DE1692039A1 - New uses of the alkaloid Raubasin and corresponding preparations - Google Patents

Description

The present invention relates to new types of use and Dosages of the alkaloid Raubasin (= * Ajmalicin = «^ -Yohimbine - Tetrahydroserpentine) for the treatment of peripheral circulatory disorders, preferably venous diseases, and corresponding preparations. The new types of use and doses of the Raubasin are based on a previously unknown and surprising mechanism of action of this alkaloid.

It is known that Raubasin lowers the resistance of the arterioles; see Kroneberg, Arch. f. exper. Path, and Pharm. 255, 72 (1958). Raubasin is therefore used for the therapy of arterial high pressure, in which the arterial resistance of all vascular areas is increased; see Bachmann, Arzneimittelforsch. 10, 815 (1960); Heintz and Losse, Dt'sch. med. Wschr. 79 » 1448 (1954) and Thiele, Med. Mschr. 11, 645 (1957) · For this reason, the therapy of peripheral circulatory disorders has also been recommended; see Lian, La Presse Medicale 65 » No. 66, p. I477 (1957) 5 Dorst and Delange, La Vie Medicale, Medecine Therapeutique No. 46 (1965) "Perrin, Gazette Medicale de France No. 7 (1965) and Pluvinage, ibid. No. 22 (1965). Here, Raubasin was administered orally in the form of tablets in doses of 1 to a maximum of 5 ng. Higher dosages were probably avoided because Raubasxn was believed to be a pure, general arterial vasodilator. For the therapy of peripheral circulatory disorders, however, general arterial vasodilation is only of doubtful value. In the case of circulatory disorders, the arterial resistance is increased only in a circumscribed vascular area. By widening all vessels, the blood is primarily directed through the healthy vascular areas, which can expand more than the diseased ones. The blood pressure drops, so that the diseased vascular areas are less well supplied after administration of an arterial vasodilator than before; See Hess, "Die obliterierenden Gefäß Krankungen", Urban and Schwarzenberg 1959.

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¹ 1 nterlagen (Art. 7, Paragraph I, Paragraph 2, No. I, Clause 3 of the amendment Q ··. * 4.9.18β7)

Surprisingly, it has now been found that Raubasin has the tone of the veins increases, although it lowers that of the arteries, and that too "at higher doses do not cause the feared drop in blood pressure, which worsens the blood supply to the diseased organs. This effect leaves

eich daduroh explain that the constriction of the capacitive vessels mobilizes the blood deposits and that the increased supply of blood to the heart increases the cardiac output. The increased cardiac output compensates for the peripheral arterial vasodilation and prevents a drop in blood pressure. In experiments on conscious dogs and on healthy subjects it was found that the increase in cardiac output and decrease in vascular resistance are balanced in such a way that the mean arterial pressure does not decrease. A deteriorated blood supply to organs with diseased vessels is excluded. It is certain that the area supplied by the diseased vessels also benefits from the increased blood circulation in accordance with the vascular reserve that is still present. As a result, Raubasin is superior to a pure vasodilator in the treatment of circulatory disorders. The aforementioned toning of the veins also opens up some other indications for the Raubasin in which the venous system itself is diseased, such as B. Thrombosis prophylaxis, varices prophylaxis, ulcus cruris varicous sum and the therapy of non-cardiac edema.

One of the novel uses of the alkaloid Raubasin according to the invention is accordingly the treatment of peripheral circulatory disorders, in doses of at least 10 ng, preferably more than 30 mg per day orally. Furthermore, we have found that you can deal with peripheral circulatory disorders Raubasin can also be administered intravenously, intraarterially or intramuscularly. Dosages of IO up to 40 mg per day generally well proven; however, in particularly severe cases, such as arterial embolism, the dosage of Raubasin can be reduced can also be increased to 100 to 200 mg (IV infusion within 18 hours).

The present invention accordingly also relates to pharmaceuticals Preparations consisting of Raubasin and a sterile injection medium or a solid pharmaceutical carrier, with pro

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Dosage unit at least 10 mg Raubasin are present - r η ^ nQQ

The injection medium used is preferably water, which the usual additives for injection solutions such as stabilizers, Solution initiator, contains buffer. Such additives are ζ-B. Tartrate and citrate buffer, ethanol, complexing agents (such as ethylenediamine-tetraacetic acid and their non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Festivals Carriers are e.g. starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicas, higher molecular fatty acids (such as Stearic acid), gelatin, agar-agar, calcium phosphate ,. Magnesia stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols); preparations suitable for oral administration may contain flavorings and sweeteners if desired. Since Raubasin has a certain sensitivity to light and after some If it turns brown over time, preparations containing Raubasin will also turn brown over time. This can be prevented by using the preparations stored in brown glass containers or - in the case of solid preparations - produces coated tablets.

For example, a solution with the following composition can be used as an injection solution use:

OHlGiNAL 109828/1786

U Predatory basin 10.00 1692039 Tartaric acid 10.00 mg Citric acid 12.25 mg spirit 32.00 mg liquid polyethylene oxide MG about 400 mg ("Lutrol 9") 200.00 Disodium salt of ethylenediamine " mg tetraacetic acid ("Titriplex III") 0.20 Sodium metabisulfite 0.50 iög Sodium hydroxide 1.63 mg least. water 3.00 log ml

For a combination of systemic effects with a "special." intensive local vasodilation can take up to 3 ampoules (30 mg) Raubasin can be injected intra-arterially into the femoral artery. This leads to a particularly strong increase in blood flow to muscles and skin in the diseased organ.

For oral dosing ■ tablets are made of the following composition used:

Raubasin 10.00 mg

Strength 30.00 mg

Milk sugar 30.00 mg

Talc 6.00 mg

Magnesium stearate 0.20 mg

Agar-agar 3 »80 mg

3-4 coated tablets are given for long-term treatment.

In the clinical trials with Raubasin, the following were in particular Effects observed:

l) Patients with congestion due to venous diseases show, according to Raubasin, a regression of the edema, which increases again when the Raubasin medication is interrupted, and when the medication is renewed Use of Raubasin to regress again.

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2) patients with congestion based on diseases of the venous system show, according to Raubasin, an almost complete regression of the congestion, so that wearing rubber stockings is superfluous became.

3) A varicose leg ulcer has been caused in a number of cases Predatory basin favorably influenced; the ulcers healed.

4) When treating fractures, the edema forms faster back if the patient is treated with Raubasin at the same time.

5) Patients with malignant tumors who show pronounced edema states in the postoperative state show a noticeable flushing out of these edema and regression of the local swelling Λ states.

This results in the following new indications for Raubasin:

1) Thrombosis prophylaxis:

Raubasin leads to flow acceleration

2) variceal prophylaxis:

The increase in venous tone counteracts the formation of varices. Ea comes to the flow acceleration in the extended Veins. This lacks the passive stretch stimulus that leads to the formation or intensification of varices.

3) Varicose leg ulcer:

Through flow acceleration and increased toning in the venous Circulatory area there is an outflow of the edema. This results better blood flow to the tissue, which avoids orural ulcers or the healing of existing ulcers is supported.

4) Therapy of non-cardiac edema:

In conditions after fractures, venous thrombosis, tumors and

other venous outflow obstacles it comes from increased

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venous tone versus tissue pressure to open venules. This results together with the Raubasin total effect an increased blood flow with flow acceleration and drainage of the edema.

The effect of the predatory basin on the venous tone and the entire circle · » The run was precisely measured by the following experiments on dogs and healthy people

l) Tests on anesthetized dogs

In 5 hybrid dogs weighing 9-14 kg, the following were measured and recorded synchronously under morphine-pernoctone anesthesia: the arterial pressure in the aorta, the central venous pressure (at the level of the right atrium), the peripheral venous pressure in a femoral vein with electrical pressure transducers; the arterial flow time volume in the abdominal aorta in front of the iliac fork and the venous flow time volume in the caudal vena cava just above the junction of the iliacal veins with electromagnetic flow meters. Raubasine was dissolved as phosphate in 5i5 $ aqueous glucose with the addition of $ 5> dimethylformamide. 2 mg / kg were injected iv as base.

The results are compiled in the following table 1:

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Table 1

Circuit parameters Control ¹
.vrte j ₁₀ 102 Seconds
20th after iv
30th 73.0 . In ^ ekti
40 on tone 2
50 70.0 66.2 , 0 mg / kg Raubasin
60 ■ 120 156 1 P _a f vm Eb J 96 ( , 101 99 73.2 94 97 68.5 64.0 95 j 92 65.0 2 ^Pr eor / " ^nln " V 141 -koine 10 sec. Me a + 30 + 19 + 14 63.5 3 y _a / ml · 10 ββο "^ 7 46.5 56.5 68.0 + 35 + 20 + 13 + 6 4th V _v / al · 10 · β <Γ ¹ 7 46.0 70.0 79.5 + 0.2 - 1.5 - 2.2 62.3 +12 5 P _V2 / * ■ » ^H ₂ ° -7 + 6 +12 + 42 + 5 + 1 - -1 ' 61.0 - 1.5 6th P _vp Γ ** H ₂ O 7 + 7 +50. + 46 + 13 + 6 7th YV / ml x 10 sec "V
TA - 0.5 +13.5 + 11.5 + 14 8th 1? - x> / "mm H ₀ O J
* vp * vz * ■ 2 «- ¹ + 1 +38 + 4 -1.3 + 1

Patellef; Effect of 2 _T 0 m <r / kg Raubasin iv "in anesthetic dogs (Mo.-Pernocton), measured using the following circulatory parameters: 1 ρ - art. Mean pressure id aorta 2 Pr» heart rate; 3 V ■ art. Plow id aorta afcdom .j 4 V ■ venous plow id Vena cava caud.j 5 "p - mean central venous pressure (at the level of the right atrium) j 6 " ^ ■ mean

peripheral Venous pressure (i.d.V. femor.). 3 and 4 result in art. Tributary and ven. Outflow in the lower river area] Extremists. 7 V - V - Plow difference between ven. Drain and art. Inflow j 8 ΐ> - * ρ - pressure gradient between periph. and centr. Venous pressure. Mean values from 5 examinations. ■ - - ■

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CD CO K) CZ) OJ to

As can be seen from Table 1, it was already 10 seconds. after Injection the arterial inflow and the venous outflow increased. However, this increase in blood flow showed arterial and venous one clearly different course, as the difference between venous outflow and arterial inflow shows (line 7): Up to 20 seconds. after Injection, the venous outflow was greater than the arterial inflow. If one compares the pressure differences between peripheral and central Venendruok shows that, in synchronism with the relatively higher venous outflow, the peripheral venous pressure also rose more sharply than the central one was (line 8). Such a rapid increase in the peripheral venous pressure is due to a constriction of capacitive vessels, i. H. on attributed to an increase in venous tone. This mechanism causes a primary mobilization and displacement of blood from the capacitive Vessels in the direction of the lower venous pressure, i.e. in the direction of the heart, which then increases its ejection volume according to the excess supply enlarged. Only in the second place does an adaptive dilatation of the arterial resistance vessels set in, caused by the direct effect of Raubasin. In the case of the primarily increased blood time volume, however, results no decrease in arterial pressure.

The venous tone or expansion resistance of the vessel wall is proportional to the increase in pressure and inversely proportional to the increase in volume per unit of time and can be mathematically defined as the volume elasticity coefficient E dur.ch:
ven

Time

The experimental set-up described above allowed the volume elasticity coefficient to be investigated before, 2 and 30 minutes after intravenous injection of 2 mg / kg of Raubasin by temporarily occluding the draining vein.
(The results are compiled in Table 2 :)

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IAD ORIGINAL Tabel

Control values minutes after i.V. injection of 2.0 mg / kg Raubasin

30th

Before I 5 see after closure Before I 5 see after
Closure

+ 5

+ + 7

58

before '5 sec after closure

+ 3 I +41

Δ VoI / "ml x 5 sec" ¹ J,

24-37

33

ven

H ₂ O x 5 sec

ml

0.96 1.38 - "-

1.15

Tab. 2 - Determination of the venous elasticity coefficient (E) before, 2 and 30 minutes after iv injection of

2.0 rag / kg raubasin.

-peripheral venous pressure before and 5 seconds after occlusion; 2. Increase "in the peripheral venous pressure

within 5 sec; 3. Volume increase in 5 see.} 4r E _ven peripheral veins, defined as

Volume elasticity coefficient of

CD CD

ro

CaJ

CD

Ao

From table 2, line 4, it can be seen that the expansion resistance, d. H. the venous tone increased under the action of the alkaloid and that this increase was still detectable 30 minutes after application.

2) experiments on conscious dogs and healthy people ,

In conscious dogs , the cardiac output in the aorta aaoendens was continuously recorded with chronically implanted electromagnetic flow meters. In terms of measurement technology and implementation, the flow measurement method corresponds to the proposals of Kolin and Kado.Proc * Nat. Acad. May be. .4Jj ₁ , 1312 (1959) as well as Khouri and Gregg.J. appl. Physiol. 18, 224 (1963) using flow meters, the company Biotronex Inc., since a calibration of the flow meters is very difficult in conscious animals, for methodological reasons, the cardiac output and the dependent values, such as stroke volume and peripheral resistance in fo of the output values were expressed.

Catheters were placed in the aorta to measure the arterial blood pressure chronically implanted. The mean arterial pressure was recorded using a Statham strain gauge type P 23 Db.

Catheters from the V. jugalaris advanced to the level of the heart and heal calmly.

In humans , the blood pressure on the upper arm was measured according to Riva-Rocci, the cardiac output according to Wezler and Böger, Naunyn-Schmiedeberg's Arch. Exp. Path, and Pharmak. 184 , 482 (1937).

The results of the dog experiments are summarized in Table 3 and in Fig. 1 and 2 are the circulatory analyzes in dogs and humans against = superior. In the dog, several analyzes were carried out at short intervals during the first minute after the injection. In this first phase of the substance's effect there is a considerable one Increase in cardiac output with predominant involvement the heartbeat volume, while the heart rate increases only slightly. Synchronous with this first increase in cardiac output a remarkable increase in pressure is observed in the right atrium.

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Fig. 1 contains the mean values from 16 experiments with conscious dogs after i.v. injection of 5 mg / kg Raubasin, Fig. 2 shows the mean values 15 experiments on healthy test persons after i.v. injection of 20 mg of Raubasin each. The abbreviations used in the figures have the following meaning:

P = blood pressure (mm Hg)

Fr = heart rate cor

V = cardiac output aor

W - peripheral vascular resistance

P,, s = central venous pressure atr.dextr.

V = heartbeat volume cor

P / p = systolic / diastolic pressure (mn Kg)

S 4 /

BAD ORiQINAL

10 9 8 2 8 / 1/78 β

Tabel

- ■ ■ 2 Circulatory parameters Control
values Seconds
20th after injections
40 Lon
60 Minutes r
10 laugh injections
20th on
30th 3 P _a ZI ™ ^{111 H} ? -7 98 96 100 98 95 97 '108 4th ^Pr cor ^ ⁱⁿ "-7 135 148 142 136 130 · 142 136 5 aor * - ' ^J 100 158 119 132 138 134 136 6th Y /> 7
cor * · '■ _. 100 145 114 122 142 128 134 w / ^ J 100 62 86 75 70 73 81 CJ
(O
OP * atr. dextr. / ™ V ^ + 0.2 . + 4.9 + 4.0 + 2.7 + 0.7, + 0 + 1.1

Tab. 3 - Circulatory effects: from 5.0 mg / kg of predatory basin in conscious dogs. 1 ρ Art. Medium pressure}

For heart rate j cor

Vessel resistance} mean values} η »

dextr.

V cardiac output}
aor

Pressure in the right gate courtyard

.. heartbeat volume;

If one takes into account the stability of the mean arterial pressure, the In the absence of a significant increase in frequency and the short-term increase in venous pressure, then there is an increase in cardiac output primarily a consequence of the mobilization on the venous side of the circulatory system and blood offered to the heart. The diminution of the peripheral Resistance is therefore predominantly pressure-passive.

Waking through a short counter-regulatory phase becomes a relatively stable "circulatory situation achieved, the characteristics of which increased cardiac output with decreased peripheral vascular resistance and arterial pressures are unchanged.

The increase in blood volume as a result of increased venous Raubasin distinguishes this offer from the multitude of so-called vasodilators insofar as it does not result in a rightly feared lowering of blood pressure comes and thus optimal conditions are given for the promotion of a pathologically reduced blood flow.

In humans , 20 mg Raubasin were given iv and circulatory analyzes were carried out at longer intervals. The result was basically the same as beinHund. The blood pressure did not drop. Corresponding to the increased stroke volume, only an increase in the amplitude of blood pressure was observed 3 minutes after the injection. The central venous pressure was not measured, but in view of the constant mean arterial pressure it can be assumed with a probability bordering on certainty that the increase in cardiac output is also the result of an increased blood supply in humans.

Claims (8)

Claims 1. Use of the alkaloid Raubasin for the manufacture of medicines for the treatment of venous diseases. 2. Use of the alkaloid Raubasin according to claim 1 for the production of drugs for thrombosis and variceal prophylaxis, as well as for the treatment of leg ulcers and non-cardiac edema. 3 · Use of the alkaloid Raubasin according to claim 1 for production of drugs that can be administered intravenously, intraarterially or intramuscularly for the treatment of peripheral circulatory disorders. 4 · Use of the alkaloid Raubasin according to claim 1 for production of orally administered drugs for the treatment of peripheral Circulatory disorders, characterized by a content of at least 10 mg, preferably 30 mg Raubasin. 5 Pharmaceutical preparations for the treatment of venous diseases, characterized by a content of predatory basin. 6. Pharmaceutical preparations for thrombosis or variceal prophylaxis as well as for the treatment of leg ulcers and non-cardiac ulcers Edema, characterized by a content of robbery. 7. Pharmaceuticals that can be administered intravenously, intraarterially or intramuscularly Preparations for the treatment of peripheral circulatory disorders, characterized by a content of raubasin. 10982 8 / 178S BATH ORIGINAL 8. Orally applicable pharmaceutical preparations for the treatment peripheral circulatory disorders, characterized by a content of at least 10 mg, preferably 30 mg Raubas in. ·· 9- Pharmaceutical preparations consisting of Raubasin and one sterile injection mediura or a solid pharmaceutical Carrier, with at least 10 mg Raubasin per dosage unit available. 109828/1788 iAD ORfQINAi