PubMed Health⌕ Search

Biomedical subjects

C E Cook

Publications and source records attributed to C E Cook.

At least 55 records · Page 3Linked to original sources
PubMed1985

Paired-ion liquid chromatographic method for the analysis of a phenanthrenemethanol antimalarial in whole blood.

A sensitive and specific high-performance liquid chromatographic (HPLC) assay was developed for the determination of the candidate antimalarial (+/-)-(1,3-dichloro-6-trifluoromethyl-9-phenanthryl)-3-di-(n-butyl )aminopropanol hydrochloride in whole blood. A reversed-phase, paired-ion (lauryl sulfate) system achieved separation of the antimalarial and internal standard from interfering constituents with a sensitivity limit of 10 ng/mL by UV detection (254 nm). Chromatographic variables (counterion concentration, pH, and column temperature) were examined to determine their effect on assay characteristics (retention, efficiency, and relative response) in clinical analysis. The antimalarial was isolated from 2.0 mL of whole blood using overnight extraction with 30% ethyl acetate in hexane followed by an acid/base partition sequence to remove major interferences. Overall recovery for the antimalarial was 84% with a CV of 5.0%, and the recovery of the internal standard was 81% (CV = 3.6%). The assay was validated by analysis of both intra- and interlaboratory samples. The assay was applied to the analysis of whole blood samples taken from a 30-year-old healthy human male who had received a single 14.1-mg/kg oral dose. The stability of the antimalarial in whole blood for up to 4 months and in sample extracts for up to 34 d at -17 degrees C was also demonstrated.

Animals↗
PubMed1985

Pyrolysis products of heroin.

Heating of heroin hydrochloride or of heroin at 250 degrees C led to extensive degradation. Major components of the pyrolysate were identified as heroin, 6-acetylmorphine, N,6-diacetylnormorphine, and N-acetylnorheroin by comparison of mass spectra and 13C- and 1H-nuclear magnetic resonance (NMR) spectra with those of authentic compounds. There was evidence for degradation of the piperidino moiety and the structure 3,4-diacetoxyphenanthrene was proposed for a minor product.

Chemical Phenomena↗
PubMed1984

Effect of influenza vaccine on warfarin anticoagulation.

Recent studies have indicated that viral infections, influenza vaccination, or drugs that increase interferon synthesis all decrease hepatic drug metabolism. We report a case in which influenza vaccination was temporally related to an increased anticoagulant effect of warfarin. A prospective study evaluating the effect of influenza vaccination on the prothrombin time of eight patients anticoagulated over the long term showed that there was prolongation of prothrombin time of 40%. In a second study, the effect of influenza vaccination on warfarin t1/2 was determined in healthy subjects. No significant effect on warfarin metabolism was observed after vaccination. We conclude that influenza vaccination is associated with increased anticoagulant response in some patients receiving anticoagulants over a long term. This effect appears to be related to some step in the coagulation pathway and not to decreased warfarin metabolism and a subsequent rise in serum concentration.

Adult↗
PubMed1983

Phencyclidine disposition in humans after small doses of radiolabeled drug.

Administration of small doses of radiolabeled phencyclidine hydrochloride (PCP X HCl) to normal volunteers has resulted in basic information on the disposition of PCP in humans. The drug and its metabolites were excreted mainly in the urine whether it was given orally or i.v. (73 +/- 4% of dose was recovered in urine after i.v. administration of 1 mg), with very little fecal excretion (3-5%) and some excretion in sweat. Oral bioavailability was 72 +/- 8%. Major metabolic pathways found involved hydroxylation of the cyclohexane and piperidine rings followed by conjugation. Oxidation to an aminopentanoic acid also occurred. PCP and phenylcyclohexene were inhaled when PCP was smoked. For PCP the weighted mean apparent terminal rate constant (beta) was 0.0395 +/- 0.0008 h-1 for 16 subjects, equivalent to a half-life of 17.6 h, but 2 subjects had half-lives of over 2 days. The volume of distribution (Vd, beta) was 6.2 +/- 0.3 liters/kg. At usual urinary pH, PCP excretion represented less than 10% of total clearance, but marked lowering of urinary pH can significantly increase the contribution of renal clearance to overall clearance.

Feces↗
PubMed1982

Free-base cocaine smoking.

Six healthy male, paid subjects smoked 50 mg of free-base cocaine in a specially designed glass pipe under a rigidly controlled smoking protocol. The method of heating the pipe and the temperature that produced the most efficient and consistent vaporization of the drug had been determined experimentally. The psychological and cardiovascular effects of smoking free-base cocaine were recorded. Approximately 26% of th original material was recovered from the pipe after smoking. Simulated smoking experiments in vitro indicated that only 44% of the material not trapped in the pipe was cocaine and that over 90% of this cocaine was delivered during the first four puffs (i.e., during the first 2 min of simulated smoking). These findings indicate that of the original 50 mg of cocaine free base placed in the pipe's bowl, only 32% could have been inhaled (16.3 +/- 0.6 mg). The cocaine free base inhaled induced psychological and cardiovascular effects similar to, or slightly more intense and pleasurable than, the effects of 20 mg of cocaine HCl (18 mg of cocaine base) taken intravenously by the same subjects and also induced a slightly more intense craving for another dose.

Adult↗
PubMed1982

Urine pH and phencyclidine excretion.

Subeffective doses (0.5 mg) of 3H-phencyclidine (PCP) were given intravenously to three healthy men under two regimens designed to alkalinize or acidify their urine (oral sodium bicarbonate or ammonium chloride). The concentrations of PCP and its metabolites in saliva, plasma, and urine for 7 hr after injection were determined by high-performance liquid radiochromatography. A sample of perspiration from one subject was analyzed. The effects of physical exercise on the plasma concentration and urinary excretion of PCP were also studied. Multiple linear regression analysis showed the logarithm of renal clearance the renal clearance of PCP. PCP and its metabolites are also excreted in perspiration. Our results support clinical reports of the importance of vigorous acidification of urine and diuresis in treatment of PCP intoxication.

Adult↗
PubMed1982

Comparison of effects of marihuana cigarettes to three different potencies.

Marihuana cigarettes containing 1.32%, 1.97%, and 2.54% delta 9-tetrahydrocannabinol (THC) were smoked by six experienced marihuana users at weekly intervals in a double-blind cross-over design under laboratory conditions. Puff duration, number of puffs taken, duration of inhalation holding, interval between puffs, and duration of smoking were recorded for each cigarette smoked. The portion of each cigarette remaining after smoking was weighed and analyzed to determine THC content. Subjective ratings of the "high" achieved and the heart rate acceleration induced by smoking the marihuana were measured. The plasma concentrations of THC and of its principle metabolite, 11-nor-delta 9-THC-9-carboxylic acid (9-carboxy THC), were determined by radioimmunoassay of blood samples drawn at frequent intervals for 6 hr. The results indicate that, irrespective of the potency of the marihuana, the pattern of smoking was much the same. The magnitude of the subjective high, heart rate acceleration, THC, and 9-carboxy THC plasma concentrations were proportional to potency. This dose response was particularly clear between the 1.32% and the 2.54% cigarettes. Peak plasma concentrations of THC consistently occurred 7 to 8 min after initiation of smoking and declined thereafter despite continued smoking for another 6 to 10 min. Peak subjective high and peak heart rate acceleration occurred several minutes after the end of smoking and at a considerable interval after maximal THC plasma concentrations were reached.

Adult↗
PubMed1982

Phencyclidine disposition after intravenous and oral doses.

[3H]-Phencyclidine (PCP) hydrochloride was given in intravenous (0.1 or 1 mg) or oral (1 mg) doses to male subjects. After 1 mg IV, drug and metabolites were recovered in urine (72.8 +/- 4.0% of dose), feces (4.7 +/- 0.9%), and perspiration. Fecal excretion was low (3.4 +/- 0.4%) after oral dosing and oral bioavailability was estimated at 72%. PCP comprised 16% of urinary radioactivity with 31% consisting of enzymatically hydrolyzable conjugates of hydroxylated metabolites. Both cis and trans isomers of 4-phenyl-4-(1-piperidinyl)cyclohexanol were found. Maximum average plasma PCP concentrations of 2.7 to 2.9 ng/ml were observed after oral and intravenous 1-mg doses. Blood/plasma ratios were approximately 1.0 and plasma binding was about 65%. Parent drug was found in saliva. Apparent terminal phase half-lifes averaged 21 +/- 3 hr (harmonic mean 17 hr, range 7 to 46 hr). The volume of distribution averaged 6.2 +/- 0.3 l/kg. Renal clearances were variable, but the average was 9% of the total clearance. Thus, PCP is cleared principally by metabolism.

Administration, Oral↗
PubMed1982

Phencyclidine and phenylcyclohexene disposition after smoking phencyclidine.

Five men who smoked parsley cigarettes containing 100 micrograms of [3H]-phencyclidine hydrochloride (PCP.HCl) inhaled 69 +/- 5(SEM) % of the total radioactivity in the cigarette. Both PCP and its pyrolysis product, 1-phenylcyclohexene (PC), were found and measured in plasma. Calculations based on the assumption that the ratio of these two products was the same as in simulated smoking studies and based on either area under the curve or urinary excretion of PCP indicated that most of the PCP in smoke was absorbed. Mean half-life (t1/2) of PCP (24 +/- 7 hr, harmonic mean 18 hr) and ratios of metabolites in plasma and urine were close to those previously reported after intravenous and oral doses. A second peak in PCP plasma concentrations was observed, possible due to show efflux from the lungs. PC plasma concentrations (maximum 0.35 +/- 0.06 pmol/ml) were lower than those of PCP (maximum 0.62 +/- 0.09 pmol/ml) and its mean t1/2 (14 +/- 3 hr, harmonic mean 12 h) was shorter than that of PCP. Only traces of PC were found in urine. Only small amounts of metabolites from PC were found nonconjugated in plasma (to about 0.1 pmol/ml) or urine (less than 2% of radioactivity), but larger quantities were found as enzyme-hydrolyzable conjugates in urine (6% of radioactivity). Conjugates were also found in plasma (to about 0.12 pmol/ml).

Adult↗
PubMed1982

Orthostatic hypotension after delta 9-tetrahydrocannabinol marihuana inhalation.

3 male glaucoma subjects experienced orthostatic hypotension within 10 min after completing 2% delta 9-THC ranging from 57 to 233 ng/ml were found 5 min after smoking. Peripheral venodilation appeared responsible for the precipitous decrease in systolic blood pressure in all 3 subjects. These orthostatic episodes which clinically simulated the typical 'faint' were characterized by the absence of tachycardia and their relief by assuming a reclining position. The postural hypotension occurred despite differences in inhalation technique, level of delta (9)-THC present in plasma, previous marihuana experience of body habitus.

Adult↗
PubMed1982

Radioimmunoassays for cannabinoids.

The simplicity, sensitivity, and specificity of radioimmunoassay have made it an attractive procedure for the analysis of delta-9-tetrahydrocannabinol (THC) in biological fluids or tissues. The presence of closely related compounds such as metabolites may interfere with radioimmunoassay results. Appropriate design of immunogens may diminish such interference. This work has been directed towards the use of the amyl side chain for linking cannabinoid compounds to proteins to form immunogens. Although the amyl side chain is metabolized to some extent, the metabolites are not quantitatively significant in most cases. 5'-Carboxy-delta-8-THC and 5'-carboxy-delta-9-THC were linked to bovine serum albumin. Immunization of rabbits with the resulting conjugates resulted in the formation of antisera with high selectivity for delta-9-THC vs. its carboxylic acid metabolite, 11-nor-9-carboxy-delta-9-THC. Delta-8-THC radioligands (4',5'-tritium and 5'-iodine-125) could be used with these antisera for analysis of delta-9-THC in plasma. Sensitivity with tritium-labeled material is about 2.5 ng/ml. 5'-Oxo-11-nor-9-carboxy-delta-8-THC was used to prepare an immunogen which led to the generation of an antiserum highly specific for 11-nor-9-carboxy-delta-9-THC. This antiserum and iodine-125-5'-iodo-11-nor-9-carboxy-delta-8-THC were used to develop a highly specific assay for 11-nor-9-carboxy-delta-9-THC in plasma.

Antibody Specificity↗
PubMed1982

Immunoassay of racemic drugs: a problem of enantioselective antisera and a solution.

Although it has been demonstrated that immunization with drug-protein conjugates derived from enantiomerically pure drug derivatives leads to stereoselective antisera, the effect of the use of conjugates of racemic drugs on antibody stereoselectivity has received little attention. Antisera were developed by immunizing rabbits with a conjugate (1) of the hemisuccinate of the antimalarial drug 1-(1,3-dichloro-6-trifluoromethyl-9-phenanthryl)-3-N, N-dibutylaminopropan-1-ol (WR 171,669) and bovine thyroglobulin. These antisera in binding competition studies with tritium-labeled racemic WR 171,669 demonstrated different stereoselective for d-, l- and dl-WR 171-669. Immunization with a conjugate (II) made from a nonchiral analog of the drug led to antisera which showed little discrimination between the optical isomers. Hydrolysis of conjugate I showed no excess of one enantiomer over the other, thus indicating that the stereoselectivity was the result of stereoslective processing of the conjugate by the immune system. The use of antisera from racemic conjugates to analyze total drug levels must be examined in each case ot avoid errors. The use of conjugate achiral drug analogs leading to the production of antisera relatively "blind" to enantiomeric differences is one solution to the problem of selective antisera.

Animals↗
PubMed1980

Radioimmunoassay for terfenadine in human plasma.

A radioimmunoassay procedure was developed for the antihistamine terfenadine (alpha[4-(1,2-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol). The keto analog of terfenadine was converted to its O-carboxymethyloxime derivative, which was conjugated to bovine thyroglobulin by a mixed anhydride technique. Rabbits were immunized with the resulting conjugate, and antiserums capable of binding radiolabeled terfenadine were obtained. Tritium-labeled terfenadine was prepared by a combination of exchange and reduction with platinum oxide in the presence of tritium gas, and the procedure yielded a specific activity of 48 Ci/mmole. Plasma containing terfenadine was diluted with sodium carbonate solution and extracted with hexane, and the hexane extracts were evaporated and analyzed. The between-assay coefficient of variation on control samples ranged from 8% at 10 ng/ml to 14% at 1 ng/ml. The lower practical sensitivity limit was at least as low as 0.25 ng/ml (25 pg measured). Two metabolites of terfenadine cross-reacted 16-30% with the antiserum used. However, extraction eliminated essentially all of these compounds. Analysis of plasma samples from human subjects given terfenadine showed marked intersubject variability and low plasma levels.

Benzhydryl Compounds↗
PubMed1979

Pharmacokinetic profile of caffeine in the premature newborn infant with apnea.

The pharmacokinetic profile of caffeine was studied in 32 premature newborn infants with apnea: 12 following a single intravenous dose; 3 after a single oral dose; 7 during treatment with an initial empirical (high) maintenance dose schedule; and 10 during treatment with a revised (lower) dose schedule. Mean (+/- SE) AV d, t 1/2, ke1, and clearance following a single intravenous dose were 0.916 +/- 0.070 1/kg, 102.9 +/- 17.9 hours, 0.009 +/- 0.001/hours and 8.9 +/- 1.5 ml/kg/hour, respectively. Rapid absorption was noted with plasma concentrations of 6 to 10 mg/l achieved within 30 minutes to two hours following an oral dose of 10 mg/kg. Cpss of caffeine in infants given a high empirical dose (11.2 +/- 1.5 mg/kg/day) ranged from 22.5 to 84.2 mg/l (mean = 45.3) whereas a dose schedule based on kinetic data (2.5 mg/kg/day) yielded plasma concentrations ranging from 7.4 to 19.4 mg/l (mean = 13.7). We suggest a loading dose of 10 mg/kg intravenously or orally followed by a daily maintenance dose of 2.5 mg/kg/day administered as a single dose for the treatment and prevention of neonatal apnea.

Administration, Oral↗