(-)-3t,4t-Dihydroxycyclohexane-1c-carboxylate, a new quinate metabolite of Lactobacillus plantarum.
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Alcohols↗
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Evidence for a cannabinoid receptor in sea urchin sperm and its role in blockade of the acrosome reaction.
Delta-9-tetrahydrocannabinol ((-)delta 9 THC), the primary psychoactive cannabinoid in marihuana, reduces the fertilizing capacity of sea urchin sperm by blocking the acrosome reaction that normally is stimulated by a specific ligand in the egg's jelly coat. The bicyclic synthetic cannabinoid [3H]CP-55,940 has been used as a ligand to demonstrate the presence of a cannabinoid receptor in mammalian brain. We now report that [3H]CP-55,940 binds to live sea urchin (Strongylocentrotus purpuratus) sperm in a concentration, sperm density, and time-dependent manner. Specific binding of [3H]CP-55,940 to sperm, defined as total binding displaced by (-)delta 9THC, was saturable: KD 5.16 +/- 1.02 nM; Hill coefficient 0.98 +/- 0.004. This suggests a single class of receptor sites and the absence of significant cooperative interactions. Sea urchin sperm contain 712 +/- 122 cannabinoid receptors per cell. Binding of [3H]CP-55,940 to sperm was reduced in a dose-dependent manner by increasing concentrations of CP-55,940, (-)delta 9THC, and (+)delta 9THC. The rank order of potency to inhibit binding of [3H]CP-55,940 to sperm and to block the egg jelly stimulated acrosome reaction was: CP-55,940 > (-)delta 9THC > (+)delta 9THC. These findings show that sea urchin sperm contain a stereospecific cannabinoid receptor that may play a role in inhibition of the acrosome reaction. The radioligand binding data obtained with live sea urchin sperm are remarkably similar to those previously published by other investigators using [3H]CP-55,940 on mammalian brain and nonneural tissues. The cannabinoid binding properties of this receptor appear to have been highly conserved during evolution. We postulate that the cannabinoid receptor may modulate cellular responses to stimulation.
Acrosome↗
[Skin absorption of volatile oils. Pharmacokinetics].
Volatile oils are frequently employed in the local treatment of pain. 1,8-Cineole, the principal component of eucalyptus oil, was used as a model substance to determine whether this active component can be detected in effective amounts at the target area in the skeletal muscles after dermal application. The investigation showed surprisingly large differences depending on the manner of application. The relative bioavailability of the model substance 1,8-cineole obtained by using an applicator was 320% as compared with that obtained by using an occlusive dressing. This has practical effects on the dosage and on the frequency of application.
Administration, Topical↗
Causal or casual?
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Antidepressive Agents, Second-Generation↗
Prevalence of risk factors for suicide in patients prescribed venlafaxine, fluoxetine, and citalopram.
PURPOSE: Three recent observational studies reported that the risk of fatal overdose is greater with venlafaxine than SSRI use. It is not clear whether patient factors could account for this finding. We evaluated whether risk factors for suicide are more prevalent among patients prescribed venlafaxine than patients prescribed fluoxetine or citalopram. METHODS: Using data from the UK General Practice Research Database (GPRD), we identified patients who were first prescribed any of the three drugs between January 1995 and April 2002. We ascertained risk factors for suicide documented in the 1 year before that first prescription. Separate analyses compared venlafaxine (N = 27 096) and fluoxetine (N = 134 996) cohorts, and venlafaxine and citalopram (N = 52 035) cohorts. RESULTS: Previous suicidal behaviors were documented for 1.0% of the venlafaxine cohort compared to 0.4% of the fluoxetine cohort (OR 2.8, 95%CI: 2.4, 3.2) and 0.4% citalopram cohorts (OR 2.4, 95%CI: 2.0, 2.9). 72.5% of venlafaxine patients had been prescribed at least one other antidepressant compared to 27.6% of fluoxetine (OR 6.9, 95%CI: 6.7, 7.1) and 39.5% of citalopram (OR 4.0, 95%CI: 3.9, 4.2) patients. Venlafaxine patients were also four to six times as likely to have been previously hospitalized for depression. CONCLUSION: In the UK, venlafaxine has been selectively prescribed to a patient population with a higher burden of suicide risk factors than patients prescribed fluoxetine and citalopram. Unless baseline population differences are accounted for, observational studies that compare the risk of suicide in patients receiving these agents may produce biased results.
Adolescent↗
Insecticidal properties of essential plant oils against the mosquito Culex pipiens molestus (Diptera: Culicidae).
The insecticidal activities of essential oil extracts from leaves and flowers of aromatic plants against fourth-instar larvae of the mosquito Culex pipiens molestus Forskal were determined. Extracts of Myrtus communis L were found to be the most toxic, followed by those of Origanum syriacum L, Mentha microcorphylla Koch, Pistacia lentiscus L and Lavandula stoechas L with LC50 values of 16, 36, 39, 70 and 89 mg litre-1, respectively. Over 20 major components were identified in extracts from each plant species. Eight pure components (1,8-cineole, menthone, linalool, terpineol, carvacrol, thymol, (1S)-(-)-alpha-pinene and (1R)-(+)-alpha-pinene) were tested against the larvae. Thymol, carvacrol, (1R)-(+)-alpha-pinene and (1S)-(-)-alpha-pinene were the most toxic (LC50 = 36-49 mg litre-1), while menthone, 1,8-cineole, linalool and terpineol (LC50 = 156-194 mg litre-1) were less toxic.
Acyclic Monoterpenes↗
Mycosporine-glutamicol-glucoside: a natural UV-absorbing secondary metabolite of rock-inhabiting microcolonial fungi.
Microcolonial ascomycetes are known to inhabit bare rock surfaces in cold and hot deserts and thus are habitually exposed to high levels of solar radiation. Several of these stress-tolerant fungal isolates, cultivated in the laboratory under daylight illumination, were studied for the presence of effective UV-radiation protection substances. Liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS) analyses allowed for efficient separation and structure clarification of two mycosporines. It was demonstrated that both mycosporine-glutamicol-glucoside and mycosporine-glutaminol-glucoside are natural and constitutive secondary metabolites of microcolonial fungi. The function and relation of these substances in the fungal cell are discussed.
Ascomycota↗
Mycosporine-glutaminol-glucoside, a UV-absorbing compound of two Rhodotorula yeast species.
High-performance liquid chromatography (HPLC), alone or in combination with mass spectrometry (MS), was used to screen the basidiomycetous yeasts Rhodotorula minuta and R. slooffiae isolated from lakes for the presence of UV-absorbing compounds. Mycosporine-glutaminol-glucoside (maximum absorption, 310 nm), a UV-photoprotective mycosporine known in terrestrial fungi, was the major UV-absorbing compound found in these species. This is the first identification of a mycosporine in yeasts. The presence of this compound seems to be a promising chemotaxonomical marker for yeast systematics.
Chromatography, High Pressure Liquid↗
Accumulation of tissue glucosylsphingosine in Gaucher-like mouse induced by the glucosylceramidase inhibitor cyclophellitol.
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Animals↗
Biosynthesis of monoterpenes: partial purification, characterization, and mechanism of action of 1,8-cineole synthase.
Geranyl pyrophosphate: 1,8-cineole cyclase (cineole synthase) catalyzes the conversion of geranyl pyrophosphate to the symmetrical monoterpene ether 1,8-cineole (1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane) by a process thought to involve the initial isomerization of the substrate to the tertiary allylic isomer, linalyl pyrophosphate, and cyclization of this bound intermediate to the alpha-terpinyl carbocation that is subsequently captured by water and undergoes heterocyclization to the remaining double bond. The enzyme was isolated from the secretory cells of the glandular trichomes of Salvia officinalis (garden sage) and partially purified, and the properties of this monoterpene cyclase, previously determined in crude cell-free extracts, were reexamined. These properties (pH optimum, divalent metal ion requirement, molecular weight, pI) were similar to those determined previously with the exception of substrate utilization; geranyl pyrophosphate was shown to be a more efficient substrate than the cis-isomer, neryl pyrophosphate, in the absence of competing phosphatase activity that contaminated earlier preparations of this enzyme. As with other monoterpene cyclases of herbaceous species, cineole synthase was inhibited by cysteine- and histidine-directed reagents, and protection against inactivation was provided by the substrate-metal ion complex. Studies with 18O-labeled acyclic precursors and H(2)18O, followed by mass spectrometric analysis of the product, confirmed that water was the sole source of the ether oxygen atom of 1,8-cineole. The electrophilic nature of the coupled isomerization-cyclization reaction was examined with a series of substrate and intermediate analogues. The overall stereochemistry of the cyclization of geranyl pyrophosphate to the symmetrical monoterpene was established by determining the enantioselectivity for (3R)- or (3S)-linalyl pyrophosphate as an alternative substrate and by oxidation of [3-3H]1,8-cineole, derived from [1-3H]geranyl pyrophosphate, to (+/-)-3-keto-1,8-cineole and radio-GLC separation of diastereomeric ketal derivatives to determine the labeled enantiomer.
Carbon-Carbon Lyases↗
The decreased in vivo clearance of CYP2D6 substrates by CYP2D6*10 might be caused not only by the low-expression but also by low affinity of CYP2D6.
CYP2D6 exhibits genetic polymorphism with interindividual differences in metabolic activity. We have found a significant influence on the pharmacokinetics of venlafaxine by the CYP2D6*10 allele in a Japanese population. CYP2D6.10, which is translated from CYP2D6*10, has two amino acid substitutions: Pro34 --> Ser and Ser486 --> Thr. In this study, CYP2D6.10 was expressed in Saccharomyces cerevisiae and its catalytic activity for CYP2D6 substrates was investigated. The CYP2D6*10B- and *10C-associated cDNA were isolated from human lymphocyte genotyped as CYP2D6*10. In addition, three forms of CYP2D6, Pro34/Thr486 (PT), Ser34/Ser486 (SS), and Pro34/Ser486 (wild type, CYP2D6.1), were constructed by PCR-site mutagenesis to clarify the effects of the two amino-acid substitutions. The expression of CYP2D6 protein was confirmed by immunoblotting using CYP2D antibody. The absorbance at 450 nm was measured by CO-reduced difference spectra from five all microsome preparations. The CYP2D6 forms with Pro34 --> Ser amino acid substitution were at a lower expression than CYP2D6.1 from the findings of immunoblotting and spectral analysis. The apparent K(m) values of CYP2D6.1, CYP2D6.10A, and CYP2D6.10C were 1.7, 8.5, and 49.7 microM, respectively, for bufuralol 1'-hydroxylation, and 9.0, 51.9, and 117.4 microM, respectively, for venlafaxine O-demethylation, respectively. The V(max) values were not significantly different among the three variants. These findings suggest that the decreased in vivo clearance by CYP2D6*10 was caused not only by low expression of but also the increased K(m) value of CYP2D6.
Alleles↗
Lipopolysaccharide downregulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes.
Lipopolysaccharide (LPS) increases the levels of the endogenous cannabinoid anandamide (N-arachidonoylethanolamine, AEA) in rat macrophages, but the mechanism responsible for this effect has not been elucidated. Here we demonstrate that LPS enhances the levels of AEA (fourfold over controls) also in human lymphocytes. We show that in these cells LPS inhibits the activity of the AEA-degrading enzyme fatty acid amide hydrolase (FAAH), by downregulating the gene expression at transcriptional level. Lymphocytes have also a specific AEA transporter and a functional CB1 cannabinoid receptor, which were not modulated by LPS. The effect of this endotoxin on FAAH was not mediated by AEA-induced activation of cannabinoid receptors. Conversely, the stimulatory action of LPS on AEA levels might be due to inhibition of FAAH, as suggested by the observation that an increase of AEA amounts was also induced by an irreversible FAAH inhibitor. These results suggest that lymphocytes take part in regulating the peripheral endocannabinoid system and endocannabinoid homeostasis.
Amidohydrolases↗
Kinetic studies on cyclophellitol analogues--mechanism-based inactivators.
The (1R,6S)- and (1R,2S,6S)-diastereoisomers of cyclophellitol were found to be effective irreversible inactivators of alpha-D-glucosidase and alpha-D-mannosidase, respectively. The (1R,6S)-diastereoisomer inactivates brewers yeast alpha-D-glucosidase according to pseudo-first order kinetics with inactivation constants of Ki = 26.9 microM, ki = 0.401 min-1 while the (1R,2S,6S)-diastereoisomer inactivates jack beans alpha-D-mannosidase in a similar manner with Ki = 120 microM, ki = 2.85 min-1. The irreversibility of these compounds was evidenced by the lack of reactivation upon dialysis of the inactivated enzyme.
Cyclohexanols↗
2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain.
The effects of anadamide, 2-arachidonoylglycerol and related compounds on the specific binding of a radiolabeled cannabinoid receptor ligand,[3H]CP55940, to synaptosomal membranes were examined. Anandamide, an endogenous cannabinoid receptor ligand, reduced the specific binding of [3H]CP55940 to synaptosomal membranes in a dose-dependent manner: the Ki value was 89 nM. 2-Arachidonoylglycerol was also shown to bind appreciably to the cannabinoid receptor in competitive inhibition experiments. The apparent binding affinity was markedly increased when the binding assay was carried out in the presence of the esterase inhibitor DFP or at 0 degrees C. Free arachidonic acid and N-palmitoylethanolamine were almost inactive in terms of binding to the cannabinoid receptor in synaptosomal membranes. 2-Arachidonoylglycerol may be an endogenous cannabinoid receptor ligand in the brain.
Animals↗
Highly selective CB(1) cannabinoid receptor ligands and novel CB(1)/VR(1) vanilloid receptor "hybrid" ligands.
Anandamide and the metabolically stabler analogs, (R)-1'-methyl-2'-hydroxy-ethyl-arachidonamide (Met-AEA) and N-(3-methoxy-4-hydroxy-benzyl)-arachidonamide (arvanil), are CB(1) cannabinoid and VR(1) vanilloid receptors agonists. We synthesized 1',1'-dimethylheptyl-arvanil (O-1839) and six other AEA analogs obtained by addition of either a hydroxy, cyano, or bromo group on the C-20 atom of 1,1'-dimethylpentyl-Met-AEA (O-1811, O-1812 and O-1860, respectively) or 1,1'-dimethylpentyl-arvanil (O-1856, O-1895 and O-1861, respectively). The compounds were tested for their (i) affinity for CB(1) and CB(2) receptors, (ii) capability to activate VR1 receptors, (iii) inhibitory effect on the anandamide hydrolysis and on the anandamide membrane transporter, and (iv) cannabimimetic activity in the mouse 'tetrad' of in vivo assays. O-1812 is the first ligand ever proven to be highly (500- to 1000-fold) selective for CB(1) vs both VR(1) and CB(2) receptors, while O-1861 is the first true "hybrid" agonist of CB(1)/VR(1) receptors and a compound with potential therapeutic importance. The activities of the seven compounds in vivo did not correlate with their activities at either CB(1) or VR(1) receptors, thus suggesting the existence of other brain sites of action mediating some of their neurobehavioral actions in mice.
Animals↗
Autoradiographic study of pre- and postnatal distribution of cannabinoid receptors in human brain.
Cannabinoid receptors have been characterized and localized in the brain of several species, including human. The pre- and postnatal distribution of human brain CB1 receptors was investigated using quantitative autoradiography with [(3)H]CP55,940 as a ligand. Normal fetal brains (N = 8, gestational age 14-24 weeks)were obtained from voluntary abortions. Normal (drug and pathology free) adult human brains (N = 16, age 18-78) were obtained from the medical examiner's offices in New York City and Jaffa, Israel. Brains were stored frozen at -70 degrees C and sectioned (40 microm) at -15 degrees C. The radioligand (5 nM) was incubated with the sections for 3 h at room temperature. Washed and dried sections were exposed to tritium-sensitive film along with standards for 7-28 days and autoradiograms quantitated using NIH Image software. In the fetal human brain, low densities of THC-displaceable, region-specific binding could be observed as early as 14 weeks gestation. Receptor density increased slowly with gestational age but did not reach adult levels by the end of the second trimester (24 weeks gestation). In addition, the distribution pattern in the fetal brains was markedly different from the adult pattern. The most striking difference was the very low density of binding in the fetal caudate and putamen. In contrast, the globus pallidus pars medialis has almost-adult levels of cannabinoid receptors by 17-18 weeks gestation. The relatively low and regionally selective appearance of cannabinoid receptors in the fetal human brain may explain the relatively mild and selective nature of postnatal neurobehavioral deficits observed in infants exposed to cannabinoids in utero.
Adolescent↗
The antitussive effects of menthol, camphor and cineole in conscious guinea-pigs.
Menthol and other aromatic vapours have been widely used in the symptomatic treatment of upper respiratory tract infections, although there is little objective evidence as to their benefit. We have investigated the action of aromatic vapours on the cough reflex in conscious guinea-pigs. Animals (n = 13) were pretreated with air or test vapours for 5 min at a rate of 1 l/min. One minute later the animal was challenged with aerosolized citric acid for 2 min. Control responses to air pretreatment were not significantly different throughout the procedures. Three concentrations of each aromatic vapour were used (3, 10 and 30 micrograms/l menthol, 50, 133 and 500 micrograms/l camphor and 0.8, 2.7 and 8 mg/l cineole). Menthol proved the most effective antitussive--10 and 30 micrograms/l produced a significant 28 and 56% reduction in cough frequency--500 micrograms/l camphor gave a significant 33% reduction, while cineole, at the concentrations used, had no significant effect. An increase in cough latency coincided with a reduction in cough frequency. These results demonstrate the efficacy of aromatic vapours as antitussives in chemically induced cough.
Administration, Inhalation↗
Cannabinoid-mediated inhibition of inducible nitric oxide production by rat microglial cells: evidence for CB1 receptor participation.
Activated brain microglial cells release inflammatory mediators such as nitric oxide (NO) that may play important roles in central nervous system antibacterial, antiviral, and antitumor activities. However, excessive release of these factors has been postulated to elicit immune-mediated neurodegenerative inflammatory processes and to cause brain injury. Recent studies using the rat animal model indicate that select cannabinoids may modulate production of these inflammatory factors. Treatment of neonatal rat brain cortical microglial cells with the cannabinoid paired enantiomers CP55940 and CP56667 resulted in a stereoselective differential effect on inducible NO production. The analog CP55940 exerted a dose-dependent inhibition of interferon gamma (IFNy)/bacterial lipopolysaccharide (LPS)-inducible NO production which was significantly greater than that exerted by CP56667. Pretreatment of microglial cells with the CB1 cannabinoid receptor-selective antagonist SR141716A reversed this CP55940-mediated inhibition. MRT-PCR demonstrated the presence of CB1 receptor mRNA within microglial cells consistent with the presence of CB1 receptors. Collectively, these results indicate that the cannabinoid analog CP55940 selectively inhibits inducible NO production by microglial cells and that this inhibition is effected, at least in part, through the CB1 receptor.
Animals↗