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Biomedical subjects

R A Fleming

Publications and source records attributed to R A Fleming.

At least 55 records · Page 3Linked to original sources
PubMed1991

Aspirin alters methotrexate disposition in rheumatoid arthritis patients.

Intravenous methotrexate (MTX) (10 mg), either alone or with oral aspirin (ASA) (3,900 mg/day), was administered to 15 patients with rheumatoid arthritis. Systemic and renal clearance of MTX were lower, and the unbound fraction of MTX was higher when patients were also receiving ASA than when taking MTX alone. No acute hematologic, renal, or hepatic toxicity was observed with either treatment. The findings of this study therefore indicate that concomitant aspirin therapy acutely alters the clearance of low-dose MTX in patients with rheumatoid arthritis.

Administration, Oral↗
PubMed1991

Relation of systemic exposure to unbound etoposide and hematologic toxicity.

The pharmacodynamics of total and unbound etoposide was studied in 28 adult patients with solid tumors who were receiving etoposide and cisplatin combination chemotherapy. Etoposide plasma concentrations were determined by use of an HPLC method, and etoposide plasma protein binding was determined by equilibrium dialysis. Patients with higher systemic exposure experienced greater hematologic toxicity. The sigmoid maximum effect model with unbound systemic exposure performed better (i.e., lower residual sum of squares) than the model using total systemic exposure; in all patients (7043 versus 9755) and in the subset of patients who had not received previous chemotherapy (1986 versus 3664). The model estimates for unbound systemic exposure were more precisely estimated than for total systemic exposure (e.g., coefficient of variation for the area under the concentration-time curve producing half of the maximal effect = 51% for total drug versus 21% for unbound drug). These findings indicate that the hematologic toxicity of etoposide is better correlated with systemic exposure to unbound drug than total drug, which may be of clinical importance because of the variable plasma protein binding of etoposide.

Adult↗
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

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

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

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↗
PubMed1982

Digital and sampled-data control of arterial blood pressure during halothane anesthesia.

A control system that maintains mean arterial pressure (MAP) at a desired level by automatically controlling halothane input has been developed. The control system is a discrete, digital type and is implemented with a small desk-top programmable calculator. Essentially, if MAP decreases, the inspired concentration of halothane will decrease; if MAP increases, the system will compensate by increasing inspired halothane concentration. The control system was tested in two ways: with a hybrid computer model of uptake and distribution of halothane and with dog experiments. The results indicate that (a) the model can be used to predict the response of the animal-anesthesia machine control system, and (b) the proposed algorithm is successful in controlling one anesthetic agent with one physiologic variable.

Anesthesiology↗