AU9523301A - Treatment of anorectal disorders - Google Patents
Treatment of anorectal disorders Download PDFInfo
- Publication number
- AU9523301A AU9523301A AU95233/01A AU9523301A AU9523301A AU 9523301 A AU9523301 A AU 9523301A AU 95233/01 A AU95233/01 A AU 95233/01A AU 9523301 A AU9523301 A AU 9523301A AU 9523301 A AU9523301 A AU 9523301A
- Authority
- AU
- Australia
- Prior art keywords
- substance
- treatment
- relaxation
- anal sphincter
- anal
- 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
- 208000015815 Rectal disease Diseases 0.000 title description 6
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 48
- 239000000126 substance Substances 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 36
- 208000014617 hemorrhoid Diseases 0.000 claims description 30
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 claims description 24
- 210000005070 sphincter Anatomy 0.000 claims description 24
- 229960003711 glyceryl trinitrate Drugs 0.000 claims description 22
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 18
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 14
- 206010002153 Anal fissure Diseases 0.000 claims description 13
- 208000016583 Anus disease Diseases 0.000 claims description 13
- 208000009531 Fissure in Ano Diseases 0.000 claims description 13
- 241001465754 Metazoa Species 0.000 claims description 11
- 229910002651 NO3 Inorganic materials 0.000 claims description 8
- -1 nitrate compound Chemical class 0.000 claims description 8
- 229940124549 vasodilator Drugs 0.000 claims description 7
- 239000003071 vasodilator agent Substances 0.000 claims description 7
- 239000002858 neurotransmitter agent Substances 0.000 claims description 6
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 4
- 229930064664 L-arginine Natural products 0.000 claims description 4
- 235000014852 L-arginine Nutrition 0.000 claims description 4
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- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
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- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 claims description 3
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 claims description 3
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 3
- 229960000528 amlodipine Drugs 0.000 claims description 3
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 claims description 3
- HSNWZBCBUUSSQD-UHFFFAOYSA-N amyl nitrate Chemical compound CCCCCO[N+]([O-])=O HSNWZBCBUUSSQD-UHFFFAOYSA-N 0.000 claims description 3
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- 239000003795 chemical substances by application Substances 0.000 claims description 3
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 3
- 229960004166 diltiazem Drugs 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
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- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 claims description 3
- 229960000201 isosorbide dinitrate Drugs 0.000 claims description 3
- OJZYRQPMEIEQFC-UAWLTFRCSA-N limaprost Chemical compound CCCC[C@H](C)C[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCC\C=C\C(O)=O OJZYRQPMEIEQFC-UAWLTFRCSA-N 0.000 claims description 3
- 229950009365 limaprost Drugs 0.000 claims description 3
- 229960001783 nicardipine Drugs 0.000 claims description 3
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 3
- 229960001597 nifedipine Drugs 0.000 claims description 3
- 229960004570 oxprenolol Drugs 0.000 claims description 3
- MNMGNPZLUMHSKK-BAONSNCKSA-N phenazocine hbr Chemical compound Br.C([C@@]1(C)C2=CC(O)=CC=C2C[C@@H]2[C@@H]1C)CN2CCC1=CC=CC=C1 MNMGNPZLUMHSKK-BAONSNCKSA-N 0.000 claims description 3
- 229960003712 propranolol Drugs 0.000 claims description 3
- 239000000026 Pentaerythritol tetranitrate Substances 0.000 claims description 2
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 claims description 2
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 claims description 2
- 229960001340 histamine Drugs 0.000 claims description 2
- 229960004321 pentaerithrityl tetranitrate Drugs 0.000 claims description 2
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- 239000003937 drug carrier Substances 0.000 claims 2
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- 230000000694 effects Effects 0.000 description 5
- 210000005072 internal anal sphincter Anatomy 0.000 description 5
- 239000002674 ointment Substances 0.000 description 5
- 206010036772 Proctalgia Diseases 0.000 description 4
- 208000005392 Spasm Diseases 0.000 description 4
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- 102000016761 Haem oxygenases Human genes 0.000 description 3
- 108050006318 Haem oxygenases Proteins 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
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- 150000002823 nitrates Chemical class 0.000 description 3
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- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 2
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 2
- YEESUBCSWGVPCE-UHFFFAOYSA-N azanylidyneoxidanium iron(2+) pentacyanide Chemical compound [Fe++].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.N#[O+] YEESUBCSWGVPCE-UHFFFAOYSA-N 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000013872 defecation Effects 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
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- 239000012188 paraffin wax Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
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- 238000007464 sphincterotomy Methods 0.000 description 2
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- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- UCTWMZQNUQWSLP-UHFFFAOYSA-N Adrenaline Natural products CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 1
- 102000000584 Calmodulin Human genes 0.000 description 1
- 108010041952 Calmodulin Proteins 0.000 description 1
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 description 1
- 229930028154 D-arginine Natural products 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
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- 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 1
- 208000034693 Laceration Diseases 0.000 description 1
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 1
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- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 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/s: Cellegy Australia Pty Ltd Actual Inventor/s: David Lubowski Address for Service: BALDWIN SHELSTON WATERS MARGARET STREET SYDNEY NSW 2000 CCN: 3710000352 Invention Title: 'TREATMENT OF ANORECTAL DISORDERS' Details of Original Application No. 88330/98 dated 6 October 1998 The following statement is a full description of this invention, including the best method of performing it known to us:- File: 33910AUP00 lP Auara .Ai Doctimcnt; received on: NOV 2a01 E-0 h NJ: 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, including S 10 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 15 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
I
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 10 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 Sassistance 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 of 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) inhibitory neurones". 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. These 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 -3tract, and have been reported as being involved in the nerve mediated relaxation 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 cofactors including the presence of Ca 2 ions, calmodulin and reduced nicotinamide adenine dinucleotide phosphate. NO is very soluble, and diffuses rapidly in the body. It has a very short half life of only three seconds, and is inactivated by the formation of nitrate (NO3') after contact with the superoxide anion CO is produced from heme by the enzyme heme oxygenase.
10 Loder et al in "'Reversible Chemical Sphincterotomy" by local application of glyceryl trinitrate', British Journal of Surgery (1994) 81, 1386-1389 describes studies in which anal sphincter pressure was measured after application of glyceryl trinitrate.
However, the question of healing did not arise, and care was taken to avoid internal anal canal application of the drug. Although it was pointed out that, in clinical use, internal application might be employed, no information is given on the results of such internal application.
The effect of a nitric oxide donor on anal sphincter tone is also mentioned in three abstracts from Loder et al: Gastroenterology, April 1993 Vol. 104: No. 4 A544 AGA Abstracts: 'Topical Application of a Nitric Oxide Donor Reduces Internal Anal Sphincter Tone: Therapeutic Implications' P.B. Loder, M. A. Kamm, R. J. Nicholls, R.
K. S. Phillips. St Mark's Hospital, London, UK; Gut, The British Society of Gastroenterology, Spring Meeting, University of Manchester Institute of Science and Technology, March 1993: 'Topical Application of a Nitric Oxide Donor Reduces Internal -3a- Anal Sphincter Tone: Therapeutic Implications'. P. B. Loder, M. A. Kanmm, R.
J. Nicholls, R. K. S. Phillips. St Mark's Hospital, London, UK T96; and American Society of Colon and Rectal Surgeons, 92nd Annual Convention, Podium and Poster Abstracts: May 1993: 'Topical Glyceryl Trinitrate (GTN): Reversible Chemical Sphincterotomy P. B Loder, M. A. Kamm, R. J. Nicholls, R. K. S. Phillips, London, UK (64).
In each of the above abstracts, glyceryl trinitrate was used as a nitric oxide donor, studying the effect on resting anal pressure. In each case, the nitric oxide donor was provided as a mix of glyceryl trinitrate and soft paraffin, was diluted to avoid severe headaches, and application of the ointment was external. It was concluded that anal sphincter tone was significantly reduced.
The invention in one form therefore concerns a method of treating various anorectal condition 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 in 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 invention is not limited to substances which modulate or influence NO or CO neurotransmitter ability. Rather, the invention extends to the use of any substance or combination of substances which mediate relaxation of the -3b 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 e e 77 4 activating 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 sphincter. Any substance which modulates or influences neurotransmitter ability in the manner described above may be utilised in this invention. Preferred substances which may be used according to the invention include nitrates, vasodilators, amino acids which break down to form NO, calcium channel blockers and the like.
*0 Any nitrate compound or compound which breaks down in the body to form NO 10 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 dinitrate, amyl nitrate, pentaerythritol tetranitrate, nitroglycerine .(glyceryl nitrate) and the like. Nitroglycerine is particularly preferred for use in treating anorectal disorders such as haemorrhoids, anal fissure and similar conditions.
a S Vasodilator compounds, paiticularly those that influence NO neurotransmitter ability, can also be utilized in the invention, and these include hydralazine, and sodium or other salts of nitroprusside (nitroprusside being known 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, metaprolol, 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 intestinal polypeptide, histamine, Larginine, and the like. Compounds which stimulate heme oxygenase production within the body may also be utilized in the invention.
-_7 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, S 10 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 administration, 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.
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% w/w to 5 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% w/w.
Composition or formulations for the administration of active agents according to the invention may be prepared with any suitable excipient or diluent as are well known in the an, such as are described in Remingtons Pharmaceutical Sciences (lOh 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 and/or 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 of the secondary ingredients present are chosen according to standard practice in the art.
15 This invention also relates to 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 o 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 relaxation substances in the treatment of anorectal conditions in animals.
The invention is now described with reference to various examples. Whilst these examples relate to the use of nitroglycerine it is to be understood that the invention is not, of course, restricted to the use of this compound.
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% w/w, with the same ointment base.
EXAMPLE 2 S. 10 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 statistically significant improvement in pain, fissure grade and anal canal pressure compared with the placebo group of nineteen patients.
EXAMPLE 3 Treatment of Haemorrhoids The 0.2% and 0.1% cream as described in Example 1 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 10 previously.
9 o 5o55* e 1 1~
Claims (26)
1. A method for the treatment of anorectal conditions in animals which comprises administering to a subject in need of such treatment an effective amount of at least one substance which mediates the relaxation of the anal sphincter.
2. A method according to claim 1 wherein said substance is a source of nitric oxide or carbon monoxide.
3. A method according to claim 1 wherein said substance is a nitrate compound.
4. A method according to claim 3 wherein said nitrate compound is selected from isosorbide dinitrate, amylnitrate, pentaerythritol, tetranitrate, and nitroglycerine. *l A method according to claim I wherein said substance is nitroglycerine.
6. A method according to claim 1 wherein said substance is a vasodilator.
7. A method according to claim 6 wherein said vasodilator is selected from alpreolol, amlodipine, atenolol, diltiazem, felodipine, limaprost, metaprolol, nicardipine, nifedipine, oxprenolol, prinadol, and propranolol.
8. A method according to claim 1 wherein said substance is selected from acetyl choline, L-arginine, vasoactive intestinal polypeptide, histamine or a prostaglandin.
9. A method according to claim 1 wherein said substance is administered in association with an analgesic and/or anti-inflammatory agent.
10. A method according to any one of claims 1 to 9 wherein said substance is administered in association with one or more pharmaceutically acceptable carriers. S S. S S *5 S. 5
11. A method according to claim 1 wherein said substance is administered topically, subcutaneously, transdermally, parenterally, or interrectally.
12. A method according to claim 1 for the treatment of haemorrhoids.
13. A method according to claim 1 for the treatment of anal fissure.
14. A method according for the treatment of anorectal conditions in an animal which comprises administering to a subject in need of such treatment an effective amount of at least one substance which modulates nitric oxide or carbon monoxide neurotransmitter ability. A method according to claim 14 wherein said substance is a source of nitric oxide or carbon monoxide.
16. A method according to claim 14 wherein said substance is a nitrate compound.
17. A method according to claim 14 wherein said nitrate compound is selected from isosorbide dinitrate, amylnitrate, pentaerythritol tetranitrate, and nitroglycerine.
18. A method according to claim 14 wherein said substance is nitroglycerine.
19. A method according to claim 14 wherein said substance is a vasodilator.
20. A method according to claim 19 wherein said vasodilator is selected from alpreolol, amlodipine, atenolol, diltiazem, felodipine, limaprost, metaprolol, nicardipine, nifedipine, oxprenolol, prinadol, and propranolol.
21. A method according to claim 14 wherein said substance is selected from acetyl choline and L-arginine. ~hl;~i .iaT ~il~il-l
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. 10 24. A method according to claim 14 for the treatment of haemorrhoids.
25. A method according to claim 14 for the treatment of anal fissure. 9999* o. 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 tfis 30th day of November 2001 CELLEGY AUSTRALIA PTY LTD Attorney: CHARLES WILLIAM TANSEY Member Institute of Patent Attorneys of Australia V00 of BALDWIN SHELSTON WATERS 0. :SO 000
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU95233/01A AU9523301A (en) | 1993-09-01 | 2001-11-30 | Treatment of anorectal disorders |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AUPM0971 | 1993-09-01 | ||
| AUPM4247 | 1994-03-04 | ||
| AUPM6395 | 1994-06-22 | ||
| AU95233/01A AU9523301A (en) | 1993-09-01 | 2001-11-30 | Treatment of anorectal disorders |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU88330/98A Division AU8833098A (en) | 1993-09-01 | 1998-10-06 | Treatment of anorectal disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU9523301A true AU9523301A (en) | 2002-01-24 |
Family
ID=3764255
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU95233/01A Abandoned AU9523301A (en) | 1993-09-01 | 2001-11-30 | Treatment of anorectal disorders |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU9523301A (en) |
-
2001
- 2001-11-30 AU AU95233/01A patent/AU9523301A/en not_active Abandoned
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