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TRPM8 in prostate cancer cells: a potential diagnostic and prognostic marker with a secretory function?

During the past 5 years it has emerged that the transient receptor potential (TRP) family of Ca(2+)-and Na(+)-permeable channels plays a diverse and important role in cell biology and in pathology. One member of this family, TRPM8, is highly expressed in prostate cancer cells but the physiological and pathological functions of TRPM8 in these cells are not known. Here we address these questions, and the issue of whether or not TRPM8 is an effective diagnostic and prognostic marker in prostate cancer. TRPM8 is known to be activated by cool stimuli (17-25 degrees C) and cooling compounds such as menthol. The activation mechanism(s) involves voltage sensing of membrane potential, phosphatidylinositol 4,5-bisphosphate and Ca(2+). In addition to prostate cancer cells, TRPM8 is expressed in sensory neurons where it acts as a sensor of cold. In prostate epithelial cells, expression of TRPM8 is regulated by androgen and is elevated in androgen-sensitive cancerous cells compared with normal cells. While there is some evidence that in prostate cancer cells Ca(2+) and Na(+) inflow through TRPM8 is necessary for survival and function, including secretion at the apical membrane, the function of TRPM8 in these cells is not really known. It may well differ from the role of TRPM8 as a cool sensor in sensory nerve cells. Androgen unresponsive prostate cancer is difficult to treat effectively and there are limited diagnostic and prognostic markers available. TRPM8 is a potential tissue marker in differential diagnosis and a potential prognostic marker for androgen-unresponsive and metastatic prostate cancer. As a consequence of its ability to convey Ca(2+) and Na(+) and its expression in only a limited number of cell types, TRPM8 is considered to be a promising target for pharmaceutical, immunological and genetic interventions for the treatment of prostate cancer.

Biomarkers, Tumor↗

A survey of smoking and quitting patterns among black Americans.

A sample of adult Black policyholders of the nation's largest Black-owned life insurance company was surveyed in 1986 to add to limited data on smoking and quitting patterns among Black Americans, and to provide direction for cessation initiatives targeted to Black smokers. Forty per cent of 2,958 age-eligible policyholders for whom current addresses were available returned a completed questionnaire. Population estimates for smoking status agree closely with national estimates for Blacks age 21-60 years: 50 per cent never-smokers; 36 per cent current smokers; 14 per cent ex-smokers. Current and ex-smokers reported a modal low-rate/high nicotine menthol smoking pattern. Current smokers reported a mean of 3.8 serious quit attempts, a strong desire and intention to quit smoking, and limited past use of effective quit smoking treatments and self-help resources. Correlates of motivation to quit smoking were similar to those found among smokers in the general population, including smoking-related illnesses and medical advice to quit smoking, previous quit attempts, beliefs in smoking-related health harms/quitting benefits, and expected social support for quitting. Methodological limitations and implications for the design of needed Black-focused quit smoking initiatives are discussed.

Adolescent↗

Smoking cessation factors among African Americans and whites. COMMIT Research Group.

OBJECTIVES: This study was undertaken to explore smoking patterns and attitudes that influence smoking cessation and relapse among African Americans. METHODS: Baseline data from eight Community Intervention Trial for Smoking Cessation (COMMIT) sites were analyzed. RESULTS: Compared with Whites, African Americans who smoke less than 25 cigarettes per day were 1.6 times more likely to smoke within 10 minutes of awakening (a behavioral indicator of nicotine dependence), adjusting for education, age, and gender (OR = 1.2 for heavier smokers). African Americans reported a stronger desire to quit smoking and reported serious quit attempts in the past year. African Americans favored tobacco restrictions (they were 1.8 times more likely than Whites to view smoking as a serious community problem, 1.7 times more likely to favor restrictions on cigarette vending machines, and 2.1 times more likely to prohibit smoking in their car). African Americans were lighter/moderate, menthol smokers. CONCLUSIONS: African Americans find smoking socially unacceptable and are strongly motivated to quit, but their "wake-up" smoking may indicate high nicotine dependence, making abstinence difficult even for lighter smokers.

Adult↗

R.J. Reynolds' targeting of African Americans: 1988-2000.

OBJECTIVES: The purpose of this study was to describe RJ Reynolds (RJR) Tobacco Company's strategy for targeting African Americans, as revealed in tobacco industry documents and magazine advertisements. METHODS: The authors searched industry documents to determine RJR's strategies and analyzed magazine advertising during 2 periods: the time of the launch of the company's Uptown cigarette (1989-1990) and a decade later (1999-2000). RESULTS: RJR's efforts to target the African American market segment existed before and after Uptown, and the company's strategy was largely implemented via other RJR brands. Advertisements featured mentholated cigarettes, fantasy/escape, expensive objects, and nightlife. CONCLUSIONS: To help all populations become tobacco-free, tobacco control practitioners must understand and counter tobacco industry strategies.

Adolescent↗

Evaluation of percutaneous absorption of midazolam by terpenes.

Midazolam is a highly lipophilic drug that is widely used in preanesthetic medication. Recently, terpenes have been reported to show an enhancing effect on percutaneous absorption of drugs. The effect of terpenes (l-menthol, d-limonene, RS-(+/-)-beta-citronellol, geraniol) on the in vitro percutaneous absorption of midazolam through rat skin was evaluated using unjacketed Franz diffusion cells. Since midazolam is a lipophilic drug, percutaneous penetration is low and a percutaneous penetration enhancer is necessary for its percutaneous absorption. The terpenes (5%, w/v) in combination with 30% ethanol, and 20% propylene glycol significantly increased the percutaneous absorption of midazolam in comparison to the control. In vitro data suggested that d-limonene is the most effective enhancer among terpenes and other penetration enhancers such as Azone. In in vivo percutaneous absorption assays, the midazolam formulation using d-limonene could penetrate through rat skin, but the other terpenes could not penetrate. In conclusion, d-limonene in combination with ethanol can be used to enhance the percutaneous absorption of the highly lipophilic drug midazolam.

Journal Article↗

The nicotine inhaler: clinical pharmacokinetics and comparison with other nicotine treatments.

Nicotine inhaled in smoke is the most rapid form of delivery of the drug. With smoking, arterial boli and high venous blood nicotine concentrations are produced within seconds and minutes, respectively. The potency of nicotine as the primary reinforcement in tobacco addiction is attributed to this rapid rate of delivery. By design, nicotine treatments reduce the rate and extent of drug delivery for weaning from nicotine during smoking cessation. Theoretically, they prevent relapse by reducing withdrawal and craving associated with the abrupt cessation of cigarettes. The nicotine inhaler treats the complexity of smoking through weaning both from the drug and from the sensory/ritual components associated with smoking. The inhaler is 'puffed' but not lit and there is considerable 'puffing' required to achieve slower rising and lower nicotine concentrations. These factors allow it to be used as a nicotine reduction treatment. One inhaler contains 10 mg of nicotine (and 1 mg of menthol) of which 4 mg of nicotine can be extracted and 2mg are systemically available. Shallow or deep 'puffing' results in similar nicotine absorption. Nicotine is delivered mainly to the oral cavity, throat and upper respiratory tract with a minor fraction reaching the lungs. This was confirmed with positron emission tomography and by assessment of arterial concentrations. A single inhaler can be used for one 20-minute period of continuous puffing or periodic use of up to 400 puffs per inhaler. With controlled puffing in laboratory testing, venous plasma nicotine concentrations from a single inhaler puffed 80 times over 20 minutes averaged 8.1 microg/L at 30 minutes. Lower concentrations of 6.4 to 6.9 microg/L have been reported for self-administration under clinical conditions. The time to peak plasma concentrations varies but is always significantly longer than with cigarette delivery. Estimates of nicotine intake from cotinine concentrations were higher than expected (60 to 70% of baseline smoking concentrations). This elevation may be due to the swallowing of nicotine and subsequent first-pass biotransformation to cotinine. In general, venous blood nicotine concentrations are considerably lower than with smoking and are within the range observed for other nicotine reduction therapies. Efficacy trials show consistent superiority of the inhaler over placebo. Despite the 'cigarette-like' appearance of the inhaler and the associated sensory/ritual elements, little treatment dependence or abuse has been reported. This is attributed to the slow rise time and low nicotine blood concentrations. The inhaler is a valuable addition to treatment of tobacco dependence and can be used alone or with other treatments.

Absorption↗

Early-phase neutrophilia in cigarette smoke-induced acute eosinophilic pneumonia.

Although cigarette smoking is a recognized cause of acute eosinophilic pneumonia (AEP), and an increase in eosinophils in the lung is a common occurrence in AEP, early-phase neutrophilia in AEP is not well understood. We describe three cases of cigarette smoke (menthol type)-induced AEP with neutrophilia in the lungs or blood. Increased in-vitro production of the neutrophil chemoattractant interleukin (IL)-8 by human bronchial epithelial cells (HBECs) was correlated with neutrophilia. We suggest that IL-8 released from HBECs is involved in neutrophilia in the lung in AEP, and is newly recognized as an important factor in the early phase of AEP development.

Acute Disease↗

A transdermal delivery system for glipizide.

Glipizide is one of the most commonly prescribed drugs for treatment of type 2 diabetes. Oral therapy with glipizide comprises problems of bioavailability fluctuations and may be associated with severe hypoglycaemia and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy, the rationale of this study was to develop a transdermal delivery system for glipizide. For this purpose, inclusion complexes of the drug in beta-cyclodextrin (beta-CyD), dimethyl-beta-cyclodextrin (DM-beta-CyD), hydroxypropyl-beta-cyclodextrin (HP-beta-CyD), and hydroxypropyl-gamma-cyclodextrin (HP-gamma-CyD) were prepared. Several percutaneous formulations of the drug and the prepared complexes in different bases (o/w emulsion, polyethylene glycol, carboxymethyl cellulose and Carbopol) were developed. Release studies revealed an improved release of the drug from formulations containing glipizide-CyD complexes. Ex vivo permeation studies through full thickness rat abdominal skin were conducted, whereby the effect of several conventional penetration enhancers (propylene glycol [PG], oleic acid, urea, dimethyl sulfoxide, menthol, limonene and cineole) was monitored. Highest flux was obtained from ointments prepared with Carbopol gel base containing a combination of PG and oleic acid as well as ointments prepared in the same base utilizing glipizide-DM-beta-CyD complex and urea. In vivo studies on diabetic male Wistar rats revealed a marked therapeutic efficacy sustained for about 48 hours. In this respect, two formulations showed best biological performance. In the first formulation, the drug was incorporated in Carbopol gel base in the presence of 20% PG together with 15% oleic acid. The second was prepared by incorporating glipizide-DM-beta-CyD complex in Carbopol gel base in presence of 15% urea. The glucose tolerance test showed suppression of hyperglycaemia induced in glucose-loaded rats. The above-mentioned results might shed a strong beam of light on the feasibility of using glipizide in a transdermal delivery system for treatment of type 2 diabetes with the aim of improving both patient compliance and pathophysiology of the disease.

Acrylic Resins↗

Peptides controlling stifness of connective tissue in sea cucumbers.

We present the first evidence of a system of four bioactive peptides that affect the stiffness of sea cucumber dermis. The body wall dermis of sea cucumbers consists of catch connective tissue that is characterized by quick and drastic stiffness changes under nervous control. The peptides were isolated from the body wall, their amino acid sequences determined, and identical peptides synthesized. Two peptides, which we named holokinins, are homologous with bradykinin. We tested the effect of the peptides on the mechanical properties of sea cucumber dermis. Both of the holokinins softened the dermis, and a pentapeptide that we designated as NGIWYamide stiffened it. Both effects were reversibly suppressed by anesthesia with menthol. We called the fourth peptide stichopin; it had no direct effect on the stiffness of the dermis but suppressed action of the neurotransmitter acetylcholine reversibly. The results suggest that the peptides are neuropeptides and are part of a sophisticated system of neurotransmitters and neuromodulators that controls the connective tissue stiffness of sea cucumber dermis.

Amino Acid Sequence↗

EMLA in local anaesthesia of the tympanic membrane.

An ideal agent for local anaesthesia of the tympanic membrane has been missing so far. Recently, however, a eutectic mixture of lignocaine and prilocaine (EMLA, Astra, Södertälje, Sweden) has proved promising. We compared the anaesthetizing efficacy of EMLA, Bonain's solution (cocain, menthol, phenol ana partes) and Xylocain-spray (Astra, Södertälje, Sweden) in 42 voluntary subjects. EMLA was applied on one tympanic membrane and either one of the other two agents in the other ear of each subject. Small cotton pledgets were used for application. Sensitivity of the ear drum was tested under otomicroscope with a cotton tipped wire before and after each local anaesthesia. Full anaesthesia could be reached with EMLA very significantly (p less than 0.001) more often than with Xylocain and almost significantly (p = 0.057) more often than with Bonain's solution. Most of the test subjects preferred EMLA to Bonain's solution of Xylocain. Undesired side effects, including two tympanic membrane perforations, appeared in most of the ears anaesthetized with Bonain's solution. In the clinical part of the study, EMLA topical anaesthesia was used in 127 minor policlinical tympanic membrane procedures like myringotomy and tympanostomy tube assembling. Eighty-three of the procedures were assessed as painless, 36 unpleasant and 8 painful. A 30-min action time of EMLA was considered sufficient in most cases. No EMLA related side effects appeared. In conclusion, Bonain's solution is recommended to be replaced by EMLA or a corresponding agent for local anaesthesia of the tympanic membrane.

Administration, Topical↗

Kinetic characteristics of UDP-glucuronosyltransferases towards a dithiol metabolite of malotilate in hepatic microsomes of rats and rabbits.

1. The kinetic activity of UDP-glucuronosyltransferases (UDPGT) towards a dithiol metabolite of malotilate, 2,2-di(isopropoxycarbonyl)ethylene-1,1-dithiol, was investigated using rat and rabbit hepatic microsomes. The thio-glucuronide formed was analysed by h.p.l.c. The Km values obtained using rat and rabbit UDPGT were 36.3 +/- 3.3 and 443 +/- 43 microM, respectively. The Vmax values were 7.14 +/- 0.61 and 29.2 +/- 6.4 nmol/min per mg (mean +/- SD, n = 3). 2. Phenobarbital, an inducer of the GT2 isoform of UDPGT, increased rat microsomal UDPGT activity towards the dithiol. In inhibitory studies, menthol and borneol (specific substrates for GT2a isoform) competitively inhibited glucuronidation of the dithiol. Thus it was concluded that formation of the thio-glucuronide was catalysed mainly by the GT2a isozyme of UDPGT, which is involved in glucuronidation of monoterpenoid alcohols.

Animals↗

Development and in vitro evaluation of nimodipine transdermal formulations using factorial design.

The in vitro permeation of nimodipine through human cadaver skin, as a preliminary step toward the development of a transdermal therapeutic system, was investigated. In vitro release studies were carried out using modified Franz diffusion cells and human epidermal membrane, taken from full-thickness cadaver skin by heat separation technique. To estimate the effect of the type of enhancer, the concentration of enhancer and the concentration of the gelling agent on the permeation of nimodipine, a 2(3) factorial design was involved. The type of enhancer was further evaluated, because it was found to be important for the permeation of nimodipine; the concentration of enhancer and the concentration of the gelling agent were kept at their optimum levels in all experiments. Six groups of enhancers (alkanols, alkanoic acids, alkanoic acids ethyl esters, caprylic acid alkyl esters, essential oils and some other enhancers) were examined for their ability to increase the permeation of nimodipine. It was found that myristyl alcohol, caprylic acid, L-menthol, and oleic acid gave better permeation rates at 24 hr, with oleic acid being the better enhancer, and higher permeation rates at 48 and 72 hr were achieved only when cineol was used.

Administration, Cutaneous↗

Ultrastructure of rumen entodiniomorphs by electron microscopy.

Thin sections of rumen ciliated protozoa of the subclass Spirotrichia were studied by electron microscopy to elucidate their ultrastructure. To prevent retraction of their adoral cilia, menthol crystals were used to relax the retrociliary region. These protozoa had a distinct ectoplasm and endoplasm with the macro- and micronuclei located in the ectoplasm. At the surface of the entodiniomorph body was a highly differentiated cortical zone of four layers. Ribosomes were abundant throughout the cytoplasm, suggesting a substantial potential for protein synthesis. These protozoa appeared to engulf bacteria into large vacuoles, and subsequently the bacteria were taken into the endoplasm in vesicles containing only one bacterium each. The bacteria were digested partially, and only in isolated cases were the bacterial cell walls still intact.

Animals↗

Young adult smoker risk perceptions of traditional cigarettes and nontraditional tobacco products.

OBJECTIVE: To explore risk perceptions of traditional and nontraditional tobacco products (NTPs) among young adult smokers. METHODS: Focus groups with African Americans, non-Hispanic whites, and Hispanics. Risk ratings of light, regular, and menthol cigarettes and of NTPs and marijuana and cigarettes were compared. RESULTS: Participants tended to view light cigarettes as safer than regular cigarettes. Shisha and herbal products were rated as safer than traditional cigarettes, but there were differences in ratings by race/ethnicity, related to preferred cigarette variety. CONCLUSIONS: Health communication messages about the use of cigarettes and NTPs should consider risk perceptions about the products and racial/ethnic differences.

Adult↗

Changes in adolescent cigarette-brand preference, 1989 to 1996.

OBJECTIVE: To understand changes in cigarette-brand choice by adolescents in the context of demographic differences and advertising. METHODS: Data from 3 nationally representative cross-sectional surveys of adolescents were analyzed. RESULTS: Marlboro, Camel, and Newport brand cigarettes accounted for over 80% of the cigarettes usually bought by adolescents in 1989, 1993, and 1996. Between 1989 and 1996, Marlboro and Camel market shares changed little, whereas preference for Newport doubled among white and Hispanic adolescents. CONCLUSIONS: Brand preference among adolescents has been steadily concentrated among 3 brands. More attention may need to be focused on mentholated brands given the increase in Newport's market share.

Adolescent↗

[Antibacterial activity of essential oils from mint in Senegal].

Three species of the Mentha gender are found in Senegal under the name of "Nana", and are essentially used in tea and juices as flavour. The aerial parts of the three species (common mint, mentholated mint and "fass" mint) have been harvested two months after they have been sown and the extraction of the essential oils was done by carrying them away with water vapour by hydrodistillation. The essential oils were used to study the antibacterial potency (typing of the Minimal Inhibitory concentrations-MIC) by the agar dilution method. This survey has been carried out on ten bacterial strains among which three (3) ATCC reference stubs, and on one fungus (Candida albicans). The MIC found was less than 25 mcg/ml; these results show an antibacterial potency according to the NCCLS norms (MIC < 256 mcg/ml). The tested strains were more sensitive to the essential oil of the "common mint" than the "fass mint". Pseudomonas aeruginosa was the most resistant strain and Candida albicans the most sensitive agent.

Anti-Bacterial Agents↗

[Update of a database on plants involved in the composition of 825 drugs: Pharmaplantes-Kénitra 98].

The main objective of this work lies in the setting up of a database on plants used in medicines which is aimed at pharmacological development of plant resources in Morocco. We have, as a first step, made an inventory of different plant species involved in medicine making in Morocco. This survey dealt with 825 miscellaneous pharmaceutical products and reveals the use of 445 different plant species in medicine making. For each plant species, we have also noted the parts of the plant which are used in the pharmaceutical industry. Furthermore, we have taken an interest in plant extracts involved in this medicine making. The results show that in all these medicines contain 46 extracts of a vegetal nature. At the top of the list, menthol is used in the manufacture of 110 pharmaceutical products. Finally, an analysis per pharmaco-therapeutic family reveals the impact of the involvement of these plants on each of these families. In fact, it turns out that 204 plant species play a part in medicines classified in the family of gastro-entero-hepatology whereas only one plant is involved in anti-inflammatory medicines.

Databases, Factual↗

[Relationship between nasal airflow sensation and nasal patency].

The relationship between nasal airflow sensation and nasal patency was evaluated by means of visual analogue test and anterior rhinomanometry. It was demonstrated that there is no significant correlation between the subjective sensation of nasal airflow and objective assessment of nasal airflow resistance. The site responsible for sensing airflow is located in the nasal vestibule. The volatile agents used in traditional Chinese medicine for nasal obstruction, such as camphor and menthol, could only improve the nasal sensation of airflow without alteration of nasal airway resistance. Our results suggested that the nasal sensation of airflow could not reflect real patency completely. Therefore, assessment of subjective sensation of airflow and measurement of nasal airway resistance combined must be used in the diagnosis and treatment of nasally obstructed patients.

Adult↗