ETO MR GEL

Indications

• Localized neuropathic pain
• Post-herpetic neuralgia
• Painful diabetic neuropathy

Dosage

Adults: Apply 3–4 times a day, using 0.075% strength, apply sparingly, and not more often than every 4 hours.

Mechanism of action

Capsaicin acts as an agonist of the TRPV1 (transient receptor potential vanilloid 1) receptor. Upon activation by capsaicin, the TRPV1 receptor opens to allow the influx of cations, particularly calcium and sodium ions, leading to depolarization of sensory neurons. This results in the induction of pain responses initially, followed by desensitization or 'defunctionalization' of nociceptor fibers, which reduces pain signaling over time. Capsaicin reduces levels of substance P, a neuropeptide associated with pain transmission, contributing to its analgesic effects.

Pharmacodynamics

Capsaicin's interaction with TRPV1 receptors leads to a series of cellular responses, including temporary loss of membrane potential and alterations in neurotrophic factor transport. The prolonged exposure to capsaicin results in persistent activation of these receptors, causing a loss of response to sensory stimuli, which is described as defunctionalization. This process results in significant changes in neuronal excitability and pain perception.

Pharmacokinetics

Capsaicin is primarily applied topically, allowing for localized effects with minimal systemic absorption. The pharmacokinetics of capsaicin involve rapid uptake into the skin and subsequent receptor-mediated effects. The duration of action can vary based on the concentration and formulation used. Capsaicin undergoes metabolism in the liver, and its effects can last for hours to days due to the desensitization of nociceptive pathways.

Contra-indications

• Known hypersensitivity to capsaicin or any of the excipients
• History of cardiovascular disease in diabetic patients
• Uncontrolled hypertension

Adverse effects

• Burning sensation at the application site
• Skin irritation
• Eye irritation if in contact with eyes
• Cough
• Dry mouth
• Nausea
• Palpitations
• Taste alterations
• Throat irritation
• Muscle spasms
• Sneezing
• Watering eyes
• Peripheral edema
• Tachycardia

Interactions

• Use with caution in patients taking other analgesics
• May enhance the effects of medications that affect blood pressure
• Avoid using with other topical agents that may irritate the skin

Precautions

• Avoid contact with broken or inflamed skin
• Wash hands immediately after use
• Wear nitrile gloves when applying patches
• Avoid contact with eyes and mucous membranes
• Avoid hot showers or baths just before or after application
• Monitored use in diabetic patients with cardiovascular disease
• Regular monitoring for side effects in long-term therapy

Pregnancy

Capsaicin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult with a healthcare provider.

Breast-feeding

Use with caution while breastfeeding. Consult a healthcare provider before use.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Topical cream (0.075%)
• Transdermal patches (Qutenza®)

Indications

• Pain and inflammation in rheumatoid arthritis
• Pain and inflammation in osteoarthritis
• Pain and inflammation in ankylosing spondylitis

Dosage

Children: Refer to the BNF for Children for appropriate dosing in paediatric patients.

Adults: The recommended dose for adults is 100 mg twice daily.

Mechanism of action

Aceclofenac acts by inhibiting the cyclooxygenase (COX) enzymes, specifically COX-2, leading to a decrease in the synthesis of prostaglandins. This results in an anti-inflammatory effect, pain relief, and reduction in swelling. The pathway involves the blockade of the arachidonic acid pathway, which is vital for the production of pro-inflammatory mediators.

Pharmacodynamics

Aceclofenac exhibits anti-inflammatory, analgesic, and antipyretic properties. By inhibiting COX-2, it reduces inflammation and pain while sparing COX-1, which helps maintain gastric mucosal integrity, thereby potentially lowering the risk of gastrointestinal side effects compared to other NSAIDs. However, it still poses risks such as gastrointestinal bleeding, renal impairment, and cardiovascular events.

Pharmacokinetics

Aceclofenac is well-absorbed after oral administration, with peak plasma concentrations occurring approximately 1-2 hours post-dose. It is extensively metabolized in the liver, primarily via glucuronidation, with its metabolites being excreted through urine. The half-life of aceclofenac is about 4 hours, necessitating twice-daily dosing for effective pain management. The drug's clearance may be reduced in patients with hepatic impairment.

Contra-indications

• Active bleeding
• Active gastrointestinal bleeding
• History of hypersensitivity to aspirin or any other NSAID
• Severe renal impairment
• Severe hepatic impairment

Adverse effects

• Constipation
• Vomiting
• Anaemia
• Angioedema
• Depression
• Drowsiness
• Dyspnoea
• Fatigue
• Haemolytic anaemia
• Headache
• Heart failure
• Hepatic disorders
• Hyperkalaemia
• Hypertension
• Inflammatory bowel disease
• Leg cramps
• Nephrotic syndrome
• Neutropenia
• Oedema
• Palpitations
• Pancreatitis
• Paraesthesia
• Respiratory disorders
• Severe cutaneous adverse reactions (SCARs)
• Sleep disorders
• Taste altered
• Thrombocytopenia
• Tinnitus
• Tremor
• Vasculitis
• Vertigo
• Visual impairment
• Weight increased

Interactions

• Increased risk of gastrointestinal side effects when combined with low-dose aspirin
• Alcohol increases risk of gastrointestinal hemorrhage
• NSAIDs may exacerbate symptoms in asthma patients

Precautions

• Use with caution in elderly patients and those at risk of gastrointestinal ulceration
• Patients with serious rheumatic diseases may become dependent on NSAIDs
• Consider gastroprotective treatment for at-risk patients

Pregnancy

Most manufacturers advise avoiding the use of NSAIDs during pregnancy unless the potential benefit outweighs the risk, particularly during the third trimester due to risks associated with fetal ductus arteriosus closure.

Breast-feeding

Use with caution during breastfeeding.

Storage

Store in a cool, dry place away from light.

Formulations

• Oral tablets

Indications

• Dietary supplement for omega-3 fatty acid intake
• Cardiovascular health support
• Anti-inflammatory effects
• Digestive health improvement
• Potential hormone balance support

Dosage

Children: Specific paediatric dosing is not established. It is advisable to consult a healthcare provider for recommendations regarding the use of linseed in children.

Adults: For general health, 1-2 tablespoons of ground linseed or flaxseed oil per day is commonly recommended. Always refer to specific product guidelines or consult with a healthcare provider for tailored advice.

Mechanism of action

The primary mechanism of action of linseed involves its high content of omega-3 fatty acids, which are known to modulate inflammatory pathways and promote cardiovascular health. ALA is converted in the body to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which exert anti-inflammatory effects and improve endothelial function. The fiber content in linseed also aids in digestion and may help in regulating cholesterol levels.

Pharmacodynamics

Linseed exhibits several pharmacodynamic properties, including the ability to reduce plasma lipid levels, decrease inflammation, and improve bowel regularity. The lignans in linseed have antioxidant properties and may exert phytoestrogenic effects, which can influence hormonal balance. The soluble fiber contributes to satiety and may assist in weight management.

Pharmacokinetics

Linseed is not extensively absorbed in the gastrointestinal tract due to its high fiber content; however, the omega-3 fatty acids can be absorbed and utilized by the body. The metabolism of ALA involves conversion to EPA and DHA, which can occur in varying degrees among individuals based on genetic and dietary factors. The elimination of fatty acids typically occurs through beta-oxidation and incorporation into cell membranes.

Adverse effects

• Diarrhea
• Abdominal pain
• Bloating
• Nausea
• Allergic reactions

Precautions

• Use with caution in individuals with gastrointestinal disorders
• Monitor for potential allergic reactions
• Ensure adequate hydration to prevent gastrointestinal blockage

Pregnancy

Linseed is generally considered safe in moderation during pregnancy, but high doses should be avoided due to potential hormonal effects.

Breast-feeding

Linseed is likely safe during breastfeeding in moderate amounts; however, consult a healthcare provider for personalized advice.

Storage

Store in a cool, dry place away from direct sunlight. Keep tightly closed and out of reach of children.

Formulations

• Whole linseed seeds
• Linseed oil
• Ground linseed meal

Indications

• Topical analgesic for muscle and joint pain
• Cough suppressant in cough drops and lozenges
• Relief of minor throat irritation
• Cooling agent in various cosmetic and personal care products

Dosage

Children: Refer to BNF for Children for specific dosing guidelines, as doses may vary based on age and formulation.

Adults: For topical use, apply a thin layer to the affected area not more than 3 to 4 times daily. For cough drops, follow the product-specific instructions as per the formulation.

Mechanism of action

Menthol acts as an agonist for the transient receptor potential subtype M8 (TRPM8), a non-selective cation channel that is activated by cold temperatures. This activation leads to calcium influx in mast cells, inducing the release of histamine, which can trigger allergic responses such as urticaria, asthma, and rhinitis. Menthol's ability to induce histamine release via TRPM8 suggests potential therapeutic applications for TRPM8 antagonists in managing cold- and menthol-induced allergies.

Pharmacodynamics

Menthol produces a cooling effect by stimulating sensory neurons that convey cold sensations. It interacts with TRPM8 channels, leading to the activation of intracellular signaling pathways that can result in vasodilation and increased blood flow to the area of application. This cooling sensation can provide symptomatic relief in conditions characterized by pain or irritation.

Pharmacokinetics

Menthol is absorbed through the skin and mucous membranes, with systemic effects depending on the route of administration. Its bioavailability can vary, and it is metabolized primarily in the liver. The elimination half-life and excretion pathways have not been extensively characterized, but menthol is generally considered to have a rapid onset of action with effects lasting for a few hours.

Adverse effects

• Allergic reactions
• Urticaria
• Asthma
• Rhinitis
• Skin irritation

Precautions

• Use with caution in patients with known allergies to menthol or related compounds
• May exacerbate asthma in sensitive individuals

Pregnancy

There are no well-controlled studies of menthol in pregnant women. Menthol should be used during pregnancy only if clearly needed.

Breast-feeding

Menthol is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Topical ointment
• Cream
• Liquid

Indications

• Allergic conditions
• Autoimmune diseases
• Asthma and chronic obstructive pulmonary disease (COPD)
• Certain cancers (e.g., leukemia, lymphoma)
• Skin conditions (e.g., dermatitis)
• Inflammatory bowel disease
• Multiple sclerosis exacerbations
• Severe infections requiring immunosuppression

Dosage

Children: Refer to BNF for Children for specific dosing; doses vary significantly based on the child's age, weight, and condition being treated.

Adults: Refer to BNF for specific dosing; typically, initial doses range from 4 to 48 mg depending on the severity of the condition.

Mechanism of action

Methylprednisolone exerts its effects by binding to glucocorticoid receptors, leading to the modulation of gene expression. This interaction influences the transcription of anti-inflammatory proteins while suppressing the expression of pro-inflammatory genes, ultimately resulting in reduced inflammation and immune response.

Pharmacodynamics

The pharmacodynamic effects of methylprednisolone are characterized by its ability to decrease inflammation, suppress the immune response, and affect carbohydrate metabolism. Therapeutic doses lead to various systemic effects, including modification of leukocyte distribution and inhibition of cytokine production.

Pharmacokinetics

Methylprednisolone is well absorbed after oral administration, with a bioavailability of approximately 50%. It has a volume of distribution that reflects extensive tissue binding. The drug is metabolized primarily in the liver through conjugation and reduction, and its metabolites are excreted in urine. The half-life varies based on the route of administration but is generally around 18 to 36 hours.

Adverse effects

• Increased blood pressure
• Hyperglycemia
• Weight gain
• Mood changes
• Insomnia
• Gastrointestinal disturbances
• Increased susceptibility to infections

Interactions

• methylphenidate+apraclonidine: Severe (decreases effects)
• methylthioninium chloride+bupropion: Severe (increases risk of severe hypertension)
• methylphenidate+linezolid: Severe (increases risk of elevated blood pressure)
• rasagiline+methylphenidate: Severe (increases risk of a hypertensive crisis)
• mao-inhibitors+methylphenidate: Severe (increases risk of a hypertensive crisis)
• dronedarone+methylprednisolone: Moderate (increases exposure)
• miconazole+methylprednisolone: Moderate (increases concentration)
• antifungals, azoles+methylprednisolone: Moderate (increases exposure)
• crizotinib+methylprednisolone: Moderate (increases exposure)

Precautions

• Use with caution in patients with hypertension
• Monitor blood glucose levels in diabetic patients
• Consider potential for infection risk due to immunosuppression
• Evaluate for psychiatric effects in susceptible individuals

Pregnancy

Corticosteroids may be used during pregnancy if the potential benefit justifies the risk to the fetus. Careful monitoring is advised.

Breast-feeding

Corticosteroids are excreted in breast milk; caution is advised. Monitor the infant for potential effects.

Storage

Store in a cool, dry place, away from light. Keep out of reach of children.

Formulations

• Tablets
• Injectable solutions
• Topical preparations

Mechanism of action

Methylsulphate functions as a methylating agent, transferring a methyl group to nucleophiles. This process involves the formation of a sulfonium ion, which is highly reactive and can readily react with nucleophilic sites on various substrates, leading to methylation reactions.

Pharmacodynamics

The pharmacodynamics of methylsulphate is primarily related to its role as a methylating agent in biochemical reactions. It can alter the structure and function of biological molecules, potentially affecting cellular processes and signaling pathways. However, detailed pharmacodynamic studies specific to therapeutic use are limited.

Pharmacokinetics

There is limited information on the pharmacokinetics of methylsulphate, given its typical use as a reagent in laboratory settings rather than a clinical drug. When used in chemical reactions, its reactivity and transformation into other compounds would dictate its pharmacokinetic profile, which could vary significantly based on the specific context of use.

Pregnancy

There is limited data on the use of methylsulphate in pregnancy. Consult relevant guidelines.

Breast-feeding

Data on the excretion of methylsulphate in human milk is not available. Caution is advised.

Storage

Store in a cool, dry place, away from direct sunlight.

Indications

• Pain relief
• Fever reduction
• Inflammatory conditions such as arthritis
• Prevention of cardiovascular events in certain populations

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines.

Adults: Refer to the BNF for specific dosing guidelines.

Mechanism of action

Salicylate works by inhibiting the enzyme cyclooxygenase (COX), which is involved in the synthesis of prostaglandins. Prostaglandins are lipid compounds that mediate inflammation, pain, and fever. By decreasing the production of these compounds, salicylate effectively reduces inflammation and provides analgesic and antipyretic effects.

Pharmacodynamics

The pharmacodynamic effects of salicylate include analgesia, antipyresis, and anti-inflammatory action. It reduces the sensitivity of pain receptors and inhibits the generation of pain signals. The antipyretic effect is achieved through action on the hypothalamus, leading to peripheral vasodilation and sweating, thereby reducing body temperature. The drug also modulates the immune response, contributing to its anti-inflammatory properties.

Pharmacokinetics

Salicylate is rapidly absorbed from the gastrointestinal tract following oral administration. Peak plasma concentrations are typically reached within 1 to 2 hours. It is extensively metabolized in the liver, primarily through conjugation, and its metabolites are excreted in the urine. The elimination half-life of salicylate varies depending on the dose and the presence of other medications, averaging around 2 to 3 hours at low doses, but can be prolonged at higher doses due to saturation of metabolic pathways.

Contra-indications

• Hypersensitivity to salicylates
• Active peptic ulcer disease
• Severe hepatic impairment
• Severe renal impairment
• Bleeding disorders
• Children with viral infections (due to risk of Reye's syndrome)

Adverse effects

• Gastrointestinal irritation
• Nausea
• Vomiting
• Tinnitus
• Hearing loss
• Allergic reactions
• Rash
• Asthma exacerbation
• Gastric ulceration

Interactions

• Anticoagulants (increased bleeding risk)
• Methotrexate (increased toxicity)
• NSAIDs (increased gastrointestinal side effects)
• Diuretics (reduced efficacy)
• Alcohol (increased risk of gastrointestinal bleeding)

Precautions

• Use with caution in patients with a history of gastrointestinal disease
• Monitor renal function in long-term use
• Caution in patients with asthma or allergies
• Consider alternative therapy in children with viral infections

Pregnancy

Use with caution during pregnancy, particularly in the third trimester, as it may affect fetal development.

Breast-feeding

Salicylate is excreted in breast milk; caution is advised when administering to breastfeeding mothers.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets
• Oral suspension
• Topical preparations
• Suppositories

Indications

• Muscle spasms
• Rheumatic pain
• Traumatic pain
• Spastic sequelae of hemiparesis
• Parkinson's disease-related symptoms
• Acute and chronic lumbar and sciatic pain
• Cervico-brachial neuralgia
• Persistent torticollis
• Post-traumatic and post-operative pain

Dosage

Children: Refer to the BNF for Children for paediatric dosing guidance.

Adults: Refer to the BNF for detailed dosing recommendations.

Mechanism of action

Thiocolchicoside selectively binds to GABA-A receptors, activating GABA inhibitory pathways and acting as a muscle relaxant. It also has an affinity for glycine receptors and partially inhibits nicotinic acetylcholine receptors, contributing to its muscle relaxant properties. The drug is noted for its potential convulsant activity, necessitating caution in individuals susceptible to seizures.

Pharmacodynamics

Thiocolchicoside functions primarily as a muscle relaxant through its action on GABA-A receptors, preventing muscle contractions and providing relief from painful muscle spasms. It exhibits competitive antagonistic properties at GABA receptors and shows significant effects on glycine and nicotinic acetylcholine receptors. It is effective in alleviating symptoms associated with central and reflex muscle contractures, as well as conditions like spastic hemiparesis and neurodyslectic syndrome.

Pharmacokinetics

The specific pharmacokinetic profile of thiocolchicoside, including absorption, distribution, metabolism, and excretion details, is not provided. For optimal therapeutic management, refer to established guidelines and consult pharmacokinetic resources.

Contra-indications

• Hypersensitivity to thiocolchicoside or any of its components
• History of seizures or epilepsy
• Severe renal impairment

Adverse effects

• Drowsiness
• Dizziness
• Gastrointestinal disturbances (nausea, vomiting)
• Allergic reactions (skin rash, urticaria)
• Muscle weakness
• Severe hypotension
• Convulsions in predisposed individuals

Interactions

• CNS depressants (e.g., alcohol, benzodiazepines) may enhance sedative effects
• Antiepileptic drugs may reduce the effectiveness of thiocolchicoside
• Other muscle relaxants may increase the risk of adverse effects

Precautions

• Use with caution in patients with hepatic impairment
• Monitor patients for signs of seizures
• Caution in elderly patients or those with a history of falls
• Not recommended for use in children unless prescribed by a specialist

Pregnancy

There are limited data on the use of thiocolchicoside during pregnancy. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether thiocolchicoside is excreted in human milk. Caution is advised when administering to nursing women.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets
• Injectable solution

Mechanism of action

Through COX-2 inhibition, aceclofenac downregulates the production of various inflammatory mediators including prostaglandin E2 (PGE2), IL-1β, and TNF from the arachidonic acid (AA) pathway. Inhibition of IL-6 is thought to be mediated by diclofenac converted from aceclofenac. Suppressed action of inflammatory cytokines decreases the production of reactive oxygen species. Aceclofenac is shown to decreased production of nitrous oxide in human articular chondrocytes. In addition, aceclofenac interferes with neutrophil adhesion to endothelium by decreasing the expression of L-selectin (CD62L), which is a cell adhesion molecule expressed on lymphocytes. Aceclofenac is proposed to stimulate the synthesis of glycosaminoglycan in human osteoarthritic cartilage which may be mediated through its inhibitory action on IL-1 production and activity. The chrondroprotective effects are generated by 4'-hydroxyaceclofenac which suppresses IL-1 mediated production of promatrix metalloproteinase-1 and metalloproteinase-3 and interferes with the release of proteoglycan from chrondrocytes.

Pharmacodynamics

Aceclofenac is a NSAID that inhibits both isoforms of COX enzyme, a key enzyme involved in the inflammatory cascade. COX-1 enzyme is a constitutive enzyme involved in prostacyclin production and protective functions of gastric mucosa whereas COX-2 is an inducible enzyme involved in the production of inflammatory mediators in response to inflammatory stimuli. Aceclofenac displays more selectivity towards COX-2 (IC50 of 0.77uM) than COX-1 (IC50 of >100uM), which promotes its gastric tolerance compared to other NSAIDs. The primary metabolite, 4'-hydroxyaceclofenac, also minimally inhibits COX-2 with IC50 value of 36uM. Although the mode of action of aceclofenac is thought to mainly arise from the inhibition of synthesis of prostaglandins (PGE2), aceclofenac also inhibits the production of inflammatory cytokines, interleukins (IL-1β, IL-6), and tumor necrosis factors (TNF). It is also reported that aceclofenac also affects the cell adhesion molecules from neutrophils. Aceclofenac also targets the synthesis of glycosaminoglycan and mediates chrondroprotective effects.

Mechanism of action

Capsaicin has been shown to reduce the amount of substance P associated with inflammation - however this is not believed to be its main mechanism in the relief of pain. Capsaicin's mechanism of action is attributed to "defunctionalization" of nociceptor fibers by inducing a topical hypersensitivity reaction on the skin. This alteration in pain mechanisms is due to many of the following: temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fiber terminals. Capsaicin, the pungent constituent of chili peppers, represents the paradigm for the capsaicinoids or vanilloids, a family of compounds shown to stimulate and then desensitize specific subpopulations of sensory receptors, including C-polymodal nociceptors, A-delta mechanoheat nociceptors and warm receptors of the skin, as well as enteroceptors of thin afferent fibers. ... ... In rats desensitized by intraperitoneal (ip) capsaicin (i.e., abdominal non-systemic desensitization), mainly the first but not the later fever phases were reduced. The postprandial hyperthermia to intragastric injection of BaSO4 suspension was attenuated by either ip or perineural capsaicin treatment. ... Heat and protons as well as capsaicin activate VR1 to induce the influx of cations, particularly Ca2+ and Na+ ions. Characteristic effects of capsaicin are the induction of a burning sensation after acute administration and the desensitization of sensory neurons after large doses and prolonged administration. ... Capsaicin alters several visceral functions. ... Capsaicin affects thermoregulation after intra-hypothalamic injection and releases glutamate from the hypothalamus and cerebral cortex slices, while VR1-like immunoreactivity is not apparent in these regions. ... 0.4 and 4 uM of capsaicin produced a significant tonic block on voltage-activated Na+ current (I(Na)) evoked by a depolarizing step to -40 mV from a holding potential of -100 mV (49 +/- 7% n=11, p<0.05 and 72 +/- 13% n=4, p<0.05 respectively). ... Capsaicin slowed the time decay of inactivation of I(Na), and increased the time constant of the recovery of inactivation. Capsaicin and tetrodotoxin (TTX) depressed contractility of isolated electrically driven left rat atria, being the depression of maximal velocity of force development (dF/dt(max)) with respect to control values of 19 +/- 3% at 1 uM of capsaicin and 22 +/- 2% at 1 uM of TTX. For more Mechanism of Action (Complete) data for CAPSAICIN (8 total), please visit the HSDB record page.

Pharmacodynamics

Capsaicin is a TRPV1 receptor agonist. TRPV1 is a trans-membrane receptor-ion channel complex activated by temperatures higher than 43 degrees Celsius, pH lower than 6, and endogenous lipids. When activated by a combination of these factors, the channel can transiently open and initiate depolarization due to the influx of calcium and sodium ions. Because TRPV1 is commonly expressed in A-delta and mostly C fibers, depolarization results in action potentials which send impulses to the brain and spinal cord. These impulses result in capsaicin effects of warming, tingling, itching, stinging, or burning. Capsaicin also causes more persistent activation of these receptors compared to the environmental agonists, resulting in a loss of response to many sensory stimuli, described as "defunctionalization". Capsaicin is associated with many enzymatic, cytoskeletal, and osmotic changes, as well as disruption of mitochondrial respiration, impairing nociceptor function for extended periods of time.

Mechanism of action

Exposure to low temperatures often causes allergic responses or urticaria. Similarly, menthol, a common food additive is also known to cause urticaria, asthma, and rhinitis. However, despite the obvious clinical implications, the molecular mechanisms responsible for inducing allergic responses to low temperatures and menthol have not been determined. Because a non-selective cation channel, transient receptor potential subtype M8 (TRPM8) is activated by cold and menthol, we hypothesized that this channel mediates cold- and menthol-induced histamine release in mast cells. Here, we report that TRPM8 is expressed in the basophilic leukemia mast cell line, RBL-2H3, and that exposure to menthol or low temperatures induced Ca(2+) influx in RBL-2H3 cells, which was reversed by a TRPM8 blocker. Furthermore, menthol, a TRPM8 agonist, induced the dose-dependent release of histamine from RBL-2H3 cells. When TRPM8 transcripts were reduced by siRNA (small interfering RNA), menthol- and cold-induced Ca(2+) influx and histamine release were significantly reduced. In addition, subcutaneous injection of menthol evoked scratching, a typical histamine-induced response which was reversed by a TRPM8 blocker. Thus, our findings indicate that TRPM8 mediates the menthol- and cold-induced allergic responses of mast cells, and suggest that TRPM8 antagonists be viewed as potential treatments for cold- and menthol-induced allergies. /DL-Menthol/ Menthol's characteristic cooling sensation is due, in part, to the activation of sensory neurons generally termed transient receptor potential (TRP) channels, in particular transient receptor potential melastatin family member 8 (TRPM8) and transient receptor potential subfamily A, member 1 (TRPA1). Menthol acts upon TRPM8 receptors by rapidly increasing intracellular calcium and mobilizing calcium flux through the channels to induce cold response signals at the application site. Aside from its cold-inducing sensation capabilities, menthol exhibits cytotoxic effects in cancer cells, induces reduction in malignant cell growth, and engages in synergistic excitation of GABA receptors and sodium ion channels resulting in analgesia. /DL-Menthol/ In recent years, the transient receptor potential melastatin member 8 (TRPM8) channel has emerged as a promising prognostic marker and putative therapeutic target in prostate cancer. We have found that forced overexpression of TRPM8 in PC-3 cells can inhibit the cell proliferation and motility probably through the TRPM8 activation. In this study, we aimed to investigate whether activating the TRPM8 channel by its selective agonist menthol can inhibit the proliferation and motility of androgen-independent prostate cancer (AIPC) with remarkable expression of TRPM8. Menthol is a naturally occurring compound, which has been widely used in cosmetics and pharmaceutical products, and also as flavoring in food. DU145 cells are androgen-independent but have a remarkable expression of TRPM8. The demonstration of the existence of TRPM8 and the absence of TRPA1 in DU145 cells provided the foundation for the following experiments, because both TRPM8 and TRPA1 are molecular targets of menthol. The outcome of MTT assay indicated that menthol inhibited the cell growth (p < 0.01). Cell cycle distribution and scratch assay analysis revealed that menthol induced cell cycle arrest at the G(0)/G(1) phase (p < 0.01). Furthermore, menthol inhibited the migration of DU145 cells by downregulating the focal-adhesion kinase. So it suggests that the activation of the existing TRPM8 channels may serve as a potential and pragmatic treatment for those AIPC with remarkable expression of TRPM8, and menthol is a useful compound for future development as an anticancer agent. /DL-Menthol/

Mechanism of action

Thiocolchicoside, is a synthetic sulfur derivative of colchicoside, a naturally occurring glucoside contained in the Colchicum autumnale plant. Thiocolchicoside has a selective and potent affinity for g-aminobutyric acid A (GABA-A) receptors and acts on muscular contractures by activating the GABA inhibitory pathways thereby behaving as a potent muscle relaxant. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex. GABAergic neurons are involved in myorelaxation, anxiolytic treatment, sedation, and anesthetics. GABA can also modulate heart rate and blood pressure. It also has an affinity for the inhibitory glycine receptors (i.e., have glycomimetic and GABA mimetic activity), therefore acts as a muscle relaxant. Glycine is an inhibitory neurotransmitter and acts as an allosteric regulator of NMDA (N-methyl-D-aspartate) receptors. It is involved in the processing of motor and sensory data, thereby regulating movement, vision, and audition. Inhibitory neurotransmitter in spinal cord, allosteric regulator of NMDA receptors. In one study, thiocolchicoside inhibited the function of recombinant human strychnine-sensitive glycine receptors composed of the alpha1 subunit with a potency (median inhibitory concentration of 47 microM) lower than that apparent with recombinant GABA(A) receptors. The drug also inhibited the function of human nicotinic acetylcholine receptors made of the alpha4 and beta2 subunits, however, this effect was partial and moreover only apparent at high concentrations. Thiocolchicoside demonstrated no effect on the function of 5-HT(3A) serotonin receptors.

Pharmacodynamics

Thiocholchicoside is a muscle relaxing agent that works through selective binding to the GABA-A receptor. It prevents muscle contractions by activating the GABA inhibitory motor pathway. This medication acts as a competitive GABA receptor antagonist and inhibits glycine receptors with similar potency as nicotinic acetylcholine receptors. It has powerful convulsant activity and should not be used in individuals at risk for seizures. Used in combination with glafenine and meprobamate to tranquilize patients undergoing hysterosalpingography. In the treatment of painful muscle spasms. Thiocolchicoside acts both in contractures with a central cause and in contractures of reflex type, rheumatic and traumatic. It also alleviates symptoms of spastic sequelae of hemiparesis, Parkinson's disease and iatrogenic Parkinson symptoms, particularly neurodyslectic syndrome. Some other conditions that may benefit from this medication are acute and chronic lumbar and sciatic pain, cervico-brachial neuralgia, persistent torticollis, post-traumatic and post-operative pain.