Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-27
2001-06-19
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06248778
ABSTRACT:
SPECIFICATION
The invention relates to a drug for treating or preventing intrahepatic cholestasis.
Cholestasis is a syndrome caused by dysfunctional bile flow. A distinction is made between extrahepatic and intrahepatic cholestasis. Extrahepatic cholestasis is usually caused by a bile duct stone or a pancreatic carcinoma. In the case of intrahepatic cholestasis there is congestion in the bile ducts. The most common causes of intrahepatic cholestasis are viral and other hepatitides, drugs used to treat cancer, for example, and alcohol-induced liver damage. Less common causes are primary biliary cirrhosis, cholestasis during pregnancy, and other diseases.
Extract from the leaves of artichokes (
Cyanara scolymus
L.) is known for its choleretic effect in the case of dyspeptic complaints. Genuine choleretic agents, which artichoke extract is considered to be, lead to an increase in the quantity of bile acids, whereas non-genuine choleretic agents lead to an increase in the volume of bile fluid. In addition to its choleretic effect, artichoke extract is described in the literature as having an anticholestatic effect (Ärzte-Ztg., 15th vol., 1996, page 16). Until now, however, it was not known which active agent is responsible for the anticholestatic effect.
The object of this invention was thus to provide a drug which contains an active agent with an anticholestatic effect of defined efficacy.
This object was established according to the invention by means of a drug for treating or preventing intrahepatic cholestasis, which is characterized by containing as active agent at least one compound of the general formula I,
where R, R
1
and R
2
are independent of each other and can each ═H, C
1-2
-alkyl or C
1-3
-acyl, R
3
═H or OR
4
and R
4
═H, C
1-2
-alkyl or C
1-4
-acyl, and there is a single or double bond between positions 2 and 3, or a physiologically acceptable salt thereof.
It was found that the compounds of formula I have an anticholestatic effect and are therefore suitable for treating intrahepatic cholestasis. An intrahepatic change in the bile ducts can be prevented or reversed with compounds of formula I, so that prophylactic treatment to prevent intrahepatic cholestasis is also possible.
With the knowledge that compounds of formula I have an anticholestatic effect, it is possible to manufacture a standardized drug with a predetermined and defined effective dose. With the drug disclosed, moreover, it is possible to achieve a fast and accurately targeted effect.
Extracts of artichoke, especially dry extracts of artichoke leaves such as are commercially available from Sertürner Arzneimittel under the name HEPAR-SL® forte, contain numerous compounds which could be potential active agents. Until now, it was not possible to attribute the anticholestatic effect of the extract to any particular one of the many compounds contained therein. It was thus difficult to manufacture a standardized drug from the artichoke extract.
It has now been found that it is compounds of formula I that show an anticholestatic effect. Free compounds with the formula I, especially luteolin, are present, if at all, in only small amounts of <0.08 wt %, expressed in terms of the overall extract, in artichoke extract. Moreover, there is no indication in the prior art that of all possible compounds precisely those of formula I might show an anticholestatic effect.
Known components of artichoke extract are caffeic acid, chlorogenic acid, cynarine (1,5-di-O-caffeoyl-chinic acid), 1,3-di-O-caffeoyl-chinic acid, scolymoside and cynaroside (luteolin-7-O-glucoside). Cynaroside (luteolin-7-O-glucoside) is cleaved in the gastrointestinal tract, thus liberating luteolin. However, cynaroside is also found in many other plants for which no such anticholestatic effect has been reported. Cynaroside itself shows no anticholestatic effect.
Anticholestatic and choleretic agents work quite differently. A condition of cholestasis which is frequently used as a model and is triggered by taurolithocholate causes an easily detectable membrane change. Known choleretics are generally not able to prevent or reverse this membrane modification (Layden et al., Gastroenterology 50 (1977), 2305 to 2312). Dehydrocholic acid, for example, which is known to have a choleretic effect, had no effect on a taurolithocholate-initiated cholestasis. Thus the use of compounds which are effective as choleretics are generally not suitable for treating cholestasis.
In compounds of the general formula I in which R, R
1
and/or R
2
are H, there is a hydroxyl group at the corresponding positions 5, 7 and/or 4′ of the flavone or flavanone basic structure. For the case that R, R
1
and/or R
2
stand for an C
1-2
-alkyl group, especially a methyl or ethyl group with methyl being particularly preferred, there is an ether grouping at the corresponding positions. If R, R
1
and/or R
2
stand for a C
1-3
-acyl group, there is an ester group at the corresponding positions. Preferred acyl groupings are a formyl radical, an acyl radical, a propionyl radical and a lactyl radical. Compounds in which there is a single bond between positions 2 and 3 have the basic structure of flavanone
while compounds in which there is a double bond between positions 2 and 3 have the basic structure of flavone.
Physiologically acceptable salts of a compound of formula I comprise all physiologically harmless, salt-like compounds which include the compound of formula I in ionic form, together with a counterion. Acid-addition salts constitute particularly good examples of such salts.
It is preferable if the drug of the invention contains a compound with the general formula I, in which R, R
1
and/or R
2
═H. Compounds of this kind, in which there are free -OH groups, especially at positions 5 (corresponds to radical R) and/or 7 (corresponds to radical R
1
), were found to exhibit particularly high efficacy.
It is also beneficial if the drug of the invention contains a compound with the general formula I, in which R
2
is an —OH group.
An especially high level of efficacy was found in the case of luteolin (R═H, R
1
═H, R
2
═H, R
3
═OH, there being a double bond between positions 2 and 3), apigenin (R═H, R
1
═H, R
2
═H, R
3
═H, there being a double bond between positions 2 and 3), and naringenin (R═H, R
1
═H, R
2
═H, R
3
═H, there being a single bond between positions 2 and 3). The greatest preference is given to luteolin. The compounds luteolin-7-O-glucoside, 3′, 4′-hydroxyflavone, genistein and daidzein showed no anticholestatic effect.
The drug of the invention preferably contains compounds of formula 1 in a quantity of >0,1 wt %, more preferably >1 wt %, more preferably still >10 wt % and, most preferably of all, >20 wt %. However, it is also possible to make up drugs which have an even higher content of at least one compound of formula I, in particular >50 wt % expressed in terms of the overall weight of the drug.
To effectively treat or prevent an intrahepatic cholestasis, patients are generally given a daily dose of 10 to 1 000 mg of a compound with the general formula I. It is of advantage to administer a daily dose of at least 20 mg, preferably at least 50 mg and best of all at least 100 mg of a compound with the general formula I, and, at the most, a daily dose of up to 750 mg, preferably up to 500 mg and best of all up to 300 mg.
If desired, the drug of the invention can be formulated with physiologically acceptable auxiliaries and carriers. Such auxiliaries must be physiologically harmless and must not impair the efficacy of the active agents. Suitable auxiliaries are known to those versed in the art, and include, for example, fillers, binders and lubricants, for example microcrystalline cellulose, amylose, lactose, mannitol, talcum, magnesium stearate, starch, microdispersed magnesium oxide, silicon dioxide, sodium carboxymethyl starch, polyvidone, macrogol etc.
The drug disclosed in the invention can be produced in all administrable drug forms known to those
Arent Fox Kintner & Plotkin & Kahn, PLLC
Reamer James H.
Sertürner Arzneimittel GmbH
LandOfFree
Anticholestatic effect of luteolin does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Anticholestatic effect of luteolin, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Anticholestatic effect of luteolin will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2532580