LIPID METABOLISM IMPROVING AGENTS

Abstract: Pharmaceutical preparations containing horse chestnut seed extract, oxyethophylline and adenosine have been found to improve lipid metabolism by increasing high density lipoprotein cholesterol in blood.

Description: lipid Hetabolism Improving Agents The present invention relates to lipid metabolism improving agents which exhibit an action of increasing high density lipoprotein (hereinafter abbreviated as HDL) cholesterol in blood. It has bean long years since abnormal lipid metabolism has been pain attention as a general cause for modern diseases. Normaliàtion oi the lipid metabolism abnormality is one of the most important means attempted in clinical fields in order for removal or alleviation of fatal factors in various diseases. Recently it has been reported that there is a negative interrelation betJee HDL cholesterol and ischemic heart diseases and, since then, attempts have been done in conducting therapy and prevention o various diseases using HDL cholesterol as a target. The present inventors have conducted extensive studies keeping the above importance of HDL cholesterol in clinical fields in our mind and, as a result, found that pharmaceutical preparations containing horse chestnut (Ro2kastanie) extract, oxyethophylline and adenosine exhibit strong action of increasing HDL cholesterol and accomplished the present invention. Clinical effects of the present invention are as follows. (1) SIethods. Patients who satisfy either a condition that his total cholesterol concentration is 220 mg/dl or more or a condition that his neutral fat concentration is 140 mg/dl or more are extracted from out-patients and they are given a pharmaceutical prepartion containing horse chestnut seed extract, oxyethophylline and adenosine in 15:55:1.5 ratio by weight. Ages of such extracted out-patients are from 26 to 69 years old. They consist of twelve males and eight females. Duration of the administration is sixteen weeks. Blood samples are collected each our weeks and concentrations of total cholesterol, neutral fat, HDL cholesterol and others in the collected blood are determined. methods for the determination are as follows. Determination of cholesterol and neutral fat is carried out by an enzyme method; determination of HDL cholesterol is done by a heparin-manganese method. Dose of the pharn2ceutical preparation is six capsules per day (each capsule contains 71.5 milligrams of the pharmaceu=ical) being given three times a day after each meal. (2) Results. In Table 1 are given ages, sexuality and changes in blood lipid levels. 1. Effect of the pharmaceutical on total cholesterol. (Tables 2 and 3) When all cases tested are taken into consideration, the initial concentration is 211 * 45 mg/dl and, after sixteen weeks, it lowers to 201 + 36 mg/dl and, therefore, the lowering rate is 4.7% from the initial concentration. When the so-called hypercholesterolemia cases where the initial concentration is not lower than 220 mg/dl are taken into consideration, the numbers of the cases are ten and their initial concentration is 246 + 26 mg/dl. The concentrations after four, eight, twelve and sixteen weeks are 230 24, 226 + 15 232 + 16 and 229 a 18 mg/dl, respectively. Thus, after eight and twelve weeks, there are significant lowering (P < 0.05); after four and sixteen weeks, there are lowering tendencies. The rate of lowering in the sixteenth week against the initial concentration is 6.9Z. It is characteristic that the lowering is observed from an early stage of the fourth week and continues thereafter. 2. Effect of the pharmaceutical on neutral fat (Tables 4 and 5). Iihen all cases tested are taken into consideration, the initial concentration is 174 + 76 mg/dl and after four, eight, twelve, and sixteen weeks, they are 179 + 89, 172 + 84, 176 + 82 and 168 i 69 mg/dl, respectively. Thus significant lowerings are observed after eight weeks (P < 0.01) and sixteen weeks (P < 0.05). When the hypercholesterolemia cases where the initial concentration is not lower than 140 mg/dl are taken into consideration, the initial concentration is 217 i 54 mg/dl and the concentrations after four, eight, twelve and sixteen weeks are 227 -' 69, 207 : 84, 210 A 80 and 201 + 63 mg/dl, respectively. Thus, significant lowering (P < 0.01) is observed after eight weeks and, after sixteen weeks, the rate of lowering from the initial concentration is about 7.4Z. 3. Effect of the pharmaceutical on HDL cholesterol (Tables 6 and 7). When all cases tested are taken into consideration, the initial concentration is 40 - 6 mg/dl and, after four, eight, twelve and sixteen weeks, the concentrations are 44 * 8, 44 + 6, 45 * 7 and 46 + 7 mg/dl and all show significant increase (four weeks, P < 0.05; eight weeks and sixteen weeks, P < 0.001; twelve weeks, P < 0.01). When low HDL cholesterol level group where the initial concentration is not higher than 40 mg/dl is taken into consideration, the initial concentration is 36 i 4 mgidl and, after four, eight, twelve and sixteen weeks, the concentrations are 41 + 9, 41 + 5, 42 # 6 ant 43 # 5 mg/dl. Thus, after four weeks, an increasing tendency is observed and then significant increase is seen (eight weeks, P < 0.01; twelve weeks, P < 0.05; sixteen weeks, P < 0.01). As obvious from the above-given clinical results, an increasing action of the present invention pharmaceutical against HDL cholesterol concentration is remarkable. In cases where KDL cholesterol is low, the effect is especially strong and the utility is much more expected as compared with the conventional lipid metabolism improving agents known in the art. Such an increasing action is probably due to lowering action for TG or to metabolism acceleration of VLDL and, in addition, due to synthesis of apoproteins caused by, for example, adenos ine. The mixing ratio of horse chestnut seed extract, oxyethophylline and adenosine used in the present invention may optionally be set and the ratio of 15:55:1.5 is particularly preferred. Owing to its characteristic properties, the present invention pharmaceutical is preferably administered by capsules. It is preferred that the dose of the present invention pharmaceutical is about six capsules a day (each capsule contains 71.5 mg) when the mixing ratio is as given above. However, the dose may be increased or decreased depending upon the symptoms. The present invention pharmaceutical is available in market as "Apoplectal" (Registered Trade Mark) as a remedy for apoplexy and circulation disorder and is widely used. Therefore it is quite easily obtainable. Acute toxicities of the present invention pharmaceutical are as given in Table 8 and are quite safe. When this pharmaceutical is administered per os to rats (both male and female) at 50, 200 and 500 mg/kg for continuous ninety days, no abnormality is observed in body weights, amounts in taking feed and water, weights in organs, blood, and pathoanatomic observations except that, in a group administered with 500. kg/mg, an increase in urine is noted. table 1 Total Cholesterol Neutral Fat HDL Cholesterol Case Age Sexu- Initial 4 8 12 16(weeks) Initial Con- 4 8 12 16(weeks) Initial Con- 4 8 12 16(wks) Number ality Conen centration centration No. 1 45 M 196 200 208 204 206 196 200 208 204 206 38 30 40 39 40 2 43 M 214 177 188 182 181 214 177 188 182 181 34 34 38 40 42 3 40 M 192 178 180 195 188 192 178 180 195 188 42 40 46 54 50 4 40 M 178 166 164 156 161 178 166 164 158 161 34 44 42 46 50 5 45 M 158 196 102 189 186 158 106 182 180 188 30 64 48 56 52 6 42 M 159 177 164 166 160 159 177 104 160 108 34 48 46 45 44 7 69 M 243 232 221 226 224 243 232 221 226 224 40 40 42 40 44 8 56 F 223 218 109 227 218 223 216 209 227 218 46 50 50 50 50 9 32 F 102 170 176 173 174 182 170 176 173 174 42 40 44 44 44 10 65 F 226 202 214 221 193 249 202 214 221 193 38 32 38 40 38 11 45 F 286 269 251 264 258 286 269 251 254 258 28 30 32 34 38 12 26 M 141 145 132 132 142 233 202 216 210 218 41 44 43 45 48 13 43 M 246 210 221 233 245 141 145 132 132 142 39 40 38 32 42 14 46 M 132 124 126 130 128 246 210 221 233 245 44 46 50 54 66 15 33 M 223 240 232 236 234 132 124 126 130 128 40 40 43 46 44 16 67 M 279 255 230 244 237 223 240 232 236 234 48 44 46 45 45 17 61 F 220 216 220 219 220 182 156 129 143 136 46 55 51 53 52 18 58 F 223 224 222 223 223 98 81 90 94 38 32 42 37 40 38 19 62 F 178 183 169 176 173 189 105 96 96 100 53 57 55 54 55 20 43 F 268 263 250 253 248 171 210 152 105 169 48 48 44 48 46 Table 2. Total Cholesterol (mg/dl) (all groups) (n = 20) Initial Con- Four Eight Twelve Sixteen thereafter centration Weeks Weeks Weeks Weeks Average 211 i 45 202 t 38 199t36 203 38 201i36 P - 0.1154 0.0112* 0.0661 0.0566 (*: P < 0.05) Table 3. Total Cholesterol (mg/dl) (hypercholesterolemia group with not less than 220 mg/dl) (n = 10) Initial Con- Four Eight Twelve Sixteen thereafter centration Weeks Weeks Weeks Weeks Average 246 t 26 230 + 24 226+15 232#16 229-18 P - 0.0673 0.0140* 0.0462* 0.0527 (*: P < 0.05) Table 4. Neutral Fat (mg/dl) (all groups) (n = 20) Initial Con- Four Eight Twelve Sixteen centration Weeks Weeks Weeks Weeks thereafter Average 174 : 76 179+89 172t84 176+82 168*69 P - 0.0963 0.0064** 0.0612 0.0304* (*: P < 0.0D) (**: P < 0.q1) Table 5. Neutral Fat (mg/dl) (group of cases with high neutral fat blood symptoms with not less than 140 mg/dl) (n = 18) Initial Con- low Eight Twelve Sixteen centracion Weeks Weeks Weeks Weeks thereafter Average 217 * 54 227i69 207+84 210+80 201+63 P - 0.1371 0.0088** 0.0692 0.2742 (**: P < 0.01) Table 6. HDL cholesterol (mg/dl) (all groups) (n = 20) Initial Con- Four Eight Twelve Sixteen centration Weeks Weeks Weeks Weeks thereafter Average 40 + 6 44i8 44+6 45#7 46#7 P - 0.0268* 0.0008**.* 0.0012** 0.0003*** (*: P < 0.05) (**: P < 0.01) (***: P < 0.001) Table 7. HDL Cholesterol (mg/dl) (group of cases with low HDL cholesterol concentrations of not more than 40 mg/dl) (n = 11) Initial Con- Four Eight Twelve Sixteen centration Weeks Weeks Weeks Weeks thereafter Average 36#4 41#9 41#5 42#6 43#5 P - 0.0866 0.0045** 0.0182* 0.0010** (*: P < 0.05) (**: P < 0.01) Table 8. Acute Toxicities of the Present Invention Pharmaceutical (LD50 -.g/kg) (Horse Chestnut Seed Extract: Oxyethophyline:Adenosine=15:55:1.5) Administration Routes per os intraperitoneal Animal (Mice) # 1437 411 e 1485 391

Claims: CLAIM: Lipid metabolism improving agents exhibiting an action of increasing high density lipoprotein cholesterol in blood, characterized by that, containing horse chestnut seed extract, oxyethophylline and adenosine therein.

Inventors: KUMAGAI, AKIRA, SAITO, YASUSHI
Applicants: KLINGE PHARMA GMBH, NIPPON SHINYAKU COMPANY, LIMITED
Application year: 1983
Main classification: A61K35
IPC codes: A61K36, A61P3, A61K31