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Biomedical subjects

C F Stewart

Publications and source records attributed to C F Stewart.

At least 73 records · Page 4Linked to original sources
PubMed1990

Prospective evaluation of a model for predicting etoposide plasma protein binding in cancer patients.

Etoposide protein binding in cancer patients is variable and has been related mathematically to a linear model consisting of serum albumin and total bilirubin [percentage unbound = (1.4 x total bilirubin) - (6.8 x albumin) + 34.4]. In this prospective evaluation of the model, plasma samples were obtained following the administration of etoposide in 31 patients, and the unbound percentage (% unbound) of etoposide in plasma was determined by equilibrium dialysis. The mean measured % unbound was 15.3 +/- 11.6 (SD), and the mean model predicted % unbound was 16.7 +/- 10.1. The relation between predicted and measured etoposide % unbound was highly correlated (r2 = 0.92, P = 0.001). The model was precise but with a slight bias toward overpredicting % unbound (mean prediction error, 1.36%; 95% confidence interval, 0.09 to 2.6%). In patients with abnormal total bilirubin (i.e., greater than 1.5 mg/dl) or with hypoalbuminemia (i.e., less than 3.3 g/dl), the model was both precise and unbiased. These results demonstrate that etoposide % unbound can be predicted using serum albumin and total bilirubin. This model should be useful in prospectively identifying patients at increased risk of experiencing altered pharmacological effects due to altered protein binding of etoposide.

Adult↗
PubMed1990

Clinical pharmacodynamics of continuous-infusion etoposide.

Continuous-infusion etoposide was given to 15 patients with newly diagnosed small-cell lung cancer (extensive disease) and 10 patients with various refractory malignancies. The untreated patients with lung cancer received 200 mg/m2 etoposide over 24 h in combination with 100 mg/m2 cisplatin, and the pretreated patients received 400 mg/m2 etoposide over 36 h as monotherapy. Pharmacokinetic studies of etoposide were carried out in all patients. High-performance liquid chromatography (HPLC) was used to measure etoposide. All patients had normal hepatic and renal function tests and were followed weekly for hematologic toxicity after therapy. In all, 14 untreated and 9 pretreated patients were evaluable. Biostatistical analysis was done to correlate pharmacokinetic results to hematologic effects. Pearson correlation coefficients were calculated for continuous variables (i.e., blood counts), and Spearman correlation coefficients were calculated for ranked variables (i.e., toxicity grades). The values for the area under the plasma concentration vs time curve (AUC) and systemic clearance varied widely among patients. However, the AUC and clearance were significantly correlated (P less than 0.05) with the WBC and platelet nadirs and the decrease in hemoglobin. The grade of leukopenia and total grade of hematologic toxicity were also correlated with AUC and clearance. Because the interpatient variability in etoposide pharmacokinetics correlates with the variable degree of hematologic toxicity, pharmacokinetic drug monitoring is suggested.

Adult↗
PubMed1990

Coadministration of naproxen and low-dose methotrexate in patients with rheumatoid arthritis.

Fifteen patients (30 to 78 years of age) with diagnoses of rheumatoid arthritis were administered oral and intravenous methotrexate (15 mg), alone or with concomitant naproxen (1000 mg/day). Serial blood samples and urine were collected for 24 hours after the dose of methotrexate and were assayed for methotrexate by a specific radioenzymatic method. In twelve patients who completed the study, methotrexate systemic clearance was not statistically different with naproxen (103.3 +/- 35.0 ml/min) versus without naproxen (113.4 +/- 48.3 ml/min; p = 0.37). Oral clearance of methotrexate was not statistically different with naproxen (161.7 +/- 55.0 ml/min) versus without naproxen (176.7 +/- 68.3 ml/min; p = 0.14). Likewise, there was not a significant difference in methotrexate renal clearance or plasma protein binding with or without naproxen. No toxicity was observed when patients received methotrexate alone or with naproxen. This study indicates that concomitant naproxen does not abruptly alter the disposition of low-dose methotrexate in patients with rheumatoid arthritis who have normal renal function.

Absorption↗
PubMed1990

Changes in the clearance of total and unbound etoposide in patients with liver dysfunction.

The disposition of total and non-protein-bound etoposide was investigated in 21 cancer patients receiving etoposide and cisplatin combination chemotherapy. Etoposide plasma concentrations were determined using a specific high-performance liquid chromatography (HPLC) method, and etoposide plasma protein binding was determined by equilibrium dialysis. The patients had a wide range of renal function (creatinine clearance, 32 to 159 mL/min/m2) and hepatic function (total bilirubin range, 0.3 to 21.5 mg/dL; aspartate aminotransferase [AST] range, 14 to 415 IU/L; serum albumin range, 2.7 to 4.1 g/dL). The mean etoposide total systemic clearance was not different in 15 patients with total bilirubin less than 1.0 mg/dL versus six patients with total bilirubin 1.1 to 21.5 mg/dL (18.7 +/- 5.9 mL/min/m2 v 26.4 +/- 10.7 mL/min/m2; t-test P = .06), with a trend toward higher total clearance in the patients with abnormal bilirubin values. However, the mean clearance of unbound etoposide was significantly lower in patients with increased total bilirubin (220 +/- 90 mL/min/m2 v 135 +/- 61 mL/min/m2; t-test P = .027). The fraction of etoposide unbound (fu) in plasma was significantly higher in patients with increased bilirubin (9% +/- 3% v 27% +/- 15%; t-test P = .002), explaining the trend toward higher total clearance in these patients. Etoposide clearance (total or unbound) in the 14 patients with measurable hepatic metastases was not different from the clearance in the seven patients without hepatic metastases. This study provides an explanation for why patients with increased bilirubin do not have lower total systemic clearance of etoposide, and indicates that such patients have a higher exposure to unbound etoposide. The results of ongoing pharmacodynamic studies of total and unbound etoposide in patients with increased bilirubin will determine the clinical relevance of altered etoposide protein binding.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Inhaled albuterol and oral prednisone therapy in hospitalized adult asthmatics. Does aminophylline add any benefit?

STUDY OBJECTIVE: To determine the efficacy of intravenous aminophylline in the treatment of adult patients hospitalized for exacerbation of asthma. DESIGN: Randomized, double-blind, placebo-controlled trial throughout the study. SETTING: University Hospital Clinical Research Center. PATIENTS: Forty-four patients admitted from the emergency room with a primary diagnosis asthma; 39 patients completed the study. INTERVENTIONS: Patients received either intravenous aminophylline or placebo in addition to frequent nebulized albuterol; prednisone 0.5 mg/kg body weight every 6 h orally; and supplemental oxygen. Aminophylline infusion rates were adjusted to achieve serum theophylline concentrations of 10 to 20 micrograms/ml. Changes were made in placebo infusion rates to maintain the double blind design. MEASUREMENTS AND RESULTS: Forced expiratory volume in 1 s (FEV1) and other spirometric measurements every 8 h by a blinded investigator or trained respiratory therapist. Subjective patient response and duration of hospitalization were compared. No difference in spirometric measurements was observed between the two groups at any time point. On admission to the study, FEV1 in the placebo group was 41.5 (+/- 2.9) percent predicted and in the aminophylline group 34.7 (+/- 2.3) percent predicted (p = 0.08). At discharge, FEV1 was 70.4 (+/- 2.9) percent predicted in the placebo group and 63.7 (+/- 2.8) percent predicted in the theophylline group (p = 0.10). There was no difference in subjective patient rating or duration of hospitalization between the two groups (placebo 1.95 days and aminophylline 1.78 days, p = 0.51). CONCLUSIONS: Our results suggest that aminophylline therapy does not add significant benefit to other standard therapies in hospitalized adult asthmatic patients. Because of the risks and cost of aminophylline treatment in the hospital setting, further research is needed to determine if there are subgroups of adult asthmatics who may benefit from the addition of aminophylline to other standard optimal therapies.

Acute Disease↗
PubMed1990

Drug-drug interactions with antirheumatic agents: review of selected clinically important interactions.

Drug therapy for rheumatoid arthritis (RA) often requires the use of more than one drug, thus drug-drug interactions are very likely in this patient population. We discuss the pharmacokinetic and pharmacodynamic mechanisms involved in drug-drug interactions. Our review focuses on selected examples involving drugs used to treat RA and other antirheumatic drugs [e.g., methotrexate and nonsteroidal antiinflammatory drugs (NSAID)] or with other therapeutic classes of drugs (e.g., NSAID and warfarin). Studies and case reports of drug-drug interactions with antirheumatic drugs are critically evaluated and the potential clinical implications are discussed.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Compatibility of cisplatin and fluorouracil in 0.9% sodium chloride injection.

The effect of drug concentration and light on the compatibility and stability of cisplatin and fluorouracil in i.v. admixtures was studied. Two sets of admixtures were prepared in 0.9% sodium chloride injection in polyvinyl chloride bags--(1) cisplatin 200 micrograms/mL and fluorouracil 1,000 micrograms/mL and (2) cisplatin 500 micrograms/mL and fluorouracil 10,000 micrograms/mL. Half of the admixtures were protected from light. All admixtures were stored at room temperature (24-26 degrees C), and those admixtures not protected from light were stored under room fluorescent light. After visual inspection, the pH of each admixture was determined, and an aliquot was assayed for drug concentration using a stability-indicating high-performance liquid chromatographic assay. Over a four-hour period, no visual changes were observed and the pH changes observed were negligible. In admixtures containing the lower concentrations of cisplatin and fluorouracil, it took approximately 1.5 hours for the concentration of cisplatin to reach 90% of the initial concentration. By four hours (lower concentration range) and three hours (higher concentration range) after the admixtures were prepared, less than 75% of the initial cisplatin concentration remained. There was less than a 5% decrease measured in the fluorouracil concentrations over the observation time. Admixtures of cisplatin and fluorouracil in 0.9% sodium chloride injection at the concentrations evaluated in this study must be used within one hour of preparation, whether or not they are protected from light. Intravenous administration of fluorouracil and cisplatin by continuous infusion will require alternative approaches to mixing the two drugs in the same container.

Chemistry, Pharmaceutical↗
PubMed1989

Altered protein binding of etoposide in patients with cancer.

Etoposide plasma protein binding (PB) is reported to be 94% based on in vitro studies using normal human serum albumin (SA). Etoposide PB in 17 patients with cancer receiving etoposide (50 to 100 mg/m2) and in plasma of 14 volunteers was determined by equilibrium dialysis with 3H-etoposide. The unbound fraction (Fu) in patients with cancer was 0.139 +/- 0.099 compared with 0.043 +/- 0.0036 in plasma from normal volunteers (p less than 0.0009; t test). Etoposide binding ratio (BR) was correlated directly with SA (r2 = 0.83; p less than 0.05). In the population with cancer Fu was significantly correlated with bilirubin (r2 = 0.837; p less than 0.05). In a multivariate analysis, SA and bilirubin were significant predictors of Fu (r2 = 0.93; p less than 0.05). This study corroborates previous reports of etoposide PB in normal human serum and demonstrates altered PB in patients with abnormal serum albumin or bilirubin levels.

Adult↗
PubMed1989

Evaluation of aminoglycoside disposition in patients previously treated with cisplatin.

The alterations in aminoglycoside disposition in patients previously treated with cisplatin were determined by reviewing the medical records of 37 cancer patients. The patients received 44 courses of an aminoglycoside antibiotic (gentamicin, n = 27; amikacin, n = 14; and tobramycin, n = 3). The mean (SD) half-life of 171 (120) min was greater than our previously published mean aminoglycoside half-life in children with cancer who were not receiving cisplatin. Twenty-five of 44 courses were completed without an aminoglycoside dosage reduction and only 5 courses were discontinued because of delayed aminoglycoside elimination. There was no significant difference in the duration of aminoglycoside therapy between the group that had a dosage reduction and the group that did not [6.6 (2.3) versus 5.8 (2.9) days, p = 0.42, respectively]. Multiple linear regression analysis of patient variables identified serum creatinine and cumulative cisplatin dose as the best predictors of aminoglycoside half-life (r2 = 46.0%, p less than 0.001). The only predictor of aminoglycoside clearance was serum creatinine (r2 = 35.2%, p less than 0.001). Patients previously treated with cisplatin are at greater risk for delayed aminoglycoside elimination. Prior administration of cisplatin is not an absolute contraindication to the use of aminoglycoside antibiotics. When clinically indicated, patients who have previously received cisplatin and have apparently normal renal function should be treated cautiously with standard doses of aminoglycoside antibiotics, and pharmacokinetic monitoring should be routinely performed.

Acute Kidney Injury↗
PubMed1989

Biotechnology products: new opportunities and responsibilities for the pharmacist.

The opportunities and responsibilities of pharmacists with respect to the new biotechnology products are described. Recent advances in the fields of molecular genetics and nucleic acid chemistry have resulted in a proliferation of biotechnology products. Those produced by recombinant DNA techniques offer particular promise for the treatment of a wide variety of medical disorders such as cancer, anemia, neutropenia, diabetes, and myocardial infarction. Since the turn of the century, the pharmacy profession has expanded its role from drug preparation and distribution to modern clinical pharmacy, in which pharmacists act as a source of drug information for physicians, nurses, and patients. In response to the new biotechnology revolution, pharmacists must once again undergo a role expansion, this time actively assuming responsibility for educating themselves about the nature and clinical use of the new biopharmaceuticals. The curriculum of students undergoing training in pharmacy should cover such areas as immunoglobulins, immunomodulators, growth hormones, targeted drug-delivery systems, and advanced diagnostic techniques that use biotechnology products. Continuing-education programs in these areas will update currently practicing pharmacists on the new biotechnology products. Although use of biologic proteins is currently targeted toward hospitalized patients, future advances may allow for dispensing these new drugs through community pharmacies as well. Therefore, change will be necessary at all levels of the pharmacy profession. As pharmacists accept the responsibility of dispensing, monitoring, and providing information about the new biotechnologic agents, they will enhance the rational use of these compounds.

Biotechnology↗
PubMed1989

Etoposide: an update.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and pharmacodynamics of etoposide are reviewed. Etoposide, although similar in chemical structure to podophyllotoxin, has a different mechanism of cytotoxicity compared with its parent compound. Etoposide may stabilize type II topoisomerase-DNA complexes, preventing rejoining of single- and double-strand DNA breaks. Etoposide may also require cellular activation into intermediates, which then bind to DNA and disrupt cellular function. Oral etoposide has an average bioavailability of 50% (range, 17%-137%), with substantial intrapatient and interpatient variability. Etoposide is widely distributed in the body and is highly bound to plasma proteins (greater than 95%). Approximately 50% (range, 20%-81%) of an etoposide dose is recovered in the urine as parent drug or glucuronide, with the remainder of the dose being unaccounted for. The disposition of etoposide in patients with renal and hepatic dysfunction is discussed. Etoposide is effective in combination with other agents against lung cancer, and response rates of 90% in small-cell lung cancer have been observed. When etoposide is used in combination with other agents, response rates of approximately 80% have been observed in patients with testicular cancer. The activity of etoposide in treating leukemia, lymphoma, and breast and ovarian carcinomas and other tumors is discussed. The impact of etoposide on prolonging survival in lung and testicular cancer is addressed, and studies evaluating the pharmacodynamics of etoposide are described. Adverse effects associated with etoposide therapy include myelosuppression, alopecia, nausea and vomiting, mucositis, and hypotension after rapid intravenous administration. Etoposide has demonstrated considerable clinical efficacy against a broad spectrum of tumors.

Etoposide↗
PubMed1989

Stability of cisplatin and etoposide in intravenous admixtures.

The stability of various concentrations of etoposide and cisplatin in intravenous admixtures under various storage conditions was studied. Admixtures containing etoposide (200 and 400 micrograms/mL) with cisplatin (200 micrograms/mL) were prepared in 0.9% sodium chloride injection and in 5% dextrose and 0.45% sodium chloride injection. The admixtures were stored in either polyvinyl chloride bags or glass bottles. Mannitol and potassium chloride were added to selected admixtures. Half of the admixtures were protected from light, while the other half were exposed to fluorescent light. All admixtures were stored at room temperature. Samples were visually inspected and assayed for etoposide and cisplatin content by high-performance liquid chromatography within 15 minutes after admixture preparation and after 8, 24, and 48 hours of storage. Etoposide and cisplatin concentrations decreased less than 10% from the initial concentration after eight hours of storage. At 24 hours, the admixtures containing etoposide 400 micrograms/mL and cisplatin 200 micrograms/mL (with additives) in 0.9% sodium chloride injection precipitated. The decrease in etoposide concentrations during the first 24 hours in the rest of the admixtures was less than 10% of the initial concentration. The change in etoposide concentration was related to the type of i.v. solution and the presence of additives. After 24 hours, the change in cisplatin concentrations was less than 10% of the initial concentration, except in the admixtures that precipitated. For cisplatin, the presence of light was related to an increased loss of cisplatin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromatography, High Pressure Liquid↗
PubMed1987

Effect of maturation on drug disposition in pediatric patients.

Maturational changes in the physiologic processes that govern drug disposition in pediatric patients are described, and evaluation of data from pediatric drug studies is discussed. Gastrointestinal absorption depends on gastric pH, gastric emptying time, intestinal transit time, and gastrointestinal enzymatic activity; the overall effect of age-related alterations in these variables is poorly understood. Maturational changes in the skin affect percutaneous absorption. Distribution of drugs is affected by alterations in vascular perfusion, body composition, tissue binding, and plasma protein binding. For most water-soluble drugs, volume of distribution is increased in neonates. Age-related changes in biotransformation are complex because the rate of development of phase 1 and phase 2 metabolic pathways varies and metabolic pathways may be induced by in utero exposure to inducing agents. For most drugs, biotransformation is decreased in the neonate, increases from one to five years of age, and decreases after puberty to adult values. The kidneys of neonates are inefficient at drug elimination, leading initially to prolonged elimination half-lives of many drugs. Clearance of some drugs may be greater in infants than in older children and adults because of disproportionate development of renal filtration and secretion in relation to reabsorption. Few data on maturational changes in physiologic processes that affect drug disposition are available for any one drug in a specific pediatric population. In the development of research protocols, careful attention should be paid to the design limitations of published studies.

Age Factors↗
PubMed1987

Influence of concomitant aspirin or prednisone on methotrexate synovial fluid concentration.

Methotrexate (MTX) is currently being used in the treatment of patients with rheumatoid arthritis. The purpose of this study was to investigate the effect of two classes of drugs, steroids and salicylates, on MTX synovial fluid concentrations. A novel canine model of monoarticular inflammation was used, in which each animal served as its own control with both inflamed and normal knees in the same animal. After the 6-week immunization process, animals in each group received either no drug (control), prednisone or aspirin (low dose and high dose) for 1 week before MTX. On the day of the study, each animal was given i.v. MTX, and serial serum and synovial fluid samples were obtained. Laboratory, histologic and clinical observations supported the presence of monoarticular inflammation. The end-of-infusion synovial MTX concentration in inflamed knees was significantly greater than in normal knees (P less than .05), but, 2 hr after the end of infusion, they were not different. The end-of-infusion ratio of synovial fluid MTX concentration to serum MTX concentration (both total and unbound) was significantly lower in the prednisone group than in the other treatment groups (P less than .05). The end-of-infusion ratio of the MTX synovial concentration in the inflamed knee compared with the normal knee at 2 hr was significantly lower in the prednisone group than in the other three treatment groups (P less than .05). These results have therapeutic implications for the use of MTX in treating rheumatoid arthritis.

Animals↗
PubMed1986

The effect of ranitidine and cimetidine on imipramine disposition.

The pharmacokinetic characteristics of imipramine were studied after a single, oral, 100 mg dose was taken by 12 healthy male subjects following 3 days of pretreatment with placebo, cimetidine (300 mg every 6 h), and ranitidine (150 mg every 12 h) in a randomized, double blind, crossover trial. After each imipramine dose plasma samples were collected for 72 h and assayed for imipramine, desipramine, 2-hydroxyimipramine and 2-hydroxydesipramine by HPLC. Cimetidine preadministration statistically prolonged imipramine t 1/2 compared to ranitidine (22.7 vs. 13.0 h) or placebo (10.8 h). Mean imipramine area under the curve (AUC) following cimetidine pretreatment was more than double that following placebo (2.633 vs. 0.966 micrograms X h X ml-1) or ranitidine (1.14 micrograms X h X ml-1) pretreatment. Imipramine apparent oral clearance was reduced in all 12 subjects after cimetidine. Compared to ranitidine or placebo, cimetidine pretreatment was associated with an increased imipramine/desipramine AUC ratio, suggesting cimetidine-induced impairment of demethylation of imipramine. Ranitidine was not observed to alter imipramine pharmacokinetics.

Administration, Oral↗
PubMed1986

Fluorescence polarization immunoassay for ethosuximide evaluated and compared with two other immunoassay techniques.

We evaluated a new fluorescence polarization immunoassay (FPIA) for ethosuximide in the Abbott TDx and compared results with those by two other ethosuximide immunoassays, EMIT (Syva Co.) and aca (DuPont). The FPIA assay produced within- and between-day CVs of less than 5% at the low, medium, and high ranges of the standard curve. For the ethosuximide FPIA assay the standard curve was stable during the 47 days of the study. By all three methods, we analyzed 100 serum and plasma samples from patients who were receiving ethosuximide. The coefficient of determination (r2) for TDx versus EMIT was 0.973 (slope, 0.96; intercept, -0.80); for TDx vs aca it was 0.985 (slope, 1.00; intercept, -2.44); both relationships were statistically significant (p less than 0.05). Values for patient's specimens were significantly lower by the TDx than by the aca or EMIT methods (p less than 0.05).

Ethosuximide↗
PubMed1984

Methotrexate systemic clearance influences probability of relapse in children with standard-risk acute lymphocytic leukaemia.

108 children with standard-risk acute lymphocytic leukaemia (ALL) were randomised to a post-induction treatment protocol including 15 doses of intermediate-dose methotrexate (1000 mg/m2) in addition to conventional oral therapy of mercaptopurine and low-dose methotrexate. After median follow-up of 26 months, 22 patients have had relapses. Among the 108 patients, rates of methotrexate systemic clearance ranged from 44.7 to 132 ml/min/m2. When the group was divided into three subgroups according to the patients' rates of methotrexate clearance, statistical analysis of the Kaplan-Meier curves estimating the probability of complete remission showed significant differences (p = 0.016) among the subgroups, patients with faster clearance having higher probability of relapse. Multivariate Cox's regression analysis incorporating other potential prognostic variables identified three significant variables influencing the risk of relapse--methotrexate clearance and white-blood-cell count and haemoglobin level at diagnosis (p = 0.0015). This study has demonstrated the potential clinical importance of the rate of drug clearance in children with ALL.

Bone Marrow Examination↗