Patent Publication Number: US-2007116754-A1

Title: Dissolution of arterial cholesterol plaques by pharmacological preparation

Description:
RELATED CASES  
      This application is the Non-Provisional Application of Applicants Provisional Patent Application No. 60/739,143 entitled “Dissolution of arterial cholesterol plaques by pharmacological preparation”, filed on Nov. 22, 2005.  
     Field of Invention  
      This application relates to pharmacological compounds useful in the treatment of atherosclerotic plaques aiming at their dissolution.  
     BACKGROUND OF THE INVENTION  
      Atherosclerosis is a pathological condition responsible of the highest mortality and morbidity in humans.  
      No known pharmacological compound has unequivocally shown in studies to effectively significantly reduce atherosclerotic lesions to the point that clinical benefits would ensue.  
      There are medications which act on the serum cholesterol by lowering it significantly, The effect of cholesterol lowering translates into reduced probability of new plaques formation, however, lowering of serum cholesterol does very little to the preexisting plaques.  
      Once an atherosclerotic plaque is formed within an artery over the years, such as coronary, cerebral, carotid, iliac, femoral, popliteal arteries, aorta and others, there is little that can be done to reduce its potential for devastating complications or make it disappear altogether and restore arterial anatomical integrity.  
      Although an atherosclerotic plaque is a rather complex pathological process including fat deposition, mainly cholesterol, in the intima layer of the arteries, cellular components, and a fibrotic component, the key target both in preventing formation of new plaques and in treating the preexisting plaques is the cholesterol deposition within the intima layer of the arteries. In fact, a number of controlled studies have shown that drastic reduction in blood cholesterol maintained for an adequate period of time appears to slow down progression of the plaque toward the two possible evolving paths of the plaque, one evolving path being a mere increase of the plaque size with resulting stenosis of the artery, the other evolving path being plaque disruption complicated with thrombus formation and sudden obstruction of blood flow which can lead to major events such myocardial infarction, cerebrovascular accident and death.  
      It appears that by removing the cholesterol and other lipids content of the plaque, the plaque may regress to the extent of reducing its size and therefore reduce the stenotic effect on the artery, and, even more importantly, to the extent of reducing or eliminating altogether the possibility of disruption of the plaque.  
      With respect to potential for disruption of an atherosclerotic plaque with the ominous complications that ensue as result of the disruption, there is plenty of evidence in the current medical literature that plaque susceptibility to disruption is proportional to the amount of soft lipid core of the plaque and inversely proportional to the thickness of the fibrous cap separating the lipid core from the blood. The larger the amount of lipid core of the plaque combined with a thin fibrous cap the higher the susceptibility to disruption and the higher the thrombogenicity of the disrupted plaque.  
      It is not illogical that attempts aimed at inducing regression of the atherosclerotic plaques or at least at reducing susceptibility to disruption have been directed to lowering the lipid content of the lipid core of the atherosclerotic plaque. A few pharmacological approaches have been attempted to reduce the lipid content of the lipid core of the atherosclerotic plaque.  
      The most promising pharmacological compounds presently under investigation are the Apoliprotein—A1 Milano discovered in Italy over thirty years ago by an Italian scientist named Carlo Sirtori, and, more recently found, a pharmacological compound named D- 4 F, which is a novel Apo A I Mimetic Peptide which acts as Apoliprotein—A1 Milano but it can be taken orally, contrary to Apoliprotein—A1 Milano which has to be administered parenterally. Quoting Steven Nissen author of a landmark study about ApoA-1 Milano published in the Jama, Volume 290 No. 17, Nov. 2003, “the mechanisms of action of ApoA-1 Milano that result in regression of atherosclerosis are unknown but presumably are related to an increase in reverse cholesterol transport from atheromatous lesions to the serum with subsequent modification and removal by the liver.” 
      Both ApoA-1 Milano and D-F4 proteins act by mobilizing the cholesterol out of the plaques with a mechanism named reverse cholesterol transport, not by dissolving the cholesterol within the plaques.  
      None of the above investigational drugs acts as detergent, as surfactant, as emulsifier, as dissolver of cholesterol aggregates or generally of the lipidic core of the atherosclerotic plaque. Applicants, in the present application, have taken a totally novel scientific approach and a novel path in the problem of reducing atherosclerotic plaque. Applicants introduce the novel concept that a cholesterol plaque can be significantly reduced and virtually eliminated by a process of emulsification of the main component of the plaque, which is the cholesterol aggregates, or any lipid content, within the plaque. Applicants propose emulsification of cholesterol plaque with a variety of emulsifiers, however, their preferred emulsifiers are compounds classified as biliary salts or acids. Biliary salts or acids are potent emulsifiers of cholesterol selected by nature to emulsify cholesterol in the intestine. Applicants have discovered and demonstrated with experiments that biliary salts or acids can also emulsify the cholesterol of the atherosclerotic plaques and actually deplete the atherosclerotic plaques of their cholesterol content.  
      An extensive worldwide search in the Patent Office and in the medical literature has shown that this approach has never been taken before, never conceived, never disclosed, never experimented, never tested before. Applicants with their provisional patent application No. 60/739,143 entitled “Dissolution of arterial cholesterol plaques by pharmacological preparation”, filed on Nov. 22, 2005, have introduced this novel concept and with their experiments in vitro disclosed below have proven its efficacy and ultimately its usefulness.  
     BRIEF SUMMARY OF THE INVENTION  
      In studying the physio-pathology of the atherosclerosis, Applicants have come to the conclusion that the removal of preexisting atherosclerotic plaques should entail the use of compounds capable of exhibiting two properties:  
      a first property consisting of being capable of dissolving the cholesterol and other lipids aggregates/deposits within the atherosclerotic plaque into such small particles or micellae, eventually even down to molecular size, to enable filtration into the blood stream of the dissolved cholesterol and other lipids through the fibrous cap which covers the cholesterol and lipids deposits in the atherosclerotic plaques;  
      a second property consisting of being capable of accessing the cholesterol aggregates or lipid content within the plaque by overcoming the barrier represented by the fibrous cap of the atherosclerotic plaque.  
      In their quest to find a compound exhibiting the first property, Applicants have focused their attention to the bile compounds responsible of solubilization of lipids during the process of digestion in the digestive system, namely the biliary salts, relying on their effectiveness in solubilizing virtually any organic lipid utilized by living beings, effectiveness which had been physiologically tested over a span of millions of years of evolution.  
      In animals, as in human bodies, bile salts however are confined to the digestive system, in the so called entero-hepatic circulation, and do not come in contact with arteries either of the systemic or pulmonary circulation, therefore the biliary salts in nature are prevented from displaying their benefits on atherosclerotic plaques.  
      Both the first and the second postulated property found confirmation in actual experiments conducted by the Applicants, experiments which will be described below in the specification section of the application.  
      As mentioned above, Applicants propose the use of compounds named emulsifiers or detergents or surfactants or generally lipid solvents that solubilize lipids in water in the field of the atherosclerosis.  
      As mentioned above, the concept of using the process of emulsification of cholesterol and of other lipids contained in atherosclerotic plaques to deplete the plaques of their cholesterol and of the other lipids contained within the plaques, as well as the use of compounds having the property of emulsifying, i.e. dissolving lipids into an acqueous phase such as blood represent an absolute novelty in the treatment of atherosclerosis.  
      A worldwide search in the medical and generally scientific literature and in the Patent Office has revealed no prior art referring to the use of the process of emulsification in the treatment of atherosclerotic plaques, nor to the use of compounds as emulsifiers, particularly emulsifiers which are highly water soluble while still maintain a high affinity for lipids, such as deoxycholate and, generally, biliary acids or salts.  
      Deoxycholate has been used widely in medicine for other purposes, precisely as an aqueous solubilizing agent of hydrophobic “liposolubil” compounds such as Amphotericin B, Diazepan, Paclitaxel, and Phosphatidylcholine.  
      As evidenced by the fact that, as already mentioned, there is no single reference in world medical literature or in the Patent Office of their use as plaque emulsifying/dissolving agents, no author has ever realized that deoxycholate or deoxycholic acid, usually abbreviated as DCA, or any compound of the class of substances generally named biliary acids or salts, has the capability of emulsifying the cholesterol or lipids contained in atherosclerotic plaques nor any author has demonstrated, or even postulated, that this class of compounds can cross the fibrous cap of atherosclerotic plaques to reach the cholesterol or lipids contained in the atherosclerotic plaques, in order to emulsify, i.e. liquefy, i.e. solubilize the plaques cholesterol or lipids into water and allow filtering of the emulsified cholesterol or lipids through the fibrous cap into the blood stream.  
      In the specific case of Phosphatidylcholine, usually abbreviated as PPC or PC, which has been used empirically as an atherosclerosis treating medication, albeit not as an emulsifier, the Deoxycholic acid which is added to the PPC, is not added as an emulsifier of cholesterol or lipids contained within the atherosclerotic plaques, but it is added, as amply documented, to the PPC exclusively for the purpose of solubilizing in water the otherwise water-insoluble phospatidylcholine.  
      To the date of the filing of Applicants PPA Nov. 22, 2005 and even up to the filing date of present application, Applicants have not found a single reference anywhere in the PTO/PCT or medical or generally scientific literature on the use of deoxycholic acid or any other biliary salt, primary or secondary, precursor or derivative, as direct atherosclerotic plaque dissolving agent. As clearly pointed out to the Applicants by the Chief Pharmacist of the largest Phoshatidylcohline manufacturer and supplier in USA, DCA is added to the PPC as “pharmacological necessity” i.e the necessity of solubilizing the PPC, otherwise non utilizable, as PPC is non water soluble. Reference is available.  
      Indeed, in the case of PPC/DCA combination, there are zero references on the use of deoxycholic acid as an antiatherogenic compound, while the emphasis is solely focused on the phosphatidylcholine as a cell membrane restoring agent.  
      Should the DCA have ever been considered the actual active compound, it would hardly make sense to combine PPC to DCA in a 2:1 ratio formulation, which is the formulation being used in empirical attempts to treat cholesterol plaques, because the entire amount of DCA would be presumably used to dissolve PPC in water leaving no fraction of DCA, or no substantial portion of DCA, available for directly acting on the atherosclerotic plaques.  
      As for the phosphatidylcholine being used for treatment of high cholesterol and vascular diseases, such use was introduced by Dr. Sam Baxas at Baxamed of Switzerland a few years ago under the name of Plaquex. Plaquex is the commercial name of a pharmacological preparation, precisely a combination of PPA and DCA, in the ratio 2:1. It is injected intravenously in patients.  
      In Dr. Baxas Website, www, Baxamed.com, at the date of Applicants PPA filing and at the date of the filing of the present Patent Application describes the action of PPA as follows:  
      “The most important effect of EPL”, an abbreviation standing for Essential PhoshoLipids, such as phosphatidylcholine and phosphatidylserine, in the respective ratio of 75% and 30%, “is its remarkable ability to reduce plaque depositions.” 
      The EPL is not disclosed as an emulsifying/solubilizing agent of the lipidic core of the plaque. The effect of EPL is explained solely as a cellular membrane restoring agent. The following paragraph is copied word by word from Baxamed Web Page in its entirety, not for the scientific pertinence of the paragraph, but as documentation that no mention is made of the deoxycholic acid as having any relevance at all as an ingredient acting upon the cholesterol plaques and as documentation that EPL is never mentioned to have any emulsifying/solubilizing effect on the lipidic core of the plaque. Indeed, the only ingredient that is discussed as active on atherosclerosis is the Essential Phospholipids, i.e. phosphatidylcholine and phosphatidylserine. More specifically, even in the empirically used PPC/DCA combination for atherosclerosis, there is no conception of the process of emulsification of the cholesterol and other lipids of the plaques, nor there is mention of DCA as an agent being used as an emulsifier/solubilizer of the cholesterol and other lipids of the plaques, nor, again, there is any mention of a possible emulsifying process of the cholesterol and other lipids of the plaques being induced or carried out by phosphatidylcholine or phosphatidylserine. This is the Baxamed paragraph:  
      “The treatment is with a mix of essential phospholipids (EPL) derived from soy beans. It is the treatment of choice for atherosclerosis—the deposit of fatty plaques in the arterial and capillary lining of the blood vessels. EPL is a natural substance, that is part of every living cell-plant cell, animal cell and human cell. The exact chemical name is phosphatidylcholine. This is a molecule made of glycerine and 2 poly-unsaturated fatty acids. It belongs to the group of Di-Ester molecules. All cell walls are mainly made out of phosphatidylcholine. 70% of a human cell wall is phosphatidylcholine and 30% is phosphatidylserin. In a watery solution, phospholipids build double layered membranes. In between the double layered phopholipid molecules structural proteins and also LDL cholesterol are inserted to help with the exchange of substances through the cell wall and to give the cell wall stability. WHY DOES EPL WORK? Damage to the cell membrane leads to LDL cholesterol being thrown out of the membrane structure, leading to elevated LDL cholesterol in the blood serum. This damage to cell walls is caused by free radicals, toxic substances and detergents that reduce the surface tension. It can also be caused by heart catheters in narrow curves ‘scratching’ the inner lining of the coronary vessels. This leads to a higher need for phosphatidylcholine. The body&#39;s own synthesis isn&#39;t enough to effect repairs. Thus scar tissue replaces the damage and plaques form inside of blood vessels. Therefore it is logical to supplement phosphatidylcholine by infusion when cell membrane damage exists. Oral supplementation is usually absorbed by the liver to repair liver damage and only minute amounts end up in other places. This is the reason oral phosphatidylcholine has little effect on blood vessels. In case of inflammation, damage to blood vessels can be stopped by phosphatidylcholine. In addition LDL cholesterol is reintegrated into the cell membrane and the serum LDL cholesterol normalizes. LDL cholesterol that has been oxidized by free radicals is bound in to micelles by phosphatidylcholine and transported to the liver where it is metabolized or excreted with gall fluid. The viscosity of the blood—the blood flow characteristics—is also improved. The main place of action by EPL is the entire capillary net. The exchange of substances such as oxygen and nutrients is improved in all tissues.  
      The most important effect of EPL is its remarkable ability to reduce plaque depositions in the arterial walls. It also lowers cholesterol and homocystein levels. Studies in lab animals have shown that it increases their life span by up to 36%. An important therapeutic application of the EPL treatment program is increasing an individuals ability to withstand cardiac stress. This application is valuable for the individuals who have suffered cardiac trauma, such as myocardial infarction or who are at high risk of heart trauma. Effect of EPL. EPL reduces Angina Pectoris pain and frequency of attacks EPL lowers LDL Cholesterol EPL increases HDL Cholesterol EPL improves walking distance EPL improves mental function EPL improves sexual potency EPL is useful in the treatment of patients with angina pectoris, with reduced blood flow to the brain and extremities and prophylactically in the treatment against fat embolus and strokes. EPL can be combined with Chelation treatments in severe cases. A good rule of thumb is one Chelation infusion for every two Plaquex treatments.” 
      End of the reported paragraph. Essentially, as a major component of cell membranes, phosphatidylcholine, is believed to be useful in the treatment of atherosclerotic plaques as a supplier of replacement material to restore cell membranes believed to be damaged in the process of atherosclerosis. Remarkably, a mention is made in the reported paragraph to the ability of phosphatidylcholine and phosphatidylserine to repair damages caused, among other factors, by detergents! 
      Being used as a membrane restoring agent, phosphatidylcholine in Baxamed Plaquex is not chemically optimized to act as an emulsifier of the cholesterol or of other lipids contained in the atherosclerotic plaques, although the very weak aqueous solubility of phosphatidylcholine does not make it an ideal emulsifier of cholesterol plaque. Its ability to cross the fibrous cap of the atherosclerotic plaques to exert its potential emulsifying capability upon the cholesterol and other lipids of the plaques is another property required to phosphatidylcholine to be effective as an emulsifier in atherosclerotic plaques has never been thought of, contemplated, envisioned, disclosed, not to say tested or demonstrated.  
      Summarizing, with the present invention, Applicants are the first to disclose the process of emulsification, i.e. water solubilization, to be applied to the cholesterol and to other lipids of the atherosclerotic plaques as a viable process to treat atherosclerotic plaques, because Applicants have discovered that certain emulsifiers are capable of crossing the fibrous cap of atherosclerotic plaques and reach the cholesterol and other lipids of the plaques, and have also discovered that when emulsified, i.e. solubilized, into water, cholesterol and other lipids contained in the plaques are capable of filtering through the fibrous cap of the atherosclerotic plaque into the blood stream.  
      With the present invention Applicants are the first to propose a novel and useful use of a physiological class of emulsifiers, namely the biliary acids or salts, and in general any water soluble emulsifier, in the treatment of atherosclerotic plaques.  
      Although, as mentioned above, in some cases biliary compounds have been used by intravenous administration in association with liposoluble medications as emulsifiers to render such medications water soluble, the amounts of biliary compound used as emulsifier for such medications were optimized to achieve the specific purpose of solubilizing the liposoluble medications in water leaving no substantial portion, or no fraction, of biliary compound available for direct pharmacological effects of the biliary compounds for instance on atherosclerotic plaques.  
     Objects of the Invention  
      It is an object of the present invention to provide a pharmacological compound capable of dissolving the lipidic core of preexisting arterial atherosclerotic plaques.  
      It is an object of the present invention to disclose a process of dissolution of the lipidic core of the atherosclerotic plaques consisting of emulsification of the lipidic content of the atherosclerotic plaques.  
      It is an object of the present invention to provide a pharmacological compound which has the ability of overcoming the barrier represented by the fibrous cap roofing the cholesterol deposits in the atherosclerotic plaques.  
      It is an object of the present invention to provide a pharmacological compound that solubilizes the cholesterol aggregates and other lipid aggregates within the atherosclerotic plaque to such fine particles to enable filtration of such solubilized particles through the fibrous cap of the atherosclerotic plaque into the blood stream.  
      It is an object of the present invention to provide a pharmacological compound that restores near physiological or physiological patency to arterial vessels obstructed by atherosclerotic plaques.  
      It is an object of the present invention to provide a pharmacological compound that, by removing the most critical component of an atherosclerotic plaque, i.e. the cholesterol and other lipid content of the plaque, has the ability of contributing to stabilization of the plaque, by minimizing the vulnerability of the plaque to rupture and the consequent ominous thrombus formation.  
      It is an object of the present invention to provide a pharmacological compound which has the potential ability of preventing the common complications of atherosclerosis such as acute coronary events and cerebrovascular accidents.  
      It is an object of the present invention to provide a pharmacological compound potentially useful in the treatment of peripheral vascular disease, having the potential ability of preventing ischemic limbs disease, and ultimately amputation.  
      It is an object of the present invention to provide a pharmacological compound which by restoring patency to the systemic and pulmonary arterial circulation to a near physiological or to a physiological level, has all the prerequisites of likely preventing and curing a number of diseases resulting from inadequate tissue perfusion due to the pathological clogging of the arterial system up to the arterioles. The compound has all the prerequisites of preventing anoxic damages to the tissues and ultimately probably preventing and in certain cases curing a myriad of pathological conditions originating from, or complicated by, the oxygen tissue deprivation, such as cardiomyopaties, heart failure, senile dementia, vascular complications from diabetes, nephrosclerosis, systemic and pulmonary hypertension, mesenteric ischemias, cerebral atherosclerosis, macular degeneration and probably the cerebral plague of the modem era, Alzheimer disease, likely a result of anoxic chronic insults of various etiology all converging into inadequate cerebral perfusion mainly to the cognition and memory centers.  
      Applicants in establishing the objects of the present invention cannot obviously foresee all the implications deriving from the clearing of the obstruction to blood flow in the human arteries. Some of these objects have been disclosed, many others will be discovered following the application of the compound.  
      The concept of exposing the atherosclerotic plaque to a biliary compound is the core of the invention. 
    
    
     FIGURES  
       FIG. 1  shows a skin patch for systemic administration of the pharmacological compound.  
       FIG. 2  is a perspective view of one of the bio-specimens, precisely a segment of an iliac artery of a pig with atherosclerotic lesions used by the applicants in their experiments.  
       FIG. 2A  is a top view of the bio-specimen of  FIG. 2  sectioned longitudinally and fully opened.  
       FIG. 3  shows a fixture used by the Applicants for first type of in vitro experiments with the pharmacological compound.  
       FIG. 3A  is a detail of the apparatus of  FIG. 3 .  
       FIG. 4  shows a detail of a stage of the first type of in vitro experiments.  
       FIG. 4 A  shows a detail of a following stage of the first type of in vitro experiments.  
       FIG. 5  shows a fixture used by Applicants for second type of in vitro experiments with the pharmacological compound.  
       FIG. 6  shows a device for the administration of the pharmacological compound, precisely a specially designed intra-arterial catheter for in loco sustained administration of the substance in arteries with atherosclerotic lesions such as coronaries or carotids or popliteal arteries.  
       FIG. 6A  is an enlarged view of the distal segment of the of the device of  FIG. 6   
       FIG. 6B  is an enlarged view of a detail of the device of  FIG. 6 . 
    
    
     SPECIFICATIONS  
      The invention includes a substance or ingredient or active principle or compound or or agent or means, namely a bile acid or bile salt or bile acid or bile salt derivative or precursor administered to human subjects via routes which bypass the enterohepatic circulation in order to become bioavailable in the systemic circulation for the purpose of dissolving the lipidic core of the arterial atherosclerotic plaques to ensue decreased vulnerability of the plaque to rupture, and reduction of arterial stenosis caused by the plaque.  
      Any water soluble bile salt with detergent/emulsifying activity, either natural, such as Cholic acid or salt, or Chenodeoxycholic acid or salt, or Deoxycholic acid or salt, or Lithocholic acid or salt, or any synthetic biliary compound in general, alone or in combination, or any precursor or derivative of such bile acid or salt, alone or in combination, can be used, as long as it has detergent/emulsifying/surfactant/dissolving properties for the purpose of clearing the arteries of the atherosclerotic plaques and as long as it is able to penetrate the fibrous cap and access the lipidic core of the plaque.  
      The list below includes a great number of the known biliary acid/salts compounds. Cholic Acids: 1,3,12-trihydroxycholanoic acid; 1,3,7,12-tetrahydroxycholanoic acid; 3beta-hydroxy-delta 5-cholenic acid; 3 beta-hydroxychol-3-en-24-oic acid; 3′-isothiocyanatobenzamidecholic acid; 3,12-dihydroxy-5-cholenoic acid; 3,4,7-trihydroxycholanoic acid; 3,6,12-trihydroxycholanoic acid; 3,7,12,23-tetrahydroxycholan-24-oic acid; 3,7,12-trihydroxy-7-methylcholanoic acid; 3,7,12-trihydroxycoprostanic acid; 3,7,23-trihydroxycholan-24-oic acid; 3,7-dihydroxy-22,23-methylene-cholan-24-oic acid (2-sulfoethyl)amide; 3-((3-cholamidopropyl)dimethylammonium)-1-propanesulfonate; 3-((3-deoxycholamidopropyl)dimethylammonio)-1-propane; 3-benzoylcholic acid; 3-hydroxy-5-cholen-24-oic acid 3-sulfate ester; 3-hydroxy-7-(hydroxyimino)cholanic acid; 3-iodocholic acid; 7,12-dihydroxy-3-(2-(glucopyranosyl)acetyl)cholan-24-oic acid; 7,12-dihydroxy-3-oxocholanic acid; allocholic acid; chapso; chol-3-en-24-oic acid; cholanic acid; Cholic Acid (which includes the Cholates: sodium cholate; methyl cholate; benzyldimethylhexadecylammonium cholate; methyl 1,3-dihydroxycholan-24-oate; and trioctylmethylammonium cholate); cholic acid glucuronide; cholyl-coenzyme A; cholyl-lysylfluorescein; cholyldiglycylhistamine; cholylhistamine; cholylhydroxamic acid; cholylsarcosine; cholyltetraglycylhistamine; ciliatocholic acid; Dehydrocholic Acid (which includes FZ 560; Gallo-Merz; Gillazym; Hepavis; Mexase; progresin Retard; and spasmocanulase); Deoxycholic Acid (which includes: 23-nordeoxycholic acid; 3,7-dioxocholanoic acid; 3-hydroxy-polydeoxycholic acid; 3-sulfodeoxycholic acid; 6-hydroxycholanoic acid; 6-methylmurideoxycholic acid; 7-ketodeoxycholic acid; 7-methyldeoxycholic acid; Chenodeoxycholic Acid; dehydrodeoxycholic acid; deoxycholyltyrosine; desoxybilianic acid; Glycodeoxycholic Acid; hyodeoxycholate-6-O-glucuronide; hyodeoxycholic acid; Taurodeoxycholic Acid; and Ursodeoxycholic Acid); Glycocholic Acid (which includes: 3-hydroxy-5-cholenoylglycine; cholylglycylhistamine; cholylglycyltyrosine; Glycodeoxycholic Acid; and sulfolithocholylglycine); hemulcholic acid; Lithocholic Acid (which includes: 12-ketolithocholic acid; 24-norlithocholic acid; 3-dehydrolithocholylglycine; 3-hydroxy-6-cholen-24-oic acid; 3-hydroxy-7,12-diketocholanoic acid; 3-hydroxy-7-methylcholanoic acid; 3-ketolithocholic acid; 3-oxochol-4-en-24-oic acid; 3-oxocholan-24-oic acid; 4-azidophenacyl lithocholate; 7-ketolithocholic acid; BRL 39924A; glycolithocholic acid; lithocholate 3-O-glucuronide; lithocholyl-N-hydroxysuccinimide; methyl lithocholate; N-carbobenzoxy-N-lithocholyl-epsilon-lysine; N-epsilon-lithocholyllysine; sulfolithocholic acid; and Taurolithocholic Acid); muricholic acid; N-(1,3,7,12-tetrahydroxycholan-24-oyl)-2-aminopropionic acid; N-(2-aminoethyl)-3,7,12-trihydroxycholan-24-amide; N-carboxymethyl)-N-(2-(bis(carboxymethyl)amino)ethyl)-3-(4-(N′-(2-((3,7,12-trihydroxycholan-24-oyl)amino)ethyl)(thioureido)phenyl)alanine; N-cholyl-2-fluoro-beta-alanine; norcholic acid; norursocholic acid; Taurocholic Acid (which includes: (N-(7-(nitrobenz-2-oxa-1,3-diazol-4-yl))-7-amino-3alpha,12alpha-dihydroxycholan-24-oyl)-2-aminoethanesulfonate; 23-seleno-25-homotaurocholic acid; 3,12-dihydroxy-7-oxocholanoyltaurine; 3-hydroxy-7-oxocholanoyltaurine; azidobenzamidotaurocholate; hexadecyltributylammonium taurocholate; tauro 1-hydroxycholic acid; tauro-3,7-dihydroxy-12-ketocholanoic acid; taurodehydrocholate; Taurodeoxycholic Acid; tauroglycocholic acid; Taurolithocholic Acid; tauromuricholic acid; tauronorcholic acid); tetrahydroxy-5-cholan-24-oic acid; ursocholic acid; vulpecholic acid; bile acid sulfates. The Glycodeoxycholic Acid includes: Glycochenodeoxycholic Acid; 7-oxoglycochenodeoxycholic acid; glycochenodeoxycholate-3-sulfate; glycohyodeoxycholic acid; the Taurodeoxycholic Acid includes: tauro-7,12-dihydroxycholanic acid; Taurochenodeoxycholic Acid; taurochenodeoxycholate-3-sulfate; taurochenodeoxycholate-7-sulfate; tauroursodeoxycholic acid; taurohyodeoxycholic acid; the Ursodeoxycholic Acid includes: 23-methylursodeoxycholic acid; 24-norursodeoxycholic acid; 3,6-dihydroxy-6-methylcholanoic acid; 3,7-dihydroxy-20,22-methylenecholan-23-oic acid; 3,7-dihydroxy-22,23-methylenecholan-24-oic acid; 3,7-dihydroxy-7-ethylcholanoic acid; 3,7-dihydroxy-7-methylcholanoic acid; 3,7-dihydroxy-7-n-propylcholanoic acid; Bamet-UD2; diamminebis(ursodeoxycholate(O,O′))platinum(II); glycoursodeoxycholic acid; homoursodeoxycholic acid; HS 1030; HS 1183; isoursodeoxycholic acid; PABA-ursodeoxycholic acid; sarcosylsarcoursodeoxycholic acid; sarcoursodeoxycholic acid; ursodeoxycholate-3-sulfate; ursodeoxycholic acid 7-oleyl ester; ursodeoxycholic acid N-acetylglucosaminide; ursodeoxycholic acid-3-O-glucuronide; ursodeoxycholyl N-carboxymethylglycine; ursodeoxycholylcysteic acid; Ursometh; the Chenodeoxycholic Acid includes: 24-norchenodeoxycholic acid; 3,7-dihydroxy-12-oxocholanoic acid; 3,7-dihydroxy-24-norcholane-23-sulfonate; 3,7-dihydroxy-25-homocholane-25-sulfonate; 3,7-dihydroxychol-5-enoic acid; 3,7-dihydroxycholane-24-sulfonate; 3-glucosido-chenodeoxycholic acid; 3-oxo-7-hydroxychol-4-enoic acid; 6-ethylchenodeoxycholic acid; chenodeoxycholate sulfate conjugate; chenodeoxycholyltyrosine; Glycochenodeoxycholic Acid which includes: 7-oxoglycochenodeoxycholic acid and glycochenodeoxycholate-3-sulfate; homochenodeoxycholic acid; HS 1200; methyl 3,7-dihydroxychol-4-en-24-oate; methyl 3,7-dihydroxycholanate; N-(2-aminoethyl)-3,7-dihydroxycholan-24-amide; N-chenodeoxycholyl-2-fluoro-beta -alanine; sarcochenodeoxycholic acid; Taurochenodeoxycholic Acid; taurochenodeoxycholate-3-sulfate; taurochenodeoxycholate-7-sulfate; tauroursodeoxycholic acid.  
      The above list is by all means not complete. It is only reported to mention instances of the class of biliary compounds, either natural as they occur in different species or synthetic. Applicants have conducted in vitro experiments which have proven the efficacy of a biliary acid in removing the lipid core of the atherosclerotic plaques from the arterial walls of mammalians.  
      The in vitro experiments, explained below in details, unequivocally have proven that a biliary compound when placed in contact with an atherosclerotic plaque has the ability of: 
      1) penetrating into the atherosclerotic plaque passing through/traversing the fibrous cap of the plaque,     2) dissolving the cholesterol aggregates within the plaque, and in general the lipidic core of the plaque, and ultimately promoting filtration of the emulsified/solubilized cholesterol and lipidic content of the plaque throughout the fibrous cap into an aqueous solution such as the blood stream leaving in situ only a virtual cavity roofed by the fibrous cap as the plaque has been emptied out of its cholesterol/lipidic content. 
 
 First Type of In Vitro Experiment: 
   

      In a first type of in vitro experiment the atherosclerotic plaques of pig arteries were exposed to an aqueous solution of DCA at concentration of 50 mg./ml to test the compound in a direct plaque application model such as intracoronaric in situ delivery via intra-arterial catheter as the one disclosed below precisely in pages 31 and 32.  
      The first type of experiments were conducted by Applicants on biospecimens of pig arteries carrying significant atherosclerotic lesions. The biospecimens were provided to the Applicants by the Pathology Department of a major US Medical College.  FIG. 2  is a perspective view of iliac artery biospecimen  7 . Arterial biospecimen  7  has wall  10  and lumen  9 . Atherosclerotic plaque  8  protrudes from wall  10  and partially obstructs lumen  9  of artery biospecimen  7 . Plaque  8  is covered by fibrous cap  11  and is contained within wall  10  of specimen  7 . The major component of plaque  8  is cholesterol in form of aggregates with other lipids; the rest of the plaque contains cellular components and calcium deposits.  
       FIG. 2A  shows iliac artery biospecimen  7  after being opened longitudinally. Atherosclerotic plaque  8  is recognized as a raised rib longitudinally oriented. A fixture, designated as  12  in  FIG. 3  for accurate exposure of the samples to an aqueous solution of deoxycholate was constructed, consisting of rectangular frame  18  hanging via hinges  17  from a horizontal bar  15  which has vertically oriented bores  29 ′ and  29 ″ on each end slideably engaging into two parallel, vertically oriented threaded pillars  19 ′ and  19 ″ secured to a base plate  16 .  
      Horizontal bar  15  is downwardly urged toward the base plate by springs  21 ′ and  21 ″ and retained from sliding further downward by nuts  22 ′ and  22 ″ threaded on each of the pillars  19 ′ and  19 ″. Positioning of the rectangular frame  18  along the threaded pillars  19 ′ and  19 ″ was therefore determined by positioning of height regulating nuts  22 ′ and  22 ″ along the threaded pillars  19 ′ and  19 ″.  
      As better shown in  FIG. 3A  which shows a detail of fixture  12  of  FIG. 3 , horizontally oriented replaceable bar  23 , adapted to support specimens  7  is formed with central segment  23 ′ protruding downward. Bar  23  is mounted at the lower end of rectangular frame  18 , being secured to lateral supports  24  of rectangular frame  18  via pins  25 .  
      Opened biospecimen  7  is everted, wrapped around bar  23  and secured to it with ties  26 ′ and  26 ″. Atherosclerotic plaque  8  is laid in correspondence of downwardly protruding central segment  23 ′ of bar  23 . Plaque  8  is the lowest region of biospecimen  7  mounted on horizontal bar  23  for exposure to the solution of deoxycholate  13 . Container  20  filled with a solution of deoxycholate  13  is placed underneath specimen  7 .  
      The above described spatial arrangement of the specimen is considered important to allow selective exposure of atherosclerotic plaque  8  to deoxycholate exclusively via the fibrous cap covering the plaque in order to determine permeability of the fibrous cap to the deoxycholate, and avoid exposure of the content of the plaque to the deoxycholate through the edges of the specimen.  
      Via rotation of the height regulating nuts  22 ′ and  22 ″ specimen  7  was lowered into the aqueous solution of deoxycholate  13  in container  20  to such a level that said lowering permitted only submersion of atherosclerotic plaque  8  which, as described above, was positioned below the rest of the specimen. without allowing exposure of the raised edges of specimen  7  to the aqueous solution deoxycholate  13 .  
      After 30 minutes of exposure of atherosclerotic plaque  7  to deoxycholate  13 , via counter-rotation of the height regulating nuts  22 ′ and  22 ″ threaded on the vertical pillars  19 ′ and  19 ″, specimen  7  was lifted from the aqueous solution of deoxycholate  13 . As shown on in  FIG. 4  upon lifting of the specimen  7 , when the lowest point of the specimen consisting of the atherosclerotic plaque  8  finally separated from the surface of the aqueous solution  13 , a clear thin column  8 ′ of about 1-2 mm diameter, depending on the specimen, extended from the atherosclerotic plaque  8  which had been exposed to aqueous solution  13 , to the surface of aqueous solution  13 . Around the base of column  8 ′ on aqueous solution  13  the column expanded to a cone shaped base down to the level of aqueous solution  13 . The clear column had a syrupy consistency and was found to be composed largely of cholesterol filtering out of the plaque through the fibrous cap covering the plaque.  
      The clear column of syrupy consistency completely dissolved into the aqueous solution becoming undistinguishable within the solution.  
      The specimen was then re-submerged in the same fashion and to the same level as the first time. After an additional 30 minutes of exposure, the specimen was lifted again, and the clear column  8 ′ was nearly double in diameter as shown in  FIG. 4A . The process was repeated every 30 minutes and the clear column continued to increase in diameter up to approximately the third hour, then it gradually decreased until, at the fourth or fifth or sixth hour, depending on the specimen, no column was any longer visible between specimen and aqueous solution.  
      At macroscopic examination, the atherosclerotic plaque of the specimen being exposed to deoxycholate appeared dramatically reduced in volume, approximately between 60 to 75 percent or more in some specimen. The fibrous cap was still present, roofing a virtual cavity which prior to the experiment was largely occupied by the cholesterol aggregates. Remarkably the arterial wall appeared intact and not altered by the compound. The wall elasticity as well appeared to be well preserved. Preservation of the arterial wall integrity is expected because in physiological condition the veins of the portal system which are part of the entero-hepatic circulation do not suffer any damage from the load of biliary acids they are exposed to on daily basis. In fact, in the Review of Medical Physiology, 22 nd  edition,  FIGS. 26-22 , page 501, Ganong reports that the Deoxycholic acid accounts for 15% of the whole pool of human biliary acids, the remaining 85% being of cholic acid, chenodeoxycholic acid and lithocholic acid which are expected to cause the same effects, and on page 502 he reports that the total bile acids pool is of 3.5 grams and that this pool of biliary acids circulates 6 to 8 times a day from the intestine to the liver, i.e. via the veins of the portal system, and from the liver to the intestine, every day of our life. Although no arteries are exposed, veins are, and the endothelium of the veins is similar if not identical to the endothelium of the arteries.  
      The specimen was then entirely bathed into the aqueous solution of deoxycholate, and after 36 hours of total exposure to deoxycholate, there were left only remnants of the atherosclerotic plaque, precisely the fibrous cap and calcium deposits.  
      Also after 36 hours of exposure, the arterial wall appeared intact and not altered by the compound and the wall elasticity appeared to be well preserved.  
      Second Type of In Vitro Experiment:  
      In a second type of in vitro experiment, the atherosclerotic plaque of a pig artery was exposed to a continuous flow of a solution containing the compound at a very low concentration, likely a non toxic concentration, of 0.25 mg./ml, obtained diluting 1000 mg of DCA into 4 liters of Normal Saline.  
      As shown in  FIG. 5 , experiment fixture  12 ′ is similar to fixture  12  of  FIGS. 3 and 3 A of the prior experiment except that circular container  20  is substituted by fenestrated pipe  30  for exposure of plaque  8  to the deoxycholate solution  13 ′. Pipe  30  mounted on pillars  19 ′ and  19 ″ is fenestrated with opening  32  for receiving bar  23  of frame  18  for exposure of plaque  8  of biospecimen  7  to circulating solution of DCA  13 ′. Biospecimen is designated as  7  in the description of all experiments but different specimens were naturally used in each experiment. Container  34  houses submersible pump  37 . Pump  37  has an inlet port  38 ′ for aspiration of solution  13 ′ and an outlet port  38 ″. Solution  13 ′ is aspirated by pump  37  via inlet port  38 ′ and ejected via outlet port  38 ″ to circulate in mini hose  31 , then in pipe  30 , and it returns into container  34  via opening  35  of pipe  30 .  
      The height of fenestrated pipe  30  is regulated by height regulating nuts  119 . Barrier  35 ′ is slideably and sealingly mounted on end of pipe  30  at opening  35 . Position of barrier  35  regulates the height of the level of solution  13  within pipe  30 .  
      Plaque  8  of specimen  7  was clearly significantly reduced after eight days of continuous flow to the point that macroscopic examination of the plaque revealed only remnants of the plaque i.e the presence of the fibrous cap which was roofing a nearly empty plaque cavity. The cholesterol content and generally the lipidic core of plaque  8  had been dissolved by the DCA solution 13′ at a concentration of 0.25 mg/ml.  
      The arterial wall appeared intact and not altered by the compound and the wall elasticity appeared to be well preserved as in the prior experiment. The observations reported with the first type of experiments in respect to the expected preservation of the integrity of the arterial wall are even more valid when a low concentration of DCA is used, such as in the case of the second type of experiments.  
      With the above experiments Applicants have proven the following: 
          1. the effectiveness of the use of an emulsifier in dissolving the atherosclerotic plaque lipidic content     2. the ability of the tested emulsifier to cross the fibrous cap of the plaque to reach the lipidic content of the plaque     3. the lipid content dissolved by the tested emulsifier can filter throughout the fibrous cap of the plaque     4. the lipidic content emulsified by the tested emulsifier and filtered through the cap is completely dissolved into an aqueous solution.        

      In order to reach the systemic and pulmonary circulation and act upon the atherosclerotic plaques, biliary compounds or substances can be administered via many routes, except that they cannot be administered via the oral digestive route because when ingested they are absorbed by the intestine and sequestered in the entero-hepatic circulation, which keeps them away from the systemic and pulmonary circulation.  
      Applicants disclose below in detail one of the routes which can be used to administer the compounds, a very convenient and easy way, the topical dermatological route by the means of a skin patch.  
      In this embodiment shown in  FIG. 1  the ingredient, a biliary compound or generally an emulsifier, is delivered to the systemic circulation thru the skin in the form of a skin patch impregnated with a biliary compound or generally an emulsifier.  
      The skin patch generally indicated at  1  shown in  FIG. 1 , contains Cholic acid or Chenodeoxycholic acid or Deoxycholic acid or Lithocholic acid or any of their salts or bile salts in general, alone or in combination, or any precursor or derivative of such bile acid or salt, alone or in combination  4 , such water soluble compound having detergent/emulsifying/surfactant activity.  
      Skin patch  1 , schematically represented in  FIG. 1  is composed of two layers, backing/adhesive layer  2  and reservoir layer  3 , filled/impregnated with the bile compound  4  above disclosed.  
      Backing/adhesive substantially impermeable layer  2  serves the purpose of preventing seeping of bile compound  4  toward the exterior from patch  1  and serves mainly the purpose of permitting adhesion of patch  1  to skin  5 . Reservoir layer  3 , composed for instance of interwoven fabric impregnated with substance  4 , in direct contact with skin  5 , serves as reservoir for the delivering of substance  4  thru skin  5  into the systemic circulation.  
      A skin permeability enhancer along with ordinary excipents can be added to the bile acid or salt in the skin patch to facilitate the penetration and absorption of the bile acid or salt thru the skin.  
      The Percutaneous Chemical Enhancers which can be added can be classified as: Sulfoxides, Alcohols, Fatty acids, Fatty acid esters, Polyols, Amides Surfactants, Terpene, Alkanones Organic acids, Liposomes, Ethosomes, Cyclodextrins. Preferably, the Percutaneous Chemical Enhancers which can be used are: Ethanol, Glyceryl monoethyl ether, Monoglycerides, Isopropylmyristate, Lauryl alcohol, lauric acid, lauryl lactate, lauryl sulfate, Terpinol, Menthol, D-limonene, Beta-cyclodextrin, DMSO acronym for dimethyl sulfoxide, Polysorbates, Fatty acids e.g. oleic, N-methylpyrrolidone, Polyglycosylated glycerides, 1-Dodecylaza cycloheptan-2-one known as Azone®, Cyclopentadecalactone known as CPE-215®, Alkyl-2-(N,N-disubstituted amino)-alkanoate ester, known as NexAct®, 2-(n-nonyl)-1,3-dioxolane known as SEPA®, phenyl piperazine.  
      The bile acid or its salt, once absorbed in the systemic circulation thru the skin, having bypassed the entheropatic circulation, will act upon the cholesterol aggregates of the atherosclerotic plaque inducing breakdown of the cholesterol aggregates of the arterial plaques, due to the well known physiological emulsifying/surfactant properties of the bile acid and or its salts.  
      As a result of such action by the above named substances, arterial cholesterol or atherosclerotic plaques are expected to be dissolved.  
      In addition to being delivered via skin patch as shown in  FIG. 1 , the Pharmacological Topical Preparation containing Cholic acid or Chenodeoxycholic acid or Deoxycholic acid or Lithocholic acid, or their salts alone or in combination or any precursor or derivative of such bile acid or salt alone or in combination, can be delivered into the systemic circulation via a cream means, ointment means, paste means, emulsion means, lotion means and the likes.  
      Physical enhancers can also be used for transdermal delivery of the above mentioned substances, such as Iontophoresis, Electroporation, Sonophoresis Thermal Poration and in general physically or chemically induced heat, Microneedles, Dermabrasion. The bile acid or salt as disclosed above can be administered via all the other pharmacological routes of administration which bypass the enteropathic circulation: 
          A) Rectal, for instance in the form of a suppository.     B) Subcutaneous via injection for prompt or slow release delivery of the substance.     C) Intramuscular for prompt or slow release of the substance in a depo form.     D) Intravenous     E) Intradermal.     F) Oral mucous membrane, such as sublingual     G) Inhalation in form of inhaled microcrystals or aerosol.     H) Others, such as vaginal or intraperitoneal route     The non enterohepatic routes of administration will allow absorption of the active substance into the systemic circulation bypassing the liver. The substance will specifically target cholesterol plaques. As shown in the above experiments it will effectively promote plaque dissolution.        

      A special and effective route of administration is the Intra-Arterial route i.e. the delivering of an emulsifying compound intra-arterially or via the use of a specialized intra-arterial catheter for a sustained contact of the substance in loco, i.e directly on to the atherosclerotic plaque and avoidance of dispersion of the substance in the systemic circulation, for treatment of identified coronary artery or peripheral arteries atherosclerotic lesions.  
      As shown in  FIGS. 6, 6A  and  6 B, catheter  130  is composed of tubular body  131  having distally tip  132 , and two generally donut shaped balloons, distal balloon,  135 ″ sealingly connected to tubular body  131  of catheter  130  via sleeves  134 ″ and a proximal balloon  135 ′ sealingly connected to tubular body  131  of catheter  130  via sleeve  134 ′. As better shown in  FIG. 6B , balloons  135 ′ and  135 ″ are spaced from each other to leave segment  82  of tubular body  131  exposed. As better shown in  FIG. 6A , tubular body  131  of catheter  130  has three longitudinal compartments: compartment  40  for passage of blood  43  from inlet openings  41  to outlet openings  42  located at tip  132 . This compartment is obliterated proximally to the most proximal inlet opening  41 . Septum  45  separates compartment  40  from the other two compartments  50  and  60 . Compartment  50  is separated from compartment  60  by septum  55  and is in flow communication with the inside of balloons  135 ′ and  135 ″ to allow inflation/deflation of balloons  135 ′ and  135 ″. As best shown in  FIG. 6B , compartment  60  has openings  61  to allow compound to enter space  80 , delimited distally by inflated balloon  135 ″, proximally by inflated balloons  135 ′, medially by tubular body  131  of catheter  130  and laterally by the arterial wall  78  of artery  77 , which in  FIG. 6B  is shown longitudinally cross sectioned. Balloons  135 ′ and  135 ″ are inflated to a degree to seal space  80  from the remaining segments of artery  77 . In use tip  132  of catheter  130 , as better shown in  FIG. 6B , is passed in the arterial lumen beyond atherosclerotic plaque  79  of arterial wall  78  of artery  77  so as to align exposed segment  82  of tubular body  131  with atherosclerotic plaque  79 . Compound is introduced into compartment  60  at the proximal end of catheter  130 , to fill space  80  in suitable concentration and for an extended period of time to exert its full dissolving effect on atherosclerotic plaque  79  of arterial wall  78  of artery  77 . The compound can then drained from the proximal end of compartment  60 , and after balloon deflation, the catheter is removed from the artery. 
          Biliary compounds can also be chemically manipulated in such a way that they are not captured by the liver in any significant amount to be sequestred into the entero-hepatic circulation once introduced into the body by any route including the oral-digestive route. The use of these types of compounds makes oral administration possible even with biliary compounds, expanding even further the possibilities of the disclosed treatment of atherosclerosis.     The biliary compounds and generally the emulsifying compounds can be used alone via the routes disclosed above or in combination with the following compounds:     1) Statins with the purpose of clearing the blood from the expected transitory cholesterol increase resulting from the lipidic dissolution of the atherosclerotic plaques induced by the emulsifying compounds object of this disclosure, to impede new plaque formation achieved by the action of the statins which effectively lower serum cholesterol.     2) EDTA with the purpose of removing the calcium deposits frequently present within the atherosclerotic plaques.     3) Lipase to add a lipolytic activity to the emulsifying activity of the compound possibly in a synergistic fashion.     4) Collagenase for the purpose of enhancing the permeability the fibrous cap of the atherosclerotic plaque and accelerating and/or facilitating and/or enhancing the penetration of DCA into the plaque.     5) Hematoporfyrins which have shown to selectively accumulate within atherosclerotic plaques in a study once administered intravenously. The complex biliary compound or generally an emulsifier with hematoporfyrins would enhance in loco delivery of the complex into the atherosclerotic plaque by selective localization and accumulation of the complex in the atherosclerotic plaques.