take time to administer. The alpha adrenoceptor antagonists have recently been proposed as an alternative therapy, but they remain incompletely evaluated both in terms of efficacy and side effects.
As such, there is still a need in the art for an effective treatment for anorectal disorders.
The present invention sets out to address this need.
In a first aspect, the present invention provides a method for the treatment of an anorectal condition in a mammal, the method comprising administering to a subject in need of such treatment an effective amount of a phosphodiesterase inhibitor.
We have now discovered that phosphodiesterase inhibitors (PDEI's) are able to cause a dose dependent reduction in the resting muscle tone of the smooth muscle of the anal sphincter which reduces muscle spasm. In this way the pain of anorectal disorders is reduced and healing of such disorders is promoted by the increased blood flow to the diseased area.
The present invention relates to any type of phosphodiesterase inhibitor. Such inhibitors act on phosphodiesterase enzymes, of which eleven families have been characterised to date. Inhibitors of all families tested so far [classes, 1,2,3,4,5,6,8,9,10 and 11] have proven effective in causing relaxation of the internal anal sphincter muscle. Accordingly, the present invention relates to the total range of phosphodiesterase inhibitors, which allows the treatment regime to be extremely flexible because the therapy of the present invention is not limited by the type of naturally occurring phosphodiesterase in the target cells or tissue. Moreover, the specificity of certain PDEI's can allow treatment to be given orally, for example, without generation of significant unwanted effects on other target tissues.
It is known that certain activities of phosphodiesterase enzymes may be related to nervous signals generated by an individual, while others are independent of such host signals. Accordingly, treatments may be developed using appropriate inhibitors to
specific phosphodiesterase families which allow co-ordination of the PDEI treatment with the body's own natural nervous signals, or which are completely independent of such signals. Byway of example, the treatment of anal fissure using PDEI's independent of such signals would be desirable to help reduce the resting tone of anal canal 24 hours a day, in order to promote wound healing, hi contrast, in Hirschsprung's disease, a treatment whose effect is dependent upon the nervous signals of the patient would be desirable, to allow muscle relaxation and hence defecation when appropriate for the patient. Accordingly, the present invention also relates to a method for the treatment of an anorectal condition in a mammal as outlined above, wherein the PDEI facilitates an action such as defecation, whilst this action remains under voluntary or nervous control. Thus after administration, the patient is able to defer defecation, for example, until an appropriate time. We prefer that PDEI's which act on class 5 phosphodiesterases, such as sildenafil, are employed in treatments which have an element of voluntary control.
Preferred phosphodiesterase inhibitors are vinpocentine, erythro-9-(2-hydroxy-3- nonyl)adenine ('EHNA'), trequinsin, rolipram, zaprinast, dipyridamole, aminophylline, 4-(3 -butoxy-4-methoxybenzyl)imidazolidin-2-one, caffeine, 1 -(3 -chlorophenylamino)- 4-phenyl-phthalazine, cilostamide, 1,7 dimethylxanthine, etazolate, β- hydroxyethyltheophylline, 3-isobutyl-l-methylxanthine (IBMX), 8-methoxymethyl-3- isobutyl-1-methylxanthine sodium salt, milrinone, papaverine, pentoxifylline, propentofylline, quazinone, tetrahydropapaverine, theobromine, theophylline, trequinsin HCL, enoximone, sildenafil and zardaverine, although any suitable inhibitor may be used in the present invention. Moreover, combinations of PDEI's may also be used.
The anorectal disorders of the present invention include all disorders of the anus and rectum, and also encompass certain disorders of the lower gastrointestinal tract. In particular, it is preferred that the anorectal disorder is anal fissure, haemorrhoids, anismus or Hirschsprung's disease. In these cases there is failure of the internal anal sphincter to relax, which would then be beneficially treated by the phosphodiesterase inhibitors of the present invention.
The present invention also relates to pharmaceutical preparations comprising a phosphodiesterase inhibitor of the present invention in combination with a pharmaceutically acceptable carrier.
Examples of pharmaceutical compositions include any solid form (such as tablets, pills, capsule or granules), or liquid form (such as solutions, suspensions or emulsions). The pharmaceutical preparations may be delivered by any delivery means such as oral, topical or parenteral administration, and they may contain the pure phosphodiesterase inhibitor or inhibitor in combination with any carrier or any pharmacologically active compound. Preferably the patient is treated using either an oral dose of the phosphodiesterase inhibitor, a topical treatment such as a paste containing the inhibitor, a suppository, intravenously or by enema.
The correct dosage of the phosphodiesterase inhibitor will vary according to the particular formulation, mode of application, and the particular host being treated. Factors such as age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease are suitably to be taken into account.
The phosphodiesterase inhibitors and compositions of the present invention may be used with other drugs to provide combination therapies. The other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or a different time. The identity of the other drug is not particularly limited, and suitable candidates include drugs known to treat anorectal disorders at present such as glyceryl trinitrate (GTN), calcium channel blocking drugs, botulinum toxins and adrenocepter antagonists. In combination with PDEI's, levels of these other agents may be reduced such that their current problematic side effects are minimised or rendered clinically tolerable.
Without wishing to be constrained by theory, the use of phosphodiesterase inhibitors in the present invention may serve to improve anorectal disorders by preventing the breakdown of cGMP or cAMP by phosphodiesterase enzymes, thus increasing the level
of cGMP/cAMP in cells or tissues. Such an increase in cGMP/cAMP may then assist in smooth muscle relaxation. Accordingly, in addition to treatment of anorectal disorders using phosphodiesterase inhibitors, the present invention also relates to treatments comprising administering phosphodiesterase inhibitors in combination with an agent which increases or stabilises the cGMP or cAMP level in cells or tissues, and compositions comprising such combinations of agents. Suitable agents to increase cGMP or cAMP levels are stimulants of the cylase enzymes which produce these compounds, for example. Whilst this additional treatment is not necessary for the invention to be worked, increased cGMP/cAMP may enhance the therapeutic effect of the invention in certain cases.
The PDEI's of the present invention are also suitable for use in combination with anti- inflammatory agents and analgesics, such as benzocaine, lignocaine, xylocaine, cinchocaine, hydrocortisone, prednisolone, prednisone, adrenalin or methylhydroxybenzoate, for example. Other suitable anti-inflammatory agents and analgesics are well known in the art.
The present invention also relates to the use of a phosphodiesterase inhibitor in the preparation of a medicament for the treatment of an anorectal disorder.
The present invention is now illustrated by the following figures and example, which serve to illustrate the present invention but are not limiting thereon, wherein:
Figure 1 illustrates a dose response curve for vinpocentine and the internal anal sphincter;
Figure 2 indicates the dose response curve for EHNA and the internal anal sphincter;
Figure 3 indicates the dose response curve for trequinsin and the internal anal sphincter;
Figure 4 illustrates the dose response curve for rolipram and the internal anal sphincter;
Figure 5 illustrates the dose response curve for zaprinast and the internal anal sphincter; and
Figure 6 illustrates the dose response curve for dipyridamole and the internal anal sphincter.
Example 1 Activity of Phosphodiesterase Inhibitors on internal anal sphincter muscle
Tissue was obtained from three patients (two male; age range 45-56) undergoing either abdominoperineal resection or proctectomy. The tissue was transferred immediately to Krebs solution at 4°C. The epithelium of the anal canal and mucosa of the rectum was removed along with the submucosa. Strips of internal anal sphincter were cut each measuring 1 x 1 x 7 mm, weighing 2 to 8 mg and containing parallel muscle bundles. Fine 5-0 silk ligatures were tied to each end and mounted for isometric tension recording in superfusion organ baths (capacity 0.2 ml). Strips were perfused continuously with Krebs solution (37°C) at a rate of 1 ml/min. Krebs solution contained 120 mM NaCl, 5.9 mM KC1, 15.4 mM NaHCO3, 1.2 mM NaH2PO4, 2.5 mM CaCl2, 1.2 M MgCl2 and 11.5 mM glucose. The Krebs solution was equilibrated with 97% oxygen and 3% carbon dioxide to maintain the pH at 7.4 ± 0.05. This apparatus allowed six strips to be studied simultaneously. The strips were initially loaded with 1 g tension and allowed to equilibrate for at least 90 minutes. Tension was measured by Pioden dynamometer UFl transducers (Pioden Controls, Canterbury, UK) and recorded on a six channel Tekman 900 pen recorder (Tekman Electronics, Leamington Spa, UK).
The tension present in strips perfused with calcium free solution (CaC12 replaced isosmotically with MgCl2, and 0.5 mM ethylene glycol tetraacetic acid; Sigma Chemical Co, Poole, UK) was regarded as zero tension. This was subtracted from observed tension to give actual tension. Increasing concentrations of drugs were added for 15 minute periods. Drugs used were vinpocentine, EHNA hydrochloride, trequinsin, rolipram, zaprinast and dipyridamole; Sigma Chemical Co, Poole, UK.
Strips from the internal anal sphincter developed spontaneous tone and myogenic activity.
All phosphodiesterase inhibitors caused a dose dependent reduction in resting tone in strips from the internal anal sphincter. The maximum reduction in tone for each type of PDE inhibitor is shown in table 1.
Selective for Maximum percentage IC50 (μM)
PDE type reduction in tone (±SE)
Vinpocentine 1 44.1 (8.2) 4.9
EHNA hydrochloride 2 46.9 (5.8) 25
Trequinsin 3 56.9 (14.3) 0.0013
Rolipram 4 59.4 (6.3) 7.8
Zaprinast 5/6/9 73.9 (4.4) 0.64
Dipyridamole 5/6/8/10/11 76.1 (6.6) 5.2
Table 1 : Maximum reduction in tone for PDE inhibitors with different subtype selectivity. The IC50 figure shown are those given in manufacturers data sheets and represent values from in vitro assays.
Dose response curves for the different PDE inhibitors on the internal anal sphincter are shown in Figures 1-6. All inhibitors caused profound reductions both in tone and spontaneous activity.
Claims
1 A method for the treatment of an anorectal condition in a mammal, the method comprising administering to a subject in need of such treatment an effective amount of a phosphodiesterase inhibitor.
2 A method according to claim 1, wherein the phosphodiesterase inhibitor is selected from the list consisting of vinpocentine, EHMA, trequinsin, rolipram, zaprinast and dipyridamole, vinpocentine, erythro-9-(2-hydroxy-3-nonyl)adenine ['EHNA'], trequinsin, rolipram, zaprinast, dipyridamole, aminophylline, 4-(3-butoxy-4- methoxybenzyl)imidazolidin-2-one, caffeine, 1 -(3 -chlorophenylamino)-4-phenyl- phthalazine, cilostamide, 1,7 dimethylxanthine, etazolate, β-hydroxyethyltheophylline, 3-isobutyl- 1 -methylxanthine [IBMX] , 8-methoxymethyl-3 -isobutyl- 1 -methylxanthine sodium salt, milrinone, papaverine, pentoxifylline, propentofylline, quazinone, tetrahydropapaverine, theobromine, theophylline, trequinsin HCL, enoximone, sildenafil and zardaverine.
3 A method according to claim 1 or 2, wherein the anorectal disorder of the present invention is anal fissure, haemorrhoids, anismus or Hirschsprung's disease.
4 A method according to any preceding claim, wherein more than one phosphodiesterase inhibitor is administered.
5 A method according to any preceding claim, additionally comprising administration of one or more of glyceryl trinitrate (GTN), a calcium channel blocking drug, botulinum toxin or an adrenocepter antagonist.
6 A method according to any preceding claim, additionally comprising administration of an agent which increases or stabilises the cGMP or cAMP level in cells or tissues of the subject.
7 A method according to any preceding claim additionally comprising administration of an anti-inflammatory agent or analgesic.
8 A method according to any preceding claim, wherein the administration is by oral or topical delivery, intravenously, by suppository or enema.
9 A method according to any preceding claim, wherein the phosphodiesterase inhibitor facilitates an effect on smooth muscle, the effect being under voluntary or nervous control of the subject.
10 A method according to claim 9, wherein the phosphodiesterase inhibitor is an inhibitor of class 5 phosphodiesterases.
11 A pharmaceutical preparation for use in the method of any preceding claim comprising a phosphodiesterase inhibitor in combination with a pharmaceutically acceptable carrier.
12 A pharmaceutical preparation according to claim 11 comprising more than one phosphodiesterase inhibitor.
13 A pharmaceutical preparation according to claim 11 or 12 additionally comprising glyceryl trinitrate (GTN), a calcium channel blocking drug, botulinum toxin or an adrenocepter antagonist.
14 A pharmaceutical preparation according to claim 11, 12 or 13 additionally comprising an agent which increases or stabilises the cGMP or cAMP level in cells or tissues of the subject.
15 A pharmaceutical preparation according to any of claims 11-14 additionally comprising an anti-inflammatory agent or analgesic.
16 Use of a phosphodiesterase inhibitor in the preparation of a medicament for the treatment of an anorectal disorder.