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Biomedical subjects

J M Collins

Publications and source records attributed to J M Collins.

At least 127 records · Page 7Linked to original sources
PubMed1985

Plasma and cerebrospinal fluid pharmacokinetics of recombinant interferon alpha A in monkeys: comparison of intravenous, intramuscular, and intraventricular delivery.

Interferons are currently undergoing clinical testing in patients with cancer and other diseases. A variety of routes of administration are being utilized, and there is particular interest in delivery of interferon to the central nervous system. A biphasic decline in plasma concentrations was observed in monkeys following an i.v. bolus, with initial half-times of 15 to 33 min and terminal half-times of 1.7 to 4.6 hours. Total body clearance ranged from 24 to 39 ml/sq. m/min and steady-state volume of distribution was similar to extracellular space. CSF exposure was 1% or less than that of plasma. Intramuscular injections produced lower peak concentrations and more sustained levels, but there was substantial variation in bioavailability (range 19-103%). Levels in the CSF were not detectable for the i.m. route. For intraventricular doses, CSF exposure was 3,000-fold greater than for i.v. doses, despite a 20-fold lower dose.

Animals↗
PubMed1985

A phase I and pharmacokinetic study of dihydro-5-azacytidine (NSC 264880).

5,6-Dihydro-5-azacytidine (DHAC; NSC 264880) is an analogue of 5-azacytidine that does not possess the hydrolytically unstable 5,6-imino bond of the parent compound. Thus, unlike 5-azacytidine, DHAC is stable in aqueous solution and may be administered by prolonged i.v. infusion, potentially avoiding acute toxicities associated with bolus administration of 5-azacytidine. In this study, patients with advanced cancer were treated with DHAC administered as a 24-h constant i.v. infusion every 28 days. Treatment began at a dose of 1 g/sq m and was escalated to the maximum-tolerated dose of 7 g/sq m, where the limiting toxicity was pleuritic chest pain. Other toxicities included nausea and vomiting, which were not limiting. There was no evidence for myelosuppression, nephrotoxicity, or hepatotoxicity. DHAC was measured in plasma, urine, and ascites by a sensitive and specific reverse-phase high-performance liquid chromatography assay capable of detecting 50 ng of drug per ml. Steady-state plasma levels were achieved with 8 h and ranged from 10.0 to 20.5 micrograms of DHAC per ml at the maximum-tolerated dose. Total-body clearance of 311 +/- 76 ml/min/sq m and postinfusion half-lives between 1 and 2 h were observed. Between 8 and 20% of the administered dose was excreted unchanged in urine. While ascites DHAC levels in a patient with ovarian cancer were comparable to plasma levels, postinfusion elimination was slower from this compartment than from plasma. No correlation was observed between DHAC plasma levels and duration or intensity of dose-limiting pleuritic chest pain. One patient with progressive Hodgkin's lymphoma demonstrated stabilization of disease for seven treatment cycles, and two patients with aggressive lymphoma demonstrated dramatic, although transient, disease responses. A dose of 7 g/sq m is recommended for Phase II trials of DHAC using this schedule.

Adult↗
PubMed1985

Pharmacokinetics of tiazofurin in the plasma and cerebrospinal fluid of rhesus monkeys.

The pharmacokinetic disposition of tiazofurin in plasma and cerebrospinal fluid was examined in rhesus monkeys. Tiazofurin was readily detectable in both plasma and cerebrospinal fluid within 20 min of commencement and for 24 h after a short i.v. infusion of the drug. The mean clearance of tiazofurin from plasma was 70 +/- 23 (SD) ml/min/sq m after a dose of 100 mg/kg and 106 +/- 38 ml/min/sq m after a dose of 500 mg/kg with no evidence of dose dependency. The data for plasma elimination of tiazofurin were fit to a triexponential equation for comparison with data from other species. The t 1/2 alpha was 0.23 h, t 1/2 beta was 1.9 to 2.0 h, and t 1/2 gamma was 6.8 to 7.1 h. The ratio of area under the cerebrospinal fluid drug concentration-time curve to the area under the plasma drug concentration-time curve was 0.28, which suggests significant penetration of the blood-brain barrier. These results demonstrate the propensity of tiazofurin to enter the cerebrospinal fluid and, probably, the brain, and suggest a potential role for this agent in the treatment of central nervous system cancer.

Animals↗
PubMed1985

Phase I and clinical pharmacological study of mercaptopurine administered as a prolonged intravenous infusion.

The bioavailability of oral mercaptopurine (MP) is poor, and plasma levels following p.o. dosing are highly variable. In an attempt to circumvent these problems, we conducted a Phase I trial and clinical pharmacological study of MP administered as a prolonged i.v. infusion. An infusion rate of 50 mg/sq m/h, which was designed to achieve therapeutic drug levels in plasma, was used in all patients. The infusion duration was escalated in 12-h increments. Thirty-eight patients were evaluated. The dose-limiting toxicity was mucositis. Other reversible toxicities were myelosuppression and hepatotoxicity. An infusion duration of 48 h was found to be safe, unassociated with dose-limiting toxicity. Objective responses were seen in five patients. The mean plasma steady-state MP concentration achieved was 6.9 microM with little interpatient variability seen. Allopurinol coadministration had no effect on the plasma pharmacokinetics of i.v. MP. However, allopurinol did alter the urinary metabolite pattern, decreasing thiouric acid and increasing MP and thioxanthine levels. The steady-state cerebrospinal fluid:plasma ratio for MP was 0.27, suggesting that this approach may be of value in the treatment of central nervous system cancer. MP can be safely administered as a 48-h i.v. infusion at a dose rate which reliably achieves MP levels associated with optimal antileukemic activity in vitro.

Drug Evaluation↗
PubMed1984

Quantification of tiazofurin in plasma by high-performance liquid chromatography.

A simple and sensitive method was developed for the separation and quantification of tiazofurin ( TCAR ) in plasma using 2-beta-D- ribofuranosylthiazole -5-carboxamide (iso- TCAR ) or [5-3H] TCAR as an internal standard. The procedure uses C18 extraction columns to clean-up the plasma samples for measurement by high-performance liquid chromatography. A sensitivity of 0.33 microM (0.08 microgram/ml) was easily achieved for 0.5-ml plasma samples. When human whole blood was incubated in vitro with TCAR for 2 h, the plasma concentrations were decreased by 10% (4 degrees C) and 25% (23 degrees C). TCAR could still be measured 22 h after injection of 220 mg/kg into mice. For a two-compartment pharmacokinetic model, the half-lives of TCAR were 18.8 and 412 min.

Animals↗
PubMed1984

Low sialic acid-bearing mouse thymocytes do not express helper T cell properties in vitro.

Immature, presumably cortical, mouse thymocytes were isolated by removing mature thymocytes by agglutination with the sialic acid-specific lectin, lobster agglutinin 1 (LAg1). These immature cells do not respond to the mitogenic effects of concanavalin A (Con A), even in the presence of interleukin 2. Moreover, they do not exhibit two properties of helper T cells; they do not secrete interleukin 2 when stimulated with Con A, nor do they provide T help for an in vitro immune response by spleen B cells to the T-dependent antigen, sheep erythrocytes. LAg1-negative thymocytes fail to provide T help even though Con A is added to the cultures, regardless of the number of LAg1-negative thymocytes added per culture, and even in the presence of exogenous macrophages. Unseparated thymocytes, LAg1-positive thymocytes and cortisone-resistant thymocytes all provide T cell help under these conditions. These experiments indicate that immature, presumably cortical mouse thymocytes, isolated by virtue of their low levels of surface sialic acid, are inherently unable to provide T cell help in vitro.

Animals↗
PubMed1984

A Phase I study of intermittent intravenous bromodeoxyuridine (BUdR) with conventional fractionated irradiation.

A Phase I trial of intravenous bromodeoxyuridine (BUdR) and conventional fractionated radiation therapy was performed in 14 patients with glioblastoma multiforme and 7 patients with other poorly radioresponsive tumors. The BUdR was given as a constant intravenous infusion for 12 hr/day for up to 14 days. Thirteen patients received a second 14 day infusion following a 10 to 14 day interruption for bone marrow recovery. Local toxicity (within the radiation field) was minor, with 7 of the 21 patients requiring a brief treatment break for moist skin desquamation. There was no significant CNS toxicity noted clinically nor by autopsy examination. Additionally, no significant enhancement of radiation injury was noted to bowel or liver. However, one patient treated for multiple pulmonary metastases experienced a clinical and radiographic pattern consistent with radiation pneumonitis. Dose-dependent systemic toxicity occurred in bone marrow and skin. Moderate myelosuppression, especially thrombocytopenia, was found following a 14 day cycle of BUdR at and above 650 mg/m2/12 hr infusion. Approximately one-third of patients developed a maculo-papular erythematous rash to the scalp, neck and upper chest. In two patients, the rash became generalized with evidence of epidermolysis on skin biopsy. Pharmacology studies revealed steady-state arterial plasma levels of 2 X 10(-6) M/1 during the 12 hr infusion of 650 to 700 mg/m2. Radiosensitization was measured by a change in the D0 of radiation survival curves of human bone marrow CFUc prior to and following the 14 day infusion in 4 patients. A trend of increasing radiosensitization was noted in most patients as the infusion rate of BUdR was increased from 500 to 870 mg/m2/12 hr. We conclude that the maximum tolerable dose of BUdR is 650 to 700 mg/m2/12 hrs when given as a 2 week intermittent intravenous infusion. Local toxicity is acceptable. The major systemic toxicities are myelosuppression and a maculopapular skin rash.

Adult↗
PubMed1984

Cytosine arabinoside cerebrospinal fluid kinetics.

To better characterize the disposition of cytosine arabinoside (Ara-C) in cerebrospinal fluid (CSF), its kinetics were studied in seven patients with meningeal leukemia in complete remission. After intraventricular injection of 30 mg Ara-C, CSF and plasma samples were obtained over a 24-hr period. Ara-C levels were measured by a reverse-phase HPLC assay (with a sensitivity of 0.5 microM in CSF and 1.0 microM in plasma) that readily separated Ara-C from its major metabolite uracil arabinoside (Ara-U). Elimination of Ara-C from CSF followed a biphasic pattern, with an initial t1/2 of 1 hr and a terminal t1/2 of 3.4 hr. Ara-C clearance from CSF was 0.42 ml/min, suggesting that drug elimination was primarily by CSF bulk flow. The ratio of the AUC of Ara-U to the AUC of Ara-C was 0.08, indicating only minor metabolism of Ara-C to Ara-U in CSF, in contrast to that after systemic Ara-C. Despite initial CSF Ara-C concentrations exceeding 2 mM, Ara-C was not detectable in plasma in any patient. Intraventricular Ara-C results in very high levels in CSF, but systemic tissues are relatively spared from exposure to Ara-C.

Adolescent↗
PubMed1984

Pharmacologic rationale for regional drug delivery.

Regional drug delivery is an approach designed to improve the selectivity of chemotherapy. When compared with systemic drug administration, regional delivery can potentially increase drug concentrations at tumor sites and/or lower systemic drug exposure. Pharmacokinetic analysis can evaluate or even predict the relative advantage of regional drug delivery. Based on a quantitative analysis of regional drug delivery, some drugs and sites of delivery are more favorable than others. The formulas for the therapeutic advantage of intraarterial, intrathecal, and intraperitoneal delivery have a similar structure. The ratio of total body clearance of a drug to its regional exchange rate is the principal determinant of therapeutic advantage. Thus, the most favorable circumstances for regional delivery are the use of drugs with high total body clearances and/or sites of delivery with low exchange rates. Pharmacodynamic factors must also be considered for the overall assessment of regional delivery.

Antineoplastic Agents↗
PubMed1984

The pharmacology of diaziquone given in intravenous or intracarotid infusion to normal and intracranial tumor-bearing puppies.

Diaziquone (also called "aziridinyl benzoquinone," or AZQ), an antitumor drug designed to penetrate the blood-brain barrier, has demonstrated activity against central nervous system (CNS) neoplasms. Four-hour infusions of carbon-14 (14C)-labeled AZQ (0.8 mg/kg) were given via the left common carotid artery or left brachial vein to two groups of puppies. A third group, harboring a transplantable canine glioma, received 14C-AZQ by intravenous infusion. Levels of chloroform (CHCl3)-extractable 14C (AZQ only) and total 14C (AZQ and metabolites) were determined in serial samples of plasma and cerebrospinal fluid (CSF). At the end of the infusion time, total and CHCl3-extractable 14C levels were determined in brain and tumor. Intra-arterial infusion of AZQ caused no histological abnormalities in the retina or brain. For the intravenous infusion group, the concentrations of CHCl3-extractable 14C (in nmol/ml or nmol/gm) were 0.68, 0.35, and 0.84 for plasma, brain, and CSF, respectively. For the intra-arterial infusion group, the concentrations were 0.25, 0.13, and 0.32 for plasma, brain, and CSF, respectively. Comparison of right and left hemispheres following intra-arterial infusion showed a slightly higher concentration of 14C in the ipsilateral (left) hemisphere, with concentrations (nmol/gm) of CHCl3-extractable 14C/total of 14C of 0.15/0.87 on the left and 0.12/0.65 on the right. Concentrations (nmol/gm) of CHCl3-extractable 14C/total 14C in brain and tumor were 0.60/1.24 and 0.58/1.65, respectively. In tumor-bearing animals, tumor and surrounding brain contained similar concentrations of AZQ, but there were higher concentrations of metabolites in tumor. This may reflect different metabolism of AZQ within brain and tumor or different permeability to metabolites. This study revealed that AZQ enters the CNS and brain-tumor tissue in substantial concentrations and that there is no significant advantage to intracarotid infusion of AZQ.

Animals↗
PubMed1984

Effect of intravenous dose and schedule on cerebrospinal fluid pharmacokinetics of 5-fluorouracil in the monkey.

There is little information regarding the pharmacology of 5-fluorouracil (5-FUra) in the central nervous system (CNS), despite its role in the treatment of diseases with CNS metastases and recent reports of neurotoxicity. In this study, the plasma and cerebrospinal fluid (CSF) pharmacokinetics of 5-FUra were examined in a primate model. Following a bolus dose, the area under the concentration versus time curves for 5-FUra in CSF was 48% of the plasma area under the concentration versus time curves. For continuous infusion of 5-FUra, the area under the concentration versus time curves ratio for CSF:plasma was 20 or 11%, depending upon the infusion rate. The mechanism for variations in CSF exposure based upon the pattern of plasma delivery is consistent with local metabolism of 5-FUra in the CNS. These findings should be considered in the evaluation of delivery schedules which are intended to maximize drug delivery to the CNS and/or minimize neurotoxicity.

Animals↗
PubMed1984

Arterial drug infusion with extracorporeal removal. I. Theoretic basis with particular reference to the brain.

The pharmacokinetic advantage of intra-arterial drug administration can be improved if blood from the infused region is perfused through a suitable extracorporeal device. The extent of improvement depends on the blood flow to the device, the fraction of the vascular drainage that can be obtained, and the drug extraction by the device. A relatively simple equation is derived to assess the pharmacokinetic advantage and to define the governing parameters. Application of the theory to the treatment of brain tumors includes a discussion of the selection of an experimental animal and interpretation of results. It is suggested that tumor exposure to carmustine comparable to that associated with very high tumor cell kill in vitro may be feasible with little or no systemic toxicity.

Animals↗
PubMed1984

Cerebrospinal fluid pharmacokinetics of intraventricular and intravenous aziridinylbenzoquinone.

The cerebrospinal fluid (CSF) pharmacokinetics of aziridinylbenzoquinone (AZQ) was studied following i.v. and intraventricular drug administration. Initial studies were performed in six rhesus monkeys with chronic indwelling Ommaya reservoirs. Following intraventricular administration of 0.2 mg of AZQ, elimination was monoexponential with half-lives of 32 and 39 min in ventricular and lumbar CSF, respectively. AZQ clearance (0.2 ml/min) was 5-fold greater than estimated CSF bulk flow, indicating that transcapillary passage and/or metabolism may be important clearance mechanisms for this drug. In spite of its rapid clearance from ventricular CSF, a substantial peak AZQ concentration was achieved in lumbar CSF (12 microM), which was 7 times higher than the peak ventricular CSF level (1.7 microM) achieved following i.v. AZQ administration (16 mg/sq m). Moreover, the mean area under the CSF concentration-time curve in ventricular CSF was 20-fold greater following intraventricular versus i.v. AZQ dosing, despite an 80-fold-lower dose. AZQ was not detectable in plasma (less than 0.06 microM) following intraventricular administration. No animals demonstrated clinical evidence of acute neurotoxicity. Subsequently, intraventricular AZQ was administered to a patient with refractory meningeal leukemia. Intraventricular AZQ (0.5 mg) resulted in a peak ventricular (56 microM) CSF level which was 80-fold higher than ventricular CSF levels achieved following systemic AZQ administration of a dose of 24 mg/sq m in humans. Moreover, intraventricular AZQ yielded substantial CSF levels without detectable plasma concentrations. These data suggest that intraventricular administration of AZQ is feasible and may have pharmacological advantages over systemic administration for the treatment of meningeal neoplasia.

Animals↗
PubMed1983

Anion influence on the binding of divalent cations to phosphatidylcholine.

We have used the osmotic pressure technique of Rand, Parsegian and co-workers (Nature 259 (1976) 601-603) to investigate the effect of anion species on the binding of M2+ to dipalmitoylphosphatidylcholine bilayers. Calcium and magnesium salts show a complex behavior which is consistent with both anion binding and screening. We observe virtually no change, within the accuracy of our experiment, in the decay of repulsive pressure with inter-bilayer separation for the acetate and nitrate salts of magnesium and calcium; however, the chloride salt does show a different pressure decay. At any given bilayer separation, 35 A less than dw less than 75 A, with calcium and magnesium salts present, the anions produce a decrease in the repulsive pressure in the order acetate- greater than Cl- greater than NO-3.

Anions↗
PubMed1983

Physiological model for the pharmacokinetics of 2,3,7,8-tetrachlorodibenzofuran in several species.

A flow-limited physiological model was developed to describe the time course of 2,3,7,8-tetrachlorodibenzofuran (TCDF) in the blood and tissues of rats, mice, and monkeys. The liver showed the greatest tendency to concentrate the material with tissue-to-blood distribution coefficients ranging from 30 in the monkey to 130 in the mouse. TCDF was also concentrated in the fat with tissue-to-blood distribution coefficients between 25 and 40 in all species. TCDF was eliminated by metabolism followed by excretion primarily to the feces. Urinary excretion was a minor route of elimination in all species. Metabolism was modeled as a linear process occurring in the liver. Intrinsic metabolic clearances ranged from 0.45 ml/min/kg in the monkey to 2.8 ml/min/kg in one species of mice. Fecal excretion of TCDF-derived radioactivity can be simulated with a series of well-mixed compartments which receive input of metabolites in the bile.

Animals↗
PubMed1983

Pharmacokinetics of intraventricular administration.

The widespread use of neurosurgical devices for intraventricular drug delivery has led to an escalation in the number of CSF pharmacokinetic studies. When experimental data for ventricular CSF concentration vs. time are normalized for dose and plotted for drugs with a wide range of physical properties, there is a remarkably narrow range. Simulations from a distributed model for the central nervous system suggest that the narrow range of observed CSF half-times following bolus administration is a consequence of physiologic limits upon rate of drug removal from CSF. Whereas bulk flow of CSF establishes minimum rate of drug washout, diffusion through brain tissue and subsequent removal by capillaries establishes a maximum rate of drug egress which is only seven times the minimum rate. Predictions of CSF concentration vs. time can be made based upon the capillary exchange rate for a particular drug, which could be estimated or calculated from CSF concentration measurements following systemic administration. Simulations are also presented of steady-state CSF concentrations during continuous ventricular infusions.

Animals↗
PubMed1983

Raman spectroscopic and X-ray diffraction studies of the effect of temperature and Ca2+ on phosphatidylethanolamine dispersions.

Raman spectroscopy and X-ray diffraction are used to study the effect of heat and Ca2+ on dimyristoylphosphatidylethanolamine dispersions. Unlike phosphatidylcholine dispersions, dimyristoylphosphatidylethanolamine bilayers (at pH 8) require heating above Tm in order for hydration to occur and apparently bind Ca2+ at very low levels. These results are related to models for membrane fusion.

Calcium↗