DE2627124A1 - Medicaments for thrombosis therapy - contg. penicillins or cephalosporins - Google Patents

Abstract

Medicaments for prophylaxis and treatment of thrombosis contain penicillin- or cephalosporin-type antibiotics or the beta-lactam cpds. from which they are derived. The medicaments, which inhibit thrombocyte aggregation by blocking the plasmatic aggregation cofactor (factor VIII antigen), have low toxicity and are compatible with conventional anticoagulants. Their effect can be controlled by administering a factor VIII concentrate.

Description

"Medicines for the prevention and treatment of thrombosis"

To avoid arterial thrombosis it is important to prevent platelet aggregation to be able to reduce in vivo down to a certain value. Thrombosis in arteries consist for the most part of platelet aggregates. Accordingly, connections are which are able to control platelet aggregation with good tolerance, has become particularly interesting for therapy. From the existing connections Acetylsalicylic acid is particularly characterized by a long-lasting and intense Influencing platelet aggregation. It has a direct impact on education of thromboxanes in the platelets and is based on the current state of knowledge not influenced by plasmatic factors. The thornbocyte aggregation to ti on in vitro and in vivo is not only dependent on the platelet qualities themselves, but also from a plasmatic cofactor, which is currently known as the factor VIII antigen, co-controlled and co-shaped; see E.M. Barrow and J.B. Graham, Physiologleal Reviews, Vol. 54 (1974), pages 23-74.

The invention is based on the object of creating medicaments that influence or block this cofactor of platelet aggregation, and which are thus suitable for the prevention and treatment of thrombophilic diathesis are. The solution to this problem is based on the surprising finding that ß-lactam ring antibiotics the penicillin and cephalosporin series and the corresponding base bodies, namely 6-hminopenicillanic acid, 7-aminocephalosporanic acid and 7-amino-3-methyl-3-cephem-4-carboxylic acid, and their salts with acids and bases depending on a time factor of some Minutes to block the plasmatic cofactor of platelet aggregation. These Blockage can be prevented by an intensive supply of the factor VIII antigen, e.g. in Fonn factor VIII concentrate, can be reversed. So it is in one certain handling under clinical conditions controllable.

Below is the experimental method of suppressing the by Ristocetin-induced platelet aggregation outlined.

Blood is taken from a cubital vein and with a 3.8 percent Sodium citrate solution diluted 10 times.

Then thrombocyte-rich plasma is obtained by slow centrifugation produced for 10 minutes at 800 to 1000 rpm. After lifting off the thrombocyte-rich Plasmas will the remainder centrifuged at 3000 rpm for 20 minutes. Included a relatively thrombocyte-free plasma is obtained. The thrombocyte-rich plasma is diluted with the obtained relatively platelet-free plasma to the platelet count set to 200,000 / mm³. With the thrombocyte-rich and relatively thrombocyte-free Plasma is calibrated using a platelet aggregometer (Born, Michal 4 type). Platelet rich Plasma is based on 10% light transmission and relatively thrombocyte-free plasma set to 100% light transmission.

1 ml of thrombocyte-rich plasma is used for 2 minutes for the individual test incubated at 370. Thereafter, the platelet-rich plasma is in the aggregometer mixed by means of a small magnet. After 30 seconds, use a pipette the aggregant, in this case 1.0 or 1.2 mg iftstocetin (Lundbeck, Sweden) added from a solution of 40 mg / nil. After adding the unit, a maximum aggregation recorded with a recorder.

After incubation of the platelet-rich plasma for 10 minutes with 1 mg of the compound to be examined per ml of plasma at 37 ° C or at room temperature after the addition of 1.0 or 1.2 mg ristocetin no or only a minimal amount occurs Aggregation, i.e. the light transmission is about 0 to 10%.

As ß-lactam ring antibiotics can be the usual, for shows in the Therapy used penicillins can be used. Spe- target Examples of these compounds are penicillin G, penicillin V, phenethicillin, Propicillin, phenbenicillin, penicillin 0, methicillin, oxacillin, cloxacollin, Dicloxacillin, elucloxacillin, quinacillin, nafcillin, ancillin, penicillin N, ampicillin, Betacin, Carbenicillin, Acidocillin, Amoxycillin, Ciclacillin, Epicillin, Indanylcarbenicillin, Ticarcillin, talampicillin and pivaloylampicillin, as well as their salts with acids and Bases. Furthermore, the basic body of these compounds, the 6-aninopeni cillan acid.

Specific examples of β-lactam ring antibiotics which can be used according to the invention of the cephalosporin series are cephalosporin C, cephaloridin, cephalothin, cephalexin, Cephaloglycine, Cephalo zin, Cephanon, Cephlnadin, Cephacetril, CepH.pirin and the corresponding ß-lactam base substances and their salts.

An advantage of the compounds mentioned for reducing the tendency to aggregate platelets in vitro and in vivo is that the compounds mentioned are practically non-toxic. Another advantage is that a combination with known compounds that are currently used for thrombosis prophylaxis and therapy, e.g. with heparin and dicoumarol derivatives such as hydroxycoumarin, acetylsalicylic acid, dipyridamole and its derivatives, sulfinpyrazone and chloroquine, is possible.

The medicaments of the invention can be used in conventional parenteral or Oraler Dariichungsfonii, for example in the form of injection preparations, tablets or powders.

The drug is delivered with a conventional carrier and / or diluent and / or additive added.

The invention also relates to a method of prevention and treatment of thrombosis or trombophilic diathesis in warm-blooded animals, which is characterized is that a warm-blooded animal to reduce the platelet aggregate i.on by acting on the pasasmic cofactor and thereby also on the interaction Endothelium and platelets sufficient amount of a ß-lactam ring antibiotic or of the corresponding ß-lactam base body administered orally or parenterally.

The thrombosis-preventing effect can be achieved by administering the drugs in daily doses of 1 to 15 g per normal weight patient (70 kg) in for example 3 subdivided doses can be achieved.

Among the advantages of the therapy it should also be mentioned that the medicinal substance also penetrates the endothelium, where the factor VIII A or the ristocetin cofactor is formed. So the antithrombotic effect can only show on the endothelium, i.e. it does not necessarily have to be associated with an inhibition of platelet aggregation in the plasma go in parallel.

The medicaments of the invention are also capable of factor VIII activity in vitro in the single-phase test system.

Claims (6)

Claims for medicinal products for the prevention and treatment of thrombosis, not indicated by a content of a ß-lactam ring antibiotic the penicillin or cephalosporin series or the corresponding ß-lactam ring base or their salt. 2. medicament according to claim 1, characterized by a content to penicillin G, penicillin V, phenethicillin, propicillin, phenbenicillin, penicillin O, methicillin, oxacillin, cloxacollin, dicloxycillin, flucloxacillin, quinacillin, Nafcillin, ancillin, penicicillin N, ampicillin, botacin, carbonicilin, acidocillin, Amoxycillin, Ciclacillin, Epicillin, Indanylcarbonicillin, Ticarcillin, Talampicillin or pivaloylampicillin or a salt of these compounds. 3. Medicament according to claim 1, characterized by a content of 6-aminopenicillanic acid or its salt. 4. Medicament according to claim 1, characterized by a content on cephalosporin C, cephaloridin, cephalothin, cephalexin cephaloglycine, cephalozin, Cephanone, cophradine, cephacetril or cephapirine or a salt of these compounds. 5. Medicament according to claim 1, characterized by a content of 7-aiflinocephalosporanic acid or its salt. 6. Medicament according to claim 1, characterized by a content of 7-amino-3-methyl-3-cephem-4-carboxylic acid or its salt.