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Biomedical subjects

P Jacob

Publications and source records attributed to P Jacob.

At least 253 records · Page 14Linked to original sources
PubMed1978

Folate antagonists. 13. 2,4-Diamino-6-](alpha,alpha,alpha-trifluoro-m-tolyl)thio]quinazoline and related 2,4-diamino-6-[(phenyl- and naphthyl)thio]quinazolines, a unique class of antimetabolites with extraordinary antimalarial and antibacterial effects.

An array of nonclassical thioquinazoline analogues (VIII) of methotrexate was prepared by cyclization of the requisite 2-amino-5-(arylthio)benzonitrile with chloroformamidine hydrochloride (28--79%). The aminonitrile precursors were obtained by SnCl2-HCl reduction (28--99%) of the corresponding 2-nitro-5-(arylthio)benzonitriles, which were synthesized by the condensation of the appropriate 5-chloro-2-nitrobenzonitriles with various arylthiols (36--83%). Many of the thioquinazolines (VIII) showed suppressive antimalarial activity comparable with or superior to chloroquine, cycloguanil, and pyrimethamine against drug-sensitive lines of Plasmodium berghei in mice and Plasmodium gallinaceum in chicks, and several displayed potent prophylactic activity with P. gallinaceum. Moreover, the thioquinazolines retained potent antimalarial effects against chloroquine-, cycloguanil-, pyrimethamine- and DDS-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of Plasmodium falciparum in owl monkeys. The most active compound, namely, 2,4-diamino-6-[alpha,alpha,alpha-trifluoro-m-tolyl)thio]quinazoline, was designated for preclinical toxicological studies. Numerous substances exhibited in vitro activity against a broad spectrum of pathogenic bacteria at concentrations of less than 0.25 microgram/mL. The thioquinazolines also prove to be potent folate antagonists, causing 50% inhibition of Streptococcus faecalis R (ATCC 8043) at drug concentrations ranging from 0.2 to 2.0 ng/mL. Structure--activity relationships are discussed.

Animals↗
PubMed1977

Monomethylthio analogues of 1-(2,4,5-trimethoxyphenyl)-2-aminopropane.

Regiospecific syntheses of the three monomethylthio analogues of 1-(2,4,5-trimethoxyphenyl)-2-aminopropane are described. The three isomeric amines were evaluated for potential psychotomimetic potency using the rabbit hyperthermia assay. Enantiomeric compositions and time-concentration curves in rat brains were determined following intraperitoneal administration of each compound. The biological data are contrasted with the corresponding results obtained with the potent human psychotogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM).

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMedDate not supplied

The in vitro metabolism of norcotinine and related biotransformation products by microsomal preparations.

Since norcotinine and 4-(3-pyridyl)-4-oxobutyramide (POBAM) are probable metabolites of nicotine and cotinine, it was of interest to investigate the further in vitro metabolism of these compounds. We now report our preliminary findings using rat microsomal preparations (induced and/or non-induced with phenobarbitone) fortified with NADPH. Following norcotinine metabolism, two compounds, i.e. the corresponding ketoamide (POBAM) and another product, were detected. The latter metabolite has an identical HPLC retention time as that of nicotinamide. Both metabolites showed identical UV spectra when compared to authentic compounds using a multi-array UV detector linked to a HPLC system. The structures of these metabolites were also confirmed by mass spectral analyses. The amount of POBAM was significantly increased when phenobarbitone induced rat microsomes was used. It indicates that the ketoamide is formed via a phenobarbitone inducible isozyme of CYP450. Following the metabolism of POBAM, two compounds, i.e. the corresponding acid (POBA) and an unidentified product, were detected. The uncharacterised compound had an identical HPLC retention time as nicotinamide. Both metabolites gave a UV spectrum identical to the authentic compounds. The detection of nicotinamide in incubates of norcotinine and POBAM suggests that it is released from NADP(H) by a stimulatory effect on glycohydrolase by the substrates. Further studies on the enzymology of these processes are in progress.

Animals↗
PubMedDate not supplied

Metabolism of (-)-(S)-nicotine by guinea pig and rat brain: identification of cotinine.

Since the brain is the major site of pharmacological activity of nicotine, it was of interest to investigate the metabolism of nicotine by this organ. We now report our findings using guinea pig and rat brain as the enzyme source. Whole brains were removed and washed with isotonic KCl, blotted dry and cut into small pieces. The tissue was weighed and homogenized in pH 7.4 Tris-KCl buffer, 2 ml/g tissue. Incubations were carried out using 0.5 ml of brain homogenate and 0.1-1 mumol of nicotine at 37 degrees C. The reactions were terminated by freezing at -80 degrees C. The samples were extracted and analyzed by capillary GC with nitrogen-phosphorus detection. Cotinine was detected as the major metabolite and its identity confirmed by GC-MS. Cotinine formation may contribute to the detoxication pathway of nicotine and may be important in controlling nicotine levels in the brain. Furthermore, the conversion of nicotine to cotinine involves the intermediacy of nicotine-delta [1'(5')]-iminium ion, which is an alkylating agent. This finding supports the concept that reactive intermediates may play a role in the pharmacology and toxicology of nicotine.

Animals↗
PubMedDate not supplied

Liver and lung microsomal metabolism of the tobacco alkaloid beta-nicotyrine.

The in vitro metabolic fate of beta-nicotyrine has been examined in rabbit lung and liver microsomal preparations as part of an effort to characterize the formation of potentially reactive metabolic species that may contribute to the toxic properties of tobacco products. HPLC analysis revealed the formation of an unstable metabolite which displayed HPLC-MS/MS characteristics consistent with the structure 1-methyl-5-(3-pyridyl)-3-pyrrolin-2-one. Attempted synthesis of this pyrrolinone, however, resulted in the isolation of the isomeric 1-methyl-5-(3-pyridyl)-2-pyrrolin-2-one. The HPLC, diode array UV, and mass spectral characteristics of this delta 4,5-isomer proved to be identical with those of the metabolite derived from beta-nicotyrine. Studies in D2O suggest that the 2- and 3-pyrrolinones are in equilibrium in aqueous solution. The metabolite undergoes autoxidation, possibly via radical intermediates, to yield 1-methyl-5-(3-pyridyl)-5-hydroxy-3-pyrrolin-2-one.

Animals↗
PubMedDate not supplied

Metabolism of nicotine by human liver microsomes: stereoselective formation of trans-nicotine N'-oxide.

Liver microsomes from humans catalyze the NADPH-dependent oxidation of (S)-nicotine. The principal product is the 5'-carbon atom oxidation product, nicotine delta 1',5'-iminium ion, which is efficiently converted to the gamma-lactam derivative cotinine in the presence of aldehyde oxidase. Another major product is nicotine N'-oxide. In contrast to previous reports describing in vitro or in vivo studies, formation of only trans-nicotine N'-oxide was observed. Demethylation of nicotine was not observed. Studies on the biochemical mechanism of nicotine 5-carbon atom oxidation strongly implicate one major cytochrome P-450 isoenzyme (i.e., P-450 2A6) as largely responsible for delta 1',5'-iminium ion formation. Stereoselective formation of trans-nicotine N'-oxide may be catalyzed in large part by the flavin-containing monooxygenase (form II). These conclusions are based on the effects of alternate substrates for the flavin-containing monooxygenase, heat inactivation studies, immunoblot studies, and selective substrates for cytochromes P-450. The results suggest that (S)-nicotine trans N'-oxygenation and delta 1',5'-iminium ion formation may be selective probes of human liver flavin-containing monooxygenase form II and cytochrome P-450 2A6 activities, respectively, useful for in vivo phenotyping of humans.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Stereoselective metabolism of (S)-(-)-nicotine in humans: formation of trans-(S)-(-)-nicotine N-1'-oxide.

The chemical synthesis and chromatographic separation of cis- and trans-(S)-nicotine N-1'-oxide diastereomers have allowed the development of methods for the quantification of (S)-nicotine N-1'-oxides during in vitro and in vivo metabolic studies. The metabolism of (S)-nicotine was investigated in the presence of microsomes, cDNA-expressed and highly purified flavin-containing monooxygenase (FMO) from pig liver, human liver, and rabbit lung. For comparison, the N-1'-oxidation of (S)-nicotine in the presence of the cytochrome P450 2B1 from rat liver, cytochrome P450 2B10 from mouse liver, and cytochrome P450 4A2 from rabbit lung was examined. The ratio of trans:cis (S)-nicotine N-1'-oxide formation for pig liver FMO1 (form 1) was 57:43. In contrast, cDNA-expressed adult human liver FMO3 (form 3) and rabbit lung FMO2 formed solely trans-(S)-nicotine N-1'-oxide. Of the cytochrome P450 enzymes examined, formation of (S)-nicotine N-1'-oxide occurred with a mean trans:cis ratio of 82:18. The stereoselectivity of (S)-nicotine N-1'-oxide formation was investigated by examining the urine of 13 healthy male smokers studied on a protocol which included free-smoking, intravenous infusion of (S)-nicotine-d2 and dermal patch administration of (S)-nicotine-d0. During cigarette smoking or administration of intravenous or transdermal (S)-nicotine, only the trans diastereomer of (S)-nicotine N-1'-oxide was observed in the urine. That the trans-(S)-nicotine N-1'-oxide metabolite was not appreciably reduced or oxidized further was investigated with infusion studies of (S)-nicotine-d2N-1'-oxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Evaluation of urinary trans-3'-hydroxycotinine as a biomarker of children's environmental tobacco smoke exposure.

The utility of urinary trans-3'-hydroxy cotinine (3HC) as a biomarker of environmental tobacco smoke (ETS) exposure was investigated in comparison with urinary cotinine (COT), the sum (3HC + COT), and ratio of the two nicotine metabolites (3HC/COT). Participants were 150 ETS exposed children (aged 1-44 months) and their parents. Child urine samples were collected during 3weekly baseline assessments and at interviews administered 3, 6, 12, and 18 months after baseline. Findings indicate that 3HC and COT can be measured reliably (rho = 0.96, 0.88) and show equivalent levels of repeated measures stability (rho = 0.71, 0.75). COT, 3HC, and 3HC + COT showed equally strong associations with air nicotine levels, reported ETS contamination, and reported ETS exposure (r=0.60-0.70). The intraclass correlations of 3HC/COT were lower than those for COT or 3HC. Older children had a higher 3HC/COT ratio than younger children (3.5 versus 2.2), and non-Hispanic White children had a higher ratio than African-American children (3.2 versus 1.9). These findings suggest that COT, 3HC, and 3HC + COT are approximately equivalent and equally strong biomarkers of ETS exposure in children. Moreover, 3HC/COT may provide a useful indicator to investigate age- and race-related differences in the metabolism of COT and 3HC.

Age Factors↗
PubMedDate not supplied

A pyrolysis product, anhydroecgonine methyl ester (methylecgonidine), is in the urine of cocaine smokers.

A method using combined gas chromatography/mass spectrometry (GC/MS) for determination of the cocaine pyrolysis product anhydroecgonine methyl ester (AEME) in urine is described. Using this method, we found that human subjects who smoked cocaine under laboratory conditions excreted substantial amounts of AEME in their urine. Little, if any, AEME was excreted in the urine when the same subjects were administered cocaine by intravenous and intranasal routes. AEME may be a useful marker for cocaine (crack) smoking. The pharmacology of AEME is unknown. The possibility that AEME may play a role in the effects associated with cocaine smoking needs to be examined.

Administration, Intranasal↗