THALIDOMIDE:

· Is in a class of medication called immunomodulatory agents.

· A type of targeted cancer drug (biological therapy) also known as Thalidomide Calgene.

· A number of skin conditions including complications of leprosy.

INTRODCUTION:

· The first paper describing the pharmacological actions of thalidomide was published in 1956. The drug, then designated as K17, was thought to have sedative effects.

· The first paper describing the pharmacological actions of thalidomide was published superior to those of comparator drugs and was thought to be virtually nontoxic. Only 2 years.

· After thalidomide's launch as Contergan in Germany, its alleged lack of toxicity came into question, with reports of the drug causing numerous side effects.

· Shortly thereafter, thalidomide was connected with anepidemic of horrific deformities in children whose mothers had taken the drug during pregnancy. This disaster brought on by

· thalidomide's teratogenic effects was responsible for the institution of some regulatory bodies, such as the United Kingdom's Committee on the Safety of Drugs, and for the

· strengthening of others, such as the U.S. Food and Drug Administration.

· An objective examination of published papers and contemporary accounts confirms that the preclinical tests on thalidomide were superficial, and there is no doubt that it was

· never administered to pregnant animals prior to its use in patients.

· Within a short time after its withdrawal from the market due to its suspected association with fetal abnormalities, the drug was shown to produce fetal toxicity in laboratory animals. Had there been more extensive testing on before the drug was launched, the disaster could have been avoided.¹

HISTORY:

· In 1952, thalidomide was synthesized by Chemical Industry Basel (CIBA), but was found "to have no effect on animals and was discarded" on that basis.

· In 1957, it was acquired by Chemie-Grunenthal in Germany in Stolberg.

· Introduced as a Sedative drug in late 1950s. Was found to act as an effective tranquilizer & painkiller and was proclaimed as a “wonder drug” for insomnia, cough, colds, and headaches.²

· Found to be effective antiemetics which have an inhibitory effect on morning sickness and so thousands of pregnant women took the drug to relieve their symptoms.

· The toxicity was examined in several animals, and the drug was introduced in 1956 as a sedative, but it was never tested on pregnant women.

· UK, Australia and New Zealand, marketed thalidomide under the brand name Distaval, as a remedy for morning sickness. Their advertisement claimed that "Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or

· child. Globally, more pharmaceutical companies started to produce and market the drug.³

· By the mid-1950s, 14 pharmaceutical companies were marketing thalidomide in 46 countries under at least. In early 1960, unsuspected side effects on the nervous system started to be attributed to thalidomide.⁴

· Was available as OTC drug

Chemistry of Thalidomide:

· Thalidomide is a synthetic derivative of glutamic acid α (Nphthalimido glutarimide. The chemical formula for thalidomide is C13H10N2O4. Consist of ring structure with an asymmetric carbon in the glutamide ring.

· Thalidomide is racemic; while R-thalidomide is the bioactive form of the molecule, the individual enantiomers can racemize to each other due to the acidic hydrogen at the chiral centre, which is the carbon of the glutarimide ring bonded to the phthalimide substituent. The racemization process can occur in vivo.

· Exists as an equal mixture of S-(-) and R-(+) enantiomers. These enantiomers rapidly get interconverted under physiological conditions.

· It is sprangly soluble in water and ethanol, which prevented its availability as an intravenous formulations.²

Thalidomide Tragedy (1962):

· Thalidomide was first marketed in 1957 in West Germany under the label of Contergan. The German drug company developed and sold the drug. Primarily prescribed as sedative or hypnotic also claimed to cure “anxiety, insomnia, gastritis, and tension”.

· Afterwards, it was used against nausea an to ease morning sickness in pregnant women. Soon it became an over the counter drug in Germany around 1960.]

· Thalidomide was also a catastrophic drug with tragic side effects, it became famous as “The Killer and Disaster of Thousands of Babies”.

Shortly after the drug was sold in Germany, between 5,000 to 7,000 infants were born with Phocomelia (malformation of the limbs). Only 40% of these children survived. Throughout the world, about 10,000 cases were reported, only 50% of these survived.

Their defects includes deformed eyes and hearts, deformed alimentary and urinary tracts, blindness and deafness.

The negative effects to thalidomide led to the development of more structured drug regulations and control drug use and development.^5-6

Chirality of Thalidomide:

· The thalidomide tragedy would probably never have occurred if, instead of using the racemate, only the R- (+) enantiomer had been brought to the market.

· Researches revealed that, only R-(+) form was therapeutically active; the S-(-) form was not only ineffective; it was the source of the birth defect: embyotoxic and teratogenic effect.[1,2]

· The two enantiomers caused distinctly different effects from one another; R-(+) enantiomer is devoid of any of those effects under the same experimental conditions.

· Unfortunately, dosing a single enantiomer of thalidomide doesn’t have a unique therapeutic

· value, because the drug converts to the racemic compound in vivo.

Pharmacology:

Thalidomide is best known for its sedative, antiemetic, and teratogenic effects but also has diverse pharmacological properties and therapeutic potential in infections, autoimmune, various inflammatory conditions.

It achieved the therapeutic effect by limiting the immune system’s powerful and harmful inflammatory responses within the body.

The precise mechanism of action for thalidomide is not known, although efforts to identify thalidomide’s teratogenic action generated 2,000 research papers. As of 2015, the main theories were:

· Inhibition of the process of angiogenesis

· Its inhibition of cereblon, a ubiquitin ligase,

· Its ability to generate reactive oxygen species which in turn kills cells.^10-12

Thalidomide also binds to and act as an antagonist of the androgen receptor and hence is a non steroidal anti androgen of some capacity. In accordance, it can produce gynecosmatia and sexual dysfunction as side effects in men.

The discovery that thalidomide inhibits angiogenesis led to preclinical and phase I/II trials as an anti cancer agent in solid tumors and hematologic malignancies. Many outstanding issues surround the pharmacology of thalidomide, including its absorption, distribution and

mechanism(s) of therapeutic activity in an array of disease states.

Research continues to establish the pharmacokinetic and pharmacodynamic properties of thalidomide and to define its role in the oncology/hematology arena.

Mechanism of Teratogenecity:

The mechanism by which thalidomide causes limb malformations and other developmental defects is a long standing question. Data suggests that it the drug initiates its teratogenic effects by binding to CRBN(cereblon) and inhibiting its ubiquitin ligase activity. CRBN was the primary target of thalidomide and critically involved in thalidomide teratogenecity and this greatly advanced the understanding of the molecular mechanism of thalidomide and its derivative.

CRBN is not only required for the teratogeinc effects but also the therapeutic effects of thalidomide and its derivative, as it was found the knockdown of CRBN by RNA interference blocked the inhinibtion of cell proloferation by lenalidomide or pomalidomide in severl multiple myeloma cell lines.

Thalidomide intercalates into DNA (the thalidomide, molecule which has a flat structure, can slide into gaps between the subunits of the DNA molecule). It does not intercalate at random into the DNA but at guanine sites. Thalidomide consists of three attached rings, two of which look in overall structure almost identical to guanine and adenine.

Attaches more strongly to guanine than adenine. Interferes with angiogenesis by inhibiting the growth of new vessels in a growth limb bud, would deprive the proliferating cells of critical nutrients, leading to a decrease in proliferation and a subsequent reduction in overall limb size.⁸

Mechanism of Action:

Vigilance History:

· 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 honours for this contribution, in United Kingdom the drug was licensed in 1958 approximately 2,000 babies were born with defects, 466 survived. The drug was withdrawn in 1961.

· An epidemic of horrific deformities confirmed that preclinical tests on thalidomide were superficial, and no doubt, it was never administered to pregnant animals prior to its use in patients.

· Within a short period of time after its withdrawal from the market due to its suspected association of fetal deformities, the drug was shown to produce fetal toxicity in laboratory animals.

· If there had been more extensive testing on laboratory animals before the drug was launched, the disaster could have been avoided.

· Researches also proved that although phocomelia exist since 1940s and 1950s, cases of severe phocomelia multiplied in the 1960s, when thalidomide was released; the direct cause was traced to thalidomide.¹¹

PHOCOMELIA:

It is a condition that involves malformation of human limbs.

· Although many factors can cause phocomelia, the prominent roots come from the use of the drug thalidomide and from genetic inheritance. The statistics was given that 50% of the

· mothers with deformed children had taken thalidomide during the first trimester of pregnancy.

· Single pill was sufficient to produce teratogenic effect.

· Throughout Europe, Australia, and United States 10,000 cases were reported of infants with phocomelia; only 50% survived. Those subjected to thalidomide while in the womb experienced limb deformities in a way that the limbs either were not developed or presented themselves as stumps. Other effects included: deformed eyes, hearts, alimentary and urinary tracts, blindness and deafness.

· Patients that receive a loss of limbs due to phocomelia are typically treated with Prosthetics-a synthetic alternative for missing limbs, teeth, and various other body parts.

The symptoms of phocomelia are undeveloped limbs and absent pelvic bones; however, various abnormalities can occur to the limbs and bones.

Usually the upper limbs are not formed and sections of “hands and arms may be missing”.

Category: People with Phocomelia:

Notable cases:

· Lorraine Mercer of the United Kingdom, born with phocomelia of both arms and legs, is the only thalidomide survivor to carry the Olympic Torch.

· Thomas Quasthoff, an internationally acclaimed bass-baritone, who describes himself: "1.34 meters tall, short arms, seven fingers — four right, three left — large, relatively well-formed head, brown eyes, distinctive lips; profession: singer".

· Mercedes Benegbi, born with phocomelia of both arms, drove the successful campaign for compensation from her government for Canadians who were affected by thalidomide.

· Mat Fraser, born with phocomelia of both arms, is an English rock musician, actor, writer and performance artist. He produced a 2002 television documentary "Born Freak".

· Michaelina Argy (born 1962) is an English thalidomide survivor and activist. She is a past chair of the National Advisory Committee of the Thalidomide Trust.

· Terry Wiles Terrence 'Terry' Wiles (born 12 January 1962) was one of the most disabled thalidomide babies born in the UK.

· Ronan Tynan Born14 May 1960 an Irish singer & former Paralympics athlete. Born with phocomelia, both of his lower legs were underdeveloped unusually short, feet were splayed

· outward, had three toes on each foot. He was one of set of twins; his twin brother died at months old.

· Dave Stevens (amputee sportsman) He is currently a reporter for the Disability Channel and interviews some of the biggest names in sports and entertainment history.

Reintroduction of thalidomide into Clinical Practice

· Thalidomide has been reintroduced into clinical practice as an anti cancer drug. In the first clinical trial conducted at the university of Arkansas, 25% of patients with advanced relapsed refractory multiple myeloma achieved a partial response to therapy.

· Shortly after the teratogenic properties of thalidomide became known, astute physicians considered the drug as a possible cancer treatment. They reasoned that a drug powerful enough to cause severe defects in rapidly growing fetal tissues & organs,

· Probably have similar effects against malignant tumors.

· At least, 3 large scale clinical trials involving approximately 200 patients were undertaken in the United States to investigate thalidomide use for treatment of advanced cancer, no notable activity was seen with this drug in any of these early trials, and enthusiasm for continuing research of thalidomide as an anticancer agent disappeared for about 3 decades.

· In clinical trial phase III, thalidomide plus dexamethasone demonstrated significantly superior response rates in newly diagnosed myeloma compared with dexamethasone alone.

· Thalidomide represents a new era in therapy for this incurable and fatal malignancies.

· The drug also is being studied in nonmalignant conditions including inflammatory bowel disease, reflex sympathetic dystrophy syndrome, and certain autoimmune disorders.

· Lenalidomide has shown considerale promise in treatment of relapsed and refractory myeloma.

HISTORY OF THALIDOMIDE REINTRODUCTION:

· Although thalidomide was taken off the market, it never disappeared from the field of medicine. In November 1964, Dr Jacob Sheskin, an Israeli physician working in Jerusalem, encountered a 44-year-old man with Erythema Nodosum Leprosum (ENL), a complication of leprosy. The patient had fever, severe muscle and joint pain, and a skin eruption and

· was unable to sleep.

· Dr Sheskin prescribed thalidomide as a sedative because he believed there was no contraindication to its use in this case.

· However, the patient had an unexpected and dramatic resolution of ENL within 3 days. Withdrawal of thalidomide led to recurrence of ENL, and reinstitution of the drug led to complete response. Dr Sheskin later confirmed remarkable activity of thalidomide for ENL in 5 consecutive patients. These findings were confirmed that subsequently by other scientists and by a randomized trial undertaken by the World Health Organization.

· Thalidomide quickly was shown to be one of the most active agents in the treatment of ENL reactions of leprosy.

· In studies, it appeared that thalidomide effectively reduces serum concentrations of tumor necrosis factor alph, a substance produced in excess in severl disease processes, including

· malignancies.

· Safety monitoring systems were set up to prevent this tragedy ever happening again and the drug was reintroduced.

REVIVAL OF THALIDOMIDE:

· One of the factors that helped most in the revival of thalidomide was the effectiveness of the drug against the oral ulcers, activity in the treatment of Bechet syndrome, graft versus host disease and effects associated with human immunodeficiency virus (HIV) infections. These findings led to the continued availability of thalidomide as part of compassionate use or clinical trials.

· The mechanism of action of thalidomide in these immune related disorders was unclear.

· In 1991, Dr Gilla Kaplan and colleagues found that the antiinflammatory and immunomodulatory properties of thalidomide probably resulted from suppression of tumor necrosis factor α release, subsequent studies confirmed these observations.

· After long deliberation period, the FDA approved thalidomide for treatment of ENL in the United States.

· The birth defects caused by thalidomide led to the development of greater drug regulation and monitoring in many countries. Use of thalidomide is strictly controlled with clear adherence to a birth control program, and close monitoring for early development of peripheral neuropathy.

Brand names:

Brand names under which thalidomide is being marketed include Contergan, Thalomid, Talidex, Talizer, Neurosedyn, Distaval and many other.

Approval of FDA:

1954: Thalidomide was introduced to the market by the company of Chemie Grunenthal.

1956: first known victim, daughter of grunenthal employee was born 1961: Thalidomide was discovered by Dr Jacob Sheskin to treat complications associated with erythema nodosum leprosum (ENL).

1998: Thalidomide was approved by the FDA for treatment of ENL.

May 2006: a combination of thalidomide and dexamethasone was FDA approved for the treatment of multiple myeloma.

June2006: Lenalidomide (Revlimid) and Pomalidomide (Actimid) derivative of thalidomide, were FDA approved for the treatment of multiple myeloma.

In U.S, the new regulations strengthened the FDA, among other ways, by requiring applicants to prove efficacy and to disclose all sie effects encountered in testing.

In 2006 the U.S Food and Drug Administration granted accelerated approval for thalidomide in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma.this cpmbination of drug probably results in an increase of the overall survival.

The use of thalidomide is incredibly restricted and requires participation in the System for Thalidomide Education and Prescription Safety (STEPS) program.

S.T.E.P.S:

System for Thalidomide Education and Prescribing Safety:

· Developed by the Calgene Corporation, Warren, New Jersey. To ensure that fetal exposure to this teratogenic agent does not occur, the manufacturer has instituted a comprehensive program to control prescribing, dispensing, and use of the drug. This program, known as the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S). In an attempt to minimize the number of women exposed to this drug during pregnancy.

· To achieve its goal of the lowest possible incidence of drug assaociated teratogenecity, S.T.E.P.S uses three step program that must be followed with all the patients who are potential candidates for the drug:

§ Patient must receive education regarding the potential benefits and side effects of thalidomide.

§ Contraceptive counseling must be provided, including emergency contraception measures, and women of childbearing potential must be given pregnancy tests

§ Patients must complete an informed consent form and participate in an ongoing mandatory and confidential survey.

Clinicians who wish to prescribe the drug must be registered in the STEPS. Prescriber Registry and agree to prescribe the drug in accordance with S.T.E.P.S patient eligibility criteria and monitoring procedures. Pharmacies must also register and agree to comply with patient identification and monitoring procedure.

Thalidomide analogues and Uses

· Thalidomide an its analogues (lenalidomide and pomalidomide) are small molecule glutamic acid derivatives IMiDs with a range of biological effects an putative molecular targets. 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 teratogenecity and peripheral neuropathy. Two groups of compounds have been identified SeICIDs (selective cytokine inhibitory drug) and IMiD inhibitory activity compared with thalidomide. The diverse biological properties of thalidomide analogues indicate that they might possess divergent mechanistic activities in different diseases.

· It is anticipated that elucidation of important IMiD targets will allow the rational development of new generation therapeutics with the potential to separate thalidomide analogue efficacy from clinical toxicity.

Uses of thalidomide:

· FDA Approved: ENL, Multiple Myeloma, Myelodysplastic syndrome

· Promising uses: Prostate Cancer, Aphthous ulcers(in HIV)

· Potential uses: Autoimmune conditions, Bechet’s disease, Inflammatory bowel disease

· Dermatological conditions: Actinic pruritis, Pyroderma gangrenosum, Leprosy

· Rheumatological: Rheumatoid Arthritis, Sarcoidosis

· Cachexia and weight loss: HIV associated, Tuberculosis, Cancer Cachexia, Heart failure

· It works in Hansen’s disease by reducing swelling and redness (inflammation)

· Graft vs host disease

· Pancreatic Cancer

· Ovarian Cancer

· AIDS related Kaposi’s Sarcomas: anti neoplastic effect

· Hodgekin Lymphoma

· Bronchial Asthma (SeICIDs)

· Macular degeneration

· Inflammatory bowel disease

Adverse effect and Contraindication:

· Common side effects include sleepiness, rash, and dizziness, dry mouth, vomiting.

· Severe side effects include tumor syndrome, blood clots, interfere with formation of various kinds of new blood cells, creating a risk of infection via neutropenia, leukopenia, and lymphopenia and peripheral neuropathy.

· Several cardiovascular adverse effects including risk of heart attacks, pulmonary hypertension, bradycardia

· Can cause liver damage and skin reactions

· Can prevent menstruation

· Reduced coordination, interstitial lung disease, lung inflammation

· Use in pregnancy, result’s in malformation of the fetal limbs.

Contraindications:

· Thalidomide should not be used by women who are breastfeeding or pregnant, trying or able to conceive a child, or cannot or will not follow the risk management program to prevent pregnancies.

· The prescribing doctor is required to ensure that contraception is being used, and regular pregnancy tests are taken.

· Those allergic to thalidomide should not take it.

· It should be used with caution in people with chronic infections like HIV or hepatitis B.

· Do not donate blood while you are taking thalidomide and for 4 weeks after your treatment.

REFERENCES:

1. https://www.heathergoodwin1/the safety profile of thalidomide.

2. Jump up Stolberg SG (17 July 1998). "Thalidomide Approved to Treat Leprosy, With Other Uses Seen". New York Times. Retrieved 8 January 2012.

3. https://www.KatieStrong/the-thalidomid- saga

4. World Health Organization (2019). "World Health Organization model list of essential medicines: 21st list 2019“.

5. "FDA Approval for Thalidomide". National Cancer Institute. R Sneader W (2005). Drug discovery: a history (Rev. and updated ed.). Chichester: Wiley. p. 367 etrieved 8 January 2012.

6. Campbell, Denis. "'Wonder drug' left babies with deformed limbs." The Guardian. 29 July 2009. "Thalidomide: The Fifty Year Fight (no longer available)".

7. "The National Advisory Council (NAC)". The Thalidomide Trust. Archived from the original on 21 January 2011. Retrieved 2 July 2020. 15 May 2014. Retrieved 13 September2015.

8. "International Drug Monitoring: The Role of National Centers" (PDF) Retrieved February 27, 2015."Preparing for a Safety Inspection" (PDF). Steve Jolley. 2011. Retrieved January 4, 2016.

9. Essentials of Medical Pharmacology 8th edition

10. Current Challenges in Pharmacovigilance: Pragmatic Approaches 2001 Geneva.

11. "The Importance of Pharmacovigilance - Safety Monitoring of Medicinal Products: Chapter 2 - A Short History of Inv 'The Times' online November 5, 2006 11) ^ Database Involvement in Drug Safety Monitoring by WHO".

Received on 27.03.2023 Modified on 22.04.2023

Asian J. Res. Pharm. Sci. 2023; 13(3):241-247.

DOI: 10.52711/2231-5659.2023.00042