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Biomedical subjects

A E Staubus

Publications and source records attributed to A E Staubus.

At least 19 recordsLinked to original sources
PubMed1990

Boron neutron capture therapy of a rat glioma.

The purpose of the present study was to utilize a well-established rat glioma to evaluate boron neutron capture therapy for the treatment of malignant brain tumors. Boron-10 (10B) is a stable isotope which, when irradiated with thermal neutrons, produces a capture reaction yielding high linear energy transfer particles (10B + 1nth----[11B]----4He(alpha) + 7Li + 2.79 MeV). The F98 tumor is an anaplastic glioma of CD Fischer rat origin with an aggressive biological behavior similar to that of human glioblastoma multiforme. F98 cells were implanted intracerebrally into the caudate nuclei of Fischer rats. Seven to 12 days later the boron-10-enriched polyhedral borane, Na2B12H11SH, was administered intravenously at a dose of 50 mg/kg body weight at varying time intervals ranging from 3 to 23.5 hours before neutron irradiation. Pharmacokinetic studies revealed blood 10B values ranging from 0.33 to 10.5 micrograms/ml depending upon the time after administration, a T1/2 of 6.2 hours, normal brain 10B concentrations of 0.5 microgram/g, and tumor values ranging from 1.1 to 12.8 micrograms/g. No therapeutic gain was seen if the capture agent was given at 3 or 6 hours before irradiation with 4 x 10(12) n/cm2 (10 MW-min; 429 cGy). A 13.5-hour preirradiation interval resulted in a mean survival of 37.8 days (P less than 0.01), compared to 30.5 days (P less than 0.03) for irradiated controls and 22.1 days for untreated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Pharmacokinetics of 2-F-ara-A (9-beta-D-arabinofuranosyl-2-fluoroadenine) in cancer patients during the phase I clinical investigation of fludarabine phosphate.

Fludara I.V. (fludarabine phosphate) (2-F-ara-adenosine monophosphate [2-F-ara-AMP], NSC 312887) is the 5'-phosphate of 2-F-ara-A-(9-beta-D-arabinofuranosyl-2-fluoroadenine), a derivative of ara-A that is resistant to deamination and selectively inhibits DNA synthesis. Concurrent with the phase I evaluation of 2-F-ara-AMP administered as a single intravenous (IV) bolus every 21 days to patients with advanced malignancy, plasma pharmacokinetic profiles of 2-F-ara-A were determined in 30 patients following the rapid infusion (2 to 5 minutes) of doses of 2-F-ara-AMP ranging from 80 to 260 mg/m2. The parent drug was almost quantitatively converted to 2-F-ara-A by apparent first-pass metabolism, with maximum levels of 2-F-ara-A and very low levels (less than 1 fmol/L) of 2-F-ara-AMP observed only in the plasma samples obtained shortly after dosing (2 to 4 minutes). The plasma concentration-time profiles exhibited three exponential phases. Plasma concentrations were computer fitted to a three-compartment open model using a zero-order input function for the injection period. The 2-F-ara-A harmonic mean half-lives were t1/2 alpha = 4.97 minutes, t1/2 beta = 1.38 hours, t1/2 gamma = 10.41 hours, and the mean residence time was 10.51 hours. The rate-limiting process for elimination of the drug from the body appeared to be release from tissue binding sites. The mean total-body plasma clearance was 67.98 +/- 19.58 mL/min/m2 (mean +/- SD). The mean central compartment volume of distribution (V1) was 7.49 L/m2 or 0.20 L/kg. The mean steady-state volume of distribution (Vdss) was 44.17 L/m2 or 1.19 L/kg, indicating that 2-F-ara-A is distributed and bound to the tissues of the body. Total-body clearance and the volume parameters Vdss and Vd gamma decreased with an increase in serum creatinine, indicating that these pharmacokinetic parameters depend upon renal function. Dose reduction in patients with renal dysfunction is recommended.

Antimetabolites, Antineoplastic↗
PubMed1989

DISIDA kinetics measure liver function in dogs.

We have investigated the ability of 99Tcm-disofenin (DISIDA) kinetics to measure liver function. Two approaches have been used: first, quantitative analysis of serial liver images, and second, clearance estimation from whole blood concentration-time data. Graded liver dysfunction was produced in 11 dogs over three months by common bile duct ligation and surgical relief of biliary obstruction one month later. The kinetic analysis of serial liver images showed clear abnormalities during biliary obstruction, with calculated rates of liver uptake falling in stages from 11.09 to 5.15 cts s-1 (p less than 0.001), and rates of elimination from the liver from 8.8 to 1.6 x 10(-4) cts s-1 (p less than 0.0001). These parameters paralleled the deterioration and recovery of liver function through the experimental period, and had not fully recovered 7 weeks after relief of biliary obstruction (10.5 and 6.2 x 10(-4) cts s-1 respectively). Serial blood sampling after injection of DISIDA permitted calculation of whole blood disposition rates (for hepatic clearance). Mean values fell from 256 to 67 ml min-1 with chronic biliary obstruction (p less than 0.001), and returned to almost normal (206 ml min-1) 10 days after surgical relief of biliary obstruction. It is clear that the gradual nature of recovering liver function was more sensitively identified by image analysis than serial blood data. Serial liver biopsies showed marked changes following biliary obstruction. These improved over a period of 7 weeks following its relief, when there was still considerable residual abnormality. This work supports the view that hepatic abnormalities caused by biliary obstruction do not recover quickly following its relief. DISIDA kinetics can quantitate both major and minor degrees of hepatic dysfunction, and may prove to be a valuable method to quantitative liver function.

Animals↗
PubMed1988

Limited sampling models for amonafide (NSC 308847) pharmacokinetics.

The limited sampling model (LSM) offers a means of estimating the area under the concentration-time curve (AUC) from only two timed plasma concentrations. In this study, pharmacokinetic profiles were simulated for 23 patients treated with amonafide, using each patient's individual pharmacokinetic parameters. Data were simulated for a dose of 250 mg/m2 administered over 1 h. The initial 15 patients formed the training data set. Based on the training data set, five different LSMs were generated, with the multiple r ranging from 0.92 to 0.98. A single model was selected as optimal: AUC (micrograms min/ml) = 292.9 (min) C45 (micrograms/ml) + 3262 (min) C1440 (micrograms/ml) + 21.8 (micrograms min/ml) dose (mg/m2)/250 mg/m2 where C45 = 45-min plasma concentration and C1440 = 24-h plasma concentration. This model was revalidated on a second test data set of seven patients actually treated with a 1-h infusion. The relative root mean square predictive error was 15.8%, acceptable for most clinical uses. We conclude that the LSM is a powerful tool for estimation of the AUC in a large patient population. The LSM may facilitate population pharmacodynamic studies in conjunction with Phase II trials.

Adenine↗
PubMed1988

Phase I clinical investigation of fludarabine phosphate by a loading-dose and continuous-infusion schedule.

Fludarabine phosphate was studied in a phase I trial of a loading-dose/continuous-infusion schedule. The schedule was chosen to rapidly achieve and maintain concentrations that have been shown in vitro to achieve maximal inhibition of cell growth. The initial level was a loading dose of 20 mg/m2 followed by a 48-hour continuous iv (CIV) infusion of 30 mg/m2 every 24 hours. For the single-dose escalation, the loading dose was held constant while the CIV dose was increased to 45 mg/m2/24 hours for 48 hours. The dose-limiting toxicity was myelosuppression, especially leukopenia. No other significant toxicity was encountered. The maximum tolerated dose was 20 mg/m2 by iv push followed by a 48-hour CIV infusion of 30 mg/m2/24 hours for 48 hours. The recommended starting dose for phase II trials is 20 mg/m2 by iv push followed by a 48-hour CIV infusion of 30 mg/m2/24 hours. This dose level achieved the target plasma levels in the 2 patients studied.

Adult↗
PubMed1988

Pharmacokinetic studies of DISIDA disposition. I. Animal studies.

The whole blood pharmacokinetics of intravenously administered 99mTc-disofenin (DISIDA) have been studied in dogs. Serial blood sampling permitted calculation of whole blood disposition rates, which principally represent liver clearance. There were striking differences in these rates between 6 normals and 7 animals in whom liver damage was induced by chronic bile duct ligation (256 vs 58 ml/min, P less than 0.001). Blood levels of radioactivity fell in a biexponential fashion characterized by rapid and slow disposition phases, whose half times were 2.4 and 58 min in normal animals. On 3 occasions, plasma was obtained from 1 animal by exsanguination 35 min after the administration of DISIDA and rapidly transfused into a 2nd animal. The whole blood pharmacokinetics of the second (recipient) animal showed a predominance of the slow disposition phase and a small rapid phase. The hepatic extraction ratio of blood radioactivity was measured in 3 dogs and was high (75%-90%) early after injection of DISIDA, but fell rapidly to remain around 10%. These experiments suggest the presence of two different species in the radiopharmaceutical studied, each being removed from the blood stream by the liver, but at different rates. The contribution of renal clearance to overall whole blood pharmacokinetics was negligible, since three nephrectomized dogs displayed similar pharmacokinetics to normals. Whole blood DISIDA pharmacokinetics are more complex than previously thought but appear to be capable of providing an accurate measure of liver function.

Animals↗
PubMed1988

Pharmacokinetic studies of DISIDA disposition. II. Clinical studies.

The whole blood pharmacokinetics of intravenously administered 99mTc-disofenin (DISIDA) has been studied in normal subjects and patients with documented liver disease. The apparent overall whole blood disposition rates of radioactivity were calculated from serial blood data, in order to evaluate liver clearance of DISIDA. The measurements obtained clearly discriminated 9 normal subjects from 7 patients with severe liver disease causing jaundice--1233 mls/min vs 384 mls/min (P less than 0.002). Nine subjects with liver disease of insufficient severity to cause jaundice also had clearly abnormal DISIDA disposition--642 ml/min (P less than 0.05 for difference to controls). The time activity curves from all subjects showed biexponential elimination of blood activity, with a rapid (T1/2 = 3.8 min) and a slow disposition phase (T1/2 = 75 min) in normals. These curves were fitted by computer to the timed rate of hepatic uptake, simultaneously obtained by gamma imaging over the liver. It was not possible to satisfactorily fit these using a model which assumed distribution of a single compound within two body compartments. However, another which assumed the administration of two radioactive agents satisfactorily fitted the two types of data. This conclusion is consistent with our animal experiments which indicate the existence of two compounds in injected DISIDA with contrasting high and low hepatic extraction efficiency (Fraser et al. 1988). A pharmacokinetic approach to DISIDA disposition can yield quantitative information which discriminates different degrees of liver dysfunction, but the mechanisms involved are more complicated than previously thought, so that further study should permit very precise quantification.

Adult↗
PubMed1988

An area function method for estimating the apparent absorption rate constant.

A new method for calculation of the apparent absorption rate constant of a drug has been derived based on the relationship between the plasma concentrations after an oral dose and the area intervals under both the oral and the intravenous plasma concentration-time curves. The method is a noncompartmental technique evolved from the convolution integral and does not use any theoretical approximation. It has been evaluated and compared with nonlinear regression analysis using NONLIN84 and moment analysis using both errorless and errant data. The approach is as adequate as nonlinear regression analysis under a variety of conditions but offers ease and simplicity in handling experimental data.

Administration, Oral↗
PubMed1987

Parenteral nutrition: short term effects on hepatic clearance of sodium taurocholate and indocyanine green.

Total parenteral nutrition (TPN) is thought to induce cholestasis. However, serum hepatic enzyme abnormalities were found in 70 percent of patients before TPN was started. Rate constants (alpha, beta, K(E] and total clearance (CIT) of sodium taurocholate (STC) and indocyanine green (ICG) were studied in 20 carefully selected patients not on TPN and who had no hepatic or renal disease. Clearance measurements were made prior to initiation and 7 days into dextrose-based TPN. Four modes of TPN administration were used; low calorie (35 cal/kg) versus high calorie (50 cal/kg), with or without protection of TPN solutions from ultraviolet light. Protein doses for all groups were isonitrogenous. TPN was uninterrupted and no patient had surgery, other major procedures, or food by mouth. While serum gamma-glutamyl transpeptidase (GGT) increased, no STC or ICG clearance parameter (total or subgroup) changed in response to TPN. These data do not support the hypothesis that TPN directly causes cholestasis, but suggest that cholestasis caused by concurrent liver disease may appear aggravated by TPN.

Adult↗
PubMed1986

Disposition of 8-methoxypsoralen in the rat: methodology for measurement, dose-dependent pharmacokinetics, tissue distribution and identification of metabolites.

The pharmacokinetics and metabolism of 8-methoxypsoralen (8-MOP) were measured in the catheterized rat after a single i.v. dose. Blood samples were collected serially and analyzed using a sensitive and specific assay for [14C]-8-MOP. Total body clearance of 8-MOP was 7.3, 3.9, 1.7, 1.0, 0.78 and 0.42 liters/kg/hr at doses of 0.2, 1.0, 2.5, 5.0, 10 and 20 mg/kg, respectively. The decline in total body clearance indicates that elimination of 8-MOP is dose-dependent in the rat. After i.v. administration of 10 mg/kg of 8-MOP, 71 and 26% of the dose was recovered within 72 hr in the urine and feces, respectively. Unchanged 8-MOP accounted for less than 1% of the excreted radioactivity. In tissue distribution studies at 0.5, 2 and 5 hr after i.v. administration, 8-MOP distributed rapidly to all tissues and concentrated in the fat and kidneys. The concentration of 8-MOP in the skin was 0.4 to 0.6 times that in the blood. Eleven metabolites of 8-MOP were detected in the urine. The metabolites identified after enzymatic hydrolysis were 8-hydroxypsoralen; 5-hydroxy-8-methoxypsoralen; 5,8-dihydroxypsoralen; 5,8-dioxopsoralen; 6-(7-hydroxy-8-methoxycoumaryl)-acetic acid and 8-MOP (formed by ring closure of a coumaric acid metabolite). Thus, these studies indicate that 8-MOP is metabolized in the rat by 1) O-demethylation; 2) hydroxylation at position 5; 3) hydrolysis of the lactone ring and 4) oxidation of the furan ring, a pathway already confirmed in insects, dogs and humans.

Animals↗
PubMed1985

Measurement of water kinetics with deuterium oxide in lactating dairy cows.

Following intravenous infusion with approximately 300 mg deuterium oxide per kg body weight, blood was drawn from lactating Holsteins (Trial 1, n = 4, and Trial 2, n = 5) at suitable intervals for up to 12 days while the cows were maintained on dietary regimens to which they were well adapted. Time results for deuterium oxide concentration in blood were described best by the three-compartment open model system, which showed that the central, shallow peripheral, and deep peripheral body water compartments contained 27.1, 25.0, and 23.2% body weight in trial 1 and 33.7, 27.1, and 19.9% body weight in trial 2. Total body water estimates averaged 75.3 and 80.7% body weight during trials 1 and 2. Estimates for biological half-life of water were 4.6 and 3.2 days and those for water turnover were 68.9 and 109.7 liters/day, respectively. The data fitted the two-compartment open model system when observations made prior to 25 min post-administration were excluded from the analyses, because the central and shallow peripheral compartments were apparently lumped into one. Blood sampling at 0.5, 1, and 1.5 days following infusion and thereafter at 1-day intervals was adequate for the estimates of the one compartment open model system. Estimates of total body water, water biological half-life, and water turnover were similar for the different models. It is concluded that the three-compartment open model provides greater detail and insight into the water dynamics of lactating dairy cows having regular access to food and water, whereas the two- and one-compartment open model systems provide good approximations only.

Animals↗
PubMed1979

Plasma naltrexone kinetics after intravenous bolus administration in dogs and monkeys.

This investigation generated data characterize a specific electron-capture GLC assay reported previously for naltrexone and applied the method to a determination of naltrexone pharmacokinetics. Extraction efficiencies are reported for the assay, and mass spectral evidence indicates that naltrexone forms a triester when derivatized for electron-capture GLC with pentafluoropropionic anhydride and a base catalyst. Plasma level-time data for intravenous naltrexone at two dose levels in monkeys yielded no evidence of dose-dependent kinetics. A two-compartment open pharmacokinetic model was fitted to plasma level-time data for naltrexone in two dogs and yielded a total body clearance of 51-55 ml/min/kg. Urine collected for 0-24 hr contained 36% of the dose as naltrexone conjugates with less than 1% as unchanged naltrexone. Plasma level-time data for intravenous naltrexone in six monkeys yielded an average terminal half-life of 7.8 hr and a total body clearance of 64 ml/min/kg. The total body clearance for naltrexone was greater than the hepatic plasma or blood flow in both dogs and monkeys. This finding, together with the extremely low renal excretion of naltrexone, suggests the existence of elimination mechanisms besides liver metabolism and renal excretion.

Animals↗
PubMed1979

Urinary iodine excretion rates following intrathecal injections of iodinated organic carbonates.

Oily iodinated organic carbonates were investigated for use as myelographic media. The urinary excretion of total iodine was used to monitor the apparent elimination rate of these compounds from the subarachnoid space. Within the chain length series of C2-C6, the decrease of elimination rates and disposition rate constants with increasing chain length was demonstrated. This observation is consistent with a dissolution rate-limited elimination model. Such a model was derived and successfully NONLIN computer fitted to the observed elimination data. The model-derived parameter of clearance from the cerebrospinal fluid through the lipid "blood-brain barrier" correlated well with the compound's water solubilities and projected octanol-water partition coefficients. Additional compounds need to be tested to evaluate the postulated model system.

Animals↗
PubMed1978

Oral cytembena absorption and phase I--II studies.

Cytembena is a nonmyelosuppressive drug that has received phase I--II trials in this country and is presently being used as a chemotherapeutic agent in Europe. Sterile abscesses at the site of im injection and "autonomic storm" after iv bolus represent the most frequent dose-limiting toxic effects, and intermittent schedules reflect reports of prolonged plasma levels of drug. This report of excellent oral absorption and a short half-life suggests that alternative routes and schedules of administration should be evaluated. The dose-limiting toxic effects observed after frequent oral administration were transient proteinuria and increased creatinine levels.

Acrylates↗
PubMedDate not supplied

Saturation kinetics of iopanoate in the dog.

Experiments were carried out in dogs with a modified Thomas cannula in the duodenum through which the common bile duct could be catheterized. Constant intravenous infusion of sodium iopanoate at different infusion rates greater than the apparent excretion maximum revealed linearity of the blood concentration with time above a threshold concentration. When the slopes of the blood curves were plotted against the known infusion rates, a straight line relationship was obtained. The X axis intercept of this straight line represents an apparent transport maximum. This value obtained from the X axis intercept matched closely with the observed excretion maximum determined from bile and urine collection. The slope of this same line equals the inverse of the volume of distribution of the drug. Although previous workers have failed to appreciate an apparent transport maximum for iopanoate, the current studies clearly demonstrate that iopanoate is excreted by a saturable mechanism. Using this technique the apparent transport maximum for iopanoate was evaluated at high and low rates of taurocholate replacement to evaluate the quantitative effect of bile salt on the apparent transport maximum. A five-fold increase in taurocholate replacement led to an average 40% increase in the apparent transport maximum of iopanoate without effecting its volume of distribution significantly.

Animals↗
PubMedDate not supplied

Saturation kinetics of iopanoate in dogs with an intact enterohepatic circulation. Before and after phenobarbital induction.

Capacity-limited elimination of sodium iopanoate and a reproducible apparent transport maximum (Tm) were demonstrated in nonoperated dogs having an intact enterohepatic circulation and normal endogenous bile salt pool. Using a multiple infusion technique, estimation of apparent Tm of iopanoate in the liver was possible without sampling either bile or urine. Values obtained for apparent Tm of iopanoate in dogs with normal bile salt pool were similar to those obtained in studies of dogs with chronic bile fistulas. Use of this technique in 4 dogs demonstrated that pretreatment with phenobarbital significantly increases apparent Tm of iopanoate.

Animals↗
PubMedDate not supplied

Saturation kinetics of iocetamic acid: Evaluation of indirect pharmacokinetic techniques and comparison with iopanoic acid.

The biliary excretion of two oral cholecystographic contrast agents, iocetamic acid and iopanoic acid, were compared during low and high taurocholate infusion rates. The pharmacokinetics of these compounds after intravenous infusion were studied in bile-fistula dogs using both indirect and direct pharmacokinetic techniques. The indirect multiple infusion technique, corrected for urinary excretion, provides a reliable estimate of the maximum biliary excretion rates of either contrast agent without necessitating the sampling of biliary output. The results indicate that taurocholate facilitates the biliary excretion of both agents. At both taurocholate infusion rates studied, the maximum biliary excretion rate of iocetamic acid is greater than that of iopanoic acid.

Animals↗