Link: Pharm/Biotech Resources
United States Patent: 6,864,247
Issued: March 8, 2005
Inventors: Doi; Toshio (495-1-102, Kaikoji-cho, Motoseiganjisagaruhigashiiru, Aburanokojidori, Kyoto-shi, Kyoto 602-0946, JP)
Appl. No.: 314389
Filed: December 9, 2002
An object of the present invention is to provide pharmaceutical compositions for inhibiting mesangial cell proliferation or mesangial matrix production without causing hypercalcemia. According to the present invention, therapeutic agents for glomerulosclerosis containing 1.alpha.,3.beta.-dihydroxy-20.alpha.-(3-hydroxy-3-methylbutyloxy)-9,10-sec o-5,7,10 (19)-pregnatriene as an active ingredient are provided.
Description of the Invention
The present invention relates to therapeutic agents for glomerulosclerosis containing 1.alpha.,3.beta.-dihydroxy-20.alpha.-(3-hydroxy-3-methylbutyloxy)-9,10-sec o-5,7,10 (19)-pregnatriene (hereinafter also referred to as 22-oxa-1.alpha.,25-dihydroxyvitamin D3) as an active ingredient.
Glomerulosclerosis is induced by irreversible progress of various glomerular diseases of different etiologies and histopathological pictures. It is mainly pathologically characterized by mesangial cell proliferation or increased mesangial matrix accompanied by atrophy, degeneration or collapse of glomerular cells. Examples of the etiologies of glomerulosclerosis include IgA nephropathy or diabetic nephropathy, which were reported to be characterized by mesangial cell proliferation or increased mesangial matrix. In order to establish a therapy for glomerulosclerosis, it seems important to clarify the mechanism of the onset or to understand the pathology. Thus, efforts have been made to develop experimental nephritis models that experimentally induce lesions with mesangial cell proliferation and mesangial matrix production, and a rat model of anti-Thy 1 antibody-induced nephritis was prepared (Bagchus, W. M. et al., Lab. Invest, Vol. 55, No. 6, pp. 680-687, 1986). This model shows glomerular nephritis with mesangial cell proliferation and mesangial matrix production caused by the reaction between Thy 1 antigen existing as a membrane protein in mesangial cells and an antibody against it, and drug efficacy tests in this model were reported (Masashi Haraguchi et al., Kidney International, Vol. 51 (1997), pp. 1838-1846).
Drugs such as antitumor agents or immunosuppressive agents based on activated vitamins D3 (i.e., 1,25-dihydroxyvitamins D3) have been developed since they were reported to have not only a calcemic action but also a differentiation-inducing effect (Abe E. et al., Proc. Natl. Acad. Sci. USA, Vol. 78, No. 8, pp. 4990-4994, 1981). 1,25-Dihydroxyvitamins D3 were also reported to have an antiproliferative effect on human mesangial cells (Weinreich T. et al., American Journal of Kidney Diseases, Vol. XVIII, No. 3, 1991, pp. 359-366). However, it was difficult to use 1,25-dihydroxyvitamins D3 for antiproliferative purposes due to hypercalcemia.
Thus, vitamin D3 derivatives with a low calcemic action were researched and some derivatives were developed. One of such vitamin D3 derivatives is 22-oxa-1.alpha.,25-dihydroxyvitamin D3, which was reported to show a differentiation-inducing effect without causing hypercalcemia (Abe J. et al., FEBS Lett., Vol. 226, No. 1, pp. 58-62, 1987). Japanese Patent No. 2854600 describes that 22-oxa-1.alpha.,25-dihydroxyvitamin D3 inhibits urinary protein excretion so that it is useful as a therapeutic agent for glomerulonephritis.
However, nothing has been shown about the effect of 22-oxa-1.alpha.,25-dihydroxyvitamin D3 on mesangial cell proliferation or mesangial matrix production.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide pharmaceutical compositions having the effect of inhibiting mesangial cell proliferation or mesangial matrix production with a low calcemic action.
As a result of careful studies to attain the above object, the inventor accomplished the present invention on the basis of the finding that 22-oxa-1.alpha.,25-dihydroxyvitamin D3 inhibits mesangial cell proliferation without causing hypercalcemia and also inhibits the expression of collagen in a rat model of anti-Thy 1 antibody-induced nephritis.
Accordingly, the present invention provides therapeutic agents for glomerulosclerosis containing 1.alpha.,3.beta.-dihydroxy-20.alpha.-(3-hydroxy-3-methylbutyloxy)-9,10-sec o-5,7,10 (19)-pregnatriene as an active ingredient.
Therapeutic agents for glomerulosclerosis of the present invention can be used as pharmaceutical compositions for inhibiting mesangial cell proliferation or excessive mesangial matrix production.
Therapeutic agents for glomerulosclerosis of the present invention can also be used as pharmaceutical compositions for inhibiting the overexpression of collagen in the mesangium.
The present application claims priority based on Japanese Patent Application No. 128566/1999, the disclosure of which is entirely incorporated herein as reference.
THE MOST PREFERRED EMBODIMENTS OF THE INVENTION
The present invention will now be described more in detail only for illustrative but non-limitative purposes.
1.alpha.,3.beta.-Dihydroxy-20.alpha.-(3-hydroxy-3-methylbutyloxy)-9,10-seco -5,7,10 (19)-pregnatriene (ie, 22-oxa-1.alpha.,25-dihydroxyvitamin D3 or OCT) used as an active ingredient in the present invention is a known compound that can be synthesized by the process described in JPA No. 267550/86, for example.
However, the compound that can be used as an active ingredient in the present invention is not limited to 22-oxa-1.alpha.,25-dihydroxyvitamin D3, and other vitamin D3 derivatives having the effect of inhibiting mesangial cell proliferation or mesangial matrix production with a low calcemic action such as 16-enevitamin D3 derivatives can also be used.
The "mesangial cell" and "mesangial matrix" are explained below.
The mesangium is a tissue supporting capillary loops in the glomerulus of the kidney and composed of mesangial cells and mesangial matrix. Mesangial cells are known to maintain the loop structure of the glomerulus as well as have a phagocytic function or the ability to regulate glomerular blood flow. Mesangial cells have angiotensin II receptors and produce platelet-activating factor, prostaglandin, type IV collagen, fibronectin, etc. The mesangial matrix is an extracellular matrix component that surrounds mesangial cells.
The pharmacological effect of 22-oxa-1.alpha.,25-dihydroxyvitamin D3 used as an active ingredient in the present invention can be evaluated on a rat model of a anti-Thy 1 antibody-induced nephritis characterized by showing increased mesangial cell proliferation and mesangial matrix production after administration of an anti-Thy 1 antibody. The pharmacological effect of test compounds can be evaluated by administering an anti-Thy 1 antibody to such a rat model followed by the test compounds, collecting renal tissue at an appropriate time and determining the glomerular cell count or glomerulosclerosis index or determining the expression of collagen by a standard method such as an immunohistochemical technique.
The mode of administration of pharmaceutical compositions of the present invention is not specifically limited, either oral or parenteral (for example, intravenous, intramuscular, intraperitoneal, etc.).
Pharmaceutical compositions of the present invention are preferably formulated and used in appropriate dosage forms including, but not limited to, tablets, granules, fine granules, capsules, powders, injections, solutions, suspensions, emulsions, transdermal patches and suppositories containing 1.alpha.,3.beta.-dihydroxy-20.alpha.-(3-hydroxy-3-methylbutyloxy)-9,10-sec o-5,7,10 (19)-pregnatriene as an active ingredient optionally in combination with pharmaceutically acceptable carriers, excipients, disintegrators, lubricants, binders, perfumes, colorants, etc.
The dose can be appropriately chosen to be effective for inhibiting excessive mesangial cell proliferation or excessive mesangial matrix (e.g., collagen) production in the subject depending on the disease to be treated, the condition, body type, constitution, age and sex of the patient, and the administration route, dosage form or other factors. The dose expressed in the weight of an active ingredient is typically in the range of 0.001-1000 .mu.g/kg/day, preferably 0.01-100 .mu.g/kg/day, more preferably 0.1-10 .mu.g/kg/day.
Claim 1 of 3 Claims
What is claimed is:
1. A method of treating diabetic nephropathy, comprising administering to a host in need of such a treatment a therapeutically effective amount of 1.alpha.,3.beta.-dihydroxy-20.alpha.-(3-hydroxy-3-methylbutyloxy)-9,10-sec o-5,7,10(19)-pregnatriene.