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About W.H.O
The World Health Organization is the United Nations
specialized agency for health. It was established on 7 April
1948. WHO's objective, as set out in its Constitution, is
the attainment by all peoples of the highest possible level
of health. Health is defined in WHO's Constitution as a
state of complete physical, mental and social well-being and
not merely the absence of disease or infirmity.
WHO is governed by 192 Member States through the World
Health Assembly. The Health Assembly is composed of
representatives from WHO's Member States. The main tasks of
the World Health Assembly are to approve the WHO programme
and the budget for the following biennium and to decide
major policy questions.
W.H.O
(World Health Organisation)
The Return of Thalidomide: New Uses and Renewed Concerns
Dr V Pannikar, Medical Officer, Communicable Diseases
(Leprosy Group), WHO
History
Thalidomide or α-(N-phthalimido) glutarimide was marketed in
1957 for morning sickness and nausea and soon became the
‘drug of choice to help pregnant women’. It went into
general use by the following year and was widely prescribed
in Europe, Australia, Asia, Africa and the Americas1.
Allegedly, the drug was harmless and a lethal dose could not
even be established2. However, in the early
1960s, in what might be described as the worst case of
pharmaceutical oversight, the drug was found to be
associated with a congenital abnormality causing severe
birth defects in children born of women who had been
prescribed this drug during pregnancy. More than 10, 000
cases of birth defects were reported in over 46 nations
following thalidomide exposure. Children were born with
missing (amelia) or abnormal (phocomelia) legs, arms, feet
and hands; spinal cord defects; cleft lip or palate; absent
or abnormal external ears; heart, kidney, and genital
abnormalities; and abnormal formation of the digestive
system. It is estimated that 40% of thalidomide victims died
within a year of birth3. Today there are
approximately 5000 thalidomide survivors1. The
‘thalidomide syndrome’ trig-gered a world wide response.
Safety monitoring systems were set up to prevent this
tragedy ever happening again and the drug was taken off the
market in many countries in 1961.
Thalidomide in Leprosy
A few years later, however, the drug thalidomide was
reintroduced as treatment for a complication of leprosy
called erythema nodosum leprosum (ENL). Although the
evidence was not fully established, very soon the drug was
heralded as the drug of choice for the management of ENL
reactions in leprosy and regulatory authorities granted
exemption from licensing requirements to enable doctors to
obtain limited supplies of thalidomide under strictly
controlled circumstances for use in named patients.
Thalidomide's effectiveness in minimizing symptoms of ENL
was mainly due to its antipyretic action. Its effectiveness
in controlling neuritis, the major cause of permanent
disabilities in leprosy, was limited.
Several controlled studies done in the 70's have
demonstrated that predni-solone is more effective in
controlling ENL and associated neuritis4-6. In
addition, it was demonstrated that clofazimine, an
anti-leprosy drug introduced on a small scale in the early
60's had anti-inflammatory action7,8. Studies
showed that clofazimine is the drug of choice for the
management of chronic, recurrent ENL reactions, as it had
both anti-reaction and anti-leprosy effect. Moreover, while
almost all patients given thalidomide relapsed after
discontinuation of the drug, none of the patients treated
with clofazimine for ENL reactions relapsed9-11.
The drug clofazimine is now a component of the multidrug
therapy (MDT), introduced by WHO in 1981 as the standard
treatment for leprosy. The presence of clofazimine in the
combination has significantly reduced the frequency and
severity of ENL reactions world-wide12,13.
Today ENL reaction is a rare complication, limited to a
small proportion of multibacillary patients. Most of the
ENL reactions are mild in nature and do not require any
specific treatment except with some
analgesics/antipyretics. In those suffering ENL associated
neuritis, the drug of choice is prednisolone. For chronic
recurrent reactions the drug of choice is clofazimine.
Thalidomide in other indications
The above points clearly demonstrate that there is no place
for thalidomide in leprosy. But very often this disease is
used as an entry point to reintroduce thalidomide for a
multitude of other indications. Millions of treatments are
being prescribed annually and almost all of it is for
non-leprosy conditions including cancer treatment and use in
HIV. There are limited trials demonstrating the efficacy of
thalidomide in other conditions14,15. Each
condition must be evaluated in its own right and there must
be put in place stringent restrictions on its availability.
In addition there must be a monitoring system in place.
There is no justification in extrapolating data from
monitoring systems for leprosy to other conditions. The
medical community that support the use of thalidomide for
other conditions should make their own case for the drug.
They cannot base it on the leprosy studies which are
anything but exhaustive.
In conclusion
Today, a large number of thalidomide babies continue to be
born each year16-18 possibly reflecting
regulatory insufficiency and widespread use under inadequate
supervision. In Brazil, which has more than 1000 registered
thalidomide victims, the last officially known case was born
in 199519,20. There is evidence that second
generation babies with similar deformities are being born to
thalidomide victims21,22. In the US, Celgene
Corporation has had FDA approval to market the drug since
1998 for the cutaneous manifestations of moderate to severe
erythema nodosum leprosum. In Europe, the US company
Pharmion Corp and French rival Laphal have both secured
orphan drug status for thalidomide and have applied to
market the drug as a therapy for multiple myeloma and for
ENL in the EU. The EU is currently holding discussions on
the re-launch of thalidomide. Whatever the outcome of the EU
discussions, it cannot be over emphasized that any potential
benefit with thalidomide must be balanced with the known
toxicity and the accompanying ethical and legal constraints
on its use. Experience has shown that it is virtually
impossible to develop and implement a fool-proof
surveillance mechanism to combat misuse of thalidomide.
References:
1.
What is Thalidomide? TVAC: Thalidomide Victims Association
of Canada, September 01, 1999.
Available: http://www.thalidomide.ca
2.
James JS. (ATN) Thalidomide and HIV: Background. AIDS
Treatment News Issue #179, July 23, 1993.
Available : http://www.aegis.com/pubs/atn/1993/ATN17902.html
3.
Lenz W. The History of Thalidomide. TVAC: Thalidomide
Victims Association of Canada, September 01, 1999.
Available: http://www.thalidomide.ca
4. Dharmendra. Leprosy Volume 1, 1978, Kothari Medical
Publishing House, Bombay, India.
5. WHO. The final push strategy to eliminate leprosy a
public health problem, questions & answers, second edition,
2003, WHO, Geneva.
6. Ramu G and Iyer CG. Treatment of reactions in leprosy.
In : A window on leprosy, 1978. Edited by Chatterjee BR.,
published by Gandhi Memorial Leprosy Foundation
7. Browne SG. B 663 - possible anti-inflammatory action
in lepromatous leprosy. Leprosy Review, 1965, 36: 9.
8. Waters MFR. Transactions of the Ninth International
Leprosy Congress, International Journal of Leprosy, 1968,
36: 560.
9.
Iyer CG et al.
WHO coordinated short term double blind trial with
thalidomide on the treatment of acute lepra reactions in
male lepromatous cases. Bull World Health Org 1971, 45: 719.
10. Iyer CG, Ramu G. An open trial with clofazimine in the
management of recurrent lepra reaction using thalidomide as
a control drug. Leprosy in India, 1976, 48: 690.
11. Ramanujam K, Iyer CG, Ramu G. Open trial with
clofazimine in the management of recurrent lepra reaction
and of sulphone sensitive cases: A preliminary report.
Leprosy Review, 1975, 46 (supplement): 117.
12. Becx-Bluemink M, Berhe D. Occurrence of reactions, their
diagnosis and management in leprosy patients treated with
multidrug therapy; experience in the Leprosy Control
Programme of All Africa Leprosy and Rehabilitation Training
Centre (ALERT) in Ethiopia. International Journal of Leprosy
and Other Mycobacterial Diseases, 1992, 60(2): 173.
13. Willcox, M.L. The impact of multidrug therapy on leprosy
disabilities. Leprosy Review, 1997, 68: 350.
14. Wines, N.Y., Cooper, A.J. and Wines, M.P. Thalidomide in
dermatology. Australian Journal of Dermatology, 2002, 43(4):
229.
15. Gaspari A. Thalidomide neurotoxicity in dermatological
patients: The next “STEP”. The Journal of Investigative
Dermatology, 2002, 119: 987.
16.
FDA tries to plug risky drug loopholes. The Associated
Press, ABCNEWS.com, December 9, 2002.
Available: http://www.boston.com/globe
17. Kranish, M. New use is found for thalidomide: Fighting
cancer. Boston Globe Online, October 20, 2002
18.
40 years after the thalidomide holocaust.
Available: www.thalidomide.org/FfdN/Grunen/Grunthl.html
19. Castilla EE et al.
Thalidomide, a current teratogen in South America.
Teratology1996, 54: 273.
20. Communication from CEATOX - Centro de Assistência
Toxicológica, Instituto da Criança Prof. Pedro de Alcantara,
Hospital das Clinicas da Faculdade de Medicina da U.S.P,
Brazil.
21. "Second generation" Thalidomide claims. BBC News,
Health, October 2, 2000.
22. A curse on my baby. Sunday Times Focus, July 20, 1997.
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