HALIDOM 50

Indications

• Multiple myeloma
• Erythema nodosum leprosum
• HIV-related wasting syndrome
• Certain immunotherapy responsive malignancies

Mechanism of action

Thalidomide's mechanism of action is not fully understood. However, it is known to bind to cerebron, a component of the E3 ubiquitin ligase complex, leading to the selective degradation of the transcription factors IKZF3 and IKZF1, which are crucial for the survival of malignant myeloma cells. Additionally, thalidomide inhibits the production of TNF-alpha by blocking MyD88, an adaptor protein involved in TNF-alpha signaling, and preventing the activation of Nuclear Factor Kappa B (NF-kB). This results in reduced inflammation and an anti-angiogenic effect.

Pharmacodynamics

Thalidomide is recognized for its immunomodulatory and anti-inflammatory effects. It lowers levels of pro-inflammatory cytokines, including TNF-alpha and IL-6. Furthermore, it inhibits growth factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), which are involved in angiogenesis, contributing to its potential anti-cancer properties. The drug contains both enantiomers, with the (+)R enantiomer being effective and the (-)S enantiomer being teratogenic, complicating its therapeutic use.

Pharmacokinetics

Thalidomide is well absorbed after oral administration and has a volume of distribution that indicates extensive tissue binding. It undergoes hepatic metabolism, primarily through cytochrome P450 enzymes, and is eliminated via renal pathways. The half-life of thalidomide can vary significantly, ranging from 5 to 7 hours, but may extend with chronic dosing. Liver function should be monitored during therapy due to the risk of hepatotoxicity.

Contra-indications

• Pregnancy
• Severe hypersensitivity to thalidomide or any excipients
• Known history of thalidomide-induced teratogenic effects
• Active hepatitis B infection

Adverse effects

• Thromboembolism
• Neutropenia
• Thrombocytopenia
• Anemia
• Dizziness
• Fatigue
• Nausea
• Constipation
• Diarrhea
• Dry mouth
• Depression
• Dermatitis
• Peripheral neuropathy
• Sepsis
• Myocardial infarction
• Stroke
• Pulmonary embolism
• Hepatitis
• Severe cutaneous adverse reactions (SCARs)

Interactions

• Combined hormonal contraceptives: Severe interaction increasing risk of venous thromboembolism
• Other medications that affect CYP450 enzymes may alter thalidomide metabolism
• Immunosuppressants may increase the risk of infections when combined with thalidomide

Precautions

• Monitor for signs of thromboembolism, particularly in patients with risk factors
• Monitor liver function for 6 months after initiation
• Ensure effective contraception in females of childbearing potential during treatment
• Regular screening for second primary malignancies
• Patients should be given a patient card regarding the Pregnancy Prevention Programme

Pregnancy

Not recommended during pregnancy due to risk of teratogenic effects; a pregnancy test should be conducted prior to treatment initiation.

Breast-feeding

Not recommended while breastfeeding due to potential risks to the infant.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Capsules

Mechanism of action

The mechanism of action of thalidomide is not fully understood. Previous research indicate that thalidomide binds to cerebron, a component of the E3 ubiquitin ligase complex, to selectively degrade the transcription factor IKZF3 and IKZF1. These 2 transcription factors are vital for the proliferation and survival of malignant myeloma cells. Regarding TNF-alpha, thalidomide seems to block this mediator via a variety of mechanism. Thalidomide can inhibit the expression myeloid differentiating factor 88 (MyD88), an adaptor protein that is involved in the TNF-alpha production signalling pathway, at the protein and RNA level. Additionally, thalidomide prevents the activation of Nuclear Factor Kappa B (NF-kB), another upstream effector of the TNF-alpha production pathway. Finally, some evidences suggest that thalidomide can block alpha-1 acid glycoprotein (AGP), a known inducer of the NF-kB/MyD88 pathway, thus inhibiting the expression of TNF-alpha. The down-regulation of NF-kB and MyD88 can also affect the cross talk between the NF-kB/MyD88 and VEGF pathway, resulting in thalidomide's anti-angiogenic effect. The sedative drug thalidomide ([+]-alpha-phthalimidoglutarimide), once abandoned for causing birth defects in humans, has found new therapeutic license in leprosy and other diseases, with renewed teratological consequences. Although the mechanism of teratogenesis and determinants of risk remain unclear, related teratogenic xenobiotics are bioactivated by embryonic prostaglandin H synthase (PHS) to a free-radical intermediates that produce reactive oxygen species (ROS), which cause oxidative damage to DNA and other cellular macromolecules. Similarly, thalidomide is bioactivated by horseradish peroxidase, and oxidizes DNA and glutathione, indicating free radical-mediated oxidative stress. Furthermore, thalidomide teratogenicity in rabbits is reduced by the PHS inhibitor acetylsalicylic acid, indicating PHS-catalyzed bioactivation. Here, we show in rabbits that thalidomide initiates embryonic DNA oxidation and teratogenicity, both of which are abolished by pre-treatment with the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (PBN). In contrast, in mice, a species resistant to thalidomide teratogenicity, thalidomide does not enhance DNA oxidation, even at a dose 300% higher than that used in rabbits, providing insight into an embryonic determinant of species-dependent susceptibility. In addition to their therapeutic implications, these results constitute direct evidence that the teratogenicity of thalidomide may involve free radical-mediated oxidative damage to embryonic cellular macromolecules. The glutamic acid derivative thalidomide is a transcriptional inhibitor of TNF-alpha but is also known to affect human blood vessels, which may underlie its teratogenicity. Thalidomide has been used in the treatment of refractory Crohn's disease (CD), but the therapeutic mechanism is not defined. We examined the effect of thalidomide on primary cultures of human intestinal microvascular endothelial cells (HIMEC), the relevant endothelial cell population in inflammatory bowel disease (IBD), to determine its effect on endothelial activation, leukocyte interaction, and VEGF-induced angiogenesis. HIMEC cultures were pretreated with thalidomide before activation with either TNF-alpha/LPS or VEGF. A low-shear-stress flow adhesion assay with either U-937 or whole blood was used to assess HIMEC activation following TNF-alpha/LPS, and a Wright's stain identified adherent leukocytes. Expression of cell adhesion molecules (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1) was assessed using radioimmunoassay. Effects of thalidomide on NF-kappaB activation, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) expression in TNF-alpha/LPS-activated HIMEC were determined by RT-PCR and Western blotting. Thalidomide blocked adhesion of both U-937 and whole blood leukocytes by 50% in HIMEC, inhib

Pharmacodynamics

Thalidomide, originally developed as a sedative, is an immunomodulatory and anti-inflammatory agent with a spectrum of activity that is not fully characterized. However, thalidomide is believed to exert its effect through inhibiting and modulating the level of various inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-a) and IL-6. Additionally, thalidomide is also shown to inhibit basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), suggesting a potential anti-angiogenic application of thalidomide in cancer patients. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: the (+)R enantiomer is effective against morning sickness, and the (−)S enantiomer is teratogenic. The enantiomers are interconverted to each other in vivo; hence, administering only one enantiomer will not prevent the teratogenic effect in humans.