INTRODUCTION:

Nimesulide, (4 nitro 2 phenoxyphenyl) methanesulplfonamide is a non steroidal anti-inflammatory drug (NSAID) with relative specificity for COX-2 that is not available in the United States, but is being used widely in other countries in the treatment of acute pain. Nimesulide has been linked to a low rate of transient serum enzyme elevations during therapy, but also to many instances of clinically apparent acute liver injury that can be severe and can result in acute liver failure, need for emergency liver transplantation and death. Nimesulide is available as tablets, granules, suppositories, oral suspensions, drops and topical gels.

Original Nimesulide is marketed in more than 50 countries mainly Europe, central and Latin America and Asia. The authorized trade names are Ainex, Aulin, Donulide, Eskaflam, Heu-gan, Mesulid, Nexen, Nimed, Nimedex, Nisulid and Scaflam. According to the summary of product characteristics (2003) Nimesulide is approved for use in the treatment of acute pain, in the symptomatic treatment of painful osteoarthritis and in primary dysmenorrhea.

Nimesulide has been marketed in France since 1998, is neither more effective nor better tolerated than other NSAIDs. Many reports and reviews published by drug regulatory agencies in Spain, Ireland and Italy have warned of the hepatic adverse effects of Nimesulide.

Pharmacology of Nimesulide^1,2:

Nimesulide is a sulfonanilide compound with anti-inflammatory properties. Its pharmacological profile (better inhibition of PG synthesis in inflammatory areas than in gastric mucosa), suggested that it might be a selective inhibitor of COX-2. In several invitro assays using either purified COX-2 and COX-1 preparations or cell preparations (both from animal and human origins) expressing COX-1 or COX-2, ten out of eleven different groups have demonstrated that Nimesulide selectively inhibits COX-2. The COX-2/ COX-1 inhibitory ratio varies, according to the assay preparation, from about 0.76 to 0.0004 i.e. a 1.3 to 2,512 fold higher selectivity for COX-2 than for COX-1. Moreover, an invivo whole blood assay performed on healthy volunteers demonstrated a significant fall in COX-2 PGE2 production without any effect on COX-1 TXB2 production in subjects treated with Nimesulide (100mg b.i.d. for 2 weeks) versus no effect on COX-2 PGE2 and an almost total suppression of COX-1 TXB2 in subjects treated with aspirin (300mg t.i.d. for 2 weeks). Nimesulide can thus be considered a relatively selective COX-2 inhibitor. At the recommended dosage of 100mg b.i.d., it is as effective an analgesic and anti-inflammatory agent as classical NSAIDs, and a well-tolerated drug with few side-effects according to large-scale open studies and a global evaluation of a large number of controlled and non-controlled comparative trials.

Nimesulide is a NSAID with good anti-inflammatory, analgesic and antipyretic activities expected of such compounds. However, in addition it has some unique therapeutic and pharmacological activities. The novel therapeutic aspects include a relatively low toxicity to the gastrointestinal tract and kidneys, it can be given to most patients who experience respiratory problems with other NSAIDs, and the onset of analgesia is comparatively quick. The main novel pharmacological actions obtained using Nimesulide invivo at therapeutic doses, or invitro at concentrations within the therapeutic range of free (unbound) drug, include: a preferential inhibition of prostaglandin synthesis via COX-2, and reductions in cytokine action/release, histamine release, the release of enzymes that degrade cartilage, and the release of superoxide anions and other toxic substances from neutrophils. Interactions with other drugs are few and of little or no clinical significance.

Ban of Nimesulide:

The Nimesulide induced toxicity and its severity lead to liver transplantation sometimes death. The cases reported throughout the world made the drug to get ban in many countries completely, the regulatory bodies involved in ban of the drug were given in table 1. But in some countries like India the drug is partially banned and also available as over the counter medication for adult use. No pharmacist warns the patient about possible interactions and drug induced toxicities of over the counter medications, as if they are bothered only about their sales and business. The inspectors also not bothered to enquire about over the counter medication records. The Indian government announced ban on the drug in 2011 for pediatric usage where as the drug is available for adult use in present day Indian market. The general procedure involved in ban of a drug in India is given in Figure 1.

The consumers are purchasing the drug from pharmacies due to lack of knowledge on drug interactions and drug induced hepatotoxicity, which are responsible to cause severe effects sometimes death. A list of agents and the drug mode of interactions are given in Table 2¹.

Table 1:Regulatory bodies involved in specific ban of Nimesulide.

Abbreviations	Regulatory Bodies	Countries
FDA	Food and drug administration	United States
EMEA	European Medicines Agency	European Union
TGA	Therapeutics Goods and Administration	Australia
CDSCO	Central Drugs Standards Control Organization	India
SIDC	State Institute For Drugs and Control	Czech Republic
NAM	National Agency for Medicines	Finland
BfArM	Federal Institute For Drugs and Medical Devices	Germany
PCHRD	Philippine Council For Health Research and Development	Philippines
SIDC	State Institute For Drug Control	Slovak Republic
MPA	Medical Products Agency	Sweden

List of Combinations Banned by Ministory of Health and Family Welfare³:

Combination of Nimesulide and Diclofenac

Combination of Nimesulide, Certizine and Caffeine

Combination of Nimesulide andTizanidine

Combination of Nimesulide and Paracetamol dispersible tablets

Combination of Nimesulide and Serratiopeptidase

Combination of Nimesulide, Pitofenone, Fenpiverinium and Benzyl alcohol

Combination of Nimesulide and Dicyclomine.

Figure 1: The general procedure involved in ban of a drug.

Acts and Sections:

Drugs like Nimesulide, Rofecoxib, Phenylpropanamine and others are banned based on Section 26a of Drugs and Cosmetics Act 1940 by the Ministry of Health and family welfare, in India, after amendment of the Drugs Act in 1982, the Government has acquired the power to prohibit manufacture and sale of certain drugs and irrational 19 FDCs.

Table 2: List of agents and the drug mode of interactions¹.

Sl. No	Agent	Mode of interaction
1.	Anticoagulants	Nimesulide increases the risk of bleeding when taken with anticoagulants.
2.	Beta-blockers	Nimesulide may diminish the antihypertensive effects of these drugs.
3.	Angiotensin converting enzyme inhibitors	Nimesulide may diminish the antihypertensive effects of these drugs.
4.	Digoxin	Nimesulide may increase serum concentrations of digoxin.
5,	Loop diuretics	Nimesulide may reduce the effectiveness of these diuretics and may increase serum concentrations of potassium.
6.	Potassium sparing diuretics	Nimesulide may reduce the effectiveness of these diuretics and may increase serum concentrations of potassium.
7.	Penicillamine	Nimesulide may increase the bioavailability of penicillamine.
8.	Methotrexate	Nimesulide may increase serum concentrations of methotrexate

CASES REPORTED:

1. Case from India⁴:

A 6 year old boy.who was suffering from fever for 4 days for which he was treated with Nimesulide (without prescription) for 4 days before coming to doctor. On examination, patient was found with jaundice and haematuria.

1a. Laboratory studies of the child were as follows:

When the LFT report comes. bilirubin total - 8.8mg/dl and bilirubin direct 5.2mg/dl. SGOT, SGPT and alkaline phosphate were 587IU and 2932IU, respectively. Liver function test after 9^th day from withdrawal of Nimesulide showed bilirubin 1.34mg/dl and bilirubin direct 0.81mg/dl. SGOT, SGPT and alkaline phosphate were 98.48IU and 189.6IU and 1603IU, respectively. these parameters of liver function showed significant improvement after withdrawing Nimesulide.

Complete blood count report Hb-11.2g/dl.TLC-9300µl, PCV-34%, RBC count-4.2mn/mm³ MCH-26.67pg, MCV-80.95 fl, MCHC-32.94%, Platelets-261 10³/µl, bleeding time and clotting time (BTCT)were normal (bleeding time-3’36” minute, clotting time 6’13” minute), while prothrombin time index: PTI test 13sec, PTI-92% was also within the normal limits.

On first day the urine was dark yellow colour, albumin bile salt and bile pigments were also detected. Microscopy shows the presence of pus cells 2-3/HPF, RBCs-40 to 50/HPF. A repeat examination of urine, at a different pathological laboratory confirms. urine culture was found to be sterile after 24hrs of aerobic incubation. Repeating this test on 9^th day of the Nimesulide withdrawal shows a normal urine sample.

Serotological test for hepatitis A, B, C and E viruses, were found negative. This eliminates the other common causes of hepatitis.

The pediatrician stopped the use of Nimesulide and managed the child conservatively on outpatient basis. The child improved subsequently without any specific intervention.

The pediatrician stops the use of Nimesulide on children’s, due to its chronic effects on liver functioning.

2. Case filed in Saudi Arabia⁵:

The objective is to report the occurrence of Nimesulide induced acute hepatitis confirmed by biopsy and an in vitro lymphocyte toxicity. A 54 year old women treaded with Nimesulide for chronic low back pain was admitted to the hospital, the biopsy report confirms that she was suffering from acute hepatitis. Her liver functioning test result where returned to normal within one month after Nimesulide discontinuation and an invitro lymphocyte toxicity confirmed that the liver injury was due to Nimesulide induce due to excess consumption of Nimesulide. These effects are might be reversible on discontinuation of the drug, but occasionally can progress to fatal hepatic failure upon longer usage.

2b. Affiliated by Department of Gastroenterology, Nahariya Hospital, B. Rappaport Faculty of Medicine, Technion, Israel.

2c. Case reported by N krivoy, Mshiller, R farah, H I cohen, Lstruminger, Rreshef. In 2001 September.

3. Case file for acute liver failure attributed to Nimesulide London England⁶:

A 58 year old woman feel uneasy 10 days after starting Nimesulide for chronic back pain. She was seen and found to have mild elevations in serum enzymes, She continued using Nimesulide, but she developed further symptoms including nausea and then she stopped using it after two weeks, she noted dark urine, jaundice and shortly she was admitted to the hospital because of chronic symptoms. She had no history of liver disease, alcohol abuse or risk factors for viral hepatitis. She had taken Nimesulide for short periods in the past. Her other medications included birth control pills which she had taken for 6 years and sertraline which she had taken for 11 months. On admission, she was acutely ill with jaundice and confused Laboratory results shows a total bilirubin of 16.9mg/dL, ALT 1046 U/L, AST 386 U/L, alkaline phosphates 114 U/L, GGT 112 U/L, albumin 2.8 g/dL and INR greater than 12. Tests for hepatitis A, B, C, E BV and CMV were negative. She had low titers of ANA (1:25). Abdominal ultrasound showed normal liver, spleen and biliary ventilation. She developed progressive hepatic failure and went into emergency liver transplantation within 3 days of admission, but had primary graft non function, multiorgan failure and died within a day of the surgery. Auto biopsy report shows massive hepatic necrosis. The values were given in table3.

3a. It was found in lancet (londan, England) in 1999 Jan 2. By P A McCormick, F Kennedy, M Curry, O Traynor

4. Case reported in France⁷:

A 49 year old women was treated with Nimesulide for 3 days. She was admitted in intensive care unit for acute liver failure which effects the functioning of the brain due to its toxicity, hepatic support by molecular absorbant recirculating system (MARS) was performed, hepatic transplantation was done within 12hours of admission it shows a rapid improvement and gets discharged with in 4 days of transplantation. Nimesulide induce hepatic toxicity is inpredictable and it shows different symptoms. cinical symptoms are progressive, delaying in the treatment. Case draws attention to the risk of hepatic failure due to the treatment with Nimesulide which leads to hepatic transplantation or death.

4a. Affiliation- department of anesthesia reanimathion, pavillon reanimation, hospital Edouard Herriot in France.

4b. Case reported by - F Christin, D HayiSlayman, J JBaillon, C-E Ber, B Delafosse, J Dumortier, T Rimmele. case reported on 27^th September 2008.

5. Case reported in spain⁸:

A 63 year old women who was treated for 7 months with Nimesulide (100mg/b.i.d) for symptomatic osteoarthritis. the patient was admitted to hospital with the clinical picture of progressive jaundice for 3 weeks. Clinical and analytical studies shows acute liver failure, this is confirmed by liver biopsy, which showed submassive necrosis. Serological test for different viral agents causing hepatitis were all negative. She shows severe haemolytic anemia in resistant to several treatments and needed multiple transfusions. After 23 days of admission. the patient shows hepatic effects on functioning of brain and received an orthotopic liver transplant on 25^th day of admission. the improvement after transplantation was good and the patient continues in good health with no evidence of haemolys is with in 2 years.

Affiliation gastroenterology service hospital universitario central de Asturias, Oviedo, spain.

6. Case reported in Southern Brazil⁹:

Department of Clinical Medicine, University Hospital, Universidade Estadual de Londrina (UEL), Londrina.

An 81years old women who was treated with Nimesulide for 6 days with hematesmesis (blood in vomiting) and epistaxis (nose bleeding) before 2 days of hospitalization.

Clinical examination shows extensive coagulation disorder (bleeding), diffuse hemeatomas, hypotension and tachypnea (abnormal rapid breathing). Laboratory tests shows Abnormalities in coagulation test, leukocytosis, reduce platelets, hemoglobin, Red Blood Cells count, high direct bilirubin, serum aspartate transaminase (AST) gamma glutanyl transpepridase (GGT) Alkaline phosphate and renal function biomarkers. test of hepatitis B and C were not reactive. Carcino embryonic antigen (CEA) cancer antigens (CA-19-9 and CA-125) levels were increased by 1,000 to 10,000 and 13 fold.but the Alpha fetoprotein level was normal.

This indicates that a malignant tumor in the bile duct was not originated from liver. after 36 hours of hospitalization the patient’s condition become worst and leads to death. The autopsy finds that includes acute hepatitis with hepatocellular collapse, as well as metastasis of a carcinoma from the bile duct.

The necropsy findings included liver acute hepatitis with inflammatory infiltrate, coagulative necrosis and hepatocellular collapse (Figure 2). Moreover, there was metastasis of moderately differentiated carcinoma, probably from the bile duct (Figure 3).

Carcinoembryonic antigen (CEA) and CA-19-9 levels were increased, respectively, by 1,000 and 10,000-fold. CA-125 was slightly increased (13-fold) and alpha-fetoprotein (AFP) levels were normal (Table 4)

● Nimesulide may have contributed in the fatal liver failure without the affect of carcinoma presented by the patient. Precautions are required in prescribing Nimesulide for liver disease in patients.

Figure 2. Histopathological features of the liver, focusing on acute liver failure: acute hepatitis with hepatocellular collapse in the patient’s liver. The arrows show extensive areas of coagulative necrosis and inflammatory infiltrate (hematoxylin and eosin stain; original magnification X 20)⁹.

Figure 3: Histopathological features of the liver, focusing on adeno carcinoma metastasis: adeno carcinoma metastasis, probably originating from the bile duct, in the patient’s liver. The arrows show the neoplastic cells (hematoxylin and eosin stain; original magnification X 40)⁹.

Table 4: Hepatitis and cancer biomarker tests⁹.

	REFERENCE VALUE	VALUE
Hepatitis C	NR	NR
Hepatitis B (HBsAg)	NR	NR
CEA	< 3 ng/ml	1,224.35
CA-19-9	< 37 U/ml	10,079.97
CA-125	< 35 U/ml	476.4
AFP	< 8 ng/ml	7.49

Different Nimesulide Brands Present in Indian Market:

1. NISE Tablet (manufactured by Dr. Reddy’s Laboratories, Ltd. composition Nimesulide 100mg).

Nise Tablet is a pain relieving medicine. It is used for treatment of inflammatory condition including joint disorders such as Rheumatoid arthritis, postoperative painful condition, fever, and period pain. Nise Tablet should be taken with food. This will prevent you from getting an upset stomach. In general, you should try to use the smallest amount necessary to control your symptoms, for the shortest possible time. You should take this medicine regularly while you need it. Try not to miss doses as this will make the medicine less effective. It is used as pain relief, fever.

2. NIMREST 100MG TABLET (manufactured by Ranbaxy Laboratories Ltd, It consist of-Nimesulide).

Nimrest 100 MG Tablet is a non-selective non-steroidal anti-inflammatory drug (NSAID) which is used as a second-line therapy to treat acute pain associated with osteoarthritis and menstruation. It is also used to treat mild to moderate pain caused due to sprains and strains of joints and muscles. This medicine is not recommended for use in patients below 12 years of age.

Availability of Banned Drugs in India¹⁰:

World wide tragedies like Jake leg paralysis, Thalidomide sealed limbs and Elixer Sulfanilamide are warning humans not to prefer self medications. Taking medications that are prescribed by physicians helps to avoid possible drug interactions and adverse drug reactions. The over the counter medications are being responsible for adverse effects like hepatotoxicity, renal failure, cardiac failure, severe skin reactions, GI toxicity, coronary artery insufficiency etc. Banned drugs like Phenyl Propanolamine, Analgin, Cisapride, Nimesulideetc are being sold in market. Cisapride an antacid drug causes heart abnormality, Phenylpropanolamine used in cough syrups increases the risk of strokes, Sibutramine an appetite suppressant used in treatment of obesity, is associated with increased risk of heart attacks. Nimesulide an Non steroidal anti- inflammatory drug is hepatotoxic which leads to liver transplantation or sometimes death. Though the Indian government in 2011 announced a late ban on Nimesulide for pediatric use, but it is still being used for adults as over the counter medication.

Figure.4: Rapidly selling banned drugs¹⁰.

Due to the cases reported in adults on Nimesulide induced Hepatotoxicity and drug interactions, it was banned in countries like United states, Ireland, Spain, Finland, Belgium etc. The drug discovered in Switzerland where it was never used. The drug which has to be banned actually, is still being used in India as Over the counter medication despite of its adverse effects and possible drug interactions.

The World health organization in the year 2008 has listed Nimesulide in "Consolidated List of Products whose Consumption and/or Sale have been Banned, Withdrawn, Severely Restricted or Not Approved by Governments" under Pharmaceuticals: Restrictions in use and availability¹¹.

Table 5: List of Abbrevations.

PPA	Phenylpropanolamine
COX	Cyclooxygenase
PGE2	Prostaglandin E₂
TXB2	Thromboxane B₂
b.i.d.	Bis-in-die (taken twice)
t.i.d.	Ter-in-die (taken thice)
LFT	Liver functioning test
SGOT	Serum glutamic oxaloaceticteansaminase
SGPT	Serum glutamic pyruvic transaminase
IU	International unit
Dl	Deciliter
Hb	Haemoglobin
TLC	Total leucocyte count
PCV	Packed cell volume
MCH	Mean corpuscular haemoglobin
MCHC	Mean corpuscular haemoglobin concentration
MCV	Mean corpuscular volume
HPF	High power field
INR	International normalized ratio
AST	Aspartate aminotransferase
GGT	Gamma glutanyltransferase
ALT	Alanine transaminase
EBV	Epstein-barr virus
CMV	Cytomegalo virus
ANA	Antinuclear antibody
R	Hepatocellular pattern of liver injury is defined as the ratio.

CONCLUSION:

Several reports and reviews made by drug regulatory agencies of Spain, Ireland and Italy have warn for hepatic adverse effects of Nimesulide. In Europe the database of European pharmacovigilance shows that Nimesulide is associated with more cases of severe liver damage. The dose of Nimesulide use was recommended in the summary of product characteristics (SPC). Liver damage occurs within 15 days after the first dose of Nimesulide in one third cases. Nimesulide was ban in many countries like Switzerland, spain, Ireland, Finland and united states. The drug which has to be banned actually, is still being used in India as Over the counter medication despite of its adverse effects and possible drug interactions. There are many drugs which are to be banned are available in Indian market, and were being sold as over the counter medications illegally without warning the patients about adverse drug reactions and drug interactions, which making the unaware consumers to suffer.

REFERENCES:

1. Monica Valentovic, et al. Nimesulide. xPharm: The Comprehensive Pharmacology Reference. https://doi.org/10.1016/B978-008055232-3.62283-4

2. aey JP. In vitro and in vivo pharmacological evidence of selective cyclooxygenase-2 inhibition by nimesulide: an overview. Inflamm Res. 1997; 46: 437–446. - PubMed

3. Complete list of 344 drugs banned by the Ministry of Health Family welfare https://www.nhp.gov.in/Complete-list-of-344-drugs-banned-by-the-Ministry-of-Health-Family-welfare_pg

4. Gupta G - A Case of Nimesulide toxicity in an Indian Child. Indian Journal of Pharmacy Practice Volume 5 Issue 2 Apr - Jun, 2012.

5. Sbeit W, Krivoy N, Shiller M, Farah R, Cohen HI, Struminger L, et al. Nimesulide-induced acute hepatitis. Annals of Pharmacotherapy. 2001;35(9):1049–52. 10.1177/106002800103500901

6. LiverTox: Clinical and Research Information on Drug Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012 – Nimesulide, [updated 2016 Mar 1].

7. Page M, Christin F, Hayi-Slayman D, Baillon JJ, Ber CE, Delafosse B, et al. Acute liver failure due to a treatment by nimesulide: Another case and review. Annales Francaisesd' Anesthesieet de Reanimation. 2008;27(9):742–6. 10.1016/j.annfar.2008.04.023.

8. Rodrigo L., De Francisco R., Pérez-Pariente J.M., Cadahia V., Tojo R., Rodriguez M., Lucena M.I., Andrade R.J. Nimesulide-induced severe hemolytic anemia and acute liver failure leading to liver transplantation. Scand J Gastroenterol. 2002;37(11):1341–1343.

9. Nimesulide-induced fatal acute liver failure in an elderly woman with metastatic biliary adenocarcinoma. A case report. Sao Paulo Med J. Jul-Aug 2015;133(4):371-6. doi: 10.1590/1516-3180.2013.7550003. Epub 2014 Sep 19.

10. JessyShaji and ShitalLodhaetal.Regulatory Status of Banned Drugs in India. Indian J.Pharm. Educ. Res. 44(1), Jan-Mar, 2010.

11. Pharmaceuticals: Restrictions in use and availability https://www.who.int/medicines/areas/quality_safety/safety_efficacy/who_emp_qsm2008.3.pdf

Received on 10.01.2021 Modified on 09.02.2021

Asian Journal of Pharmaceutical Research. 2021; 11(2):132-137.

DOI: 10.52711/2231-5691.2021.00025

Time after starting	Time after stopping	ALT (U/L)	AIK P (U/L)	Bilirubin (mg/Dl)	Other
Pre	0	23	51		Routine
10 days	0	187	50		Nonspecific symptoms
32 days	0	504	54	0.9	Nausea
50 days	2weeks	2857	114	7.0	Admission, confusion
53days		Liver transplantation, primary non function, death.
Normal values		<40	<100	<1.2

Pharmacology of Nimesulide1,2: