Perception of trigeminal chemosensory qualities in the elderly.
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One hundred healthy elderly subjects (65-88 years) were tested for their ability to: (i) assign verbal labels from a list of trigeminal type descriptors to six odorants known to have a strong trigeminal component; (ii) discriminate between intensity-matched pairs of these odorants in an odd-ball paradigm. Their performance was compared with that of 100 young controls (23--36 years). Young controls judged menthol and cineole as distinctly cool and fresh, acetic cid as pungent and sour and acetone as pungent, but showed no clear descriptive profile for ethanol and propanol. The descriptive profiles given by the elderly subjects correlated significantly with those given by the young controls for all six odorants and thus indicate a high degree of conformity in trigeminal perception of chemosensory qualities between the two age groups. In the odd-ball test the young controls correctly discriminated an average of 8.0 of 9 stimulus pairs presented, with most mistakes occurring in response to pairs with a similar trigeminal profile. With an average of 6.4 of 9 items correct, the discrimination performance of the elderly subjects was significantly poorer than that of the young controls but nevertheless significantly above chance at the group level with all 9 stimulus pairs. These results suggest that the nasal trigeminal system may experience some degree of age-related impairment but still contributes considerably to the perception and discrimination of chemosensory qualities in the elderly. (+info)
Promoting mechanism of menthol derivative, 1-O-ethyl-3-buthylcyclohexanol, on the percutaneous absorption of ketoprofen.
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Menthol derivatives were synthesized and evaluated for their promoting activity on the percutaneous absorption of ketoprofen and skin irritation in vivo, choosing O-ethylmenthol (MET) as the mother compound. The compound having a C-3 positionned n-butyl group (1-O-ethyl-3-n-buthylcyclohexanol, OEBC) indicated the most promoting activity and caused relatively little skin irritation. In order to understand enhancement mechanism of OEBC an in vitro permeation study of ketoprofen was performed. The time course of the cumulative amounts of drug permeated through the rat skin exhibited a linear relation after an initial lag time. This was analyzed in membrane diffusion model and the diffusion and partition parameters of ketoprofen were estimated. Both parameters were remarkably enhanced when a hydrogel containing a small quantity of OEBC (0.5%) was applied. Furthermore, to clarify the site of action of OEBC, we also investigated in vitro permeation study of ketoprofen employing different skins of state, reversed skin and stratum corneum stripped skin. When OEBC was added to the hydrogels which were applied to the reversed and stripped skins, almost no changes of the flux were observed compared with the control (without OEBC). These results suggested that the site of action of OEBC was stratum corneum. Morphological changes of the stratum corneum surface were microscopically observed with 0-2% OEBC. The spaces between the stratum corneum cells treated with 0.5-2% OEBC became extended and the shape of each cell became clear. This may suggest that the site of action of OEBC was the intercellular of stratum corneum. Furthermore, an electron spin resonance study was performed to investigate the effect of OEBC on the intercellular lipid bilayer fluidity of the stratum corneum and the rotational correlation times were calculated. 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) were used as the spin label. In use of OEBC, the fluidity of TEMPO labeled the stratum corneum lipid increased as the addition of OEBC. The results suggested that OEBC promote the penetration of drugs by enhancing fluidity of the local lipid bilayers around TEMPO. (+info)
A model of the pressure dependence of the enantioselectivity of Candida rugosalipase towards (+/-)-menthol.
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Transesterification of (+/-)-menthol using propionic acid anhydride and Candida rugosa lipase was performed in chloroform and water at different pressures (1, 10, 50, and 100 bar) to study the pressure dependence of enantioselectivity E. As a result, E significantly decreased with increasing pressure from E = 55 (1 bar) to E = 47 (10 bar), E = 37 (50 bar), and E = 9 (100 bar). To rationalize the experimental findings, molecular dynamics simulations of Candida rugosa lipase were carried out. Analyzing the lipase geometry at 1, 10, 50, and 100 bar revealed a cavity in the Candida rugosa lipase. The cavity leads from a position on the surface distinct from the substrate binding site to the core towards the active site, and is limited by F415 and the catalytic H449. In the crystal structure of the Candida rugosa lipase, this cavity is filled with six water molecules. The number of water molecules in this cavity gradually increased with increasing pressure: six molecules in the simulation at 1 bar, 10 molecules at 10 bar, 12 molecules at 50 bar, and 13 molecules at 100 bar. Likewise, the volume of the cavity progressively increased from about 1864 A(3) in the simulation at 1 bar to 2529 A(3) at 10 bar, 2526 A(3) at 50 bar, and 2617 A(3) at 100 bar. At 100 bar, one water molecule slipped between F415 and H449, displacing the catalytic histidine side chain and thus opening the cavity to form a continuous water channel. The rotation of the side chain leads to a decreased distance between the H449-N epsilon and the (+)-menthyl-oxygen (nonpreferred enantiomer) in the acyl enzyme intermediate, a factor determining the enantioselectivity of the lipase. Although the geometry of the preferred enantiomer is similar in all simulations, the geometry of the nonpreferred enantiomer gets gradually more reactive. This observation correlates with the gradually decreasing enantioselectivity E. (+info)
Metabolism of (R)-(+)-pulegone in F344 rats.
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(R)-(+)-Pulegone, a monoterpene ketone, is a major component of pennyroyal oil. Ingestion of high doses of pennyroyal oil has caused severe toxicity and occasionally death. Studies have shown that metabolites of pulegone were responsible for the toxicity. Previous metabolism studies have used high, near lethal doses and isolation and analysis techniques that may cause degradation of some metabolites. To clarify these issues and further explore the metabolic pathways, a study of (14)C-labeled pulegone in F344 rats at doses from 0.8 to 80 mg/kg has been conducted. High-pressure liquid chromatography (HPLC) analysis of the collected urine showed the metabolism of pulegone to be extensive and complex. Fourteen metabolites were isolated by HPLC and characterized by NMR, UV, and mass spectroscopy. The results demonstrated that pulegone was metabolized by three major pathways: 1) hydroxylation to give monohydroxylated pulegones, followed by glucuronidation or further metabolism; 2) reduction of the carbon-carbon double bond to give diastereomeric menthone/isomenthone, followed by hydroxylation and glucuronidation; and 3) Michael addition of glutathione to pulegone, followed by further metabolism to give diastereomeric 8-(N-acetylcystein-S-yl)menthone/isomenthone. This 1,4-addition not only took place in vivo but also in vitro under catalysis of glutathione S-transferase or mild base. Several hydroxylated products of the two mercapturic acids were also observed. Contrary to the previous study, all but one of the major metabolites characterized in the present study are phase II metabolites, and most of the metabolites in free forms are structurally different from those previously identified phase I metabolites. (+info)
In vitro skin permeation of morphine hydrochloride during the finite application of penetration-enhancing system containing water, ethanol and l-menthol.
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The effects of composition of applied solutions, containing water, ethanol (EtOH) and l-menthol (LM) as penetration enhancers, on the in vitro permeation of morphine hydrochloride (MPH) through excised hairless rat skin were examined in finite application experiments. Three of the five different applied solutions contained almost saturated LM and two contained levels of LM below the limit of solubility. Despite similar pseudo steady-state fluxes (maximum fluxes observed) of MPH from the solutions, lag time for the permeation of MPH from the saturated systems was shorter than that from the unsaturated systems. Lag times for the permeation of EtOH and LM from the saturated systems were also shorter than those from the unsaturated systems. Thermodynamic activity of LM is important for the enhancing effect against MPH permeation. At the beginning for the permeation experiment, the activity of LM in the unsaturated systems was lower than that in the saturated solutions. As the skin permeability of EtOH was higher than that of other components, the content of EtOH in the applied solution gradually decreased with time, while the activity of LM increased eventually showing a sufficient enhancing effect. Solvent drag effect was not important for the permeation of MPH, since penetration rate of MPH was independent of the time course of that of EtOH. The amount of LM migrating into skin appeared to be the most important parameter for the penetration-enhancing effect of the mixed system in the in vitro permeation of MPH through excised hairless rat skin. (+info)
A TRP channel that senses cold stimuli and menthol.
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A distinct subset of sensory neurons are thought to directly sense changes in thermal energy through their termini in the skin. Very little is known about the molecules that mediate thermoreception by these neurons. Vanilloid Receptor 1 (VR1), a member of the TRP family of channels, is activated by noxious heat. Here we describe the cloning and characterization of TRPM8, a distant relative of VR1. TRPM8 is specifically expressed in a subset of pain- and temperature-sensing neurons. Cells overexpressing the TRPM8 channel can be activated by cold temperatures and by a cooling agent, menthol. Our identification of a cold-sensing TRP channel in a distinct subpopulation of sensory neurons implicates an expanded role for this family of ion channels in somatic sensory detection. (+info)
The C-terminal region of Escherichia coli UvrC contributes to the flexibility of the UvrABC nucleotide excision repair system.
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Nucleotide excision repair in Escherichia coli involves formation of the UvrB-DNA complex and subsequent DNA incisions on either site of the damage by UvrC. In this paper, we studied the incision of substrates with different damages in varying sequence contexts. We show that there is not always a correlation between the incision efficiency and the stability of the UvrB-DNA complex. Both stable and unstable UvrB-DNA complexes can be efficiently incised. However some lesions that give rise to stable UvrB-DNA complexes do result in a very low incision. We present evidence that this poor incision is due to sterical hindrance of the damage itself. In its C-terminal region UvrC contains two helix-hairpin-helix (HhH) motifs. Mutational analysis shows that these motifs constitute one functional unit, probably folded as one structural unit; the (HhH)2 domain. This (HhH)2 domain was previously shown to be important for the 5' incision on a substrate containing a (cis-Pt).GG adduct, but not for 3' incision. Here we show that, mainly depending on the sequence context of the lesion, the (HhH)2 domain can be important for 3' and/or 5' incision. We propose that the (HhH)2 domain stabilises specific DNA structures required for the two incisions, thereby contributing to the flexibility of the UvrABC repair system. (+info)
Mentholated cigarettes and smoking cessation: findings from COMMIT. Community Intervention Trial for Smoking Cessation.
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OBJECTIVE: To examine the association between the use of menthol cigarettes and smoking cessation, amount smoked, and time to first cigarette in the morning. BACKGROUND: The majority of African American smokers smoke mentholated cigarettes. Some evidence suggests that African Americans may be more nicotine dependent than whites. One theory is that menthol in cigarettes is responsible for enhancing the dependence producing capacity of cigarettes; however, few studies have prospectively examined the association between menthol use and indicators of nicotine dependence. METHODS: Baseline smokers from the Community Intervention Trial for Smoking Cessation (COMMIT) completed a telephone tobacco use survey in 1988 and were re-interviewed in 1993. Use of mentholated cigarettes was assessed by self report at baseline. Indicators of dependence examined were six month cessation in 1993, amount smoked among continuing smokers in 1993, and time to first cigarette in the morning in 1988. Multivariate regression techniques were used to assess the association of baseline menthol use with these outcomes while controlling for other factors related to dependence. RESULTS: Overall, 24% of the sample smoked a mentholated brand in 1988. No consistent associations were observed for menthol use and indicators of dependence in both overall and race specific analyses. Factors significantly associated with increased menthol use were female sex, age 25-34 years, African American and Asian race/ethnicity, greater education, greater than 60 minutes to the first cigarette in the morning, two or more past quit attempts, and use of premium brand cigarettes. Canadian respondents and those who smoked 15-24 cigarettes per day had lower rates of menthol use. Use of mentholated cigarettes was not associated with quitting, amount smoked, or time to first cigarette in the morning. CONCLUSION: Future work is needed to clarify the physiological and sociocultural mechanisms involved in mentholated cigarette smoking. (+info)