Pancreatic protease inhibitors

Pancreatic secretion for many, if not most, species is regulated in order to insure adequate protein digestion. Correspondingly, protease inhibitors have a greater impact on pancreatic secretion than do inhibitors of amylase and lipase (Toskes, 1986). The secretory response of the exocrine pancreas to protease inhibitors can be rapid (< 10 min), does not involve parallel increases in the secretion of all enzymes (Holm et al., 1992), and is probably mediated by a signaling pathway (see below). 

There is evidence that protease inhibitors selectively regulate the activity of specific digestive enzymes at the level of gene expression (Rosewicz et al., 1989). Specifically, soybean trypsin inhibitor increases secretion of proteases, including a form of trypsin that is resistant to inhibition but does not cause an increase in amylase secretion. Although the relationships between protease inhibitors and exocrine pancreatic secretion have received the most attention, pancreatic secretion is increased when potato fiber is added to the diet (Jacob et al., 2000), although the mechanism and signaling pathway have not been elucidated. 

Hexokinase Pyruvate kinase Adenylate kinase Phosphoglycerate kinase Phosphofructokinase Protease inhibitors Pancreatic trypsin inhibitor Soybean trypsin inhibitor Streptomyces subtilisin inhibitor Nucleases... 

Lopinavir is available in the United States only as a fixed-dose combination with ritonavir (Kaletra). In this regimen, a low dose of ritonavir is used to inhibit the rapid inactivation of lopinavir by CYP3A4. Side effects, which are generally mild, include diarrhea, nausea, asthenia, and headache. Pancreatitis occurs rarely. Ritonavir is a potent inhibitor of CYP3A4 and also inhibits CYP2D6. In addition to the drugs contraindicated for all protease inhibitors, fiecainide, propafenone, pimozide, and rifampin should not be given with lopinavir-ritonavir combination therapy. 

The protease-inhibitor system imbalance is the key element of alterations in purulent inflammatory diseases such as purulent peritonitis and destructive pancreatitis. This imbalance is the result of a massive release of cellular proteases. 

Pathogenesis of systemic abnormalities during pancreatitis is associated with a high concentration of pancreatic proteases in the blood, which reduce activation of the blood proteolytic systems. Alteration of the balance between proteases and their natural inhibitors is a trigger of endogenous intoxication syndrome, which controls disease severity and the clinical outcome. Therefore, drugs which act as inhibitors of proteases are an important component of a complex treatment of acute pancreatitis. 

A high fatality rate associated with this disease suggests that the effectiveness of conservative and surgical treatment is not sufficient in the case of acute pancreatitis. New methods of extracorporeal detoxification using hemoperfusion over carbon sorbents has made it possible to improve the outcome of pancreatitis treatment. However, hemosorption leads to only a transient decrease in blood proteolytic activity and does not correct the imbalance in the protease-inhibitor system, and the carbon hemosorbents are nonspecific. The development and application of antiprotease hemosorbents with specific bioligands therefore has potential in pancreatitis treatment. 

The fatality rate was also analyzed in the group of 97 randomly-selected patients with acute pancreatitis, treated in Minsk hospitals prior to 1988 by a similar treatment program using HS over uncoated activated carbon sorbents of the SKN type [5], Eighteen healthy donors served as control. It should be noted that patients in both groups were treated with intravenous infusion of the protease inhibitor from bovine lung (Contrykal, Dresden, Germany 5,000 U per body mass per day). 

Otsuki, M., Ohki, A., Okabayashi, Y., Suehiro, I., and Baba, S. (1987). Effect of synthetic protease inhibitor camostate on pancreatic exocrine function in rats. Pancreas, 2, 164-169. 

Lopinavir/Ritonavir (Kaletra) [Anrirelroviral/Protease Inhibitor] Uses HIV Infxn Action Protease inhibitor Dose Adults. Tx naive 2 tab PO daily or 1 tab PO bid Tx experiencedpt 1 tab PO bid (T dose if w/ amprenavir, efavirenz, fosamprenavir, nelfinavir, nevirapine) Peds. 7-15 kg 12/3 mg/kg PO bid 15-40 kg 10/2.5 mg/kg PO bid >40 kg Adult dose w/ food Caution [C, /-] Numerous interactions Contra w/drugs dependent on CYP3A/CYP2D6 (Table VI-8) Disp Tab, soln SE Avoid disulfiram (soln has EtOH), metronidazole GI upset, asthenia, T cholesterol/triglycerides, pancreatitis protease metabolic synd Interactions T Effects Wl clarithromycin, erythromycin T effects OF amiodarone, amprenavir, azole andfungals, bepridil, cisapride, cyclosporine, CCBs, ergot alkaloids, flecainide, flurazepam, HMG-CoA reductase inhibitors, indinavir, lidocaine, meperidine, midazolam, pimozide, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, tacrolimus, terfenadine, triazolam, zolpidem 1 effects Wl barbiturates, carbamazepine, dexamethasone, didanosine, efavirenz, nevirapine, phenytoin, rifabutin, rifampin, St. John s wort 1 effects OF OCPs, warfarin EMS Use andarrhythmics and benzodiazepines... 

One of the goals of synthetic medicinal chemistry is to design potent inilibitors of clinically important proteases. Elastase inhibitors may be useful for treatment of emphysema, pancreatitis, and arthritis,a/b while inhibitors of the angiotensinogen-converting enzyme or of renin (Box 22-D) can help control blood pressure. Inhibition of thrombin, factor Xa, or other blood clotting factors (Fig. 12-17) may prevent blood clots and inhibition of the cytosolic tryptase may provide a new treatment for asthma. Inhibition of the cysteine protease cathepsin K may help combat osteoporosis and inhibition of cysteine proteases of corona viruses may fight the common cold. Cysteine proteases of schistosomes are also targets for protease inhibitors.c... 

About 20 families of protein inhibitors of proteases have been described.488 The egg white ovomucoids comprise one family. Turkey ovomucoid is a three-domain protein whose 56-residue third domain is a potent inhibitor of most serine proteases.455 489 The 58-residue pancreatic trypsin inhibitor490 is a member of another family of small proteins. A 36-residue insect (locust) protease inhibitor is even smaller.491... 

Several inhibitor-protease complexes have been crystallized and details of their interactions are known. For example, the pancreatic trypsin inhibitor binds at the active site of trypsin with K( >1013 M-1 at neutral pH 496 Tire two molecules fit snugly together,490 497 the inhibitor being bound as if it were a peptide substrate with one edge of the inhibitor molecule forming an antiparallel (1 structure with a peptide chain in the enzyme. Lysine 15, which forms part of this P structure, enters the specific Pj binding site for a basic amino acid in a substrate. Thus, the protease inhibitor is a modified substrate which may actually undergo attack at the active site. However, the fit between the two... 

Most protease inhibitors act by mechanisms similar to that of the pancreatic trypsin inhibitor. They are very slow substrates with a reactive loop that carries suitable Pj, P2, and P/ residues that meet the specificity requirements of the enzyme. Additional noncovalent interactions prevent dissociation and make the energy barrier for hydrolysis so high that the reaction is extremely slow.488 494 495... 

Diabetes mellitus in a 36-year-old man with acute pancreatitis could not be controlled with continuous subcutaneous insulin infusion, even with doses up to 1800 U/ day, because of insulin resistance (168). Intravenous insulin by pump had to be stopped because of a catheter infection. The continuous subcutaneous infusion of freeze-dried insulin and the addition of aprotinin, a protease inhibitor, soluble dexamethasone or prednisolone, and intravenous immunoglobulin was ineffective. An implantable pump for intraperitoneal delivery established good regulation at a dosage of 30 U/day. 

G7. Gross, V., Scholmerich, J., Leser, H. G., Salm, R., Lausen, M., and Ruckauer, K., Granulocyte elastase in assessment of severity of acute pancreatitis. Comparison with acute-phase proteins C-reactive protein, alpha 1-antitrypsin, and protease inhibitor alpha 2-macroglobulin. Dig. Dis. Sci. 35, 97-105 (1990). 

Diazetidin-2,4-dione has been found to be a chymase inhibitor (IC50 4.0nM). It has been found that 1,3-diazetidin-2,4-dione derivatives possess high activities against bovine pancreatic cr-chrymotrypsin, human cathepsin G, and human neutrophil elastase. Some of the derivatives of l,3-diazetidin-2,4-diones have been shown to be effective as a scaffold for serine protease inhibitors <2001BML1691>. Further, 1,3-diazetidinone containing scaffolds have been found to possess potential antibacterial properties (Section 2.13.7.3). 

A number of protease inhibitors are being used currently for treating disease. Trasylol [Bayer s trademark for pancreatic trypsin inhibitor (Kunitz)] is being used currently in Europe for treating pancreatitis. This disease, which is often fatal in young alcoholic men and older women, results in the leakage of pancreatic proteases into the plasma. 

Ghosh and Kim recently disclosed a new chiral auxiliary (47) that exhibits an enhanced diastereoselectivity over the previously utilized auxiliary (44) in the anti -aldol reaction196 (Scheme 2.2s). Based on this anti -aldol strategy, Ghosh and Fidanze achieved an asymmetric synthesis of (-)-tetrahydrolipstatin (50), which was isolated from Streptomyces toxytricini20 (Scheme 2.2t). (-)-Tetrahydrolipstatin is a potent inhibitor of pancreatic protease and has been... 

A. L. Goldberg, Purification from Escherichia coli of a periplasmic protein that is 10 a potent inhibitor of pancreatic proteases. 

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