Search PubMed⌕ Search

Biomedical subjects

J C Cradock

Publications and source records attributed to J C Cradock.

At least 19 recordsLinked to original sources
PubMed1987

Arabinosyl-5-azacytosine: a novel nucleoside entering clinical trials.

Arabinosyl-5-azacytosine is a new compound which has been selected by the Division of Cancer Treatment, National Cancer Institute for clinical development as an antineoplastic agent based on its high degree of activity against a broad range of tumor types in preclinical studies. Therapeutic activity has been observed against murine and human leukemias, transplantable murine solid tumors, and human tumor xenografts. Arabinosyl-5-azacytosine exhibited a broader spectrum of activity against human solid tumors than cytosine arabinoside. Arabinosyl-5-azacytosine is phosphorylated to the nucleotide level by deoxycytidine kinase. Upon further anabolism to the triphosphate level, it can be incorporated into DNA. The mechanism of cytotoxicity is thought to be related to inhibition of DNA synthesis. Leukemic and solid tumor cell lines that are resistant to cytosine arabinoside due to deletion of deoxycytidine kinase activity are cross-resistant to arabinosyl-5-azacytosine. Unlike cytosine arabinoside, arabinosyl-5-azacytosine does not readily undergo deamination. Schedule dependence has been demonstrated in mice bearing L1210 leukemia, with superior activity seen with multiple doses administered on each treatment day compared to administration of larger but less frequently administered doses. From preliminary data in solid tumor models, however, antitumor activity did not appear to be superior with continuous infusion compared to that observed on a bolus schedule. Preclinical toxicology studies indicated that the bone marrow and gastrointestinal tract were the main target organs. A single large dose of arabinosyl-5-azacytosine could be tolerated by both mice and dogs. When administered as a continuous infusion, the toxicity was related to both the dose and duration of exposure, suggesting that toxicity resulted from a critical time above a threshold concentration as opposed to the total area under the concentration-time curve. Phase I clinical trials have been initiated to determine the maximum tolerated dose on a low dose continuous infusion schedule for 72 hours and also on a high dose short infusion daily times five schedule.

Antiviral Agents↗
PubMed1987

Stability of cisplatin, iproplatin, carboplatin, and tetraplatin in commonly used intravenous solutions.

The stability of cisplatin, iproplatin, carboplatin, and tetraplatin in common intravenous solutions was studied. Admixtures of each drug in each of the following vehicles were prepared in glass containers: 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose and 0.45% sodium chloride injection (admixtures were prepared in plastic bags also), and 5% dextrose and 0.225% sodium chloride injection. Drug concentrations were monitored for 24 hours using stability-indicating high-performance liquid chromatographic methods. The stability of cisplatin and tetraplatin was related to the chloride ion content of the infusion fluid; when the infusion fluid contained 0.9% sodium chloride, each of these drugs was present at greater than 90% of the original concentration after six hours. The stability of iproplatin was not related to chloride concentration. A slight increase in the decomposition rate of carboplatin was observed in the presence of chloride ion. Carboplatin and iproplatin are stable for 24 hours in all the infusion fluids studied, but carboplatin should not be diluted with solutions containing chloride ions because of possible conversion to cisplatin. Cisplatin is stable for 24 hours in admixtures containing sodium chloride concentrations of 0.3% or greater. Tetraplatin is stable for six hours in admixtures containing sodium chloride concentrations of at least 0.018%.

Antineoplastic Agents↗
PubMed1986

Tricyclo[4.2.2.0(2,5)]dec-9-ene-3,4,7,8-tetracarboxylic acid diimide: formulation and stability studies.

The experimental antitumor drug, tricyclo[4.2.2.0(2,5)]dec-9-ene-3,4,7,8-tetracarboxylic acid diimide, NSC 284356, was formulated as the disodium salt in a stable freeze-dried form suitable for parenteral administration. The stability of the drug was determined in buffers at various temperatures using liquid chromatography. The drug was found to undergo hydrolysis in aqueous solutions. The rate of hydrolysis followed pseudo-first-order kinetics and is accelerated by increases in temperature and pH of the solutions. The hydrolysis product was isolated, and its structure was determined by unambiguous chemical methods.

Antineoplastic Agents↗
PubMed1986

Uridine-induced hyperthermia in the rabbit.

Uridine injection in 0.6% saline elevated rabbit temperatures (mean = 0.9 degree C) in the USP XX pyrogen test. Hyperthermia was delayed in onset and peaking 3-4 h post injection, but the injection was negative in the limulus amoebocyte lysate (LAL) assay. Uridine from five lots of different sources exceeded USP XX limits in the rabbit pyrogen test and proved negative in the LAL assay. Because the dose of uridine was high, several procedures were used to determine if an impurity was the cause of temperature elevation. Uridine remained pyrogenic in spite of ultrafiltration (10 000 nominal mol. wt), recrystallization and preparative scale HPLC. Sterile filtration and autoclaving also did not affect the response. Hyperthermia, therefore, appears to be an inherent property of uridine. Uridine was also found to release endogenous pyrogen in-vitro from human mononuclear cells. Uridine has been reported to induce fever in man, thus the USP rabbit pyrogen test predicted for the clinical response.

Animals↗
PubMed1986

Therapeutic and pharmacokinetic relationships of flavone acetic acid: an agent with activity against solid tumors.

Flavone acetic acid is a novel structure which exhibits an interesting spectrum of antitumor activity in preclinical studies. It has little antitumor activity in the leukemias and pronounced antitumor activity in solid tumors. Preclinical therapeutic, toxicologic, and pharmacokinetic studies are summarized and considered together to introduce the concept of a therapeutic window of effective plasma concentrations and effective exposure times in attempts to maximize therapeutic effects and minimize toxic effects. Plasma concentrations, predicted to fall from 600 to 100 micrograms/ml over 10 hours resulting from 267 mg/kg ip bolus injections in mice are curative to sc implanted colon 38. Doses of 356 mg/kg and higher cause acute lethality in many mice. Iv doses cause acute lethality in mice more frequently than ip doses, which suggests a peak toxic effect. However, iv infusions in mice, which also can be curative to colon 38, can also result in a lethal effect, although more delayed, even though the predicted plasma concentrations are much below the peak plasma concentrations that appear to be necessary for acute lethality. Plasma concentrations, 100 to 600 micrograms/ml predicted to result from single doses that are therapeutic and not acutely lethal in mice, if maintained by infusion in dogs for 28 hours or longer result in delayed lethality. We conclude that relatively high plasma concentrations (greater than 100 micrograms/ml) are needed for therapeutic activity with this antitumor agent and that lethality can result from two distinctly different causes. An acute lethality can result from an excessively high peak plasma concentration (greater than 600 micrograms/ml). A delayed lethality can result from a too-long exposure (greater than 24 hrs) at therapeutically effective plasma concentrations (100-600 micrograms/ml). We also note that unexpected kinetic differences exist among the mouse, dog, and man. Whereas usually with antitumor agents plasma clearances are proportional to body surface area, and hence faster in small species, quite the opposite is true with flavone acetic acid. Mice exhibit a slower plasma clearance relative to dogs and man.

Animals↗
PubMed1985

Disposition and bioavailability of various formulations of tetrahydrocannabinol in the rhesus monkey.

Oral delta 9-tetrahydrocannabinol (THC) in gelatin capsules is under evaluation as an antiemetic agent in cancer patients, but knowledge concerning its bioavailability is incomplete and, furthermore, alternative routes of administration may be desirable. In this study, the disposition of THC was determined in four rhesus monkeys given 2.5-mg/kg doses using the following routes of administration and formulations: intravenous (iv); orally (po) on a cookie and in gelatin capsules; intramuscularly (im) in Tween-80 and in Emulphor-EL620; rectally in various suppository bases. Serum THC concentrations were measured by RIA and analyzed by weighted nonlinear regression. Serum concentrations were best described by a sum of two exponentials with alpha and beta half-lives (mean +/- SD) of 0.74 +/- 0.59 and 14.9 +/- 12.5 h. Apparent bioavailability (%F +/- SD) of various formulations of THC were: gelatin capsules, 26 +/- 14; cookie, 89 +/- 16; intramuscularly in Tween-80 and in Emulphor, 39 +/- 13 and 102 +/- 15, respectively. Using the method of statistical moments, mean residence times in the body (h +/- SD) were: intravenous, 6.08 +/- 1.60; cookie, 21.92 +/- 3.11; gelatin capsule, 26.80 +/- 23.61; intramuscularly in Emulphor, 10.92 +/- 3.46 (in Tween-80, not calculated). THC was not bioavailable by the rectal route. We conclude from this study that THC formulated as a gelatin capsule exhibits a low and variable extent of bioavailability and that intramuscular THC may be a useful alternative route of administration since it is more completely bioavailable.

Administration, Oral↗
PubMed1984

Menogaril: a new anthracycline agent entering clinical trials.

Menogaril [menogarol, 7(R)-O-methylnogarol, 7-OMEN] is a new anthracycline agent which was chosen for clinical trials based on: broad spectrum activity against a panel of murine tumors, lower cardiotoxicity than doxorubicin in the chronic rabbit model, differences in biochemical effects from other anthracyclines suggesting a possible difference in mechanism of action, murine antitumor activity by oral as well as parenteral routes. Biochemical studies indicated that, in comparison to doxorubicin, menogaril is bound weakly to DNA, inhibits RNA synthesis less, and has different cell cycle phase-specific cytotoxicity. Pharmacology studies in the mouse and dog using HPLC analytical methodology have shown multiexponential clearance from plasma and metabolism of menogaril to a material which co-chromatographs with N-demethylmenogaril in addition to at least two other metabolites of unknown structure. Oral bioavailability studies in the mouse showed significant absorption of menogaril from the gastrointestinal tract followed by first-pass metabolism. In acute toxicity studies in the rat, the dog, and the monkey, dose-related myelosuppression and gastrointestinal toxicity predominated. Phase I clinical trails on menogaril are currently in progress on a variety of schedules.

Administration, Oral↗
PubMed1984

Compatibility of plastic infusion devices with diluted N-methylformamide and N,N-dimethylacetamide.

Leaching of the plasticizer di-2-ethylhexyl phthalate (DEHP) from i.v. sets and polyvinyl chloride bags was studied with solutions of a new anticancer drug, N-methylformamide (NMF), and N,N-dimethylacetamide (DMA), a structurally related solvent used in the formulation of some anticancer drugs. Solutions of 0.9% sodium chloride, 5 and 10% DMA in 0.9% sodium chloride, and 20, 40, and 60% NMF in 0.9% sodium chloride were used to fill i.v. administration sets ( Venoset -60, Abbott Laboratories) and polyvinyl chloride bags ( Viaflex -500, Travenol Laboratories). The solutions were kept in the containers for 20 hours at ambient temperature. Simulated infusions were also studied using 0, 20, and 40% NMF plus 5 and 10% DMA in 0.9% sodium chloride; both glass bottles and Viaflex -500 bags were used with the i.v. administration sets. DEHP was assayed using gas chromatography. Very small or unmeasurable amounts of DEHP were leached into 0.9% sodium chloride and 5 or 10% DMA solutions during 20-hour storage. DEHP concentrations increased exponentially with increasing NMF concentrations after 20-hour storage in both the i.v. sets and bags. Similar results were found in the simulated-infusion portion of the study. DEHP extraction from i.v. sets and polyvinyl chloride bags containing NMF and DMA in 0.9% sodium chloride is related directly to the concentrations of these organic compounds. The amount of DEHP leached into solutions is important only for solutions containing 60% NMF.

Acetamides↗
PubMed1982

Determination of ellipticine in biological samples by high-performance liquid chromatography.

Ellipticine, a plant alkaloid effective against murine leukemias and solid tumors, is presently undergoing toxicological assessment prior to clinical trial. A rapid, sensitive, reversed-phase high-performance liquid chromatographic method employing an internal standard was developed for the detection of ellipticine and its principal metabolite 9-hydroxyellipticine after extraction from biological samples. The method was successfully applied to the quantitation of ellipticine in mouse blood and tissues after intravenous administration of ellipticine and to mouse blood levels of drug after oral administration. Similar success was achieved in determinations of ellipticine and 9-hydroxyellipticine in samples of spiked human blood and plasma. Mouse blood ellipticine levels monitored over 3 h after the intravenous administration of drug demonstrated a biphasic decline with a terminal half-life of 52 min.

Alkaloids↗
PubMed1982

The hydrolysis of spirohydantoin mustard.

Spirohydantoin mustard (I) is a rationally designed anti-tumor agent with substantial in vivo activity against intracranially implanted tumors in mice. However, hydrolysis of I was much faster than that of mechlorethamine hydrochloride or melphalan, two parenterally administered mustards. The hydrolysis products of I were identified by GC-MS of their silylated derivatives. The decomposition of I (at 25 degrees in 10% dimethylacetamide at pH 4-6), as monitored by GLC was pseudo first-order. The half-life of I ranged from 20 min at pH 4.0 to 14 min at pH 6.0. Nonionic surfactants enhanced the stability of I, but this effect was diminished at lower pH, presumably due to decreased solubility of I in the micelle as more drug was protonated. Several dilute parenterally suitable solvents exhibited no marked effect on the hydrolysis of I. The drug was most stable in a 10% fat emulsion system where the time for 10% decomposition of I was 49 +/- 5 min. Plots of the concentration of I versus time were linear indicating the disappearance was zero order in the 10% fat emulsion system.

Animals↗
PubMed1981

Determination of delta 9-tetrahydrocannabinol in pharmaceutical vehicles by high-performance liquid chromatography.

A procedure for the determination of delta 9-tetrahydrocannabinol (delta 9-THC) in the presence of its degradation products in pharmaceutical vehicles by high-performance liquid chromatography (HPLC) is described. The method compares favorably with a standard gas-liquid chromatographic procedure used for the analysis of delta 9-THC in sesame oil USP. The HPLC method is suitable for quantitating delta 9-THC in the presence of several pharmaceutical vehicles and excipients including: sesame oil USP, polyvinylpyrrolidone, Emulphor EL620 and Cremophor EL. Extractions are not required and samples require little preparation. Only the addition of an internal standard in an appropriate solvent is necessary before injection. The procedure has been applied to stability studies of delta 9-THC in various pharmaceutical vehicles.

Chromatography, Gas↗
PubMed1981

2,5-Diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone I: Kinetics in aqueous solutions by high-performance liquid chromatography.

The application of a rapid, selective, and sensitive reversed-phase high-performance liquid chromatographic method to the analysis of 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone (I) and its degradation products is described. The method was used to study the kinetics of degradation of I over pharmaceutically useful pH ranges. The overall reaction rate followed pseudo-first-order kinetics. The pH-rate profile demonstrated optimal stability between pH 6.0 and 6.5. The degradation behavior suggests the existence of multiple pathways. The temperature dependence of th disappearance of I also was evaluated from the regression equation derived from the Arrhenius plot.

Antineoplastic Agents↗
PubMed1981

Stability of anthracycline antitumor agents in four infusion fluids.

The stabilities of doxorubicin hydrochloride, daunorubicin hydrochloride, zorubicin, and aclacinomycin A hydrochloride were studied in various infusion fluids at ambient temperature. Reversed-phase high-pressure liquid chromatographic procedures developed and used in these studies employed internal standards and readily separated each drug from its degradation products. Dilute solutions of the anthracyclines were prepared by appropriate dilutions of the reconstituted solutions of the formulated products with 5% Dextrose Injection, USP (D5W); 0.9% Sodium Chloride Injection, USP (NS); Lactated Ringer's Injection, USP (LR); and Normosol-R pH 7.4. The stability of the anthracyclines was dependent on the pH of the admixture solution which, in turn, was dependent on infusion fluid composition. Daunorubicin and aclacinomycin A exhibited acceptable stability (equal to 90% of the original concentration) in D5W, NS, and LR for more than 48 hours. Doxorubicin manifested similar stability in the first two fluids. Zorubicin showed similar stability only in Normosol-R pH 7.4 fluid for 22 hours.

Aclarubicin↗
PubMed1980

Morphine acetate.

Explore the source record for details and available documents.

Morphine Derivatives↗
PubMed1980

Stability of Brompton mixtures: determination of heroin (diacetylmorphine) and cocaine in presence of their hydrolysis products.

The application of a rapid, selective, and sensitive reversed-phase high-performance liquid chromatographic method to the separation of the hydrochloride salts of heroin (diacetylmorphine) and cocaine and their hydrolysis products is described. The method was used to study the stability of heroin and cocaine in Brompton mixtures in pharmaceutically useful pH range and vehicles at different temperatures. The pH range of optimal stability for both heroin and cocaine was 3.0-3.5. The disappearance of heroin and cocaine in Brompton mixtures followed pseudo-first-order kinetics in buffered solutions. Increased alcohol and decreased syrup concentrations diminished heroin hydrolysis but did not influence cocaine stability. Substitution of morphine for heroin in Brompton mixtures markedly increased the rate of cocaine hydrolysis.

Chemistry, Pharmaceutical↗
PubMed1979

Application of a simple high-performance liquid chromatographic method for the determination of melphalan in the presence of its hydrolysis products.

A procedure for the separation and quantitation of melphalan (L-PAM) and its hydrolysis products by high-performance liquid chromatography is described. The hydrolysis of L-PAM at 25 +/- 0.1 degrees and 41 +/- 0.1 degrees was studied between pH 3.0 and 9.0. The pattern of hydrolysis suggested that L-PAM decomposes via two consecutive pseudo first-order reactions. Pseudo first-order rate constants (k1) were determined for the disappearance of L-PAM at various pH values in buffered solutions and in a formulated product. At both temperatures L-PAM solutions were found to be most stable at low pH. Chloride ion was found to reduce the rate of hydrolysis.

Chromatography, High Pressure Liquid↗