Cladribine (2CdA) • 3F8 And 3TC Medical Uses



Cladribine is a medication used to treat hairy cell leukemia (HCL, leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia. Its chemical name is 2-chloro-2'-deoxyadenosine (2CdA).

As a purine analog, it is a synthetic chemotherapy agent that targets lymphocytes and selectively suppresses the immune system. Chemically, it mimics the nucleoside adenosine and thus INHibits the enzyme adenosine deaminase, which interferes with the cell's ability to process DNA. cladribine is activated only by lymphocytes, and non-activated cladribine is removed quickly from all other cells. This means that there is very little non-target cell loss.



Medical uses 

cladribine is used for as a first and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukemia and is administered by intravenous infusion.

It used, often in combination with other cytotoxic agents, to treat various kinds of histiocytosis, including Erdheim–Chester disease and Langerhans cell histiocytosis,

Clabridine can cause fetal harm when administered to a pregnant woman and is listed by the FDA as Pregnancy Category D; safety and efficacy in children has not been established.



Adverse effects

Injectable cladribine suppresses the body's ability to make new blood cells (called Myelosuppression); data from HCL studies showed that about 70% of people taking the drug had fewer white blood cells and about 30% developed infections and some of those progressed to septic shock; about 40% of people taking the drug had fewer red blood cells and became severely anemic; and about 10% of people had too few platelets.

At the dosage used to treat HCL in two clinical trials, 16% of people had rashes and 22% had nausea, the nausea generally did not lead to vomiting.


3F8

3F8 is a murine IgG3 monoclonal antibody which binds to GD2.

It has been used in the detection and treatment of neuroblastoma. For imaging neuroblastoma, it is labelled with one of the radioisotopes iodine-124 and iodine-131.


3TC

lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically used in combination with other antiretrovirals such as zidovudine and abacavir. lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. lamivudine is taken by mouth as a liquid or tablet.


Common side effects include nausea, diarrhea, headaches, feeling tired, and cough. Serious side effects include liver disease, lactic acidosis, and worsening hepatitis B among those already infected. It is safe for people over three months of age and can be used during pregnancy. The medication can be taken with or without food. lamivudine is a nucleoside reverse transcriptase INHibitor and works by blocking the HIV reverse transcriptase and hepatitis B virus polymerase.


lamivudine was first approved for use in the United States in 1995. It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system. It is available as a generic medication. The wholesale cost in the developing world as of 2014 is about 0.06 USD per day. As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.

Medical uses

lamivudine has been used for the treatment of chronic hepatitis B at a lower dose than for treatment of HIV/AIDS. It improves the seroconversion of e-antigen positive hepatitis B and also improves histology staging of the liver. Long-term use of lamivudine leads to the emergence of a resistant hepatitis B virus (YMDD) mutant. Despite this, lamivudine is still used widely as it is well tolerated.


Resistance

In HIV, high-level resistance is associated with the M184V/I mutation in the reverse transcriptase gene as reported by Raymond Schinazi's group at Emory University. GlaxoSmithKline claimed that the M184V mutation reduces "viral fitness", because of the finding that continued lamivudine treatment causes the HIV viral load to rebound but at a much lower level, and that withdrawal of lamivudine results in a higher viral load rebound with rapid loss of the M184V mutation; GSK, therefore, argued that there may be a benefit in continuing lamivudine treatment even in the presence of high-level resistance because the resistant virus is "less fit". The COLLATE study has suggested that there is no benefit to continuing lamivudine treatment in patients with lamivudine resistance. A better explanation of the data is that lamivudine continues to have a partial anti-viral effect even in the presence of the M184V mutation.

In hepatitis B, lamivudine resistance was first described in the YMDD (tyrosine-Methionine-aspartate-aspartate) locus of the HBV reverse transcriptase gene. The HBV reverse transcriptase gene is 344 amino acids long and occupies codons 349 to 692 on the viral genome. The most commonly encountered resistance mutations are M204V/I/S. The change in amino acid sequence from YMDD to YIDD results in a 3.2 fold reduction in the error rate of the reverse transcriptase, which correlates with a significant growth disadvantage of the virus. Other resistance mutations are L80V/I, V173L, and L180M.



Side effects

  1. Minor side effects may include nausea, fatigue, headaches, diarrhea, cough, and nasal Congestion.
  2. Do not prescribe lamivudine/zidovudine, abacavir/lamivudine, or abacavir/lamivudine/zidovudine to patients taking emtricitabine.
  3. Long-term use of lamivudine can trigger a resistant hepatitis B virus (YMDD) mutant.
  4. HIV or HBV-infected women on lamivudine are warned to discontinue breastfeeding as this puts the baby at risk for HIV transmission and medication side effects.
  5. Patients who are infected with HIV and HCV and are on both interferon and lamivudine can experience liver damage.
  6. The drug can trigger an inflammatory response to opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii).
  7. Autoimmune disorders have been reported and symptoms can occur many months after initiation of the antiretroviral therapy.
  8. Use with caution for patients with impaired renal function and do not prescribe this treatment to patients with impaired hepatic function.


Mechanism of action

lamivudine is an analog of cytidine. It can INHibit both types (1 and 2) of HIV reverse transcriptase and also the reverse transcriptase of hepatitis B virus. It is phosphorylated to active metabolites that compete for incorporation into viral DNA. They INHibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analog prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.

lamivudine is administered by mouth, and it is rapidly absorbed with a bio-availability of over 80%. Some research suggests that lamivudine can cross the blood-brain barrier. lamivudine is often given in combination with zidovudine, with which it is highly synergistic. lamivudine treatment has been shown to restore zidovudine sensitivity of previously resistant HIV. lamivudine showed no evidence of carcinogenicity or mutagenicity in vivo studies in mice and rats at doses from 10 to 58 times those used in humans.

It has a half-life of 5-7 hours in adults and 2 hours in HIV-infected children.



Formulations

  • Epivir tablets (GlaxoSmithKline; US and UK) for the treatment of HIV
  • Epivir-HBV tablets (GlaxoSmithKline; US only) for the treatment of hepatitis B
  • Zeffix tablets (GlaxoSmithKline; UK only) for the treatment of hepatitis B
  • 3TC tablets (GlaxoSmithKline; South Africa) for the treatment of HIV
  • lamivudine is available in fixed-dose combinations with other HIV drugs such as:
    • lamivudine/zidovudine (with zidovudine)
    • abacavir/lamivudine (with abacavir)
    • abacavir/lamivudine/zidovudine (with zidovudine and abacavir)


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