US3326757A - Compositions and method for producing skeletal muscle relaxation - Google Patents
Compositions and method for producing skeletal muscle relaxation Download PDFInfo
- Publication number
- US3326757A US3326757A US410790A US41079064A US3326757A US 3326757 A US3326757 A US 3326757A US 410790 A US410790 A US 410790A US 41079064 A US41079064 A US 41079064A US 3326757 A US3326757 A US 3326757A
- Authority
- US
- United States
- Prior art keywords
- muscle
- muscle relaxation
- compositions
- cyclopropylmethyl
- skeletal muscle
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton
Definitions
- This invention relates to a novel method of producing skeletal muscle relaxation and relates more particularly N 0 Drawing.
- R represents a cycloalkylmethyl group such as cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl and R represents hydrogen, lower alkyl, lower alkoxy or halogen such as chlorine or bromine, and the corresponding medicinally acceptable acid addition salts thereof.
- the invention also includes within its scope novel pharmaceutical compositions containing the above compounds.
- the therapeutic basis for the use of a muscle relaxant is the release of muscle spasms and spasticity resulting from various neuro-muscular and musculo-skeletal disorders which may result from dire-ct trauma to muscle, multiple sclerosis, arthritis, bursitis, sciatica, etc., or may result in low back pain.
- drugs for the relief of these conditions there are several available drugs for the relief of these conditions and they can be classified according to their site of activity in the neuro-m-uscular system.
- true muscle relaxant such as quinine which acts directly on the muscle to achieve relaxation.
- myoneuro junction type of drug such as curare, gallamine and the like which achieves muscle relaxation by blocking the myoneuro transmission of impulses and there is a miscellaneous group of drugs which act by a variety of complex mechanisms on the interneuronal systems such as meprobamate, carisoprodol, metaxolone and the like.
- Another object of this invention is to provide muscle relaxation by administration of a drug composition which is effective orally.
- clinically desirable and effective muscle relaxation may be produced by the administration of a composition containing as active ingredient a compound corresponding to structure (-1) above or its corresponding acid addition salt.
- useful acid addition salts include, for example, the hydrochlorides, the nitrates, the phosphates, the sulfates and the like The preparation of these compounds (I) is fully described in aforesaid copending application Ser. No. 262,846.
- compositions of the present invention comprise as active ingredient a compound of the structure (I) in combination with a nontoxic pharmaceutical carrier adapted for human or veterinary medication; the selected active ingredient being present in an amount from about 10 to about 100 mg. per dosage unit.
- oral dosage forms include, for example, solid compositions such as tablets and pills; dispersible powders or granules; or semisolid and liquid formulations in the form of syrups, solutions, suspensions or dispersions.
- compositions may also include other known therapeutic agents such as, for example, analgesics, antiinfiammatory agents, cardiovascular agents, sedatives, steroids, tranquilizers, antacids, and the like.
- analgesics include, for example, aspirin, namol xenyrate, N-acetayl-p-aminophenol and the like.
- the anti-inflammatory agents in these compositions may include, for example, prednisolone, cortisone, N- methyl-yohimbane and the like.
- Cardiovascular agents includes, for example, quindonium bromide, pentaerythritol tetranitrate and the like.
- Sedatives include, for example, phenobarbital, butylbarbital, and the like.
- the steroids may include, for example, estrogen, testosterone, and the like.
- Tranquilizers which may be included are, for example, the phenothiazines such as mep-azine, the rauwolfia alkaloids such as reserpine, and the like.
- tranquilization may also be achieved accompanied by the desired muscle relaxation by administering the active ingredient at higher doses, that is to say, the separation of the muscle relaxant activity from the tranquilizing activity of the compounds of this invention is achieved by suitably modifying the dos-age thereby giving the prescriber a choice, which, of course, is a great advantage.
- a dosage of to 25 mg. administered several times daily is sufiicient to maintain adequate muscle relaxation; a higher dose such as 50 mg. several times daily producing, in addition, a tranquilizing action.
- Example 1 In order to demonstrate the muscle relaxant effect of 7 chloro-l-cyclopropylmethyl-1,3-dihydro-5-phenyl-2H- l,4-benzodiazenpine-2-one, graded doses of this drug are administered orally to a series of unanesthetized adult mice divided into groups of ten.
- the pharmacological test employed consists in placing the treated mice on an inclined screen having a mesh size of 1. Muscle relaxant activity in the mouse is observed as the inability of the treated animals to remain on the screen inclined at 30. The treated mice are observed at hourly intervals for about six hours. Untreated mice are included in the test as controls.
- Approximate effective dose 50 is that dose at which 50% of the treated animals are unable to remain on the screen.
- the effective oral dose of this compound has been found to be 74 mg./kg. whereas that of meprobamate is found to be 282 mg./kg.
- the same compound is also administered to cats at graded doses.
- the treated animals are observed for muscle relaxant activity by noting the ability of the drug to produce alterations in gait and palpitation of muscle tone.
- the ED of this compound is found to be 5 mg./ kg. whereas the ED of meprobamate is found to be at 25 mg./kg.
- Example 2 The lack of central depressant effect of 7-chloro-1- cyclopropylmethyl 1,3 dihydro-5-phenyl-2H-1,4-benzodiazepine-2-0ne is noted by its failure to produce hypnosis as demonstrated in the following test procedure.
- mice weighing about 18 to 2 4 grams are given orally a 1% by weight solution of the above compound in polyethylene glycol at graded doses.
- Example 5 A mixture of 25 parts of 7-chloro-1-cyclopropylmethyl- 1,3 dihydro 6 phenyl-ZH-1,4-benZodiazepine-2-one and parts of milk sugar are intimately blended together. 200 mg. of this mixture is filled into hard gelatin capsules each of which will contain 25 mg. of the active ingredient.
- Example 6 Illustrative of the muscle relaxant activity of 7-chloro- 1 cyclopropylmethyl 1,3 dihydro-5-phenyl-2H-1,4- benzodiazepine-Z-one in human beings is the following clinical case:
- a method of producing skeletal muscle relaxation in warm-blooded mammals which comprises administer- 5 ing orally to said mammals an effective amount of a compound of the formula:
- R is cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl and R is a member of the group con- 20 sisting of hydrogen, halogen, lower alkyl and lower alkoxy and the medicinally acceptable acid addition salts.
- a method of producing skeletal muscle relaxation in warm-blooded mammals which comprises administering orally to said mammals about 5 to 25 mg. of a member of the group consisting of 7-chloro-l-cyclopropylmethyl- 1,3-dihydro 5 phenyl-2H4,4-benzodiazepine-2-one and 0 the medicinally acceptable acid addition salts several times daily.
- composition for oral administration consisting essentially of about 5 to 25 mg. of a compound of the formula:
Description
United States Patent This application is a continuation-in-part of copending application Ser. No. 262,846 filed Mar. 5, 1963 now US. Patent No. 3,192,200.
This invention relates to a novel method of producing skeletal muscle relaxation and relates more particularly N 0 Drawing.
.to a novel method of producing skeletal muscle relaxation by the administration of a compound of the formula:
in which R represents a cycloalkylmethyl group such as cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl and R represents hydrogen, lower alkyl, lower alkoxy or halogen such as chlorine or bromine, and the corresponding medicinally acceptable acid addition salts thereof.
The invention also includes within its scope novel pharmaceutical compositions containing the above compounds.
The therapeutic basis for the use of a muscle relaxant is the release of muscle spasms and spasticity resulting from various neuro-muscular and musculo-skeletal disorders which may result from dire-ct trauma to muscle, multiple sclerosis, arthritis, bursitis, sciatica, etc., or may result in low back pain.
There are several available drugs for the relief of these conditions and they can be classified according to their site of activity in the neuro-m-uscular system. Thus, for example, there is the so-called true muscle relaxant such as quinine which acts directly on the muscle to achieve relaxation. There is also the myoneuro junction type of drug such as curare, gallamine and the like which achieves muscle relaxation by blocking the myoneuro transmission of impulses and there is a miscellaneous group of drugs which act by a variety of complex mechanisms on the interneuronal systems such as meprobamate, carisoprodol, metaxolone and the like.
While there are many such drugs, none of them is ideal for true' muscle relaxant therapy either because of lack of Specificity of action, lack of oral activity or because ofundesirable side-effects which accompany their administration. Thus, for example, curare which is one of the more potent muscle relaxants has to be administered parentally in order to achieve its effect. Obviously, such route of administration besides its discomfort and low safety margin is also highly impractical to. patients Where repeated dosages are required. These drugs are 3,326,757 Patented June 20, 1967 therefore of limited application. On the other hand, meprobamate while orally active actually achieves its muscle relaxant activity by way of its tranquilizing and sedative activity. In other words, the muscle relaxant activity is one which is subsidiary to its tranquilizing activity. Therefore, in order to achieve the desired muscle relaxant effect, for example, the patient is subject to the undesired side-effects of a central depressant such as tranquilization, sedation or hypnosis. These central depressant effects are clearly undesirable if one wishes to produce muscle relaxation, particularly in instances with organic neurological syndromes such as cerebral palsy, Parkinsons disease or others where uncontrolled motor activity is a primary factor. The shortcomings of having to administer the drug by intravenous or intramuscular administration or the undesirable production of concomitant sedation or other central nervous systems depressant efi'ect clearly indicates that there has been a long-felt need for a reliable and orally eifective muscle relaxant free of the aforementioned disadvantages.
Accordingly, a primary object of this invention is to provide a novel method for the production of muscle relaxation without other central depressant elfects.
Another object of this invention is to provide muscle relaxation by administration of a drug composition which is effective orally.
Other objects and advantages of this invention will become apparent from the following detailed description.
According to this invention clinically desirable and effective muscle relaxation may be produced by the administration of a composition containing as active ingredient a compound corresponding to structure (-1) above or its corresponding acid addition salt. Useful acid addition salts include, for example, the hydrochlorides, the nitrates, the phosphates, the sulfates and the like The preparation of these compounds (I) is fully described in aforesaid copending application Ser. No. 262,846.
It has been found, for example, that the compound 7 chloro-l-cyclopropylmethyl-1,3-dihydro-5-phenyl-2H- 1,4-benzodiazepine-2-one and its acid addition salts prodnces significant muscle relaxant activity on oral administration to warm-blooded mammals, without any observable central nervous system depressant effects.
Thus, in a laboratory test using warm-blooded mammals such as mice as the experimental animal, for example, effective muscle relaxation has been achieved at an oral dose of 74 mg./kg. whereas the well-known meprobamate required an oral dose of 282 mg./kg. to produce the equivalent effect but this degree of muscle relaxation with meprobamate is also accompanied by an appreciable degree of sedation. On the other hand, in human beings an oral dose three times a day of 25 mg. is capable of producing a clinically effective degree of muscle relaxation in a variety of neuro-muscular disorders but without observable sedation. This remarkable effect is believed to be due to the specific interneuronal blockage within the spin-a1 cord produced by these compounds rather than by the collateral depression of the central nervous system such as that caused by other known muscle relaxants. In addition, the muscle relaxant activity produced by the compounds of this invention has a rapid yet very smooth onset of very long duration.
The pharmaceutical compositions of the present invention comprise as active ingredient a compound of the structure (I) in combination with a nontoxic pharmaceutical carrier adapted for human or veterinary medication; the selected active ingredient being present in an amount from about 10 to about 100 mg. per dosage unit. These oral dosage forms include, for example, solid compositions such as tablets and pills; dispersible powders or granules; or semisolid and liquid formulations in the form of syrups, solutions, suspensions or dispersions.
The above compositions may also include other known therapeutic agents such as, for example, analgesics, antiinfiammatory agents, cardiovascular agents, sedatives, steroids, tranquilizers, antacids, and the like. These analgesics include, for example, aspirin, namol xenyrate, N-acetayl-p-aminophenol and the like.
The anti-inflammatory agents in these compositions may include, for example, prednisolone, cortisone, N- methyl-yohimbane and the like. Cardiovascular agents includes, for example, quindonium bromide, pentaerythritol tetranitrate and the like. Sedatives include, for example, phenobarbital, butylbarbital, and the like. The steroids may include, for example, estrogen, testosterone, and the like. Tranquilizers which may be included are, for example, the phenothiazines such as mep-azine, the rauwolfia alkaloids such as reserpine, and the like.
As stated, it has been found that the above compounds produce muscular relaxation without tranquilizing effect. However, tranquilization may also be achieved accompanied by the desired muscle relaxation by administering the active ingredient at higher doses, that is to say, the separation of the muscle relaxant activity from the tranquilizing activity of the compounds of this invention is achieved by suitably modifying the dos-age thereby giving the prescriber a choice, which, of course, is a great advantage. Generally, a dosage of to 25 mg. administered several times daily is sufiicient to maintain adequate muscle relaxation; a higher dose such as 50 mg. several times daily producing, in addition, a tranquilizing action.
The following examples are included in order further to illustrate the invention:
Example 1 In order to demonstrate the muscle relaxant effect of 7 chloro-l-cyclopropylmethyl-1,3-dihydro-5-phenyl-2H- l,4-benzodiazenpine-2-one, graded doses of this drug are administered orally to a series of unanesthetized adult mice divided into groups of ten. The pharmacological test employed consists in placing the treated mice on an inclined screen having a mesh size of 1. Muscle relaxant activity in the mouse is observed as the inability of the treated animals to remain on the screen inclined at 30. The treated mice are observed at hourly intervals for about six hours. Untreated mice are included in the test as controls. Approximate effective dose 50 (ED for muscle relaxant activity is that dose at which 50% of the treated animals are unable to remain on the screen. By this test, the effective oral dose of this compound has been found to be 74 mg./kg. whereas that of meprobamate is found to be 282 mg./kg. In another series of experiments the same compound is also administered to cats at graded doses. The treated animals are observed for muscle relaxant activity by noting the ability of the drug to produce alterations in gait and palpitation of muscle tone. The ED of this compound is found to be 5 mg./ kg. whereas the ED of meprobamate is found to be at 25 mg./kg.
Example 2 The lack of central depressant effect of 7-chloro-1- cyclopropylmethyl 1,3 dihydro-5-phenyl-2H-1,4-benzodiazepine-2-0ne is noted by its failure to produce hypnosis as demonstrated in the following test procedure.
Adult female albino mice weighing about 18 to 2 4 grams are given orally a 1% by weight solution of the above compound in polyethylene glycol at graded doses.
10 follows:
ED50, (1) 7-chloro-l-cyclopropylmethyl-1,3-dihydro-5- phenyl-ZH-1,4-benzodiazepine-2-one 1000 (2) Diazepam 104 (3) Meprobamate 300 (4) chlordiazepoxide 415 Example 3 The following toxicity test demonstrates the safety of 7 chloro 1 cyclopropylmethyl-l,3dihydro-5-phenyl- 2H-l,4-benzodiazepine-2-one. Incarrying out this test several groups of adult female albino mice weighing about 18 to 24 grams each are employed. Each group receives orally a 1% by weight solution in polyethylene glycol of the above compound in graduated doses and the mice are then observed for one week. The particular dosage of the material administered at which 50% of the test mice survive, expressed in milligrams, is reported as the average lethal dose is referred to as the ALD The higher the ALD the lower the toxicity and the greater the safety of the material.
The following tabulation gives the ALD of the above compounds as determined by this procedure. The ALD values for chlordiazepoxide and diazepam are also included for comparative purposes:
' ALD mg./kg.
(l) 7-chloro-l-cyclopropylmethyl-1,3-dihydro- 5-phenyl-2H-1,4-benzodiazepine-2-one 1000 (2) chlordiazepoxide 680 (3 Diazepam 750 Example 4 A mixture of 10 parts of 7-chloro-l-cyclopropylmethyl- 1,3 dihydro 5 phenyl-ZH-1,4-benzodiazepine-2-one and parts of calcium phosphate is granulated by admixture with a sufficient quantity of aqueous 10% starch paste. The granules are passed through a No. 12 screen and are then dried at 50 C. for about 10 hours. The dry granules are then passed through a No. 16 screen, 1 part of magnesium stearate is then added thereto and the mixture is then compressed into tablets on a rotary press at about mg. each, with each tablet containing about 10 mg. of active ingredient.
Example 5 A mixture of 25 parts of 7-chloro-1-cyclopropylmethyl- 1,3 dihydro 6 phenyl-ZH-1,4-benZodiazepine-2-one and parts of milk sugar are intimately blended together. 200 mg. of this mixture is filled into hard gelatin capsules each of which will contain 25 mg. of the active ingredient.
Example 6 Illustrative of the muscle relaxant activity of 7-chloro- 1 cyclopropylmethyl 1,3 dihydro-5-phenyl-2H-1,4- benzodiazepine-Z-one in human beings is the following clinical case:
A female patient, 37 years of age, was diagnosed to be suffering from a neuropastic disease. She was treated with the above compound at an oral dose of 10 mg. three times a day. Complete relief was observed after two days medication.
It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of my invention.
Having described my invention, what I desire to secure by Letters Patent is:
I claim:
1. A method of producing skeletal muscle relaxation in warm-blooded mammals which comprises administer- 5 ing orally to said mammals an effective amount of a compound of the formula:
in which R is cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl and R is a member of the group con- 20 sisting of hydrogen, halogen, lower alkyl and lower alkoxy and the medicinally acceptable acid addition salts.
2;. The method according to claim 1 wherein said compound is administered at about 5 to 25 mg. several times daily.
3. A method of producing skeletal muscle relaxation in warm-blooded mammals which comprises administering orally to said mammals about 5 to 25 mg. of a member of the group consisting of 7-chloro-l-cyclopropylmethyl- 1,3-dihydro 5 phenyl-2H4,4-benzodiazepine-2-one and 0 the medicinally acceptable acid addition salts several times daily.
4. A composition for oral administration consisting essentially of about 5 to 25 mg. of a compound of the formula:
15 in which R is cyclopropylmethyl, cyclobutylmethyl and No references cited.
ALBERT T. MEYERS, Primary Examiner.
JULIAN S. LEVITI, Examiner.
S. J. FRIEDMAN, Assistant Examiner.
Claims (1)
1. A METHOD OF PRODUCING SKELETAL MUSCLE RELAXATION IN WARM-BLOODED MAMMALS WHICH COMPRISES ADMINISTERING ORALLY TO SAID MAMMALS AN EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA:
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19641470422 DE1470422A1 (en) | 1963-03-05 | 1964-02-24 | Process for the preparation of substituted 1,4-benzodiazepines |
GB8156/64A GB1029741A (en) | 1963-03-05 | 1964-02-27 | Substituted 1,4-benzodiazepines and a process for their manufacture |
CH249164A CH427830A (en) | 1963-03-05 | 1964-02-28 | Process for the preparation of substituted 1,4-benzodiazepines |
BR157243/64A BR6457243D0 (en) | 1963-03-05 | 1964-03-02 | PROCESS OF PREPARING DERIVATIVES 1-CYCLE-ALKYL OF 1,4-BENZODIAZEPINE |
FR966092A FR1426890A (en) | 1963-03-05 | 1964-03-04 | Process for the preparation of new substituted 1,4-benzodiazepines |
BE644705A BE644705A (en) | 1963-03-05 | 1964-03-04 | |
FR966091A FR3452M (en) | 1963-03-05 | 1964-03-04 | Therapeutic compounds based on novel substituted 1,4-benzodiazepines. |
SE2730/64A SE309779B (en) | 1963-03-05 | 1964-03-05 | |
US410790A US3326757A (en) | 1963-03-05 | 1964-11-12 | Compositions and method for producing skeletal muscle relaxation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US262846A US3192200A (en) | 1963-03-05 | 1963-03-05 | 1-cycloalkyl methyl derivatives of 1, 4-benzodiazepine |
US410790A US3326757A (en) | 1963-03-05 | 1964-11-12 | Compositions and method for producing skeletal muscle relaxation |
Publications (1)
Publication Number | Publication Date |
---|---|
US3326757A true US3326757A (en) | 1967-06-20 |
Family
ID=26949494
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US410790A Expired - Lifetime US3326757A (en) | 1963-03-05 | 1964-11-12 | Compositions and method for producing skeletal muscle relaxation |
Country Status (8)
Country | Link |
---|---|
US (1) | US3326757A (en) |
BE (1) | BE644705A (en) |
BR (1) | BR6457243D0 (en) |
CH (1) | CH427830A (en) |
DE (1) | DE1470422A1 (en) |
FR (1) | FR3452M (en) |
GB (1) | GB1029741A (en) |
SE (1) | SE309779B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8778264B2 (en) | 2010-10-28 | 2014-07-15 | Guy L. McClung, III | Fluid treatment systems |
US8911676B2 (en) | 2010-10-21 | 2014-12-16 | Guy L. McClung, III | Treatment systems for fluids |
-
1964
- 1964-02-24 DE DE19641470422 patent/DE1470422A1/en active Pending
- 1964-02-27 GB GB8156/64A patent/GB1029741A/en not_active Expired
- 1964-02-28 CH CH249164A patent/CH427830A/en unknown
- 1964-03-02 BR BR157243/64A patent/BR6457243D0/en unknown
- 1964-03-04 FR FR966091A patent/FR3452M/en active Active
- 1964-03-04 BE BE644705A patent/BE644705A/xx unknown
- 1964-03-05 SE SE2730/64A patent/SE309779B/xx unknown
- 1964-11-12 US US410790A patent/US3326757A/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
---|
None * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8911676B2 (en) | 2010-10-21 | 2014-12-16 | Guy L. McClung, III | Treatment systems for fluids |
US8778264B2 (en) | 2010-10-28 | 2014-07-15 | Guy L. McClung, III | Fluid treatment systems |
Also Published As
Publication number | Publication date |
---|---|
BE644705A (en) | 1964-09-04 |
DE1470422A1 (en) | 1969-11-13 |
BR6457243D0 (en) | 1973-07-17 |
FR3452M (en) | 1965-07-26 |
SE309779B (en) | 1969-04-08 |
CH427830A (en) | 1967-01-15 |
GB1029741A (en) | 1966-05-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0188810B1 (en) | Use of dipeptide derivatives for the prevention or treatment of post-traumatic spinal and/or cerebral nerve disorders | |
HU206042B (en) | Process for producing pharmaceutical compositions comprising indole-3-carboxylic acid-endo-8-methyl-8-azabicyclo/3.2.1./oct-3-yl ester and/or 1,2,3-9-tetrahydro-9-methyl-3-(2-methyl-1h-imidazol-1-yl)-methyl-4h-carbazol-4-one, with an activity preventing or reducing opiate-, alcohol- and nicotine-dependence | |
IE893690L (en) | Treatment of obesity | |
EP0103636A1 (en) | Use of opium antagonists for the manufacture of medicaments for controlling gastrointestinal dysmotility. | |
DE3101644A1 (en) | MEDICINAL PRODUCTS AND METHOD FOR THE PRODUCTION THEREOF | |
Condit et al. | Studies on the folic acid vitamins: VII. The effects of large doses of amethopterin in patients with cancer | |
US4489080A (en) | Process for analgesic treatment | |
US5248678A (en) | Methods for increasing arousal and alertness and for the amelioration of comatose states | |
US4156013A (en) | Method for treating patients suffering from anxiety neurosis and anxietylike neurosis, and alcoholism | |
JPS61500728A (en) | Pharmaceutical composition for appetite loss | |
US3865933A (en) | Analgesic composition | |
US3326757A (en) | Compositions and method for producing skeletal muscle relaxation | |
Kozol | Epilepsy: treatment with new drug: 3-methyl 5, 5-phenyl-ethyl-hydantoin (phenantoin) | |
US4800209A (en) | Method of alleviating withdrawal symptoms | |
US3795738A (en) | Use of l-propyl l-leucyl glycine amide to treat parkinson's disease | |
US5661142A (en) | Anti-emetic composition | |
US4017614A (en) | Compositions for the relief of migraine | |
US2817623A (en) | Tabernanthine, ibogaine containing analgesic compositions | |
SCHERBEL | Newer concepts of amine oxidase inhibitors | |
US4189478A (en) | Medicinal composition and its use as antidepressive agent | |
US3218233A (en) | Analgesic compositions | |
US4879298A (en) | Novel method and composition | |
SK76696A3 (en) | Pentoxifyllin allone or in combination with corticosteroid | |
Kushner | Experience with greater than recommended doses of fluphenazine and triflupromazine | |
US3538224A (en) | Composition for treating human mental disorders |