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Nicotine & Tobacco Research : Official... Jan 2014The use of novel oral nicotine delivery devices and compositions for human consumption and for animal research studies has been increasing in the last several years.
INTRODUCTION
The use of novel oral nicotine delivery devices and compositions for human consumption and for animal research studies has been increasing in the last several years.
METHODS
Studies were undertaken to examine whether the systemic administration of methoxsalen, an inhibitor of human CYP2A6 and mouse CYP2A5, would modulate nicotine pharmacokinetics and pharmacological effects (antinociception in the tail-flick, and hot-plate tests, and hypothermia) in male ICR mouse after acute oral nicotine administration.
RESULTS
Administration of intra peritoneal (ip) methoxsalen significantly increased nicotine's Cmax, prolonged the plasma half-life (fourfold decrease) of nicotine, and increased its area under the curve (AUC) compared with ip vehicle treatment. Methoxsalen pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (15mg/kg, po) for periods up to 6- and 24-hr postnicotine administration, respectively. Additionally, methoxsalen potentiated nicotine-induced antinociception and hypothermia as evidenced by leftward shifts in nicotine's dose-response curve. Furthermore, this prolongation of nicotine's effects after methoxsalen was associated with a parallel prolongation of nicotine plasma levels in mice. These data strongly suggest that variation in the rates of nicotine metabolic inactivation substantially alter pharmacological effects of nicotine given orally.
CONCLUSION
We have shown that the pharmacological effects of inhibiting nicotine's metabolism after oral administration in mice are profound. Our results suggest that inhibiting nicotine metabolism can be used to dramatically enhance nicotine's bioavailability and its resulting pharmacology, which further supports this inhibitory approach for clinical development of an oral nicotine replacement therapy.
Topics: Animals; Aryl Hydrocarbon Hydroxylases; Chromatography, Liquid; Cotinine; Cytochrome P-450 CYP2A6; Cytochrome P450 Family 2; Drug Interactions; Injections, Intraperitoneal; Male; Methoxsalen; Mice; Nicotine; Tandem Mass Spectrometry
PubMed: 23884323
DOI: 10.1093/ntr/ntt105 -
BMJ (Clinical Research Ed.) Feb 1994
Topics: Administration, Topical; Humans; Lymphoma, T-Cell, Cutaneous; Mechlorethamine; Methoxsalen; Randomized Controlled Trials as Topic; Skin Neoplasms; Ultraviolet Therapy
PubMed: 8031362
DOI: 10.1136/bmj.308.6928.551 -
Neuropharmacology Oct 2014Metabolism of nicotine to inactive cotinine by hepatic enzyme CYP2A6 is the principal pathway by which active nicotine is removed from circulation. We therefore...
Metabolism of nicotine to inactive cotinine by hepatic enzyme CYP2A6 is the principal pathway by which active nicotine is removed from circulation. We therefore hypothesized that inhibition of mouse CYP2A5, the ortolog of human CYP2A6, by methoxsalen (8-methoxypsoralen) alter dependence-related behaviors of nicotine in the mouse. Conditioned place preference (CPP) test was used to assess the appetitive reward-like properties and precipitated nicotine withdrawal to assess physical (somatic and hyperalgesia) and affective (anxiety-related behaviors) measures. The nicotine plasma levels were also measured with or without methoxsalen pretreatment. Methoxsalen (15 and 30 mg/kg, intraperitoneally) pretreatment enhanced nicotine-induced preference in mice (p<0.05). However, there was a lack of enhancement of nicotine in the CPP test after the highest dose of the CYP-2A5 inhibitor. Similarly to the CPP results, repeated administration of methoxsalen increased the intensity of mecamylamine-precipitated withdrawal signs. The potentiation of nicotine preference and withdrawal intensity by methoxsalen was accompanied by significant increase in nicotine plasma levels in mice (p<0.05). Finally, methoxsalen enhanced the ability of a very low dose of nicotine (0.05 mg/kg) to reverse withdrawal signs in mice undergoing spontaneous withdrawal after chronic nicotine infusion (p<0.05). In conclusion, inhibition of nicotine metabolism by methoxsalen alters the behavioral effects of nicotine in the mouse. Combining CYP2A6 inhibitors with low dose nicotine replacement therapies may have a beneficial role in smoking cessation because it will decrease the drug elimination rate and maintain plasma and brain nicotine levels.
Topics: Animals; Anxiety; Aryl Hydrocarbon Hydroxylases; Conditioning, Psychological; Cytochrome P450 Family 2; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hyperalgesia; Male; Mecamylamine; Methoxsalen; Mice, Inbred ICR; Motor Activity; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Reward; Severity of Illness Index; Substance Withdrawal Syndrome; Tobacco Use Disorder
PubMed: 24859605
DOI: 10.1016/j.neuropharm.2014.05.006 -
Molecules (Basel, Switzerland) Sep 2022essential oils are routinely adulterated because of the lack of regulations or reliable authentication methods. Unfortunately, the relatively simple chemical makeup and...
essential oils are routinely adulterated because of the lack of regulations or reliable authentication methods. Unfortunately, the relatively simple chemical makeup and the tremendous price variations among varieties encouraged the interspecies adulteration of citrus oils. In this study, a sensitive UPLC-MS/MS method for the quantitation of 14 coumarins and furanocoumarins is developed and validated. This method was applied to screen the essential oils of 12 different species. This study, to our knowledge, represents the most comprehensive investigation of coumarin and furanocoumarin profiles across commercial-scale oils to date. Results show that the lowest amount was detected in calamansi oil. Expressed oil of Italian bergamot showed the highest furanocoumarin content and the highest level of any individual furanocoumarin (bergamottin). Notable differences were observed in the coumarin and furanocoumarin levels among oils of different crop varieties and origins within the same species. Potential correlations were observed between bergapten and xanthotoxin which matches with known biosynthetic pathways. We found patterns in furanocoumarin profiles that line up with known variations among the ancestral taxa. However, contrary to the literature, we also detected xanthotoxin in sweet orange and members of the mandarin taxon. Using multivariate analysis, we were able to divide the oils into 5 main groups and correlate them to the coumarin compositions.
Topics: 5-Methoxypsoralen; Chromatography, Liquid; Citrus; Coumarins; Furocoumarins; Methoxsalen; Oils, Volatile; Plant Oils; Tandem Mass Spectrometry
PubMed: 36234812
DOI: 10.3390/molecules27196277 -
The Cochrane Database of Systematic... Aug 2017Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for... (Review)
Review
BACKGROUND
Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as important.We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) from genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, as well as for other unknown reasons.Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain, reduce fever, and for their anti-inflammation properties. They are commonly used within paediatric pain management. Non-steroidal anti-inflammatory drugs are currently licensed for use in Western countries, however they are not approved for infants under three months old. The main adverse effects include renal impairment and gastrointestinal issues. Common side effects in children include diarrhoea, headache, nausea, constipation, rash, dizziness, and abdominal pain.
OBJECTIVES
To assess the analgesic efficacy and adverse events of NSAIDs used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, as well as online clinical trial registries.
SELECTION CRITERIA
Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing any NSAID with placebo or an active comparator.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE and created three 'Summary of findings' tables.
MAIN RESULTS
We included seven studies with a total of 1074 participants (aged 2 to 18 years) with chronic juvenile polyarthritis or chronic juvenile rheumatoid arthritis. All seven studies compared an NSAID with an active comparator. None of the studies were placebo controlled. No two studies investigated the same type of NSAID compared with another. We were unable to perform a meta-analysis.Risk of bias varied. For randomisation and allocation concealment, one study was low risk and six studies were unclear risk. For blinding of participants and personnel, three studies were low risk and four studies were unclear to high risk. For blinding of outcome assessors, all studies were unclear risk. For attrition, four studies were low risk and three studies were unclear risk. For selective reporting, four studies were low risk, two studies were unclear risk, and one study was high risk. For size, three studies were unclear risk and four studies were high risk. For other potential sources of bias, seven studies were low risk. Primary outcomesThree studies reported participant-reported pain relief of 30% or greater, showing no statistically significant difference in pain scores between meloxicam and naproxen, celecoxib and naproxen, or rofecoxib and naproxen (P > 0.05) (low-quality evidence).One study reported participant-reported pain relief of 50% or greater, showing no statistically significant difference in pain scores between low-dose meloxicam (0.125 mg/kg) and high-dose meloxicam (0.25 mg/kg) when compared to naproxen 10 mg/kg (P > 0.05) (low-quality evidence).One study reported Patient Global Impression of Change, showing 'very much improved' in 85% of ibuprofen and 90% of aspirin participants (low-quality evidence). Secondary outcomesAll seven studies reported adverse events. Participants reporting an adverse event (one or more per person) by drug were: aspirin 85/202; fenoprofen 28/49; ibuprofen 40/45; indomethacin 9/30; ketoprofen 9/30; meloxicam 18/47; naproxen 44/202; and rofecoxib 47/209 (very low-quality evidence).All seven studies reported withdrawals due to adverse events. Participants withdrawn due to an adverse event by drug were: aspirin 16/120; celecoxib 10/159; fenoprofen 0/49; ibuprofen 0/45; indomethacin 0/30; ketoprofen 0/30; meloxicam 10/147; naproxen 17/285; and rofecoxib 3/209 (very low-quality evidence).All seven studies reported serious adverse events. Participants experiencing a serious adverse event by drug were: aspirin 13/120; celecoxib 5/159; fenoprofen 0/79; ketoprofen 0/30; ibuprofen 4/45; indomethacin 0/30; meloxicam 11/147; naproxen 10/285; and rofecoxib 0/209 (very low-quality evidence).There were few or no data for our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning as defined by validated scales; and quality of life as defined by validated scales (very low-quality evidence).We rated the overall quality of the evidence (GRADE rating) for our primary and secondary outcomes as very low because there were limited data from studies and no opportunity for a meta-analysis.
AUTHORS' CONCLUSIONS
We identified only a small number of studies, with insufficient data for analysis.As we could undertake no meta-analysis, we are unable to comment about efficacy or harm from the use of NSAIDs to treat chronic non-cancer pain in children and adolescents. Similarly, we cannot comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.We know from adult randomised controlled trials that some NSAIDs, such as ibuprofen, naproxen, and aspirin, can be effective in certain chronic pain conditions.
Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Juvenile; Arthritis, Rheumatoid; Aspirin; Celecoxib; Child; Child, Preschool; Chronic Disease; Chronic Pain; Fenoprofen; Humans; Ibuprofen; Lactones; Meloxicam; Methoxsalen; Naproxen; Randomized Controlled Trials as Topic; Sulfones; Thiazines; Thiazoles
PubMed: 28770976
DOI: 10.1002/14651858.CD012537.pub2 -
Heterocyclic Letters 2018The natural product 8-methoxypsoralen (methoxsalen or 8-MOP) in combination with long wavelength ultraviolet light (UVA, 320-400 nm), also referred to as PUVA therapy,...
The natural product 8-methoxypsoralen (methoxsalen or 8-MOP) in combination with long wavelength ultraviolet light (UVA, 320-400 nm), also referred to as PUVA therapy, is used for the treatment of cutaneous proliferative disorders including psoriasis, vitiligo and mycosis fungoides. The use of 8-MOP () is limited by its poor water solubility and there remains a need to develop more water-soluble psoralens to enhance bioavailability following oral administration of the drug. In the present studies a water-soluble dimethylaminoethyl ether analog of 8-MOP was synthesized and analyzed for biological activity. This analog, (8-[2-(N,N-dimethylamino)ethoxy]-psoralen hydrochloride () [or CAS name: 9-[2-(dimethylamino)ethoxy]-7-furo[3,2-][1]benzopyran-7-one, hydrochloride], was found to be significantly more active than in keratinocyte growth inhibition assays (IC = 12 nM and 130 nM for and , respectively). The partially reduced dihydro derivative of , 8-[2-(N,N-dimethylamino)ethoxy]-4',5'-dihydropsoralen hydrochloride () [or CAS name: 9-[2-(dimethylamino)ethoxy]-2,3-dihydro-7-furo[3,2-][1]benzopyran-7-one, hydrochloride] and the partially reduced 4',5'-dihydro-8-methoxypsoralen () lacking the water-solubilizing side-chain were significantly less active. As inhibitors of keratinocyte growth they ranked as IC = 13,000 nM and 70,000 nM for and , respectively, indicating that an unsaturated furan ring in the psoralen was required for maximal activity. Compound () was found to readily intercalate and damage DNA following UVA light treatment as determined by plasmid DNA nicking and unwinding experiments in neutral and alkaline agarose gels. Taken together, these data demonstrate that a water-soluble dimethylaminoethyl ether psoralen targets DNA, is highly active as a photosensitizer, and may be useful in the treatment of skin diseases involving abnormal keratinocyte proliferation.
PubMed: 33575202
DOI: No ID Found -
Molecules (Basel, Switzerland) Nov 2020The psoralens 8-methoxypsoralen (8-MOP), 4,5',8-trimethylpsoralen (TMP) and 5-methoxypsoralen (5-MOP) find clinical application in PUVA (psoralen + UVA) therapy. PUVA...
The psoralens 8-methoxypsoralen (8-MOP), 4,5',8-trimethylpsoralen (TMP) and 5-methoxypsoralen (5-MOP) find clinical application in PUVA (psoralen + UVA) therapy. PUVA treats skin diseases like psoriasis and atopic eczema. Psoralens target the DNA of cells. Upon photo-excitation psoralens bind to the DNA base thymine. This photo-binding was studied using steady-state UV/Vis and IR spectroscopy as well as nanosecond transient UV/Vis absorption. The experiments show that the photo-addition of 8-MOP and TMP involve the psoralen triplet state and a biradical intermediate. 5-MOP forms a structurally different photo-product. Its formation could not be traced by the present spectroscopic technique.
Topics: DNA; DNA Damage; Furocoumarins; Humans; Kinetics; Methoxsalen; Pharmaceutical Preparations; Photochemistry; Quantum Theory; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet; Trioxsalen; Ultraviolet Rays
PubMed: 33182821
DOI: 10.3390/molecules25225242 -
Evidence-based Complementary and... 2019Linn (PCL) is an herb that is commonly used for alleviating osteoporosis and vitiligo. Although accumulating evidence has demonstrated the antiosteoporotic effect of...
BACKGROUND AND AIM
Linn (PCL) is an herb that is commonly used for alleviating osteoporosis and vitiligo. Although accumulating evidence has demonstrated the antiosteoporotic effect of PCL, the identities of the osteogenic compounds in PCL and their functional targets remain elusive. To investigate the osteogenic ingredients in PCL and their functional mechanisms, network pharmacology analysis was performed on the targets of PCL and osteogenesis.
METHODS
The active components of PCL were screened by literature review. The potential protein targets of the active PCL components were predicted with the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Search Tool for Interactions of Chemicals (STITCH), SwissTargetPrediction, and PubChem. The target networks related to PCL and osteogenic differentiation were constructed by using Cytoscape. MC3T3-E1 cells were used to verify the targets.
RESULTS
Twenty-three active components of PCL and 162 potential target proteins were identified. Further analysis reduced the number of potential target proteins to 71. Of the 23 components, bavachalcone, psoralen, bavachinin, neobavaisoflavone, methoxsalen, psoradin, bakuchiol, and angelicin may be the main active components of PCL that promote bone formation. PPAR and aryl hydrocarbon receptor (AhR) were verified as targets of PCL in MC3T3-E1 cells, and the western blot and immunofluorescence staining results showed that compared to the control, PCL reduced the expression of these targets.
CONCLUSIONS
The active components of PCL and the mechanisms by which they promoted osteogenic differentiation were successfully identified using network pharmacology.
PubMed: 31781261
DOI: 10.1155/2019/2160175 -
The Journal of Investigative Dermatology Feb 1982To test the validity of the common hypothesis that patients with psoriasis have an inherently lower susceptibility to cancer, we prospectively studied 1367 patients with...
To test the validity of the common hypothesis that patients with psoriasis have an inherently lower susceptibility to cancer, we prospectively studied 1367 patients with severe psoriasis who enrolled in a clinical trial of oral methoxsalen photochemotherapy for treatment of psoriasis for an average of 3.2 yr. The incidence of non-cutaneous cancers and the number of deaths from such cancers were slightly but not significantly higher than that expected for the general population (relative risk = 1.1; standard mortality ratio = 1.3). Among 318 patients (23%) in this cohort who were over 35 yr of age and who lacked appreciable exposure to suspected cutaneous carcinogens, the observed incidence for cutaneous carcinoma was 1.4 times that expected, based on rates for the general population (90% confidence interval = .8 to 2.7). These data suggest that patients with psoriasis have a risk of systemic and cutaneous cancer that is comparable to the risk for the general population.
Topics: Adult; Female; Humans; Male; Neoplasms; PUVA Therapy; Prospective Studies; Psoriasis; Risk; Skin Neoplasms; Ultraviolet Therapy
PubMed: 7057050
DOI: 10.1111/1523-1747.ep12506290 -
The Journal of Investigative Dermatology Feb 1959
Topics: Furans; Hair; Humans; Methoxsalen; Pigmentation; Vitiligo
PubMed: 13641802
DOI: No ID Found