US3564094A - Method of treating venous diseases - Google Patents

Method of treating venous diseases Download PDF

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Publication number
US3564094A
US3564094A US700875*A US3564094DA US3564094A US 3564094 A US3564094 A US 3564094A US 3564094D A US3564094D A US 3564094DA US 3564094 A US3564094 A US 3564094A
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Prior art keywords
raubasine
venous
pressure
blood
arterial
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US700875*A
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English (en)
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Karl Dietmann
Gunter Steinorth
Wolfgang Schaumann
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Roche Diagnostics GmbH
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Boehringer Mannheim GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine

Definitions

  • the instant invention relates to therapeutic compositions containing the alkaloid raubasine, which is also known as ajmalicine, -yohimbine and tetrahydroserpentine and methods of using the same for the treatment of peripheral circulatory disturbances and particularly for the treatment of venous diseases.
  • the alkaloid raubasine which is also known as ajmalicine, -yohimbine and tetrahydroserpentine
  • the new methods of use and dosage of raubasine as disclosed herein depend upon a previously unknown and surprising mechanism of the action of this alkaloid.
  • the present invention is also concerned with new pharmaceutical compositions in dosage unit form containing raubasine as active ingredient.
  • raubasine acts to reduce the resistance of the arterioles (Kroneberg, Arch. f. exper. Path. and Pharm., 233, 72/ 1958). Because of this effect, raubasine is used in the therapy of high arterial pressure in which the arterial resistance of all regions of the vessels is increased (Bachmann, Arzneistoffforsch., 10, 813/ 1960; Heintz and Losse, Dtsch, med. Wschr., 79, 1448/1954; and Thiele, Md. Wschr., l1, 645/1957).
  • raubasine has also been recommended for use in the therapy of peripheral circulatory disturbances (Lian, La Presse Medicale, 65, (66), 1477/1957; Dorst and Delange, La Vie Medicale, Medecine Therapeutique, N o. 46/ 1965; Perrin, ⁇ Gazette Medicale de France, No. 7/ 1965; and Pluvinage, ibid. No. 22/ 1965).
  • raubasine has been administered orally in the form of tablets at a dosage level of from l to at the most mg. Higher dosages have, apparently, been avoided because raubasine was considered to be a purely general arterial vasodilator.
  • a general arterial vasodilator is of no or only doubtful value.
  • the arterial resisance is only increased in a limited region of the vessels. Through a dilation of all of the vessels, the blood is, in particular, passed through the healthy regions of vessels which are able to dilate to a much greater extent than are the diseased ones.
  • the blood pressure thereby drops so that the diseased regions of the vessels are, following the administration of an arterial vasodilator, more poorly supplied with fresh ice blood than previously (Hess, Die obliterierenden Gefsserkrangungen, pub. Urban and Schwartzenberg, 1959).
  • raubasine is of value as a medicament in the treatment of conditions in which the venous system is itself diseased, as, for example, thrombosis prophylaxis, varicose prophylaxis, ulcus cruris varicosum and the therapy of edemas of non-cardiac origin.
  • one of the new methods of use, according to the present invention, utilizing the alkaloid raubasine is in the treatment of peripheral blood circulatory disturbances utilizing orally the raubasine in dosage of at least 10 mg. per day and preferably of more than 30 mg. per day.
  • raubasin in the case of peripheral blood circulatory disturbances, raubasin can also be administered intravenously, intra-arterially or intramuscularly.
  • dosages of 10 to 40 mg. of raubasine per day have, in general, proved to be very useful.
  • the dosage of raubasine can be further increased to -200 mg. (intravenous infusion within a period of 18 hours) without untoward results.
  • compositions comprising raubasine in admixture with a sterile, liquid injectable pharmaceutical carrier therefor or in admixture with a solid, or liquid, orally administerable pharmaceutical carrier therefor and in the form of a dosage unit containing at least l() mg. raubasine.
  • the preferred liquid carrier is water which may contain the conventional additives employed for injectable solutions, such as stabilizers, solubilizers and buffers.
  • Additives of this type include tartrate and citrate buffers, ethanol, complex-forming agents, such as ethylenediamine-tetraacetic acid and its nontoxic salts, and high molecular weight polymers, such as liquid polyethylene oxide, for viscosity adjustment.
  • the raubasine can also be administered orally in the form of a liquid, as, for example, in the form of a syrup containing the conventional additives such as stabilizers, flavoring agents, colorants, solubilizers, buffering agents, etc.
  • the syrups are preferably aqueous in nature but need not be so. It is also possible to provide the raubasine in the form of a highly concentrated solution or dispersion thereof in suitably prepared capsules.
  • the raubasine can also be administered in the form of tablets, capsules, powders, dragees and other like forms intended for oral administration.
  • the raubasine is provided in admixture with a solid pharmaceutical carrier.
  • solid pharmaceutical carriers there may be mentioned starch, lactose, mannitol, methyl cellulose, talc, highly-dispersed silicic acid, high molecular weight fatty acid, such as stearic acid, gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers, such as the polyethylene glycols.
  • Such compositions intended for oral administration can, if desired, also contain a llavoring and/or sweetening agent.
  • compositions containing raubasine should be formulated and/or packaged so that this phenomenon is avoided. This difliculty can be overcome either by providing the compositions in brown glass tubes or, in the case of solid compositions, by making them in the form of dragees whereby each dosage unit has its own protection against light.
  • Lutrol 9 Disodium salt of ethylene-diamine-tetraacetic acid (Titriplex III) mg 0.20 Sodium metabisulfite mg 0.50 Sodium hydroxide mg 1.63 Distilled water ml 3.00
  • raubasine In order to provide a combined systematic action with an especially intensive local vasodilation, up to 3 ampoules mg.) of raubasine can be injected intraarterially into the femoral artery. ⁇ In this case, there is obtained an especially marked increase of circulation in the muscle and skin of the diseased organ.
  • composition in accordance with the invention adapted for oral administration and constituting tablets of the following composition:
  • the venous outow had increased.
  • this increase in circulation demonstrates, arterially and venously, a clearly different course, as the difference between venous outflow and arterial inflow clearly shows (line 7 of Table 1).
  • the venous outflow was greater than the arterial inflow.
  • the peripheral venous pressure has also increased more markedly than the central venous pressure (line 8 of Table 1).
  • Such a rapidly commencing increase of the peripheral venous pressure is to be attributed to a constriction of the capacitative vessels, i.e., to an increase of venous tone.
  • This mechanism brings about a primary mobilization and displacement of blood from the capacitative vessels in the direction of lower venous pressure, i.e., in the direction of the heart, which then increases its output volume corresponding to the increased supply. Only in the second place does there take place an adaptive dilation of the arterial resistance vessels caused by the direct action of the raubasine. However, in the case of the primarily increased blood time volume, a decrease of the arterial pressure does not result.
  • the venous tone or the expansion resistance of the vessel wall is proportional to the pressure increase and inversely proportional to the volume increase per unit time and can be mathematically dened as the volume elasticity coeflicient 13en given by the equation:
  • catheters were inserted from the vena jugularis up to the height of the heart and first allowed to heal in situ.
  • the blood pressure was measured on the upper arm by the method of Riva-Rocci and the heart minute volume by the method of Wezler and Boger (Naunyl-Schmiedebergs Arch. exp. Path und Pharmak., 184, 482/1937).
  • FIG. 1 there are graphically shown the mean results obtained from 16 experiments on non-anaesthetized dogs following the intravenous injection of 5 mg./ kg. raubasine and in FIG. 2 there are graphically shown the mean results obtained from experiments on human volunteers following the intravenous injection of 20 mg. raubasine.
  • the following abbreviations have been used:
  • a method of treating a human subject afflicted with a venous disease selected from the group consisting of venous thromboses, venous varicoses, non-cardiac edemas, cruris varicosum and peripheral venous circulatory disturbances which comprises administering to said subject raubasine in an amount of from 10 to 200 mg.
  • a method according to claim 1 which comprises administering said raubasine in an amount of from l0 to 30 mg. per day.
  • a method according to claim 1 which comprises administering said raubasine in an amount of from 30 to 200 mg. per day.
  • venous disease is venous thrombosis.
  • venous disease is arterial embolism and said raubasine is administered daily in an amount of from 10() to 200 mg. by intravenous infusion Within a period of 18 hours.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
US700875*A 1967-02-10 1968-01-26 Method of treating venous diseases Expired - Lifetime US3564094A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB6396/67A GB1115417A (en) 1967-02-10 1967-02-10 Compositions containing raubasine and a new method of using raubasine

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US3564094A true US3564094A (en) 1971-02-16

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US (1) US3564094A (fa)
BE (1) BE710562A (fa)
DE (1) DE1692039A1 (fa)
FR (1) FR7342M (fa)
GB (1) GB1115417A (fa)
NL (1) NL142593B (fa)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2671727A1 (fr) * 1991-01-18 1992-07-24 Nawrocki Thadee Utilisation de la raubasine pour traiter un mauvais metabolisme de fer.

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2092608B1 (fa) * 1970-06-01 1973-08-10 Roussel Uclaf

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2671727A1 (fr) * 1991-01-18 1992-07-24 Nawrocki Thadee Utilisation de la raubasine pour traiter un mauvais metabolisme de fer.

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Publication number Publication date
DE1692039A1 (de) 1971-07-08
GB1115417A (en) 1968-05-29
BE710562A (fa) 1968-08-09
FR7342M (fa) 1969-10-13
NL142593B (nl) 1974-07-15
NL6801841A (fa) 1968-08-12

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