US3284304A - Compositions and methods of using corticosteroids and thiamine derivatives - Google Patents

Compositions and methods of using corticosteroids and thiamine derivatives Download PDF

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Publication number
US3284304A
US3284304A US200050A US20005062A US3284304A US 3284304 A US3284304 A US 3284304A US 200050 A US200050 A US 200050A US 20005062 A US20005062 A US 20005062A US 3284304 A US3284304 A US 3284304A
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Prior art keywords
thiamine
cortisone
group
derivatives
derivative
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US200050A
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English (en)
Inventor
Montandraud Jean
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APPLIC CHIMIQUES SOC D
D'APPLICATIONS CHIMIQUES Ste
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APPLIC CHIMIQUES SOC D
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Classifications

    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • 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
    • A61K31/66—Phosphorus compounds
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

Definitions

  • compositions for therapeutic usage presenting, relatively to their constituents which are individually well known and used, new and unexpected favourable effects. From their more general aspect, these compositions may be designated by the generic term of the compounding or other association of at least one corticosteroid with at least one thiamine derivative.
  • corticosteroids are understood derivatives of the cortisone type, such as cortisone itself, hydrocortisone, deltacortisone or prednisone, delta hydrocortisone or prednisolone and derivatives thereof, such as the ftuoric derivatives of cortisone, whether these compounds are of natural or synthetic origin.
  • thiamine derivatives are understood thiamine itself, thiamine hydrochloride, phosphoryi-thiamine and the like derivatives, including these having an open thiazol cycle, such as diacetylthiamine, dithiopropylthiamine or its hydrochloride and the like.
  • the invention concerns the field of medical preparations responding to the general indications of cortisone and its derivatives, but due to which astheniant and hypoxiant side effects of cortisone are eliminated.
  • the compounds consist of at least one derivative of cortisone and at least one thiamine derivative; the relative proportions of each constituent of these compounds may also vary within very wide limits; again the favourable effects of the association of thiamine with steroid substantially in the proportion of 1:5 by weight have been discovered, as also are compositions containing steroid and thiamine substantially in the proportion of 1:50 by weight.
  • the range of proportions of steroid to thiamine may be from 5:1 to 1:50.
  • the preferred proportion is one part by weight of steroid for five parts by weight of thiamine, for example, 10 mg. of cortisone and 50 mg. thiamine. These proportions are intended for daily doses to be administered to human patients.
  • the first group of rats comprised those fed under normal conditions and receiving no treatment.
  • the second group comprised rats treated with doses of corticosteroid varying in weight from 1:5 mg. per kg. of Weight of the animal or other subject, for one week by intramuscular injection.
  • the third group of rats were treated under the conditions of group 2 but also received a thiamine derivative (thiamine hydrochloride) in daily oral doses of 5 to 25 mg. per kg. (expressed in thiamine).
  • Group 1 normal control subjects: Average duration of swimming with 24 animals on the first day, 14 minutes, with a difference of 6 minutes in the times of performance of the 24 animals.
  • Group 2 (subjects treated with cortisone alone): Average duration of swim after 8 days treatment; the reduction, without being strictly proportional to the doses is, despite everything, a maximum with the biggest doses of cortisone employed. The average, evaluated from a group of 6 rats, was 4.25 minutes and the difference between the longest and the shortest time was 8 minutes 6 seconds.
  • Group 3 (subjects treated with the cortisone-l-thiamine): The average duration of swim after 8 days treatment was found to be 11.05 with a difference of 3.50 minutes.
  • the measure of the notion of a standardised preparation of digitalis makes it possible to compare measurements of two groups of animals as regards the intensity of their cardiac operation.
  • Group (b) which included animals treated by corticoids in doses varying from 1 to 10 rng./kg., by intra-mus-cular injection, and
  • Group (0) which was constituted by animals treated by corticoids as for Group (b) and also receiving from 10 to 25 mg./kg. of a thiamine derivative.
  • the lethal dose of digitalin was from 1.50:0.21 to 1.72:0.13 mg. per kg. according to the doses of corticoid employed while in:
  • the lethal dose was 1.82:0.21 to 2.05:0.11 mg. per kg., according to the doses employed.
  • cortisone or corticoid derivatives Since the sensitivity of a heart depends on its state of weakening (anoxia or ischemia), it is apparent that prolonged treatment with cortisone or corticoid derivatives shows an increase in sensitivity, this increase being reduced by the cortisonethiamine treatment.
  • the rats are weighed each morning and at the end of about one month the surviving rats are sacrified and some specific organs are weighed. Moreover measures of nitrogen elimination are conducted in the same time upon urine samples.
  • the average weight of the controls is of 157 g., i.e. an increase of 18%;
  • the average weight of the rats receiving hydrocortisone alone is of 80 g., i.e., a decrease of 39%;
  • the average weight of the rats receiving hydrocortisone in association with diacetylthiamine is of 112 g., i.e. a decrease of 15% only.
  • thiamine has a particular capacity for reducing postcortisone biological disequilibrium.
  • the invention from one aspect comprises medical preparations responding to the general indications of cortisone and more generally of corticosteroids, but which eliminate the astheniant and hypoXiant side effects of corticosteroids by compounds or associations of at least one derivative selected from the family of corticosteroids with at least one thiamine derivative.
  • Subsidiary features include treatment with at least one corticosteroid and at least one thiamine derivative in the relative proportion of 7 to by weight, and preferably of one part by weight of steroid for five parts by weight of thiamine, and again a treatment of this nature in daily doses of the order of 50-500 mg.
  • a further illustration of the surprisingly favourable activity of the association of the invention resides in the study of the action of the cortisone derivative, administered respectively alone or in association with the thiamine derivative, upon the metabolism of the rat, such action being expressed in terms of variations of total weight of the animal, of variations of the weight of specific organs and of nitrogen elimination.
  • Nitrogen content of urine (mg./kg./24 hrs.) Group 1st week 2d week 3d week 4th week Controls 48B 560 532 490 485 663 669 730 HO plus DAT 568 842 667 558 rats as above the following variations have been noted (content in m-g./l):
  • Vitamin B and all its acid salts, including benzoate and phosphate.
  • esters of vitamin B acting more efficiently e.g. monophosphorylthiamine.
  • Open thiamine molecule blocked by a S--S-R linkage (i.e. di-thio-alkyl-thiamines); by a -S-COR linkage (the primary alcohol group of the thiamine molecule being also esterified by the same or a different alkyl group, e.g. di-acetyl-thiamine).
  • S--S-R linkage i.e. di-thio-alkyl-thiamines
  • a -S-COR linkage the primary alcohol group of the thiamine molecule being also esterified by the same or a different alkyl group, e.g. di-acetyl-thiamine.
  • a method of counteracting the adverse side efiect of digitalis sensitivity in a subject resulting from the administration of a pharmaceutical dose of a corticosteroid comprising jointly administrating to said subject together with said pharmaceutical dose of the corticosteroid a thiamine derivative in a weight ratio With said corticosteroid of between 1:5 and :1, said thiamine derivative being selected from the group consisting of thiamine, phosphoryl-thiamine, diacetylthiamine, dithiopropylthiamine, and the hydrochlorides of the same and then administering digitalis to the subject requiring same.
  • a method of counteracting the adverse side effect of reduction of tissular respiration in a subject resulting from the administration of a pharmaceutical dose of a corticosteroid comprising jointly administrating to said subject together with said pharmaceutical dose of the corticosteroid a thiamine derivative in a Weight ratio with said corticosteroid of between 1:5 and 50:1, said thiamine derivative being selected from the group consisting of thiamine, phosphoryl-thiamine, diacetylthiamine, dithiopropylthiamine and the hydrochlorides of the same.
  • a composition for use in counteracting in a subject the adverse side effects of a pharmaceutical does of a corticosteroid comprising a thiamine derivative mixed with said corticosteroid for joint administration to said subject in a weight ratio of between 1:5 and 50:1, said thiamine derivative being selected from the group consisting of thiamine, phosphoryl-thiamine, diacetyl-thiamine, dithiopropylthiamine, and the hydrochlorides of the same.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US200050A 1961-06-21 1962-06-05 Compositions and methods of using corticosteroids and thiamine derivatives Expired - Lifetime US3284304A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB22357/61A GB992581A (en) 1961-06-21 1961-06-21 Improvements in or relating to therapeutic compositions comprising steroids and thiamine derivatives

Publications (1)

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US3284304A true US3284304A (en) 1966-11-08

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US (1) US3284304A (fr)
BE (1) BE618448A (fr)
FR (1) FR2136M (fr)
GB (1) GB992581A (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4317816A (en) * 1979-08-13 1982-03-02 Osaka Chemical Laboratory Co., Ltd. Saponin containing composition effective against adrenal atrophy

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2841527A (en) * 1955-11-07 1958-07-01 Us Vitamin Corp Medicinal emulsions
US2970944A (en) * 1958-04-04 1961-02-07 Merck & Co Inc Parenteral solutions of steroid phosphates stabilized with creatinines
US3067098A (en) * 1959-11-02 1962-12-04 Baxter Don Inc Intravenous nourishment of patients
US3105010A (en) * 1959-06-19 1963-09-24 Schering Corp Steroid-amino acid compositions for preventing negative nitrogen balance

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2841527A (en) * 1955-11-07 1958-07-01 Us Vitamin Corp Medicinal emulsions
US2970944A (en) * 1958-04-04 1961-02-07 Merck & Co Inc Parenteral solutions of steroid phosphates stabilized with creatinines
US3105010A (en) * 1959-06-19 1963-09-24 Schering Corp Steroid-amino acid compositions for preventing negative nitrogen balance
US3067098A (en) * 1959-11-02 1962-12-04 Baxter Don Inc Intravenous nourishment of patients

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4317816A (en) * 1979-08-13 1982-03-02 Osaka Chemical Laboratory Co., Ltd. Saponin containing composition effective against adrenal atrophy

Also Published As

Publication number Publication date
GB992581A (en) 1965-05-19
FR2136M (fr) 1963-11-12
BE618448A (fr) 1962-10-01

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