REBIRTH OF THALIDOMIDE

REBIRTH OF THALIDOMIDE

N. Swetha, Randeep Rajendran, Teena Tom

National College of Pharmacy, Manassery, Calicut

Cite this: N. Swetha, Randeep Rajendran, Teena Tom, "REBIRTH OF THALIDOMIDE", B. Pharm Projects and Review Articles, Vol. 1, pp. 1722-1763, 2006. (http://farmacists.blogspot.in/)

 

INTRODUCTION

 

Thalidomide, first synthesized in 1953, was widely prescribed for morning sickness of pregnant woman from 1957 to 1961, when it was found to be seriously teratogenic, having caused serious birth defects. More than 8000 children's worldwide were born with such thalidomide deformities as flipper like arms and legs.

 

Thalidomide was never approved in the US until recently, when it was approved for use in the treatment of leprosy – related conditions. However, there has been renewed interest in thalidomide over the past several years particularly in the treatment of AIDS –related conditions, cancers and HIV induced wasting complications of leprosy and bone marrow transplant related graft – versus host disease.

 

Thalidomide is a derivative of glutamic acid and glutethimide but has a different activity profile. It has sedative hypnotic, anti-inflammatory and immunosuppressive effects.

 

 

THE BIRTH OF THALIDOMIDE:

 

    Thalidomide is off-white, nearly odorless and crystalline powders. It first appeared in Germany in 1953. The discover, a west Germany company called Ciba, discarded the drug after it was found to have no pharmacological effect in animals. A few years later another west German company Chemic Grunenthal, found that it worked as a hypnotic producing a deep sleep without hangover. The company launched Thalidomide under the name contergan on October 1, 1957.

 

    In pregnancy and during the lactation period, the females are under great strain. Sleepless, unrest and tension is constant complaints. The administration of a sedative and hypnotic that will hurt neither mother nor child is often necessary.
During this period Thalidomide was given to pregnant woman for morning sickness. The company had not engaged in prior animal testing yet the physicians were assured that the drug was safe. Pregnant women were given the drug but the drug sent shock waves around the world when it was proven that the purportedly harmless drug given to pregnant women as a sedative to combat morning sickness was the cause of debilitating birth defects. While more than 8000 children worldwide were born with such deformities as flippers like arms and legs. The first Thalidomide baby was born on Christmas day, 1956 in Stolberg, Germany.

 

    Thalidomide lacked the typical addictive properties of barbiturates and produced a natural, calm sleep. Further more a median lethal dose (LD 50) could not be established in rodent models and death in humans from accidental or intentional over dosing was practically impossible. Thus, Thalidomide was believed to be basically nontoxic compared with others available sedatives and become popular as both a sedative and a morning sickness treatment during pregnancy. Thalidomide was marketed under various commercial names such as Contergan, Distaral , Softenon, Neurosedyn Isomin ,Kedavon, Telargan and Sedalis. By late 1961, thalidomide was withdrawn from the world market. ⁽¹⁾

 

CHEMISTRY

 

    Thalidomide also known as alpha (N- Phthalimido) glutarimide, consist of a two –ringed structure with an asymmetric carbon in the glutarimide ring. Thalidomide exist as an equal mixture of S-C-(-) and R- (+) enantiomers that interconvert rapidly under physiologic conditions. Thalidomide is sparingly soluble in water and ethanol which to date has prevented the availability of an intravenous formulation ⁽²⁾.

 

 

 

 

 

 

    
 

 

 

PHARMACOKINETICS:

 

    Due to poor aqueous solubility, the absolute bioavailability of Thalidomide is unknown. Time to maximal concentration (Tmax) ranged from 2.9 to 5.7 has in patients with Hansen's disease and healthy volunteers.⁽⁸⁾ Mean peak levels of 0.47 and 1.5 rncg / ml are evident at 4 and 6 hours following 100 and 200 mg doses. Doses of 800 mg/ day yield peaks of 5 mcg/ml. The mean volume of distribution is 120 L with high levels found in the a GI tract, liver and kidney and lower levels detected in muscle, brain and adipose tissue Thalidomide appears to be highly protein bound.Degradation appears to be mainly by non - enzymatic hydrolytic cleavage with only the parent compound possibly being modified by the P4W system. Total body clearance is 10.5 L/hr with an elimination half life of 8.7 hrs. Urinary excretion accounts for 0.6% of the total dose indicating predominantly a non – renal route of elimination. Renal dysfunction would be expected to have minimal effects on Thalidomide's pharmacokinetics.

 

THE HISTORY OF THALIDOMIDE

 

    On November 18, 1961, four years after Thalidomide entered the market, Widukind Lenz a German physician and geneticist, indicated that Thalidomide was associated with severe teratogenic malformations. He had observed more than 50 malformed infants whose mothers had taken the drug during pregnancy. ⁽³⁾ The first child afflicted by Thalidomide damage to the ears was born on Dec.25, 1956.

 

 

 

    More than 10,000 children around the world were born with major malformations many missing arms and legs, because their mother's had taken the drug during early pregnancy. Mother who had taken the drug when arms and legs were beginning to form had babies with a widely varying but recognizable pattern of limb deformities. The most well known pattern, absence of most of the arm with the hands extending flippers like from the shoulders, is called phocomelia. Another frequent arm malformation called radical aplasia was absence of thumb and the adjoining bone is the lower arm. Similar limb malformation occurred in the lower extremities. The effected babies almost always had both sides affected and often had both the arms and the legs malformed. In addition to the limbs, the drug caused malformations of the eyes and ears, heart, genitals, kidneys digestive tract (including the lips and mouth) and nervous system. Thalidomide was recognized as a power full human teratogen (A drug or other agent that causes abnormal development in the embryo or fetus). Taking even a single dose of thalidomide during early pregnancy may cause major birth defects.

 

    Thalidomide may cause quite different malformations in different children. In one case, the ears are missing, there is deafness and paralysis of the muscle of the eyes and the face, but the limbs are normal. In another case, the ears are normal, but the arms are missing. In a third case there are severely shortened arms with only 2 or 3 fingers. In a fourth case, only the thumbs are abnormal with three joints, possibly accompanied by narrowing of the anus. The individual type of Thalidomide malformation depends on the time of intake. Thalidomide does not produce malformations if only taken before the 34^th day after the last menstruation and usually no malformations if taken only after the 50^th day.

 

 

    Within the sensitive period from day 35 to day 49 there is the following sequence:

1. Absence of ears and deafness : 35 – 37^th day
2. Absence of arms : 39 – 41^st day
3. Phocomelia with 3 fingers: 43^rd - 44^th day
4. Thumps with 3 joints : 46^th - 48^th day

 

If Thalidomide has been taken throughout the sensitive period, the consequence may be series defects of ears, arms, legs and of internal malformations which often led to early death.

 

    About 40% of Thalidomide victims died before their first birthday. ⁽⁴⁾

 

    After decades passing, the nightmare drug responsible for over so many human birth deformities continues to rear its ugly head with the appearance of its dreadful effects being passed on to the children of the victims.

 

    In the British Sunday Mirror of July 3, 1994(Thalidomide dad's tragedy), it was reported that the babies of 6 young men who were born deformed because of Thalidomide have also been born with malformed limbs. Two of the babies have almost identical deformities to their father's ⁽⁵⁾.

 

    There are 8000 survivors of Thalidomide in the world today. There are 3000 in Germany, 1000 in Europe and others in Japan, Asia and Latin America. There is a small group of 230 in Brazil who are still fighting today for compensation and recognition. Brazil is an example to day of Thalidomide use out of control. Several organizations for these affected individuals exist including the Thalidomide victims associations of Canada.

 

 

THE REBIRTH OF THALIDOMIDE

    In 1965 article, an Israeli doctor reported the remarkable effects thalidomide had in alleviating complications of leprosy. Since then, through controlled clinical trials and FDA compassionate-use programs, the drug has been found to be effective in treating a myriad of disorders, including certain mycobacterial and autoimmune diseases, HIV and AIDS-related afflictions, cancer, and miscellaneous skin conditions.

 

A. Microbacterial Diseases

Approximately ten to fifteen million people worldwide suffer from leprosy, or Hansen's Disease, a chronic disease of the skin and peripheral nervous system. In 1965 Israeli dermatologist Jacob Sheskin accidentally discovered that thalidomide rapidly alleviated ENL symptoms.⁶ Following the ingestion of thalidomide, the lesions of six patients, all of whom suffered from the lepromatous form of leprosy, showed significant clearing after a mere twenty-four to forty-eight hours.⁷ The dermatologist then embarked on a fifteen-year worldwide study that included 4522 ENL patients. The results were remarkable: 99% showed improvement with thalidomide treatment. Sheskin also noted the remission of other side effects such as headache, anorexia, and vomiting.⁶

 

In 1991, a team of Rockefeller University scientists discovered that thalidomide aided the immune system by suppressing a protein responsible for inflammation called tumor necrosis factor-alpha (TNF-alpha).⁷ Once researchers determined that increased TNF-alpha was present in patients with TB and ENL, they hypothesized that thalidomide would treat both diseases effectively.⁸

 

B. HIV and AIDS-related disorders

The combination of the Rockefeller findings and the discovery that patients with HIV possessed increased levels of TNF-alpha led researchers to test the efficacy of thalidomide on HIV and AIDS-related disorders. Preliminary success has been found in cachexia (or wasting syndrome), recurrent aphthous ulceration, and Kaposi's Sarcoma.

 

Thalidomide has proven to aid weight gain in small clinical trials. For example, in a trial sponsored by the National Institute of Nutrition in Mexico City, researchers found that in a twelve-week trial of twenty-eight patients, eleven of the fourteen receiving thalidomide either gained weight or remained stable (79% efficacy) compared to four of fourteen in the placebo group (29%).⁸ Similarly, another study reported a mean percentage body weight increase of 2.07% after one week and 3.06% after two weeks of thalidomide therapy in a trial of thirteen HIV-infected patients.
Presently, FDA has approved an expanded-access program for cachexia patients experiencing an involuntary loss of 20% or more body weight and for whom alternative treatments have failed. ⁸

 

Another complication of AIDS thought to be relieved by thalidomide is recurrent aphthous ulceration. In 1997, an article in the New England Journal of Medicine reported that thalidomide is an effective treatment for aphthous ulceration of the mouth ^{8, 15} .As part of a large AIDS Clinical Trials Group study (ACTG #251) the group of researchers found that the ulcers of 55% of the patients taking thalidomide completed healed within four weeks and 90% exhibited either complete or partial healing. ⁸ These results were compared to healed ulcers in only 7% of the placebo group, with 28% showing complete or partial healing.⁸ Furthermore, patients reported that thalidomide alleviated the pain associated with aphthous ulcers and improved their ability to eat. ⁸

 

Despite the promising results described above, The New England Journal of Medicine article disclosed a disturbing result: thalidomide increased the patients' HIV-viral load.
Although earlier studies had found thalidomide to suppress TNF-alpha, the thalidomide-treated patients in this study actually experienced increased and higher levels of TNF-alpha than those in the placebo group.
Because increases in TNF-alpha enhance the production of HIV and the strength of the disease, the researchers discouraged the use of thalidomide in HIV-infected patients for longer than a two to four week period of time.

 

Thalidomide is also under investigation for the treatment of Kaposi's sarcoma (KS), the cancerous lesions commonly associated with AIDS.⁸ Prevalent in HIV-infected homosexual men,⁵ the lesions, sometimes over a hundred in number, may appear anywhere on or in the body. While lesions on the skin are most common initially, they later appear in the mouth in approximately one-third of HIV patients and in the gastrointestinal tract in 40%. Social isolation, anguish, and depression are common as a result of the unsightly lesions.

 

The study of thalidomide treatment for Kaposi's sarcoma is still young and researchers continue to recommend conventional available treatments like chemotherapy and radiotherapy. ⁹ A few researchers report efficacy in individual cases,
but others caution that the results may have arisen from mechanisms other than thalidomide.

 

C. Autoimmune diseases

Thalidomide's ability to suppress TNF-alpha and affect other cell activity⁶ has sparked scientific interest in the drug's ability to combat certain autoimmune diseases like lupus and rheumatoid arthritis. Currently, clinical trials are testing thalidomide's usefulness in lupus erythematosus, rheumatoid arthritis, and Crohn's disease.¹⁰

 

Thalidomide's efficacy has been established in certain forms of lupus. Simply stated, there are two major forms of lupus: discoid lupus erythematosus (DLE), a generally mild, but sometimes chronic, form of the disease manifesting in a red, scaly rash usually located on the face, and systemic lupus erythematosus (SLE), the more common and severe form of lupus that includes rash, swelling of the joints, organ inflammation, and ulcers in the mouth or nose. ¹⁰ The effectiveness of thalidomide in DLE patients was established early in the 1980s and the drug has shown similar promise for SLE. For example, a study of 23 SLE patients reported that 90% had complete remission with thalidomide treatment.

 

The drug has also shown some promise in small rheumatoid arthritis studies. For example, in an open study of seven female patients, thalidomide was found to relieve pain and joint inflammation in all cases.
Four of the women even enjoyed remission long after withdrawal of the drug. ¹⁰ Similarly, in a later thalidomide study involving seventeen patients, seven experienced complete remission and five partial remissions.

 

D. Cancer and Related Disorders

Aside from suppressing TNF-alpha, thalidomide prevents angiogenesis, the formation of new blood vessels. ¹⁰ This property, which was responsible for stunting the uterine limb growth of the 1950s and 60s thalidomide babies, may prove useful in combating breast and prostate cancer by preventing new tumor growth. ¹⁶ Preliminary results from the National Cancer Institute's prostate cancer study showed the drug stabilized the disease and lowered the PSA (or prostate-specific antigen) levels of all eighteen participants.¹⁰ Presently, over 100 individual cancer patients use thalidomide on what FDA calls "an emergency basis."

 

Thalidomide's antiangiogenesis properties have given researchers at Harvard Medical School and the University of Pennsylvania hope of using the drug for macular degeneration, a blinding eye disorder caused by harmful blood vessel growth and retinal bleeding.¹⁰ The two institutions have teamed up to study the early stages of the disease in a small clinical trial.

 

Chronic graft-versus-host disease (CGvHD) is another area of study. The disease, a complication of leukemia associated with bone marrow transplants, occurs in approximately 40% of patients who survive 100 days following their transplant.¹⁰ Research shows that 52% of all patients with CGvHD do not survive.
Like many of the aforementioned disorders, the increased level of TNF-alpha in CGvHD sufferers led researchers to believe thalidomide would be an effective treatment.¹¹ Several studies have confirmed this hypothesis in chronic cases.¹²

 

E. Miscellaneous Skin Conditions

One final area of general thalidomide study involves special skin disorders, including Behçet's syndrome. Numerous individual case studies have found thalidomide useful in treating Behçet's disease, a multisystem disorder presenting oral and genital ulcers, arthritis, colitis, and painful lesions on the skin and eyes, ¹² but not until last year were researchers able to replicate the results in a controlled trial. In that instance, a group from the Behçet's Syndrome Research Center in Istanbul, Turkey found thalidomide effective in suppressing existing oral and genital ulcers as well as preventing the formation of new ones.
Not surprisingly, the ulcers recurred after thalidomide treatment ceased.⁹ A disturbing and unique side effect was an increase in the number of ENL lesions during the first eight weeks of the thalidomide treatment.¹²

 

SIDE EFFECTS

Despite the great strides made with thalidomide, researchers have been unable to prevent the dangerous side effects responsible for its notoriety. Aside from the drug's teratogenicity,¹⁷ nerve damage, or neuropathy, remains the leading concern of widespread thalidomide use. Since the drug has been tested in such a wide range of diseases, the overall incidence of the condition is difficult to determine. While one retrospective study found thalidomide-induced neuropathy to occur in 21-50% of various dermatologic cases, others focus on specific disorders, citing rates as high as 70%.¹² Early reports that neuropathy does not strike ENL patients taking thalidomide (or occurs in as little as 1% of patients) have recently come into question by those who argue that the distinction between nerve damage caused by the leprosy itself and that caused by thalidomide was not properly made. ¹⁷ Furthermore, the use of thalidomide for complications of AIDS has presented special problems since preexisting neuropathy is common in HIV patients and such patients as a whole have been shown to be particularly sensitive to the drug. ¹⁷, ¹⁸

 

While many studies report that the neuropathic symptoms (which include numbness of the arms, hands, legs, or feet as well as general muscle weakness) ceased upon discontinuation of the drug, ¹⁷ it is well known that thalidomide-induced nerve damage can be irreversible and can occur when even small doses of the drug are administered. ^{17, 19}

 

Aside from neuropathy and birth defects, thalidomide patients have reported, among other things, drowsiness, dizziness, mood swings, nausea, and headaches.

 

Management of thalidomide Side effect
Side effect	Management strategy
Drowsiness	May decrease after several weeks of the therapy, but may require schedule or dose adjustment .Can be minimized by taking thalidomide between 7:00 and 10:00in the evening or by twice –daily dosing. If severe, may be treated with dose reduction +/- temporarily stopping thalidomide. Discontinuation of therapy is not normally required.
Constipation	Managed with adequate fluid intake, high fiber intake, daily use of stool softener, and laxatives, as required
Dizziness	Patients should sit upright for a few minutes, if they have been lying down, before they stand up. If severe, require dose adjustment.
Dry skin/Rash	Dry skin may be confused with a mild rash, but can be relived with lotion. Rash can range from mild to severe, and stopping therapy usually brings prompt relief. Itching can be managed with antihistamines or topical steroids. After clinical evaluation to rule out serious skin reactions, thalidomide can be restated at a lower dose, with close monitoring over the first few doses
Peripheral neuropathy	In cancer patients receiving thalidomide, the appearance of neuropathy may be related to long term use of the drug /or previous exposure to large doses of chemotherapy drugs, which also cause neuropathy. Symptoms may resolve if therapy is disconnected when they first appear, but neuropathy is often not reversible. Mild neuropathy is very common; in the absence of progression, the dose of Thalidomide should be kept the same. However, for symptomatic neuropathy, a dose reduction may be helpful. In more severe cases, stopping the drug temporarily may improve symptoms and allow thalidomide to be reinitiated at a lower dose.

 

 

STEPS

    

    In order to support the safe and appropriate use of drug, due to cancer about the teratogenic potential of Thalidomide in humans when the drug is taken during pregnancy, celgene has developed a unique and comprehensive patient physician and pharmacist education and distribution system to be called the system for Thalidomide education and prescribing safely (steps).

 

Major components of STEPS program include:

 

• Physicians prescribing Thalidomide and pharmacists dispending the drug will register and receive educational materials explaining risks and pregnancy prevention methods, as well as expected side effects of therapy.

 

• All females who are candidates for thalidomide therapy will be required to undergo pregnancy testing before starting treatment and periodically thereafter.

 

• Women will also be required to use effective birth control while taking the drug.

 

• Men using the drug will be required to use condoms when having sexual relations with women.

 

• All candidates for Thalidomide therapy will be provided with counseling by the physician and comprehensive multicultural and multilingual educational material clearly explaining the risk of use.

 

• Patients will be required to sign an informed consent form after an explanation of the risk of Thalidomide use by the physician.

 

• Before a prescription is filled, a copy of the informed consent form must be presented at a pharmacy pre-registered to dispense Thalidomide.

 

• Persons using Thalidomide will be required to participate in a patient survey designed to determine compliance with the STEPS program and any situations involving pregnancy.

 

• Patients will be instructed never to share the drug with other persons, including friends or relatives with the same symptoms for which Thalidomide was prescribed.

 

• Thalidomide packaging will contain clear and prominent warnings about the risks associated with use. Prescriptions for Thalidomide will be no more than a 28 day supply with no automatic renewals.

 

 

CONCLUSION AND DISCUSSION

 

 

    Thalidamide is currently being investigated for several different conditions. Despite serious safety issues (ex. Teratogenicity and peripheral neuropathy) it may be useful in select patients. Presently it is used in the treatment of microbacterial diseases like leprosy and TB, cancer and related conditions, HIV and AIDS related conditions.

 

 

REFERENCE:

 

1. Lenj.W. Thalidomide and congenital abnormalities (letter).Lancet.1962; 1:45; SP Ward,  Thalidomide and congenital abnormalities Br Med J. 1962 Sep 8; 2(5305): 646–647. [Cross Reference PDF ]
2. Thalidomide capsules (Thalidomide) prescription product insert. Wareen, NJ: celgenc corp; revised August 1998.
3. Mc Bride W.G Thalidomide & congenital abnormalities(letter) Lancet 1961; 2:1358
4. Http://www.thalidomidecalen/index.html
5. Thalidomide horrors show up in the children of victims, Gold coast bulletin, Australia, April 26,1995.
6. Sharon M. Martin & Graeme J. Kutt, Leprosy: Medieval Myth or Modern Menace?, 7 Clinical Laboratory Sci. 283, 283 (1994).
7. Jacob Sheskin, Thalidomide in the Treatment of Lepra Reactions, 6 Clinical Pharmacological Therapy 303 (1965).
8. See Jacob Sheskin, The Treatment of Lepra Reaction in Lepromatous Leprosy: Fifteen Years' Experience with Thalidomide, 19 Int'l J. Dermatology 318, 319 (1980)
9. E.P. Sampaio et al., Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes, 173 J. Experimental Med. 699 (1991).
10. Cytokine Regulation of Disease Progression in Leprosy and Tuberculosis, 191 Immunobiology 564, 566 (1994).
11. Gilla Kaplan, Cytokine Regulation of Disease Progression in Leprosy and Tuberculosis, 191 Immunobiology 564, 566 (1994).
12. Gilla Kaplan, Cytokine Regulation of Disease Progression in Leprosy and Tuberculosis, 191 Immunobiology 564, 566 (1994).
13. Gilla Kaplan, Cytokine Regulation of Disease Progression in Leprosy and Tuberculosis, 191 Immunobiology 564, 566 (1994).
14. Paul J. Weidle, Thalidomide for aphthous ulcers in patients infected with the human immunodeficiency virus, 53 Am. J. Health-Sys. Pharm. 368, 368 (1996).
15. Debra Birnkrant, Thalidomide for Aphthous Ulcers in HIV Infection: Letter to the Editor, 336 New Eng. J. Med. 1086, 1086 (1997).
16. E. Krown, Acquired Immunodeficiency Syndrome-Associated Kaposi's Sarcoma: Biology and Management, 81 Med. Clinics N. Am. 471, 484 (1997).
17. Rolf A. Solèr et al., Regression of AIDS-Related Kaposi's Sarcoma During Therapy with Thalidomide, 23 Clinical Infectious Diseases 501, 503 (1996).
18. David Stirling, Celgene, Personal Communication, Jan, 1997.
19. Powell RJ, Garner-Medwin JMM Postgred Med, J. 1994; 70 901-904.

 

Cite this: N. Swetha, Randeep Rajendran, Teena Tom, "REBIRTH OF THALIDOMIDE", B. Pharm Projects and Review Articles, Vol. 1, pp. 1722-1763, 2006. (http://farmacists.blogspot.in/)