THALIDOMIDE
TRAGEDY
Thalidomide is a drug that was developed in the
1950s by the West German pharmaceutical company Chemie Grünenthal GmbH. It was
originally intended as a sedative or tranquiliser, but was soon used for
treating a wide range of other conditions, including colds, flu, nausea and
morning sickness in pregnant women. It is now known that these teratogenic
effects are due to potent anti-angiogenic and immunomodulatory actions.
Thalidomide(Thal) is a derivative of glutamic acid
and is pharmacologically classified as an immunomodulatory agent .
Structurally, thalidomide contains 2 amide rings and a single chiral center,
and its full chemical name is alpha-N{phthalimido}glutarimide [C13H10N2O4] The currently available formulation is a
non-polar racemic mixture present as the optically active S and R isomers at
physiologic pH, which can effectively cross cell membranes.The S isomer has
been linked to thalidomide’s teratogenic effects, whereas the R isomer appears
to be primarily responsible for its sedative properties. The isomers rapidly
interconvert at physiologic pH in vivo, and thus efforts at
formulating only the R isomer have failed to Obviate The Teratogenic Potential
Of Thalidomide.
History
Thalidomide was discovered in 1953 by Wilhelm
Kunnz. Thalidomide was first synthesized in Germany in 1954 from the glutamic
acid derivative α-phthaloylisoglutamine and soon thereafter animal studies
showed it to be extremely nontoxic. It first entered the German market in 1957
as an over-the-counter remedy, based on the maker’s safety claims. In a leaflet
sent to thousands of doctors, it claimed that thalidomide was safe for use by
pregnant women. By 1960, thalidomide was marketed in 46 countries, with sales
nearly matching those of aspirin.
The error in this presumption of good efficacy with
limited toxicity became apparent when reports of deformed babies started appearing
from late 1956. By the time it was withdrawn in 1961, ~5000 to 12000 deformed
babies (and an unknown number of aborted fetuses) from 46 countries were
already born.
However, In 1961, McBride began to associate this
so-called harmless compound with severe birth defects in the babies he
delivered. The drug interfered with the babies' normal development, causing
many of them to be born with phocomelia, resulting in shortened, absent, or
flipper-like limbs. March of 1962, the drug was banned in most countries where
it was previously sold.
Despite its harmful side effects, thalidomide is
FDA-approved for two uses today. The drug is used to treat patients with
illnesses such as cancer and Hansen's disease (also known as
leprosy) .Thalidomide has also been associated with a higher occurrence blood
clots and nerve and blood disorders.
Mechanism of action
Thalidomide possesses immunomodulatory,
anti-inflammatory, and anti-angiogenic properties related to complex modulation
of inflammatory cytokines . One of the primary effects of thalidomide is
selective inhibition of TNF-α production in human monocytes, presumably via
enhanced degradation of TNF-α mRNA. In addition, thalidomide has been shown to
inhibit nuclear factor (NF)-KB activity through a process involving inhibition
of I-κB kinase activity .
Proposed mechanisms of action of thalidomide upon
tumorous plasma cell and surrounding microenvironment. In addition to direct
inhibitory effects on the malignant plasma cell, thalidomide enhances the
immune system effector cells, suppresses angiogenesis, inhibits various
cytokine mediators and interferes with the bone marrow stromal cell-malignant
plasma cell interaction .
Cancer treatment
In 1994 Harvard Professor Robert D'Amato at Boston
Children's Hospital discovered that thalidomide was a potent inhibitor of new
blood vessel growth (angiogenesis), which is required for tumor growth. He then
showed in a rabbit cancer model that thalidomide suppressed tumor growth in
animals. many studies have shown that thalidomide, in combination with
dexamethasone, has increased the survival of multiple myeloma patients. The activity of
thalidomide in solid tumors is less prominent. Limited activity was
demonstrated in patients with glioma, while thalidomide appears to be inactive
in patients with head and neck cancer, breast or ovarian cancer. In a small trial,
researchers found thalidomide caused a doubling of the number of T cells in
patients, allowing the patients' own immune system to attack cancer cells.
Thalidomide Analogues
The use of angiogenesis inhibitors for the treatment
of cancer was first conceptualized over 30 years ago, Thalidomide (α -N-phthalimido-glutarimide)
has emerged as a potent treatment for several disease entities. The exploration
of the antiangiogenic and immunomodulatory activities of thalidomide has led to
the study and creation of thalidomide analogues. These thalidomide analogs can
be used to treat different diseases
Author: Ms.Madu Abesundara
Sabaragamuwa University of Sri Lanka.
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