LETZGO GEL

Indications

• Pain and inflammation in musculoskeletal disorders
• Acute gout
• Osteoarthritis
• Rheumatoid arthritis
• Ankylosing spondylitis

Dosage

Children: For children aged 16-17 years, the recommended dose is 120 mg once daily for a maximum of 8 days.

Adults: 120 mg once daily for a maximum of 8 days.

Mechanism of action

Etoricoxib selectively inhibits isoform 2 of the cyclo-oxygenase enzyme (COX-2), preventing the conversion of arachidonic acid to prostaglandins (PGs), which are mediators of inflammation and pain. This selective inhibition results in reduced inflammatory responses without significantly affecting the COX-1 pathway, which is important for maintaining gastrointestinal mucosal integrity.

Pharmacodynamics

Etoricoxib exhibits a high selectivity for COX-2, being about 106 times more selective for COX-2 than for COX-1. This selective action minimizes the gastrointestinal side effects commonly associated with non-selective NSAIDs, as COX-1 plays a protective role in the gastric mucosa. Etoricoxib provides analgesic and anti-inflammatory effects by lowering prostaglandin levels involved in the inflammatory process.

Pharmacokinetics

Etoricoxib is well-absorbed following oral administration, with peak plasma concentrations typically occurring about 1 to 2 hours after ingestion. The drug has a half-life of approximately 22 hours, allowing for once-daily dosing. It is extensively metabolized in the liver, primarily via CYP2C9 and CYP3A4 pathways, and is excreted mainly through urine as metabolites. The presence of food does not significantly affect its absorption.

Contra-indications

• Active gastrointestinal bleeding
• Active gastrointestinal ulceration
• Severe cutaneous adverse reactions (SCARs)
• Cerebrovascular disease
• Uncontrolled hypertension (persistently above 140/90 mmHg)
• Severe renal failure
• Hypersensitivity to aspirin or other NSAIDs
• Ischaemic heart disease
• Active inflammatory bowel disease

Adverse effects

• Hypertension
• Fluid retention
• Gastrointestinal discomfort
• Nausea
• Vomiting
• Headache
• Dizziness
• Chest pain
• Heart failure
• Palpitations
• Skin reactions
• Malaise
• Nephrotoxicity
• Insomnia
• Anemia
• Visual impairment
• Aseptic meningitis
• Tinnitus

Interactions

• Increased exposure when used with combined hormonal contraceptives
• Increased exposure when used with hormone replacement therapy
• May interact with other NSAIDs

Precautions

• Caution in patients with cardiac impairment
• Caution in patients with renal impairment
• Dehydration risk
• Caution in patients with allergic disorders
• May mask symptoms of infection

Pregnancy

Avoid unless the potential benefit outweighs the risk, especially during the third trimester due to risk of closure of the fetal ductus arteriosus.

Breast-feeding

Use with caution during breastfeeding; the manufacturer advises avoiding use if possible.

Storage

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

Formulations

• Modified-release tablet
• Dispersible tablet
• Oral suspension
• Oral solution

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

Mechanism of action

Like any other COX-2 selective inhibitor Etoricoxib selectively inhibits isoform 2 of cyclo-oxigenase enzyme (COX-2), preventing production of prostaglandins (PGs) from arachidonic acid.

Pharmacodynamics

Etoricoxib is a COX-2 selective inhibitor (approximately 106 times more selective for COX-2 inhibition over COX-1).

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/