AU8833098A - Treatment of anorectal disorders - Google Patents
Treatment of anorectal disorders Download PDFInfo
- Publication number
- AU8833098A AU8833098A AU88330/98A AU8833098A AU8833098A AU 8833098 A AU8833098 A AU 8833098A AU 88330/98 A AU88330/98 A AU 88330/98A AU 8833098 A AU8833098 A AU 8833098A AU 8833098 A AU8833098 A AU 8833098A
- Authority
- AU
- Australia
- Prior art keywords
- substance
- treatment
- relaxation
- anal
- anal sphincter
- 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.)
- Abandoned
Links
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- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 18
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- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
-1-
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT
ORIGINAL
Name of Applicant: Actual Inventor: KOREN LABORATORIES PTY. LTD., A.C.N. 003 279 794 David LUBOWSKI Address of Service: BALDWIN SHELSTON WATERS 60 MARGARET STREET SYDNEY NSW 2000 Invention Title: "TREATMENT OF ANORECTAL DISORDERS" Details of Original Application No. 74545/94 dated 19th August 1994 The following statement is a full description of this invention, including the best method of performing it known to us:la TREATMENT OF ANORECTAL DISORDERS The present invention relates to a new method of treating anorectal disorders in animals, and particularly in humans, by administering to a patient requiring such treatment specific compounds, as described hereafter. The invention is particularly concerned with the treatment of haemorrhoids and anal fissure in humans.
The treatment can be used with various anorectal disorders, includil haemorrhoids, both internal and external, anal fissure, and generalised anal pain.
Various anal conditions such as haemorrhoids and fissure-in-ano, are associated with spasm of the internal anal sphincter. Up to the present time, no effective treatment is known for these conditions, other than various local surgical procedures. These surgical procedures involve stretching or cutting the anal sphincter in order to relieve the spasm.
Also, topical ointments and creams are available, but these are not believed to have any direct influence on the anal conditions, but simply have analgesic or anti-inflammatory activity, in order to temporarily relieve the symptoms and pain. Sometimes these conditions occur when there is no measurable spasm. To date, no agent is known which can effectively relax the spasm of the anal sphincter muscle, or relax the muscle, _and surgical treatment has been the only effective method of treatment of these conditions before the present time.
More specifically, haemorrhoids (also known as piles) are a varicose condition of the haemorrhoidal veins, causing painful swellings at the anus, as well as bleeding in some cases. With external haemorrhoids, the dilated veins form tumours on the outer side of the external sphincter, or are covered by the skin of the anal canal. Internal haemorrhoids occur when the swollen veins are beneath the mucous membrane within the sphincter. By the age of fifty, as many as 50% of people have haemorrhoids. The reason why haemorrhoids occur is not fully understood at present but may be caused by increased intra-abdominal pressure which may be caused by pregnancy, or straining in passing 2 stools, or alternatively it is believed that some hormonal influence may affect the rich network of blood vessels at the anus in such a way as to cause haemorrhoids to form.
The usual symptoms of haemorrhoids are bleeding, protrusion and pain. Ulcerated or thrombosed haemorrhoids are very painful. The pain caused by haemorrhoids can be severe or even incapacitating and methods of treatment of haemorrhoids have changed hardly at all in recent times. For severe pain, local anaesthetic can be applied topically and protruding internal haemorrhoids can be treated by rubber-band ligation. The usual therapy for haemorrhoids that cause only slight bleeding or minimal discomfort is warm sitz baths and stool softeners. Internal haemorrhoids that bleed persistently are treated by injection or by rubber-band ligation. Sometimes ointments and suppositories which are advertised widely for therapy of haemorrhoids can be used, but these, while of some assistance in relieving pain and discomfort, have no real therapeutic effect in curing the condition.
Anal fissure (fissure-in-ano) is a condition involving an acute longitudinal tear, or a chronic ovoid ulcer, in the stratified squamous epithelium of the anal canal. The exact causes of this condition is not known, though traumatic laceration from a hard or large stool may be involved. Fissures cause pain and bleeding with defecation. The pain typically occurs with or shortly following defecation, lasts for several hours, and then subsides until the next bowel movement.
It has been known for some time that the internal anal sphincter relaxes in response to rectal distension, which is known as "the rectanal inhibitory reflex". However little is known -f the chemical mechanisms involved in this reflex. 'The nerves mediating the rectanal inhibitory reflex lie within the walls of the gut ahd are known as "enteric (intrinsic) inhib:itorv n r~e- These neurones descend from the rectum to the internal anal sphincter and are known not to. use classical neurotransminer substances, such as acetylcholine or noradrenaline. fThese nerves are classified as non-adrenergic. noncholinergic (NANC) nerves. Recently. a variety of substances such as nitric oxide (NO).
and carbon monoxide (CO) are thought to act as neurotransmitters in the gastrointestinal tract, and have been reported as being involved in the nerve mediated relaxa'ion of the internal anal sphincter. In the body, nitric oxide is synthesised from L-arginine in a reaction catalysed by NO synthase. The NO synthase enzyme exhibits a high degree of substrate specificity, (for example NO is not produced from D-arginine), and is dependent on several cofactcrs including the presence of Ca 2 ions, calmodulin and reduced nicotinamide adenine dinucleotide phosphate. NO is very soluble, anc diffu.es rapidly in the body. It has a very short half life of only three seconds, and is ,!nctivted by the formation of nitrate after contact with the superoxide anion CO is produced from heme by tde e nyme heme oxygenase.
Until the present invention, it had not been realised that substances which mediate either directly or indirectly relaxation of the anal sphincter may be used in the treatment of haemorrhoids, anal fissure, and other anorectal disorders.
The invention in one form therefore concerns a method of treating various anorectal conditions in an animal (including a human) which comprises administering to a subject in need of such treatment an effective amount of at least one substance which mediates relaxation of the anal sphincter. Preferably the substance modulates or influences NO or CO neurotransmitter ability. By this is meant that the substance has one or more of the effects of increasing the levels of NO or CO in the anorectal region, increasing the half life of endogenous NO or CO, increasing the affinity of NO or CO for their receptor ii the anal sphincter. blocking inhibitors of NO or CO binding to their respective receptors, and increasing access of NO or CO to their receptor. It is to be understood that this Sinvention is not limited to substances which modulate or influence NO or CO neurotransmitter ability. Rather, the invention extends to the iise of any substance or combination of substances which mediate relaxation of the anal sphincter, which may hereinafter be referred to as anal sphincter relaxation substances.
Levels of NO or CO in the anorectal region may be increased by substances which are a source of NO or CO themselves (ie breakdown to form NO or CO in the presence of enzymes and/or other compounds in the body, or form NO or CO as a result of I4 actvating compounds which form part of the composition) or which stimulate endogenous compounds (such as L-arginine or heme oxygenase) within the body to produce NO or CO for subsequent relaxation of the anal sphincrer. Any substance which modulates or influences :-urotransmitter ability in the manner described above may be utilised in this invention. Preferred substances which may be used according to the invention include anitrates, vasodilators, amino acids which break down to form NO, calcium channel blockers and the like.
Any nitrate compound or compound which breaks down in the body to form NO and which is non-toxic may be utilized according to this invention compounds which may be utilized include compounds which fall within the classes known as mononitrate, dinitrates, trinitrates, tetranitrates and the like. For example, nitrate compounds may be selected from isosorbide dinirate, amyl nitrate, pentaerythritol teuanitrate, nirroolycerine (glyceryl nitrate) and the like. Nitroglycerine is particularly preferred for use in treating anorectal disorders such as haemorrhoids. anal fissure and similar conditions.
Vasodilator compounds, particularly those that influence NO neurotransmiEter ability, can also be utilized in the inventio. and these include hvdralazine, and sodium or other salts of nitroprusside (nitroprusside being kn;wn as a donor of NO). Any vasodilator compound which is pharmaceutically acceptable and which relaxes the anal sphincter may be used in the invention. Examples of such compounds include alpreolol, amlodipine. atenolol, diltiazem, felodipine, limaprost. mem2prolol, nicardipine, nifedipine, oxprenolol prinadol, propranolol and the like.
Still other anal sphincter relaxation substances which may be used in the invention include acetyl choline, prostaglandins, vasoactive inrestina polk pipide, histamine. Larginine, and the like. Compounds which stinilate heme oxv-nase production within the body may also be utilized in the invention.
'i@a Mixtures of more than one of the aforementioned active ingredients can also be utilized in the invention. For example, nitroglycerine can be utilized together with a longacting nitrate, to allow longer lasting relief from haemorrhoid and other anorectal pain.
As mentioned previously, many anorectal conditions can be treated in accordance with the invention, including internal and external haemorrhoids, anal fissure, anal pain, and other, similar, conditions.
The active ingredients of the invention may be administered orally, topically, transdermally, parenterally such as by direct injection into the site of anorectal pain, by inhalation, transdermally, intrarectally, or to tissue surrounding the anus. Preferably, the active ingredients of the invention are administered directly to the anus. Non-oral administration routes are preferred for nitrate compounds such as nitroglycerine which may be inactivated by the liver. For topical administation, formulations such as ointments, creams, lotions and solutions are preferred. Long acting slow release dermal or other such device patches which release nitroglycerine or other active ingredients may be utilised.
Rectal suppositories containing active ingredients as described are also contemplated by the invention.
20 The amount of active ingredient to be applied will vary, in accordance with the method of application chosen the activity of the active ingredient. For example, an active ingredient may be present in a composition in an amount from about 0.0001% wlw to w/w or more. When nitroglycerine is the active ingredient, therapeutic compositions may contain the nitroglycerine in an amount of approximately 0.001 to 0.2% w/w, together with an hormone carriers component or other components. More preferably the amount of nitroglycerine present in a therapeutic composition is between about 0.1% and 0.2% wlw.
Comoosition or formulations for the administration of active agents according to the invention may be prepared with any suitable excipient or diluent as are weli known in the an. such as are described in Remingtons Pharmaceutical Sciences (10th Edition. Mack 6 Publishing Company, Philadelphia. USA) which is incorporated herein by reference.
Particularly preferred are those carriers and excipients well known in the art for anorectal administration, such as for the treatment of haemorrhoids, fissure and the like The formulations of the present invention may also include other ingredients which act as analgesics or anti-inflammatory agents. For example, in addition to the active ingredients, as described above; further analgesic andlor anti-inflammatory agents include benzocaine, lignocaine, xylocaine, cinchocaine, hydrocortisone, prednisolone, prednisone, adrenalin or methylhydroxybenzoate, are just some examples. Calcium channel blockers 10 may also be further active ingredients. Preferred secondary ingredients include compounds which have previously been used to treat haemorrhoids, anal fissure, and other anal conditions. The amounts cf the secondary ingredients present are chosen according to standard practice in the art.
This invention also relates to a method for the manufacture of a medicament for the teatment of anorectal conditions in an animal, which comprises admixing at least one substance which mediates relaxation of the anal sphincter with one or more pharmaceutically acceptable excipients or diluents.
The invention further relates to the use of one or more anal sphincter relaxation substance in the manufacture of a medicament for the treatment of anorectal conditions in animals.
In still another aspect;,the invention relates to the use of one or more anal sphincter T 25 relaxation substances in the treamerif-of anorectal conditions in animals.
The invention is now described with reference to various examples. Whilst these exampies relate to the use6f nitroilycerine it is to be understood that the invention is not.
of course, restricted to the use of this compound.
i 7 EXAMPLE 1 Ointment Formulation A formulation was prepared containing glyceryl trinitrate (GTN nitroglycerine) in an amount of 0.2% w/w, with the remainder of the formulation being soft yellow paraffin BP. A second formulation was made in the same manner, but with the glycerol trinitrate being present in an amount of 0.1% wlw, with the same ointment base.
EXAMPLE 2 Treatment of Anal Fissure Condition A number of patients presenting to the Colorectal Unit attached to a large Sydney Hospital were entered into a trial. All the patients had symptomatic anal fissure, which would otherwise have required surgery. Subjects having anal fissure were chosen for the trial since the effects of the treatment are able to be monitored very easily.
Forty three patients were entered into a double-blind, randomised placebocontrolled trial. Subjects were randomly allocated either a 0.2% GTN paste, as described in Example 1, or otherwise a placebo containing no active ingredients, but identical in all other respects. Each subject underwent a detailed anorectal physiology study to--test pressures within the anal canal. Each subject also filled in a pain score on a linear analogue scale, and progress in the healing of the fissure was monitored by two observers who were blinded to the form of treatment being given_ The twenty four patients who received GTN all experienced a successful chemical sphincterotomy resulting in a statisticaliv significant improvement in pain, fissure grade and anal canal pressure compretd with the placebo group of nineteen patients.
I
EXAMPLE 3 Treatment of Haemorrhoids The 0.2% and 0.1 cream as described in Example I was tested with ten patients suffering from internal haemorrhoids. All patients exhibited haemorrhoid relief including reduction in haemorrhoid size, extent of bleeding, and less discomfort.
While the present invention is described with reference to various Examples, these Examples are not intended to be limiting on the invention, and other obvious modifications :of the present invention can be utilized without departing from its broad scope as described previously.
o
Claims (24)
- 2. A method accordinga to cla im wherein said substance is a source of nitric oxide or carbon monoxide.
- 3. A method accordinq to, claim 1 wherein said substance is a nitrate compound-
- 4. A method according to claim 3 wherein said nitatecmoidi eetdfo isosorbide dinitrate, amyLnirrate, pentaetythrritoI, tetranirrate, and nitroglycerine. A method accor.ding to claim 1 wherein said substance is nitrozlvcerine.
- 6- A method accordinsE to claim I wherein said substance is a .asodilator.
- 7- A method accordinsi to claim 6 wherein said vasodilator is Selected from alpreolol, amlodipine, atenolol, diltiazeem, felodipine, lirnaprost, met aprolol, nicardipine. nifedipine. oxprenolol, prinladol, and propranolol. 8& A method accordine to claim 1 wherein said subs5tance Is Selected from acety)l choline. L-arsiinirje. vasoactive intestinal polvo~eptide. histamine or a prostaglandin.
- 9. A method according to claim I wherein said substance is administ-tred in association with an, analgzesic and/or anti-inflamnmatory agent.
- 10. A method according to. anv one of claims 1 to. 9 wherein said substance is administered in association with one or more pharmaceutical v acceptablecarr. A method according to claim I wherein said substance is administered topically, subcutaneously, transdermnall', parenterally, or interrectally.
- 12. A method accordinea to claim I for the treatment of haetnorrhoids-
- 13. A method accordin-a to claim 1 for the LreaM~entE of anal fissure-
- 14. A method according for the treactmenE of anorectal conditions in an animnal which comprises administeri to a subject in need of such treauncor[ an effrective amount of at least one substance which modulates nitric oxide or carbon monoxide neurotransiter ability- A methdod acc-ordine to claim 14 wherein said substance is a source of nitric oxide or carbon monoxide.
- 16. A method accordinz to claim wherein said substance is a nitrate compound.
- 17. A method accordine to claim 14 wherein said nitrate compound is selected fr~om isosorbide dinitrate, ainylnitrate, pentaetythritoi Eetranitrar, and nitroglycerine-
- 18. Al method accordinig to claim 14 wherein said substance is niroglcen-ne.
- 19. A method accordina to claim 14 wherein said substance- is a vasodila-or-
- 20. A method accordins ta claim 19 wherein said vasodila:oi is selected From aipreolol, amlodipine. atenol&~, diltiaze-M, felodipine. limaprosc. maetaprolol. nicardipine. mifedivine, oxprenolol. prinadol. and propranolot-
- 21. A method according to claim 14 wherein said substance is selected from acervi choline and L-arsinine- 11
- 22. A method according to claim 14 wherein said substance is administered in association with an analgesic and/or anti-inflammatory agent. 22. A method according to 14 wherein said substance is administered in association with one or more pharmaceutically acceptable carriers.
- 23. A method according to claim 14 wherein said substance is administered topically, subcutaneously, transdermally, parenterally, or interrectally.
- 24. A method according to claim 14 for the treatment of haemorrhoids. A method according to claim 14 for the treatment of anal fissure.
- 26. A method for the manufacture of a medicament for the treatment of anorectal conditions in an animal, which comprises admixing at least one substance which mediates relaxation of the anal sphincter with one or more pharmaceutically acceptable excipients or diluents.
- 27. A method according to claim 26 wherein said substance which mediates relaxation of the anal sphincter is selected from a compound according to any one of claims 2 through 8.
- 28. Use of one or more anal sphincter relaxation substances in the treatment of anorectal conditions in animals.
- 29. Use of one or more anal sphincter relaxation substances in the manufacture of a medicament for the treatment of anorectal conditions in animals. An agent for the treatment of anorectal conditions in animals which comprises at least one substance which mediates the relaxation of the anal sphincter. 12
- 31. An agent according to claim 30 wherein said substance which mediates the relaxation of the anal sphincter is a substance according to any one of claims 1 through 8. DATED this 6th Day of October, 1998 ~.KOREN LABO0RATORTES PTY LTD. fl±~:Attorney: IAN T ERNST Fellow Institute of Patent Attorneys of Australia of BALDWIN SHELSTON WATERS
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU88330/98A AU8833098A (en) | 1993-09-01 | 1998-10-06 | Treatment of anorectal disorders |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AUPM0971 | 1993-09-01 | ||
| AUPM4247 | 1994-03-04 | ||
| AUPM6395 | 1994-06-22 | ||
| AU74545/94A AU708694C (en) | 1993-09-01 | 1994-08-19 | Treatment of anorectal disorders |
| AU88330/98A AU8833098A (en) | 1993-09-01 | 1998-10-06 | Treatment of anorectal disorders |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU74545/94A Division AU708694C (en) | 1993-09-01 | 1994-08-19 | Treatment of anorectal disorders |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU95233/01A Division AU9523301A (en) | 1993-09-01 | 2001-11-30 | Treatment of anorectal disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU8833098A true AU8833098A (en) | 1999-01-28 |
Family
ID=25637679
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU88330/98A Abandoned AU8833098A (en) | 1993-09-01 | 1998-10-06 | Treatment of anorectal disorders |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU8833098A (en) |
-
1998
- 1998-10-06 AU AU88330/98A patent/AU8833098A/en not_active Abandoned
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| Date | Code | Title | Description |
|---|---|---|---|
| PC1 | Assignment before grant (sect. 113) |
Owner name: CELLEGY AUSTRALIA PTY LTD Free format text: THE FORMER OWNER WAS: KOREN LABORATORIES PTY. LTD. |
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| MK5 | Application lapsed section 142(2)(e) - patent request and compl. specification not accepted |