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Biomedical subjects

R A Fleming

Publications and source records attributed to R A Fleming.

At least 19 recordsLinked to original sources
PubMed1992

Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients.

Dihydropyrimidine dehydrogenase (DPD) is the initial key enzyme in the catabolism of 5-fluorouracil (5-FU). We measured DPD activity in lymphocytes from 57 consecutive head and neck cancer patients while simultaneously monitoring 5-FU pharmacokinetics during 5-day, continuous infusion (1000 mg/m2/day) 5-FU therapy (82 cycles in total). The mean value for DPD activity was 0.186 +/- 0.068 (SD) nmol/min/mg of protein (range, 0.058 to 0.357). The mean value for 5-FU clearance was 2522.6 +/- 684.2 ml/min/m2 (range, 1052 to 4029). A significant linear correlation was observed between DPD activity and 5-FU clearance (r = 0.716, P less than 0.0001). DPD activity was poorly correlated to plasma uracil concentrations (r = -0.260, P = 0.0215). Likewise, plasma uracil concentrations were poorly correlated to 5-FU clearance (r = -0.214, P = 0.0595). In patients evaluated for more than one cycle (n = 18), there was large intrapatient variability in both DPD activity and 5-FU clearance. No significant difference was noted between cycles for DPD activity or 5-FU clearance (Kruskal-Wallis test). Monitoring DPD activity in lymphocytes may be useful in identifying patients at risk for altered 5-FU disposition.

Adult↗
PubMed1992

Factors affecting in vitro protein binding of etoposide in humans.

Clinical studies have demonstrated that the plasma protein binding of etoposide, a widely used anticancer drug, is extensive (approximately 94%), highly variable among patients (10-fold range), and significantly related to serum albumin and total bilirubin concentration. The present study was designed to more thoroughly evaluate factors likely to affect etoposide protein binding under controlled in vitro conditions where single variables could be changed. Protein binding was determined using an equilibrium dialysis method with tritiated etoposide. The binding of etoposide was similar in serum or plasma, and heparin had no effect on binding. Etoposide binding decreased with increased pH, but no clinically significant difference was noted within the range of physiologic pH. Etoposide binding evaluated in single-source donor plasma was concentration-dependent over a concentration range of 1 to 250 micrograms/mL. Etoposide binding parameters determined in normal human plasma were characterized by a single class of binding sites of moderate affinity (K = 2.88 +/- 0.47 x 10(4)) and high capacity (nP = 5.07 +/- 0.5 x 10(-4); where n is the number of binding sites). The etoposide binding ratio was significantly correlated with albumin concentration (r2 = 99%, p less than 0.05). The characteristics of etoposide binding in a 4.0-g/dL solution of human serum albumin (K = 3.56 +/- 1.22 x 10(4) and nP = 5.58 +/- 0.16 x 10(-4)) suggest that the single class of binding sites is on albumin. Bilirubin caused a significant decrease in K, consistent with competitive binding, but only at higher bilirubin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Bilirubin↗
PubMed1992

An interlaboratory comparison of data on brain cholinesterase activity in forest songbirds exposed to aerial application of Zectran.

Zectran (4-dimethylamino-3,5-xylyl N-methyl-carbamate), a carbamate insecticide (active ingredient [AI] mexacarbate), was aerially applied to two 300 ha plots of coniferous forest at dosage rates of 70 and 140 g AI/ha, respectively. The brains of 288 birds collected from the treated areas and 84 birds from untreated areas were sagittally sectioned into approximately equal halves. Each of the laboratories participating in the study, the Forest Pest Management Institute (FPMI) and the Canadian Wildlife Service, Atlantic Region (CWS), assayed one half of each brain for cholinesterase (ChE) activity and the results were compared. The ChE estimates of the two laboratories on half brains from the same birds were poorly correlated (R = 0.136, P less than 0.05) and differed significantly (P less than 0.00005). The reasons for this are uncertain. Despite the discrepancy in ChE estimates, however, separate statistical analysis of each data set produced the same general conclusion: the ChE response to Zectran exposure was statistically significant but biologically unimportant. In both data sets, statistically significant ChE responses by niche and time since spraying were found. The dosage rate emitted from the airplane was a better predictor of ChE activity in the canopy niches than was volume deposited at ground level, but volume deposited was a more useful predictor for ground birds in most situations. These results are discussed in the context of a proposal to develop a reference file of normal brain ChE activities of common wildlife species.

Acetylthiocholine↗
PubMed1992

No effect of dose, hepatic function, or nutritional status on 5-FU clearance following continuous (5-day), 5-FU infusion.

One hundred and eighty seven patients (155 males, 32 females) with histologically proven and previously untreated head and neck cancer were entered in the study. A total of 222 cycles of therapy were analyzed (cisplatin 100 mg m-2 on day 1 and 5-day continuous intravenous infusion of 5-FU 550-1069 mg m-2 day-1, mean 875.5 mg m-2 day-1). Significant interpatient variability for various 5-FU pharmacokinetic parameters was observed including an almost ten-fold range in 5-FU clearance (5-FU Cl, ml min-1 m-2 = 791-7769, mean 2820.7). Log 5-FU Cl was not modified by 5-FU dose (r = -0.1034, P = 0.124, n = 222). Poor linear correlations between log 5-FU Cl and hepatic function tests were observed (respective r and P values for 222 cycles, log AST:0.0526, 0.4365; Log ALT: -0.1167, 0.0842; Log A1K. Phos.:0.154, 0.0214; Log GGT: 0.0652, 0.3436; Log LDH: -0.0984, 0.1563; Log bilirubin: 0.1278, 0.0601). The log 5-FU Cl was also poorly correlated with the serum concentration of various nutritional proteins (respective r and P values for 222 cycles, Albumin: 0.0110, 0.8714; prealbumin: -0.1067, 0.1129; transferrin: 0.0439, 0.5226). Laboratory data including indices of hepatic function and nutritional status cannot account for the interpatient variability in 5-FU disposition.

Blood Proteins↗
PubMed1992

Measurement of human exposure to ultraviolet-B solar radiation using a CR-39 dosimeter.

CR-39 (allyl diglycol carbonate) dosimeters were tested for measurements of ultraviolet-B (erythemal dose) solar radiation with a rotating model head and a human survey during solar exposure. The ratio of summer dose to winter dose for the vertex is 3.3, and for the eye and lower face is greater than 1. A survey suggests the relation of the ultraviolet-B dose to outdoor activities.

Face↗
PubMed1992

[Dihydropyrimidine dehydrogenase activity in lymphocytes: predictive factor for 5-fluorouracil clearance].

We previously have shown that pharmacokinetic monitoring of 5-fluorouracil (5-FU) could significantly improve the 5-FU therapeutic index when given in continuous venous infusion (Br J Cancer 59, 287-290, 1989). However, the more rational approach would be to find individual biological factors which could predict 5-FU clearance. Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-FU. DPD activity was measured in 57 head and neck cancer patients receiving CDDP (100 mg/m2, day 1) plus 5-FU (1 g/m2/day x 5, day 2-day 6). DPD activity was measured in lymphocytes using a radioenzymatic assay (2.5 mM MgCl2, 250 microM NADPH, 20 microM 14C-5-FU) with separation of 14C-5-FU from 14C-5-FUH2 by HPLC coupled with a radiodetector. The average DPD activity measured in lymphocytes was 0.186 +/- 0.068 nmol/min/mg protein (range 0.058-0.357) and the average 5-FU clearance (Cl) was 2,523 +/- 684 ml/min/m2 (range 1,052-4,029). A significant linear correlation was demonstrated between DPD activity and 5-FU clearance (Cl = 1,099 + 7,580 DPD, r2 = 0.613, P < 0.0001). In patients evaluated for more than one cycle (n = 18), variations in 5-FU clearance were associated with corresponding variations in DPD activity. The individual determination of DPD activity measured in lymphocytes could be useful for identifying patients at risk for altered 5-FU pharmacokinetics and could be used to adjust the optimal 5-FU dose for each patient before starting the treatment.

Adult↗
PubMed1991

Disposition of high-dose methotrexate in an obese cancer patient.

The disposition of many drugs in obesity is altered, although little is known of the effect of obesity on the pharmacokinetics of anti-cancer drugs. In this report the authors describe the pharmacokinetics of high-dose methotrexate in an obese woman (184% ideal body weight) with osteosarcoma. For this patient, both the volume of distribution at steady-state (0.398 l/kg) and systemic clearance (0.0956 l/h/kg) of methotrexate were increased compared with values observed in adult patients with osteosarcoma. The terminal elimination half-life (9.29 hours) of methotrexate was similar to other reported values in adult patients, thus indicating that increases in methotrexate volume of distribution and clearance may offset each other in obesity. Based on the experience gained from this patient, the authors suggest that renal function and methotrexate serum concentrations should be monitored in obese patients receiving high-dose methotrexate with leucovorin rescue.

Adult↗
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↗