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Biomedical subjects

J G Wagner

Publications and source records attributed to J G Wagner.

At least 55 records · Page 3Linked to original sources
PubMed1990

Estimation of the amount of alcohol ingested from a single blood alcohol concentration.

Capillary blood alcohol concentrations (BAL) measured in 22 young adult male volunteers each of whom received three different treatments of alcohol (total N = 66) have been related quantitatively to the dose of alcohol ingested. Linear regression with reasonably homogeneous variances have been found when the BAL at 2, 2.5 and 3 hr are divided by the person's body weight and plotted versus the g/kg (D/W) dose. Error analysis indicated that the least error in the predicted dose (D/W) was obtained for BAL measured at 2 hr post dosing. In the latter case the mean absolute error was 6.23%, 59% of the errors were within +/- 5% and 88% of the errors were within +/- 10%.

Adult↗
PubMed1989

Effects of altered platelet number on pulmonary hypertension and platelet sequestration in monocrotaline pyrrole-treated rats.

To study the role of platelets in monocrotaline pyrrole (MCTP)-induced pulmonary hypertension, pulmonary sequestration of 111In-labeled platelets in rats treated with MCTP and anti-rat platelet serum (PAS) was examined. Lung injury from a single, intravenous injection of MCTP (3.5 mg/kg) at Day 8 was evident as elevated lung weight and lavage fluid protein and lactate dehydrogenase activity. Additionally, right ventricular hypertrophy and elevated pulmonary arterial pressures (PAP) occurred. Treatment with PAS on Days 6-8 did not affect the lung injury but resulted in an attenuation of the pulmonary hypertensive response. Pulmonary platelet sequestration was also decreased in PAS-treated rats, yet the sequestration in the lungs of MCTP-treated rats that received PAS was significantly higher than that in the lungs of N,N-dimethylformamide (DMF) controls. MCTP-treated rats receiving control serum (CS) tended to sequester more 111In-labeled platelets than respective DMF controls, but this was not statistically significant. Blood platelet half-life was unaltered in rats receiving CS. When rats were treated similarly with MCTP and PAS and were killed at 18 days, the attenuation of the pulmonary hypertensive response previously described was not observed, and lung injury was more extensive than when CS was given. Apparently, platelet depletion delayed the development of the pulmonary hypertensive response. Supranormal platelet numbers produced by splenectomy did not affect MCTP-induced lung injury or the elevation in PAP. These results support the hypothesis that the development of MCTP-induced pulmonary hypertension is mediated in part by platelets.

Animals↗
PubMed1989

Gas chromatographic determination of gallopamil and norgallopamil in human plasma.

A highly sensitive gas chromatographic assay is described for the simultaneous determination of gallopamil, a calcium channel blocking agent, and its major metabolite, norgallopamil. A multi-step extraction procedure is employed followed by on-column capillary gas chromatographic analysis using nitrogen-selective detection. Acetylation of norgallopamil is performed to enable accurate quantification of the metabolite. Linearity was achieved over the range 1-50 ng/ml for both analytes. Assay specificity, precision and accuracy were investigated.

Chemical Phenomena↗
PubMed1989

5-Bromo-2'-deoxyuridine incorporation into DNA in hepatic VX2 tumor-bearing rabbits.

The halogenated pyrimidine 5-bromo-2'-deoxyuridine (BrdUrd) possesses both radiosensitizing and antimetabolite effects through its incorporation as a thymidine analog in replicating DNA. To evaluate the regional advantage for treatment of hepatic malignancy by hepatic arterial infusion, BrdUrd was infused into either the hepatic artery (HA) or a central vein (iv) in 26 rabbits with intrahepatic VX2 tumor. After a 24-hr constant rate infusion of 10, 20, or 40 mg/kg/24 hr, the percentage BrdUrd incorporation into the DNA of bone marrow, duodenal mucosa, liver, and hepatic VX2 tumor was measured by gas chromatography/mass spectrometry methods. VX2 tumor BrdUrd incorporation was greater by HA than by iv routes (P less than 0.001). At doses of 10 and 20 mg/kg/day, HA to iv BrdUrd incorporation ratios for VX2 tumor significantly exceeded those for bone marrow and duodenum (P less than 0.05). At appropriate dose rates, hepatic arterial administration of BrdUrd provides a regional advantage for DNA BrdUrd incorporation in the rabbit intrahepatic VX2 tumor.

Animals↗
PubMed1989

The theophylline-enoxacin interaction: II. Changes in the disposition of theophylline and its metabolites during intermittent administration of enoxacin.

The pharmacokinetics of theophylline and its three major metabolites, 3-methylxanthine, 1-methylurate, and 1,3-dimethylurate, were studied during intermittent administration of enoxacin. The addition of enoxacin (400 mg, twice daily) to a theophylline dosing regimen (150 mg, twice daily) resulted in an immediate fall in plasma theophylline metabolite concentrations. Mean steady-state theophylline concentration in plasma during the dosing interval increased from 3.17 to 8.23 micrograms/ml. The mean 12-hour recovery of total theophylline metabolite decrease from 76.3 to 38.6 mg. After the discontinuation of enoxacin, but not theophylline, the plasma theophylline metabolite levels immediately increased to near or above the concentrations observed before enoxacin coadministration. Concurrently, theophylline concentrations decreased to levels equivalent to those observed before enoxacin coadministration. In general, the changes in plasma theophylline concentrations observed after the addition of discontinuation of enoxacin were complete within 3 days.

Adult↗
PubMed1989

Steady-state arterial and hepatic venous plasma concentrations of 5-bromo-2'-deoxyuridine and 5-iodo-2'-deoxyuridine in animals--drugs which are subject to both splanchnic and extra-splanchnic elimination.

We have previously shown that 5-fluorouracil (FUra) in humans obeys Michaelis-Menten elimination kinetics. In this article we show that the related bromine and iodine-containing analogs in animals obey similar kinetics. Steady-state arterial (CssA) and hepatic venous plasma (CssV) concentrations of 5-bromo-2'-deoxyuridine (BrdUrd) are reported for 7 rabbits given 5 different infusion rates of BrdUrd and 5 dogs given 4 or 5 different infusion rates of BrdUrd. Steady-state arterial and hepatic venous plasma concentrations of 5-iodo-2'-deoxyuridine (IdUrd) are reported for 5 rabbits and 2 dogs given 5 different infusion rates of IdUrd. Each set of data could be fitted by a nonlinear least squares method to the equation: (equation; see text) where Vm/Q is the maximum difference, (CssA) - (CssV), and Km is the Michaelis constant. The estimated parameter Vm/Q and Km are compared for the two drugs and different species and also with the same parameters derived in the same manner from previously published data on fluorouracil in 8 cancer patients. The infusion rate needed to saturate the splanchnic elimination system (Rs in mumol/kg/min) was also estimated. For BrdUrd the mean value of Rs in the rabbit, namely 1.23, and in the dog, namely 1.25 mumol/kg/min are essentially the same.

Animals↗
PubMed1989

Parameters Vm' and Km for elimination of alcohol in young male subjects following low doses of alcohol.

Seventy-four (44 under fasting conditions and 30 following oral liquid meals) sets of post-absorptive human capillary blood alcohol concentration-time data were computer-fitted to the integrated form of the Michaelis-Menten equation by numerical integration by nonlinear least squares to provide 74 pairs of the kinetic Vm' and Km parameter values. The parameters were highly correlated (r = 0.915) by orthogonal least squares. Eight of the fasting subjects received four different oral doses of alcohol and fourteen subjects each received three different alcohol treatments. Intra-subject variances of Vm', Km and the ratio Vm' Km were calculated from the multiple treatments. Inter-subject variances were calculated from the 22 mean values of each parameter. Each parameter and the intra-subject variances of the parameters were found to be log normally distributed. The liquid meals (carbohydrate, fat and protein separately) appeared not to affect the parameter values. The computer fittings were all excellent as evidenced by the relatively small standard deviations of the estimated parameters and other statistical measures of fit.

Adult↗
PubMed1989

Pharmacokinetics of flurbiprofen in man. II. Plasma protein binding.

The plasma protein binding of flurbiprofen was studied using equilibrium dialysis. Dialysis was carried out using plasma samples obtained from five of 15 subjects participating in a crossover bioavailability study. During the course of this study subjects received doses of 100, 200, and 300 mg of flurbiprofen as tablets, and 100 mg as an aqueous solution. Seven samples from each of the four treatments (28 samples/subject) were utilized. An additional 14 samples (seven concentrations prepared in duplicate were prepared using blank plasma obtained from each subject. Concentrations of bound (Cbd) and free (Cfd) flurbiprofen were determined at dialysis equilibrium using a radiotracer technique. Binding curves were constructed for each subject using data obtained from these 42 (28 ex vivo and 14 in vitro) samples. The data was well fitted to a modified Scatchard equation with the addition of a linear term. Although the plasma protein binding of flurbiprofen was nonlinear, within the range of concentrations encountered in the clinical setting, it is minimally so. The Cb/Cf ratio averaged 1524, indicating that in plasma, flurbiprofen is greater than 99.9% bound. The results support the observation that for doses of flurbiprofen usually encountered clinically, the drug obeys linear kinetics.

Adult↗
PubMed1988

Tissue-specific pharmacodynamics of 5-bromo-2'-deoxyuridine incorporation into DNA in VX2 tumor-bearing rabbits.

The thymidine analog 5-bromo-2'-deoxyuridine (BrdUrd) is felt to exert its cytotoxic effects primarily through incorporation into DNA. We have evaluated the incorporation of BrdUrd into the DNA of relevant normal tissues (bone marrow, gut mucosa, and liver) and tumor in rabbits with the VX2 tumor growing intrahepatically. Using constant i.v. infusions, steady state plasma drug concentrations ranging from 0.4 to 65.4 microM were maintained for 24 h and tissues were harvested and processed so that a sensitive gas chromatography/mass spectrometry (GC/MS) method could be used to analyze the thymine and 5-bromouracil content of hydrolyzed DNA. In all tissues, DNA incorporation showed saturating effects as plasma BrdUrd concentration was increased and, BrdUrd incorporation as a function of plasma concentration could be fitted to a Langmuir-like equation generating tissue-specific pharmacodynamic parameters: Imax for percentage thymine replacement at infinite plasma BrdUrd concentrations, and C50 for the arterial BrdUrd concentration generating incorporation that is Imax/2. At all plasma concentrations of BrdUrd the incorporation into DNA of bone marrow was greater than that observed in VX2 tumor. However, BrdUrd labeling index (with a BrdUrd monoclonal antibody) was greater in tumor than bone marrow. Thus, pharmacodynamic differences in incorporation do not result solely from cytokinetic differences between tissues. This model may prove useful in evaluating the pharmacodynamics of incorporation in studies using hepatic arterial infusion and biochemical modulation to improve selectivity.

Animals↗
PubMed1988

Improved high-performance liquid chromatographic assay for the quantification of 5-bromo-2'-deoxyuridine and 5-bromouracil in plasma.

A sensitive and specific procedure using high-performance liquid chromatography (HPLC) was developed for the quantification of 5-bromo-2'-deoxyuridine (BUdR) and 5-bromouracil (BU) in plasma. BUdR and BU were first extracted with a mixture of ethyl acetate and 2-propanol from plasma presaturated with solid ammonium sulfate. Following evaporation of the organic extract, the remaining residue was reconstituted in saturated ammonium sulfate solution, washed with a mixture of n-pentane-methylene chloride and re-extracted with the original solvent mixture. The organic extract was evaporated, reconstituted in mobile phase and chromatographed on a regular-bore ODS HPLC column using ultraviolet absorbance detection. The BUdR and BU quantification limits were both 0.1 microM, the mean intra-assay coefficients of variation were 5.0 and 5.6%, respectively, and the mean inter-assay coefficients of variation were 5.4 and 10.7%, respectively. This method was used to determine steady-state femoral arterial and hepatic venous plasma concentrations of BUdR and BU in a patient receiving a continuous intravenous infusion of BUdR (20 mg/kg per day).

Aged↗
PubMed1988

Radiosensitivity of head and neck cancer cells in vitro. A 96-well plate clonogenic cell assay for squamous cell carcinoma.

Radiation sensitivity was determined for nine University of Michigan squamous cell carcinoma (UM-SCC) cell lines, MCF-7 and HeLa, using a 96-well plate clonogenic assay. Plating efficiencies (PE) of the UM-SCC cell lines were between 0.16 and 0.36. Higher PE values obtained were with MCF-7 (0.4) and HeLa (0.5). The UM-SCC cell lines were used at low passages (passage 13 to passage 20) to minimize artifacts attributable to long-term culture. Cells were irradiated in suspension using a cobalt 60 gamma source at a dose rate of 0.94 Gy/min (94 rad/min). Survival data were fitted well by either a linear quadratic function F = e-(alpha D + beta D2) or by a monoexponential function F = Ae-alpha D. Mean inactivation dose, equivalent to the area under the survival curve (AUC), was used as a measure of radiation sensitivity. The UM-SCC-1, 9, 11A, 11B, MCF-7, and HeLa were the most radiation resistant lines we tested (AUC greater than 2.1), while UM-SCC-14A was the most sensitive (AUC = 1.591). The assay was highly reproducible, and the difference in radiation sensitivity between cell lines were statistically significant.

Carcinoma, Squamous Cell↗
PubMed1988

The intraperitoneal delivery of radiolabeled monoclonal antibodies: studies on the regional delivery advantage.

The i.p. delivery of murine monoclonal antibody was compared with i.v. delivery in normal mice and rats, in normal nude mice and in those with i.p. human ovarian carcinoma xenografts. In normal rats, all classes of antibodies and antibody fragments evaluated were cleared from the peritoneal cavity at comparable rates. The regional delivery (Rd1) advantage to the peritoneal cavity following i.p. delivery was thus most dependent on the rate of clearance of the antibody or fragment from the blood stream. Determining the exact i.p. delivery advantage was problematic due to the difficulty in reliably obtaining peritoneal fluid later than 9-10 h after i.p. injection in normal animals. During the first 9 h following i.p. injection, the Rd(0-9/0-9) was, for a murine IgG2ak Fab greater than F(ab')2 greater than IgG (at 13.6 greater than 10 greater than 7.9). Two murine IgMs evaluated differed in Rd(0-9) at 27.1 and 9.2 respectively. When blood levels were extrapolated to infinity, these Rd (0-9/affinity) values were considerably lower with the Fab having the highest Rd at 4.67. The i.p. Rd advantage was almost solely due to the i.p. antibody levels seen in the first 24 h after injection, as after that time, blood levels become comparable to those seen following i.v. injection. Normal tissues obtained at sacrifice 5-7 days after i.p. injection. Normal tissues obtained at sacrifice 5-7 days after i.p. or i.v. injection in rats showed comparable levels of radioantibody activity, whether the injection was i.p. or i.v. (except for higher diaphragmatic levels following i.p. delivery). In nude mice with i.p. human-derived ovarian tumors, intact IgG clearance from the peritoneal cavity to the blood was considerably slower than in normal animals, and early i.p. tumor uptake of specific antibody was significantly higher than that following i.v. antibody delivery. With higher early tumor uptake and lower systemic exposure, early tumor/nontumor ratios were significantly greater than those for i.v. delivery, though not beyond 48 h after i.p. injection. This study demonstrates the pharmacokinetic rationale for i.p. monoclonal antibody delivery, especially for agents cleared rapidly from the blood, such as antibody fragments. In addition, definite i.p. delivery benefit for antibody specific to i.p. tumors in the i.p. ovarian cancer system was shown soon after injection. These data regarding i.p. antibody delivery should be useful in rationally planning diagnostic and therapeutic studies involving the i.p. delivery of unmodified and immunoconjugated monoclonal antibodies.

Animals↗
PubMed1988

Clinical applicability of current pharmacokinetic models: splanchnic elimination of 5-fluorouracil in cancer patients.

What can be inferred from limited clinical data by using current models of hepatic elimination? We examined this question by analyzing previously published data on the steady-state uptake of the anticancer agent 5-fluorouracil (5-FU) in seven cancer patients in terms of the venous equilibration model, the undistributed and distributed forms of the sinusoidal perfusion model, and the convection-dispersion model. Because of appreciable extrasplanchnic removal of 5-FU, the value of the steady infusion rate was not used in our analysis. When the data from all patients were pooled by plotting the measured hepatic venous concentration against the measured hepatic arterial concentration, the high concentration data fell on a limiting straight line of slope 1, indicating that at high dose rates elimination of 5-FU in both the liver and gastrointestinal tract was close to saturation. The intercept of this line gave a model-independent estimate of Vmax/Q = 48.0 +/- 11.6 (SD) microM for the pooled data set, where Vmax is the maximum splanchnic elimination rate of 5-FU, and Q is the hepatic blood flow. The low concentration data points fell on a limiting straight line through the origin, from which model-dependent values of the Michaelis constant were determined. The venous equilibration model gave Km = 9.4 microM, while the undistributed sinusoidal perfusion model gave Km* = 26.5 microM. With these values of Km, both models fit the pooled data equally well. These methods were applied to analyses of the five individual data sets which contained sufficiently high concentration data points. The resulting mean values were Vmax/Q = 41.0 +/- 5.1 (sem) microM, Km = 8.4 +/- 1.3 microM and Km* = 23.2 +/- 3.2 microM. However, the splanchnic region is a highly heterogeneous organ system, for which an undistributed analysis provides no more than an upper bound on the Michaelis constant Km+ (Km+ less than or equal to Km*). A perfusion model distributed to represent total splanchnic elimination is developed in the Appendix. Using previous estimates of the degree of functional heterogeneity in the liver alone, this model yields Km+ values for individual patients which have a mean of 20.3 +/- 2.8 microM.

Fluorouracil↗
PubMed1988

Dynamics of bromodeoxyuridine incorporation into DNA of squamous carcinoma cells during mid and late logarithmic growth.

Head and neck squamous carcinoma cell lines, UM-SCC 1, 5, 9, 11B, and 14B, were exposed in vitro to bromodeoxyuridine (BUdR) during logarithmic growth to determine the effects of drug concentration (0.01 to 10 microM) and duration of exposure (3, 7, and 10 days) on cell growth and on incorporation of BUdR into DNA. Concentrations of less than 1.0 microM were not growth inhibitory except with UM-SCC-11B. After 10 days of exposure to 5 microM BUdR, survival fractions for all lines ranged from 2 to 65% of controls. Replacement of thymidine by BUdR in DNA was assessed by gas chromatography/mass spectroscopy. Percentage replacement (% R) was described by the equation % R = 100 (C/t)s/[(C/t)50s + (C/t)s], where C is the concentration of BUdR (microM), t is the time in days, s is a constant, and (C/t)50 is a constant corresponding to % R = 50%. BUdR incorporation reached a time- and concentration-dependent maximum that, after 3 to 7 days of culture in 10 microM BUdR, ranged from 30 to 60% R. Subsequently, % R declined with time even though the cells were fed daily with fresh BUdR-containing medium.

Bromodeoxyuridine↗
PubMed1988

The theophylline-enoxacin interaction: I. Effect of enoxacin dose size on theophylline disposition.

Theophylline interacts pharmacokinetically with a variety of other drugs. Recently enoxacin was found to change theophylline's disposition. In a four-subject, four-way crossover study enoxacin was administered every 12 hours at four levels (0, 25, 100, and 400 mg) for 14 doses. With the ninth dose of enoxacin, 200 mg theophylline was coadministered. Blood and urine samples were assayed by sensitive and specific assays for the parent drugs and their metabolites. Significant reduction in the formation of theophylline's three major metabolites occurred on coadministration of enoxacin. At the 400 mg dose level, enoxacin caused a threefold decrease in theophylline's plasma clearance, a fourfold decrease in the urinary recovery of 3-methylxanthine and 1,3-dimethylurate, and a threefold decrease in the recovery of 1-methylurate.

Adult↗
PubMed1988

Pulmonary hypertension due to monocrotaline pyrrole is reduced by moderate thrombocytopenia.

To elucidate further the role of the platelet in the development of monocrotaline pyrrole (MCTP)-induced lung injury and pulmonary hypertension, MCTP-treated rats were made thrombocytopenic by cotreatment with an anti-rat platelet serum (PAS). Lung injury was assessed from increases in lung weight, lavage fluid protein concentration, and lactate dehydrogenase activity and from accumulation in lung tissue of 125I-labeled albumin. These indexes of injury were not different in MCTP-treated rats with normal or reduced platelet numbers at day 4,8, or 14. In MCTP-treated rats not receiving the PAS, pulmonary arterial pressure was elevated by day 8. However, pulmonary arterial pressure was the same as controls at both day 8 and day 14 in MCTP-treated rats made moderately thrombocytopenic by cotreatment with PAS. More marked reduction of platelet number abolished the protective effect of thrombocytopenia against pulmonary hypertension. In a separate series of experiments, treatment with antibodies to platelet-derived growth factor (PDGF), a potential mediator in the response to MCTP-induced injury, did not protect rats from the cardiopulmonary effects of MCTP. These data indicate that moderate reduction of the number of circulating platelets prevents MCTP-induced pulmonary hypertension but not MCTP-induced lung injury, suggesting that the platelet is involved in the pulmonary hypertensive response to MCTP-induced lung injury by unknown mechanisms.

Animals↗
PubMed1988

Direct method of simulating concentration-time data for Michaelis-Menten elimination.

For pharmacokinetic models such as those indicated by the title, one obtains an implicit equation in concentration, which cannot be used to directly obtain a value of C corresponding to a given value of t. Usually numerical integration is employed to simulate concentration-time data. By introducing f = concentration (C)/initial concentration (C0), or f = C/steady-state concentration (Css), one can replace C by either fC0 or fCss then obtain time as an explicit solution, by letting f equal an arbitrary series of values such as 0.95, 0.9, . . . 0.05, 0.04, . . . , 0.01 when C0 is involved, or 0.05, 0.10, . . . , 0.95 when Css is involved. This procedure allows data to be simulated with just a pencil and paper, a hand-held calculator, or a microcomputer. The accuracy of the method depends only on the number of decimal places carried during the calculations. The method can provide a series of C, t values where delta C is constant, whereas with numerical integration one obtains a series of C, t values where delta is constant.

Humans↗