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N K Brown

Publications and source records attributed to N K Brown.

At least 19 recordsLinked to original sources
PubMed1992

Serum proteolytic activity during the growth of C6 astrocytoma.

Tumor growth is dependent on the ability of neoplastic cells to induce angiogenesis. Blood-vessel remodeling requires the reconstruction of the nonfibrous proteins and type IV collagen components of the basement membrane. This study has assessed the influence of the growth of C6 astrocytoma cells in the rat spheroid implantation model on serum general protease and type IV collagenase activity. The results demonstrate that general protease activity increased in serum, reaching maximum values on Day 6 and Day 13 following spheroid implantation, and that type IV collagenase activity increased in serum, obtaining maximum values on Day 8 and Day 15. The measurement of serum proteolytic activity may be of value in the detection of recurrent tumors.

Animals↗
PubMed1991

Identification of cannabichromene metabolites by mass spectrometry: identification of eight new dihydroxy metabolites in the rabbit.

Metabolites of cannabichromene (CBC) produced by hepatic microsomal incubates from rabbits and mice were examined by gas chromatography/mass spectrometry (GC/MS) as trimethylsilyl (TMS) and (2H9)TMS derivatives. Most metabolites were hydroxylated compounds whose mass spectra gave very little information on metabolite structure as fragmentation was dominated by formation of the substituted chromenyl ion. This prevented charge localization and diagnostic fragmentation at the site of metabolic attack. This paper describes the identification of these metabolites by GC/MS techniques using both deuterium-exchange reactions and hydrogenation of the metabolites to tetrahydro derivatives; the latter method was used to suppress chromenyl ion formation and to enhance the relative abundance of diagnostic fragment ions. Twenty-one metabolites were identified. Metabolites were found hydroxylated in all positions of both aliphatic chains, with additional compounds formed by epoxidation and reduction of the aliphatic double bond in the methylpentenyl chain. Dihydroxy metabolites were hydoxylated in both the pentyl and methylpentenyl chains in positions common to those hydroxylated in the monohydroxy metabolites.

Animals↗
PubMed1991

Electron impact-induced fragmentation of the trimethylsilyl derivatives of monohydroxy-hexahydrocannabinols.

Monohydroxylated derivatives of hexahydrocannabinols were synthesized by catalytic hydrogenation of hydroxytetrahydrocannabinols over a rhodium/alumina catalyst, reduction of tetrahydrocannabinol epoxides with lithium aluminium hydride, or by reaction of tetrahydrocannabinols with hydrogen peroxide. The electron impact-induced fragmentation of their trimethylsilyl ethers was investigated with the aid of deuterium labelling. Most of the compounds gave characteristically different mass spectra with abundant, diagnostically useful fragment ions. As hexahydrocannabinols containing hydroxy groups in all metabolically sensitive positions were readily prepared by the above methods, these provided reference samples for identification of new hydroxylated metabolites of isomeric tetrahydrocannabinols following hydrogenation. The method was validated by application to metabolites of delta-9(11)-tetrahydrocannabinol.

Animals↗
PubMed1991

In vivo metabolism of the ethyl homologues of delta-8-tetrahydrocannabinol and delta-9-tetrahydrocannabinol in the mouse.

Ethyl-delta-8-tetrahydrocannabinol (ethyl-delta-8-THC) and ethyl-delta-9-THC were synthesized by condensation of 5-ethyl-1,3-dihydroxybenzene and 1S-cis-verbenol. The two cannabinoids were administered to male Charles River CD-1 mice and hepatic metabolites were extracted with ethyl acetate and isolated by chromatography on Sephadex LH-20. Metabolite identification was by gas chromatography/mass spectrometry as trimethylsilyl (TMS), (2H9)TMS, methyl ester/TMS and dihydro/TMS derivatives. Metabolites from ethyl-delta-8-THC, of which six were identified, were similar with respect to the positions substituted on the terpene ring to those produced by higher homologues; the major metabolite, accounting for about 95% of the metabolic fraction, was ethyl-delta-8-THC-11-oic acid. Side-chain hydroxy metabolites were not detected. Metabolism of ethyl-delta-9-THC was also similar to that of the higher homologues with the exception that less metabolism occurred at C-8 and a higher percentage of the total metabolic fraction was accounted for by the 11-oic acid metabolite. Five metabolites were identified; minor metabolites were mainly dihydroxylated compounds and hydroxylated derivatives of ethyl-delta-9-THC-11-oic acid. A dihydro-metabolite, the C-9-axial-COOH isomer of ethyl-hexahydrocannabinol-11-oic acid, was produced by both compounds and a trace of ethyl-CBN-11-oic acid was produced by ethyl-delta-9-THC.

Animals↗
PubMed1991

Comparative in vitro metabolism of the cannabinoids.

The metabolism of delta-9-tetrahydrocannabinol (delta-9-THC), delta-8-THC, delta-11-THC, cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabigerol (CBG) and the equatorial-isomer of hexahydrocannabinol (HHC) was studied in microsomal preparations obtained from rats, mice, guinea pigs, rabbits, hamsters, gerbils and a cat. Identification of metabolites was by GC/MS and quantification by gas chromatography. Major metabolites were monohydroxylated compounds but the pattern of hydroxylation varied considerably between the species, no doubt reflecting the variable nature of the cytochrome P-450 mixed-function oxidases. Although the primary carbon allylic to the endocyclic double bond of tricyclic cannabinoids was usually the major site of attack, the 4' (side-chain, omega-1 position) and the terpene ring were usually favoured by the cat and hamster respectively. The guinea pig generally produced more metabolites hydroxylated in the side-chain (all positions) than did the other species. The results from HHC were very similar to those from THC, namely hydroxylation at C-11 in most species, and the production of high concentrations of 8 alpha-hydroxy-HHC in the mouse and 8 beta-hydroxy-HHC in the hamster. As this molecule lacks the double bond of the THCs and, hence, the allylic nature of C-11 and C-8, the results suggest that it is the orientation of the molecule to the active site of the cytochrome P-450 mixed-function oxidase rather than the reactivity of the C-H bond that governs the position of hydroxylation.

Animals↗
PubMed1990

In vitro metabolism of cannabigerol in several mammalian species.

Microsomal incubations were prepared from the livers of male mice, rats, cats, guinea-pigs, hamsters and gerbils and both male and female rabbits and were incubated with cannabigerol (CBG), a constituent of marihuana. Metabolites were extracted with ethyl acetate, concentrated by chromatography on Sephadex LH-20 and examined as trimethylsilyl (TMS) and (2H9)TMS derivatives by gas chromatography/mass spectrometry. Structural elucidation was aided by hydrogenation of the metabolites to tetrahydro derivatives. Similar metabolites were produced by each of the species but the ratios of the individual compounds differed considerably. Twelve metabolites were identified. The major metabolites were monohydroxy compounds with the hydroxyl group at C-8', C-9', C-4' or at one of any position of the pentyl chain. Reduction of the delta-6' double bond was prominent in the cat to give 8'-hydroxy-6',7'-dihydro-CBG. The other major metabolic route was epoxidation of this double bond and hydrolysis to give 6',7'-dihydroxy-6',7'-dihydro-CBG. Although epoxidation of the other double bond was detected, the resulting metabolite was present in low concentration and hydrolysis was not observed. The mass spectral fragmentation of CBG and its metabolites was dominated by formation of the tropylium ion by cleavage of the C-1'--C-2' bond and by ions formed by cleavage of the C-3'--C-4' and C-4'--C-5' bonds. In addition, compounds containing hydroxylation at C-1"--C-4" (pentyl chain) gave rise to the same abundant diagnostic ions that have been observed for corresponding metabolites of other cannabinoids.

Animals↗
PubMed1990

In vitro metabolism of cannabidiol in the rabbit: identification of seventeen new metabolites including thirteen dihydroxylated in the isopropenyl chain.

The metabolism of cannabidiol (CBD) was studied in liver microsomes from the female New Zealand white rabbit. Metabolites were extracted with ethyl acetate, concentrated by chromatography on Sephadex LH-20 and examined as trimethylsilyl (TMS), methyl ester/TMS and (2H9)TMS derivatives by gas chromatography/mass spectrometry. Thirty-nine metabolites, mainly mono-, di- and tri-hydroxy compounds, were identified; 17 of these have not been reported before. New metabolites included 8,9-dihydroxy-8,9-dihydro-CBD (two isomers) and seven monohydroxy derivatives of each of these two compounds. The mass spectra of the TMS derivatives of metabolites not hydroxylated in the isopropenyl group were generally dominated by the ion produced by retro-Diels-Alder cleavage of the terpene ring. Other structurally informative ions included the tropylium ion and fragments diagnostic of hydroxylation at C-1", C-2", C-3", C-4" and C-7. The spectra of the TMS derivatives of metabolites hydroxylated in the isopropenyl group were generally dominated by the ion at m/z 143. This involved loss of CH2OTMS and a retro-Diels-Alder fragmentation analogous to that seen in the other metabolites, but with charge retention by the other (smaller) fragment. Other, related fragment ions also characterized these metabolites.

Animals↗
PubMed1990

Metabolites of the 1',2'-dimethylheptyl analogue of delta-8-tetrahydrocannabinol in the mouse and their identification by gas chromatography/mass spectrometry.

Metabolism of the 1,2-dimethylheptyl analogue of delta-8-tetrahydrocannabinol (delta-8-DMHP) was studied in vitro using mouse hepatic microsomes and in vivo in mouse liver. Metabolites were extracted with ethyl acetate, concentrated by chromatography on Sephadex LH-20 and examined by low-resolution mass spectrometry as trimethylsilyl (TMS), (2H9)TMS and methyl ester/TMS derivatives. Reduction of metabolites with lithium aluminium deuteride also provided structural information. The electron-impact-induced mass spectrum of the TMS derivative of DMHP differed from that of its unbranched side-chain analogues in that prominent ions were produced by fragmentation of the side-chain at the expense of the retro-Diels-Alder fragmentation that was prominent in the spectra of the latter compounds. This, however, was found to reduce the relative abundance of ions diagnostic of side-chain hydroxy substitution in the spectra of the metabolites. In vitro, the only significant metabolite was 11-hydroxy-delta-8-DMHP. This is in contrast with metabolism of the corresponding delta-8-tetrahydrocannabinol (delta-8-THC, n-C5-side-chain) where a number of other monohydroxy metabolites are produced. Fifteen metabolites were found in vivo, of which nine were identified. Mass spectral information was not sufficient to determine the position of one of the hydroxy groups in the other six metabolites. The major site of hydroxylation was at C-11 and the resulting hydroxy metabolite was oxidized to delta-8-DMHP-11-oic acid. In this respect metabolism paralleled that of delta-8-THC. Dihydroxylation of the double bond also occurred, presumably via the epoxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

A method for the structural determination of cannabichromene metabolites by mass spectrometry.

Ready identification of hydroxy metabolites of cannabichromene (CBC) by mass spectrometry of their trimethylsilyl derivatives is prevented by the dominant fragmentation to give a substituted chromenyl ion; this suppresses ions diagnostic of the position of metabolic hydroxylation. To overcome this difficulty, metabolites were hydrogenated over a rhodium/alumina catalyst to reduce the double bond responsible for chromenyl ion formation and to redirect the fragmentation to the site of metabolic attack. This resulted in the production of abundant diagnostic fragment ions enabling all monohydroxy-CBCs to be readily identified.

Animals↗
PubMed1990

In vitro metabolism of delta-11-tetrahydrocannabinol in the mouse, rat, guinea pig, rabbit, hamster, gerbil and cat.

1. Liver microsomes were prepared from rats, rabbits, guinea pigs, hamsters, gerbils, a cat and three strains of mice, and were incubated with delta-11-tetrahydrocannabinol (delta-11-THC). The extracted metabolites were separated by chromatography on Sephadex LH-20 and examined by gas chromatography and combined gas chromatography/mass spectrometry. 2. Eleven metabolites were identified; these were formed by aliphatic hydroxylation of all positions of the pentyl chain, allylic hydroxylation at C-10 and C-8 (alpha and beta), and by the epoxide-diol pathway. 3. The ratio of the metabolites varied considerably between the species. Mice and rats favoured hydroxylation at C-8-alpha with very little hydroxylation of the pentyl chain. 4. In the guinea pig, however, hydroxylation of the pentyl chain, particularly at C-4', produced the major metabolites; very little hydroxylation occurred at C-8. 5. Side-chain hydroxylation was also favoured by the gerbil. 6. In the cat and hamster, 8-beta-hydroxylation was by far the major metabolic route, accounting, in the cat, for nearly 70% of the recovered metabolites. 7. The rabbit, on the other hand, favoured the epoxide-diol pathway with over 70% of the recovered metabolites being accounted for by the 9,11-dihydro-diols. 8. The results emphasise the need to make appropriate choices of animal models for metabolic and toxicological studies in humans.

Animals↗
PubMed1988

In vivo metabolism of the methyl homologues of delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol and abn-delta-8-tetrahydrocannabinol in the mouse.

Methyl-delta-8-tetrahydrocannabinol (methyl-delta-8-THC), methyl-delta-9-THC and abn-methyl-delta-8-THC were synthesized by condensation of orcinol and (1S)-cis-verbenol and were administered to male Charles River CD-1 mice. Extracted hepatic metabolites were isolated by chromatography on Sephadex LH-20 and examined by gas chromatography/mass spectrometry as trimethylsilyl (TMS), (2H9)TMS and methyl ester/TMS derivatives. In addition, metabolic fractions were reduced with lithium aluminium deuteride to convert carboxylic acids to alcohols for structural correlation. Metabolites from methyl-delta-8-THC were similar with respect to the positions substituted to those produced by higher homologues; the major metabolite was methyl-delta-8-THC-11-oic acid. abn-Methyl-delta-8-THC was metabolized in a different manner. The location of the aromatic methyl group at the position adjacent to ring fusion appeared to inhibit metabolism at C(11) to a considerable extent and also to reduce the amount of the resulting alcohol from being oxidized to a carboxylic acid. This caused other metabolic pathways to become dominant, with the result that a compound containing a hydroxy group at the gem-methyl position was the major metabolite. Hydroxylation at this position has not been confirmed with any other cannabinoid, although it is thought to result in trace concentrations of hydroxy metabolites from some compounds. Metabolism of methyl-delta-9-THC was also similar to that of the higher homologues, with the exception that less metabolism occurred at C(8) and a higher percentage of the total metabolic fraction was accounted for by the 11-oic acid metabolite. Minor metabolites were mainly dihydroxy compounds and hydroxylated derivatives of delta-9-THC-11-oic acid.

Aluminum↗
PubMed1988

In vivo metabolism of the n-propyl homologues of delta-8- and delta-9-tetrahydrocannabinol in the mouse.

n-Propyl-delta-8-tetrahydrocannabinol (n-propyl-delta-8-THC and n-propyl-delta-9-THC were synthesized by condensation of (1S)-cis-verbenol with 5-n-propyl-1,3-dihydroxybenzene and administered to male Charles River CD-1 mice. Hepatic metabolites were isolated by solvent extraction and chromatography on Sephadex LH-20 and identified by gas chromatography/mass spectrometry. Seven metabolites were identified from each cannabinoid. Metabolism was similar to that previously observed from the penyl homologues, with the major biotransformation pathway being the production of 11-hydroxy-propyl-THCs and their oxidation to carboxylic acid metabolites. Other metabolites were mainly hydroxylated derivatives of these compounds and the corresponding 11-alcohol. Less hydroxylation at C(8) was found with n-propyl-delta-9-THC than with the pentyl homologue, and the monohydroxy metabolite, 8-alpha-hydroxy-n-propyl-delta-9-THC, was not observed, even though it was a prominent metabolite from delta-9-THC itself. Hydroxylation occurred in the side-chain at C(2').

Aluminum↗
PubMed1988

In vivo metabolism of the n-butyl-homologues of delta 9-tetrahydrocannabinol and delta 8-tetrahydrocannabinol by the mouse.

1. n-Butyl-homologues of delta 8-tetrahydrocannabinol (delta 8-THC) and delta 9-THC were synthesized from 5-butyl-1,3-dihydroxybenzene and (1S)-cis-verbenol, and the delta 9-isomer was shown to have the same g.l.c.-mass spectral characteristics as the natural product. 2. Metabolism of these cannabinoids was studied in mice following i.p. injection. Metabolites were extracted from the livers, separated from endogenous lipids by chromatography on Sephadex LH-20 and examined by g.l.c.-mass spectrometry. 3. Thirteen metabolites were identified from both n-butyl-delta 8-THC and n-butyl-delta 9-THC. 4. Major metabolic routes were hydroxylations in the 2', 3', 8 and 11 positions and oxidation of the resulting 11-hydroxy-metabolites to carboxylic acids. 5. Metabolism was very similar to that of the pentyl homologues, the major constituents of cannabis, but with the production of a greater proportion of acidic metabolites at the expense of alcohols.

Animals↗
PubMed1987

Factors affecting place of death in Washington State, 1968-1981.

A study was carried out to determine factors affecting place of death (home, hospital, nursing home or "other places") among all 426,115 resident deaths in Washington State during 1968-1981, using death certificate information. Sixteen percent of deaths occurred at home, 74% in institutions (51% in hospitals, 23% in nursing homes) and 9% at "other places." Age, marital status and cause of death all strongly affect place of death. Further, the effect of each factor was strongly dependent on the others. Sex had no effect on place of death after controlling for other factors. Elderly people died relatively more frequently in nursing homes, infants and middle aged people in hospitals and young adults in "other places." The frequency of deaths at home was quite constant by age. Hospitals were the most common place of death following both vascular disease (including heart attack) and neoplasms, and nursing homes were the most common place of death following cerebrovascular disease (including "stroke"). Race, socioeconomic status and urban or rural residents affected the place of death only slightly or not at all. The place of death pattern changed little during the time period 1968-1981, except for a slight increase in frequency of home deaths and a corresponding decrease in the frequency of deaths in other places. Among cancer patients, the likelihood of death at home was positively associated with longer periods of survival after diagnosis. Cancer patients of hospitals serving targeted populations, such as veterans, were relatively more likely to die in a hospital and less likely to die in a nursing home compared to other cancer patients, suggesting that the "targeted" hospitals are sometimes serving a nursing home function. There was a marked difference in the terminal cancer caseload by hospital. The number of cancer deaths per cancer diagnosis varied widely across hospitals (0.1 to 1.6) and was unrelated to size of the hospital or level of services offered. Intervention aimed at affecting place of death, such as increasing the number of deaths at home, will need to take account of the joint effect of age, marital status and disease.

Adolescent↗
PubMed1979

Nontreatment of fever in extended-care facilities.

In a study of decisions not to treat febrile patients, we reviewed the medical records of 1256 people admitted to nine extended-care facilities in Seattle during 1973. Fever, defined as two temperatures of 38.33 degrees C to 38.83 degrees C (101 to 101.9 degrees F), within 24 hours or one temperature greater than or equal to 38.88 degrees C (102 degrees F), developed in 190 patients before two years of stay. Active treatment, defined as antibiotics or hospitalization (or both), was ordered for fever in 109 patients, of whom 10 (9 per cent) died. Active treatment was not ordered for 81 patients, of whom 48 (59 per cent) died. The pre-decision factors that showed a significant relation (P less than 0.05) to such nontreatment were: diagnosis, mental status, mobility, pain, narcotics prescribed, size of the facility, relation of the physician to the patient and medical-record statements documenting the patient's deterioration or plans for nontreatment in general. This pattern of nontreatment suggests that physicians and nurses did not intend to treat these patients actively and that high mortality was expected.

Aged↗
PubMed1971

Views on euthanasia.

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Attitude of Health Personnel↗