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Method of treating side effects induced by therapeutic agentsMethod of treating side effects induced by therapeutic agents description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080153753, Method of treating side effects induced by therapeutic agents. Brief Patent Description - Full Patent Description - Patent Application Claims
The invention relates to agents for the prevention of organ damage, in particular of the kidneys and the inner ear, induced by the administration of therapeutic agents. BACKGROUNDIt is known that aminoglycosides are some of the most important antibiotics for the treatment of severe bacterial infections. They are the preferred agents against a number of Gram-negative bacteria. Their annual market potential in Germany is about 500 million DM. At present, the market share of the aminoglycosides in the field of anti-infectious agents is even rapidly increasing. This is above all due to the general increase in the occurrence of pathological strain resistance to other classes of antibiotics. The main obstacle in the clinical use of aminoglycosides is their severe oto- and nephrotoxic side effects which especially lead to complete loss of hearing and to renal failure in the long term. The use of aminoglycosides is thus not only associated with a high risk, but also entails high resulting costs. Their use is therefore restricted to incidences of the most severe infections in the industrial countries. In the developing countries in which aminoglycosides are more often used because of their low production costs, these antibiotics account for 70% of all cases of acquired deafness. As for the causes of their toxicity, it is so far only known that aminoglycosides bind to the surface of cells in the kidneys and the inner ear and are taken up into the cells through unknown mechanisms. As aminoglycosides are only weakly degradable in the cells, they accumulate in large numbers and lead to destruction of the cell structures and thus to renal damage and loss of hearing. Various surface structures or receptors have been made responsible for the binding and uptake of the antibiotics; however, a clear demonstration of the binding sites of aminoglycosides on the body cells has not yet been possible. Decorti et al. have postulated that the uptake of aminoglycosides is a receptor-independent diffusion process (Decorti et al. 1999, Life Sciences 65, 1115-1124). On the other hand, Moestrup et al. were of the opinion that megalin, a surface receptor of the kidneys, is responsible for the uptake of antibiotics (Moestrup et al., J. Clin. Invest. 96, 1404-1413, 1995). However, Moestrup et al. could only show the binding of aminoglycosides to megalin in test tubes and in cultivated cells. On the contrary, in an animal model, the use of receptor antagonists did not lead to any significant inhibition of the aminoglycoside uptake into the kidneys. Moreover, the aminoglycosides also bind to other surface receptors (so-called LRP's) found in the liver, but not in the kidneys. However, as aminoglycosides are only taken up into the organism in the kidneys and in the inner ear, the value of these in vitro experiments is unclear. Schmitz et al. has shown that megalin deficiency offers protection from renal aminoglycoside accumulation however no effective way for inhibition of aminoglycoside accumulation in megalin sufficient individuals is discussed or shown (Schmitz, C. et al. The Journal of Biological Chemistry, Vol 277, No. 1, Issue of January 4, pp. 618-622, 2002). Up to now, various strategies have been used in order to reduce the toxic effects of the aminoglycosides. Originally, about 40% of all patients experienced nephro- and ototoxic side effects. As these were directly related to the plasma concentration of the antibiotics, concomitant plasma concentration determinations were introduced to control the concentrations of the antibiotics. Moreover, it was shown that administration with intervals of 12 or 24 hours is accompanied by fewer side effects than dosage regimens with a more frequent administration. By such measures, the number of patients with side effects could be reduced to 10% (Burton, M. E., Vasko, M. R. & Brater, D. C. Clin. Pharmacokinetics 10, 1-37 (1985)). However, they led to an increase in the treatment costs. These include the laboratory work for plasma concentration determinations (DM 200-600 for a treatment time of 10 days), further resources for medical staff and costs of about DM 800 per patient for diagnosis and therapy of renal disease. In another strategy to prevent toxic effects, novel aminoglycosides having fewer side effects were developed. An example of these is amikacin, a semi-synthetic derivative of kanamycin (Begg, E. J. & Barclay, M. L. Br. J. Clin. Pharmac. 39, 597-603, 1995). The use of amikacin reduced the rate of toxicity to 1-4%. However, this use is also connected with a further increase in the therapy costs as amikacin (DM 180 per day) is clearly more expensive than usual gentamicin compositions (DM 35 per day). In general it is doubtful whether this strategy of changing aminoglycoside has any effect at all, since a direct correlation between bactericidal effect and toxic effect is seen. Accordingly, Moestrup et al. could show that amikacin has an about 5 times poorer binding than gentamicin to megalin (Moestrup et al., 1995). The apparently direct correlation between toxicity and bactericidal properties is illustrated by the example of amikacin. It is true that this antibiotic has a clearly poorer binding to megalin (lower toxicity), but it has to be used in a 10 times higher dosage than usual aminoglycosides (lower bactericidal activity). As a third attempt to reduce the toxicity associated with aminoglycosides, the simultaneous administration of the antibiotics and substances such as neutrophin-3 (Emfors, P., Duan, M. L., ElShamy, W. M. & Canlon, B. Nat. Med. 2, 463-467 (1996)), nitrendipine (Lee, S. M., Pattison, M. E. & Michael, U. F. J. Cardiovasc. Pharmacol. 9, S65-S69 (1997)), Pyrola rotundifolia (Xuan, W. & Dong, M. Ann. Otol. Rhinol. Laryngol. 104, 374-380 (1995)) or antioxidants was tested (Schacht, J. Head and Neck Surgery 118, 674-677 (1998)). The exact mechanisms of the effect of these substances are still not clear. So far, none of these uses have been implemented clinically. Furthermore, Ford et al. have shown that aminoglycosides are taken up into the kidneys both from the circulation and from the renal filtrate. As megalin is only exposed to the renal filtrate, the scientific community assumes that alternative receptors exist (Ford et al., Am. J. Physiol. 1994, 266, C52-C57). A recent article by Girton et al. questions whether the toxicity of aminoglycosides is due to uptake mediated by megalin (Girton R. A. et al (2002) Am. J. Renal Physiol., 282: F703-709). SUMMARY OF THE INVENTIONThus, it is an object of the invention to provide substances capable of reducing or inhibiting the accumulation of aminoglycosides as well as other toxic medicaments in cells, in particular in the kidneys and the inner ear and, in order to avoid damage to organs consisting of the cells. Accordingly, in one aspect the present invention relates to the use of a substance capable of binding to one or more of the following:
1) a megalin receptor, and/or
2) a cubilin receptor, and/or
3) a therapeutic agent, said therapeutic agent being capable of binding to the megalin receptor and/or the cubilin receptor,
for the preparation of a medicament for the treatment of side effects of medical treatment with said therapeutic agent in humans.
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