MARZO 2.004
MARCH 2.004
THE NIMESULIDE,
FALLEN ANGEL !!!
Don't give this drug to your
son because it can become a new fallen angel!!!
1.) 2 YEARS OLD BOY DIED FOR PRESUMED BAD MEDICAL PRACTICE
in Venezuela Aragua State, Maracay/ (A fallen Angel !!!. )
2.) The Origin of the Nimesulide.
3.) Nimesulide not safe, insist doctors.
4.) PIL seeks ban on manufacture, sale
of Nimesulide.
5.) INDIA: MEDICAMENTO VINCULADO A MUERTES DISPONIBLE EN EL MERCADO.
6.) [Bleeding gastric
ulcers and acute hepatitis: 2 simultaneous adverse reactions due to nimesulide
in a case].
7.) Nimesulide-induced severe hemolytic anemia and
acute liver failure leading to liver transplantation.
8.) Nimesulide-induced fulminant hepatitis.
9.) Efficacy of Nimesulide in Pain Relief after Day Care Surgery.
10.) Hepatitis tóxica en gestante por nimesulida.
1.) 2 YEARS OLD BOY DIED FOR PRESUMED BAD MEDICAL
PRACTICE in Venezuela Aragua State, Maracay. / (A fallen Angel !!!)
Source: The Century: Maracay Venezuela Aragua State. THURSDAY MARCH 18 2004
Francisco Ronny, a 2 year-old boy's father, I denounce to the representatives
of the press that last Tuesday to the 10.30 30 Pm of the night died in the
Service of Pediatrics of the Central Hospital of Maracay, his small son because
of a presumed bad medical practice carried out in the population of Villa of
Cure.
Ronny who resides in the marked house with the number 93, located in the Sector
5 Guayabal, in San Francisco of Asis, and that he works as electrician, I show
that their son transfers it to the Anticancerous of Villa of Cure with a nasal
problem, this happened 8 days ago behind.
There, the Dra XXXXX XXXXXXXX prescribed him 2 medications, ONE WELL-KNOWN AS
KLAS (ambroxol-teofilinate) and the other
NIMESULIDE, which it should be given them together with the intention
to counterattack the affection that harmed the boy.
Then the boy's mother, Rosa Aponte, continued to the I tweeted of the letter the
surgeon's recommendations and the Tuesday, in hours of the morning, KEVIN RONNY
APONTE presents an impairment of his health.
Subsequently it was transferred - she relates - to the Central Hospital of
Maracay, where the medical staff manifested him that these chemical products
should not be given them together, with the intention of avoiding a strange
reaction.
The Physicians ordered him immediately to practice him exams of toxicology in
the Central Hospital of Maracay whose results gave as positive that the cause of
the worsening was the medicins. The death took place as consequence of a heart
arrhythmia....
NIÑO DE 2 AÑOS MURIO NIÑO POR PRESUNTA MALA PRAXIS
MEDICA en Venezuela, Maracay Estado Aragua./ (Un angel caido !!!)
Source: EL SIGLO . MARACAY JUEVES 18 DE MARZO DE 2004
Francisco Ronny, padre de un niño de 2 años, denuncio ante los representantes de
la prensa, que el pasado martes a las 10 y 30 Pm de la noche fallecio en el
Servicio de Pediatría del Hospital Central de Maracay, su pequeño vastago a
causa de una presunta mala praxis medica realizada en la poblacion de Villa de
Cura.
Ronny, quien reside en la casa marcada con el número 93, situada en el Sector
5 Guayabal, en San Francisco de Asis, y que se desempeña como electricista,
manifesto que su hijo lo traslado al Anticanceroso de Villa de Cura con un
problema nasal, esto ocurrio hace 8 dias atras.
Alli la Dra XXXXX XXXXXXX le recetó 2 medicamentos, UNO CONOCIDO COMO
KLASS (Ambroxol y teofilina) y el otro
NIMESULIDE, los cuales debia
suministrarselos juntos con la intencion de contraatacar la afección que lo
perjudicaba.
Luego la madre del niño, Rosa Aponte, siguió al pié de la letra las
recomendaciones de la cirujana y este martes, en horas de la mañana, KEVIN RONNY
APONTE presento una dolencia señala la denunciante.
Seguidamente fue transferido - relata - al Hospital Central de Maracay, donde
los médicos tratantes le manifestaron que estos productos químicos no debían
darselos juntos, con la intencion de evitar una reaccion extraña.
Los Galenos le ordenaron de inmediato practicarle exámenes de toxicología en
el Hospital Central de Maracay, cuyos resultados dieron como positivo que la
causa del agravamiento eran los farmacos. La muerte se produjo como consecuencia
de una taquicardia...
2.) The Origin of the Nimesulide.
Source:
Http://www.essentialdrus.org/
Dr. Chandra M. Gulhati,
Editor, MIMS
e-mail: [email protected]
Dear All,
While reading all the comments on Nimesulide, it is
noticed that many facts (not opinions) on this drug
are not widely known. Briefly,
1. Nimesulide was discovered by 3M Pharmaceuticals, an
American manufacturer at St. Paul, Minnesota, United
States. Therefore the origin of the molecule is United
States, where it is not approved.
2. As per latest figures, the total world
pharmaceutical market is worth US$ 460 billion out of
which US alone accounts for 50% i.e. US$ 130 billion,
Europe about 25% and rest of the world 25%. Indian's
share is US$ 3.8 billion or less than 1%. Why would an
American company not launch its research product in
its home country? All other products (except
Nimesulid)discovered by 3M Pharmaceuticals are being
marketed in USA. The cost of discovery of a molecule
is US$ 500 to US$ 800 million in USA. This kind of
research expenses can never be recovered without entry
to US market.
3. 3M Riker - the parent company of 3M Pharmaceuticals
- is worth US$ 17 billion and spends over US$ 1
billion every year on research. It sold the molecule
to a small private company in Switzerland called
Helsinn. Helsinn, instead of launching Nimesulide in
Switzerland, licensed the drug to Boehringer in Italy
where it was launched in 1985. In Italy, it is
licensed for use in musculo-skeletal inflammation and
accompanying pain only. Its use in children below 6
years is prohibited.
4. Nimesulide was launched in Switzerland, the home
country of Helsinn, in 1995 i.e. 10 years after Italy
based on the human data from Italy. The Swiss
Government permitted its use in adults only. Its use
in children below 12 years is prohibited.
5. Everyone connected with pharma business around the
world knows that introducing new molecules in USA,
Britian, Australia, Denmark etc. is not very easy
while it is not very difficult in Italy and Brazil.
6. Today Nimesulide is licensed for use in just under
40 countries which also means that it is not permitted
for use in just over 150 countries.
7. In South East Asia (Thailand, Malaysia, Singapore
etc), Nimesulide is permitted to be used only in
adults for "Musculo-skeletal inflamation accompanied
by hyperpyrexia (temperature above 106.7 degree F)"
and no other condition.
8. India is the ONLY country on earth where Nimesulide
drops are marketed for use in neonates and infants.
The only other country where nimsulide is permitted in
children (apart from Italy) is Brazil where it is
prohibited below 3 years.
9. As per Rule 122 (E) of the Drugs & Cosmetics Act
read with Schedule Y, all drugs require mandatory
prior permission from Drugs Controller, India (DCI).
Fresh permission is required if a new formulation of
approved drug is to be launched such as sustained
release etc. In India only two formulations are
approved i.e. 100mg tablet and 50mg/5ml suspension.
The following formulations are being marketed without
DCI permission: 50mg tablets for kids, 25mg/ml drops,
200mg tablets, 400mg tablets, 100mg EF tablets, 100mg
MD tablets. Even when one company obtains permission
for any formulation, another company needs fresh DCI
approval if introducing the same drug within 4 years.
Over 170 companies in India are marketing nimesulide
single ingredient formulations without mandatory DCI
approval.
10. ALL fixed-dose combinations of nimesulide with
other agents such as paracetamol, diclofenac,
tizanidine etc are being marketed without mandatory
DCI approval. This fact has been admitted by DCI in
reply to a starred question in Loksabha on 20-08-2000.
India is the ONLY country on earth where nimesulide
with other agents is being marketed.
11. The retail price of Nimesulide for 10 tablets
ranges between Rs. 14.50 to Rs. 29. It is not the
cheapest "analgesic" or "antipyretic." It is about 200
to 400% more expensive. Besides the cost price of 10
tablets of nimesulide 100mg is Rs. 1.80. As per
ORG-MARG data, no other NSAID has such a huge profit
margin.
12. Several laboratory, animal and human studies in
Canada and USA have shown that Nimesulide is
partially, but not fully, COX-2 Selective. Besides,
Nimesulide inhibits COX-1 much BEFORE and AT MUCH
LESSER SERUM LEVELS. Thus it is not gastro-protective.
This was one of the reasons for aborting an attempt to
get USFDA approval in 1998.
13. All studies submitted to DCI in India by
manufacturers of Nimesulide were sponsored and
financed by Helsinn - many of them actually written by
Helsinn employees.
I will be happy to provide references for above facts
to anyone who needs them.
Dr. Chandra M. Gulhati,
Editor, MIMS
e-mail: [email protected]
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3.) Nimesulide not safe, insist doctors.
Source:
Http://www.indiatimes.com
KALPANA JAIN
TIMES NEWS NETWORK[ MONDAY, JANUARY 13, 2003 09:59:20 PM ]
DELHI : The `opinion poll' on Nimesulide conducted by the Indian Medical
Association calling it `safe' may not end the controversy over the popular fever
drug yet. For not only have medical researchers questioned the process but some
leading doctors have directly written to the Drug Controller of India to ban its
use.
Dr Meharban Singh, a leading pediatrician who is the former head of the
pediatrics department at the All India Institute of Medical Sciences, said that
it was not correct to issue blanket statements saying the drug is safe. He said
he was not part of this IMA opinion poll. ``IMA did not approach me.
I don't know who these 50 people are.'' He said the severe side-effects of the
drug have been documented and it needs to be used with caution.Among the doctors
who have written to the DCI asking for a ban of the drug are head of pediatrics
department at MS Ramaiah Medical College, Bangalore, Dr PP Maiya, past president
of National Neonatology Foundation and professor neonatology, KJ Samaiya Medical
College, Dr Simen Irani, head of pediatrics department at Calicut Medical
College, Calicut, Dr CK Shasidharan, general secretary of the Indian Academy of
Pediatrics, Jaipur branch, Dr Susheel Sanghi and president of the Indian Academy
of Pediatrics, Jaipur branch, Dr HS Bhasin.
The Nimesulide controversy arose as a result of the government ordering a review
of the drug following its ban in several countries. The Drug Controller of
India, Dr Ashwini Kumar, who was not available for comment on Monday, had said
earlier that the monitoring system in the country was highly inadequate and a ``scientific
conclusion''on this top-selling formulation would be difficult.Editor of the
Monthly Index of Medical Specialities, Dr CM Gulhati, says with the exception of
one or two, no country in the world, allows the use of this drug in children and
particularly infants. He said adverse drug reactions are not determined by
professional bodies of doctors anywhere in the world.
It is a science by itself and is done through certain mechanisms. Moreover, a
word from 50 doctors is not adequate when there are four lakh doctors in the
country.Honorary secretary general of the Indian Medical Association, Dr Sanjiv
Malik, however, said, the evaluation is as scientific as any evaluation done in
the past.
``I am confident we chose a good cross-section of people,'' he said.Optional
trim:Researchers point out that the only studies done on the drug have been by
the manufacturers themselves. But one of these also showed adverse drug
reactions in 261 patients out of a total of 4097. In all the package inserts
liver toxicity had not been mentioned as a common adverse drug reaction. On the
contrary, they said that ``rarely, a rise in liver enzymes has been reported.''
4.) PIL seeks ban on manufacture, sale
of Nimesulide.
Source: Http://www.hindu.com/
By Our Staff Reporter
CHENNAI SEPT. 26. A public interest litigation petition seeking to ban the
manufacture and sale of Nimesulide, a non-steroidal and anti-inflammatory drug,
has been filed in the Madras High Court.
The First Bench comprising the Chief Justice, B. Subhashan Reddy, and Justice A.
Kulasekaran, admitted the petition filed by the Tamil Nadu Health Development
Forum, and ordered notices to the Union Health Secretary and the Drugs
Controller-General of India.
The forum secretary and the former Director of the Institute of Child Health at
the Government Children's Hospital here, C.S. Rex Sargunam, contended that
though it was not an anti-fever drug it can bring down the temperature faster
than other anti-fever drugs like paracetamol.
He said the drug could cause severe sideeffects. ``A person does not die of
fever and joint pain, but dies of liver or kidney damage caused by the repeated
use of Nimesulide''.
According to Dr. Sargunam it was the most expensive non-steroided anti-inflammatory
drug and was not under the price control regime of the respondent-authorities.
In developed countries such as the United States, Britain, Canada and Australia,
Nimesulide is not approved for use even for adults, whereas Finland, Spain,
Turkey, etc., have banned the drug, the petition claimed.
Dr. Sargunam prayed for a direction to ban the manufacture and marketing of
Nimesulide.
5.) INDIA: MEDICAMENTO VINCULADO A MUERTES DISPONIBLE EN EL MERCADO.
Source:
Http://www.bolentinfarmacos.org/
Sanjay Kumar, BMJ, 2003; 326:70
El nimesulide, un anti-inflamatorio no esteroideo, se ha retirado de muchos
mercados europeos pero sigue estando disponible en India. Se sabe que es un
medicamento hepatotóxico y que ha provocado la muerte a varios niños. La India
aprobó este medicamento en 1994 para uso en casos de inflamación
musculoesquelética, sin embargo se utiliza frecuentemente como analgésico y
antipirético.
Según el Dr Chandra Mohan Gulhati, editor del Boletín de Información sobre el
Medicamento de India, el medicamento no está aprobado en EE.UU., Canadá,
Australia, y partes de Europa; y Finlandia, España y Turquía lo retiraron del
mercado el año pasado.
Después de que los medios de comunicación denunciaran el hecho, el responsable
de controlar los medicamentos en India, Ashwini Kumar, dijo que el gobierno
designaría a un comité de expertos para que estudiase el problema. El asistente
del Sr. Kumar, Ram Teke, dijo a BMJ que el medicamento sigue estando disponible
y que no había intención de reconsiderar su utilización o de retirarlo del
mercado. El volumen de ventas de este medicamento es del orden de 1900 millones
de rupíes (39,5 millones de dólares).
El nimeluside además de estar disponible como producto activo único, también
esta presente en otros 30 medicamentos y en gotas para niños menores de un año.
Todas estas combinaciones son ilegales porque no cuentan con el registro
correspondiente.
El Dr. Gulhati dice que no hay un buen sistema para informar sobre reacciones
adversas en India. Hay 12 medicamentos que se han retirado de los mercados
globales, o que son de prescripción limitada, que están disponibles en la India,
estos son: anagen, cerivastatina, droperidol, furazolidone, lynestrenol,
nitrofurazona, fenformin, fenolftaleina, fenilbutazona, piperazina, y
quiniodoclor.
Es más, cuando se decide retirar un medicamento del mercado, la implementación
de esta decisión es muy deficiente, dijo el Dr Gulhati. Por ejemplo, en junio
pasado se tomo la decisión de retirar los antialérgicos astemizole y terfenadine;
la notificación no se hizo hasta octubre y en ella se indicaba que no se
retirarían hasta agosto del 2003.
Según el Dr. Gulhati los medicamentos deberían retirarse del mercado tan pronto
como se determina que son nocivos, y la única explicación plausible es que hay
interés en proteger a la industria. Dice que las decisiones de la autoridad
reguladora están afectadas por los intereses comerciales de los cabilderos de la
industria y la corrupción; y que es una autoridad a la que no se le exige
transparencia ni que justifique sus actividades.
Las acciones de los medios de comunicación han provocado que dos laboratorios
recorten sus volúmenes de producción de nimesulide.
Ajay Kumar Handa, presidente de marketing para Centaur Pharmaceutical, dijo: "
Ya no estamos produciendo jarabe de nimesulide." Y añadió “Por lo que yo sé no
hay problemas con la administración de este medicamento a adultos.”
El grupo Social Jurist presentó un caso a la Corte Suprema de Delhi donde
cuestiona la disponibilidad de nimesulide y de otros medicamentos que se han
retirado de otros mercados pero que siguen estando disponibles en India.
6.) [Bleeding gastric ulcers and acute hepatitis: 2 simultaneous
adverse reactions due to nimesulide in a case]
Rev Med Chil. 2000
Dec;128(12):1349-53.
[Article in Spanish]
Tejos S, Torrejon N, Reyes H, Meneses M.
Servicios de Medicina y de Anatomia Patologica, Hospital del Salvador,
Departamento de Medicina (Campus Oriente), Facultad de Medicina, Universidad de
Chile, Santiago, Chile. [email protected]
A 66 year-old obese woman with arthrosis, self-medicated with oral nimesulide,
200 mg daily. After 6 weeks she developed nausea, jaundice and dark urine. Two
weeks later she had recurrent hematemesis and was hospitalized. Besides obesity
and anemia her physical examination was unremarkable. An upper GI endoscopy
revealed 3 acute gastric ulcers and a 4th one in the pyloric channel. Abdominal
ultrasonogram showed a slightly enlarged liver with diffuse reduction in
ecogenicity; the gallbladder and biliary tract were normal. Blood tests
demonstrated a conjugated hyperbilirubinemia (maximal total value: 18.4 mg/dl),
ALAT 960 U/l, ASAT 850 U/l, GGT 420 U/l, alkaline phosphatases mildly elevated,
pro-time 49% and albumin 2.7 mg/dl. Serum markers for hepatitis A, B and C
viruses were negative. ANA, AMA, anti-SmA, were negative. Ceruloplasmin was
normal. A liver biopsy showed bridging necrosis and other signs of acute toxic
liver damage. Gastric ulcers healed after conventional treatment and hepatitis
subsided after 2 months leaving no signs of chronic liver damage. The diagnosis
of toxic hepatitis due to nimesulide was supported by the time-course of drug
usage, sex, age, absence of other causes of liver disease, a compatible liver
biopsy and the improvement after drug withdrawal. Peptic ulcers or toxic
hepatitis have been previously described as independent adverse reactions in
patients taking nimesulide or other NSAIDs but their simultaneous occurrence in
a single patient is a unique event that deserves to be reported.
7.) Nimesulide-induced severe hemolytic anemia and acute
liver failure leading to liver transplantation.
Scand J Gastroenterol. 2002 Nov;37(11):1341-3.
Rodrigo L, de Francisco R, Perez-Pariente JM, Cadahia V, Tojo R, Rodriguez M,
Lucena MI, Andrade RJ.
Gastroenterology Service, Hospital Central de Asturias, Oviedo, Spain.
We present the case of a 63-year-old woman who had undergone 7 months of
treatment with Nimesulide (100 mg/b.i.d.) for symptomatic osteoarthritis. The
patient was admitted to our unit with a clinical picture of progressive jaundice
over 3 weeks. Clinical and analytical studies revealed acute liver failure, this
being confirmed by liver biopsy, which showed submassive necrosis. Serological
tests for different viral agents causing hepatitis were all negative. In
addition, she presented a picture of severe haemolytic anaemia resistant to
several treatments and needed multiple transfusions. Twenty-three days after
admission, the patient presented hepatic encephalopathy and received an
orthotopic liver transplant on day 25. The evolution after transplantation was
good and the patient continues in good health with no evidence of haemolysis
almost 2 years later. Liver toxicity due to Nimesulide is well known, but to our
knowledge the occurrence of haemolytic anaemia has not been related to this drug
previously. For these reasons, Nimesulide has been restricted or removed from
the market in several countries in recent months.
8.) Nimesulide-induced fulminant hepatitis.
Turk J Gastroenterol. 2003 Sep;14(3):208-10.
Ozgur O, Hacihasanoglu A, Karti SS, Ovali E.
Division of Gastroenterology, School of Medicine, Karadeniz Technical University,
Trabzon, Turkey. [email protected]
An 18-year-old boy was brought to the hospital with jaundice, confusion,
abdominal discomfort and distension. He had a history of oral intake of
nimesulide for three days. Clinical and laboratory findings were compatible with
fulminant hepatitis. Exclusion of other causes of liver injury strongly favored
drug-induced toxicity. All of the signs, symptoms and laboratory abnormalities
returned to normal after cessation of the nimesulide and supportive treatment,
and he was discharged on the 15th day after admission. This case differs from
the other cases in the literature regarding the time of onset, and indicates
that nimesulide may induce fulminant hepatitis in the first few days of
administration. Therefore, patients receiving nimesulide should be frequently
monitored with serial serum transaminases, beginning from the first week of
intake.
9.)
Efficacy of Nimesulide in Pain Relief after Day Care
Surgery
Indian Pediatrics 2002; 39:886-867
I have certain queries and concerns regarding the article(1) published in Indian
Pediatrics. How soon post-operatively was the first dose of the drug given and
were the drugs were given round the clock or only on a need basis? The type of
anesthesia used is not mentioned and this would obviously affect the appearance
and extent of pain during the first few hours after surgery. The authors have
mentioned that the efficacy of treatment was evaluated by physiological
responses, wound hyperthermia and pain behavior. Since this study was done on
day care patients it is assumed that they were sent home after a few hours. Who
assessed these parameters at home and were they incorporated into the final
scores? As we know, facial expression scores are ambiguous at the best and
difficult to appreciate in a crying child. The revised pain scale, which has
been validated for children between 4-16 years and is based on how a child feels
rather than how the face looks, would have been more appropriate(2). Since the
study was blinded, I would also like to know who provided the paracetamol to the
control group (sponsors or investigators) and why randomization was not done, as
the type of surgery would also have affected the degree of pain. Lastly, though
there is no information on any side effects in the study population, > 50% were
lost to follow-up and hence it is difficult to comment on the safety of the
drug. Finally and most importantly, we know that there is controvery regarding
Nimesulide which is still not approved by USFDA, Canada, UK, Australia, New
Zealand and the Scandinavian countries. It is pertinent to mention that
countries like Portugal have withdrawn the drug for Pediatric use since 1999.
Developing countries like Sri Lanka have still not approved the drug mainly
because they prefer to go along with the USFDA. The study was funded by Panacea
Biotec which is a leading manufacturer of the drug in India. Any new drug should
be assessed with caution. As responsible members of the medical fraternity in
India, where new drugs are readily approved, we need to be careful not to allow
competing interests to potentially affect our scientific evaluation(3).
10.) Hepatitis tóxica en gestante por nimesulida.
.
Hepatitis tóxica en gestante por nimesulida
Viernes 1 Diciembre 2000. Volumen 23 - Número 10 p. 498 - 499
SOURCE: Http://db.doyma.es/
J. PÉREZ-MORENOa R.M. LLERENA GUERREROb M. PUERTAS MONTENEGROc M.J. JIMÉNEZ
ARJONAc
aServicio de Aparato Digestivo. Hospital Universitario de Puerto Real. Puerto
Real. Cádiz.
bResidente de Medicina Familiar y Comunitaria. Hospital Universitario de Puerto
Real. Puerto Real. Cádiz.
cServicio de Aparato Digestivo. Hospital Universitario de Puerto Real. Puerto
Real. Cádiz.
Nimesulide-induced toxic hepatitis in pregnancy
Sr. Director: Es bien conocida la potencial capacidad de provocar daño hepático
de los antiinflamatorios no esteroides (AINE) en grado variable, desde pequeñas
elevaciones de las enzimas hepáticas hasta cuadros graves de hepatonecrosis
aguda y/o colestasis1. La incidencia comunicada resulta globalmente baja si se
tiene en cuenta la enorme difusión de prescripción de este grupo terapéutico2.
La nimesulida es un AINE comercializado en España en 1997, cuya molécula deriva
del grupo de la sulfonanilida, con una acción inhibidora selectiva de la enzima
ciclooxigenasa 2 (COX-2), lo que le proporciona un potente efecto
antiinflamatorio, analgésico y antipirético3. Su perfil farmacodinámico reduce
los efectos secundarios gastrointestinales, y aunque se había observado la
posibilidad de provocar leves alteraciones analíticas hepáticas, no es hasta
1998 cuando se implica en fenómenos de hepatotoxicidad con la comunicación de
seis casos de hepatitis aguda bien documentados4. Recientemente, se han
publicado los tres primeros casos acontecidos en España5; no obstante, queremos
reseñar la comunicación de una serie de 12 casos de toxicidad hepática por
nimesulida, ocurridos en Argentina entre 1986 y 1996, al XXII Congreso Nacional
de la Asociación Española para el Estudio del Hígado de 19976.
Caso clínico. Mujer de 22 años, gestante de 5 semanas, con antecedentes de asma
extrínseca por alergia a ácaros y pólenes, y hepatitis A. Niega consumo de
alcohol. Tres años antes había sido estudiada en el servicio de hematología por
macrocitosis sin causa aparente, recibiendo tratamiento con ácido fólico.
Ingresa por cuadro de malestar abdominal, náuseas y vómitos bilioalimenticios y
sensación de malestar general, instaurándose a las 24 h tinte amarillento de
piel y orinas colúricas. En la anamnesis se recogió el antecedente de ingesta de
nimesulida, 100 mg/12 h, durante 5 días, prescrita por un esguince de tobillo, 4
semanas antes. La exploración física no fue relevante salvo la constatación de
ictericia cutaneomucosa sin megalias ni dolor en la palpación abdominal. El
servicio de ginecología confirmó su embarazo tras la exploración, test
enzimático de detección de HCG en orina y hallazgos ecográficos. La analítica
evidenció normalidad hematimétrica y de la coagulación, con elevación de AST:
298 U/l; ALT: 635 U/l; GGT: 255 U/l; FA: 309 U/l y bilirrubina total: 4,7 mg/dl,
a expensas de la fracción directa. El resto de parámetros bioquímicos,
incluyendo estudio férrico, ceruloplasmina y alfa-1-antitripsina, fueron
normales, así como los anticuerpos antinucleares, antimitocondriales,
antimúsculo liso y anti-LMK. Los marcadores virales VHB y VHC, incluido ARN por
PCR, resultaron también negativos, del mismo modo que el estudio serológico
frente a CMV, VEB y VHS I y II. La ecografía abdominal no presentó hallazgos
patológicos. La evolución clínica fue favorable, normalizándose transaminasas y
bilirrubina en 10 días y persistiendo una GGT de 141 U/l que resultó normal al
mes del ingreso. El embarazo de la paciente evolucionó sin incidencias clínicas
relevantes, llegando a término con un posterior parto eutócico.
Durante el embarazo se pueden reconocer distintos tipos de hepatopa tías,
algunas directamente relacionadas con la gestación, otras existentes previamente
y otras que aparecen de forma intercurrente, como hepatitis virales o tóxicas,
colecistitis y colelitiasis o síndrome de Budd-Chiari. En nuestro caso se
estableció el diagnóstico diferencial con la hiperémesis gravídica, entidad que
aparece en el primer trimestre del embarazo, pero se descartó dada la falta de
correlación clínica y analítica, no considerándose otros cuadros propios de la
gestación, tales como la colestasis intrahepática, la esteatosis aguda, la
hepatopatía asociada a preeclam psia y eclampsia o el síndrome. HELLP, por ser
propios de estadios más avanzados de la gestación7. El control del embarazo de
la paciente que nos ocupa se realizó sin que apareciesen nuevas manifestaciones
clínicas o analíticas de afectación hepática.
La incidencia de hepatotoxicidad farmacológica durante el embarazo no parece
diferir de la observada en el resto de la población, aunque en teoría podría ser
más frecuente o grave ya que está disminuido el aclaramiento hepático y hay
inhibición de la función excretora8.
Descartada la relación con la gestación, así como otras posibles causas de
hepatitis aguda, tales como la etiología viral, alcohólica, autoinmune,
metabólica y patología biliar, la asociación con nimesulida se basó en la
relación temporal entre la ingesta del fármaco y la aparición de la hepatitis,
la especificidad del cuadro con casos similares de hepatotoxicidad descritos en
la bibliografía y la remisión del proceso con la interrupción del fármaco, no
considerándose su readministración.
En las dos series publicadas4,5, los casos incidieron fundamentalmente en
mujeres con una edad media de 60 años (rango: 39-81), predominando un cuadro de
hepatitis aguda colestásica que remitió entre 8 y 120 días después de su
aparición. En los dos únicos casos que afectaron a varones, se presentó un daño
colestásico intrahepático grave, habiéndose apuntado la posibilidad de
diferentes patrones lesivos asociados al sexo4.
En cuanto al mecanismo lesional, y como ocurre en la mayoría de las reacciones
hepáticas adversas por AINE9, parece corresponder a un mecanismo idiosincrásico
de tipo metabólico dependiente del paciente, que aparece tras un período
variable de exposición al tóxico por la existencia de vías metabólicas
aberrantes10. No obstante también se han observado signos de hipersensibilidad
en dos de los casos descritos4,5 en probable relación con la molécula
sulfonanilida de la nimesulida, que provocaría una reacción alérgica similar a
la dapsona o la sulfapiridina4.
Con la comunicación de nuestra experiencia con este nuevo antiinflamatorio, y a
pesar de que se trate de una reacción adversa muy infrecuente, consideramos que
una monitorización adecuada permitiría predecir y objetivar la hepatotoxicidad
de fármacos de reciente introducción en el arsenal terapéutico.
Referencias Bibliográficas:
1. Manoukian AV, Carson JL Nonsteroidal anti-inflammatory drug-induced hepatic
disorders. Incidence and prevention. Drug Saf 1996; 15: 64-71.
2. García Rodríguez LA, Williams R, Derby LE, Dean AD, Jick H Acute liver injury
associated with nonsteroidal antiinflammatory drugs and the role of risk factors.
Arch Intern Med 1994; 154: 311-316.
3. Davis R, Brogden RN Nimesulide. An update of itspharmacodynamic and
pharmacokinetic properties, and therapeutic efficacy. Drugs 1994; 48: 431-454.
4. Van Steenbergen W, Peeters P, De Bondt J, Staessen D, Büscher H, Laporta T et
al Nimesulide-induced acute hepatitis: evidence from six cases. J Hepatol 1998;
29: 135-141.
5. Romero-Gómez M, Nevado Santos M, Fobelo MJ, Castro Fernández M Hepatitis
aguda por nimesulida: descripción de tres casos. Med Clin (Barc) 1999; 113:
357-358.
6. Bessone F, Fay F, Fay O, Vorobioff J, Passamonti M, Tanno H Toxicidad
hepática por nimesulida. Presentación de 12 casos. Gastroenterol Hepatol 1997;
20 (Supl 1): 35.
7. Muñoz R, Castellano G Hepatopatía y gestación. Rev Gastroenterol
Interhospitalaria 1997; 1: 38-44.
8. Knox TA, Olans LB Liver disease in pregnancy. N Engl J Med 1996; 335:
569-576.
9. Boelsterli UA, Zimmerman HJ, Kretz-Romme A Idisyncratic liver toxicity of
nonsteroidal antiinflammatory drugs: molecular mechanisms and pathology. Crit
Rev Toxicol 1995; 25: 207-235
10. Banks AT, Zimmerman HJ, Ishak KG, Harter JG Diclofenac-associated
hepatotoxicity: analysis of 180 cases reported to the food and drug
administration as adverse reactions. Hepatology 1995; 22: 820-827
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DATA-MEDICOS/DERMAGIC-EXPRESS /MARCH JOURNAL 2.004/ DR. JOSE
LAPENTA R.
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