US2967130A - p-sulfamyl beta-hydroxyethyl carbanilate diuretic compositions - Google Patents
p-sulfamyl beta-hydroxyethyl carbanilate diuretic compositions Download PDFInfo
- Publication number
- US2967130A US2967130A US682076A US68207657A US2967130A US 2967130 A US2967130 A US 2967130A US 682076 A US682076 A US 682076A US 68207657 A US68207657 A US 68207657A US 2967130 A US2967130 A US 2967130A
- Authority
- US
- United States
- Prior art keywords
- carbanilate
- sulfamyl
- compositions
- diuretic
- hydroxyethyl
- 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
- 239000000203 mixture Substances 0.000 title claims description 24
- 230000001882 diuretic effect Effects 0.000 title claims description 9
- 239000002934 diuretic Substances 0.000 title claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 18
- 239000003937 drug carrier Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 description 12
- 102000003846 Carbonic anhydrases Human genes 0.000 description 7
- 108090000209 Carbonic anhydrases Proteins 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- -1 hydrogen ions Chemical class 0.000 description 5
- 210000002700 urine Anatomy 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 3
- 239000008116 calcium stearate Substances 0.000 description 3
- 235000013539 calcium stearate Nutrition 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910001415 sodium ion Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229910001868 water Inorganic materials 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VUZPPFZMUPKLLV-UHFFFAOYSA-N methane;hydrate Chemical compound C.O VUZPPFZMUPKLLV-UHFFFAOYSA-N 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
Definitions
- This invention relates to therapeutic compositions and more particularly to therapeutic compositions which are efiective to inhibit carbonic anhydrase activity.
- compositions comprising a compound having the formula:
- carbonic anhydrase activity indirectly determines the number of hydrogen ions which are available to replace sodium ions in buffer compounds from the blood, such as, for example, disodium phosphate and sodium bicarbonate.
- the sodium ions thus replaced are conserved and return to the blood, and carbonic acid formed in the above reaction catalyzed by carbonic anhydrase also returns to the blood.
- I SOZNHQ NHCOOR wherein R is ethyl, B-hydroxy ethyl or allyl.
- the inhibition of carbonic anhydrase activity by the compositions of the present invention results in a reduction of hydrogen ions available for the acidification of the urine.
- the pH of the urine increases, fewer sodium ions of the buffer compounds are replaced by hydrogen ions, and larger amounts of sodium, chloride and bicarbonate are excreted in the urine.
- water excretion is increased.
- the diuretic action provided by the compositions of the invention is useful to relieve edema, for example, caused by congestive heart failure or other causes.
- the p-sulfamyl carbanilate compounds specified herein are not only compatible with other components employed in therapeutic compositions, "but they are also stable and nontoxic.
- intraperitoneal doses of p-sulfamyl fl-hydroxy ethyl carbanilate up to 1600 mg./ kg. were tolerated by male White rats, and only three animals out of a group of nine receiving 1800 mg./kg. intraperitoneally died.
- oral doses up to 1500 mg./kg. of this carbanilate compound did not produce any ill effect in male white rats.
- Three groups of white rats, with six animals in each group received 600, 900 and 1200 mg./kg. respectively of p-sulfamyl fl-hydroxy ethyl carbanilate per day for twelve days and showed a normal gross pathology after being sacrificed and autopsied on the thirteenth day.
- the carbanilate compounds of the novel therapeutic compositions of the invention have the formula:
- compositions of the present invention comprise a compound of the above-mentioned class and a pharmaceutical carrier which may be either a liquid or solid material.
- a pharmaceutical carrier be a solid material such as, for example, starch, gelatin, lactose, talc, calcium stearate or the like.
- Any of the pharmaceutical carriers conventionally used in therapeutic compositions may be utilized where such materials are compatible with the aforementioned carbanilate compounds.
- These compositions include tablets, capsules and the like, and may include a liquid pharmaceutical carrier and be in the form of solutions, dispersions, suspensions, elixirs and the like.
- compositions of the invention may be varied considerably.
- Exemplary compositions may contain approximately by weight of one of the above-mentioned carbanilate compounds, although greater or smaller amounts than 80% may also be used in the practice of the invention.
- the daily dosage administered to a patient may also vary considerably, depending upon the patients condition and the amount prescribed by the physician in charge.
- Example Therapeutic diuretic tablets were prepared having the following composition:
- Component G p-Sulfamyl fl-hydroxy ethyl carbanilate 0.5 Corn starch, U.S.P 0.1 Calcium stearate 0.005
- the tablets were prepared by grinding the p-sulfamyl 3 hydroxy ethyl carbanilate through a No. 24 screen, adding the corn starch and calcium stearate and, after thoroughly mixing the components, compressing into tablets.
- a therapeutic composition useful as a diuretic comprising a dosage form of p-sulfamyl fi-hydroxy ethyl carbanilate in combination with a pharmaceutical carrier.
- a therapeutic composition useful as a diuretic comprising a dosage unit form of p-sulfamyl B-hydroxy ethyl carbanilate in combination with a solid pharmaceutical carrier.
- a therapeutic composition useful as a diuretic comprising a dosage unit form of p-sulfamyl fi-hydroxy ethyl carbanilate in combination with a liquid pharmaceutical carrier.
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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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
I p-SULFAMYL fi-HYDROXYETHYL CARBANILATE DIURETIC COMPOSITIONS Robert G. Sanders, Pompton Lakes, and Roland R. Read,
Morristown, NJ., and Richard J. Palazzolo, Northbrook, Ill.
No Drawing. Filed Sept. 5, 1957, Ser. No. 682,076
3 Claims. (Cl. 167-65) This invention relates to therapeutic compositions and more particularly to therapeutic compositions which are efiective to inhibit carbonic anhydrase activity.
This application is a continuation-in-part of our application Serial Number 456,639, filed September 16, 1954, now abandoned, and of copending application Serial Number 532,113, filed September 1, 1955, now US. Patent No. 2,920,012.
Briefly, the present invention is directed to therapeutic compositions comprising a compound having the formula:
NHCOOR wherein R is ethyl, fl-hydroxy ethyl and allyl, and a pharmaceutical carrier. Of the above-noted compounds, we preferably employ p-sulfarnyl fi-hydroxy ethyl carbanilate.
Among the several objects of the invention may be noted the provision of therapeutic compositions and methods which are effective to inhibit the activity of the enzyme carbonic anhydrase; the provision of such therapeutic compositions which are effective diuretic compositions; and the provision of therapeutic compositions of the class described which are stable and nontoxic. Other objects and features will be in part apparent and in part pointed out hereinafter.
The invention accordingly comprises the products and methods hereinafter described, the scope of the invention being indicated in the following claims.
The enzyme carbonic anhydrase plays an important role in the acidification of the urine through its catalysis of the reversible reaction:
The carbonic acid so form yields hydrogen and bicarbonate ions through the reversible reaction:
Thus, carbonic anhydrase activity indirectly determines the number of hydrogen ions which are available to replace sodium ions in buffer compounds from the blood, such as, for example, disodium phosphate and sodium bicarbonate. The sodium ions thus replaced are conserved and return to the blood, and carbonic acid formed in the above reaction catalyzed by carbonic anhydrase also returns to the blood.
In accordance with the present invention, it has been found that carbonic anhydrase activity can be effectively inhibited and the excretion of water, sodium and potassium in the urine increased by the use of therapeutic 2,967,130 Patented Jan. 3, 1961 compositions including a p-sulfamyl carbanilate compound having the following formula:
I SOZNHQ NHCOOR wherein R is ethyl, B-hydroxy ethyl or allyl. The inhibition of carbonic anhydrase activity by the compositions of the present invention results in a reduction of hydrogen ions available for the acidification of the urine. As a consequence, the pH of the urine increases, fewer sodium ions of the buffer compounds are replaced by hydrogen ions, and larger amounts of sodium, chloride and bicarbonate are excreted in the urine. Further, because the formation of carbonic acid from carbon dioxide and water is inhibited, water excretion is increased. Thus, the diuretic action provided by the compositions of the invention is useful to relieve edema, for example, caused by congestive heart failure or other causes.
The p-sulfamyl carbanilate compounds specified herein are not only compatible with other components employed in therapeutic compositions, "but they are also stable and nontoxic. For example, intraperitoneal doses of p-sulfamyl fl-hydroxy ethyl carbanilate up to 1600 mg./ kg. were tolerated by male White rats, and only three animals out of a group of nine receiving 1800 mg./kg. intraperitoneally died. Moreover, oral doses up to 1500 mg./kg. of this carbanilate compound did not produce any ill effect in male white rats. Three groups of white rats, with six animals in each group, received 600, 900 and 1200 mg./kg. respectively of p-sulfamyl fl-hydroxy ethyl carbanilate per day for twelve days and showed a normal gross pathology after being sacrificed and autopsied on the thirteenth day.
The carbanilate compounds of the novel therapeutic compositions of the invention have the formula:
NHCOOR wherein R represents ethyl, fl-hydroxy ethyl or allyl. The therapeutic compositions of the present invention comprise a compound of the above-mentioned class and a pharmaceutical carrier which may be either a liquid or solid material. 'It is preferred that the pharmaceutical carrier be a solid material such as, for example, starch, gelatin, lactose, talc, calcium stearate or the like. Any of the pharmaceutical carriers conventionally used in therapeutic compositions may be utilized where such materials are compatible with the aforementioned carbanilate compounds. These compositions include tablets, capsules and the like, and may include a liquid pharmaceutical carrier and be in the form of solutions, dispersions, suspensions, elixirs and the like.
The percentage of the carbanilate compound incorporated in the therapeutic compositions of the invention may be varied considerably. Exemplary compositions may contain approximately by weight of one of the above-mentioned carbanilate compounds, although greater or smaller amounts than 80% may also be used in the practice of the invention. The daily dosage administered to a patient may also vary considerably, depending upon the patients condition and the amount prescribed by the physician in charge. In the case of Example Therapeutic diuretic tablets were prepared having the following composition:
Component G. p-Sulfamyl fl-hydroxy ethyl carbanilate 0.5 Corn starch, U.S.P 0.1 Calcium stearate 0.005
The tablets were prepared by grinding the p-sulfamyl 3 hydroxy ethyl carbanilate through a No. 24 screen, adding the corn starch and calcium stearate and, after thoroughly mixing the components, compressing into tablets.
It will be understood, of course, that the therapeutic p itio s of t invention ma b mpl ed in the treatment of any condition Where the inhibition of earbonic anhydrase activity will produce a beneficial result.
In viewvof the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.
As various changes could be made in the above products and methods without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.
' We claim:
1. A therapeutic composition useful as a diuretic comprising a dosage form of p-sulfamyl fi-hydroxy ethyl carbanilate in combination with a pharmaceutical carrier.
2. A therapeutic composition useful as a diuretic comprising a dosage unit form of p-sulfamyl B-hydroxy ethyl carbanilate in combination with a solid pharmaceutical carrier.
3. A therapeutic composition useful as a diuretic comprising a dosage unit form of p-sulfamyl fi-hydroxy ethyl carbanilate in combination with a liquid pharmaceutical carrier.
References Cited in the file of this patent UNITED STATES PATENTS 2,789,938 Wilcox et 1. Apr. 23, 1957 OTHER REFERENCES 'J.A.C.S., 72, pp. 4893-4896, November 1950. Chem. Abst., 41, pp. 4809:4811, 1947. I.A.M.A., 151:16, p. 1430, April 18, 1953.
Claims (1)
1. A THERAPEUTIC COMPOSITION USEFUL AS A DIURETIC COMPRISING A DOSAGE FROM OF P-SULFAMYL B-HYDROXY ETHYL CARBANILATE IN COMBINATION WITH A PHARMACEUTICAL CARRIER.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US682076A US2967130A (en) | 1957-09-05 | 1957-09-05 | p-sulfamyl beta-hydroxyethyl carbanilate diuretic compositions |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US682076A US2967130A (en) | 1957-09-05 | 1957-09-05 | p-sulfamyl beta-hydroxyethyl carbanilate diuretic compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2967130A true US2967130A (en) | 1961-01-03 |
Family
ID=24738099
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US682076A Expired - Lifetime US2967130A (en) | 1957-09-05 | 1957-09-05 | p-sulfamyl beta-hydroxyethyl carbanilate diuretic compositions |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2967130A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3101339A (en) * | 1958-10-30 | 1963-08-20 | Boehringer Sohn Ingelheim | Quaternary salts of normorphine and its acylated derivatives |
| US3133066A (en) * | 1964-05-12 | X-amino-z- | ||
| US3209002A (en) * | 1962-12-17 | 1965-09-28 | Galat Alexander | Novel urinary antiseptics |
| US3290312A (en) * | 1963-09-26 | 1966-12-06 | Squibb & Sons Inc | Triamino pteridine compounds |
| US3344188A (en) * | 1963-10-09 | 1967-09-26 | Bayer Ag | d (-)-n-tert.butyl- and -n-isopropyl-1-phenyl-2-amino-ethanols |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2789938A (en) * | 1952-11-24 | 1957-04-23 | Merck & Co Inc | Method of producing a diuretic effect with p-carboxybenzenesulfonamide |
-
1957
- 1957-09-05 US US682076A patent/US2967130A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2789938A (en) * | 1952-11-24 | 1957-04-23 | Merck & Co Inc | Method of producing a diuretic effect with p-carboxybenzenesulfonamide |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3133066A (en) * | 1964-05-12 | X-amino-z- | ||
| US3101339A (en) * | 1958-10-30 | 1963-08-20 | Boehringer Sohn Ingelheim | Quaternary salts of normorphine and its acylated derivatives |
| US3209002A (en) * | 1962-12-17 | 1965-09-28 | Galat Alexander | Novel urinary antiseptics |
| US3290312A (en) * | 1963-09-26 | 1966-12-06 | Squibb & Sons Inc | Triamino pteridine compounds |
| US3344188A (en) * | 1963-10-09 | 1967-09-26 | Bayer Ag | d (-)-n-tert.butyl- and -n-isopropyl-1-phenyl-2-amino-ethanols |
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