DICLAZOR

Indications

• Multiple sclerosis
• Psoriasis (under expert supervision)

Dosage

Children: There is limited evidence regarding the use of dimethyl fumarate in pediatric populations. For pediatric dosing

Adults: The dosing regimen for adults is typically initiated at a lower dose, gradually increased based on tolerance and clinical response. For specific dosing information, please refer to the BNF.

Mechanism of action

The mechanism of action of dimethyl fumarate involves its conversion to monomethyl fumarate (MMF). MMF up-regulates the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which is activated in response to oxidative stress, and suppresses pro-inflammatory gene expression through the inhibition of nuclear factor kappa B. Additionally, MMF acts as a nicotinic acid receptor agonist, influencing immune cell composition and function, leading to a reduction in central nervous system infiltration and a shift from a pro-inflammatory to an anti-inflammatory immune phenotype.

Pharmacodynamics

Dimethyl fumarate exhibits anti-inflammatory and cytoprotective effects, which are particularly relevant in the context of multiple sclerosis. Although its precise physiological effects are not fully understood, it has been associated with the modulation of immune responses, potentially lowering the risk of relapse in multiple sclerosis patients. However, treatment with dimethyl fumarate can lead to serious adverse effects, including progressive multifocal leukoencephalopathy (PML), opportunistic infections, and severe lymphopenia.

Pharmacokinetics

Dimethyl fumarate is rapidly absorbed after oral administration, with peak plasma concentrations reached within hours. The drug is extensively metabolized to its active form, monomethyl fumarate, which is primarily eliminated via renal excretion. The pharmacokinetics may be influenced by factors such as liver function and concurrent medications. Monitoring of lymphocyte counts is recommended during treatment due to the risk of lymphopenia.

Contra-indications

• Severe lymphopenia (lymphocyte count below 0.5 x 10^9/litre)
• Active infection
• Severe active gastro-intestinal disease

Adverse effects

• Progressive multifocal leukoencephalopathy (PML)
• Lymphopenia
• Serious opportunistic infections
• Liver injury
• Anaphylaxis
• Angioedema
• Decreased leukocyte count
• Constipation
• Diarrhea
• Feeling hot
• Gastrointestinal discomfort
• Fatigue
• Eosinophilia

Interactions

• Live vaccines (unknown interaction, increases risk of generalized infection, possibly life-threatening)

Precautions

• Monitor lymphocyte counts at least every 3 months during treatment
• Re-evaluate treatment in patients with sustained moderate reductions of absolute lymphocyte counts (between 0.5 and 0.8 x 10^9/litre) for longer than 6 months
• Patients should be vigilant for new or worsening neurological or psychiatric symptoms

Pregnancy

There are limited data on the use of dimethyl fumarate in pregnancy. Caution is advised.

Breast-feeding

It is not known whether dimethyl fumarate is excreted in human milk. Caution is advised.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Dimethyl fumarate 120 mg and 240 mg delayed-release capsules

Indications

• Coccidiosis in poultry
• Coccidiosis in livestock
• Prevention of coccidiosis in young animals

Dosage

Children: Refer to the BNF for Children for appropriate dosing based on age, weight, and specific conditions.

Adults: Refer to the BNF for specific dosing recommendations based on the type of animal and severity of the condition.

Mechanism of action

Diclazuril functions by inhibiting mitochondrial respiration in the apicomplexan parasites. It disrupts the electron transport chain, leading to decreased ATP production, which is essential for the parasite's survival and reproduction.

Pharmacodynamics

The pharmacodynamics of diclazuril involve its selective action on the coccidian parasites, leading to effective inhibition of their growth and reproduction. The drug primarily affects the intracellular stages of the parasites, with a significant impact on the sporulated oocysts and meronts. This selective toxicity limits its effects on host cells, making it a preferred agent in veterinary medicine.

Pharmacokinetics

Diclazuril is absorbed well when administered orally, with peak plasma concentrations occurring within a few hours post-administration. It is metabolized in the liver and has a relatively long half-life, allowing for once-daily dosing. The drug is primarily excreted in feces, with minimal renal excretion. Its pharmacokinetic profile supports effective treatment with sustained therapeutic levels.

Adverse effects

• Gastrointestinal disturbances
• Neurological effects
• Hypersensitivity reactions

Precautions

• Use with caution in animals with known hypersensitivity to the drug.
• Monitor for signs of toxicity, especially in the presence of hepatic impairment.

Pregnancy

There is limited information on the use of diclazuril in pregnant individuals. Consult relevant guidelines for specific recommendations.

Breast-feeding

Limited data available; consult relevant guidelines for specific recommendations regarding use during breastfeeding.

Storage

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

Formulations

• Oral formulation
• Injectable formulation

Indications

• Relapsing forms of multiple sclerosis
• Multiple sclerosis exacerbation

Dosage

Children: Refer to the BNF for Children for specific dosage recommendations for paediatric patients.

Adults: Refer to the BNF for specific dosage recommendations for adults.

Mechanism of action

Dimethyl fumarate is thought to activate the Nrf2 pathway, which leads to the induction of antioxidant proteins and a subsequent reduction in oxidative stress. This activation may also promote an anti-inflammatory response and modulate immune system activity, contributing to its beneficial effects in conditions such as multiple sclerosis.

Pharmacodynamics

Dimethyl fumarate exhibits immunomodulatory properties, influencing T-cell activation and promoting a shift from pro-inflammatory to anti-inflammatory immune responses. This modulation can help reduce the inflammatory processes associated with autoimmune diseases like multiple sclerosis. Additionally, the drug is associated with increased production of neuroprotective factors and a decrease in neuroinflammation.

Pharmacokinetics

Dimethyl fumarate is rapidly absorbed after oral administration, with peak plasma concentrations occurring within a few hours. It undergoes extensive first-pass metabolism, primarily converting to its active metabolite, monomethyl fumarate. The elimination half-life is approximately 30 minutes to 2 hours. Dimethyl fumarate and its metabolites are primarily excreted in the urine. Its pharmacokinetics may be influenced by food intake, with higher bioavailability observed when taken with meals.

Interactions

• live vaccines + dimethylfumarate: Unknown (increases risk of generalised infection (possibly life-threatening))

Dosage

Children: Refer to the BNF for Children for appropriate dosing information in paediatric cases, especially in instances of overdose.

Adults: Refer to the BNF for specific dosing information based on clinical circumstances, particularly in cases of overdose.

Mechanism of action

Ethylene glycol is metabolized by alcohol dehydrogenase to glycoaldehyde, which is subsequently converted to glycolic, glyoxylic, and oxalic acids. These metabolites contribute to anion gap metabolic acidosis and are responsible for tissue injury through the formation of insoluble calcium oxalate crystals.

Pharmacodynamics

The toxicity of ethylene glycol arises from its metabolites, particularly glycolic and oxalic acids. These compounds induce metabolic acidosis, lead to renal failure through calcium oxalate crystal deposition in the kidneys, and can cause neurological impairment. The anion gap increases due to the accumulation of these acids, leading to complications such as cardiovascular instability and potential multi-organ failure.

Pharmacokinetics

Ethylene glycol is rapidly absorbed after oral ingestion. It undergoes first-pass metabolism primarily in the liver, where it is converted into its toxic metabolites. The elimination half-life of ethylene glycol varies but is generally prolonged in cases of renal impairment. Renal excretion of metabolites contributes to the duration of toxicity, necessitating prompt medical intervention in cases of overdose.

Adverse effects

• Metabolic acidosis
• Renal failure
• CNS depression
• Hypocalcemia
• Cardiovascular collapse
• Pulmonary edema

Precautions

• Use with caution in patients with renal impairment
• Monitor for signs of metabolic acidosis
• Evaluate electrolyte levels, particularly calcium

Pregnancy

There is limited data on the safety of ethylene glycol in pregnancy. It should only be used if clearly needed.

Breast-feeding

It is unknown if ethylene glycol is excreted in human milk. Caution is advised.

Storage

Store in a tightly closed container at room temperature, away from heat and moisture.

Formulations

• Liquid

Indications

• Plant growth regulation
• Agricultural applications as a growth inhibitor

Dosage

Children: Not applicable.

Adults: Refer to the relevant agricultural guidelines for specific applications.

Mechanism of action

In an in vitro study, propylene acts as a plant growth inhibitor by inhibiting the oxidation of indole-3-acetic acid by peroxidase in the presence of superoxide anion radicals. This inhibition is linked to the activation of an iron complex (compound III) shuttle, which enhances the reaction rate between superoxide and peroxidase, ultimately affecting plant growth processes. Propylene is a less effective inhibitor compared to ethylene.

Pharmacodynamics

The pharmacodynamic effects of propylene are primarily observed in its role as a growth inhibitor in plants. By modulating the oxidation of phytohormones like indole-3-acetic acid, propylene can influence various growth responses in plants, potentially affecting processes such as cell elongation and division.

Pharmacokinetics

Information on the pharmacokinetics of propylene in humans is not well-documented, as its primary uses are industrial and agricultural. Its metabolism may be influenced by environmental factors, and its effects are primarily studied in the context of plant biology rather than human pharmacology.

Indications

• Insecticide synergist
• Enhancement of insecticidal efficacy

Dosage

Children: Refer to specific product guidelines for paediatric dosing, as it varies based on formulation and intended use.

Adults: Refer to specific product guidelines for adult dosing, as it varies based on formulation and intended use.

Mechanism of action

Sulfoxide functions by inhibiting hepatic microsomal oxidase enzymes, which are involved in the detoxification of drugs and chemicals in the body. It acts as a competitive substrate for these enzymes, thereby increasing vulnerability to various toxic substances due to impaired detoxification processes.

Pharmacodynamics

The pharmacodynamics of sulfoxide involve its ability to modify the metabolism of other drugs and chemicals through enzyme inhibition. This can lead to increased systemic exposure to co-administered substances, affecting their efficacy and safety profiles.

Pharmacokinetics

The pharmacokinetics of sulfoxide, including its absorption, distribution, metabolism, and excretion, are not well-documented in humans. However, similar compounds suggest that it may undergo hepatic metabolism and could be subject to variations in individual responses based on enzyme activity.

Pregnancy

Use in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Use with caution during breastfeeding, as it is not known whether sulfoxide is excreted in human milk.

Storage

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

Mechanism of action

The mechanism of action of dimethyl fumarate in multiple sclerosis is not well understood. It is thought to involve dimethyl fumarate degradation to its active metabolite, monomethyl fumarate (MMF). Both dimethyl fumarate and MMF up-regulate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway that is activated in response to oxidative stress. Dimethyl fumarate also suppresses pro-inflammatory genes through nuclear factor kappa B inhibition. Additionally, MMF acts as an agonist at the nicotinic acid receptor, but the relevance of this is unknown. It has been suggested that dimethyl fumarate exerts its immunomodulatory effects through changes in the composition and phenotype of immune cells. It reduces CNS infiltration and alters the composition of all lymphocyte subpopulations, especially for cytotoxic and effector T cells. This causes a shift from a mainly pro-inflammatory phenotype to an anti-inflammatory one. Dimethyl fumarate (DMF) is a fumaric acid ester that is used to treat psoriasis and multiple sclerosis. Recently, DMF was found to exhibit anti-tumor effects. However, the molecular mechanisms underlying these effects have not been elucidated. In this study, we investigated the mechanism of DMF-induced apoptosis in different human hematopoietic tumor cell lines. We found that DMF induced apoptosis in different human hematopoietic tumor cell lines but it did not affect the normal human B lymphocyte cell line RPMI 1788. We also observed a concurrent increase in caspase-3 activity and in the number of Annexin-V-positive cells. Furthermore, an examination of the survival signals, which are activated by apoptotic stimuli, revealed that DMF significantly inhibited nuclear factor-kB (NF-kB) p65 nuclear translocation. In addition, DMF suppressed B-cell lymphoma extra-large (Bcl-xL) and X-linked inhibitor of apoptosis (XIAP) expression whereas Bcl-2, survivin, Bcl-2-associated X protein (Bax), and Bim levels did not change. These results indicated that DMF induced apoptosis by suppressing NF-kB activation, and Bcl-xL and XIAP expression. These findings suggested that DMF might have potential as an anticancer agent that could be used in combination therapy with other anticancer drugs for the treatment of human hematopoietic tumors. Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's as well as Huntington's disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). ... In vitro, application of dimethylfumarate (DMF) leads to stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE. Multiple sclerosis (MS) is the most common multifocal inflammatory demyelinating disease of the central nervous system (CNS). Due to the progressive neurodegen

Pharmacodynamics

The physiological effects of dimethyl fumarate on the body are not well understood. It has anti-inflammatory and cytoprotective effects, likely involved in its actions in multiple sclerosis (MS) patients. Dimethyl fumarate does not cause clinically significant QT interval prolongation. However, cases of progressive multifocal leukoencephalopathy, serious opportunistic infections, lymphopenia and liver injury have been reported in MS patients treated with this drug. Dimethyl fumarate may also cause anaphylaxis and angioedema.

Mechanism of action

Ethylene glycol is metabolized by alcohol dehydrogenase to glycoaldehyde, which is then metabolized to glycolic, glyoxylic, and oxalic acids. These acids, along with excess lactic acid are responsible for the anion gap metabolic acidosis. Oxalic acid readily precipitates with calcium to form insoluble calcium oxalate crystals. Tissue injury is caused by widespread deposition of oxalate crystals and the toxic effects of glycolic and glyoxylic acids.

Mechanism of action

In an in vitro study of the mechanism of action of ethylene as a plant growth inhibitor, the effects of ethylene and some of its analogs, including propylene, on the oxidation of indole-3-acetic acid were examined. Ethylene and its analogs inhibited the oxidation of indole-3-acetic acid by peroxidase under conditions where the iron complex (compound III, an oxy-ferrous complex of peroxidase) shuttle was activated. Inhibition occurred only in the presence of the superoxide anion radical 02(-). Spectral and kinetic data indicated that ethylene and its analogs enhanced the rate of reaction of 02(-) with peroxidase; ie, the iron complex (compound III) shuttle, resulting in the formation of compound III. Propylene was a less effective inhibitor than ethylene.

Mechanism of action

Piperonyl butoxide, like other methylenedioxybenzene synergists (eg, sesamex, sulfoxide, n-propyl isome, piperonyl cyclonene, etc), inhibits hepatic microsomal oxidase enzymes in lab rodents & by inference in man; it also inhibits a related group of enzymes in insects apparently by serving as a competitive substrate. Because these enzymes act to detoxify many drugs & other exogenous chemicals, a heavy exposure to one of these insecticidal synergists might make a person temporarily vulnerable to a variety of toxic insults that would normally be tolerated with ease.