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Biomedical subjects

J M Collins

Publications and source records attributed to J M Collins.

213 records · Page 12Linked to original sources
PubMed1969

The cardio-toxicity of isoprenaline during hypoxia.

1. The effects of the intravenous injection of isoprenaline on heart rate and arterial pressure has been studied in dogs artificially respired with room air or with 12% oxygen-88% nitrogen.2. In dogs breathing room air, isoprenaline in doses from 0.02 to 500 mug/kg increased heart rate and reduced arterial pressure. Ventricular fibrillation was produced in one out of three dogs given 250 mug/kg. This was the only dog breathing room air which was killed by isoprenaline.3. In dogs breathing room air the repeated intravenous injection at 5-min intervals of 2.5 mug/kg increased heart rate and reduced arterial pressure. No ill effects were produced by six doses.4. In dogs respired with 12% oxygen-88% nitrogen the PaO(2) was reduced from 84 to 38 mm Hg with no changes in PaCO(2). In these dogs death was produced by doses of isoprenaline which in dogs breathing room air produced normal responses.5. The fatal dose of isoprenaline (10-50 mug/kg) reduced heart rate and arterial and pulse pressures; sinus rhythm persisted until arterial pressure was less than 50 mm Hg. Ventricular fibrillation did not occur; death occurred from cardiac asystole.6. Death was produced in a similar way in dogs with hypoxaemia by giving four or five doses of isoprenaline (2.5 mug/kg) at 5-min intervals or by two doses of 25 mug/kg.7. The final reduction in arterial pressure during a fatal response resulted from a reduction in cardiac contractility.8. These lethal effects of isoprenaline could be prevented by pretreatment with propranolol.

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Accuracy of assessment of the extent of examination by experienced colonoscopists.

One hundred colonoscopies were done. The colonoscopist noted whether the cecum had been intubated as well as the markers used to make this determination. With the colonoscope in position at maximum penetration, a radiologist independently determined its position using fluoroscopy, with a contrast agent delivered through the colonoscope. The cecum was entered in 86 of 100 cases. The tip of the colonoscope was at the level of the ileocecal valve in nine additional cases; the colonoscopist judged that the cecum was well seen in five of these nine. In one case, the colonoscopist overestimated the extent of the examination when transillumination in the right lower quadrant was the only confirming marker. When the more reliable markers (ileocecal valve, appendiceal orifice, converging indentations of the taenia coli in the cecal pole) were seen, no errors were made. Experienced colonoscopists are accurate in assessing the extent of colonoscopy and fluoroscopic confirmation is not routinely needed. When reliable markers are not seen during the examination, a barium enema, preferably with air contrast, should be done.

Cecum↗
PubMedDate not supplied

Analysis of "early" thymidine/inosine protection as an adjunct to methotrexate therapy.

The feasibility of "early" thymidine and inosine protection of methotrexate (MTX) toxicity is evaluated in this paper. This approach is based on the proposition that the most vulnerable period for susceptible host cells to MTX toxicity is an interval following a pulse of MTX when the MTX monoglutamate level is high. In contrast, tumor cells that accumulate active MTX polyglutamyl derivatives are exposed to the cytotoxic effects of MTX, not only when the monoglutamate levels are high, but also over the much longer interval during which polyglutamyl derivatives are retained within these cells. The protecting agents employed, thymidine and inosine, circumvent the antipurine and antipyrimidine effects of MTX, but neither agent inhibits the transport or the polyglutamylation of MTX. Nucleoside protection given over 6 hours after MTX markedly decreased toxicity to normal BDF1 mice at MTX doses up to 150 mg/kg/day for 3 consecutive days. The LD10 for unprotected mice was 14 mg/kg/day, while the LD10 for the protected mice was 114 mg/kg/day, a greater than eightfold increase in the drug dose delivered. MTX with early nucleoside protection produced a 50% increase in median life span in tumor-bearing mice at doses of drug that were toxic to unprotected mice. Flow cytometric analyses indicated that consecutive daily pulses of MTX with early nucleoside protection alter the cell cycle distribution. By 24 hours after the last of three daily pulses of MTX, the G1 component was maximal (80% of the cell population), with less than 2% of the cells in G2M and 17% of the cells in S phase. This distribution persisted for 24 hours, after which a normal pattern emerged, a process that was accelerated by neither thymidine/inosine nor leucovorin. These studies support the concept that toxicity to the host is initiated largely in the interval shortly after MTX administration. The data indicate that early nucleoside protection permits the repetitive administration of much higher doses of MTX than can be given with MTX alone. This approach may be useful not only in the treatment of human neoplasms but in the treatment of other disorders, such as rheumatoid arthritis, psoriatic arthritis, or psoriasis. Finally, this paper considers the potential advantages of early thymidine/inosine protection in comparison to leucovorin rescue with the administration of low or moderate doses of MTX.

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Influence of pregnancy and folic acid on phenytoin metabolism by rat liver microsomes.

Liver microsomal suspensions from pregnant and nonpregnant Sprague-Dawley rats were assayed for NADPH-dependent metabolism of phenytoin to the hydroxylated products, 5-(rho-hydroxyphenyl)-5-phenylhydantoin (rhoHPPH) and 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)5-phenylhydantoin (H2DIOL). UDP-glucuronic acid-dependent glucuronyltransferase activity for conjugating rhoHPPH was also measured. The specific activity for formation of rhoHPPH decreased by 35% in 21-day pregnant rats compared with nonpregnant rats, whereas specific activity for production of H2DIOL was increased approximately 2-fold on the 7th and 14th but not the 21st day of pregnancy. Because of a 25% increase in liver weight during pregnancy, the total hepatic phenytoin hydroxylase activity in pregnant rats (day 21) was not significantly different from that of nonpregnant controls. Folic acid treatment during pregnancy prevented the decrease in phenytoin hydroxylase specific activity. The KM for production of either rhoHPPH or H2DIOL was similar (90 micrometer) in pregnant (day 21) and nonpregnant animals. Thus, overall hepatic microsomal enzyme activity for metabolizing phenytoin was not significantly reduced during pregnancy in rats, although the ratio of H2DIOL to rhoHPPH was increased during the first two weeks. Folic acid may play a role in pregnancy-associated changes in phenytoin hydroxylase activity.

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Improving the use of anticancer drugs: clinical pharmacokinetic approaches.

There are many areas in which clinical oncologists and pharmacologists can work together to improve the chemotherapy of cancer. In new drug development, the conduct of Phase I clinical trials is greatly facilitated by cooperative selection of appropriate schedules and dose escalation procedures. For established anticancer agents, continual surveillance is necessary to assure that new insights regarding a drug's mechanism of action can be translated into rational clinical trends, which are intended to improve response rates and/or reduce toxicity. Specific areas of optimization include alternate schedules or routes of drug delivery and selection of agents that penetrate the CNS. Adjustment of drug dosage for an individual patient and assessment of drug interactions can also be facilitated by collaboration between clinicians and pharmacologists.

Antineoplastic Agents↗
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The murine disposition and pharmacokinetics of the antineoplastic agent, diaziquone (NSC 182986).

We have studied the murine disposition and pharmacokinetics of diaziquone (AZQ), a new aziridinylbenzoquinone antitumor agent that is currently undergoing clinical trials. 14C-AZQ, dissolved in dimethylacetamide/0.01M phosphate buffer, pH 6.5, 5:95 (v/v), was administered iv to mice at a dosage of 6 mg/kg (18 mg/m2). After injection, mice were killed and plasma and organs were obtained and analyzed for total radioactivity and for chloroform-extractable 14C. Both total plasma radioactivity and chloroform-extractable plasma 14C declined very rapidly. By 3 hr, chloroform-extractable 14C was about 0.2% of its initial concentration. Within 30 min after injection, more radioactivity remained in the aqueous phase than was extracted into chloroform. When analyzed by TLC, all chloroform-extractable radioactivity in plasma as well as in brain, heart, liver, and skeletal muscle co-chromatographed with parent AZQ. Tissue distribution of 14C was extensive. 14C concentrations (dpm/g tissue wet weight) were initially greatest in heart and lung, but by 2 min after injection, were greatest in kidney, and by 10 min were second greatest in liver. Substantial amounts of total and chloroform-extractable 14C were found in brains. By 3 hr after injection, total 14C in all tissues exceeded total 14C in plasma. The apparent volume of distribution of AZQ was approximately 1 ml/g and the total body clearance of AZQ was 0.9 ml/min or 130 ml/min/m2. Extraction of tissues with chloroform showed conversion of AZQ into non-chloroform-extractable metabolites. This conversion was reproduced in vitro by mouse liver homogenate at 37 degrees C but not at 0 degree C.

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PubMedDate not supplied

Effect of cimetidine, probenecid, and ketoconazole on the distribution, biliary secretion, and metabolism of [3H]taxol in the Sprague-Dawley rat.

Male Sprague-Dawley rats had their bile ducts cannulated and were dosed with [3H]taxol (2 mg/kg, 68-77 microCi/mg) as a continuous intravenous infusion for 6 hr so that the plasma concentrations, tissue distribution, metabolism, and biliary secretion of taxol could be studied. Defining potential drug-drug interactions of taxol with cimetidine (90 mg/kg), probenecid (360 mg/kg), and ketoconazole (50 mg/kg) was motivated by frequent concomitant clinical use or the potential to reduce clearance of taxol so that lower doses could be used. At 6 hr, rats were killed. Samples of blood (plasma), lung, spleen, liver, kidney, heart, skeletal muscle, brain, testes, and fat were obtained. Taxol and metabolites were measured by total radioactivity counting and HPLC separation using on-line radioactivity detection. Concentrations of taxol in plasma increased to 0.19 microM in the control rats and did not reach steady-state by 6 hr. Lung, spleen, liver, and kidneys had the greatest tissue taxol concentrations [4.7-5.7 nmol/g (microM)] and were > 25-fold higher than the simultaneous 6-hr plasma taxol concentration. Taxol concentrations in brain and testes were negligible, 0.06 and 0.07 nmol/g, respectively. Radioactive metabolites were not found in plasma or most tissues. Only liver had appreciable concentrations of taxol and metabolites; however, > 80% of hepatic radioactivity was parent taxol. Through 6 hr of collection, 24% of the dose was secreted in the bile approximately 38% of which was as parent taxol. Cimetidine had no effect on the distribution, metabolism, or elimination of [3H]taxol. Probenecid did not effect tissue distribution or plasma concentrations of taxol.(ABSTRACT TRUNCATED AT 250 WORDS)

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