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Title:  Method of treating leishmaniasis using methyl-beta-cyclodextrin
United States Patent: 
7,186,702
Issued: 
March 6, 2007

Inventors: 
Chattopadhyay; Amitabha (Hyderabad, IN), Madhubala; Rentala (Hyperabad, IN)
Assignee: 
Council of Scientific and Industrial Research (New Delhi, IN)
Appl. No.:  11/141,573
Filed: 
May 31, 2005


 

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Abstract

The present invention relates to a composition useful for the treatment of leishmaniasis said composition comprising pharmaceutically effective amount of methyl-beta-cyclodextrin, optionally along with other anti-leishmanial agent(s) and/or pharmaceutically acceptable additives, and a method thereof, wherein the said method reduces the cholesterol levels of the plasma membrane of the infected host cells by about 50%.

SUMMARY OF THE PRESENT INVENTION

The present invention relates to a composition useful for the treatment of leishmaniasis said composition comprising pharmaceutically effective amount of methyl-beta-cyclodextrin, optionally along with other anti-leishmanial agent(s) and/or pharmaceutically acceptable additives, and a method thereof, wherein the said method reduces the cholesterol levels of the plasma membrane of the infected host cells by about 50%.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

Accordingly, the present invention relates to a composition useful for the treatment of leishmaniasis said composition comprising pharmaceutically effective amount of methyl-beta-cyclodextrin, optionally along with other anti-leishmanial agent(s) and/or pharmaceutically acceptable additives, and a method thereof, wherein the said method reduces the cholesterol levels of the plasma membrane of the infected host cells by about 50%.

The main embodiment of the present invention is a method of treating leishmaniasis said method consisting of step of administering a composition comprising pharmaceutically effective amount of methyl-beta-cyclodextrin optionally along with other anti-leishmanial agent(s) and/or pharmaceutically acceptable additives, to a subject in need thereof.

In another main embodiment of the present invention, wherein the said method reduces the cholesterol levels of the plasma membrane of the infected host cells by about 50%.

In still another main embodiment of the present invention, wherein said additives are selected from a group of nutrients comprising proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, starch-gelatin paste, and/or pharmaceutically acceptable carrier, excipient, diluent, or solvent.

In still another main embodiment of the present invention, wherein the composition is administered orally, inhaled, or implanted.

In still another main embodiment of the present invention, wherein the composition for the oral route is in form of capsule, tablet, syrup, concentrate, powder, granule, aerosol, and/or beads.

In still another main embodiment of the present invention, wherein the subject is useful animals or human beings.

In still another main embodiment of the present invention, wherein said method shows no adverse effect on subject.

In still another main embodiment of the present invention, wherein the dosage of the methyl-beta-cyclodextrin is ranging between 20 to 500 mg/kg body weight of the subject.

In still another main embodiment of the present invention, wherein the ratio of methyl-beta-cyclodextrin to additives is ranging between 1:10 to 10:1.

In still another main embodiment of the present invention, wherein the said method shows no effect on the other forms of lipids.

In still another main embodiment of the present invention, wherein the anti-leishmanial effect increases with an increase in the amount of methyl-beta-cyclodextrin administered to a subject.

In still another main embodiment of the present invention, wherein the anti-leishmanial effect increases with an increase in the time duration of exposure of methyl-beta-cyclodextrin to a subject.

In another main embodiment of the present invention, wherein a composition useful for the treatment of leishmaniasis said composition comprising pharmaceutically effective amount of methyl-beta-cyclodextrin, optionally along with other anti-leishmanial agent(s) and/or pharmaceutically acceptable additives.

In still another main embodiment of the present invention, wherein the concentration of methyl-beta-cyclodextrin is ranging between between 20 to 500 mg/kg body weight of the subject

In still another main embodiment of the present invention, wherein the ratio of methyl-beta-cyclodextrin to additives is ranging between 1:10 to 1:1.

In still another main embodiment of the present invention, wherein said additives are selected from a group of nutrients comprising proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, starch-gelatin paste, and/or pharmaceutically acceptable carrier, excipient, diluent, or solvent.

In still another main embodiment of the present invention, wherein the composition is administered orally, inhaled, or implanted.

In still another main embodiment of the present invention, wherein the composition for the oral route is in form of capsule, tablet, syrup, concentrate, powder, granule, aerosol, and/or beads.

Accordingly, the present invention relates to a method of treating leishmaniasis, using methyl-beta-cyclodextrin wherein said cyclodextrin depletes cholesterol from the plasma membrane of the cells infected with Leishmania donovani.

In an embodiment of the present invention, wherein cholesterol is a major constituent of eukaryotic membranes and plays a crucial role in cellular membrane organization, dynamics, function and sorting.sup.1. It is often found distributed non-randomly in domains in membranes.sup.2,3. Recent observations suggest that cholesterol exerts many of its actions by maintaining a specialized type of membrane domain, termed "lipid rafts", in a functional state.sup.4. The lipid rafts have been implicated as platforms through which signal transduction is coordinated.sup.5 and pathogens gain entry to infect host cells.sup.6.

In another embodiment of the present invention, wherein Leishmania donovani is an obligate intracellular parasite that infects macrophages of the vertebrate host resulting in visceral leishmaniasis in humans which is usually fatal if untreated.sup.7,8. The estimated annual number of new cases of leishmaniasis is thought to be 2 million.sup.9 and visceral leishmaniasis is about 500,000.sup.7. The molecular mechanisms involved in parasite-host interaction leading to attachment and internalization are poorly characterized. We report here that cholesterol depletion from macrophage plasma membranes using methyl- -cyclodextrin results in a significant reduction in the extent of leishmanial infection. Our results show that plasma membrane cholesterol plays a crucial role in efficient attachment and internalization of the parasite to macrophage cells.

In yet another embodiment of the present invention, wherein the objective of the present study was to determine the role of cholesterol in bringing about a productive leishmanial infection in mammalian host cells. The murine macrophage cell line J774A.1 was used as a host.sup.10 to a virulent Leishmania donovani strain AG83 (MHOM/IN/1983/AG83). Selective cholesterol depletion from the plasma membranes of the host macrophages was achieved by treatment with methyl-cyclodextrin, a compound that specifically extracts cholesterol from the plasma membranes leaving other lipids intact.sup.11,12 and disrupts lipid rafts.sup.13.

In still another embodiment of the present invention, the extent of leishmanial infection in control cells and macrophages that were depleted of cholesterol using methyl-.beta.-cyclodextrin (M CD) was assessed at the levels of (i) parasite interaction with the host cell surface as monitored by ligand binding assays using metabolically radiolabeled promastigotes, the extracellular form of the parasites and confirmed by flow cytometric analysis using fluorescently labeled promastigotes and (ii) the eventual presence of the intracellular amastigote form of the parasite in macrophages.
 


Claim 1 of 18 Claims

1. A method of treating leishmaniasis comprising administering to a subject in need thereof a pharmaceutically effective amount of methyl-beta-cyclodextrin to treat the leishmaniasis.

 

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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
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