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J L Woolley

Publications and source records attributed to J L Woolley.

35 records · Page 2Linked to original sources
PubMed1987

Preclinical biochemical pharmacology and toxicology of piritrexim, a lipophilic inhibitor of dihydrofolate reductase.

Piritrexim (PTX), 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin e, formerly called BW 301U, is a potent small-molecule inhibitor of dihydrofolate reductase (DHFR) that enters cells rapidly by passive diffusion and thus does not depend upon the transport-mediated uptake that can limit cell entry of methotrexate (MTX). PTX is as active as MTX in inhibiting DHFR and mammalian cell growth. In vivo, PTX is active against Walker 256, L1210, P388, Sarcoma 180, and Ehrlich ascites tumors. After iv administration of [14C]PTX to rats, the elimination profile of intact drug from plasma was first order with a half-life (t1/2) of 38 minutes. PTX penetrates extensively into tissues and its tissue:plasma concentration ratios are generally 10-fold higher than those reported for MTX. When administered systemically, PTX inhibits the DHFR-dependent conversion of sepiapterin or 7,8-dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4), demonstrating that PTX enters brain at pharmacologically relevant concentrations. Pharmacokinetic studies in the dog indicated a mean plasma t1/2 (after iv dose) of 2.15 hours, total body clearance of 0.625 liters/hr/kg and steady-state volume of distribution of 1.82 liters/kg; the absolute bioavailability was 0.64. Toxicologic studies were conducted in rats and dogs that received daily doses for 1, 5, or 90 days. In dogs, oral doses of 480 (single dose), 25 (5 daily doses), and 2.5 mg/kg (90 daily doses) were lethal, whereas 240 (single dose), 2.5 (5 daily doses), and 0.5 mg/kg (90 daily doses) produced reversible alterations in clinical toxicity and histopathologic parameters. The lethal toxicity of PTX in dogs given 25 mg/kg/day for 5 days is prevented by oral calcium leucovorin rescue with either 0.75 or 3.0 mg/kg every hour for 4 hours on any of the 5 treatment days. The general pharmacologic profile indicates that PTX should be free of CNS, cardiovascular, and respiratory side effects at clinically useful doses.

Animals↗
PubMed1986

Superiority of intralesional immunotherapy with Corynebacterium parvum and Allium sativum in control of murine transitional cell carcinoma.

Immunotherapy with bacillus Calmette-Guerin (BCG), Corynebacterium parvum (CP), keyhole limpet hemocyanin (KLH) and an extract of Allium sativum (AS) was studied in a transitional cell carcinoma (MBT-2) in mice. Comparison was made between intraperitoneal (IP) versus intralesional (IL) administration of these agents. C3H/He mice were transplanted subcutaneously in the hind limb with 5 X 10(4) tumor cells. After transplantation, mice were randomized into groups to receive either IP or IL treatments with BCG (2 X 10(6) CFU), CP (250 micrograms.), KLH (50 micrograms.) or AS (25 mg.). At weekly intervals the tumor volume was determined. To assess the local cellular events following these treatments, histopathological studies were performed 10 days after tumor transplant with tissues removed from the injected sites. IL route was much more effective than IP route in inhibiting tumor growth. CP and AS exhibited more significant therapeutic effect than BCG or KLH. No tumor developed in mice which received five IL treatments of CP or AS. The data indicate that CP or AS may serve as effective biological response modifiers in controlling transitional cell carcinoma. The study further emphasizes that route and frequency of administration are crucial variables determining efficacy of immunotherapy.

Animals↗
PubMed1984

Emission and transmission tomography of the brain in cerebrovascular disease.

Transmission and emission computed tomography (T-CT and E-CT, respectively) scans of the brain in 149 patients with cerebrovascular disease were compared to establish the diagnostic accuracy of the two methods. The T-CT scan yielded an overall rate of true-positive results of 80.75% in major infarcts, 80% in intracerebral hematomas, and 75.9% in subarachnoid hemorrhage. In contrast, the percentages of true-positive results yielded by the E-CT scan were 92.3, 55, and 34.5%, respectively, in each type of cerebrovascular disease. The false-negative results obtained with the T-CT scan were higher in infarcts but lower in hematomas and subarachnoid hemorrhage; the reverse was true for the diagnoses obtained with the E-CT scan. The false-positive diagnoses produced by the T-CT scan were high for hemorrhagic strokes compared to those of the E-CT scan. The diagnostic sensitivity of each scan was not affected by the location of the lesion. Thus, the E-CT scan is more sensitive for thromboembolic disease and less so for hemorrhagic types of stroke. The reverse is true for the T-CT scan.

Adolescent↗
PubMed1982

The role of dietary nitrate and nitrite in the reductive deamination of sulfadiazine by the rat, guinea pig, and neonatal calf.

Previous metabolic depletion studies of 14C-sulfadiazine (SDZ) in the neonatal calf led to identification of two novel metabolites, 2-benzenesulfonamidopyrimidine (desNH2SDZ) and 2-benzenesulfonamido-4-hydroxypyrimidine. The novelty of the biotransformation prompted examination of mechanisms for the reductive deamination of SDZ in vivo. In subsequent work, it was found that neonatal calves did not consistently convert SDZ to desNH2SDZ; however, calves that were treated simultaneously with nitrite did. Further, when SDZ was given orally to guinea pigs, whose diet is high in nitrate and who demonstrate the capacity to reduce nitrate to nitrite in the oral cavity, SDZ was transformed to desNH2SDZ. Rats did not reductively deaminate SDZ even if they consumed a diet high in nitrate for two weeks prior to treatment with SDZ. However, they did so when nitrite was added to their diet. These observations strongly suggest that reductive deamination of sulfonamides is dependent on the ingestion of nitrite or the reduction of dietary nitrate to nitrite. This reduction of nitrate to nitrite proceeds in the oral cavity, presumably via microflora residing there.

Animal Feed↗
PubMed1981

Pharmacokinetics of trimethoprim and sulfadiazine in the dog: urine concentrations after oral administration.

Serial blood samples were obtained from 12 healthy adult dogs given equivalent subcutaneous and oral doses of the antibacterial combination, trimethoprim-sulfadiazine (1:5). By using a 1-compartment open model, pharmacokinetic parameters for both drugs were estimated from the mean serum concentration data after oral administration. Trimethoprim and sulfadiazine were rapidly absorbed, reaching maximum concentrations in 1 and 4 hours with serum elimination half-lives of 2.5 and 9.9 hours, respectively. After a single oral dose (30 mg/kg, combined ingredients) was given, both drugs were present in urine for up to 24 hours at concentrations exceeding the minimum inhibitory concentrations for common pathogenic bacteria.

Administration, Oral↗
PubMed1978

Thin layer chromatographic screening method for sulfadiazine residues in calf tissues, plasma, and urine.

Because of the lack of specificity of the Bratton-Marshall procedure for assaying sulfonamides, a sensitive, specific tissue residue assay for sulfadiazine (SDZ) was developed. The methodology has been extended to provide a highly sensitive screen for sulfonamide residues, which employs 2-dimensional thin layer chromatography in conjunction with fluorescamine derivatization. The procedure described, which has been developed for SDZ in calf tissues, involves direct ethyl acetate extraction of tissue homogenates. Following evaporation of the organic phase, a portion of the residue is spotted on a 20 X 20 cm silica gel 60 plate, which is then developed in 2 dimensions with solvent systems devised to separate SDZ from endogenous substances as well as from 12 other sulfonamides that might be present in calf tissues. The presence of SDZ at a concentration of 0.1 ppm or its absence is easily demonstrated in calf kidney, liver, muscle, plasma, and urine. The basic method can be modified for a particular sulfonamide in a target tissue and can be used as a quantitative assay for sulfonamide residues.

Animals↗
PubMed1977

Cranial isotopic section scanning.

Some results of isotopic cranial section scanning are presented from a busy neurosurgical practice. Isotopes have been used for parenchymal lesions and also CSF pathway imaging. Comparisons with information yielded by other neuroradiological techniques have indicated that tomographic sections are a worthwhile addition to rectilinear isotope scans. In particular comparison with X-ray transmission (EMI) scans has confirmed the anatomical accuracy of the method and the two techniques have proved complementary in patient management.

Brain↗
PubMed1977

Lipid-soluble diaminopyrimidine inhibitors of dihydrofolate reductase.

On the basis of activity against experimental tumors and potency as inhibitors of human dihydrofolate reductase, two compounds were selected for pharmacokinetic evaluation: metoprine ((2,4-diamino-5-(3',4'-dichlorophenyl)-6-methyl pyrimidine, DDMP, B.W. 197U) and etoprine, the corresponding 6-ethyl analog (DDEP, B.W. 276U). These lipid-soluble compounds readily cross the blood-brain barrier and penetrate rapidly into brain and brain tumors induced in rats by ethylnitrosourea. Both compounds are extensively bound to human plasma protein and their slow elimination from plasma and tissues contrasts with the kinetics of methotrexate. Cerebrospinal fluid levels of "folate" were elevated following oral administration of citrovorum factor to rats but not following equivalent doses of folic acid. The balance between selective action of the drug and selective protection by the vitamin is discussed with regard to differential distribution into separate compartments.

Administration, Oral↗
PubMed1975

Specific TLC tissue residue determination of sulfadiazine following fluorescamine derivatization.

A spectrodensitometric method for the direct determination of sulfadiazine at the tissue residue level (0.1 ppm) is based upon the measurement of the fluorescence of a sulfadiazine-fluorescamine derivative formed directly on a TLC plate by dipping it into a fluorescamine solution. The linear dynamic range for the assay is about 150 from 200 to 0.2 ng, the lower limit of sensitivity. Recoveries from various spiked tissues including milk, eggs, liver, kidneys, muscle, skin, and fat varied with the tissue type but were reproducible. The assay technique has also been used for the assay of sulfamethoxazole and has been explored for use in specifically assaying sulfonamide mixtures.

Animals↗
PubMedDate not supplied

Disposition, metabolism, and excretion of the anticancer agent crisnatol in the rat.

Disposition and metabolism of crisnatol (14C-labeled), a novel antitumor agent, was examined after po and iv administration to rats. After both routes of drug administration, there was rapid elimination of the administered radioactivity in the urine (6-12% of the dose) and feces (81-92% of the dose). The drug appeared to be rapidly absorbed after oral dose and there was substantial "first-pass" metabolism. Analysis of the excreta indicated extensive metabolism of crisnatol by the rat, with the intact compound being the major radiolabeled component in the feces (17-20% of dose). Intact drug was not present in urine. Biotransformation of crisnatol by the rat mainly involves oxidation and conjugation pathways. Hydroxylation and dihydrodiol formation in the chrysene ring and oxidation of the propanediol side chain resulted in the formation of the three major fecal metabolites. The principal metabolite in the urine was also a dihydrodiol. Concentrations of intact drug in each tissue assayed exceeded those in plasma, and in the lungs the tissue/plasma ratio approached 300 and 82 at 2 hr after iv and po doses, respectively.

Animals↗
PubMedDate not supplied

The disposition and metabolism of [14C]piritrexim in rats after intravenous and oral administration.

The disposition of [14C]piritrexim in male rats after iv (5 and 10 mg/kg) and po (5, 10, and 20 mg/kg) doses was studied. After an iv dose of 10 mg/kg, rats excreted an average of 57% of the dose in feces and 32% in urine; after a po dose of 10 mg/kg, 84% of the dose was excreted in feces and 9% in urine. After iv doses, the elimination of unchanged drug from plasma was first order, with a t1/2 of 0.6 hr; at any time point, unchanged drug accounted for less than 50% of the total radiocarbon in the plasma. Oral bioavailability of unchanged drug was less than 5%. O-Demethylation and subsequent conjugation were the main pathways of metabolism; the demethyl metabolites of piritrexim were potent inhibitors of dihydrofolate reductase and were cytotoxic to cells in culture. Concentrations of radiocarbon were highest in liver 24 hr after an iv dose, but less than 1% of the radiocarbon was unchanged drug. Concentrations of radiocarbon in liver after po doses were approximately 40% of those attained after equivalent iv doses.

Administration, Oral↗
PubMedDate not supplied

The disposition and metabolism of [14C]piritrexim in dogs after intravenous and oral administration.

The disposition of [14C]piritrexim ([14C]PTX) in male dogs after iv and po doses of 1.8 mg/kg was examined. After either route of administration, greater than 90% of the dose was recovered in the exreta within 72 hr; approximately 20% was recovered in urine and 70% in feces. [14C]PTX was extensively metabolized by dogs; unchanged drug accounted for less than 15% of the dose in the excreta. The O-demethylated metabolites, 2'- and 5'-demethyl PTX, the glucuronide conjugate of 2'-demethyl PTX, and the sulfate conjugate of 5'-demethyl PTX were the major metabolites. Unchanged drug accounted for a large proportion of the drug-related radiocarbon in plasma. The average plasma half-life of PTX after iv administration was 2.6 +/- 0.3 hr, and the average total body clearance was 0.33 +/- 0.13 liter/hr/kg. After po administration, peak plasma concentrations of 0.9 +/- 0.3 micrograms/ml occurred about 1.1 hr after the dose; the absolute oral bioavailability of PTX was 0.63 +/- 0.14. Because the O-demethyl metabolites were active dihydrofolate reductase inhibitors, 2'- and 5'-demethyl PTX were synthesized, and the pharmacokinetics and bioavailability of these compounds in dogs after iv and po administration (5 mg/kg) were examined. The plasma concentration-time data for both compounds after iv doses were described by a two-compartment model, with t1/2 beta = 1.3 and 0.8 hr for the 2'- and 5'- demethyl compounds, respectively. Neither compound showed significant advantages over PTX in terms of pharmacokinetics or bioavailability.

Administration, Oral↗
PubMedDate not supplied

Metabolism and disposition by the rat of 35S-sulfadiazine alone and in the presence of trimethoprim.

The tissue distribution and metabolism of 35S-sulfadiazine (I, SDZ) alone and in the presence of trimethoprim (TMP) was studied in the male rat. In the 72-hr period following a single oral dose (30 mg/kg) of 35S-SDZ/TMP (5/1, w/w), 87% of the radioactivity was recovered in the urine and 15% of the radioactivity was recovered in the feces. The concentrations of drug-related material in the plasma or tissues after 72 hr were less than 0.1 ppm with the exception of the liver (0.13 ppm). Aside from intact drug, the two major urinary metabolites (greater than 5% of the radioactivity in urine) were N4-acetylsulfadiazine (II) and sulfadiazine N4-glucuronide (VI). Three minor urinary metabolites (less than 5%) were identified as N4-acetyl-2-sulfanilamido-4-hydroxypyrimidine (IV), 2-sulfanilamido-4-hydroxypyrimidine (III) and 2-sulfanilamido-5-hydroxypyrimidine (V). Metabolites IV and V are novel metabolites of SDZ and have not been reported previously for any species. The relative amounts of sulfadiazine and its metabolites excreted in the urine and feces as well as the distribution of intact drug and 35S in rat tissues were determined. The metabolites were screened for antibacterial activity; the N4-acetylated metabolites II and IV were inactive, whereas the hydroxypyrimidine metabolites III and V were active against a few organisms but in general much less active than I.

Animals↗