Preparatory clinical studies of Pi-mesons at TRIUMF.

Eighty patients have been treated with Pi-mesons (pions) at TRIUMF between 1979-1984. The patients had tumors rarely curable by standard methods and had no prior radiotherapy. The distribution by site included skin, metastatic nodules (13), brain, glioblastoma multiforme (32), pelvis, rectosigmoid (15), prostate (12), bladder (7), and ovary (1).

Arterial and venous blood sampling in pharmacokinetic studies: griseofulvin.

The pharmacokinetics of griseofulvin were evaluated simultaneously using both arterial and venous plasma in three dogs and one rabbit after a rapid bolus intravenous dosing. Initial arterial-venous ratios 20 sec after injection were the highest and ranged from 15- to 752-fold for dogs; the ratio was 3240-fold for the rabbit. Both curves decayed paralleling each other at the terminal phase with the venous levels higher than arterial levels by 14-43 and 8.

Radiobiology of pions at TRIUMF.

Radiobiological studies at TRIUMF of the effects of pion beams have been carried out using cultured cells, mice and pigs. CHO cells in gel/medium were used for RBE determinations throughout the dose distributions. The RBE was shown to increase with depth in the stopping region, while the average RBE value decreased with increasing width of the stopping peak and also increased with increasing field size.

Pions, Vancouver.

Clinical treatments at TRIUMF started in November, 1979. Ten patients with malignant subcutaneous nodules had 14 lesions treated with pions and 37 other nodules treated with 280 kV X rays. Three different fractionation regimens were used with X ray doses spanning the expected RBE range of pions.

Changes in cell surface antigen expression during hemopoietic differentiation.

Human bone marrow cells were separated on a fluorescence activated cell sorter (FACS) according to their binding of a series of monoclonal antibodies; the positive and negative fractions were cloned for erythroid burst and colony-forming units (BFU-E and CFU-E) and myeloid colony-forming units (CFU-GM), and cytocentrifuge slides were prepared for microscopy of maturing precursors. The pattern of antigen expression on hemopoietic progenitor and precursor populations has been established using antibodies defining blood group (A, I/i), HLA-associated (*A, B, C, DR, DC1), lineage specific, and transferrin receptor antigens. Like monomorphic HLA-DR, the antigen defined by monoclonal antibody OKT10 is expressed on the earliest progenitors and lost during differentiation, suggesting a role in interactions regulating the differentiation of these cells.

The significance of the arterial-venous plasma concentration difference in clearance studies.

Arterial-venous blood or plasma concentration differences and their implications for renal clearance studies are reviewed. In common practice peripheral venous blood or plasma is used for absolute clearance studies employing timed-interval methods following single dosing. However, this is theoretically inappropriate or incorrect because of the systemic arterial-venous blood or plasma concentration difference.

Determination of tissue to blood partition coefficients in physiologically-based pharmacokinetic studies.

The partition coefficient between tissue and blood used in physiologically-based pharmacokinetic modeling analysis was investigated using the concept of clearance. New equations were derived and compared with previously reported equations in constant intravenous infusion and bolus injection methods. The importance of differentiating arterial from venous blood is discussed.

Digoxin pharmacokinetics in premature infants.

An analysis of pharmacokinetic parameters of digoxin was carried out in six premature infants after the administration of a single total digitalizing dose of 20 microgram/kg. The data was analyzed using both a 2 and 3 exponential model. In the premature infant, the plasma half-life of digoxin is prolonged, while the volume of the central compartment, total body clearance, volume of distribution and volume of distribution at steady state are reduced compared to other aged patients.

Effect of arterial-venous plasma concentration differences on the determination of mean residence time of drugs in the body.

Using dogs or rabbits as model animals the effect of arterial-venous plasma concentration differences of propranolol, procainamide, griseofulvin, furosemide and theophylline on the determination of mean residence time (MRT) following intravenous administration was evaluated using standard methods. The MRT values calculated from femoral venous data were always higher (ranging from 1.5 to 109%) than those from femoral arterial data.

Systmatic method of formulating liquid phantoms with a given elemental composition and density.

A general method of formulating tissue equivalent liquid mixtures of a given chemical composition and density using the technique of linear programming is described. It is used to generate mixtures with equivalent atomic composition as ICRP Standard Man and mammalian muscle (NBS Handbook 85) using eight compounds to cover the range of densities from 1.0 to 1.

Instantaneous input hypothesis in pharmacokinetic studies.

Observed venous plasma concentrations of furosemide, propranolol, griseofulvin, and theophylline at 0.33 and 0.66 min after intravenous bolus injections to unanesthetized dogs were compared with those extrapolated using the instantaneous input hypothesis.

Arterial and venous blood sampling in pharmacokinetic studies: propranolol in rabbits and dogs.

Significant and persistent arterial-venous (A-V) plasma concentration differences of propranolol in unanesthetized rabbits and dogs following intravenous bolus injection or intravenous infusion were found. Both arterial and venous data were then subjected to extensive pharmacokinetic analyses utilizing standard procedures. Marked differences in calculated noncompartmental pharmacokinetic parameters such as the steady-state volume of distribution, absolute amount present in the body, and relative contribution of the terminal phase were obtained.

Arterial-venous plasma concentration differences of six drugs in the dog and rabbit after intravenous administration.

The arterial blood from the femoral artery and venous blood from the femoral vein wee simultaneously collected following intravenous administration of propranolol, lidocaine, procainamide, furosemide, theophylline and griseofulvin to dogs or rabbits. The preliminary results of arterial-venous (A-V) plasma concentration profiles are reported in this communication. The maximum A/V ratios shortly after a rapid intravenous bolus dose were 277-, 15-, 34-, 33-, 5.

The clinical pharmacokinetics of buflomedil in normal subjects after intravenous and oral administration.

A dose-ranging pharmacokinetic study of buflomedil was carried out in eight subjects to determine the pharmacokinetic parameters of the drug after oral and intravenous administration. Based on AUC infinity analyses, the pharmacokinetics of buflomedil were found to be linear within the dose ranges studied (50 to 200 mg for i. v.

High performance liquid chromatographic analysis of urinary catecholamines employing amperometric detection: references values and use in laboratory diagnosis of neural crest tumors.

We have developed an high performance liquid chromatographic procedure employing amperometric detection for the measurement of urinary free norepinephrine, epinephrine and dopamine. The between-day precision (C.V.

Uniform depth dose distribution for biological irradiation using negative pions.

A simple, flexible technique has been developed to generate uniform depth dose profiles for the biomedical pion beam at TRIUMF using dynamic momentum control and linear programming. Either the entrance dose or the irradiation time required for a certain dose over the uniform region can be minimised. The dynamic momentum control can operate automatically under computer control even with a highly unstable beam.