US2778772A - Dimethyl phenyl piperazinium iodide compositions and process for stimulation of the autonomic ganglion system - Google Patents
Dimethyl phenyl piperazinium iodide compositions and process for stimulation of the autonomic ganglion system Download PDFInfo
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- US2778772A US2778772A US318761A US31876152A US2778772A US 2778772 A US2778772 A US 2778772A US 318761 A US318761 A US 318761A US 31876152 A US31876152 A US 31876152A US 2778772 A US2778772 A US 2778772A
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- stimulation
- dimethyl
- compositions
- dimethyl phenyl
- sympathetic
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- Expired - Lifetime
Links
- 239000000203 mixture Substances 0.000 title claims description 13
- 230000000638 stimulation Effects 0.000 title claims description 8
- 210000003192 autonomic ganglia Anatomy 0.000 title description 5
- 238000000034 method Methods 0.000 title description 4
- XFZJGFIKQCCLGK-UHFFFAOYSA-M 1,1-dimethyl-4-phenylpiperazinium iodide Chemical compound [I-].C1C[N+](C)(C)CCN1C1=CC=CC=C1 XFZJGFIKQCCLGK-UHFFFAOYSA-M 0.000 title 1
- 210000000192 parasympathetic ganglia Anatomy 0.000 claims description 12
- 210000000331 sympathetic ganglia Anatomy 0.000 claims description 11
- 230000002889 sympathetic effect Effects 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- CIFWTDOEMTUUAO-UHFFFAOYSA-N naphthofluorescein diacetate Chemical compound O1C(=O)C2=CC=CC=C2C21C(C=CC=1C3=CC=C(OC(C)=O)C=1)=C3OC1=C2C=CC2=CC(OC(=O)C)=CC=C21 CIFWTDOEMTUUAO-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 7
- 230000004936 stimulating effect Effects 0.000 description 6
- 239000003457 ganglion blocking agent Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 4
- 229930182837 (R)-adrenaline Natural products 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229960005139 epinephrine Drugs 0.000 description 4
- 210000001943 adrenal medulla Anatomy 0.000 description 3
- 230000001766 physiological effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 2
- 208000003098 Ganglion Cysts Diseases 0.000 description 2
- 208000005400 Synovial Cyst Diseases 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 210000000609 ganglia Anatomy 0.000 description 2
- 230000000574 ganglionic effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229960002715 nicotine Drugs 0.000 description 2
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000001834 epinephrinelike Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- -1 halide compound Chemical class 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 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
Definitions
- This invention relates to compositions useful for stimulating the autonomic ganglia containing as the effective ingredient 1,1-dimethyl-4-phenylpiperazinium iodide.
- this previously known compound Chemical Abstracts 29, 4013 (1935)
- This newly discovered property makes it possible to use the compound for the laboratory determination of the effectiveness of potential ganglionic blocking agents.
- the autonomic ganglion system is composed of the sympathetic ganglia and the parasympathetic ganglia. Stimulation of the sympatthetic ganglia causes release of an epinephrine-like substance by the postganglionic fibers while stimulation of the parasympathetic ganglia causes release of acetyl choline by both the preand post-ganglionic fibers.
- compositions of the present invention are prepared by dissolving l,l-dimethyl-4-phenylpiperazinium iodide in water, isotonic saline or isotonic glucose and sterilizing the resulting solutions by heat or by Zeitz filtration. It will also be appreciated that the compositions can be prepared under aseptic conditions using sterile ingredients.
- the solutions which are the most useful in the detection of ganglionic disorders are those containing 0.5 to 5 milligrams of the quaternary halide compound in each milliliter of the solution. These solutions are administered by the parenteral route and preferably intravenously.
- compositions of the invention can be demonstrated on the sympathetic ganglia using pentobarbitalized cats and measuring the contraction of the nictating membrane caused by injection of a measured quantity of the composition.
- 200 micrograms per kg. of 1,1-dimethyl-4-phenylpiperazinium iodide give the same degree of response as 5 micrograms per kg. of
- the physiological effect on the parasympathetic ganglia can be demonstrated by the increase in bladder pressure of female dogs under pentobarbital anesthesia following intravenous injection of a solution of 1,1-dimethyl-4- phenylpiperazinium iodide. In this test it only required 10 to 20 micrograms per kg. of 1,1-dimethyl-4-phenylpiperazinium iodide in order to bring about a change in bladder pressure and it was possible to block this pressure change completely by the administration of 10 milligrams per kg. of triethylammonium chloride.
- compositions of the invention exert a stimulating effect upon the ganglion-like material of the adrenal medulla and are therefore useful in determining the ability of the adrenal medulla to produce epinephrine.
- compositions of the invention are relatively nontoxic.
- the LDso of 1,1-dimethyl-4-phenylpiperazinium iodide is 27.5 milligrams per kg. in mice given intramuscularly and l milligram per kg. in rabbits intravenously.
- Example 1 milligrams of 1,1-dimethyl-4-phenylpiperazinium iodide is dissolved in 100 ml. of an isotonic salt solution containing 850 milligrams of sodium chloride. 1 ml. portions of the solution are placed in 2 m1. ampoules and the ampoules sealed. The ampouled material is sterilized by heating the ampoules in an autoclave for twenty minutes at C. The material in the ampoules is assayed for its effect upon the sympathetic and parasympathetic ganglia by the methods mentioned above. Each ampoule should contain approximately one milligram per milliliter of 1,1-dimethyl-4-phenylpiperazinium iodide.
- Example 2 50 mg. of 1,1-dimethyl-4-phenylpiperazinium iodide is dissolved in 100 ml. of distilled water. 1 ml. portions of the solution are placed in glass ampoules and the ampoules sealed. The ampouled material is sterilized by heating in a steam autoclave for fifteen minutes at fifteen pounds pressure steam. The material in the ampoules is assayed by the methods mentioned in Example 1. Each ampoule should contain 0.5 milligram of 1,1-dimethyl-4- phenylpiperazinium iodide.
- a composition for the stimulation of the sympathetic and parasympathetic ganglia comprising an aqueous solution containing 0.5 to 5 milligrams per milliliter of 1,1- dimethyl-4-phenylpiperazinium iodide.
- a composition for the stimulation of the sympathetic and parasympathetic ganglia consisting of a sterile, aqueous, isotonic, saline solution containing 1 milligram per milliliter of l,l-dimethyl-4-phenylpiperazinium iodide.
- a composition for the stimulation of the sympathetic and parasympathetic ganglia consisting of a sterile, aqueous solution containing 0.5 milligram per milliliter of 1,1-dimethy1-4-phenylpiperazinium iodide.
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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)
- Medicinal Preparation (AREA)
Description
United States Patent Graham Chen, Detroit, Mich., assignor to Parke, Davis & Company, a corporation of Michigan Application November 4, 1952, Serial No. 318,761
No Drawing.
4 Claims.
This invention relates to compositions useful for stimulating the autonomic ganglia containing as the effective ingredient 1,1-dimethyl-4-phenylpiperazinium iodide. I have discovered that this previously known compound, Chemical Abstracts 29, 4013 (1935), has the physiological property of exerting a stimulating effect on both the sympathetic and parasympathetic ganglia. This newly discovered property makes it possible to use the compound for the laboratory determination of the effectiveness of potential ganglionic blocking agents.
The autonomic ganglion system is composed of the sympathetic ganglia and the parasympathetic ganglia. Stimulation of the sympatthetic ganglia causes release of an epinephrine-like substance by the postganglionic fibers while stimulation of the parasympathetic ganglia causes release of acetyl choline by both the preand post-ganglionic fibers.
In many clinical conditions the normal functions of the autonomic ganglion system are impaired or stimulated and it is of great value to the practitioner to be able to ascertain whether this is due to the ganglion system itself or some other cause. In order to test the functioning of the autonomic ganglion system it is necessary to utilize some substance which will disturb in a controllable fashion the normal operation of the sympathetic and parasympathetic ganglia. It is known that nicotine is capable of stimulating both the sympathetic and parasympathetic ganglia. However, nicotine is a relatively weak stimulant and is unsatisfactory and dangerous to use clinically due to the depressive, toxic and paralyzing effects which it produces. Epinephrine and norepinephrine exert a stimulating effect upon the effector cells but they do not act on either the sympathetic or parasympathetic ganglia.
The compositions of the present invention are prepared by dissolving l,l-dimethyl-4-phenylpiperazinium iodide in water, isotonic saline or isotonic glucose and sterilizing the resulting solutions by heat or by Zeitz filtration. It will also be appreciated that the compositions can be prepared under aseptic conditions using sterile ingredients. The solutions which are the most useful in the detection of ganglionic disorders are those containing 0.5 to 5 milligrams of the quaternary halide compound in each milliliter of the solution. These solutions are administered by the parenteral route and preferably intravenously.
The physiological effect of the compositions of the invention can be demonstrated on the sympathetic ganglia using pentobarbitalized cats and measuring the contraction of the nictating membrane caused by injection of a measured quantity of the composition. When tested in accordance with this method 200 micrograms per kg. of 1,1-dimethyl-4-phenylpiperazinium iodide give the same degree of response as 5 micrograms per kg. of
'" ice (iiii'iiizvhfiiii: tiiiiiiig'l'i the areas; cells: The errataof the l,l-dimethyl-4-phenylpiperazinium iodide are completely blocked by the administration of 10 milligrams perkg. of the ganglionic blocking agent, triethylammoniurn chloride. Under these same conditions the stimulating effect of epinephrine was not blocked because it does not act upon the ganglia.
The physiological effect on the parasympathetic ganglia can be demonstrated by the increase in bladder pressure of female dogs under pentobarbital anesthesia following intravenous injection of a solution of 1,1-dimethyl-4- phenylpiperazinium iodide. In this test it only required 10 to 20 micrograms per kg. of 1,1-dimethyl-4-phenylpiperazinium iodide in order to bring about a change in bladder pressure and it was possible to block this pressure change completely by the administration of 10 milligrams per kg. of triethylammonium chloride.
The compositions of the invention exert a stimulating effect upon the ganglion-like material of the adrenal medulla and are therefore useful in determining the ability of the adrenal medulla to produce epinephrine. In utilizing the compositions for this purpose one injects a measured quantity of the ganglionic stimulating agent and measures the amount of stimulation obtained with and without a ganglionic blocking agent. The difference in the response obtained under these two conditions is a measure of the adrenal medullas ability to produce epinephrine.
The compositions of the invention are relatively nontoxic. For example, the LDso of 1,1-dimethyl-4-phenylpiperazinium iodide is 27.5 milligrams per kg. in mice given intramuscularly and l milligram per kg. in rabbits intravenously.
The invention is illustrated by the following examples:
Example 1 milligrams of 1,1-dimethyl-4-phenylpiperazinium iodide is dissolved in 100 ml. of an isotonic salt solution containing 850 milligrams of sodium chloride. 1 ml. portions of the solution are placed in 2 m1. ampoules and the ampoules sealed. The ampouled material is sterilized by heating the ampoules in an autoclave for twenty minutes at C. The material in the ampoules is assayed for its effect upon the sympathetic and parasympathetic ganglia by the methods mentioned above. Each ampoule should contain approximately one milligram per milliliter of 1,1-dimethyl-4-phenylpiperazinium iodide.
Example 2 50 mg. of 1,1-dimethyl-4-phenylpiperazinium iodide is dissolved in 100 ml. of distilled water. 1 ml. portions of the solution are placed in glass ampoules and the ampoules sealed. The ampouled material is sterilized by heating in a steam autoclave for fifteen minutes at fifteen pounds pressure steam. The material in the ampoules is assayed by the methods mentioned in Example 1. Each ampoule should contain 0.5 milligram of 1,1-dimethyl-4- phenylpiperazinium iodide.
What I claim is:
1. A composition for the stimulation of the sympathetic and parasympathetic ganglia comprising an aqueous solution containing 0.5 to 5 milligrams per milliliter of 1,1- dimethyl-4-phenylpiperazinium iodide.
2. A composition for the stimulation of the sympathetic and parasympathetic ganglia consisting of a sterile, aqueous, isotonic, saline solution containing 1 milligram per milliliter of l,l-dimethyl-4-phenylpiperazinium iodide.
3. A composition for the stimulation of the sympathetic and parasympathetic ganglia consisting of a sterile, aqueous solution containing 0.5 milligram per milliliter of 1,1-dimethy1-4-phenylpiperazinium iodide.
4. The method of testing the efiectiveness of ganglionic blocking agents, comprising administering to an experimental animal- 1,1-dimethyl-4-phenylpiperazinium iodide for the laboratory determination of the effectiveness of potential ganglionic blocking agents.
References Cited in the file of this patent Howard: Modern Drug Encyclopedia, fifth ed. Drug Publications 1952, New York, pages 113-114.
Claims (1)
1. A COMPOSITION FOR THE STIMULATION OF THE SYMPATHETIC AND PARASYMPATHETIC GANGLIA COMPRISING AN AQUEOUS SOLUTION CONTAINING 0.5 TO 5 MILLIGRAMS PER MILLILITER OF 1,1DIMETHYL-4-PHENLPIPERAZINIUM IODIDE.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US318761A US2778772A (en) | 1952-11-04 | 1952-11-04 | Dimethyl phenyl piperazinium iodide compositions and process for stimulation of the autonomic ganglion system |
| US619925A US2991227A (en) | 1952-11-04 | 1956-11-02 | Dimethyl phenyl piperidinium iodide compositions for stimulation of the autonomic ganglion system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US318761A US2778772A (en) | 1952-11-04 | 1952-11-04 | Dimethyl phenyl piperazinium iodide compositions and process for stimulation of the autonomic ganglion system |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2778772A true US2778772A (en) | 1957-01-22 |
Family
ID=23239484
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US318761A Expired - Lifetime US2778772A (en) | 1952-11-04 | 1952-11-04 | Dimethyl phenyl piperazinium iodide compositions and process for stimulation of the autonomic ganglion system |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2778772A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2991227A (en) * | 1952-11-04 | 1961-07-04 | Parke Davis & Co | Dimethyl phenyl piperidinium iodide compositions for stimulation of the autonomic ganglion system |
| US20040132737A1 (en) * | 2001-03-23 | 2004-07-08 | Yvon Cormier | Nicotinic receptor agonists for the treatment of inflammatory diseases |
| US20050130990A1 (en) * | 2001-03-23 | 2005-06-16 | Universite Laval | Nicotinic receptor agonists for the treatment of inflammatory diseases |
| US20080221085A1 (en) * | 2004-07-15 | 2008-09-11 | Universite Laval | Nicotinic Receptor Agonists for the Treatment of Inflammatory Diseases |
| US8557804B2 (en) | 2002-03-25 | 2013-10-15 | Universite Laval | Nicotinic receptor agonists for the treatment of inflammatory diseases |
-
1952
- 1952-11-04 US US318761A patent/US2778772A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2991227A (en) * | 1952-11-04 | 1961-07-04 | Parke Davis & Co | Dimethyl phenyl piperidinium iodide compositions for stimulation of the autonomic ganglion system |
| US20040132737A1 (en) * | 2001-03-23 | 2004-07-08 | Yvon Cormier | Nicotinic receptor agonists for the treatment of inflammatory diseases |
| US20050130990A1 (en) * | 2001-03-23 | 2005-06-16 | Universite Laval | Nicotinic receptor agonists for the treatment of inflammatory diseases |
| US20070249622A1 (en) * | 2001-03-23 | 2007-10-25 | Universite Laval | Nicotinic receptor agonists and analogues and derivatives thereof for the treatment of inflammatory diseases |
| US7601720B2 (en) | 2001-03-23 | 2009-10-13 | Universite Laval | Nicotinic receptor agonists for the treatment of inflammatory diseases |
| US8377936B2 (en) | 2001-03-23 | 2013-02-19 | Universite Laval | Nicotinic receptor agonists for the treatment of inflammatory diseases |
| US8551983B2 (en) | 2002-03-25 | 2013-10-08 | Universite Laval | Nicotinic receptor agonists for the treatment of inflammatory diseases |
| US8557804B2 (en) | 2002-03-25 | 2013-10-15 | Universite Laval | Nicotinic receptor agonists for the treatment of inflammatory diseases |
| US20080221085A1 (en) * | 2004-07-15 | 2008-09-11 | Universite Laval | Nicotinic Receptor Agonists for the Treatment of Inflammatory Diseases |
| US8039459B2 (en) | 2004-07-15 | 2011-10-18 | Universite Laval | Nicotinic receptor agonists for the treatment of inflammatory diseases |
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