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Biomedical subjects

C K Chiang

Publications and source records attributed to C K Chiang.

14 recordsLinked to original sources
PubMed1991

Evidence for the stability and cytochrome P450 specificity of the phenobarbital-induced reductive halothane-cytochrome P450 complex formed in rat hepatic microsomes.

The hypothesis that the reduced spectral halothane-cytochrome P450 complex formed in rat hepatic microsomes is a stable cytochrome P450 specific species was examined. Comparisons of the cytochrome P450 inducers, phenobarbital (PB), pregnenolone-16 alpha-carbonitrile (PCN) and beta-naphthoflavone (beta-NF) showed that PB was the most effective inducer of the halothane-cytochrome P450 complex and the cytochrome P450 which liberates the halothane metabolites, 2-chloro-1,1-difluoroethene (CDE) and 2-chloro-1,1,1-trifluoroethane (CTE). However, the ratio of CDE produced to quantity of complex was found to be reduced 70-77% in these microsomes. A large portion of total microsomal cytochrome P450 was destroyed upon halothane reduction (up to 39%), yet the complexed cytochrome P450, particularly in microsomes from PB-treated animals, was resistant to the irreversible inactivation mechanisms of halothane reduction. The effects of reductive halothane metabolism on subsequent warfarin metabolism showed that 7-hydroxywarfarin formation from either (R)- or (S)-warfarin in microsomes from PCN-treated, PB-treated or untreated rats was highly susceptible to irreversible inhibition. In microsomes from PB-treated, but not PCN or untreated rats, the formation of one warfarin metabolite, 4'-hydroxywarfarin from (R)-warfarin, could be shown to be increased when complex was eliminated by photodissociation. These results suggest that PB-B is preferentially bound as complex and resistant to inactivation because of complex stability, and that halothane reduction readily destroys the cytochrome P450 form, PB-C.

Animals↗
PubMed1990

Metabolites of methohexitone do not contribute to its prolonged action on the central nervous system.

Methohexitone has been reported to have a prolonged action on the central nervous system (CNS) despite its relatively short elimination half-life. A hydroxy metabolite of methohexitone was identified, purified and isolated from the urine collected from eight surgical patients and five mongrel dogs anaesthetized with methohexitone. Using a rotarod device, the CNS-activity of the human and canine metabolites was tested in mice and compared to that of methohexitone. In this test, the metabolites showed CNS-depressant activity, but the ED50 (dose needed to affect 50% of the animals) of the metabolites was ten times higher than the ED50 of the parent drug. Because in patients, no traces of the hydroxy metabolite could be found in blood, and in dogs the plasma concentration of the metabolite was about two-thirds of that of the parent compound, it is unlikely that the residual CNS-effects of methohexitone are due to its major metabolite, hydroxymethohexitone.

Animals↗
PubMed1989

Intrapleural bupivacaine--technical considerations and intraoperative use.

The authors evaluated the incidence and type of technical problems associated with blind insertion of intrapleural catheters placed in 21 anesthetized patients and then injected in a double-blind fashion with 0.5% bupivacaine (1.5 mg/kg) or isotonic saline. The patients' chests were then opened, catheter positions located, and the lungs inspected. Eleven of the catheters were located with the tips intrapleurally, three extrapleurally, and seven actually in lung tissue. Eight patients had holes in the lung surface. Three patients had a pneumothorax, two of which were under tension. Plasma bupivacaine levels reached maximal concentrations at about 20 minutes in those with intrapleurally placed catheters, but not until 60 minutes when the catheter had actually penetrated the lung. Significant variations in plasma bupivacaine levels were achieved when the catheter entered lung tissue, with potentially toxic levels in one patient. To evaluate intraoperative analgesic effects, all patients were given a standard anesthetic with isoflurane, oxygen, and a muscle relaxant. There was no significant difference in isoflurane requirement between the groups who had bupivacaine v saline injected into their intrapleural catheters before surgery. It is concluded that blind insertion of intrapleural catheters can be hazardous, especially if followed by positive-pressure ventilation. In addition, catheter placement in lung tissue, which was not uncommon, delays the time for peak plasma concentrations and may increase risk of toxicity. Intrapleural bupivacaine was not found to be a useful adjunct to general anesthesia during thoracotomies.

Adult↗
PubMed1987

Transport of diphenhydramine in the central nervous system.

The transport and metabolism of diphenhydramine was studied in vitro in the isolated rabbit choroid plexus and in vivo in New Zealand white rabbits and Sprague-Dawley rats. In vitro, [14C] diphenhydramine was accumulated by a saturable, energy-requiring system in choroid plexus. In vivo, 20 min after intraventricular injection into rabbits, [14C]diphenhydramine was cleared from cerebrospinal fluid much more rapidly than [3H]sucrose, a molecule transported in the central nervous system by simple diffusion. In vivo, employing the in situ rat brain perfusion technique, [14C]diphenhydramine was cleared from the cerebral perfusion fluid as rapidly as [14C]diazepam. However, the clearance of [14C]diphenhydramine, but not [14C]diazepam, was inhibited by the addition of 10 mM unlabeled diphenhydramine to the perfusate. These in vivo and in vitro results show that diphenhydramine, unlike diazepam, is transported between blood, brain and cerebrospinal fluid, in part, by saturable, carrier-mediated transport processes at both the blood-brain and blood-cerebrospinal fluid barriers.

Animals↗
PubMed1986

Pharmacokinetic and pharmacodynamic interactions between caffeine and diazepam.

The pharmacokinetic and dynamic interactions of caffeine and diazepam after single doses were investigated in six young healthy adults. Subjects received 6 mg/kg of caffeine, 0.3 mg/kg of diazepam, and their combination at 2-week intervals according to a Latin square design and a double-blind procedure. Subjects had blood samples withdrawn at 0, 5, 10, 20, 30, 45, 60 minutes and every 30 minutes thereafter until 210 minutes after treatment. A battery of behavioral tests were administered before treatment and after each blood sampling, starting with the 20-minute period. The coadministration of caffeine with diazepam resulted in a 22% reduction in diazepam plasma levels. Caffeine produced hand tremors and diazepam produced sedation and impaired memory and cognition. The two drugs did not antagonize the effects of each other except in the symbol cancellation task. There were significant correlations between the caffeine and diazepam plasma levels and performance on several tasks and evidence for the development of acute tolerance to both drugs.

Adolescent↗
PubMed1985

The pharmacokinetics of methohexital in young and elderly subjects.

The pharmacokinetics of methohexital were investigated in ten young adult volunteers and in seven young and seven elderly patients. The latter two groups underwent enflurane and nitrous oxide anesthesia and surgery. Each subject received a bolus dose of 2 mg/kg of methohexital intravenously. Plasma levels of the drug were measured for 8 h after injection by gas chromatography using a nitrogen detector. Anesthesia (combined with surgery) and increase in age did not separately affect the kinetics of the drug; however, the elimination half-life was longer in the elderly patients group than in the young non-anesthetized volunteers.

Adult↗
PubMed1982

Diphenhydramine: kinetics and psychomotor effects in elderly women.

Kinetics and sedative and psychomotor effects of diphenhydramine were investigated in elderly Caucasian women (greater than 64 yr. old). In a double-blind trial, each of 12 healthy subjects received on one of three occasions 50 mg/70 kg IV or oral diphenhydramine HCl or oral placebo. Plasma levels of diphenhydramine were measured in six subjects and tests of sedation and psychomotor performance were performed hourly for 8 hr in all subjects. Kinetic analysis showed that the volume of distribution (295 +/- 50 [SEM] l/70 kg), clearance (42 +/- 5 l/70 kg/hr), and plasma t1/2 (4.9 +/- 0.7 hr) were of the same order as in young adults. As in young adults, there was minimal psychomotor impairment after oral and after intravenous diphenhydramine. In contrast to young adults, however, elderly women did not report significant sedation after diphenhydramine. These results suggest that diphenhydramine may not be an effective sedative/hypnotic in elderly women.

Administration, Oral↗
PubMed1981

Diazepam effects and kinetics in Caucasians and Orientals.

Mental and psychomotor effects and diazepam kinetics were studied in Caucasian and Orientals. 12 Caucasian and 13 Oriental young adults received on one of two occasions, separated by 2 weeks, either 0.2-mg/kg diazepam or saline intravenously. Serum diazepam and desmethyldiazepam concentrations were measured by electron-capture gas-liquid chromatography in samples drawn up to 72 hr after injection. Serum protein binding was measured by equilibrium dialysis. Subjects were tested on a battery of psychological tests before and 0.5, 2, and 4 hr after treatment. While the free fraction of diazepam was identical in both races (0.02), volume of distribution at steady state (Vdss) was different when calculated as absolute volume (Vdss = 76.55 +/- 9.63 l in Caucasians and 54.96 +/- 4.55 l in Orientals, p = 0.04) and marginally significant when corrected for body weight (Vdssl/kg = 1.10 +/- 0.11 in Caucasian and 0.88 +/- 0.05 in Orientals, p = 0.07). total body clearance (Cl), but not elimination half-life (t 1/2), was higher in Caucasians than Orientals, p less than 0.01; t 1/2 = 37.70 +2- 5.53 hr in Caucasians and 41.77 +/- 3.80 in Orientals). Desmethyldiazepam levels were higher in Orientals than Caucasians. Mental and psychomotor effects were maximal at the first session (0.5 hr), followed by complete recovery by the 4-hr session. Effects were similar in both groups. If repeated dosing causes a higher rate of cumulated diazepam serum levels in Orientals, as expected, there might be deeper brain depression in that group.

Adult↗
PubMed1980

Diphenhydramine in Orientals and Caucasians.

The kinetics and psychomotor effects of diphenhydramine were investigated in Orientals and Caucasians. Each of 5 Oriental and 5 Caucasian young adults received on 1 of 3 occasions diphenhydramine 50 mg/70 kg body weight either intravenously or orally, or placebo. Plasma levels of diphenhydramine were measured hourly for 8 hr at each session. Tests of subjective sedation and psychomotor performance were performed at hourly intervals. The results showed that after both intravenous and oral diphenhydramine, at all times Orientals had plasma levels approximately half those of Caucasians. With the assumption of linear kinetics and a 1-compartment open model, analysis of the data showed that the volume of distribution (VD) and plasma clearance (Cl) but not plasma half-life (t 1/2) were higher in Orientals than Caucasians: [VD = 480 +/- 24 (SEM) and 292 +/- 36 1/70 kg; Cl = 79 +/- 7 and 51 +/- 7 1/70 kg/hr; t 1/2 = 4.1 +/- 0.4 and 4.3 +/- 0.4 hr]. Unbound diphenhydramine in fresh plasma was higher in Orientals than Caucasians [24.0 +/- 1.9% (SEM) and 14.8 +/- 1.5%] and probably explains the increased VD in Orientals. Orientals had significantly less sedation and deterioration in psychomotor performance.

Adult↗
PubMed1978

Studies on macromomycin, an antitumor protein.

Macromomycin is a protein isolated from the culture filtrate of Streptomyces macromomyceticus. It is an antibiotic and also cytotoxic to a broad spectrum of carcinoma cells, the ID50 for P388 leukemia cells being 1 X 10(-9) M. Macromomycin binds rapidly and tightly to the P388 cell membrane and the eventual death of the cell cannot be reversed by either washing the toxin away or treating the cell with trypsin. The cytotoxicity does not appear to be specific for any phase of the P388 cell cycle. Macromomycin is a single polypeptide, pI 5.38, devoid of methionine and arginine residues and contains 4 cysteine residues joined by two intramolecular disulfide bonds. The cytotoxicity results in inhibition of DNA, RNA, and protein synthesis in P388, the latter inhibition occurring a few hours after the inhibition of nucleic acid synthesis. The antibiotic and antitumor activities are destroyed rapidly by ultraviolet light, which gives a product that differs little in amino acid composition, molecular weight, and antigenic property, but can be separated from the native macromomycin by ion exchange chromatography. It is proposed that macromomycin has an ultraviolet-sensitive prosthetic group upon which much of the biological activity is based.

Amino Acids↗
PubMedDate not supplied

Metabolism of 2-chloro-1,1-difluoroethene to glyoxylic and glycolic acid in rat hepatic microsomes.

The complete metabolic fate of the volatile anesthetic halothane is unclear since 2-chloro-1,1-diflurorethene (CDE), a reductive halothane metabolite, is known to readily release inorganic fluoride upon oxidation by cytochrome P-450. This study sought to clarify the metabolism of CDE by determining its metabolites and the roles of induce cytochrome P-450 forms in its metabolism. Upon incubation of [14C]CDE with rat hepatic microsomes, two major radioactive products were found which accounted for greater than 94% of the total metabolites. These compounds were determined to be the nonhalogenated compounds, glyoxylic and glycolic acids, which were formed in a ratio of approximately 1 to 2 of glyoxylic to glycolic acid. No other radioactive metabolites could be detected. Following incubation of CDE with hepatic microsomes isolated from rats treated with cytochrome P-450 inducers, measurement of fluoride release showed that phenobarbital induced CDE metabolism to the greatest degree at high CDE levels, isoniazid was the most effective inducer at low CDE concentrations, and beta-naphthoflavone was ineffective as an inducer. These results suggest that CDE biotransformation primarily involves the generation of an epoxide intermediate, which undergoes mechanisms of decay leading to total dehalogenation of the molecule, and that this metabolism is preferentially carried out by the phenobarbital- and ethanol-inducible forms of cytochrome P-450.

Animals↗