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Thalidomide & its Thalidomide & its analogues: analogues: Importance in Importance in Pharmacology Pharmacology
Dr. Harmanjit SinghDepartment of Pharmacology, GMC, Patiala
History History Developed by German pharmaceutical
company Grünenthal in Stolberg
Introduced as a Sedative drug in the late 1950s Was found to act as an effective tranquilizer
and painkiller and was proclaimed a "wonder drug" for insomnia, coughs, colds and headaches.
Found to be an effective antiemetic which had an inhibitory effect on morning sickness, and so thousands of pregnant women took the drug to relieve their symptoms
Thalidomide – the sleeping Thalidomide – the sleeping pillpill
Hailed as a "wonder drug" that provided a "safe, sound sleep".
However the drug was also found to cure morning sickness in pregnant women
Was available as OTC drug
Chemistry of thalidomideChemistry of thalidomide
Thalidomide, a-(N-phthalimido) glutarimide, Consists of ringed structure with an asymmetric
carbon in the glutarimide ring.
Exists as an equal mixture of S-(-) and R-(+) enantiomers.
These enantiomers rapidly get interconverted under physiological conditions
Thalidomide is sparingly soluble in water and ethanol, which to date had prevented its availability as an intravenous formulation
R(+) acts as sedative
S(-) potently inhibits the release of TNF-α.
It is the teratogenic form of Thalidomide
Pharmacokinetics Pharmacokinetics
Absorption and EliminationAbsorbed in GIT, not affected by food consumption
Metabolized through a nonenzymatic pathway, undergoing spontaneous hydrolysis in the blood and tissues
Found to be present in semen, not clear if it is in breast milk
Eliminated from the body in about 5-7 hours (not through feces) (only a very small amount is metabolized by cytochrome P-450)
ACTIONS OF THALIDOMIDE.
1.Inhibits leukocyte chemotaxis into site of inflammation
2. A potent sedative and increases the duration of REM sleep 3. Reduces phagocytosis by polymorphonuclear leukocytes
4. Enhances mononuclear cell production of cytokines like IL-2, , IL-10 and inhibits IL-6 & IL-12 production
5. Increases mean plasma levels of IL-2 receptors
6. Reduces TNF-a production by decreasing the half-life of related mRNA
7. Inhibits FGF-2 mediated angiogenesis, Possesses potent teratogenic actions
The Thalidomide Disaster The Thalidomide Disaster In the late 1950s and early 1960s, more than 10,000
children in 46 countries were born with deformities such as phocomelia as a consequence of thalidomide use
The Australian obstetrician William McBride and the German pediatrician Widukind Lenz suspected a link between birth defects and the drug
They were later awarded a number of honors for this contribution
In the United Kingdom the drug was licensed in 1958. Of the approximately 2,000 babies born with defects, 466 survived. The drug was withdrawn in 1961.
In US , Dr. Frances Kelsey, Ph.D., M.D., (born 24 July 1914) a Pharmacologist, most famous as the reviewer for the U.S. FDA, refused to authorize thalidomide for market from the Richardson-Merrell company because of lack of studies regarding its toxicity profile (peripheral neuropathy)
Reduced impact of thalidomide in US patients. Never approved for sale in the United States, but
millions of tablets had been distributed to physicians during a clinical testing program.
It was impossible to know how many pregnant women were given this drug to help alleviate morning sickness or as a sedative
DAMAGE
10,000-12,000 thalidomide babies46 affected countries 40% of victims died within a year of birth Today, there are approximately 5000 thalidomide survivors.
Symptom PatternSymptom Pattern
Phocomelia i.e. abnormal limbs
Amelia i.e. missing limbs
Other Teratogenic Effects
Abnormal number of digits
Missing/malformed eye(s) and ear(s)
Anal atresia
Brain damage/autism
spinal cord defects
Cleft lip or palate
Heart, Kidney ,GIT and Genital defects
MECHANISM OF MECHANISM OF TERATOGENICITYTERATOGENICITY
MECHANISM OF MECHANISM OF TERATOGENICITYTERATOGENICITYThalidomide intercalates into DNA (the thalidomide
molecule, which has a flat structure, can slide into gaps between the subunits of the DNA molecule.
Thalidomide does not intercalate at random into the DNA but intercalates at guanine sites.
Thalidomide, which is composed of three attached rings, two of which look in overall structure almost identical to guanine and adenine,
Attaches more strongly to guanine than adenine.
Mech. Of teratogenicity
Interfere with the production of certain proteins necessary for limb development such as the integrin subunit beta 3
Without this critical cell-surface adhesion protein, angiogenesis could be inhibited and truncation of the limb could result.
Interferes with angiogenesis by Inhibiting the growth of new vessels in a growing limb bud, would deprive the proliferating cells of critical nutrients, leading to a decrease in proliferation and a subsequent reduction in overall limb size.
Thalidomide TodayThalidomide Today“What was once the most feared drug in
pharmaceutical armory could become one of its most valuable.”
Gained FDA approval & Reintroduced in market in 1998 for ENL
Gained FDA approval for MDS associated with 5q syndrome in 2005 & for Multiple Myeloma in 2006
Now under consideration for various cancers and other conditions
Various off label uses
Thalidomide analogues Thalidomide analogues The exploration of the antiangiogenic and immunomodulatory
activities of thalidomide has led to the study and creation of thalidomide analogues.
Structural analogues of thalidomide have been developed in an attempt to enhance therapeutic efficacy while minimizing toxicity, particularly teratogenicity and peripheral neuropathy
Two groups of compounds have been identified by Celgene Corporation that exhibit distinctive spectra of biological activity, termed SelCIDs and immunomodulatory drugs (IMiDs), respectively , with enhanced TNF- inhibitory activity compared with thalidomide
CAUTION: All are assigned pregnancy category X….contraindicated because of structural resemblance to thalidomide
IMiDs – NOVEL THALIDOMIDE IMiDs – NOVEL THALIDOMIDE ANALOGUES AS ANTICANCER ANALOGUES AS ANTICANCER AGENTSAGENTSThe search for thalidomide analogues with increased
immunomodulatory activity and an improved safety profile led to the testing of amino-phthaloyl-substituted thalidomide analogues.
These 4-amino analogues, in which an amino group is added to the fourth carbon of the phthaloyl ring of thalidomide, brought about the class termed“IMiDs”.
Various N substituted and tetrafluorinated compounds have been investigated for therapeutic efficacy in several neoplasms.
Bioactivities follow the parent drug thalidomide closely, but with some increase in potency
In 2005, Celgene received FDA approval for lenalidomide
(Revlimid) for MDS as the first commercially useful derivative.
2000 times more potent than Thalidomide
FDA approved for MM in conjunction with Dexamethasone & Bortezomib
Lenalidomide is only available in a restricted distribution setting to avoid its use during pregnancy
Pomalidomide (Actimid): 20,000 times more potent than thalidomide: currently in clinical trials for various cancers,
ENMD- 0095 is another potent analogue currently undergoing clinical trials
IMiDs as ImmunomodulatorsIMiDs as Immunomodulators
Potent inhibition of TNF-alpha .This inhibition is due to increased degradation of TNF-alpha mRNA by IMiDs
Inhibit TNF-alpha more potently, as well as inhibiting LPS induced monocyte IL1-beta and IL12 production, and increase the production of IL-10.
Partial inhibitory effect on IL-6.
Stimulation of IFN-γ secretion
Induction of NK cell activity and number. This helps in lysis of Tumor cells
IMiDs as Pro-apoptotic agentsIMiDs as Pro-apoptotic agents
Inhibited the proliferation of chemoresistant multiple myeloma cells by 20% to 50%.
The anti-proliferative mechanism of action is thought to be by
- inhibition of IL-6 production.
- Arrest of cell growth at the G1 phase and trigger activation of caspase-8, enhance cell sensitivity to Fas-induced apoptosis
- Downregulate nuclear factor (NF)-κB activity as well as the expression of apoptosis inhibitory protein
IMiDs as Angiogenesis inhibitors
Antiangiogenic activities of the IMiDs,secondary to the inhibition of secretion of two angiogenic cytokines, VEGF and FGF
100-fold increased antiangiogenic potency as compared to thalidomide
Also inhibit endothelial cell migration and adhesion perhaps due to downregulation of endothelial cell integrins
Significant in the MM, where treatment with thalidomide and IMiDs inhibited the upregulation of VEGF and IL-6.
SelCIDs (Selective cytokine inhibitory drugs) The SelCIDs are potent inhibitors of Phosphodiesterase
Type 4
Evaluated in animal models of asthma, found to be potent anti-inflammatory agents with minimal A/E.
Superior in cellular activity to other PDE4 inhibitors & significantly, are without the emetic effects typically associated with PDE4 inhibitors
Potently inhibit TNF-alpha
Little or no effect on T-cell activation
possess antitumor activity .
SelCIDs
Significantly enhanced antiangiogenic activity compared with thalidomide.
Decrease the vascularity and inhibit the growth of tumors
The studies indicate that SelCIDs represent a novel group of angiogenesis inhibitors with potential as cancer therapeutic agents
Two SelCIDs : CDC-801 and CDC-998 are presently being evaluated in clinical trials for Crohn’s disease, Hematological cancers and other conditions
CDC-998 is 100-fold more potent than CDC-801 against PDE4, without any serious A/E
Adverse effects of Thalidomide & its Adverse effects of Thalidomide & its analogues analogues Teratogenesis : “species – specific” teratogenesis”Non-teratogenic in animal models of rats, mice, hamster &
chick embryos. Teratogenic in rabbit & Humans are also highly sensitive
(maximum risk at 34-50 days of gestation). CNS effects: sedation, tremors, Peripheral (Sensory)
Neuropathy Hypersensitivity: skin rashes, urticaria, eosinophilia Haematological: neutropenia GIT: Constipation Venous Thromboembolism: more risk when
combined with dexamethasone for MM(Black Box Warning by FDA)
↓ PROPHYLAXIS SHOULD BE GIVEN
Uses of Thalidomide & its Uses of Thalidomide & its analogues analogues
FDA approved :ENL Multiple Myeloma : Myelodysplastic syndrome Promising uses Prostate cancer Aphthous ulcers (in HIV) Anti-neoplastic effects : AIDS related Kaposi’s
sarcoma Potential usesAutoimmune conditions GVHD RA & Ankylosing Spondylitis Inflammatory bowel disease SLE & Bechet’s disease
Cachexia and weight loss
HIV associated Tuberculosis Cancer cachexia Heart failure Dermatological
conditions Discoid lupus
erythematosus Actinic prurigo Prurigo nodularis pyoderma
gangrenosum
ENL (ENL (Erythema Nodosum Erythema Nodosum LeprosumLeprosum) ) A cutaneous manifestation of leprosy, characterized
by painful vasculitic rash, fever, muscle pain, joint pain, malaise, lymphadenopathy, insomnia, weight loss & peripheral neuritis
In 1964 Jacob Sheskin, Professor at the Hebrew University of Jerusalem administered thalidomide & successfully treated a critically ill patient with ENL
Approved by the US-FDA on July,16, 1998 for the treatment, prevention and suppression of ENL
Also WHO recommended thalidomide for use in ENL
Various studies have shown a 92% response rate with thalidomide
6 weeks 200 mg1 week 200 mg
Its antipyretic & steroid sparing effect is an added advantage for its use in ENL. The effectiveness of thalidomide is due to its inhibition of TNF-α.
Changes body’s immunological and inflammatory response to bacteria
Heals lesions and skin ulcerations
Before
Multiple MyelomaMultiple MyelomaThalidomide appears to inhibit the disease progression
in MM by several mechanisms,:
Inhibition of the production of IL-6, which is a growth factor for the proliferation of myeloma cells.
Activation of apoptotic pathways through caspase 8-mediated cell death.
Inhibit angiogenesis through inhibition of growth factors
Activation of T cells to produce IL-2, thereby altering the amount and function of NK cells, thus augmenting the activity of NK-dependent cytotoxicity
Thal + Dexamethasone / lenalidomide + dexa+ bortezomib
Demonstrated Mechanisms of Action of Demonstrated Mechanisms of Action of Thalidomide/IMiDs in MMThalidomide/IMiDs in MM
Myelodysplasia
Preliminary studies showed that lenalidomide at 10 or 25 mg/day or 10 mg/day for 21 days with a 7-day treatment free period produced significant responses in patients with low and intermediate risk MDS characterized by 5q syndrome .
29% achieved a complete morphologic remission In addition, transfusion requirement decreased in 76% of
patients while 67% became red-cell- transfusion-independent.
This lead to approval of lenalidomide for the treatment of MDS
PROSTATE CANCER
The involvement of angiogenesis in prostate cancer has been demonstrated by increased microvessel density, which has been shown as a predictor of tumor stage
Encouraging early studies using thalidomide in prostate cancer led to several studies utilizing thalidomide alone or in combination with chemotherapy in androgen-independent prostate cancer (AIPC)
Patients treated with thalidomide showed reduction in the serum prostate specific antigen (PSA) of ≥ 50%.
(a) IN TREATING AIDS RELATED APHTHOUS ULCERSAphthous ulcers is a common problem patients with
HIV Often extremely painful, necrotic lesions Involving
hypopharynx and esophagus, these ulcers lead to decrease in nutritional intake and subsequent wasting. In such conditions, thalidomide treatment has been found to exert beneficial effects
(b) IN AIDS RELATED WASTING SYNDROMEDuring late stage of AIDS, wasting syndrome occurs
either associated with opportunistic infections or as chronic progressive weight loss.
As thalidomide selectively inhibits the production of TNF-a , it is proposed that it has a role in treating wasting syndrome.
(e) IN RHEUMATOID ARTHRITISThe process of bone and cartilage destruction related to
rheumatoid arthritis is considered to involve T-cells cytokines such as TNF-a, interleukin-1 and metalloproteinases.
Hence, thalidomide, by its action on the cytokine production may have a role in the treatment on rheumatoid arthritis.
(f) In ankylosing spondylitis Thalidomide has been reported to markedly improve the
symptoms of ankylosing spondylitis, like motor disability and spinal pain.
However, its beneficial effects were found to subside after the cessation of treatment
(g) In Crohn's disease and Behcet's syndrome
Clinical trials related to efficacy of thalidomide in treatment of the refractory cases of other autoimmune diseases like Crohn's disease and Behcet's syndrome are also being conducted
It has a steroid sparing effect in these conditions.
(h)In cachexia associated with cancer and CHF :
There is probable role for inflammatory cytokines such as TNFα (nicknamed cachexin ), and IL-6, as well as Proteolysis Inducing Factor (PIF). Thalidomide inhibits these cytokines and is useful for the treatment of cachexia
Other Potential Uses Other Potential Uses
Hodgkin Lymphoma Non Hodgkin Lymphoma Glioma Pancreatic Cancer Hepatocellular carcinoma Ovarian Cancer Macular DegenerationsGVHD AIDS related Kaposi’s Sarcoma Bronchial Asthma: SelCIDs Various Skin Disorders
Precautions and ConcernsPrecautions and Concerns
Required pregnancy test in most casesEducation about the drug is requiredDrug may enter semen and men could affect
female partners
To avoid this thalidomide’s marketing and use is restricted through the mandatory System for Thalidomide Education and Prescribing Safety (STEPS) program.
This unique system of monitoring oversees the
prescribing, dispensing, and dosing of thalidomide.
S.T.E.P.SSystem for Thalidomide Education and Prescribing
Safety Developed by the Celgene Corporation An attempt to minimize the number of women exposed to
this drug during pregnancy, Thalidomide can only be prescribed by physicians who are
registered in the STEPS program, and both male and female patients must comply with mandatory contraceptive measures, patient registration, and patient surveys.
Three-step program that must be followed with all patients who are potential candidates for the drug:
- (1) patients must receive education regarding the potential benefits and side effects of thalidomide
- (2) contraceptive counseling must be provided, including emergency contraception measures, and women of childbearing potential must be given pregnancy tests
S.T.EP.SS.T.EP.S
- 3. patients must complete an informed consent form and participate in an ongoing mandatory and confidential survey.
No > 4-week supply of the drug can be prescribed at any one time, with no automatic refills
in fact, during the first 4 weeks of treatment, it is recommended that females receive only a 1-week supply until the results of weekly pregnancy tests become available.
Women must also use two reliable forms of contraception while taking the drug.
Summary Summary Thalidomide is a double-edged weapon. The 1961 tragedy remains as a bitter lesson in our
minds and serves as a reminder to exercise extreme caution and vigilance when using any new drug.
Still believed that licensed thalidomide will mean more thalidomide babies
Although approval of Drug presents controversy, if used judiciously, it can work miracles in many recalcitrant conditions
Newer analogues are more effective but still contraindication during pregnancy exists
Programs like S.T.E.P. S ensure more safe and effective use of this drug
THANK YOU