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Ulinastatin (or urinary trypsin inhibitor, UTI) is a glycoprotein which acts as a trypsin inhibitor. It can be derived from urine or it can be synthetically produced. It may be effective in treatment of acute pancreatitis, chronic pancreatitis, toxic shock, Stevens–Johnson syndrome, burn patients, severe sepsis and toxic epidermal necrolysis (TEN).
Currently, the drug is being used in Japan, where its brand name is Miraclid. The drug is also available in Korea, China and India. In India, it is marketed by Bharat Serums and Vaccines, Ltd. under the brand name U-Tryp, where it is indicated to treat severe sepsis and acute pancreatitis. The drug is also known by the name of Bikunin and Urinastatin.
Studies in Japan have documented reduction in the incidence of ERCP-induced pancreatitis with the use of ulinastatin. In one study, the incidence of hyperenzymemia and pancreatitis was significantly lower in the ulinastatin group than in the placebo group.[1] Ulinastatin reduced the levels of serum and drain amylase and the incidence of postoperative pancreatitis following pancreaticoduodenectomy in another study.[2]
A study conducted in India for pancreatitis concluded that, 22-day all-cause mortality in subjects with severe pancreatitis receiving ulinastatin was lower than those receiving placebo (2.8% vs 18.8%; p=0.048), resulting in a 16% absolute reduction in the risk of death and a relative reduction of 85%. Results also indicate that in this population, one life would be saved for every 6.25 subjects treated with ulinastatin. New organ dysfunction was seen in 12 subjects with severe pancreatitis on ulinastatin and 29 on placebo (p=0.0026) thus, ulinastatin reduced the rate of this complication. It also observed that the median hospital stay till discharge in survivors was shorter in the ulinastatin group, but this difference was not statistically significant.[3]
Mechanism of Action
Ulinastatin is an acid-resistant protease inhibitor found in human urine. It is released from the high-molecular weight precursor I alpha T1. Proteins of the I alpha T1 family are composed of two heavy chains (HCs) and one light chain. UTI is composed of two Kunitz-type domains. The inhibitor ulinastatin shows an apparent molecular mass of 30 kDa. This protein may arise from a gene duplication event of BPTI followed by diversification only within the portion of the gene coding for the functional Kunitz domain. Ulinastatin inactivates many serine proteases such as trypsin, chymo-trypsin, kallikrein, plasmin, granulocyte elastase, cathepsin, thrombin, factors IXa, Xa, XIa, and XlIa.
Although ulinastatin is a protease inhibitor, its activity towards various proteases was found to be relatively weak. The C-terminal domain is responsible for antitryptic activity. Ulinastatin protein was found to be distributed in the brain, liver, kidney, gastrointestinal tract, cartilage, plasma, ovarian follicular fluid, amniotic fluid, and urine. The mRNA was detected only in the liver, kidney, heart, lung, and pancreas. Ulinastatin in the tissues may localize independently of I alpha T1. The presence of ulinastatin in certain tissues appears to be due to diffusional uptake and retention through cell surfaces. It also potentiates the local anti- proteolytic activity on the ECM during tissue remodeling possibly through noncovalent binding to TSG-6.
Its secretion was up-regulated by proinflammatory cytokines, including IL-6, IL-1beta, and TNF-alpha. The proinflammatory cytokines also enhanced the synthesis of the intracellular I alpha T1 proteins, and IL-1beta up-regulated ulinastatin. Ulinastatin is implicated in down-regulating or suppressing the production of proMMP-1 and proMMP, prostaglandin H2 synthase-2, uPA, C-X-C chemokine (cytokine-induced neutrophil chemoattractant), Proinflammatory cytokine, inducible nitric oxide synthase (iNOS), tissue factor, P-selectin, intercellular adhesion molecule-1, phosphorylation of the extracellular signal regulated protein kinases, and NF-kappaB activation.
Ulinastatin also suppresses neutrophil accumulation and activity. These genes and proteins regulated by Ulinastatin are implicated in the inflammatory process. Indeed, concomitant administration of ulinastatin inhibited the LPS-induced plasma levels of the inflammatory cytokines. Therefore, ulinastatin is not just a protease inhibitor, but can prevent inflammation and cytokine-dependent signaling pathways possibly via the suppression of the phosphorylation of ERK1/2, JNK, as well as NF-κB or Egr-1 signaling in response to a diverse array of stresses such as oxidative stress and inflammatory stress.
In the preclinical and clinical studies, ulinastatin protects against acute lung injury, graft ischemia–reperfusion injury, renal function after cardiopulmonary bypass, severe burn injury, septic shock, preterm delivery, tumor invasion and metastasis. Thus, ulinastatin might play a role as a potent anti-inflammatory agent. Ulinastatin has been identified to have anti-metastatic properties, possibly through inhibition of cell-bound plasmin activity. Ulinastatin also prevents tumor progression partially by inhibiting cathepsin B activity. In particular, ulinastatin is thought to inhibit CD44 dimerization and suppress the MAP kinase signalling cascade, thus preventing ECM degradation, tumor cell invasion, and angiogenesis. Taken together, ulinastatin is considered to play an important role not only in the protection of organ injury during severe inflammation but also in the inhibition of tumor invasion and metastasis. Thus, ulinastatin treatment is possibly an additional therapeutic approach to inflammatory disease and cancer.[4]
Dosage and administration
Administer 1 to 2 vials of 100,000 I.U. of ulinastatin (Reconstituted in 100 ml of Dextrose 5% or 100 ml of 0.9% Normal Saline) by intravenous infusion over 1 hour each time, 1-3 times per day for 3 to 5 days. The dosage may be adjusted according to the age of patients and the severity of symptoms[5][better source needed]
Storage temperature 2 °C to 8 °C. Protect from light. Any unused portion should be discarded. Lupin's brand 'Upxiga' is available in lyophilized for injection dosage form and does not require cold storage facility. It can be stored below 25 degree Celsius.
References
- ^ Sujino T, Komatsu Y, Isayama H, Hirano K, Sasahira N, Yamamoto N, Toda N, et al. Ulinastatin for pancreatitis after endoscopic retrograde cholangiopancreatography: A randomized, controlled trial. Clin Gastroenterol Hepatol2005;3:376.
- ^ Uemura K, Murakami Y, Hayashidani Y, Sudo T, Hashimoto Y, Ohge H, Sueda T. Randomized clinical trial to assess the efficacy of ulinastatin for postoperative pancreatitis following pancreaticoduodenectomy. J Surg Oncol2008;98:309-13.
- ^ Journal of the association of physicians of India •August 2013 •VOL. 61 :15-18
- ^ Inflamm. Res. (2010) 59:679–687 DOI 10.1007/s00011-010-0205-5, J.Clin.Biochem. Nut., 43,139-142, November 2008
- ^ https://www.google.co.in/?gws_rd=cr&ei=otZDUomXFYLrrQeE2IGIDg#q=ulinastatin+prescribing+information
