revival of thalidomide
TRANSCRIPT
![Page 1: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/1.jpg)
REVIVAL OF THALIDOMIDEREVIVAL OF THALIDOMIDE
From tragedy to From tragedy to promisepromise
Dr.J.Thirunavukkarasu M.D
![Page 2: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/2.jpg)
History of ThalidomideHistory of Thalidomide• 1954: synthesized
• 1956: introduced and marketed as a non-barbiturate sedative in Germany
– “Safest available sedative of its time”– Very effective in alleviating morning sickness – Over the counter
1957: Europe, Australia, Asia, South America, Canada (but never the USA)
Thalidomide history J Am Med Asso 1990; 263; 1474
![Page 3: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/3.jpg)
Tragedy
Lancet (1961) 2, 1358Widulind Lenz- pediatric geneticist
![Page 4: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/4.jpg)
To promise…To promise…1998(Aug) - FDA (USA)-Approvel
ENL
WHO recommendation
Lenalidomide-multiple myelomamyelodysplastic syndrome
Scheffler MA. Et al.Microbes infect 2002; 4; 1193-202
WHO Tech. Rep. ser. 874 7th Rep
![Page 5: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/5.jpg)
USES OF THALIDOMIDEUSES OF THALIDOMIDE
1. NON BARBITURATE HYPNOTIC Insomnia
2. SEDATIVE Restlessness in elderly
3. ANTIEMETIC MORNING SICKNESS Hyperemesis gravidaris
4. ADJUVANT ANALGESIC PAIN
![Page 6: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/6.jpg)
Novel uses of Thalidomide in Novel uses of Thalidomide in Specific conditions Specific conditions
1. Leprosy, Erthema Nodosum Leprosum (ENL) 2. Chronic illness syndrome e.g. Cachexia 3. Tuberculosis, Sarcoidosis 4. Aphthous ulcers in HIV syndrome and Behcet's disease. 5. Graft - versus - host disease 6. Pyoderma gangrenosum 7. Inflammatory bowel disease 8. Rheumatoid arthritis 9. Sjogren's syndrome 10. Discoid lupus erythematosis 11. Multiple myeloma 12. Advanced solid tumours eg. Renal cell carcinoma
![Page 7: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/7.jpg)
Potential uses of thalidomide in Potential uses of thalidomide in palliative carepalliative care
1. Cancer Cachexia/anorexia 2. Chronic nausea 3. Insomnia 4. Neoplastic fever 5. Profuse sweating 6. Angiogenesis 7. Pain
![Page 8: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/8.jpg)
How is this possible?
??????
![Page 9: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/9.jpg)
α –N-phthalimidoglutarimide
Pthalidimide ring-Teretogenicity
Glutarimide ring-Sedation
Thalidomide PharmacologyThalidomide Pharmacology
Bartlett et al. 2004 Nature Reviews Cancer
![Page 10: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/10.jpg)
Kinetics….
Oral Liver Well distriUrine
![Page 11: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/11.jpg)
Effects …
Anti-inflammatory
Immunomodulatory effects
![Page 12: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/12.jpg)
CYTOKINES
MacrophageNKcell, mono
lympho
![Page 13: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/13.jpg)
“CYTOKINESAre molecular
ChemicalBombs
Of Tissue
Destruction”(i.e. the pro-inflammatory ones)
![Page 14: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/14.jpg)
Pro-Inflammatory
cytokines
Anti-Inflammatory
cytokines
‘Cytokine-balance’Normal
![Page 15: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/15.jpg)
RAChron’s disease
TBCancercachexia
![Page 16: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/16.jpg)
Thalidomide Therapeutic Thalidomide Therapeutic PropertiesProperties
Immunomodulatory properties a. Inhibition and stimulation of cytokinesb. Co-stimulation of primary human T cellsc. Modification of surface cell adhesion
molecules(ICAM-1, VCAM-1)d. Inhibits NF-kB gene-TNFα
IL-6IL-12
IL-2
J infect Dis 1999; 180;216-9.
![Page 17: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/17.jpg)
Thalidomide Therapeutic Thalidomide Therapeutic Properties…Properties…
Non-immunomodulatory propertiesa. Anti-angiogenic activityb. Anti-proliferative and pro-apoptotic activity c. COX inhibition
![Page 18: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/18.jpg)
Tumor AngiogenesisTumor Angiogenesis
Angiogenesis: formation of new blood vessels from pre-existing vasculatureAngiogenesis: formation of new blood vessels from pre-existing vasculature
Tumor Cells
Endothelial Cells
Extracellular Matrix
Basement Membrane
VEGF
bFGF
PDGFR
Supporting cells
proteases
PDGF
![Page 19: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/19.jpg)
Angiogenesis
![Page 20: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/20.jpg)
• Removes waste from growing tumor
• Provides tumor cells with oxygen and nutrients to grow
• Inhibition of tumor angiogenesis is promising as a cancer treatment
Tumor Tumor angiogenesisangiogenesis
![Page 21: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/21.jpg)
1994: Anti-angiogenesis properties,1994: Anti-angiogenesis properties,Rationale for anticancer agentRationale for anticancer agent
• D’Amato et al. 1994 show…
Thalidomide
Markedly reduces neovascularization
D’Amato et al. (1994) Proc. Natl. Acad. Sci. USA, 91, 4082-4085
VEGFbFGFIL-6
Multiple myelom
a
![Page 22: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/22.jpg)
COX inhibition COX inhibition
Thalidomide
partly reduces neovascularization
Cox 2
angiogenes
![Page 23: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/23.jpg)
OLDER USESOLDER USES
• MORNING SICKNESS SEDATION
![Page 24: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/24.jpg)
DERMATOLOGICAL USESDERMATOLOGICAL USES
(a) Very effective: ENL, aphthous stomatitis, Behcet's disease, LE, and prurigo nodularis
(b) Moderately effective: Actinic prurigo, Langerhans cell histiocytosis, cutaneous sarcoidosis, erythema multiforme, graft- vs -host disease (GVHD), Jessner's infiltrate, and uremic pruritus
(c) Possibly effective: Kaposi's sarcoma, lichen planus, melanoma, and pyoderma gangrenosum
(d) Contraindicated: Toxic epidermal necrolysis (paradoxical increase in TNF-a activity
![Page 25: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/25.jpg)
Erythema nodosum leprosumErythema nodosum leprosum
TYPE 2 -LEPRA REACTION
400 mg/day for patients above 35-50 kg body weight
300 mg/day, to be tapered by 100 mg every 2-4 weeks with a maintenance dose of 50-00mg for 6
months
• Sheskin, in 1965,
• 1998(Aug) - FDA (USA)-Approvel
ENL
WHO recommendation
WHO Tech. Rep. ser. 874 7th Rep
Sheskin, J. (1965) Clin. Pharmacol. Therap. 6, 303-306
![Page 26: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/26.jpg)
• BEHCET’S DISEASE • APTHOUS ULCER
• Antiangiogenic property
![Page 27: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/27.jpg)
ACTINIC PRURIGO ACTINIC PRURIGO SCLERODERMASCLERODERMA
![Page 28: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/28.jpg)
• SARCOIDOSIS • KAPOSIS SARCOMA
![Page 29: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/29.jpg)
Aphthous ulcerBechcet’s disease
![Page 30: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/30.jpg)
HEART FAILUREHEART FAILURE
Stephens TD,Filmore BJ-teatology 2000;61;189-95
![Page 31: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/31.jpg)
RHEUMATOID ARTHRITIS
![Page 32: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/32.jpg)
Successfulstrategy-1
Neutralize with antibodies
![Page 33: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/33.jpg)
ANTI-CYTOKINEWEAPONS
“CYTOKINEBOMBERCELLS”
![Page 34: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/34.jpg)
INFLIXIMAB(Remicade)
![Page 35: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/35.jpg)
Recombinant human anti TNF monoclonal antibody
Similarly to Infliximab
![Page 36: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/36.jpg)
Second strategy against
TNF- Alpha
![Page 37: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/37.jpg)
“ATTRACT &
DIVERTAWAY”
![Page 38: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/38.jpg)
SOLUBLE RECEPTORS
made by RECOMBINANT
DNATECHNOLOGY
![Page 39: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/39.jpg)
“Soluble Receptors Will “mop up’
The TNFbefore they
Can ATTACK theJOINTS”
![Page 40: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/40.jpg)
Femur
Tibia
TNFAll
“Mopped
Up”
![Page 41: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/41.jpg)
Etanercept
![Page 42: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/42.jpg)
Interlukin-1(IL-1)
ANAKINRA
![Page 43: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/43.jpg)
Naturally Occurring
IL-1 Receptor ANTAGONIST
![Page 44: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/44.jpg)
TARGET CELL
IL-1RECEPTOR
IL-1
IL-1 R A
![Page 45: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/45.jpg)
IL-1
IL-1 R A
Normal Balance
![Page 46: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/46.jpg)
Naturally Occurring
IL-1 Receptor ANTAGONIST
RecombinantAnalogue of
![Page 47: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/47.jpg)
IL-1
IL-1 R A (Naturally OccurringIL-1 Receptor Antagonist)
(Recombinant Analogue)
R IL-1RA
![Page 48: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/48.jpg)
TARGET CELL
IL-1RECEPTOR
IL-1
IL-1 R A
RIL-1
RA
![Page 49: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/49.jpg)
TARGET CELL
IL-1RECEPTOR
IL-1
RIL-1
RA
ReceptorsAlready Blocked
IL-1CannotAct on theReceptor
![Page 50: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/50.jpg)
ANAlogue ofInterluKIN-1ReceptorAntagonist
![Page 51: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/51.jpg)
IBD( chron’s disease)
• 50-300mg/day
• Dec severity of mucosal disease
![Page 52: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/52.jpg)
Thalidomide use in Thalidomide use in Hematological MalignanciesHematological Malignancies
• Multiple myeloma
• AL amyloidosis
• Myelofibrosis with myeloid metaplasia
• Myelodysplastic syndrome
• Acute myeloid leukemia
![Page 53: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/53.jpg)
Thalidomide use in Solid TumorsThalidomide use in Solid Tumors
• Brain tumors
• Renal cell carcinoma
• Prostate cancer
• Melanoma
• Kaposi’s sarcoma
![Page 54: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/54.jpg)
Sites of activity of thalidomide in Sites of activity of thalidomide in the bone marrowthe bone marrow
Bone marrow stromal cells
MM cells
Thalidomide
X proliferation cell cycle arrest or apoptosis
Thalidomide
XInhibition of myeloma cell adhesion to BMSC
IL-1IL-1ββTNFTNFαα
IL-6IL-6X
Bone marrow blood vessels
Thalidomide
Thalidomide
XInhibition of angiogenesis
VEGF bFGF
Thalidomide
T - cells
T cell activation& proliferation
Il-2Il-2IFN-IFN- γγRelease cytotoxic
mediators
Lysis of MM
NK cells
![Page 55: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/55.jpg)
First line of treatment or,After resistance to conventional chemotherapy
Multiple MyelomaMultiple Myeloma
![Page 56: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/56.jpg)
Thalidomide For Ovarian Treatment
Topotecan plus thalidomide
![Page 57: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/57.jpg)
CONTRAINDICATION
![Page 58: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/58.jpg)
PREGNANCYPREGNANCY
![Page 59: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/59.jpg)
TOXIC EPIDERMAL NECROLYSIS
![Page 60: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/60.jpg)
ADVERSE EFFECTSADVERSE EFFECTS
![Page 61: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/61.jpg)
category-X drug
![Page 62: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/62.jpg)
Thalidomide Fetal ExposureThalidomide Fetal Exposure• Species specific
• 10 000 – 12 000 severely deformed babies born• Unknown number of aborted fetuses• Fetus malformations included:
– Amelia, complete limb absence– Phocomelia, decrease in limb development– Hypoplasia and absence of bones
• 40% thalidomide effected babies died in neonatal period from atresia of the bowel, renal dysgenesis and heart malformations
![Page 63: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/63.jpg)
IGF-1/FGF-2 Transcription of alpha v & βunit gene
Outgrowth of bud
Angiogenesis in developing limb bud
Alpha v β3 integrin dimer
Thalidomide
Limb growth
![Page 64: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/64.jpg)
![Page 65: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/65.jpg)
Adverse EffectsAdverse EffectsPNS Numbness, paresthesia, pain in extremities, burning sensation
(30%)
CNS Hangover, nervousness, tremor (10%), Confusion, ear buzzing, fatigue (20-50%), Depression (5-20%), Dizziness, somnolence (>50%), Headache, fluctuation of blood pressure, bradycardia (5%)
GI Constipation (>50%), Nausea (5-20%)
Hematological Deep vein thrombosis (5-30%)
Skin Red palms, skin rash (25%), brittle fingernails, itching (20-50%)
Genital system
Teratogenicity (Critical Window, 21-56 days after conception. Effects outside this time frame unknown), menstrual irregularities, decreased libido
Endocrine Hypothyroidism and edema (5-20%)
Eleutherakis-Papaiakovou et al. (2004) Ann. Oncol. 15, 1151-1160
![Page 66: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/66.jpg)
Challenges of thalidomide in Challenges of thalidomide in government, society and scientific government, society and scientific
communitycommunity
![Page 67: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/67.jpg)
Celgene Corporation (Warren, New Jersey) has developed a comprehensive program to monitor the thalidomide’s prescribing, dispensing and use
GOAL: to ensure that fetal exposure to thalidomide does not occur
S.T.E.P.S.S.T.E.P.S.TMTM (Celgene Corp.) (Celgene Corp.) System for Thalidomide Education and Prescribing System for Thalidomide Education and Prescribing
SafetySafety
![Page 68: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/68.jpg)
S.T.E.P.S.S.T.E.P.S.TMTM requiresrequires• Registration of prescribing physicians,
patients and pharmacists • Patient counseling• Informed consent • Pregnancy tests, compliance with measures
to prevent pregnancy, educational materials (including video)
• Limited prescription supply of 28 days
![Page 69: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/69.jpg)
Monitoring guidelinesMonitoring guidelines
Baseline pregnancy test Complete blood count absolute neutrophil count, HIV RNA Electromyography (EMG) or nerve conduction velocity (NCV) study. Pregnancy testing
![Page 70: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/70.jpg)
Interesting Facts…Interesting Facts…
• According to the FDA, recent usage patterns of Thalidomid® under the S.T.E.P.S.TM program revealed:
Almost 90% of prescription from 1998-2003 were for oncological conditions
• From 1998-2003, ~77 000 patients were prescribed Thalidomid®
• ~4000 patients were women of childbearing potential
![Page 71: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/71.jpg)
From Tragedy to PromiseFrom Tragedy to Promise
1954 1956 1961 1965 1991 1994 1998 2000 Today
Thalidomide is synthesized
Introduced in Germany as
sedative
Thalidomide withdrawn
Report showingeffectiveness
in patients with leprosy
![Page 72: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/72.jpg)
From Tragedy to PromiseFrom Tragedy to Promise
1954 1956 1961 1965 1991 1994 1998 2000 Today
Thalidomide is synthesized
Introduced in Germany as
sedative
Thalidomide withdrawn
Report showingeffectiveness
in patients with leprosy
Shown to inhibit TNFα expression
![Page 73: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/73.jpg)
From Tragedy to PromiseFrom Tragedy to Promise
1954 1956 1961 1965 1991 1994 1998 2000 Today
Thalidomide is synthesized
Introduced in Germany as
sedative
Thalidomide withdrawn
Report showingeffectiveness
in patients with leprosy
Shown to inhibit TNFα expression
Anti-angiogenic properties shown
![Page 74: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/74.jpg)
From Tragedy to PromiseFrom Tragedy to Promise
1954 1956 1961 1965 1991 1994 1998 2000 Today
Thalidomide is synthesized
Introduced in Germany as
sedative
Thalidomide withdrawn
Report showingeffectiveness
in patients with leprosy
Shown to inhibit TNFα expression
Anti-angiogenic properties shown
FDA approves for ENL
Reports of effectiveness in
Multiple myeloma
![Page 75: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/75.jpg)
From Tragedy to PromiseFrom Tragedy to Promise
1954 1956 1961 1965 1991 1994 1998 2000 Today
Thalidomide is synthesized
Introduced in Germany as
sedative
Thalidomide withdrawn
Report showingeffectiveness
in patients with leprosy
Shown to inhibit TNFα expression
Anti-angiogenic properties shown
FDA approves for ENL
Reports of effectiveness in
Multiple myeloma
Fast-track approval of IMiDs
![Page 76: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/76.jpg)
22ndnd Generation Thalidomide: Generation Thalidomide:IMiDIMiD®®ss
• Immunomodulatory Drugs (IMiD®s)
• Lead compound in drug discovery
• Show increased immune and anticancer properties (prevent angiogenesis and co-stimulation of T-cells)
• Lack toxicity associated with thalidomide
• Examples– Lenalidomide (REVLIMIDTM)– CC-4047 (ACTIMIDTM)
![Page 77: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/77.jpg)
LENALIDOMIDELENALIDOMIDEMULTIPLE MYELOMA: - lenalidomide and dexamethasone is a highly active
regimen which provides survival benefits for patients with relapsed or refractory MM
MYELO DYSPLASTIC SYNDROME: - Abnormally low amount of thrombocytes as well as
neutrophils
SICKLE CELL ANEMIA: - Lenalidomide and pomalidomide
![Page 78: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/78.jpg)
ConclusionsConclusions• Thalidomide was first marketed in the late ’50s as a sedative to
treat morning sickness
• 1961: withdrawn for teratogenic effects related to fetal exposure to thalidomide
• Thalidomide shown to have immunomodulatory and non-immunomulatory properties
• S.T.E.P.S.TM are in place to prevent fetal exposure
• Promising future as the lead compound in the development of IMiD®s
![Page 79: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/79.jpg)
double-edged weapon Thalidomide must always remain the drug of last resort
Try to make sure that a thalidomide tragedy never occurs again.
Conclusions…Conclusions…
![Page 80: Revival of Thalidomide](https://reader035.vdocuments.mx/reader035/viewer/2022081715/546a8973b4af9f83288b4cb4/html5/thumbnails/80.jpg)
Thank YouThank You