WO2006023073A1 - Utilisation medicale de 24-epibrassinolide - Google Patents

Utilisation medicale de 24-epibrassinolide Download PDF

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Publication number
WO2006023073A1
WO2006023073A1 PCT/US2005/022780 US2005022780W WO2006023073A1 WO 2006023073 A1 WO2006023073 A1 WO 2006023073A1 US 2005022780 W US2005022780 W US 2005022780W WO 2006023073 A1 WO2006023073 A1 WO 2006023073A1
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WO
WIPO (PCT)
Prior art keywords
cholesterol
ebl
epibrassinolide
hiv
plant
Prior art date
Application number
PCT/US2005/022780
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English (en)
Inventor
Mikhail Samusevich
Vladimir Khripach
Konstantin Altsivanovich
Vladimir Zhabinski
Original Assignee
Drebsk Comptech, Inc.
Mikonik Technologies, Ltd.
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Filing date
Publication date
Priority claimed from US10/710,613 external-priority patent/US6998397B2/en
Priority claimed from US10/711,162 external-priority patent/US20040253289A1/en
Application filed by Drebsk Comptech, Inc., Mikonik Technologies, Ltd. filed Critical Drebsk Comptech, Inc.
Publication of WO2006023073A1 publication Critical patent/WO2006023073A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine

Definitions

  • the present invention provides a new method for cholesterol control and treatment of viral infections, which is based on the administration of steroidal plant hormone 24-epibrassinolide (EBl). More particularly, the invention relates, to the use of a compound known as steroidal plant hormone EBl for the improving blood cholesterol and its conjugates levels in mammals and treatment of infections caused by virus responsible for human immune deficiency (HIV).
  • EBl steroidal plant hormone 24-epibrassinolide
  • EBl belongs to a relatively new class of plant hormones called brassinosteroids. Among numerous effects in plants, a substantial influence on the permeability of biological membranes was noted for brassinosteroids. At the whole plant level, it is manifested in the increase of resistibility towards infectious diseases and enhancement of stability to unfavorable factors of environment [V. Khripach, V. Zhabinskii, A. de Groot, Brassinosteroids, Academic Press, San Diego, 1999].
  • brassinosteroids influence in the same way biological membranes of higher organisms (insects, animals, and human) which are evolutionary younger. Although being far from complete understanding, useful properties of brassinosteroids provide new preparations for agriculture in a number of countries [V. Khripach, V. Zhabinskii, A. de Groot. Twenty years of brassinosteroids: steroidal plant hormones warrant better crops for the XXI century. Annals of Botany. 2000; 86: 441-447]. Toxicological studies showed that brassinosteroids (including EBl) were free of any over toxicity in all tests. Provided that these compounds reveal some interesting biological activity, the aforementioned toxicological studies opened perspectives for design of new medicines.-
  • Hypercholesterolemia is an important risk factor definitively connected with cardiovascular disease and, particularly, with atherosclerosis and coronary heart disease. Millions people in the world suffer from coronary heart disease, which is the leading cause of death and morbidity in a productive age, especially in Western Europe and in the United States. For this reason it is also a significant drain on healthcare resources in the western world. For example, in the USA total costs (direct and indirect) connected with the disease were estimated as about $118 billion in 2000 for 1.1 million citizens experienced myocardial infarction, more than 40% of those died [T. A. Jacobson, Clinical Context: Current Concepts of Coronary Heart Disease Management, Am J Med. 2001; 110 (6A): 3S-IlS].
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • Cellular cholesterol homeostasis is very important for the prevention of coronary heart disease.
  • the plasma concentration of cholesterol in the body is regulated by the dietary cholesterol absorption, by the biosynthesis of cholesterol itself and its esterified forms, by the dietary cholesterol absorption, by the biosynthesis of cholesterol itself and its esterified forms, by the metabolic removal of circulating cholesterol, and by the excretion of cholesterol via bile and feces.
  • Oxygenated derivatives of cholesterol seem to control the biosynthesis of the responsible enzymes in a receptor-mediated process, providing in this way feedback regulation for the biosynthesis of cholesterol.
  • modern approaches to prevention of atherosclerosis are based on the correction of both external and internal factors ruling the cholesterol level in blood: dietary supply and absorption of exogenic cholesterol, on the one hand, and the biosynthesis of endogenic cholesterol and related structures, on the other hand.
  • the first approach is realized via diet modification, such as reduction of dietary supply of cholesterol, for example by partial substitution of food animal fats by plant fats that do not contain cholesterol.
  • the reduction of dietary cholesterol absorption can be reached via application of special food additives or foods enriched by the abundant phytosterols, such as beta-sitosterol or campesterol, or their saturated derivatives (stands).
  • Plant sterols produce anticholesterolemic effect which is considered to be connected with the inhibition of cholesterol absorption in the intestine because of competition with cholesterol for incorporation into micelles, although other absorption steps may also be involved. When the plant sterols replace cholesterol of the micelles, free cholesterol is excreted with feces.
  • a limitation of the approach is that relatively large doses of sterols are required for modest reduction in plasma cholesterol.
  • Other agents blocking cholesterol absorption such as stanols, aminoglycoside antibiotic neomycin, which appears to inhibit cholesterol absorption by forming complexes with cholesterol that are excreted, and the bile salt binder cholestyramine, an anion exchanger that indirectly alters cholesterol levels by limiting the resorption of cholesterol-derived bile salts.
  • statins are available commercially and widely used. Although being relatively safe and efficient in treatment and prevention of coronary heart disease, statins have certain limitations in their use and they need care in application because of possible side effects. Thus, patients taking them respond very often to the lowering of cholesterol biosynthesis by a compensatory enhancement of cholesterol absorption from food and, especially for the cases when statins are used as a monotherapy, failed to reach treatment goals. Risk of liver complications, dictates the use of statins under medical control. Taking additionally into account relatively high costs of the therapy, which vary from $20,000 to $40,000 per quality-adjusted life-year saved [J. A.
  • oxygenated derivatives of cholesterol oxygenated derivatives of cholesterol (oxysterols) [C Moog, A.M. Aubertin, A. Kirn, B. Luu. Oxysterols, but not cholesterol, inhibit human immunodeficiency virus replication in vitro. Antivir. Chem. Chemother. 1998; 9(6): 491-496]. It was shown that 7 ⁇ -hydroxycholesterol, 25-hydroxycholesterol, and 7 ⁇ ,25-dihydroxycholesterol inhibited viral replication at micromolar concentrations.
  • brassinosteroids are plant hormones, and most biological assays were carried out on plant systems, there are data on their antiviral and immunoactivating properties outside of plant kingdom. Brassinosteroids were tested for antiviral activity against measles virus via a virus-yield reduction, herpes simplex and arenavirus and showed inhibitory activity [J.A. Ramirez, O. M. Teme Centurion, E.G. Gros, LR. Galagovsky. Synthesis and bioactivity evaluation of brassinosteroid analogs. Steroids. 2000; 65(6): 329-337; M.B. Wachsman, EM. Lopez, J.A. Ramirez et al. Antiviral effect of brassinosteroids against herpes virus and arenaviruses.
  • ⁇ -globulin level in the experimental group was from 10 to 65 % higher than in the control, and this difference was statistically significant during certain period.
  • bacteriolytic activity of lysozyme increased up to 50 % in treated group in comparison with the control fish.
  • brassinosteroids have not yet been investigated for treatment of ⁇ TV- infection [V. A. Khripach, V.N. ZhabinsMi, Ae de Groot. Brassinosteroids - A New Class of Plant Hormones. Academic Press, 1999].
  • a promising area for search of the desirable agents includes naturally occurring sterol-like compounds and, especially, oxygenated sterols.
  • One of the new possibilities of this type is presented by brassinosteroids, recently discovered class of plant hormones of steroid origin responsible for a wide spectrum of growth and adaptive reactions in plants [V. Khripach, V. ZhabinsMi, A. de Groot, Brassinosteroids, Academic Press, San Diego, 1999].
  • brassinosteroids As oxygenated derivatives of sterols structurally very close to cholesterol and its putative metabolites, brassinosteroids theoretically could be expected to fulfill both mentioned above functions including protection from viruses and the prevention of high level cholesterol in blood.
  • the present invention relates to EBl belonging to natural steroidal plant growth hormones. Extensive experiments in vitro and in vivo have been carried out by the inventors, and they showed that EBl is useful for treatment of diseases which are internationally recognized as diseases of socio-economic and public health importance such as atherosclerosis and HFV.
  • the invention relates to the use of EBl for the lowering of elevated levels of cholesterol or lipids and for the improving some protective blood factors, hi addition, EBl was shown to be useful for the preparation of a medicine for the treatment of HIV-infection.
  • EBl is effective as lipid-normalizing tool. More particularly, EBl can be used for lowering serum cholesterol, low-density lipoprotein and triglyceride levels and increasing high-density lipoprotein, vitamin E and vitamin A levels under cholesterol-enriched and normal diet in a mammal, especially in a human, by administering an effective amount of EBl, a plant hormone of brassinosteroid series.
  • EBl is administered to mammals diagnosed as having elevated blood serum cholesterol levels, or to those who have a tendency for the development of hypercholesterolemia.
  • the mammals treated will be humans and EBl will be prepared synthetically from available natural sterols, for example, ergosterol or brassicasterol.
  • the presently preferred method of administration is oral administration with a daily dose from about 0.03 to 200 mcg/kg of patient's body weight. More preferably EBl is administered for a period of 4-12 weeks in a daily amount of 0.03 to 2 mcg/kg.
  • EBl revealed a marked antiviral effect against HIV.
  • the in vitro antiviral activity of the EBl was able to increase significantly the capability of the cell's living. More precisely, it was observed that the amount of the living cells in the infected culture treated with EBl was more than 50 % higher in comparison with untreated control at 4-5 111 days after infecting. Moreover, it has been observed a significantly decreased production of viral- specific antigens on the cell's surface at 3 rd day after infecting.
  • EBl may be used in the treatment of HTV-infection and related conditions ("AIDS related complex"), both symptomatic and asymptomatic, or when exposure to HIV virus is suspected.
  • Dosages will vary depending on the severity of the disease, the general conditions and age of the patient, and will usually range in a daily dose from 0.03 to 200 micrograms per kilogram of body weight or in other doses, which will be effective, based on the results of clinic testing.
  • EBl will be suitably formulated with pharmaceutically acceptable carriers and excipients.
  • suitable forms for the oral, parenteral or inhalatory administrations will be, for example, capsules, powders, granules, suppositories, solutions, suspensions, syrups, emulsions, injectable solutions, spray solutions or suspensions.
  • the pharmaceutical compositions will be formulated according to conventional techniques, as described, for example, in. Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., NY, USA, XVII Ed
  • EBl may be used in a combination with other anti-HIV preparations, which will be currently available.
  • Nucleoside and non- nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors can be mentioned as examples.
  • the invention also relates to pharmaceutical compositions in the form of combined preparations, for the simultaneous, separated or sequential use in the treatment of HIV- infection, comprising EBl in addition to anti-HIV agent selected from the group of nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, etc.
  • this compound may be used as food additive for HIV/AIDS prophylaxis.
  • HTV it means any measures, which are aimed at preventing AIDS-related infections and illnesses.
  • EBl is a plant hormone, which is an obligatory component of all plant tissues. Its content in plants is very low, ranging from 10 ⁇ 5 to 10 ⁇ 13 % [V. A. Khripach, V.N. ZhabinsMi, Ae de Groot. Brassinosteroids - A New Class of Plant Hormones. Academic Press, 1999]. The highest levels of EBl were documented in reproductive tissues (seeds, pollen, etc.). This amount may be enough to provide pharmaceutical properties to certain plant stuff. Thus, pollen is used for many years as a drug in traditional medicine. Content of EBl in this plant source is comparable in order with the doses used with the aims of the present invention.
  • EBl is safe and non-toxic compound for a wide application in medicine and in prophylactic purposes. This assumption has got confirmations in different toxicological studies. They showed low acute toxicity of EBl (LD 5O in mice is more than 1000 mg/kg, in rats - more than 2000 mg/kg) and confirmed no postponed negative effects in prolonged and chronic experiments.
  • EBl is considered as a non-toxic compound having cholesterol lowering and antiviral properties that have been confirmed by experimental data (see below). Therefore, this substance is useful for treatment and/or for prophylaxis of diseases associated with dislipidemias and for treatment of viral infections, particularly AIDS.
  • White rats (mails) were fed with a standard food and drink diet.
  • Experimental and control groups (7 animals in each) were formed by randomization using body mass as the principal feature. EBl was administered orally to the experimental animals as a water solution during 36 weeks. The control group received an equivalent amount of placebo.
  • animals were decapitated under light ether narcosis 18 hours after food withdrawal. Total cholesterol in blood serum was measured enzymatically.
  • This example shows that application of EBl decreases total cholesterol in rats under normal diet in a dose-dependent mode.
  • mice were decapitated under light ether narcosis 18 hours after food withdrawal.
  • Total cholesterol and triglycerides in blood serum were measured enzymatically, Lipoproteins were divided by electrophoresis in agar gel, then dyed with lipid-specific stuff and measured by a direct densitometry.
  • rats fed with high-cholesterol diet showed a level of cholesterol that was more than twice (109 %) higher than in the control group.
  • groups fed with high-cholesterol diet and treated with EBl in doses of 2 and 20 mcg/kg a significant decrease of total cholesterol (34-44 %) and triglycerides (58-68 %) took place.
  • Administration of EBl in a dose of 20 mcg/kg decreased significantly LDL (11 %) and VLDL (11 %) levels.
  • EXAMPLE 3 Volunteers with a high level of cholesterol were selected for clinical study. During the experiment, each patient had his normal personal diet without any special limitations (fats, high-cholesterol food, etc.). All the patients received daily EBl (2.5 meg) dissolved in ethanol (0.03 ml) and mixed with water (50 ml). Administering the EBl was not adjusted with the meal-receiving time. The intake of this dose of EBl during four weeks led to the results showed in Table 3.
  • the examples show a high efficacy of EBl as a cholesterol-lowering agent in mammals for a wide range of doses.
  • the tests have been carried out under therapeutic circuit when the testing compound and virus were put into the cell culture simultaneously.
  • Formazan assay (FA). Analysis is based on the metabolic reduction of the 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) that has been used to measure virus-induced cytopathic effects and cell proliferation [T. Mosmann. Rapid coloremetric assay for cellular growth and survival application to proliferation cytotoxicity assays. J. Immunol. Meth. 1983; 65: 55-63]. The cellular reduction of MTT results in the formation of a colored, insoluble formazan products that must be solubilized by DMSO (dimethyl sulfoxide) prior to colorimetric determination.
  • DMSO dimethyl sulfoxide
  • EBl had an ability to protect the living cells against HIV-I -cytopathic action in a concentration of 10 "75 - 10 "95 mol/L (10.0 - 0.1 ng/mL).
  • Supravital cell staining by the trypan blue This technique is based on the ability of living cells to impede the penetration of trypan blue dye into cell cytoplasm.
  • the indicator was applied as a 0.2 % concentration solution.
  • the amounts of living (unstained) and dead (blue stained) cells were counted under light microscope. Those probes were estimated as positive ones, where the amount of the living cells was 75 % higher than in EBl-untreated virus control. The calculations showed that EBl was able to impede HTV-induced cell death at a concentration of 10 "6 - lO "75 mol/L (500.0 - 10.0 ng/mL).
  • the indirect immunofluorescence assay is a useful means for determining the number of cells productively infected with HIV [V. A. Johnson, R.E. Byington. HW indirect immunofluorescence assay. In “Techniques in HIV Research”: Stockton Press, 1990; 87-91].
  • This assay is quantitative and can be done using living cells. The technique gives the possibility to determine HTV-specific antigens expressed on cell surface membranes of the virus-infected cells. On the 3 rd day after infecting, cells have been transferred onto wells of the laminated multiwell slides and fixed by cold (4° C) acetone.
  • the samples with fixed cells were treated by HIV-I -seropositive serum and then by FTC-conjugated sheep anti-human IgG.
  • the resulting effect was estimated via evaluation of percentage of positive cells that was calculated using fluorescent microscope and taking into account 200 cells. Uninfected cells appear red, and infected cells exhibit yellow-green fluorescence. Those samples were estimated as positive ones, where the amount of fluorescent cells was 75 % less than in EBl-untreated virus control.
  • EBl as a plant hormone, is an obligatory component of plants and vegetable food. Although its content in plants is extremely low with the highest levels in reproductive tissues (seeds, pollen, etc.), it might be enough to provide pharmaceutical properties to a certain plant stuff, for example, to pollen that is used as a drug in traditional medicine and that has an EBl-content comparable in order with the doses used with the aims of the present invention. It may be speculated that being normal constituent of plants and a food component, EBl is safe and non-toxic product for a wide application in medicine and in prophylactic nutrition. This assumption got confirmations in different toxicological studies that showed low acute toxicity (LDs 0 in mice is more than 1000 mg/kg, in rats - more than 2000 mg/kg) and showed no postponed negative effects in prolonged and chronic experiments.
  • LDs 0 in mice is more than 1000 mg/kg, in rats - more than 2000 mg/kg
  • compositions that comprise one or more compounds of the invention may be formulated, as is well known in the prior art, such as by reference to known compilations as Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., USA.
  • the dosage ranges for administration of the compounds of the invention are those needed to produce the desired effect without undue toxicity, whereby symptoms of infection are ameliorated.
  • EBl For treatment of HIV virus EBl can be applied in compositions at doses 0.03-200 micrograms per kilogram of body weight having in mind toxicological aspects obtained in the course of practical application.
  • an effective daily dose was equivalent to 0.03 mcg/kg of body weight.
  • Other doses cannot be excluded provided that their effectiveness will be proved by clinic trials.
  • the preferred route of administration is oral, although other routes of administration are acceptable.
  • the compounds may be mixed with inert materials for pharmaceutical efficacy as is known in the art.
  • the compounds may be formulated in aqueous solution for intravenous (i.v.) 5 intraperitoneal (i.p.), or subcutaneous (s.c.) administration.
  • Topical applications include mixtures of the compounds with oils or fatty acid esters or as components of skin patches that are capable of delivering the drugs across the dermal layer.
  • Aqueous solutions, or solutions in suitable carriers, may be administered intranasally.
  • the pharmaceutical composition may contain other pharmabiologically active compounds in a mixture with the compound of the invention, to treat (therapeutically or prophylactically) acquired immunodeficiency syndrome (AIDS).
  • other active compounds may include, but are not limited to, other antiviral compounds (e.g., AZT, ddC, TiBO derivatives, acyclovir, alpha-interferon), immunostimulants (e.g., various interleukins and cytokines), immunomodulators and antibiotics (e.g., antibacterial, antifungal, anti-pneumocystis agents), even when these do not show potent activity in the NCI Weislow protocol.
  • antiviral compounds e.g., AZT, ddC, TiBO derivatives, acyclovir, alpha-interferon
  • immunostimulants e.g., various interleukins and cytokines
  • immunomodulators and antibiotics e.g., antibacterial, antifungal, anti-pneumo
  • Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier, which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • formulations of this invention might include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
  • EBl can be considered as a promising compound for treatment of HIV disease and related conditions as well as a blood serum cholesterol-decreasing agent for therapeutic and prophylactic use in medicine and in specialized nutrition.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne de nouvelles utilisations de l'hormone de croissance végétale 24-épibrassinolide, une hormone végétale de formule structurelle (I) appartenant à la série des brassinostéroïdes, comme agent thérapeutique pour soigner un certain nombre d'états pathologiques associés à la mauvaise régulation du métabolisme lipidique, et comme traitement de l'infection par le virus VIH et des états pathologiques afférents, en particulier le sida.
PCT/US2005/022780 2004-07-23 2005-06-25 Utilisation medicale de 24-epibrassinolide WO2006023073A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US10/710,613 2004-07-23
US10/710,613 US6998397B2 (en) 2004-07-23 2004-07-23 Method for decreasing cholesterol level in blood
US10/711,162 US20040253289A1 (en) 2004-08-28 2004-08-28 Natural plant compound with anti-HIV activity
US10/711,162 2004-08-28

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WO2006023073A1 true WO2006023073A1 (fr) 2006-03-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA015277B1 (ru) * 2008-04-22 2011-06-30 Государственное Научное Учреждение "Институт Биоорганической Химии Национальной Академии Наук Беларуси" Конъюгат 28-норбрассинолида с бычьим сывороточным альбумином в качестве иммуногена
EA015684B1 (ru) * 2008-06-10 2011-10-31 Государственное Научное Учреждение "Институт Биоорганической Химии Национальной Академии Наук Беларуси" Дансилгидразид 24-эпикастастерона в качестве меченого антигена для иммунохимического анализа (24r)-метилбрассиностероидов

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA015277B1 (ru) * 2008-04-22 2011-06-30 Государственное Научное Учреждение "Институт Биоорганической Химии Национальной Академии Наук Беларуси" Конъюгат 28-норбрассинолида с бычьим сывороточным альбумином в качестве иммуногена
EA015684B1 (ru) * 2008-06-10 2011-10-31 Государственное Научное Учреждение "Институт Биоорганической Химии Национальной Академии Наук Беларуси" Дансилгидразид 24-эпикастастерона в качестве меченого антигена для иммунохимического анализа (24r)-метилбрассиностероидов

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