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28-617: The Irish Medicines Board suspended Nimesulide from the Irish market and referred it to the EU Committee for Human Medicinal Products for a review of its benefit/risk profile due to the reporting of six cases of potentially-related liver failures by the National Liver Transplant Unit at St. Vincent's University Hospital between 1999 and 2006. In July 2018 the authority recalled a number of medicines containing

56-554: A glycosyl phosphatidyl inositol linkage to the external face of the plasma membrane. The enzyme is used as a marker of lymphocyte differentiation. Consequently, a deficiency of NT5 occurs in a variety of immunodeficiency diseases (e.g., see MIM 102700, MIM 300300). Other forms of 5-prime nucleotidase exist in the cytoplasm and lysosomes and can be distinguished from ecto-NT5 by their substrate affinities, requirement for divalent magnesium ion, activation by ATP, and inhibition by inorganic phosphate. Rare allelic variants are associated with

84-760: A prescription from a physician that is kept as a receipt at the chemist shop, nominally allowing strong control over selling. The original manufacturer of nimesulide is Helsinn Healthcare SA, Switzerland, which acquired the rights for the drug in 1976. After the patent protection terminated in 2015, a number of other companies started production and marketing of Nimesulide. Ecto-5%27-nucleotidase 4H2B , 4H1Y , 4H2F , 4H2I , 4H1S , 4H2G 4907 23959 ENSG00000135318 ENSMUSG00000032420 P21589 Q61503 NM_002526 NM_001204813 NM_011851 NP_001191742 NP_002517 NP_035981 5′-nucleotidase (5′-NT), also known as ecto-5′-nucleotidase or CD73 ( cluster of differentiation 73),

112-486: A syndrome of adult-onset calcification of joints and arteries (CALJA) affecting the iliac , femoral , and tibial arteries reducing circulation in the legs and the joints of the hands and feet causing pain. NT5E (CD73) is a surface enzyme which is expressed on multiple cells. This enzyme mediates the gradual hydrolysis of the autocrine and paracrine danger signals of ATP and ADP to anti-inflammatory adenosine . Immune suppression mediated by adenosinergic pathways

140-424: A top-ranking official at Italy's medicines agency AIFA had been filmed by police while accepting bribes from employees of pharmaceutical companies. The money allegedly was being paid to ensure that certain drugs would be spared scrutiny from the drugs watchdog. The investigation had started in 2005 following suspicions that some AIFA drug tests had been faked. Eight arrests were made. Nimesulide can be bought carrying

168-443: Is a nonsteroidal anti-inflammatory drug (NSAID) with pain medication and fever reducing properties. Its approved indications are the treatment of acute pain, the symptomatic treatment of osteoarthritis , and primary dysmenorrhoea in adolescents and adults above 12 years old. Side effects may include liver problems . It has a multifactorial mode of action and is characterized by a fast onset of action. It works by blocking

196-522: Is an enzyme that in humans is encoded by the NT5E gene . CD73 commonly serves to convert AMP to adenosine . NT5E contains binding sites for transcription factors AP-2, SMAD proteins, SP-1 and elements responsive to c-AMP , which can be found in c-AMP promoter parts. SMADs 2, 3, 4 and 5 and SP-1 are binding to the NT5E promoter in rats, as was proven in chromatin immunoprecipitation assays. Due to

224-454: Is an important key molecule in cancer regulation and development and is involved in tumor progression. In addition, NT5E functions as an adhesion and signaling molecule and can regulate cellular signaling with extracellular matrix components such as fibronectin and laminin . This can mediate the metastatic and invasive properties of cancer. In mouse breast and prostate cancer tumor models as well as in breast cancer xenograft model , NT5E

252-490: Is available to support a particularly good profile in terms of gastrointestinal tolerability. Nimesulide was launched in Italy for the first time as Aulin and Mesulid in 1985 and is available in more than 50 countries worldwide, including among others France , Portugal , Greece , Switzerland , Belgium , Russia , Thailand , and Brazil . Nimesulide has never been filed for Food and Drug Administration (FDA) evaluation in

280-436: Is contraindicated. Nimesulide has a relatively rapid onset of action, with meaningful reductions in pain and inflammation observed within 15 minutes from drug intake. The therapeutic effects of nimesulide are the result of its complex mode of action, which targets a number of key mediators of the inflammatory process such as: COX-2 mediated prostaglandins, free radicals, proteolytic enzymes, and histamine. Clinical evidence

308-481: Is missing, which shows an impaired regulatory function of T cells. NT5E can act as an immune inhibitory control molecule. Free adenosine generated by NT5E inhibits cellular immune responses and thereby promotes immune escape of tumor cells. Due to enzymatic and non-enzymatic properties, CD73 is involved in cancer-related processes and is upregulated in many cancers such as leukemia , glioblastoma , melanoma , oesophageal , prostate , ovarian and breast cancer . It

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336-523: Is the ecto-5'-nucleotidase (e-5′NT/CD73)/ adenosine A 2A receptor pathway. Nimesulide is absorbed rapidly following oral administration. Nimesulide undergoes extensive biotransformation, mainly to 4-hydroxynimesulide (which also appears to be biologically active). Food, sex, and advanced age have negligible effects on nimesulide pharmacokinetics. Moderate chronic kidney disease does not necessitate dosage adjustment, while in patients with severe chronic kidney disease or liver disease, nimesulide

364-446: Is very important for maintaining immune system homeostasis. Immune suppressive functions of T regulatory cells are also dependent on CD73 expression. Treg's generally suppress the immune response. They affect proliferation and function of T cell. CD73 also occurs on anergic CD4 + T cells, thereby maintaining self tolerance to healthy tissues as well as protecting the fetus from the mother's immune system during pregnancy. Also described

392-777: The European Medicines Agency (EMA) concluded that the overall benefit/risk profile of nimesulide is favourable and in line with that of the other NSAIDs such as diclofenac , ibuprofen , and naproxen provided that the duration of use is limited to 15 days and the dose does not exceed 200 mg/day. Less than 10 days of nimesulide does not appear to increase the risk of hypothermia, gastrointestinal bleeding, epigastric pain, vomiting, diarrhea, or transient, asymptomatic elevation of liver enzymes compared to ketoprofen , paracetamol , mefenamic acid , aspirin , or ibuprofen in children. However, data does not speak to populations less than 6 months old. Women should use

420-1576: The United States , where it is not marketed. Nimesulide is available throughout the world as original product with the following trademarks: Sulide, Nimalox, Mesulid (Novartis, Brazil, Boehringer Ingelheim, Greece, Italy), Coxtal (Sanofi, China, Bulgaria), Sintalgin (Abbott, Brazil), Eskaflam (GSK, Brazil, Mexico), Octaprin, Nimside (Teva, Pakistan), Nise (Russia, Venezuela, Vietnam, Ukraine), Nilsid (Egypt); Aulin (Bulgaria, Czech Republic, Italy, Romania, Poland), Ainex, Drexel, Donulide, Edrigyl, Enetra, Heugan, Mesulid, Minapon, NeRelid, Nexen, Nidolon, Nilden (Mexico); Emsulide, Nimed, Nimedex, Nimesil (Czech Republic, Moldova, Latvia, Lithuania, Kazhakhstan, Georgia, Poland), Nimulid (Trinidad & Tobago), Nimutab, Nimdase, Nimopen-MP Nise, Nimuwin, Nisulid, Nodard Plus, Nicip, Nimcap, Nic-P, Nic-Spas, Nimupain (India); Mesulid, Novolid, Relmex (Ecuador); Remisid (Ukraine); Coxulid, Emulid, Frenag, Fuzo, Motival, Nimeksil, Nimelid, Nîmes, Nimesdin, Romasulid, Sulidin, Suljel, Thermo Sulidin (Turkey), Xilox (Hungary); Modact-IR (Pakistan); and ad Sulidene and Zolan for veterinary use. Many generic and copy-products also exist (Lusemin, Medicox, Nidol, Nimalox, Nimesil, Nimotas, Nimulid, Nizer, Sorini, Ventor, Vionim, Neolide, Willgo among others), new-aid, Nexulide (Syria), Nims, Nice, Nimulide (Nepal) Several reports have been made of adverse drug reactions in India. On February 12, 2011, Indian Express reported that

448-555: The EMA released a press release on their review on the liver-related safety of nimesulide. The EMA has concluded that the benefits of these medicines outweigh their risks, but that there is a need to limit the duration of use to ensure that the risk of patients developing liver problems is kept to a minimum. Therefore, the EMA has limited the use of systemic formulations (tablets, solutions, suppositories) of nimesulide to 15 days. The Irish Medicines Board has decided to suspend Nimesulide from

476-512: The Irish market and refer it to the EU Committee for Human Medicinal Products (CHMP) for a review of its benefit/risk profile. The decision is due to the reporting of six cases of potentially-related liver failures to the IMB by the National Liver Transplant Unit, St. Vincent's University Hospital . These cases occurred in the period from 1999 to 2006. In May 2008, Italy's leading daily paper Corriere della Sera and other media outlets reported that

504-494: The Union Ministry of Health and Family Welfare finally had decided to suspend the pediatric use of the analgesic, Nimesulide suspension. From 10 March 2011 onward Nimesulide formulations are not indicated for human use in children below 12 years of age. On September 13, 2011 Madras High Court revoked a suspension on manufacture and sale of paediatric drugs nimesulide and phenylpropanolamine (PPA). On September 21, 2007

532-791: The active ingredient Valsartan when an impurity was identified in a valsartan active substance manufactured at a facility in China. It produced a report on medicinal cannabis in 2018 which suggested a controlled access programme for cannabis products that are not capable of being authorized as a medicinal product. In 2017 it confiscated large quantities of counterfeit “high-end” beauty products, some of which were found to contain arsenic and lead. It also detained 948,915 dosage units (tablets, capsules, vials etc.) of fake or other illegal medicines, 40% more than in 2016. 47% were anabolic steroids , 23% sedatives and 13% erectile dysfunction medicines. It brought six prosecutions. Nimesulide Nimesulide

560-425: The cancer treatment. MicroRNA are small non-coding RNA molecules which regulate gene expression at posttranscriptional level via binding to mRNA. This leads to degradation of the target mRNA molecule or translational repression . In tumor cells the miRNA expression pattern often change and therefore affect the surface NT5E, which as result interfere the anti-tumor immune response. For example, studies confirm

588-415: The drug with caution during lactation and nimesulide is contraindicated during pregnancy, and research suggest that it is also contraindicated in lactating women. Nimesulide is available in a variety of forms: tablets, powder for dissolution in water, suppositories, mouth dissolving tablets, and topical gel . It should be avoided by children under 12 and people with liver problems. Due to concerns about

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616-400: The fact, that the human and rat NT5E transcripts are 89% identical, human NT5E could be also regulated by SMAD proteins. Ecto-5-prime-nucleotidase (5-prime-ribonucleotide phosphohydrolase; EC 3.1.3.5) catalyzes the conversion at neutral pH of purine 5-prime mononucleotides to nucleosides, the preferred substrate being AMP . The enzyme consists of a dimer of 2 identical 70-kD subunits bound by

644-426: The function of these immune cells. In addition, the tumor cells may also express adenosine A1 and A3 receptors associated with Gαi proteins, promoting both the migration and proliferation of tumor cells. Especially due to its beneficial effects in mouse tumor model , anti-CD73 therapy is now a promising approach to cancer treatment in the future. CD73 inhibitor are currently being tested in clinical trials for

672-454: The medication. Continuous use of nimesulide (more than 15 days) may cause the following side effects: Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID), acting specifically as a relatively selective cyclooxygenase-2 inhibitor . However, the pharmacological profile of nimesulide is peculiar, and additional, unknown/yet-to-be-identified mechanisms appear to also be involved. One pathway that has been implicated in its actions

700-401: The production of prostaglandins (a chemical associated with pain), thereby relieving pain and inflammation. It may be used for pain, including period pains. Nimesulide is not recommended long-term, as for chronic conditions such as arthritis. This is due to its association with an increased risk of liver toxicity, including liver failure. Despite its risk of hepatotoxicity, a 2012 evaluation by

728-443: The risk of liver toxicity , nimesulide has been withdrawn from market in several countries (Mexico, Spain, Finland, Belgium, and Ireland). Liver problems have resulted in both deaths and the need for transplantation. Although the frequency of nimesulide-induced liver injury is estimated at around 1 in 50,000 patients and is less common when use is limited to 15 days, severe injury has occurred in as little as three days after starting

756-631: Was adenosine generated by NT5E, which limits the inflammatory immune response by negative feedback in neutrophil which express the adenosine receptor . Some tumours have upregulation and overexpression of CD73 so it has been proposed as a drug target for cancer therapy. An anti-CD73 antibody CPI-006 has started early stage clinical trials as a treatment for advanced cancers. Specialized immune cells such as myeloid-derived suppressor cells and regulatory T cells also mediate their effects via adenosine generated by local ectonucleotidase. In some cases of lupus patients, adequate T cell expression of CD73

784-551: Was confirmed to support tumor angiogenesis . His expression promotes invasion and metastasis of murine and human melanoma cells and human breast cancer cells. Tumor infiltration by cells which express NT5E such as myeloid derived suppressor cells (MDSC), Treg's, dendritic cells (DC) leads to accumulation of adenosine. Subsequently, cAMP signaling is triggered in T cell that express the adenosine A2A receptor . Adenosine receptor are also expressed on macrophage , DCs, MDSC and natural killer cell (NK). Thus, adenosine may inhibit

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