MYELOPAST 10

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

• Newly diagnosed multiple myeloma in patients who have undergone autologous stem cell transplantation
• Newly diagnosed multiple myeloma in patients not eligible for transplant (in combination with melphalan and prednisone)

Mechanism of action

Lenalidomide alters cytokine production and regulates T cell co-stimulation, enhancing NK cell-mediated cytotoxicity. It directly inhibits the cullin ring E3 ubiquitin ligase complex by binding to cereblon, leading to the degradation of substrate proteins such as Ikaros (IKZF1) and Aiolos (IKZF3), which are essential for the differentiation and survival of malignant B cells. This degradation results in increased production of interleukin-2 (IL-2) and enhanced proliferation of NK and T cells, while also inhibiting pro-inflammatory cytokines like TNF-α, IL-1, IL-6, and IL-12.

Pharmacodynamics

Lenalidomide demonstrates antitumor effectiveness through its immunomodulatory, anti-inflammatory, and anti-angiogenic properties. It induces apoptosis and inhibits the proliferation of hematopoietic malignant cells, thereby delaying tumor growth. Lenalidomide enhances immune responses by stimulating T cell proliferation and NK cell activity, making it significantly more potent than thalidomide in these actions. It also limits tumor cell invasion and metastasis, contributing to its therapeutic efficacy in hematological cancers.

Pharmacokinetics

Lenalidomide is absorbed quickly after oral administration, with peak plasma concentrations occurring within 1-6 hours. It has a bioavailability of approximately 50%. The drug is primarily metabolized in the liver, with renal excretion of both unchanged drug and metabolites. The elimination half-life is approximately 3-4 hours in patients with normal renal function, and dosage adjustments are necessary in cases of renal impairment.

Contra-indications

• Active tuberculosis
• Pregnancy
• Breastfeeding

Adverse effects

• Leukopenia
• Thrombocytopenia
• Nephrotoxicity
• Stomatitis
• Mucositis
• Ulcer
• Eye disorders
• Erythema nodosum
• Confusion
• Anemia
• Fatigue
• Nausea
• Vomiting
• Diarrhea
• Hypertension
• Increased risk of infection

Interactions

• Combined hormonal contraceptives: increased risk of venous thromboembolism

Precautions

• Screen for active tuberculosis before treatment
• Monitor blood counts regularly
• Use with caution in patients with renal impairment
• Risk of embryo-fetal toxicity

Pregnancy

Avoid use during pregnancy due to potential risk to the fetus.

Breast-feeding

Avoid use while breastfeeding due to potential risks.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Capsules
• Powder for suspension for infusion

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))

Indications

• Insect pest control
• Synergist in pesticide formulations

Mechanism of action

Piperonyl butoxide inhibits hepatic microsomal oxidase enzymes, as well as a related group of enzymes in insects, by acting as a competitive substrate. This inhibition reduces the detoxification of various drugs and chemicals, potentially increasing susceptibility to toxic substances.

Pharmacodynamics

The pharmacodynamic profile of sulphoxide reflects its role as a synergist in enhancing the potency of insecticides. By inhibiting the metabolic pathways that would typically detoxify these substances, sulphoxide facilitates increased insect mortality rates and efficacy in pest control. However, this also poses a risk of increased toxicity to non-target organisms, including humans.

Pharmacokinetics

The pharmacokinetics of sulphoxide involve absorption, distribution, metabolism, and excretion pathways that may vary between species. Generally, the compound is absorbed after oral intake and distributed throughout the body. It undergoes hepatic metabolism, primarily through cytochrome P450 enzymes, followed by excretion through urine. Specific rates of these processes can depend on various factors including dosage, formulation, and individual metabolic differences.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether this drug is excreted in human milk. Caution should be exercised when administering to a nursing mother.

Storage

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

Lenalidomide is a drug with multiple mechanisms of action. Lenalidomide exerts immunomodulating effects by altering cytokine production, regulating T cell co-stimulation, and enhancing the NK cell-mediated cytotoxicity. Lenalidomide directly inhibits the cullin ring E3 ubiquitin ligase complex: upon binding to cereblon, a substrate adaptor of the complex, lenalidomide modulates substrate specificity of the complex to recruit substrate proteins of the ligase, including Ikaros (IKZF1), Aiolos (IKZF3), and CK1α. These substrates are then tagged for ubiquitination and subsequent proteasomal degradation. IKZF1 and IKZF3 are B-cell transcription factors that are essential for B-cell differentiation and survival of malignant cells. IKZF3 also regulates the expression of interferon regulatory factor 4 (IRF4), which is a transcription factor that regulates the aberrant myeloma-specific gene. The immunomodulatory actions of lenalidomide can be partly explained by the degradation of IKZF3, since it is a repressor of the interleukin 2 gene (IL2): as lenalidomide decreases the level of IKZF3, the production of IL-2 increases, thereby increasing the proliferation of natural killer (NK), NKT cells, and CD4+ T cells. Lenalidomide inhibits the production of pro-inflammatory cytokines TNF-α, IL-1, IL-6, and IL-12, while elevating the production of anti-inflammatory cytokine IL-10. Lenalidomide acts as a T-cell co-stimulatory molecule that promotes CD3 T-cell proliferation and increases the production of IL-2 and IFN-γ in T lymphocytes, which enhances NK cell cytotoxicity and ADCC. It inhibits the expression and function of T-regulatory cells, which are often overabundant in some hematological malignancies. Lenalidomide directly exerts antitumour effects by inhibiting the proliferation and inducing apoptosis of tumour cells. Lenalidomide triggers the activation of pro-apoptotic caspase-8, enhances tumour cell sensitivity to FAS-induced apoptosis, and downregulates NF-κB, an anti-apoptotic protein. Independent of its immunomodulatory effects, lenalidomide mediates anti-angiogenic effects by inhibiting angiogenic growth factors released by tumour cells, such as vascular endothelial growth factor (VEGF), basic fibroblastic-growth factor (BFGF), and hepatocyte-growth factor. _In vitro_, lenalidomide inhibits cell adhesion molecules such as ICAM-1, LFA-1, β2 and β3 integrins, as well as gap-junction function, thereby preventing metastasis of malignant cells. Multiple myeloma is a B-cell malignancy characterized by an excess of monotypic plasma cells in the bone marrow. The molecular mechanisms that are involved in disease progression depend on the interaction between the multiple myeloma cells and the bone microenvironment. Because these mechanisms have been well characterized, it is possible to develop regimens that are more specific to pathways involved in the pathogenesis of multiple myeloma than is typical for conventional chemotherapy in disease management. Thalidomide and immunomodulatory drugs (IMiDs) have now been shown to block several pathways important for disease progression in multiple myeloma. First established as agents with antiangiogenic properties, thalidomide and IMiDs inhibit the production of interleukin (IL)-6, which is a growth factor for the proliferation of myeloma cells. In addition, they activate apoptotic pathways through caspase 8-mediated cell death. At the mitochondrial level, they are responsible for c-jun terminal kinase (JNK)-dependent release of cytochrome-c and Smac into the cytosol of cells, where they regulate the activity of molecules that affect apoptosis. By activating T cells to produce IL-2, thalidomide and IMiDs alter natural killer (NK) cell numbers and function, thus augmenting the activity of NK-dependent cytotoxicity. Data delineating these events have been derived from experiments done in resistant and sensitive multiple myeloma cell lines. Although thalidomide and IMiDs demonstrate similar biologic

Pharmacodynamics

In hematological malignancies, the immune system is deregulated in the form of altered cytokine networks in the tumour microenvironment, defective T cell regulation of host-tumour immune interactions, and diminished NK cell activity. Lenalidomide is an immunomodulatory agent with antineoplastic, antiangiogenic, and anti-inflammatory properties. Lenalidomide exerts direct cytotoxicity by increasing apoptosis and inhibiting the proliferation of hematopoietic malignant cells. It delays tumour growth in nonclinical hematopoietic tumour models _in vivo_, including multiple myeloma. Lenalidomide also works to limit the invasion or metastasis of tumour cells and inhibits angiogenesis. Lenalidomide also mediates indirect antitumour effects via its immunomodulatory actions: it inhibits the production of pro-inflammatory cytokines, which are implicated in various hematologic malignancies. Lenalidomide enhances the host immunity by stimulating T cell proliferation and enhancing the activity of natural killer (NK) cells. Lenalidomide is about 100–1000 times more potent in stimulating T cell proliferation than [thalidomide]. _In vitro_, it enhances antibody-dependent cell-mediated cytotoxicity (ADCC), which is even more pronounced when used in combination with rituximab. Due to its anti-inflammatory properties, lenalidomide has been investigated in the context of inflammatory and autoimmune diseases, such as amyotrophic lateral sclerosis.

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.