Dicloday Gel

Indications

• Pain and inflammation in musculoskeletal disorders
• Rheumatic disease
• Osteoarthritis of the knee
• Postoperative pain
• Control of anterior segment inflammation following ophthalmic surgery

Dosage

Children: For paediatric dosing, please refer to the BNF for Children as specific dosages are not provided in this text.

Adults: For topical application, apply 3–4 times a day to the affected area. For injection, 75 mg may be administered intravenously, then 75 mg after 4–6 hours if required, up to a maximum of 150 mg per day for no more than 2 days.

Mechanism of action

Diclofenac sodium primarily acts as a selective inhibitor of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). By blocking these enzymes, diclofenac decreases the production of prostaglandins, which are mediators of inflammation and pain. This mechanism leads to reduced inflammatory responses and alleviation of pain.

Pharmacodynamics

The pharmacological effects of diclofenac include anti-inflammatory, analgesic, and antipyretic properties. The onset of action is typically within a few hours following administration, with peak effects seen within 1 to 2 hours. The duration of analgesia can vary depending on the formulation and dosage used.

Pharmacokinetics

Diclofenac is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1 to 2 hours. It is extensively metabolized in the liver to active metabolites and has a half-life of approximately 1 to 2 hours. The drug is primarily excreted in the urine, with both unchanged drug and metabolites being eliminated. Food can affect the absorption, so it is often recommended to take it on an empty stomach.

Contra-indications

• History of hypersensitivity to diclofenac or other NSAIDs
• Active gastrointestinal ulceration
• History of recurrent gastrointestinal bleeding
• History of cerebrovascular bleeding
• Severe renal impairment
• Severe hepatic impairment
• Dehydration
• Hypovolaemia
• History of asthma precipitated by NSAIDs
• History of gastro-intestinal perforation related to previous NSAID therapy
• History of confirmed or suspected hemorrhagic diathesis

Adverse effects

• Gastrointestinal discomfort
• Nausea
• Vomiting
• Diarrhea
• Constipation
• Headache
• Dizziness
• Rash
• Tinnitus
• Elevated liver enzymes
• Renal impairment
• Fluid retention
• Increased blood pressure

Interactions

• Increased risk of gastrointestinal bleeding when used with other NSAIDs or anticoagulants
• Caution with diuretics due to potential for renal impairment
• May enhance the effects of anticoagulants like warfarin
• Caution with antihypertensive medications due to potential for reduced efficacy

Precautions

• Use with caution in patients with a history of cardiovascular disease
• Monitor renal function in patients with pre-existing renal impairment
• Long-term use may affect female fertility, reversible upon discontinuation
• Use with caution during pregnancy, especially in the third trimester

Pregnancy

Avoid unless the potential benefit outweighs the risk. Avoid during the third trimester due to risks of fetal ductus arteriosus closure and pulmonary hypertension of the newborn.

Breast-feeding

Use with caution; amount in milk is generally too small to be harmful.

Storage

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

Formulations

• Diclofenac sodium 1% gel
• Diclofenac sodium 75 mg injection
• Diclofenac sodium eye drops 0.1% (Voltarol Ophtha)

Indications

• Pain and inflammation in musculoskeletal disorders
• Rheumatic diseases
• Acute gout
• Postoperative pain

Dosage

Children: For children aged 9–13 years (body weight 35 kg and above), up to 2 mg/kg daily in 3 divided doses; maximum 100 mg per day. For children aged 14–17 years, 75–100 mg daily in 2–3 divided doses.

Adults: 75–150 mg daily in 2–3 divided doses.

Mechanism of action

Diclofenac potassium works primarily by inhibiting the cyclooxygenase (COX) enzymes, specifically COX-1 and COX-2. This inhibition decreases the synthesis of prostaglandins, which are mediators involved in inflammation, pain, and fever. This action results in reduced inflammation and pain sensation in affected tissues.

Pharmacodynamics

The analgesic effects of diclofenac potassium are evident within a few hours after administration. It shows a dose-dependent response in reducing pain and inflammation, making it effective for managing acute pain and inflammatory conditions. The drug can also have a beneficial effect on reducing fever.

Pharmacokinetics

Diclofenac potassium is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring within 1-2 hours after oral administration. It has a half-life of approximately 1-2 hours, but its anti-inflammatory effects can last longer due to its active metabolites. The drug is extensively metabolized in the liver, and its metabolites are excreted primarily in the urine.

Contra-indications

• Active gastrointestinal bleeding
• Active gastrointestinal ulceration
• History of recurrent gastrointestinal haemorrhage
• Cerebrovascular disorders
• History of hypersensitivity to aspirin or any other NSAID
• Severe cardiac impairment
• Severe hepatic impairment
• Severe renal impairment
• History of allergic disorders

Adverse effects

• Diarrhoea
• Gastrointestinal disturbances
• Headache
• Insomnia
• Malaise
• Acute gout pain
• Palpitations
• Skin reactions
• Vertigo
• Angioedema
• Decreased appetite
• Dyspepsia
• Hypertension
• Nephritis
• Neutropenia
• Photosensitivity
• Severe cutaneous adverse reactions
• Syncope
• Tachycardia
• Thrombocytopenia
• Tinnitus
• Blurred vision

Interactions

• Increased risk of gastrointestinal bleeding with other NSAIDs
• Caution with anticoagulants due to potential increased bleeding risk
• Caution with antihypertensives as NSAIDs may reduce their efficacy
• Caution with diuretics due to potential renal impairment

Precautions

• Caution in patients with dehydration
• Caution in elderly patients due to increased risk of serious side effects
• Caution in patients with a history of cardiovascular disease
• Use with caution in patients with renal impairment
• Monitor for signs of gastrointestinal bleeding

Pregnancy

Avoid unless the potential benefit outweighs the risk. Avoid during the third trimester due to risk of fetal ductus arteriosus closure and possible persistent pulmonary hypertension in the newborn.

Breast-feeding

Use with caution during breastfeeding; no specific information available.

Storage

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

Formulations

• Oral tablets
• Oral suspension

Indications

• Rheumatoid arthritis
• Osteoarthritis
• Ankylosing spondylitis
• Acute pain
• Dysmenorrhea
• Postoperative pain
• Inflammatory conditions

Dosage

Children: For children, the dosage must be determined based on weight and the specific indication. It is essential to refer

Adults: The usual oral dose for adults is 50 mg taken two to three times daily, with a maximum daily dose of 150 mg. In specific cases, doses may vary based on the condition being treated and the patient's response.

Mechanism of action

Diclofenac inhibits cyclooxygenase-1 and -2 (COX-1 and COX-2), enzymes responsible for the conversion of arachidonic acid to prostaglandins. This inhibition reduces the levels of prostaglandins G2, leading to decreased inflammation, pain, and fever. Prostaglandin E2 (PGE2), a primary mediator of nociception, is suppressed, which lowers pain sensitivity and peripheral sensitization via G-protein coupled receptors.

Pharmacodynamics

Diclofenac reduces inflammation and nociceptive pain while also exhibiting antipyretic effects. Its action can increase the risk of gastrointestinal ulceration due to the inhibition of protective mucus secretion in the stomach, which is a common side effect of NSAIDs.

Pharmacokinetics

Diclofenac is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1 to 2 hours. It has a high volume of distribution and is extensively metabolized in the liver, primarily by cytochrome P450 enzymes. The elimination half-life is approximately 1 to 2 hours, with metabolites excreted in urine. Its pharmacokinetics can be influenced by factors such as age, liver function, and concurrent medications.

Contra-indications

• Untreated local infection

Adverse effects

• Gastrointestinal ulceration
• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Headache
• Dizziness
• Rash

Interactions

• Ciclosporin: Unknown (increases concentration)
• Iron chelators: Unknown (increases exposure)
• Deferiprone: Unknown (increases exposure)

Precautions

• Use with caution in patients with a history of gastrointestinal disease
• Monitor renal function in long-term use
• Consider cardiovascular risks in patients with pre-existing conditions

Pregnancy

Manufacturer advises to avoid unless essential.

Breast-feeding

Manufacturer advises to avoid unless essential.

Storage

Store below 25°C. Protect from light and moisture.

Formulations

• Diclofenac 50 mg oral tablet
• Diclofenac 100 mg extended-release oral tablet
• Diclofenac 75 mg injection
• Diclofenac 1% gel

Mechanism of action

Diethylamine acts primarily as a weak base, facilitating nucleophilic substitution reactions. Its basicity allows it to accept protons, which can enhance the reactivity of other compounds in chemical processes.

Pharmacodynamics

The pharmacodynamic properties of diethylamine are largely related to its role as a chemical reagent rather than a pharmaceutical agent. It does not exert therapeutic effects in the same way that many drugs do but is involved in various chemical pathways as a reactant.

Pharmacokinetics

Detailed pharmacokinetic data for diethylamine is limited due to its primary use in laboratory and industrial applications rather than as a therapeutic agent. However, it is expected to be readily absorbed through mucous membranes and the skin, with potential metabolic pathways involving N-dealkylation and oxidation.

Pregnancy

There is limited data on the use of diethylamine in pregnancy. Caution is advised.

Breast-feeding

There is insufficient data on the excretion of diethylamine in human milk. Caution is advised.

Storage

Store in a cool, dry place, away from light.

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

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines in cases of methanol poisoning in pediatric patients.

Adults: In cases of methanol poisoning, immediate medical attention is required. Treatment typically involves the administration of fomepizole or ethanol as antidotes, along with supportive care and correction of metabolic acidosis. Dosing should be guided by clinical protocols.

Mechanism of action

Methanol is metabolized in the liver by alcohol dehydrogenase to formaldehyde, which is further oxidized to formic acid. Formic acid is responsible for many of the toxic effects of methanol, including metabolic acidosis and visual impairment. The severity of toxicity can depend on individual susceptibility and the activity of metabolic pathways, particularly those involving folic acid metabolism, which is necessary for formate metabolism.

Pharmacodynamics

Methanol toxicity manifests through its metabolic products, primarily formic acid, which decreases blood pH, leading to metabolic acidosis. This acidosis can cause complications such as respiratory distress and cardiovascular instability. The accumulation of formic acid also impacts mitochondrial function and can lead to cellular hypoxia and damage, particularly in the optic nerve, resulting in visual impairment or blindness.

Pharmacokinetics

Methanol is rapidly absorbed through the gastrointestinal tract and can cross the blood-brain barrier. It is metabolized primarily in the liver, with a significant portion converted to formaldehyde and then to formic acid. The elimination half-life of methanol varies and can be prolonged in cases of intoxication due to saturation of metabolic pathways. The time to peak concentrations can vary significantly; toxicity can develop long after initial ingestion, complicating management.

Adverse effects

• Metabolic acidosis
• Visual impairment
• Headaches
• Nausea
• Vomiting
• Dizziness
• Coma
• Death

Precautions

• Use with caution in individuals with liver impairment
• Monitor for signs of toxicity, especially in cases of suspected overdose

Pregnancy

Methanol is classified as a teratogen and should be avoided during pregnancy due to the risk of fetal toxicity and developmental harm.

Breast-feeding

Methanol is not recommended while breastfeeding due to potential harmful effects in the nursing infant.

Storage

Store in a cool, dry place away from light and heat. Keep container tightly closed and out of reach of children.

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

Diclofenac inhibits cyclooxygenase-1 and -2, the enzymes responsible for production of prostaglandin (PG) G₂ which is the precursor to other PGs. These molecules have broad activity in pain and inflammation and the inhibition of their production is the common mechanism linking each effect of diclofenac. PGE₂ is the primary PG involved in modulation of nociception. It mediates peripheral sensitization through a variety of effects. PGE₂ activates the G_q-coupled EP₁ receptor leading to increased activity of the inositol trisphosphate/phospholipase C pathway. Activation of this pathway releases intracellular stores of calcium which directly reduces action potential threshold and activates protein kinase C (PKC) which contributes to several indirect mechanisms. PGE₂ also activates the EP₄ receptor, coupled to G_s, which activates the adenylyl cyclase/protein kinase A (AC/PKA) signaling pathway. PKA and PKC both contribute to the potentiation of transient receptor potential cation channel subfamily V member 1 (TRPV1) potentiation, which increases sensitivity to heat stimuli. They also activate tetrodotoxin-resistant sodium channels and inhibit inward potassium currents. PKA further contributes to the activation of the P2X3 purine receptor and sensitization of T-type calcium channels. The activation and sensitization of depolarizing ion channels and inhibition of inward potassium currents serve to reduce the intensity of stimulus necessary to generate action potentials in nociceptive sensory afferents. PGE₂ act via EP₃ to increase sensitivity to bradykinin and via EP₂ to further increase heat sensitivity. Central sensitization occurs in the dorsal horn of the spinal cord and is mediated by the EP₂ receptor which couples to G_s. Pre-synaptically, this receptor increases the release of pro-nociceptive neurotransmitters glutamate, CGRP, and substance P. Post-synaptically it increases the activity of AMPA and NMDA receptors and produces inhibition of inhibitory glycinergic neurons. Together these lead to a reduced threshold of activating, allowing low intensity stimuli to generate pain signals. PGI₂ is known to play a role via its G_s-coupled IP receptor although the magnitude of its contribution varies. It has been proposed to be of greater importance in painful inflammatory conditions such as arthritis. By limiting sensitization, both peripheral and central, via these pathways NSAIDs can effectively reduce inflammatory pain. PGI₂ and PGE₂ contribute to acute inflammation via their IP and EP₂ receptors. Similarly to β adrenergic receptors these are G_s-coupled and mediate vasodilation through the AC/PKA pathway. PGE₂ also contributes by increasing leukocyte adhesion to the endothelium and attracts the cells to the site of injury. PGD₂ plays a role in the activation of endothelial cell release of cytokines through its DP₁ receptor. PGI₂ and PGE₂ modulate T-helper cell activation and differentiation through IP, EP₂, and EP₄ receptors which is believed to be an important activity in the pathology of arthritic conditions. By limiting the production of these PGs at the site of injury, NSAIDs can reduce inflammation. PGE₂ can cross the blood-brain barrier and act on excitatory G_q EP₃ receptors on thermoregulatory neurons in the hypothalamus. This activation triggers an increase in heat-generation and a reduction in heat-loss to produce a fever. NSAIDs prevent the generation of PGE₂ thereby reducing the activity of these neurons. Diclofenac has pharmacologic actions similar to those of other prototypical NSAIAs. The drug exhibits anti-inflammatory, analgesic, and antipyretic activity. The exact mechanisms have not been c

Pharmacodynamics

Diclofenac reduces inflammation and by extension reduces nociceptive pain and combats fever. It also increases the risk of developing a gastrointestinal ulcer by inhibiting the production of protective mucus in the stomach.

Mechanism of action

... The metabolic mechanisms of methanol toxicity /are/ reviewed. ... It is noted that the most severe toxicity occurs many hours following peak blood and tissue methanol concentrations so that these do not necessarily provide an accurate indication of toxicity. Individual differences are seen both in this latent period and in individual susceptibility to methanol. This susceptibility may depend on the activity of folic acid requiring metabolic reactions involved in formate metabolism, formate being an intermediate produced during methanol oxidation and responsible for many toxic effects of methanol. Studies of the characteristics of methanol poisoning in non-primates and monkeys are examined. Despite the ingestion of lethal doses of methanol, non-primates generally do not develop significant metabolic acidosis nor impairment of vision, and no consistent histopathology has been demonstrated in these species. In monkeys, results suggest that the latent period represents a period of compensated metabolic acidosis; when compensatory mechanisms are exhausted, blood pH begins to drop. Formate accumulates and produces acidosis in the methanol poisoned monkey, but not in the rat, apparently due to a slower rate of formate metabolism to carbon dioxide in the monkey. ... Studies demonstrating the role of alcohol dehydrogenase in methanol metabolism in the monkey are reported; however, the catalase/peroxidative system which participates in methanol metabolism in rats apparently does not function in the monkey. Formaldehyde and formate metabolism are also examined. The regulation of the rate of formate metabolism is governed by regulation of the hepatic tetrahydrofolate concentrations. ... Further research is needed to determine what step or process it is which places the primate at a distinct liability in the metabolic disposition of one carbon moieties. Methanol toxicity is observed in monkeys and humans but is not seen in rats or mice. The expression of methanol poisoning is related to the ability of an animal to metabolize formate to carbon dioxide. Since the rate of formate oxidation is related to hepatic tetrahydrofolate content and the activites of folate dependent enzymes, studies were designed to determine hepatic concentrations of hepatic tetrahydrofolate and activites of folate dependent enzymes of human liver and livers of species considered insensitive to methanol poisoning. An excellent correlation between hepatic tetrahydrofolate and maximal rates of formate oxidation has been observed. In human liver, levels were only 50% of those observed for rat liver and similar to those found in monkey liver. Total folate was also lower (60% decreased) in human liver than that found in rat or monkey liver. Interestingly, mouse liver contains much higher hepatic tetrahydrofolate and total folate than rat or monkey liver. This is consistent with higher formate oxidation rates in this species. A second important observation has been made. 10-Formyltetrahydrofolate dehydrogenase activity, the enzyme catalyzing the final step of formate oxidation to carbon dioxide, was markedly reduced in both monkey and human liver. Thus, two mechanisms may be operative in explaining low formate oxidation in species susceptible to methanol toxicity, low hepatic tetahydrofolate levels and reduced hepatic 10-formyltetrahydrofolate dehydrogenase activity. Formic acid, the toxic metabolite of methanol, has been hypothesized to produce retinal and optic nerve toxicity by disrupting mitochondrial energy production. It has been shown in vitro to inhibit the activity of cytochrome oxidase, a vital component of the mitochondrial electron transport chain involved in ATP synthesis. Inhibition occurs subsequent to the binding of formic acid to the ferric heme iron of cytochrome oxidase, and the apparent inhibition constant is between 5 and 30 mM. Concentrations of formate present in the blood and tissues of methanol-intoxicated humans, non-human primates and rodent m