CA1197465A - Pharmaceutical composition containing a dibenzocycloheptadiene anti-depressant and an ergot alkaloid - Google Patents
Pharmaceutical composition containing a dibenzocycloheptadiene anti-depressant and an ergot alkaloidInfo
- Publication number
- CA1197465A CA1197465A CA000424059A CA424059A CA1197465A CA 1197465 A CA1197465 A CA 1197465A CA 000424059 A CA000424059 A CA 000424059A CA 424059 A CA424059 A CA 424059A CA 1197465 A CA1197465 A CA 1197465A
- Authority
- CA
- Canada
- Prior art keywords
- active agent
- depressant
- preparation according
- codergocrine
- dibenzocycloheptadiene
- 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
Links
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Abstract
Pharmaceutical composition containing a dibenzocycloheptadiene anti-depressant and an ergot alkaloid Abstract Concomitant administration of a dibenzocycloheptadiene-type anti-depressant such as nortriptyline and codergocrine for example in the form of codergocrine mesylate (BAN). Concomitant administra-tion enhances the anti-depressant effect e.g. of the nortriptyline and is effective in treating depression especially in association with senile dementia.
Description
Case 600-6936 Pharmaceutica1 compositions containing a dibenzocycloheptadiene anti-depressant and an ergot alkaloid The present invention relates t~ pharmaceutical preparations active as anti-depressants as well as to methods of treating depression.
Depression is one of the most common psychiatric disturbances 5 seen by the physician, especially in the elderly patient. The treatment of depression has generally been improved dramatically by the development of tricyclic anti-depressive agents such as the di-benzocycloheptadiene-type anti-depressants. Unfortunately, the therapeutic effect of such agents is often accompanied by 10 troublesome side effects such as anticholinergic, cardiovascular and central nervous system (CNS) reactions. In the geriatric patient, these side effects are especially problematical, necessitating the use of lower daily doses of the anti-depressant. At lower doses, however, the effect of the drug is often less than that 15 desired.
In accordance with the present invention it has now surprisingly been found that co-administration of a di-benzocycloheptadiene anti-depressant with codergocrine is particularly advantageous in the treatment of depression, allowing dosages of the di-benzocyclohep-20 tadiene to be lowered thus reducing occurrence and severity ofundesired side-effects.
This is particularly so on co-administration of a compound of formula I
Rl2 Rl ~ R3 CH2CH2N~
.' ~
7~
Depression is one of the most common psychiatric disturbances 5 seen by the physician, especially in the elderly patient. The treatment of depression has generally been improved dramatically by the development of tricyclic anti-depressive agents such as the di-benzocycloheptadiene-type anti-depressants. Unfortunately, the therapeutic effect of such agents is often accompanied by 10 troublesome side effects such as anticholinergic, cardiovascular and central nervous system (CNS) reactions. In the geriatric patient, these side effects are especially problematical, necessitating the use of lower daily doses of the anti-depressant. At lower doses, however, the effect of the drug is often less than that 15 desired.
In accordance with the present invention it has now surprisingly been found that co-administration of a di-benzocycloheptadiene anti-depressant with codergocrine is particularly advantageous in the treatment of depression, allowing dosages of the di-benzocyclohep-20 tadiene to be lowered thus reducing occurrence and severity ofundesired side-effects.
This is particularly so on co-administration of a compound of formula I
Rl2 Rl ~ R3 CH2CH2N~
.' ~
7~
- 2 - 600-69 wherein Rl, R2 and R3 represent independently hydrogen, chloro or bromo, and R4 and R5 represent independently hydrogen, Cl 6alkyl, benzyl or C3 8cycloalkyl or 5 a pharmaceutically acceptable acid addition salt thereof with codergocrine in free base or pharmaceutically acceptable acid addition salt form.
Accordingly in one aspect of the invention there is provided a pharmaceutical preparation comprising as active agen~
a) a compound of formula I
Rl ~ R~3 2 2 ~
wherein Rl, R2 and R3 represent independently hydrogen, chloro or bromo, and R4 and R5 represent independently hydrogen, Cl 6-alkyl, benzyl or C3 8cycloalkyl, 15 or a pharmacetically acceptable acid addition salt thereof, and b) codergocrine in free base or pharmaceutically acceptable acid addition salt form i5 ~ 3 ~ 600-6936 The compounds of formula I are known and can be prepared e.g.
as described in USP 3,922,305.
A preferred anti-depressant agent of ~ormula I is 5-(3 methyl-aminopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene referred 5 to herein as nortriptyline.
Codergocrine as used herein stands for a mixture comprising dihydroergocryptine (2:1, a:~), dihydroergocornine and dihydroergocristine in the ratio of 1 : 1 : 1 by weight and may be employed in free base form or in pharmaceutically 10 acceptable acid addition salt form. A particularly preferred form is the mesylate known as "codergocrine mesylate" (BAN) or "ergoloid mesylates" (USAN).
The preparation according to the invention may be prepared in conventional manner using conventional diluents, carriers and 15 conventional galenical techniques.
Forms suitable for oral administration are for example tablets, dispersible powders, granules, capsules, syrups and elixirs or for parental administration e.g. solutions such as sterile injectible solutions. Compositions for oral use may contain one or more 2D conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredients in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium 25 carbonate, sodium carbonate, lactose, and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and 30 adsorption in the gastrointestinal tract and thereby provide a ;t ~79~6~
sustained action over a longer period. Similarly, suspensions, syrups and elixirs may con~ain the ac~ive ingredients in admixture with any of the conventional excipients utilized in the preparation of such compositions, e.g., suspending agents such as methyl-5 cellulose, tragacanth and sodium alginate; wetting agents such aslecithin, polyoxyethylene s~earate and polyoxyethylene sorbitan monooleate; and preservatives such as ethyl p-hydroxybenzoate.
Capsules may contain the active ingrledients alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate lO and kaolin. The injectable compositions are formulated as known in the art. These pharmaceutical preparations may contain up to about 90% of the active ingredients in combination with the carrier or adjuvant. Preferably the preparations are put up in unit dosage form particularly in unit dosage form for oral administration. Such 15 forms may contain the active ingredients separately, e.g. in separate layers in a layer or mantle tablet or in split capsules~
A further aspect of the invention concerns a process for the production of a pharmaceutical preparation as stated above which comprises formulating active agent a) with active agent b) as stated above and optionally putting up the preparation in unit dosage form.
In an in-patient study, five patients ranging in age from 26 to 66 years suffering from depression and having a score of l9 to 30 on the Hamilton Depression Scale (A Rating Scale for Depression, M. Hamilton, Nerosurg. Psychiat. 239 56-62, 1960) were given 25 20 milligrams of nortriptyline and 2 milligrams of codergocrine mesylate three times a day for 4 weeks. [This dosage is below the recommended minimum therapeutic dose for nortriplyline of 75 mg/day.]
All five patients had a good response and improved significantly on the combination. The Hamilton Depression Scale score for each patient 30 dropped below 8 and the onset oF relief from the depression came much earlier than is normal with the antidepressant alone. Several patients noticed a significant improvement at the end of the first week. The incidence of side effects was very accepta~le and their seYerity was mtnimal to mild. All five patients in the study felt they were getting effective treatment for their depress;on. These results were confirmed in a multi-centre trial involving 53 patients whose ages range from 18 to 55 years.
Treatment is characterised by a rapid onset of action, steady continued improvement often leading to complete remission and low 10 incidence and intensity of side effects compared with treatment using anti-depressant alone.
The combined administration according to the invention is thus indicated for the treatment of depression.
The combined administration according to the invention is also 15 indicated for use in the treatment of the symptoms of senile dementia.
The combined administration according to the invention is thus particularly advantageous for the treatment of elderly people suffering from senile dementia associated with depression.
The co-administration of active agents a) and b) is accordingly 20 indicated in the treatment of depression and senile dementia parti-cularly when associated with each other.
Accordingly the invention further provides a method of treating depression and senile dementia with depression in a subject in need of such treatment, which method comprises concomitantly administering 25 to said subject an effective amount of an active agent a) and an active agent b) as stated above.
An indicated weight ratio of active agent a) to active agent b) is from about 50 : 1 to about 3 : 1, preferably 20 : 1 to 5 : I, especially 12 : 1 to 8 : 1.
7~L~ii5 For the preferred co-administration of nortriptyline and codergocrine mesylate a suitable ratio is e.g. ca. 10 : 1.
Compounds of formula I alone are normally administered orally in dosages ranging from 30 to 300 milligrams per day. The Maintainance 5 dosage range after remission and for administration according to the invention is from 30 to 150 milligrams per day. In the adolescent and elderly patient~ the dosage range may be much lower e.g. between 30 and 75 milligrams per day, the preferred range of the invention.
The especially preferred range is 50 to 60 milligrams per day. When 10 the compound of formula I is administered to the patient at the lower ranges in combination with 3 to 9 milligrams per day of codergocrine e.g. as codergocrine mesylate, the response is essentially equivalent to that obtained with the higher doses of anti-depressant. Examples of combined daily dosages are 3~ to 150 mg 15 of active agent a) with 3 to 9 mg of active agent b); espe~ially 30 to 75 mg, particularly 50 to 60 mg of nortriptyline with 3 to 9 mg of codergocrine mesylate. A particular combined daily dosage is 60 mg of nortriptyline ~ith 6 mg of codergocrine mesylate.
Conveniently the active agents are administered in sustained 20 release form or alternatively in divided doses 2 to 4 times a day containing e.g. 7.5 to 75 mg of active agent a) and either addition-ally or as a separate dosage form e.g. 0.5 to 6 mg of actiYe agent b).
Examples are dosage forms containing 10, 20, 25 or 75 mg of active agent a) and those containing additionally or as a separate 25 dosage form e.g. 0.5, 1.0, 1.5, 2 or 6 mg of active agent b). A parti-cular dosage form contains 20 mg of nortriptyline and 2 mg of codergocrine mesylate.
The invention also provides a pack comprising separately a plurality of dosage units of each of active agents a) and b) together 30 with instructions for their concomitant administration.
The following Example is illustrative of compositions for use in the invention.
- 7 ~ 600-6936 EXAMPLE
Tablets and Caesules Suitable for Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treat-ing e.g. depression at a dose of one tablet or capsule three times a day.
Weight (mg.) Ingredient TaBle Nortriptyline HCL (-20 mg Base) 22.7 22.7 Ergoloid mesylate 2 2 10 Tragacanth lo Lactose 172.8 225.3 Corn Starch 25 Talcum 15 Magnesium Stearate 2.5 250 ~ 250 Other capsules and tablets as well as e.g. suppositories, dispersible powders, syrups, elixirs, suspensions or solutions may also be made using conventional carriers and diluents for the desired formulation and may be administered enterally or parenterally 20 as apporpriate to a patient.
.~,.j . . ~ ..
Accordingly in one aspect of the invention there is provided a pharmaceutical preparation comprising as active agen~
a) a compound of formula I
Rl ~ R~3 2 2 ~
wherein Rl, R2 and R3 represent independently hydrogen, chloro or bromo, and R4 and R5 represent independently hydrogen, Cl 6-alkyl, benzyl or C3 8cycloalkyl, 15 or a pharmacetically acceptable acid addition salt thereof, and b) codergocrine in free base or pharmaceutically acceptable acid addition salt form i5 ~ 3 ~ 600-6936 The compounds of formula I are known and can be prepared e.g.
as described in USP 3,922,305.
A preferred anti-depressant agent of ~ormula I is 5-(3 methyl-aminopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene referred 5 to herein as nortriptyline.
Codergocrine as used herein stands for a mixture comprising dihydroergocryptine (2:1, a:~), dihydroergocornine and dihydroergocristine in the ratio of 1 : 1 : 1 by weight and may be employed in free base form or in pharmaceutically 10 acceptable acid addition salt form. A particularly preferred form is the mesylate known as "codergocrine mesylate" (BAN) or "ergoloid mesylates" (USAN).
The preparation according to the invention may be prepared in conventional manner using conventional diluents, carriers and 15 conventional galenical techniques.
Forms suitable for oral administration are for example tablets, dispersible powders, granules, capsules, syrups and elixirs or for parental administration e.g. solutions such as sterile injectible solutions. Compositions for oral use may contain one or more 2D conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredients in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium 25 carbonate, sodium carbonate, lactose, and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and 30 adsorption in the gastrointestinal tract and thereby provide a ;t ~79~6~
sustained action over a longer period. Similarly, suspensions, syrups and elixirs may con~ain the ac~ive ingredients in admixture with any of the conventional excipients utilized in the preparation of such compositions, e.g., suspending agents such as methyl-5 cellulose, tragacanth and sodium alginate; wetting agents such aslecithin, polyoxyethylene s~earate and polyoxyethylene sorbitan monooleate; and preservatives such as ethyl p-hydroxybenzoate.
Capsules may contain the active ingrledients alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate lO and kaolin. The injectable compositions are formulated as known in the art. These pharmaceutical preparations may contain up to about 90% of the active ingredients in combination with the carrier or adjuvant. Preferably the preparations are put up in unit dosage form particularly in unit dosage form for oral administration. Such 15 forms may contain the active ingredients separately, e.g. in separate layers in a layer or mantle tablet or in split capsules~
A further aspect of the invention concerns a process for the production of a pharmaceutical preparation as stated above which comprises formulating active agent a) with active agent b) as stated above and optionally putting up the preparation in unit dosage form.
In an in-patient study, five patients ranging in age from 26 to 66 years suffering from depression and having a score of l9 to 30 on the Hamilton Depression Scale (A Rating Scale for Depression, M. Hamilton, Nerosurg. Psychiat. 239 56-62, 1960) were given 25 20 milligrams of nortriptyline and 2 milligrams of codergocrine mesylate three times a day for 4 weeks. [This dosage is below the recommended minimum therapeutic dose for nortriplyline of 75 mg/day.]
All five patients had a good response and improved significantly on the combination. The Hamilton Depression Scale score for each patient 30 dropped below 8 and the onset oF relief from the depression came much earlier than is normal with the antidepressant alone. Several patients noticed a significant improvement at the end of the first week. The incidence of side effects was very accepta~le and their seYerity was mtnimal to mild. All five patients in the study felt they were getting effective treatment for their depress;on. These results were confirmed in a multi-centre trial involving 53 patients whose ages range from 18 to 55 years.
Treatment is characterised by a rapid onset of action, steady continued improvement often leading to complete remission and low 10 incidence and intensity of side effects compared with treatment using anti-depressant alone.
The combined administration according to the invention is thus indicated for the treatment of depression.
The combined administration according to the invention is also 15 indicated for use in the treatment of the symptoms of senile dementia.
The combined administration according to the invention is thus particularly advantageous for the treatment of elderly people suffering from senile dementia associated with depression.
The co-administration of active agents a) and b) is accordingly 20 indicated in the treatment of depression and senile dementia parti-cularly when associated with each other.
Accordingly the invention further provides a method of treating depression and senile dementia with depression in a subject in need of such treatment, which method comprises concomitantly administering 25 to said subject an effective amount of an active agent a) and an active agent b) as stated above.
An indicated weight ratio of active agent a) to active agent b) is from about 50 : 1 to about 3 : 1, preferably 20 : 1 to 5 : I, especially 12 : 1 to 8 : 1.
7~L~ii5 For the preferred co-administration of nortriptyline and codergocrine mesylate a suitable ratio is e.g. ca. 10 : 1.
Compounds of formula I alone are normally administered orally in dosages ranging from 30 to 300 milligrams per day. The Maintainance 5 dosage range after remission and for administration according to the invention is from 30 to 150 milligrams per day. In the adolescent and elderly patient~ the dosage range may be much lower e.g. between 30 and 75 milligrams per day, the preferred range of the invention.
The especially preferred range is 50 to 60 milligrams per day. When 10 the compound of formula I is administered to the patient at the lower ranges in combination with 3 to 9 milligrams per day of codergocrine e.g. as codergocrine mesylate, the response is essentially equivalent to that obtained with the higher doses of anti-depressant. Examples of combined daily dosages are 3~ to 150 mg 15 of active agent a) with 3 to 9 mg of active agent b); espe~ially 30 to 75 mg, particularly 50 to 60 mg of nortriptyline with 3 to 9 mg of codergocrine mesylate. A particular combined daily dosage is 60 mg of nortriptyline ~ith 6 mg of codergocrine mesylate.
Conveniently the active agents are administered in sustained 20 release form or alternatively in divided doses 2 to 4 times a day containing e.g. 7.5 to 75 mg of active agent a) and either addition-ally or as a separate dosage form e.g. 0.5 to 6 mg of actiYe agent b).
Examples are dosage forms containing 10, 20, 25 or 75 mg of active agent a) and those containing additionally or as a separate 25 dosage form e.g. 0.5, 1.0, 1.5, 2 or 6 mg of active agent b). A parti-cular dosage form contains 20 mg of nortriptyline and 2 mg of codergocrine mesylate.
The invention also provides a pack comprising separately a plurality of dosage units of each of active agents a) and b) together 30 with instructions for their concomitant administration.
The following Example is illustrative of compositions for use in the invention.
- 7 ~ 600-6936 EXAMPLE
Tablets and Caesules Suitable for Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treat-ing e.g. depression at a dose of one tablet or capsule three times a day.
Weight (mg.) Ingredient TaBle Nortriptyline HCL (-20 mg Base) 22.7 22.7 Ergoloid mesylate 2 2 10 Tragacanth lo Lactose 172.8 225.3 Corn Starch 25 Talcum 15 Magnesium Stearate 2.5 250 ~ 250 Other capsules and tablets as well as e.g. suppositories, dispersible powders, syrups, elixirs, suspensions or solutions may also be made using conventional carriers and diluents for the desired formulation and may be administered enterally or parenterally 20 as apporpriate to a patient.
.~,.j . . ~ ..
Claims (9)
1. A pharmaceutical preparation comprising as active agents (a) a compound of formula I
I
wherein R1, R2 and R3 represent independently hydrogen, chloro or bromo, and R4 and R5 represent independently hydrogen, C1-6alkyl, benzyl or C3-8cycloalkyl, or a pharmaceutically acceptable acid addition salt thereof, and b) codergocrine in free base or pharmaceutically acceptable acid addition salt form.
I
wherein R1, R2 and R3 represent independently hydrogen, chloro or bromo, and R4 and R5 represent independently hydrogen, C1-6alkyl, benzyl or C3-8cycloalkyl, or a pharmaceutically acceptable acid addition salt thereof, and b) codergocrine in free base or pharmaceutically acceptable acid addition salt form.
2. A preparation according to Claim 1, wherein active agent a) is nortriptyline or the hydrochloride thereof.
3. A preparation according to Claim 1, wherein active agent b) is codergocrine mesylate.
4. A preparation according to Claim 1, 2 or 3, wherein the ratio of active agent a) to active agent b) is from about 50 : 1 to about 3 : 1 parts by weight.
5. A preparation according to Claim 1, 2 or 3, wherein the ratio of active agent a) to active agent b) is about 10 : 1 parts by weight.
6. A preparation according to Claim 1 in unit dosage form.
7. A preparation according to Claim 6 containing 10 to 25 mg of active agent a).
8. A process for the production of a pharmaceutical preparation according to Claim 1 which comprises formulating active agent a) with active agent b) as defined in Claim 1.
9. A pack comprising separately a plurality of dosage units of each of active agents a) and b) as defined in Claim 1, 2 or 3, together with instructions for their concomitant administration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36046382A | 1982-03-22 | 1982-03-22 | |
| US360,463 | 1982-03-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1197465A true CA1197465A (en) | 1985-12-03 |
Family
ID=23418055
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000424059A Expired CA1197465A (en) | 1982-03-22 | 1983-03-21 | Pharmaceutical composition containing a dibenzocycloheptadiene anti-depressant and an ergot alkaloid |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS58174317A (en) |
| AU (1) | AU1262283A (en) |
| BE (1) | BE896170A (en) |
| CA (1) | CA1197465A (en) |
| CH (1) | CH652927A5 (en) |
| DE (1) | DE3308855A1 (en) |
| FR (1) | FR2527077B1 (en) |
| GB (1) | GB2116843B (en) |
| GR (1) | GR77165B (en) |
| HU (1) | HU190714B (en) |
| IL (1) | IL68184A (en) |
| IT (1) | IT1163156B (en) |
| NL (1) | NL8300986A (en) |
| NZ (1) | NZ203632A (en) |
| PH (1) | PH22086A (en) |
| PT (1) | PT76417B (en) |
| SE (1) | SE8301530L (en) |
| ZA (1) | ZA832005B (en) |
-
1983
- 1983-03-10 CH CH1296/83A patent/CH652927A5/en not_active IP Right Cessation
- 1983-03-12 DE DE19833308855 patent/DE3308855A1/en not_active Withdrawn
- 1983-03-16 FR FR8304428A patent/FR2527077B1/en not_active Expired
- 1983-03-16 BE BE1/10740A patent/BE896170A/en not_active IP Right Cessation
- 1983-03-18 JP JP58044528A patent/JPS58174317A/en active Pending
- 1983-03-18 GR GR70832A patent/GR77165B/el unknown
- 1983-03-18 NL NL8300986A patent/NL8300986A/en not_active Application Discontinuation
- 1983-03-21 PT PT76417A patent/PT76417B/en unknown
- 1983-03-21 IT IT20186/83A patent/IT1163156B/en active
- 1983-03-21 AU AU12622/83A patent/AU1262283A/en not_active Abandoned
- 1983-03-21 HU HU83934A patent/HU190714B/en unknown
- 1983-03-21 CA CA000424059A patent/CA1197465A/en not_active Expired
- 1983-03-21 IL IL68184A patent/IL68184A/en unknown
- 1983-03-21 NZ NZ203632A patent/NZ203632A/en unknown
- 1983-03-21 SE SE8301530A patent/SE8301530L/en not_active Application Discontinuation
- 1983-03-21 GB GB08307751A patent/GB2116843B/en not_active Expired
- 1983-03-22 ZA ZA832005A patent/ZA832005B/en unknown
- 1983-06-01 PH PH28998A patent/PH22086A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU190714B (en) | 1986-10-28 |
| IL68184A (en) | 1986-04-29 |
| GB2116843A (en) | 1983-10-05 |
| PT76417A (en) | 1983-04-01 |
| NL8300986A (en) | 1983-10-17 |
| PH22086A (en) | 1988-05-20 |
| NZ203632A (en) | 1986-09-10 |
| DE3308855A1 (en) | 1983-09-29 |
| BE896170A (en) | 1983-09-16 |
| PT76417B (en) | 1985-12-16 |
| SE8301530L (en) | 1983-09-23 |
| IT1163156B (en) | 1987-04-08 |
| CH652927A5 (en) | 1985-12-13 |
| IT8320186A0 (en) | 1983-03-21 |
| JPS58174317A (en) | 1983-10-13 |
| AU1262283A (en) | 1983-09-29 |
| GB2116843B (en) | 1986-01-15 |
| ZA832005B (en) | 1984-11-28 |
| GR77165B (en) | 1984-09-10 |
| IL68184A0 (en) | 1983-06-15 |
| FR2527077A1 (en) | 1983-11-25 |
| SE8301530D0 (en) | 1983-03-21 |
| GB8307751D0 (en) | 1983-04-27 |
| FR2527077B1 (en) | 1986-08-22 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEC | Expiry (correction) | ||
| MKEX | Expiry |