A way to slow the progression of atherosclerosis of the coronary arteries using pravastatin
(57) Abstract:The invention relates to medicine, particularly cardiology, and for slowing the progression of corneoscleral. To do this, enter pravastatin at a dose of 10 mg to 80 mg daily for at least one to two months. A drug can be made throughout the life of the patient. The method allows to decrease the rate of disease progression by at least 40%. 8 C. p. F.-ly, 1 tab., 5 Il. The invention relates to a method of slowing the rate of progression of atherosclerosis of the coronary arteries, in particular, in patients with established disease coronary artery disease and hypercholesterolemia, with long-term use of pravastatin.According to the present invention it has been unexpectedly found that patients with disease of the coronary arteries and hypercholesterolemia, which was treated with pravastatin showed a significant and pronounced slowing the progression of atherosclerosis of the coronary arteries.Thus, according to the present invention, created a method of reducing the rate of progression of atherosclerosis of the coronary arteries, wherein the patient in need of such leelee or parenteral. Patients subjected to this treatment are usually installed disease of the coronary arteries and/or hypercholesterolemia.In addition, according to the present invention created a method of reducing the rate of progression of atherosclerosis of the coronary arteries with an efficiency of at least about 40%, which includes an introduction to a patient in need of such treatment, of pravastatin in the amount of from about 10 to 80 mg daily for a period of time sufficient to reduce the rate of progression of atherosclerosis in the coronary arteries, at least about 40%.Pravastatin, an inhibitor of HMG-COA reductase, is disclosed in U.S. patent N 4346227. Used in the present description, the term "pravastatin" refers to the free acid form or its salt, preferably sodium salt of pravastatin is available commercially under the trademark Pravacol.
The term "disease coronary artery disease" (CAD) used in the present invention, refers to diseases, including coronary artery disease, previous myocardial infarction, angina and/or heart failure.The term "hypercholesterolemia", promenaea (LDL) greater than or equal to 130 and less than 190 mg/DL. Patients may also applies to other groups at risk for coronary artery disease, including risk factors such as high triglycerides, hypertension, myocardial infarction in anamnesis, Smoking, etc.It should also be noted that patients under treatment, may or may not have installed the disease of the coronary arteries and/or hypercholesterolemia, as defined above, and nevertheless achieve significant slowing down of progression of atherosclerosis of the coronary arteries with the use of pravastatin in accordance with the present invention.In the process of the present invention pravastatin, you can enter different types of mammals, such as cats, dogs, people, etc. and place in accepted dosage forms for systemic administration, such as tablets, capsules, elixirs or injectable form. The above dosage forms also include the necessary carriers, fillers, lubricating buffers, antibacterial agents, antioxidants (ascorbic acid or sodium bisulfite), etc. are Preferred dosage forms for oral administration, however, parenteral forms also rate, as well as the route of administration, dosage form and mode of administration.So, when administered orally, you can get satisfactory results with the use of pravastatin in the amount of from about 10 to 80 mg per day in single or divided doses, preferably from about 30 to 50 mg per day in single or divided dose, more preferably about 40 mg / day as a single dose.The preferred dosage form for oral administration such as tablets or capsules, contains pravastatin in the amount of from about 10 to 80 mg, preferably from about 10 to 40 mg, and more preferably approximately 20 mg.Tablets of various sizes can be prepared, for example, weighing from 15 to 2000 mg and contain the active ingredient in amounts described above, and the rest in the form of a physiologically acceptable carrier or other materials, widely used in pharmaceutical practice. On these tablets, of course, can be applied markings for fractionation of the dose. Similarly you can prepare and gelatin capsules.You can also make a liquid dosage form by dissolving or suspendirovanie is desired to dose were placed in 1 - 4 teaspoons.Examples of excipients that can be included in tablets, can serve as: binders, such as tragakant, acacia, corn starch or gelatin; excipients, such as secondary acidic calcium phosphate or cellulose; dezintegriruetsja agents such as corn starch, potato starch, alginic acid, etc.; lubricating agents such as stearic acid or magnesium stearate; sweeteners such as sucrose, aspartame, lactose or saccharin; fragrances such as orange, mint, cherry or Wintergreen oil. If the dosage form is manufactured in the form of a capsule, it may contain, in addition to the above mentioned substances, liquid carrier such as fatty oil. Various other substances may serve as a floor or any other way to modify a single dosage form. For example, tablets or capsules may be coated with shellac, sugar or both. Elixir or syrup may contain the active ingredient, water, alcohol, etc. as a carrier, glycerin as solubilizing agent, sucrose as a sweetener, methyl - and propylparaben as preservatives, a dye and flavoring, such da time sufficient to significantly reduce the rate of progression of atherosclerosis in the coronary arteries. The dosage form with the gradual release of these drugs can be used twice a week, once a week or even monthly. To achieve the minimum results required period of administration of drugs, at least a duration of 1 - 2 months, or until such time as the rate of progression of atherosclerosis of the coronary arteries will not decrease significantly. In order to secure slowing the progression of atherosclerosis of the coronary arteries and maintain its use of pravastatin may continue during the life of the patient.Fig. 1 is a schematic diagram showing a portion of the coronary arteries, demonstrating a variety of quantitative criteria for the assessment of the coronary arteries (A, B, C and D).Fig. 2 is a graph showing the effect of treatment with pravastatin at medium and minimum diameters of the lumen of the coronary arteries and the percentage of stenosis in all subjects using the control angiography.The following examples represent preferred embodiments of the present invention.Ingredient Weight parts
Pravastatin - 7
Lactose - 67
Microcrystalline cellulose - 20
Croscarmellose sodium - 2
Magnesium stearate - 1
Magnesium oxide - 3
Pravastatin magnesium oxide and a portion (30%) of lactose were mixed for 2 to 10 minutes using an appropriate mixer. The resulting mixture was passed through a sieve mesh from 12 to 40. Added microcrystalline cellulose, croscarmellose sodium and the remainder of the lactose and the mixture was stirred 2 - 10 minutes. After this was added magnesium stearate and mixing continued for another 1 to 3 minutes.The obtained homogeneous mixture was then pressed into tablets containing 5 mg, 10 mg, 20 mg or 40 mg of pravastatin each, which can be used according to the present invention, to slow the progression of coronary artery atherosclerosis.Example 2
Tablets pravastatin were prepared by standard pharmaceutical techniques. These tablets contain 2 mg of pravastatin and inert ingredients, namely microcrystalline cellulose, providin, lactose, magnesium stearate and croscarmellose sodium, as described in the 1994 PDR.According to the present invention, these tablets pravastatin can example describes a large national research project on the topic "Pravastatin, Zimitation of Atherosclerosis of the Coronary Arteries (PZAC I)", which was carried out by 47 scholars from 13 research centers in the United States. The Protocol discussed in Am. J. Cardiol. 1993; 72:31-35. The study lasted from December 29, 1987 June 23, 1993.Goals
To determine whether treatment with pravastatin cause reverse the development or delay the progression of atherosclerosis of the coronary arteries and reduce cardiovascular complications in patients with moderate hypercholesterolemia and coronary artery disease (CAD).The duration of treatment
Patients were treated for 36 months.The study design and methods
Studies were conducted on the groups, which are selected by randomly selecting, with placebo control. Patients investigated in many parameters. Patients for the study were selected on the basis of the initial coronary angiography. After evaluating diets and discussion of selected patients were divided by random selection into the group receiving pravastatin, 40 mg, and the group receiving placebo (1:1). Dose remained unchanged throughout the treatment period; coronary angiography was repeated at the end of the treatment period.Patient distribution and demographic characteristics
ing the course of study within 36 months from the final angiography. The average age of selected patients (77% males, 23% females) amounted to 56.8 years in the pravastatin group and 57.3 years in the placebo group.Diagnosis and selection criteria
In the list admitted to the study enrolled men and women in menopause or sterile as a result of operation under the age of 75 years if they met the following conditions: past angiography of coronary vessels after recent myocardial infarction (mi) or percutaneous transluminal coronary angioplasty (PTCA), provided that angiography did not reveal only normal coronary artery; undergoing diagnostic angiography of coronary vessels about chronic or unstable angina, which revealed at least one angiographically documented stenosis greater than or equal to 50% of the main coronary artery; with the level of serum LDL-X is greater than or equal to 130 and less than 190 mg/DL and triglycerides (TG) less than or equal to 350 mg/DL. Were not allowed to study patients under one of the following conditions: unmanaged hypertension; endocrine diseases; hyperlipoproteinemias type III; congestive heart failure; debilitating chronic neserbeznyh diseases; serious pocetni; unmanaged or insulin-dependent glucose; the likelihood of bypass surgery vascular coronary artery bypass grafting (OSSCA) or PTCA within 6 months; cerebrovascular diseases in anamnesis; serious gastrointestinal diseases; excessive alcohol use; high sensitivity to inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme-a reductase (HMG-COA reductase inhibitors); treatment (which cannot be undone) corticosteroids, extragenomic more than 1.24 mg per day, androgens, fish oil, barbiturates, antacids or other drugs that lower lipid levels; the treatment with investigational medication for at least 30 days before the selection for inclusion in this study.Investigational product.Pravastatin 20 mg tablet (as in example 2).Placebo in slowing the pravastatin 20 mg tablets.Evaluation criteria
Quantitative angiographic variable effectiveness included the rate of progression between the main and control angiograms diameters average, minimum and maximum diameters of the lumen of the coronary arteries and the percentage of stenosis lumen diameter (% DM), on average for ogramme, received 90 days after selection of patients were admitted for inclusion in the analysis. Bypass segments and vessels that underwent PTCA ( not later than 9 months before the main angiography or immediately after selection) were excluded from the analysis. Estimated impact of the studied drugs on cardiovascular events and levels of lipids (total cholesterol (total X), LDL's and triglycerides). Cardiovascular events was assessed in two ways: 1) more than 90 days after selection, to get the maximum effect of pravastatin on serum lipids; and 2) from the time of the selection.Security
The researchers were given instructions to document the emergence of any adverse clinical manifestations (PP; ailments, signs or symptoms that appeared or worsened during the time of the research), as those complained patients and those identified in the General survey, at all scheduled visits. Periodically during the time the research was also evaluated in laboratory safety parameters. Other safety tests include a comprehensive medical history and periodic therapeutic examinations, x-ray chest and ECG with 12 leads.Stat is dressirovannye for medium, the minimum and maximum diameters of the lumen and % DM, averaged over all available natural (necessary, not-PTCA) coronary arteries were analysed using analysis of covariance (ANCOVA) in relation to the treatment site, the impact of treatment on the plot and the original diameter of the lumen as covariants, assessed each plot is inversely proportional to its variant of the difference in treatment. The reliability of the results was evaluated on the effect of treatment on the site with a confidence level of 10%. Clinical cardiovascular events were analyzed according to the time. The average percentage changes in lipid levels and clinical laboratory data were evaluated using ANCOVA. Comparison of the frequency of side effects between groups and marked laboratory abnormalities were assessed by the Fisher test.Results
Angiographic variables efficiency, including the rate of progression in average, minimum and maximum diameters of the coronary arteries and % DM, averaged over all available natural segments (N less than or equal to 10) were analyzed (see Fig. 1). The average diameter of the coronary artery, as shown in Fig. 1A, rasschityvaet maximum diameter (y) of the coronary artery.Fig. 1D shows the percentage of diameter stenosis
where y is adjacent normal diameter.Fig. 2 demonstrates the effect of treatment with pravastatin on the medium and minimum diameters of the lumen of the coronary arteries and the percentage of stenosis for all subjects with a control angiography.As can be seen from the table, and Fig. 2, the narrowing of the coronary vessels, as determined by measurement of average and minimum diameters of the lumen and the percentage of stenosis lumen diameter was reduced by 40 - 50% during treatment with pravastatin. Change the maximum lumen diameter (pravastatin = -0,02 mm/year; placebo = -0,04 mm/year; P = 0,20) is consistent with observations.As can be seen from the table, compared with placebo (N = 157 pravastatin (N = 163) was reduced by 40 - 50% of the rate of progression for the average (pravastatin = -0,02 mm/year; placebo = -0,04 mm/year; P = 0,16) and minimum (pravastatin = -0,03 mm/year; placebo = -0,05 mm/year; P = 0.04) diameter of the lumen of coronary arteries and % DM (pravastatin = 0,69%/year; placebo = 1,12 %/year; P = 0,13). A corresponding decrease was observed on the maximum lumen diameter (pravastatin = -0,02 mm/year; placebo = -0,04 mm/year; P = 0,20).Analysis of clinical cardiovascular manifestations showed brinich and fatal myocardial infarction (pravastatin, 2,7%; placebo, of 10.5%; P = 0.006), non-fatal myocardial infarction or all deaths (pravastatin, 4,4%; placebo, of 11.6%; P = 0,020), and non-fatal myocardial infarction and death from coronary heart disease (CHD) (pravastatin, 3.9% of placebo 11,0%; P = 0.016). For displays from the start of treatment with pravastatin comparable effects were observed in relation to levels of non-fatal and fatal myocardial infarction (pravastatin, 4.2 percent; placebo, of 10.5%; P = 0,0498), non-fatal myocardial infarction and all deaths (pravastatin, 5,9%: placebo, 12.0 percent; P = 0,0720), and non-fatal myocardial infarction and death from coronary heart disease (pravastatin, 5.3 percent; placebo, of 11.4%; P = 0,0652).With respect to the amount of nonfatal myocardial infarction, all deaths, strokes or PTCA/OSSCA pravastatin showed a direct effect in comparison with other clinical events (after research) > 90 days from the start of treatment: pravastatin = 18,6%, placebo = 23,9%, P = 0,249; from the beginning of treatment: pravastatin = 23,3%; placebo = 26,8%, P = 0,4843). For this category of manifestations, in the case of > 90 days from the start of treatment, 3.9% of patients in the pravastatin group had more than one clinical manifestations compared with 9.9% of patients in the placebo group. Similarly, in the case of starting from the beginning of treatment, 5.3% of patients in the pravastatin group had during the whole time of the study pravastatin was well tolerated by the patients. No serious side effects were observed. Six patients died during the treatment period or less than one month after treatment, two of the pravastatin group and four in the placebo group. None of the deaths were related to treatment
The results show that the introduction of pravastatin in a period of 36 months patients with established CAD and moderate hypercholesterolemia slowed the progression of atherosclerosis of the coronary arteries and reduced adverse cardiovascular complications. 1. A way to slow the progression of coronary artery atherosclerosis in humans, comprising the administration to a patient in need of treatment of pravastatin in the range from 10 to 80 mg / day, at least during the period from one to two months and may continue throughout the life of the patient.2. The method according to p. 1, characterized in that use sodium salt of pravastatin.3. The method according to p. 1, wherein the patient in need of treatment, has hypercholesterolemia and installed disease of the coronary arteries.4. The method according to p. 1, characterized in that pravastatin is administered in an amount of from 30 to 50 mg per day is the procedure under item 1, characterized in that pravastatin is administered a single dose.7. The method according to p. 1, characterized in that the treatment to the patient, in which the content of low-density lipoprotein - cholesterol in serum ranges from 130 to less than 190 mg/DL and triglyceride levels as well as triglycerides 350 mg/DL or less.8. The method according to p. 1, characterized in that it comprises the administration to a patient in need of treatment of pravastatin in the range from 10 to 80 mg per day, for a period of time sufficient to reduce the rate of progression of atherosclerosis of the coronary arteries, at least 40%.9. The method according to p. 8, wherein the patient in need of treatment, has hypercholesterolemia and installed disease of the coronary arteries.
FIELD: organic chemistry, natural compounds, medicine, oncology.
SUBSTANCE: invention represents new saponin mixtures used for inhibition of initiation and activation of mammalian epithelial cell in pre-malignant or malignant state, for stimulation of apoptosis of mammalian malignant cell, prophylaxis of anomalous proliferation of mammalian epithelial cell, for treatment of inflammatory and regulation of angiogenesis in mammal. These mixtures are isolated form plants of species Acacia victoriae. Also, invention relates to methods for their applying. These compounds can comprise triterpene component, such as acacic or oleanolic acid to which oligosaccharides and monoterpenoid components are joined. Mixtures and compounds elicit properties associated with regulation of apoptosis and cytotoxicity of cells and strong anti-tumor effect with respect to different tumor cells.
EFFECT: valuable medicinal properties of compositions.
43 cl, 53 tbl, 50 dwg, 44 ex
FIELD: organic chemistry, chemical technology, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to new derivative of taxane of the formula (I):
that elicits strong antitumor effect. Also, invention relates to intermediates substances, a method for preparing compound of the formula (I), a method for preparing 1,14-β-hydroxy-1,14-carbonate-baccatin III-derivatives substituted with isoserine residue at position 3 and to pharmaceutical composition based on compounds of the formula (I). Invention provides preparing new derivative of taxane that elicits higher activity and reduced toxicity as compared with paclitaxel.
EFFECT: improved preparing method, enhanced and valuable medicinal properties of compound.
10 cl, 7 tbl, 6 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new derivatives of borrelidin of the general formula (I)
wherein R represents the group of the general formulae -COOR1, -CONR2R3, -CONR4CONR2R5 or -CH2OR6 wherein R1 represents (C2-C6)-alkyl group, (C1-C6)-alkyl group substituted with hydroxyl group or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprise oxygen atom in addition to nitrogen atom) or 5-6-membered nitrogen-containing aromatic heterocyclic group or (C3-C6)-cycloalkyl group; R2 and R3 are similar or different and represent independently hydrogen atom or (C1-C6)-alkyl group that can be substituted optionally with hydroxyl, (C2-C5)-alkoxycarbonyl or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprises oxygen atom in addition to nitrogen atom) or 5-6-membered aromatic homocyclic group or aromatic heterocyclic group comprising oxygen and/or nitrogen atom, 5-6-membered cycloalkyl or heteroaryl group; R4 and R5 are similar or different and represent independently hydrogen atom or (C3-C6)-cycloalkyl group; R6 represents hydrogen atom; also, invention relates to tautomers, solvates of these compounds, their mixtures and acid-additive salts. Also, invention relates to pharmaceutical compositions comprising compounds of the general formula (I) as an active component. Angiogenesis inhibitors of the present invention inhibit formation of new vessels in tissues of live organisms and can be used for prophylaxis and inhibition of the angiogenesis process arising in the tumor proliferation, and for prophylaxis of formation of tumor metastasis. Invention provides preparing new derivatives of borrelidin eliciting the value physiological effect.
EFFECT: valuable medicinal properties of compounds.
8 cl, 15 ex
FIELD: medicine, hepatology.
SUBSTANCE: at achieving alkaline phosphatase of 580 U and more one should introduce ursodesoxycholic acid at the dosage of 15-20 mg/kg and orlistate at the dosage of 90-100 mg twice or thrice daily for patients with steatohepatitis. According to normalization of clinical and biochemical values of blood analyses it is possible to conclude upon successfulness of therapy performed. The method provides clinic-laboratory remission of the disease.
EFFECT: higher efficiency of therapy.
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.
EFFECT: improved and valuable properties of compounds.
6 cl, 5 tbl, 19 ex
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:
wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.
EFFECT: valuable medicinal properties of compound.
13 cl, 1 dwg, 4 tbl, 16 ex
FIELD: woodworking industry.
SUBSTANCE: invention relates to methods for recovering and purifying native bioflavonoids: dihydroquercitine and dihydrokaempferol from larch wood extracts. Method of recovering bioflavonoids from larch wood extracts is characterized by that freeze-dried extract is dissolved in ethylacetone/water mixture composed in specified proportion, specified amount of resulting solution is introduced into column filled with urea (sorbent) preliminarily equilibrated with ethylacetate, and column is then eluted with an ester and/or ketone having boiling point below 120°C, or with ethylacetate/acetone mixture at specified ratio. Eluate is collected and evaporated until crystallization is observed and then cooled. Separated crystals are rinsed and dried.
EFFECT: enabled single-step process for separating dihydroquercitine and dihydrokaempferol from resinous impurities and other polymeric compounds, reduced process expenses, and reduced environmental impact.
4 cl, 1 dwg
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new semi-synthetic taxanes of the formula (1):
wherein R and R1 can be similar or different and represent hydrogen atom (H), (C1-C18)-acyl group, benzoyl group; R2 and R3 represent hydrogen atom (H) or R2 and R3 in common form carbonate or thiocarbonate residue; R4 represents benzoyl group optionally substituted at meta-position; R' represents hydrogen atom (H) or (C1-C4)-alkyl; R'' represents (C1-C4)-alkyl or phenyl; R''' represents tert.-butoxy-group under condition that R and R1 both can't represent hydrogen atom (H). Also, invention relates to a pharmaceutical composition based on compounds of the formula (1) eliciting an anti-tumor, anti-angiogenic and anti-arthrosis effect. Invention provides preparing new compounds eliciting cytotoxicity comparable with cytotoxicity of other taxanes but showing reduced systemic toxicity that can be administrated by intravenous and oral routes.
EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.
6 cl, 1 tbl, 7 ex
FIELD: medicine, therapy, gastroenterology.
SUBSTANCE: method involves preliminary assay of the disorder type in gallbladder motor contraction and bile-excretion ways followed by prescribing thermal low-mineralized hydrocarbonate-sodium-sulfate-calcium-magnesium mineral water in the dose by 200-300 ml, 3 times per a day, 1 h before eating, tubages № 3 with mineral water, bathes and shower with mineral water every day for 10-14 days. In the hypotonic type of motor activity method involves mineral water at temperature 25-30°C, and in the hypertonic type - at temperature 38-40°C. Method provides accelerating in scars formation of ulcers and epithelization of erosions in gastroduodenal system, to prevent frequent exacerbations and to reduce activity of Chelicobacter-induced inflammation.
EFFECT: improved therapy method.
4 tbl, 2 ex
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to new taxanes of the general formula (I)
wherein R2 means benzoyloxy-group; R7 means hydroxyl (OH); R9 means keto-group; R10 means R10aCOO-; R10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-6-membered heteroaromatic group wherein heteroatom represents oxygen atom (O), sulfur atom (S) or nitrogen atom (N); R14 means hydrogen atom (H); X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted possibly with nitro-group (-NO2), 5-6-membered heteroaromatic group wherein heteroatom represents O, S or N; X5 means -COX10, -COOX10; X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl or 5-6-membered heteroaromatic group wherein heteroatom represents O, S, N; Ac means acetyl. Compounds of the formula (I) elicit antitumor activity.
EFFECT: valuable medicinal properties of compounds.
68 cl, 1 tbl, 6 ex