Patent Publication Number: US-2016220671-A1

Title: Method Of Administration To A Patient Suffering From Disturbances In Vascular Tone

Description:
This application is a division of pending U.S. application Ser. No. 13/547,737, filed Jul. 12, 2012, which is a division of U.S. patent application Ser. No. 10/499,072, filed Oct. 30, 2009, which issued as U.S. Pat. No. 8,241,625, which claims the benefit of International Application No. PCT/RU2002/00385, filed Aug. 13, 2002, and Russian Federation Application No. 2001135015, filed on Dec. 26, 2001, all of which are hereby incorporate herein by reference in their entireties. 
    
    
     FIELD OF THE INVENTION 
     The invention belongs to the field of medicine and can be utilized to normalize the vascular tone and prevent acute and chronic illnesses accompanied by disturbances of the vascular tone, primarily in the arteries. 
     BACKGROUND 
     The art includes use of antibodies in the treatment of pathological syndromes (SU 1331508 A, A 61 K 39/00, 1984; SU 1730144 A1, C 12 N 7/00, 1992). 
     Medications such as sera and immunoglobulins based on antibodies in therapeutic concentrations, have also been described (e. g., see “Register of remedies used in Russia. The encyclopaedia of remedies”, 7 th  edition, 2000, pp. 358-359 (in Russian)). 
     None of the mentioned medications, however, are used in the treatment of diseases characterized by disturbances of the vascular tone. 
     There has been described a method of treating diseases accompanied by disturbances of the vascular tone through administration of substances specifically interacting with endogenous factors involved in the vascular tone regulation (e. g., see “Register of remedies used in Russia. The encyclopaedia of remedies”, 7 th  edition, Moscow, R L S, 2000, pp. 178, 406 (in Russian)). The most important disadvantage of such medications is their adverse effects. 
     DESCRIPTION OF THE INVENTION 
     The invention is aimed at producing an effective and safe medicament for treatment and prevention of diseases accompanied by disturbances of the vascular tone (primarily in the arteries), wherein activated (potentiated) antibodies are used. 
     This task is solved by the presence in the medicament of ultra low doses of monoclonal, polyclonal, immune or natural antibodies to a protein or a peptide involved in the vascular tone regulation or mediating the effects of other regulators; these antibodies are used in activated (potentiated) form produced by multiple subsequent dilution and external impact, primarily in accordance with homeopathic technology. 
     The method of treatment for diseases accompanied by disturbances of the vascular tone, primarily in the arteries, presents the use of antibodies to a protein or a peptide involved in the vascular tone regulation or mediating the effects of other regulators; these antibodies are used in activated form produced by multiple subsequent dilution and external impact. 
     The use of a mixture of different, preferably centesimal, homeopathic dilutions is most beneficial. 
     Experiments have been carried out to prove that the administered activated (potentiated) antibodies to a protein or a peptide involved in the vascular tone regulation exert a modifying, instead of inhibiting, effect on physiological and pathological processes mediated or regulated by this protein or peptide; the latter is responsible for the therapeutic efficiency of the medication presented. 
     The medication produced in accordance with the invention presents a new pharmacological preparation characterized by the presence of specific pharmacological activity, the absence of adverse effects as well as drug tolerance and dependence; by ecological purity and a low prime cost. 
     Variants of the Invention Implementation 
     The drug preparation is produced as follows. 
     To treat a disease or a pathological syndrome caused or accompanied by disturbances of the vascular tone, clinical experiments are used to discover a protein or peptide regulating the vascular tone, which alterations characterize this disease or accompany its development. 
     Biochemical methods are used to separate this peptide or protein. Thereafter, the whole protein or its fragment (not less than 3 amino acids) is utilized as an immunogen in the immunization of laboratory animals and producing immune antibodies, or in a hybridizomatechnology to produce monoclonal antibodies. The antibodies produced are purified by affinity chromatography. 
     The technique of immune and monoclonal antibody production is described, for example, in: Immunological methods (Ed. by H. Friemel), Moscow, Medicine publishers, 1987, pp. 9-23 (book in Russian). 
     Multiple subsequent dilutions and external impact, usually mechanical, are exerted on the isolated antibodies until ultra low or low doses are produced, e. g., preferably in accordance with homeopathic technology of potentiation (dynamization) (see V. Shvabe, Homeopathic Pharmaceutical Agents. A Manual on Description and Preparation, Moscow, 1967, p. 12-38). (In Russian)). To do so, a uniform concentration reduction is employed wherein 1 volume unit of the antibodies is diluted in 9 volume units (for a decimal dilution D) or in 99 volume units (for a centesimal dilution C) of a neutral diluent with multiple vertical shaking of every dilution; for the most part, separate containers are used for every subsequent dilution until the needed concentration (potency) is reached. 
     External impacts in the concentration reduction process can also include ultrasound, electromagnetic or other physical influences. 
     The medication thus prepared is utilized preferably in common homeopathic dosage forms and dilutions, in alcohol or aqueous solutions or tablets (granules) prepared by impregnation until saturation of the excipient with a potentiated solution or by direct instillation of the latter into a liquid dosage form. To enhance the therapeutic effect of the preparation, a mixture of different homeopathic dilutions is employed. 
    
    
     EXAMPLES 
     Example I 
     An experimental study was performed to evaluate the effect of antibodies to angiotensin II receptor (Anti-R-angiotensin II-c), activated forms of ultra low doses, on blood pressure in ISIAH strain rats with hereditary arterial hypertension. Blood pressure in the caudal artery was measured after 5 days of peroral administration of potentiated polyclonal rabbit antibodies against the C-terminal fragment of the human angiotensin II receptor, antibodies being employed in a mixture of homeopathic dilutions C12-C30+C200 (0.5 ml of water solution). The blood pressure figures before and after drug administration are presented in Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Effect of Anti-R-angiotensin-II-c on blood pressure 
               
               
                 in hypertensive ISIAH strain rats. 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Blood 
                   
                 Blood 
                   
               
               
                   
                   
                 Baseline 
                   
                   
                 Pressure 
                   
                 Pressure 
               
               
                   
                   
                 blood 
                 Blood 
                   
                 after 
                   
                 after 
               
               
                   
                   
                 pressure 
                 Pressure 
                 Decrease 
                 subsequent 
                 Increase 
                 second 5- 
                 Decrease 
               
               
                   
                   
                 (average 
                 after 5 
                 in Blood 
                 7 days 
                 in Blood 
                 day 
                 in blood 
               
               
                   
                   
                 of 3 
                 days of 
                 pressure 
                 without 
                 pressure 
                 treatment 
                 pressure 
               
               
                 # 
                 Rat # 
                 measurements) 
                 treatment 
                 (3)-(4) 
                 medicatio 
                 (6)-(4) 
                 course 
                 (6)-(8) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
               
               
                 1 
                 31 
                 175 
                 151 
                 24 
                 166 
                 15 
                 150 
                 16 
               
               
                 2 
                 32 
                 184 
                 163 
                 21 
                 186 
                 23 
                 170 
                 16 
               
               
                 3 
                 33 
                 186 
                 169 
                 17 
                 165 
                 −4 
                 150 
                 15 
               
               
                 4 
                 4 
                 171 
                 165 
                 6 
                 189 
                 24 
                 170 
                 19 
               
               
                 5 
                 34 
                 187 
                 172 
                 15 
                 190 
                 18 
                 175 
                 15 
               
               
                 6 
                 10 
                 181 
                 166 
                 15 
                 185 
                 19 
                 170 
                 15 
               
               
                 7 
                 11 
                 171 
                 162 
                 9 
                 169 
                 7 
                 155 
                 14 
               
               
                 8 
                 38 
                 182 
                 160 
                 22 
                 185 
                 25 
                 165 
                 20 
               
               
                 9 
                 16 
                 180 
                 169 
                 11 
                 183 
                 14 
                 165 
                 18 
               
               
                 10 
                 19 
                 186 
                 166 
                 20 
                 186 
                 20 
                 170 
                 16 
               
               
                   
                 X ± m 
                 180 + 1.91 
                 164 + 1.86 
                 16 ± 1.88 
                 180 ± 3.08 
                 16.1 ± 2.81 
                 164 ± 2.87 
                 16.4 ± 0.62 
               
               
                   
               
            
           
         
       
     
     The data in the table show that the medication exerts a hypotensive effect. 
     Example 2 
     An experimental study was performed to evaluate the effect of antibodies to angiotensin II (activated forms of ultra low doses) on blood pressure in ISIAH strain rats with hereditary arterial hypertension. Blood pressure in the caudal artery was measured after 5 days of peroral administration of potentiated monoclonal antibodies to angiotensin II employed in a mixture of homeopathic dilutions C12+C30+C200 (0.5 ml of water solution). 
     The blood pressure figures before and after drug administration are given in Table 2. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                   
                   
                   
                   
                 Change in 
                 Change in 
               
               
                   
                   
                   
                   
                 blood pressure 
                 blood pressure 
               
               
                   
                 Baseline 
                 Blood pressure 
                 Blood pressure 
                 after a single 
                 after 5 days of 
               
               
                   
                 blood 
                 3 hours after a 
                 after 5 days of 
                 shot ((3) − (2) 
                 treatment ((4) − 
               
               
                 Rat # 
                 pressure 
                 single shot 
                 treatment 
                 difference) 
                 (2) difference) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                  1 
                 2 
                 3 
                 4 
                 5 
                 6 
               
               
                 11 
                 200 
                 167 
                 161 
                 −33 
                 −39 
               
               
                 12 
                 189 
                 150 
                 189 
                 −39 
                 0.0 
               
               
                 16 
                 200 
                 189 
                 160 
                 −11 
                 −40 
               
               
                 19 
                 167 
                 178 
                 144 
                 11 
                 −23 
               
               
                 21 
                 211 
                 189 
                 167 
                 −22 
                 −44 
               
               
                 22 
                 178 
                 167 
                 205 
                 −11 
                 27 
               
               
                 23 
                 189 
                 167 
                 205 
                 −22 
                 16 
               
               
                 27 
                 178 
                 194 
                 200 
                 16 
                 22 
               
               
                 28 
                 178 
                 172 
                 144 
                 −6 
                 −34 
               
               
                 30 
                 189 
                 178 
                 178 
                 −11 
                 −11 
               
               
                 Mean + 
                 187.9 ± 4.16 
                 175.1 ± 4.21 
                 175.3 ± 7.48 
                 −12.8* ± 5.49 
                 −12.6 ± 8.65 
               
               
                 SEM 
                   
                   
                   
                 *(p &lt; 0.05) 
               
               
                   
               
            
           
         
       
     
     The data in this table present a pronounced hypotensive effect of the medication. 
     Example 3 
     An experimental study was performed to evaluate the effect of antibodies to angiotensin I (activated forms of ultra low doses) on blood pressure in ISIAH strain rats with hereditary arterial hypertension. Blood pressure in the caudal artery was measured after 5 days of peroral administration of potentiated polyclonal mouse antibodies to angiotensin I employed in a mixture of homeopathic dilutions D6+C12+C200 (0.5 ml of water solution). 
     The blood pressure figures before and after drug administration are presented in Table 3. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                   
                   
                   
                   
                 Change in 
                 Change in 
               
               
                   
                   
                   
                   
                 blood pressure 
                 blood pressure 
               
               
                   
                   
                 Blood pressure 
                 Blood pressure 
                 after a single 
                 after 5 days of 
               
               
                   
                 Baseline blood 
                 3 hours after a 
                 after 5 days of 
                 dose ((3) − (2) 
                 treatment ((4) − 
               
               
                 Parameter 
                 pressure 
                 single dose 
                 treatment 
                 difference 
                 (2) difference) 
               
               
                   
               
             
            
               
                 Mean + 
                 189.0 ± 4.1 
                 178.1 ± 5.3 
                 175.8 ± 8.2 
                 −10.9* ± 5.9 
                 −13.2 ± 8.5 
               
               
                 SEM 
                   
                   
                   
                 *(p &lt; 0.05) 
               
               
                   
               
            
           
         
       
     
     The data in the table show that the medication exerts a hypotensive effect. 
     Example 4 
     Patient D., 50 years old, presented with a 10-year history of essential hypertension. On clinical and instrumental examination, he was diagnosed with “essential hypertension with primary heart involvement, 2 nd  degree, myocardial hypertrophy of the left ventricle”. He was administered polyclonal rabbit antibodies against the C-terminal fragment of the angiotensin II receptor (a mixture of homeopathic dilutions C12+C30+C200), I tablet BID. The blood pressure stabilized at 130-135/85 mm Hg within 7 days of the start of treatment. After 2 months of treatment, electrocardiography revealed a decrease in the myocardial hypertrophy and overload of the left ventricle. 
     Example 5 
     Patient Z., 50 years old, had a 10-year history of essential hypertension with primary kidney involvement. Prior to the start of antihypertensive treatment, her blood pressure was as high as 180/110 mm Hg. On clinical interview, she complained of headaches, edema, and fatigue. After the conventional antihypertensive measures had proved to be ineffective, she was administered monoclonal antibodies against the angiotensin II receptor (a mixture of homeopathic dilutions C12+C30+C200) and monoclonal antibodies against angiotensin II (a mixture of homeopathic dilutions D12+C30+LM2), 1 tablet BID. After 7 days of treatment, the patient reported an increase in energy levels, subsidence of the edema, and a stable blood pressure decrease to 140/95 mm Hg. After 2 months of treatment, blood pressure levels stabilized at 130/90 mm Hg, proteinuria went down from 0.3 g/l to 0.06 g/l. 
     Example 6 
     Patient V., 42 years old, had suffered from moderate Cushing&#39;s disease for 5 years. To treat her pronounced hypertension (up to 175/100 mm Hg), she was administered a compound preparation containing the following: polyclonal rabbit antibodies against the angiotensin II receptor (a mixture of homeopathic dilutions C12+C30+C200) and monoclonal antibodies against adrenocorticotropin (a mixture of homeopathic dilutions C12+C30+C200), 1 tablet TID. After 2 weeks of treatment, her blood pressure fell to 140/90 mm Hg, she was generally feeling better. After I month of treatment, serum ACTH levels decreased from 200 to 130 pg/ml, the body mass index went down from 37 to 35 kg/m 2 . The patient was advised to go on with the treatment. 
     Example 7 
     Patient N., 52 years, diagnosed with “coronary artery disease, angina of effort, functional class 3; peripheral atherosclerotic disease of the lower extremities”. This patient was administered activated polyclonal rabbit antibodies against the C-terminal fragment of human endothelial NO synthase (type III nitrogen oxide synthase) as a monotherapy, in a mixture of homeopathic dilutions C12+C30+C200, 1 tablet 3 TID, After 7 days of treatment, the patient noticed an improvement in exercise tolerance and general health. Pain in the lower extremities on fast walking appeared within 30 to 40 minutes (instead of 10 to 15 minutes prior to treatment). After 3 weeks of treatment, ECG showed an improvement in left ventricular myocardial ischemia and class 2 angina of effort. 
     Example 8 
     Patient 0., 67 years old, suffered from hypertension and decompensated type II diabetes mellitus. She had been having heart failure symptoms (cardiac asthma, congestive rales in the lungs) for 2 years and peripheral edema in the lower extremities for 2 months. In view of inefficiency of conventional treatment, she was administered a compound including activated monoclonal antibodies against tumor necrosis factor alpha (TNF-α) (a mixture of homeopathic dilutions C12+C30+C200) and activated antibodies against the TNF-α receptor (a mixture of homeopathic dilutions D12+LM10), 1 tablet BID. After 10 days of treatment, the heart failure improved, the peripheral edema was gone, there were no signs of pulmonary congestion, the patient was feeling better. The insulin dosage enough to control glycemia fell from 40 to 20 IU per day. 
     Example 9 
     Patient D., 62 years old, suffered from circulatory encephalopathy clue to atherosclerosis with predominant involvement of the cerebral arteries. He had a history of multiple transient ischemic attacks (TIAs) and presented with an on-going attack accompanied by right-side hemiparesis and aphasia. The patient was given polyclonal antibodies against endothelial nitrogen oxide synthase (a mixture of homeopathic dilutions C12+C30+C200), 1 tablet dissolvable in the mouth every 30 minutes. After 4 hours of treatment, TIA symptoms (vertigo, tinnitus, weakness in the right arm, aphasia) showed signs of subsidence. Within 12 hours of the start of treatment, the attack was completely overcome. 
     Example 10 
     Patient M., 32 years old, had Raynaud&#39;s phenomenon secondary to a connective tissue disorder. Because of the worsening condition, she was administered monoclonal antibodies against endothelial nitrogen oxide synthase (a mixture of homeopathic dilutions C12+C30+C200), 1 tablet TID. After 7 days of treatment, the patient noticed that attacks precipitated by exposure of the extremities to cold had become less frequent, less painful and shorter. The patient was advised to continue the treatment. 
     Example 11 
     Patient V., 19 years old. She was evaluated for headaches and vertigo and diagnosed. with hypotensive neurocirculatory asthenia (blood pressure 80/60 mm Hg). The patient was administered monoclonal antibodies against angiotensin I (a mixture of homeopathic dilutions C12+C30+C200) combined with activated angiotensin I (a mixture of homeopathic dilutions C12+C30+C200), 1 tablet TID. After 2 weeks of treatment, blood pressure stabilized at 100/80 mm Hg, the headaches had subsided and become less frequent. 
     Example 12 
     Patient 0., 42 years old. On examination at the Labour Medicine Research Institute, he was diagnosed with vibration disease, 2 nd  stage localized variant. Due to the angiospastic syndrome accompanied by vegetosensory polyneuropathy and skin atrophy, which was resistant to conventional treatment, the patient was administered polyclonal rabbit antibodies against endothelin-1 (a mixture of homeopathic dilutions C12+C30+C200) combined with monoclonal antibodies against bradykinin (a mixture of homeopathic dilutions D6+C30+LM2), 1 tablet TID. After 10 clays of treatment, the angiospastic syndrome improved, which was also shown on capillaroscopy. After 2 months of treatment, the polyneuropathy and skin atrophy significantly subsided. The patient was advised to continue the treatment.