Interleukin clearance

Multiple factors play a role in the development of AOM. Viral infection of the nasopharynx impairs eustachian tube function and causes mucosal inflammation, impairing mucociliary clearance and promoting bacterial proliferation and infection. Children are predisposed to AOM because their eustachian tubes are shorter, more flaccid, and more horizontal than adults, which make them less functional for drainage and protection of the middle ear from bacterial entry. Clinical signs and symptoms of AOM are the result of host immune response and damage to cells caused by inflammatory mediators such as tumor necrosis factor and interleukins that are released from bacteria.4... 

Knauf MJ, Bell DP, Hirtzer P, Luo ZP, Young JD, Katre NV (1988) Relationship of effective molecular size to systemic clearance in rats of recombinant interleukin-2 chemically modified with water-soluble polymers. J Biol Chem 263 15064—15070... 

In Table 32.6 the predicted parameter estimates derived from the allometric equations in Table 32.5 are compared with the corresponding parameter estimates reported in humans. The observed values of Pi for the macromolecules listed fall within the expected range of observed results. However the observed clearances of Factor IX (FIX) and interleukin-12 (IL-12) were not predicted from allometry. Factors such as species specificity in the endothelial binding of FIX (22) or saturation of clearance mechanisms may account for the inability to predict these parameters in humans. 

Causes The following causes are seen as being responsible for an acquired immune deficiency syndrome in liver cirrhosis (B.A. Runyon, 1995) (i.) hypofunction of the RES (a decrease in the filter or clearance function and phagocytosis capacity as well as reduced formation of immune modulators) (s. p. 65), (2.) reduction in hepatic synthesis of opsonins (s. p. 66), (3.) compromised function of leucocytes, (4.) impaired proliferation and activation of T lymphocytes, and (5.) increased mucosa permeability to bacteria. Both bacteria and bacterial lipopolysaccharides enter the organism in large numbers. They are responsible for increased serum levels of the cytokines (e. g. interleukins 1 and 6, TNF, y-interferon), and there is increased production of these substances together with their reduced breakdown in the cirrhotic liver. Cytokines are formed in the monocytes of blood and in the mononuclear cells of various organs (above all in ascites). 

Chen G, Castro WL, Chow HH, Reichlin S (1997) Clearance of 1-labelled interleukin-6 from brain into blood following intracere-broventricular injection in rats. Endocrinology 138 4830-4836. 

Heys SD, Eremin O, Franks CR, Broom J, Whiting PH. Lithium clearance measurements during recombinant interleukin 2 treatment tubular dysfunction in man. Ren Fail 1993 15(2) 195-201. 

IL-2 has been used in the treatment of sohd tumors such as metastatic melanoma, metastatic renal cell carcinoma, and colorectal carcinoma. Interleukin-2 infusions are associated with significant dose-dependent toxicity characterized by fevers, malaise, nausea, vomiting, diarrhea, hepatic dysfunction, pulmonary edema, somnolence, confusion, dysrhythmias, myocardial infarction, hematopoietic suppression, and renal insufficiency [10]. IL-2 has a short serum half-life of 6-10 min and a clearance of 30-60 min after bolus intravenously infusion [11]. Resultant toxicity is generally transient and reversible. It is possible that IL-2 induced renal failure only occurs in the setting of profound hypotension, prior volume depletion, concurrent administration of potentially nephrotoxic drugs, or the presence of underlying renal disease. 

The pharmacokinetics and pharmacodynamics of recombinant interleukin-2 (IL-2) in patients with human immunodeficiency virus (HIV) infection have been evaluated (75). Patients were administered IL-2 either by continuous infusion or by SC injection for 5 days over multiple cycles. Following repeated injection, soluble IL-2 receptors were substantially but transiently increased. A dose-dependent decrease in area under the concentration-time curve (AUC) between days 1 and 5 was attributed to a receptor-mediated change in clearance. Concentrations were described using an unusual model that employed an indirect stimulatory PD model to link the time-dependent changes of the pharmacokinetics with the change in IL-2 receptor density following repeated administration. 

Assenat, E., Gerbal-Chaloin, S., Larrey, D., Saric, J., Fabre, J. M., Maurel, P., Vilarem, M. J., and Pascussi, J. M. (2004) Interleukin lbeta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance. Hepatology 40, 951-960. 

Thymosins. Thymosins are hormone-like polypeptides produced by thymus epithelial cells. They regulate the maturation of T-cells moreover, they modulate interferon production and stimulate the expression of interleukin-2 and its receptor. A trial of thymosin fraction-5 in four homosexual patients with chronic hepatitis B demonstrated no effect after six months of treatment (202), while treatment of WHV-infected woodchucks with thymosin alpha-1 resulted in clearance of circulating WHV-DNA and a 50-300-fold decline in the levels of replicative intermediates in liver tissue (203). Subsequently, thymosin alpha-1 and thymosin fraction-5 were used to treat chronic hepatitis B in a human pilot study (204). Results were encouraging, and this was followed by several randomized, controlled multicenter trials of thymosin alpha-1 in the U.S. The primary action of thymosin is unknown, but it is probably related to its immune-enhancing effects. 

Piscitelli SC, Vogel S, Figg WD, Raje S, Forrest A, Metcalf JA, Baseler M, Falloon J. Alteration in indinavir clearance during interleukin-2 infusions in patients infect with the human immunodeficiency virus. Pharmacotherapy ( 99 ) 18,1212-16. 

Brooks DG, Trifilo MJ, Edelmann KH et aL Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 2006 12(11) 1301-1309. 

A raw polysaccharide fraction of Echinacea angustifolia ( . pallida ) roots stimulated phagocytosis in mice, determined in the carbon-clearance assay, at a dosis of 10 mg/kg b.w. and also enhanced phagocytosis of human PMN in vitro by 32% at a concentration of 0.01 mg/ml [50]. Purified extracts containing a glycoprotein-polysaccharide complex exhibited B-cell stimulating activity and induced the release of interleukin 1, TNFa und IFNa,P both in vitro and in vivo [57-59]. 

Kim, D.C. Reitz, B. Carmichael, D.P. Bloedow, D.C. Kidney as a major clearance organ for recombinant human interleukin-1 receptor antagonist, J.Pharm.Sci., 1995,84, 575-580. 

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