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Biomedical subjects

P Jacob

Publications and source records attributed to P Jacob.

At least 235 records · Page 13Linked to original sources
PubMed1982

Gas chromatographic analysis of meperidine and normeperidine: determination in blood after a single dose of meperidine.

A method is described for the determination of meperidine and its pharmacologically active metabolite, normeperidine, in blood, plasma, and urine using gas chromatography with nitrogen-phosphorus detection. Structural analogs of both meperidine and normeperidine were used as internal standards. Unlike previously reported assays, this procedure was sensitive and convenient enough for use in pharmacokinetic studies of both meperidine and normeperidine following single doses of meperidine. The assay was sensitive to 5 ng of meperidine/ml and 2.5 ng of normeperidine/ml extracted from a 1-ml biological sample. The between-assay coefficients of variation at these concentrations were 9.4 and 10.4%, respectively.

Adult↗
PubMed1982

Circadian blood nicotine concentrations during cigarette smoking.

To estimate daily nicotine consumption from the smoking of cigarettes delivering different amounts of nicotine, we studied 12 healthy subjects who smoked 30 cigarettes a day of their usual brand (x = 1.2 mg nicotine) or high- (2.5 mg) or low-nicotine (0.4 mg) research cigarettes. Blood nicotine and carboxyhemoglobin concentrations were measured every 2 hr. Nicotine consumption was estimated by the 24-hr area under the blood concentration-time curve (AUC) and compared across smoking conditions. There was considerable interindividual variation in the nicotine AUC among subjects smoking research cigarettes or while smoking usual brands, even when the latter were normalized on the basis of machine-predicted nicotine delivery. Most subjects smoked the high-nicotine research cigarettes less intensively so that nicotine levels were only modestly higher after smoking high-nicotine cigarettes than after usual brands. Low-nicotine research cigarettes were not smoked more intensively than usual brands and blood nicotine levels were substantially lower than those after smoking a usual brand. Nicotine consumption while smoking usual brands correlated strongly with consumption while smoking high- (r = 0.91) and low-nicotine (r = 0.85) research cigarettes. Circadian studies of blood concentration of nicotine while smoking cigarettes provided a direct estimate of the level of nicotine in the body throughout the day. Results confirm observations by others that levels of nicotine in the body vary widely among individuals even when smoking the same number of identical cigarettes. Thus, neither number of cigarettes smoked nor smoking-machine delivery predict daily nicotine exposure very well.

Adult↗
PubMed1982

Increased brain uptake of lidocaine during bicuculline-induced status epilepticus in rats.

Following rapid IV injection (0.1 mg per kilogram) lidocaine HCl concentrations were measured in the blood and brain of paralyzed, ventilated rats during bicuculline-induced status epilepticus and in identically prepared controls. The concentration of lidocaine in blood and brain was consistently higher in convulsing than in nonconvulsing rats. At 1 minute, increased brain lidocaine reflected elevated blood concentrations; increased brain and blood partitioning after 1 minute is responsible for subsequent increases in brain lidocaine uptake. The therapeutic index of lidocaine is low; the concentration of lidocaine is increased in the convulsing brain. Our data suggest that conventional lidocaine doses may perpetuate rather than control refractory convulsions.

Animals↗
PubMed1982

Impaired metabolism of methylphenobarbital after a combined drug overdose: treatment by resin hemoperfusion.

A 38-yr-old woman who by history ingested 13 g methylphenobarbital, alcohol, and 6 g acetaminophen became comatose slowly over 4 d. Acute hepatic injury appeared to impair the oxidative N-demethylation of methylphenobarbital to its product, phenobarbital. On the eighth day after ingestion she was treated because of protracted coma with Amberlite XAD-4 resin hemoperfusion. Hemoperfusion, which removed 0.83 g methylphenobarbital and 2.10 g phenobarbital, led to transient clinical improvement. When supportive patient management fails to produce a satisfactory clinical course in a methylphenobarbital-intoxicated patient, hemoperfusion could be a useful adjunct to therapy.

Acetaminophen↗
PubMed1981

Sulfur analogues of psychotomimetic agents. Monothio analogues of mescaline and isomescaline.

Two monothio analogues of mescaline and three monothio analogues of 2,3,4-trimethoxyphenethylamine (isomescaline) have been synthesized and characterized. Only the two mescaline analogues (3-and 4-thiomescaline) were found to be psychotomimetics in man, being 6 and 12 times more potent than mescaline, respectively. All five compounds can serve as substrates for bovine plasma monoamine oxidase in vitro, but no positive correlation is apparent between the extent of enzymatic degradation and human psychotomimetic potency.

Adult↗
PubMed1981

Presystemic metabolism of meperidine to normeperidine in normal and cirrhotic subjects.

Plasma concentrations and urinary excretion of meperidine and its metabolite normeperidine were determined after intravenous and oral administration to 11 men; five men had hepatic cirrhosis and six were normal. Systemic clearance of meperidine was smaller and bioavailability and half-life greater in the cirrhotic patients than in the normal subjects. Plasma concentrations and 24-hr urinary excretion of normeperidine was lower and persistence of normeperidine in plasma longer in the patients with cirrhosis. The route of administration did not alter the fraction of normeperidine generated from meperidine. The results suggest that in patients requiring repeated meperidine dosage the drug should be taken parenterally rather than orally to allow maximal analgesia and minimal formation of normeperidine. Patients with cirrhosis may be relatively protected from normeperidine toxicity because of impaired formation, but the risk of cumulative toxicity may be greater than in normal subjects because of slower elimination of the metabolite and greater sensitivity to the effects of narcotics on the central nervous system.

Administration, Oral↗
PubMed1980

Disposition kinetics and effects of intravenous nicotine.

Nicotine was given intravenously to subjects during acid and alkaline urine conditions in doses and a dosing schedule to simulate cigarette smoking. Total clearances were greater, terminal half-lifes shorter, but volumes of distribution much the same in acid (pH < 5) and alkaline (pH > 7) urine conditions. The effect of urinary pH on total clearance was due entirely to changes in renal clearance, which accounted for 23% and 2% of total clearance in acid and alkaline urine conditions. Nicotine injections induced a sensation of arousal and increased heart rate and blood pressure over the short term, but with repeated injections tolerance to these effects developed rapidly. No differences in subjective or physiologic responses to intravenous nicotine were observed and we consider it unlikely that the effects of smoking a cigarette differ as a function of urinary pH.

Adult↗
PubMed1980

Enhanced bioavailability of pethidine and pentazocine in patients with cirrhosis of the liver.

We studied the bioavailability and disposition kinetics of pethidine and pentazocine in patients with alcoholic cirrhosis and age-matched healthy subjects. In the presence of liver disease, the bioavailability of pethidine was 31% and pentazocine 233% greater than in normals. Systemic clearance was approximately half and terminal half-life double normal for both drugs, whereas volumes of distribution were unchanged. Because of greater bioavailability, oral doses of pethidine and pentazocine should be reduced substantially in patients with cirrhosis. When multiple oral or parenteral doses are required, dosing interval should be lengthened or repeated doses reduced below initial doses because of lower systemic clearance.

Administration, Oral↗
PubMed1979

Chemical and biological studies of 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane, an analogue of 6-hydroxydopamine.

Autoxidation of the bis(O-demethyl)-p-hydroquinone metabolite of the psychotomimetic amine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) at pH 7.4 leads exclusively to a bicyclic imino quinone. This imino quinone is a good alkylating agent, forming covalent adducts via 1,4 addition to thiols. The autoxidation appears to be dependent on trace metal catalysis and is dramatically inhibited by components of the 10000g supernatant fraction of rabbit liver homogenates. Incubation of tritium-labeled hydroquinone with bovine serum albumin under oxidizing conditions leads to significant amounts of nonextractable radioactivity which presumably is dependent on imino quinone alkylation of nucleophilic functionalities present on macromolecules. Incubation of tritium-labeled DOM with rabbit microsomes in the presence of NADPH leads to irreversible binding of the label to macromolecular components of the microsomes. Since this binding is NADPH dependent, it is likely that metabolic conversion of DOM to the hydroquinone is involved. The imino quinone oxidation product is highly lypophilic and is capable of crossing the blood-brain barrier. Intravenous administration of tritium-labeled imino quinone to rats resulted in significant nonextractable radioactivity in brain tissue. These properties of the hydroquinone metabolite parallel those reported for the structurally related sympatholytic compound 6-hydroxydopamine and have led to the hypothesis that the psychotomimetic properties of DOM may be mediated through 6-hydroxydopamine-type interactions of the hydroquinone with important macromolecules in the brain.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1979

Folate antagonists. 15. 2,3-Diamino-6-(2-naphthylsulfonyl)quinazoline and related 2,4-diamino-6-[(phenyl and naphthyl)sulfinyl and sulfonyl]quinazolines, a potent new class of antimetabolites with phenomenal antimalarial activity.

Oxidation of an array of 2,4-diamino-6-(arylthio)quinazolines provided the corresponding arylsulfinyl and arylsulfonyl analogues. A variety of these nonclassical analogues of methotrexate exhibited suppressive antimalarial activity superior to that of the parent thioquinazolines against drug-sensitive lines of Plasmodium berghei in mice and P. gallinaceum in chicks, and several displayed potent prophylactic activity against P. gallinaceum. The sulfinyl- and sulfonylquinazolines also retained antimalarial effects against chloroquine-, cycloguanil-, and DDS-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of P. falciparum in owl monkeys. Coadministration of one of the most active of these compounds, 2,4-diamino-6-(2-naphthylsulfonyl)-quinazoline (35), with sulfadiazine to monkeys infected with P. falciparum of P. vivax led to greatly enhanced activity and prevented the development of quinazoline resistance.

Animals↗
PubMed1978

Folate antagonists. 12. Antimalarial and antibacterial effects of 2,4-diamino-6-[(aralkyl and alicyclid)thio-, sulfinyl-, and sulfonyl]quinazolines.

A series of 2,4-diamino-6-[(aralkyl and alicyclic)thio-, sulfinyl-, and sulfonyl]quinazolines was prepared via condensation of 5-chloro-2-nitrobenzonitrile or 5,6-dichloro-2-nitrobenzonitrile with the appropriate aralkyl or alicyclic thiopseudourea, reduction of the resulting 2-nitro-5-[(aralkyl or alicyclic)thio]benzonitrile with stannous chloride to the amine, and cyclization with chloroformamidine hydrochloride. Oxidation was effected with hydrogen peroxide or the bromine complex of 1,4-diazabicyclo[2.2.2]octane. These analogues when examined for suppressive activity against drug-sensitive lines of Plasmodium berghei in mice were not as active as 2,4-diamino-6-[3,4-dichlorobenzyl)amino]quinazoline (Ia).

Animals↗