability of zidovudine in 5% dextrose injection and 0.9% sodium chloride injection.

The stability of zidovudine at a concentration of 4 mg/mL in 5% dextrose injection and 0.9% sodium chloride injection in polyvinyl chloride infusion bags stored at room and refrigerated temperatures for up to eight days was studied. Zidovudine was diluted in 5% dextrose injection and in 0.9% sodium chloride injection to a concentration of 4 mg/mL. Six admixtures were prepared with each diluent; three were stored at room temperature (25 +/- 1 degree C) and three were refrigerated (4 +/- 1 degree C). At 0, 3, 6, 24, 48, 72, and 192 hours, 2-mL aliquots were removed. One milliliter of each aliquot was diluted to a zidovudine concentration of approximately 40 micrograms/mL and assayed in duplicate by a stability-indicating high-performance liquid chromatographic method. Visual inspection was performed at each sampling time for precipitation, turbidity, color change, and gas formation. Sample pH was recorded at 0 and 192 hours. In all admixtures, more than 97% of the initial zidovudine concentration remained throughout the study period. No visual or pH changes were observed. Zidovudine 4 mg/mL in admixtures with 5% dextrose injection or 0.9% sodium chloride injection stored in polyvinyl chloride infusion bags was stable for up to 192 hours (eight days) at room temperature and under refrigeration.