Attenuation of mu-opioid tolerance and cross-tolerance by the competitive N-methyl-D-aspartate receptor antagonist LY235959 is related to tolerance and cross-tolerance magnitude. (1/99)

Although NMDA receptor antagonists attenuate the development of morphine tolerance, it is not clear whether NMDA receptor antagonists also prevent tolerance and cross-tolerance to other mu-opioid agonists and, if so, whether prevention is related to the efficacy of the agonist used to examine tolerance. A rat tail-withdrawal procedure was used to test the antinociceptive effects of the mu-opioids etorphine, morphine, and dezocine before and after twice-daily subcutaneous injections with either 0. 003 mg/kg etorphine, 10 mg/kg morphine, or 3.0 mg/kg dezocine, each administered alone or in combination with 3.0 mg/kg of the competitive NMDA antagonist LY235959. After chronic etorphine, the etorphine, morphine, and dezocine curves were shifted rightward 1.0-, 2.2-, and 3.4-fold, respectively. LY235959 prevented cross-tolerance to morphine and dezocine. After chronic morphine, the etorphine and morphine curves were shifted rightward 2.5- and 2. 9-fold, respectively, and the dezocine curve was flattened. LY235959 prevented morphine tolerance and cross-tolerance to etorphine and reduced the magnitude of cross-tolerance to dezocine. After chronic dezocine, the etorphine, morphine, and dezocine curves were shifted rightward 4.1-, 3.5-, and 9.6-fold, respectively. LY235959 did not prevent but reduced the magnitude of tolerance and cross-tolerance. In a separate experiment, the following rank order of efficacy was determined from the magnitudes of rightward shift in each dose-effect curve after administration of 1.0 mg/kg of the irreversible antagonist clocinnamox: etorphine > morphine > dezocine. These data show that differences in tolerance magnitude are related to opioid efficacy and that attenuation of mu-opioid tolerance and cross-tolerance by LY235959 depends upon the magnitude of opioid tolerance.  (+info)

Biodegradation of n-alkylcycloalkanes and n-alkylbenzenes via new pathways in Alcanivorax sp. strain MBIC 4326. (2/99)

The degradation of long-chain n-alkylbenzenes and n-alkylcyclohexanes by Alcanivorax sp. strain MBIC 4326 was investigated. The alkyl side chain of these compounds was mainly processed by beta-oxidation. In the degradation of n-alkylcyclohexanes, cyclohexanecarboxylic acid was formed as an intermediate. This compound was further transformed to benzoic acid via 1-cyclohexene-1-carboxylic acid.  (+info)

Particulate matter and manganese exposures in Indianapolis, Indiana. (3/99)

The distribution of PM(2.5) and manganese (Mn) personal exposures was determined over a 4-month period in Indianapolis, IN, at a time when the gasoline additive, methylcyclopentadienyl manganese tricarbonyl (MMT), was not being used. The data collection period coincided with the data collection period in the Toronto, ON, study, where MMT had been used as a gasoline additive for over 20 years. The inferential or target population consisted of noninstitutionalized residents of the Indianapolis area during the monitoring period (from May 1996 through August 1996) who were at least 16 years old. The survey instruments used in this study (and also in Toronto) included a household screener form (HSF), a study questionnaire (SQ), and a time and activity questionnaire (TAQ). The SQ was administered to elicit information about the participant and his/her activities, occupation, and surroundings that might be relevant to his/her exposure to particles and Mn. In addition to the personal particulate matter (PM) and elemental 3-day monitoring, 240 participants completed a TAQ on a daily basis during the actual monitoring period. Also, a subset of participants had 3-day outdoor and indoor stationary monitoring at their home (approximately 58 observations), and sampling was conducted at a fixed site (approximately thirty-three 3-day observations). The quality of data was assessed and compared to the Toronto study in terms of linearity of measurement, instrument and method sensitivity, measurement biases, and measurement reproducibility. Twenty-six of the sample filters were subjected to two analyses to characterize the within-laboratory component of precision in terms of relative standard deviations (RSDs). The median RSD for Mn was 8.7%, as compared to 2.2% for Toronto. The quality assurance (QA) laboratory exhibited a clear positive bias relative to the primary laboratory for Al and Ca, but no systematic difference was evident for Mn. A high interlaboratory correlation (>0.99) was also attained for Mn. Mean field blank results for PM and Mn were 0.87 microg/m(3) and 0.71 ng/m(3), respectively, which were comparable to the Toronto study. The median RSDs for colocated fixed site and residential samples ranged from 2.2% to 9.0% for PM and from 8.8% to 15.3% for Mn, which were close to those observed in Toronto. For the PM(10), the 90th percentile indoors was 124 microg/m(3) compared with 54 microg/m(3) outdoors. This pattern was even more pronounced for the PM(2.5) data (90th percentiles of 92 microg/m(3) indoors vs 30 microg/m(3) outdoors). Personal PM(2.5) was somewhat higher than the indoor levels, but the percentiles seemed to follow the more highly skewed pattern of the indoor distribution. This difference was largely due to the presence of some smokers in the sample; e.g., exclusion of smokers led to a personal exposure distribution that was more similar to the outdoor distribution. The estimated 90th percentile for the nonsmokers' personal exposures to PM was 43 microg/m(3) compared with 84 microg/m(3) for the overall population. In general, the Indianapolis PM levels of a given type and cut size were somewhat higher than the levels observed in Toronto, e.g., the median and 90th percentile for the personal PM(2.5) exposures were 23 and 85 microg/m(3), respectively, in Indianapolis, while in Toronto, the corresponding percentiles were 19 and 63 microg/m(3). The cities' distributions of the proportion of the PM(10) mass in the 2.5-microm fraction appeared similar for the residential outdoor data (medians of 0.67 and 0.65 for Indianapolis and Toronto, respectively, and 90th percentiles of 0.83 for both cities). For the indoor data, Indianapolis tended to have a larger portion of the mass in the fine fraction (median of 0.80 compared to 0.70 for Toronto). Unlike the PM, the Indianapolis indoor Mn concentration levels were substantially lower than the outdoor levels for both PM sizes, and the median personal levels for Mn in PM(2.5) appeared to fall between the median indoor and outdoor levels. The personal Mn exposure distributions exhibited more skewness than the indoor or outdoor distributions (e.g., the means for the personal, indoor, and outdoor distributions were 7.5, 2.6, and 3.5 ng/m(3), respectively, while the medians were 2.8, 2.2, and 3.2 ng/m(3), respectively). At least a substantial portion of the high end of the personal exposure distribution appeared to be associated with occupational exposures to Mn. In general, the Mn levels in both cut sizes in Indianapolis were approximately 5 ng/m(3) smaller than those in Toronto (e.g., the estimated median and mean levels for personal Mn exposures in PM(2.5) were 2.8 and 7.5 ng/m(3), respectively, in Indianapolis, but were 8.0 and 13.1 ng/m(3) in Toronto). For the nonoccupational subgroups with no exposure to smoking and no subway riders in the two cities, the medians (2.6 ng/m(3) in Indianapolis and 7.8 ng/m(3) in Toronto) were similar to those for the overall populations, but the means were substantially smaller (3.1 ng/m(3) in Indianapolis and 9.2 ng/m(3) in Toronto). The median proportion of Mn in the fine fraction (relative to the PM(10) Mn) for Indianapolis was 0.39 for outdoors and 0.55 for indoors; these ratios were somewhat smaller than the corresponding Toronto medians (0.52 and 0.73). The study found high correlations for particulates and Mn between personal exposures and indoor concentrations, and between outdoor and fixed site concentrations, and low correlations of personal and indoor levels with outdoor and fixed site levels. The pattern was similar to that observed for Toronto, but slightly more pronounced. The PM(10) Mn concentrations (log scale) generally exhibited stronger associations among these various measures than the PM(2.5) Mn concentrations. Comparisons of the particulate distributions between PTEAM (Riverside, CA) and the Indianapolis and Toronto studies were also made.  (+info)

Synthesis of (R)- and (S)- muscone. (4/99)

(R)-(-)-Muscone (3-methylcyclopentadecanone, 1) the key perfumery component isolated from the male musk deer, Moschus moschiferus,* was synthesized from the easily available chiral building block, (R)-3-tert-butoxycarbonyl-2-methylpropanoic acid (2), by employing ring-closing olefin metathesis (RCM). Antipode (+)-1 was also synthesized in a similar manner from tert-butyl (S)-3-methoxycarbonylbutanoate (10). *(a) Walbaum, H. J. J. Prakt. Chem., 73, 488 (1906); (b) Ruzicka, L., Further considerations on the constitution of muscone. Helv. Chim. Acta, 9, 715, 1008-1017 (1926).  (+info)

Capsaicin-induced hyperalgesia and mu-opioid-induced antihyperalgesia in male and female Fischer 344 rats. (5/99)

The influence of sex in determining responses to opioid analgesics has been well established in rodents and monkeys in assays of short-lasting, phasic pain. The purpose of this investigation was to use a capsaicin model of tonic pain to evaluate sex differences in hyperalgesia and mu-opioid-induced antihyperalgesia in Fischer 344 (F344) rats. Capsaicin injected into the tail produced a dose-dependent thermal hyperalgesia in males and females, with the dose required to produce a comparable level of hyperalgesia being 3.0-fold higher in males than in females. These sex differences were modulated by gonadal hormones, inasmuch as gonadectomy increased the potency of capsaicin in males and decreased its potency in females. Morphine, buprenorphine, and dezocine administered by various routes [systemic (s.c.), local (in the tail), and central (i.c.v.)] generally produced marked antihyperalgesic effects in males and females. Although in most instances these opioids were equally potent and effective in males and females, selected doses of local and i.c.v. administered buprenorphine produced greater effects in females. When administered locally, the antihyperalgesic effects of morphine were mediated by peripheral opioid receptors in both males and females, since this effect was not reversed by i.c.v. naloxone methiodide. These data contrast with the finding that mu-opioids are more potent in male rodents in assays of phasic pain, thus suggesting that distinct mechanisms underlie male and female sensitivity to opioid antinociception in phasic and tonic pain models. These findings emphasize the need to test male and female rodents in tonic pain assays that may have greater relevance for human pain conditions.  (+info)

Kedarcidin, a new chromoprotein antitumor antibiotic. II. Isolation, purification and physico-chemical properties. (6/99)

Kedarcidin, a new chromoprotein antitumor antibiotic, was isolated from the culture broth of a novel actinomycete strain L585-6 (ATCC 53650). The antibiotic was recovered from the culture filtrate by adsorption to QAE ion exchanger and purified by successive application of gel filtration and ion exchange chromatography with Sephadex G-50 and DEAE-Sephadex, respectively. Kedarcidin is an acidic complex (pI 3.65) with an apparent molecular weight of 12,400. The complex consists of a highly unstable, solvent extractable chromophore and a water soluble peptide. The apoprotein is a single chain polypeptide of 114 residues.  (+info)

CONJUGATIONS WITH GLUTATHIONE. THE ENZYMIC CONJUGATION OF SOME CHLOROCYCLOHEXENES. (7/99)

1. alpha-3,4,5,6-Tetrachlorocyclohex-1-ene and gamma-2,3,4,5,6-pentachlorocyclohex-1-ene are conjugated with glutathione in vitro by a rat-liver enzyme that is probably glutathione S-aryltransferase. 2. Chlorocyclohexane and the alpha-, beta-, gamma- and delta-isomers of hexachlorocyclohexane were not substrates for rat-liver glutathione S-aryltransferase. 3. Glutathione-S-aryltransferase activity was present in tissue preparations of houseflies of insecticide-resistant and -susceptible strains. More activity was found in a dieldrin-resistant strain of houseflies fed on dieldrin than in either a dieldrin-resistant strain not fed on dieldrin or a control strain of dieldrin-susceptible houseflies. 4. Housefly soluble supernatant preparations converted S-(2-chloro-4-nitrophenyl)glutathione into the corresponding cysteine and mercapturic acid derivatives.  (+info)

THE METABOLISM OF METHYLCYCLOHEXANE. (8/99)

1. When [U-(14)C]methylcyclohexane is fed to rabbits (dose 2-2.5m-moles/kg. body wt.), 65% of the radioactivity is excreted in the urine as metabolites, 0.5% appears in the faeces and about 15% in the expired air, some 4-5% remaining in the body in about 60hr. after dosing. The 15% of the dose appearing in the expired air consists of unchanged methylcyclohexane (10%) and (14)CO(2) (5%). The low output of (14)CO(2) shows that reactions leading to complete oxidation of methylcyclohexane are of minor importance. 2. The main metabolite found in the urine was the glucuronide of trans-4-methylcyclohexanol which was isolated. Seven methylcyclohexanols were found in the urine as conjugated glucuronides. The amounts of these were determined by isotope dilution to be as follows: cis-2-, 0.6%; trans-2-, 1.2%; cis-3-, 11.5%; trans-3-, 10.5%; cis-4-, 2.4%; trans-4-methylcyclohexanol, 14.7%, cyclohexylmethanol, 0.3%. No 1-methylcyclohexanol was found. There was evidence also that a small amount (approx. 1%) of the hydrocarbon aromatized to benzoic acid, probably via cyclohexylmethanol and cyclohexane-carboxylic acid. 3. The pattern of hydroxylation and the various amounts of the isomers found suggest that the hydroxylation in vivo of methylcyclohexane is dependent on steric factors in the molecule, hydroxylation occurring to the greatest extent at the carbon atom furthest away from the methyl group.  (+info)

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