WO2014080162A1

WO2014080162A1 - Vip and an alpha-adrenergic blocker for use in the diagnosis of erectile dysfunction and vascular ischaemia

Info

Publication number: WO2014080162A1
Application number: PCT/GB2013/000509
Authority: WO
Inventors: Mike WYLLIE
Original assignee: Mens Health Ltd
Priority date: 2012-11-22
Filing date: 2013-11-21
Publication date: 2014-05-30
Also published as: GB201221046D0

Abstract

The present invention provides a method of providing an objective, repeatable measure of the severity of an erectile dysfunction condition comprising: a) the administration in a therapeutically effective amount of a physiological mediator of penile erection, generally a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker; b) measuring the erectile response; c) grading the severity of the ED condition through the erectile response measurements. There is also provided a method of diagnosing a patient suffering from vascular ischaemia comprising: • identifying an area of the body (typically a limb) exhibiting symptoms of vascular ischaemia; • administering a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker; wherein if the symptoms of vascular ischaemia are alleviated, eliminated or relieved within a predetermined period from administration, the patient is likely to be suffering from vascular ischaemia. The VIP is generally included in a composition having a pH of from around 6 to around 9.

Description

VIP AND AN ALPHA-ADRENERGIC BLOCKER FOR USE IN THE DIAGNOSIS OF ERECTILE DYSFUNCTION AND VASCULAR ISCHAEMIA

The present invention relates to products, compositions, methods and uses which are useful in relation to the diagnosis of the severity of erectile dysfunction. The erectile dysfunction may be of any origin or cause. There is also provided to products, compositions, methods and uses which are useful in relation to the diagnosis and treatment of vascular ischaemia, in particular large vessel ischaemia. The present invention provides an objective measure of the severity of a vascular ischaemia condition, and this is useful in the standardising diagnosis of the presence and severity of such a condition.

BACKGROUND TO THE INVENTION

US 5,447,912 discloses methods and compositions for inducing penile erections, in particular in a male suffering from severe atherosclerosis. The composition disclosed in this document comprise a VIP and/or peptide N-terminal histidine C-terminal methionineamide (PHM) and an alpha-adrenergic blocker.

WO 95/05188 discloses compositions for inducing penile erections comprising a vasoactive intestinal peptide (VIP) and peptide N-terminal histidine C-terminal methionineamide (PHM). Additionally this document discloses a composition VIP or PHM and an alphaadrenergic blocker. There is no suggestion that the compositions may be used in the diagnosis of the severity of an erectile dysfunction condition. The compositions disclosed in this document have a pH of about 2 to about 4.5, generally about 3.

WO 91/04039 discloses the treatment of ED through intracavernosal injection of peptide N- terminal histidine C-terminal methionineamide. Where the ED is caused by artherosclerosis, there is disclosed the administration of a combination of PHM or VIP in combination with an alpha-adrenergic blocker such as phentolamine. There is no suggestion that the compositions may be used in the diagnosis of the severity of an erectile dysfunction condition. There is no teaching of the pH of the composition.

Scientific article "Vasoactive intestinal polypeptide/phentolamine for intracavernosal injection in erectile dysfunction" (BJU International; Vol. 102, pp 933 to 937 (2008) (Dinsmore & Wyllie)) discusses the use of a composition comprising 25 μg VIP and 2 mg phentolamine mesylate as an intracavernosal therapy in the treatment of erectile dysfunction, in particular moderate to severe ED, including for older patients who may have advanced organic impairment (see page 935, column 2, paragraph 3). There is no suggestion that the compositions may be used in the diagnosis of the severity of an erectile dysfunction condition. There is no teaching of the pH of the composition.

Scientific article "A pilot study of the role of intracaveraous injection of vasoactive intestinal peptide (VIP) and phentolamine mesylate in the treatment of erectile dysfunction" (Int. J Impotence Res; Vol. 8, pp223-236 (1996)) discusses the use of a composition comprising 25 μg VIP and 2 mg phentolamine mesylate as an intracavernosal therapy in the treatment of erectile dysfunction. There is no suggestion that the compositions may be used in the diagnosis of the severity of an erectile dysfunction condition. There is no teaching of the pH of the composition.

Intracavernosal injections of alprostadil are known in the treatment of ED. However, this is painful and is associated with important and serious treatment limiting adverse events, including priapism. The risk-benefit ration of such treatment is generally considered to be unacceptable.

Erectile dysfunction has many diverse possible causes including systemic cardiovascular, metabolic and endocrine causes, neurological causes, including as a result of radical prostatectomy procedures, hormonal causes, drug side effects and psychological causes.

Although a patient will generally be aware of whether they are suffering from ED, it is difficult to obtain an objective, quantifiable measure of the severity of the condition. This can be useful in assessing whether treatment regimes are effective, as well as measuring whether events such as surgery have affected the severity of the condition.

When a patient has been suffering from ED for prolonged periods of time, it is likely that he would have tried several different therapies to address this condition. In particular, it is likely that he would have been prescribed oral ED treatments including phosphodiesterase type 5 inhibitors (PDE5i's) such as Viagra^® and Cialis^®. Where these therapies are not effective, and the symptoms of the ED condition have been experienced over a prolonged period, penile implants or prostheses are often recommended. Commonly used surgical prostheses include malleable rods implanted into the erection chamber of the penis, and hydraulic or inflatable implants. The implantation of a penile prosthesis is a surgical procedure with associated risks. According to some estimates, 2 to 10% of penile prostheses are associated with complications including uncontrolled bleeding, scrotal swelling, moderate to long term pain, formation of scar tissue and the erosion of tissue around the implant. In addition, penile prostheses are associated with awkwardness of sexual relations including penetration, and difficulties in deflation. Most patients would be keen to avoid penile prostheses if other treatments were available. However, in general where oral therapies are not successful, penile implants are considered to be the next therapy recommended to sufferers of ED. Oral therapies such as Viagra^® and Cialis^® are associated with side effects including headache, flushing, dyspepsia, nasal congestion and impaired vision, including photophobia blurred vision and loss in peripheral vision. Of more concern are side-effects including priapism, severe hypotension, myocardial infarction (heart attack), ventricular arrhythmias, stroke, increased intraocular pressure, and sudden hearing loss.

According to estimates, such therapies are not appropriate for around 10% of those suffering from ED due to these contra-indications. For such patients, investigations into the possible causes of the ED condition are generally limited. Penile implants can be recommended as the only therapy. However, the severity of ED conditions vary markedly between sufferers and the possible causes of an ED condition are diverse.

The method of the present invention provides an indication of the severity of the disorder, providing guidance to the patient and his medical advisors as to whether an extreme therapy such as penile prostheses is appropriate or whether further investigations should be made into possible causes and/or less extreme therapies.

The present invention provides a method of assessing the severity of an ED condition. Where the condition is severe, treatments such as penile implants may be deemed appropriate. Where the condition is moderate or mild, further investigations may be deemed appropriate to identify a non-surgjcal therapy.

Radical prostatectomy (RP) is an appropriate and potentially curative option for patients with prostate cancer where the likelihood is high that the cancer is confined to the gland and where the predicted lifespan of the patient is ten years or more. However, RP carries with it a high risk of complications. Foremost amongst these, a profound degree of sexual dysfunction almost invariably affects patients following surgery. Erectile dysfunction and reduced penile size are associated with physical and mental discomfort during sexual intimacy, less sexual enjoyment, and the perception of diminished masculinity.

Because of the rising trend in recent years to screen for prostate cancer, patients with the disease are increasingly youthful at the time of initial diagnosis. In 2005 almost 25% of prostate cancers were first diagnosed in men aged less than 60 years. For the same reason, prostate cancers at the time of discovery are increasingly early stage. In patients such as these, with asymptomatic, clinically localised disease, continuing good quality of life is of particular importance.

Where a patient is suffering from ED RP, penile tissue becomes unresponsive to oral ED treatments including phosphodiesterase type 5 inhibitors (PDE5i's) such as Viagra^®. Oral PDE5i's cannot modulate local blood flow if nerve-dependent generation of nitric oxide is compromised. As a result, PDE5i's fail to induce penile engorgement and erection in most patients with early stage ED RP.

Currently it is difficult for patients and their medical practitioners to obtain an objective, repeatable measure of the severity of an ED condition, which may be compared with changes in the severity of the condition over time.

STATEMENT OF INVENTION

According to an aspect of the present invention there is provided a method of treating a patient suffering from vascular ischaemia comprising the administration of a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker.

Generally the VIP is included in a composition having a pH of from around 6 to around 9, typically from around 6.5 to 9, suitably from around 7 to 9.

Generally the method includes the administration of a composition comprising a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker. According to one embodiment, the composition has a neutral to alkali pH typically wherein the pH is above around 5.5, generally wherein the pH is between around 6 and around 9, typically from around 6.5 to 9, suitably from around 7 to 9. According to an aspect of the present invention there is provided a method of diagnosing a patient suffering from vascular ischaemia comprising:

• identifying an area of the body (typically a limb) exhibiting symptoms of vascular ischaemia;

• administering a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker;

wherein if the symptoms of vascular ischaemia are alleviated, eliminated or relieved within a predetermined period from administration, the patient is likely to be suffering from vascular ischaemia. Generally the method includes the administration of a composition comprising a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker. According to one embodiment, the composition has a neutral to alkali pH typically wherein the pH is above around 5.5, generally wherein the pH is between around 6 and around 9, typically from around 6.5 to 9, suitably from around 7 to 9.

According to a further aspect of the present invention there is provided a VIP and an alpha- adrenergic blocker for use in the treatment or diagnosis of vascular ischaemia. According to one embodiment, the method or use involves the administration of one or more of testosterone and a PDE5i compound.

There is also provided, a pharmaceutical product comprising at least a VIP and an alpha- adrenergic blocker for use in the treatment or diagnosis of vascular ischaemia.

The pharmaceutical product may have a neutral to alkali pH typically wherein the pH is above around 5.5, generally wherein the pH is between around 6 and around 9 typically from around 6.5 to 9, suitably from around 7 to 9. According to one embodiment, the pharmaceutical product comprises one or more of testosterone and a PDE5i compound. According to a further aspect of the present invention there is provided the use of a VIP and an alpha-adrenergic blocker in the manufacture of a medicament for the treatment or diagnosis of vascular ischaemia.

According to a further aspect of the present invention, there is provided a kit of parts for use in the treatment or diagnosis of vascular ischaemia, said kit of parts comprising a VIP, an alpha-adrenergic blocker and an injecting device, typically a syringe.

According to an aspect of the present invention there is provided a method of providing an objective, repeatable measure of the severity of an erectile dysfunction condition comprising:

1. the administration in a therapeutically effective amount of a physiological mediator of penile erection, generally a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker;

2. measuring the erectile response;

3. grading the severity of the ED condition through the erectile response measurements.

Generally the method provides a diagnosis of the severity of an ED condition.

Typically the method involves the sequential or combined administration in a therapeutically effective amount of a VIP and an alpha-adrenergic blocker, suitably phentolamine or phentolamine mesylate.

According to a further aspect of the present invention there is provided a method of assessing the efficacy of potentially therapeutic compounds in the treatment of an ED condition comprising the steps of:

a) providing a measure of the severity of the ED condition using the method as described above;

b) identifying at least one potentially therapeutic compound;

c) administering the potentially therapeutic compound to the patient; d) providing a measure of the severity of the ED condition during or after the administration of the potentially therapeutic compound using the method of step a);

e) comparing the severity of the ED condition as provided in steps a) and d) wherein a severity measurement in step d) less than the severity measurement in step a) is indicative of a compound potentially effective in the treatment of the ED condition.

According to a further aspect of the present invention there is provided a VIP and an alpha- adrenergic blocker for use in the diagnosis of the severity of an ED condition, wherein the diagnosis generally involves providing an objective, repeatable measure of the severity of the ED condition.

Generally the VIP is included in a composition having a pH of more than 5.5, typically from around 6 to around 9 typically from around 6.5 to 9, suitably from around 7 to 9.

There is also provided, a pharmaceutical product comprising at least a VIP and an alpha- adrenergic blocker for use in the diagnosis of the severity of an ED condition. According to a further aspect of the present invention there is provided the use of a VIP and an alpha-adrenergic blocker in the manufacture of a medicament for the diagnosis of the severity of an ED condition.

According to a further aspect of the present invention, there is provided a kit of parts for use in the diagnosis of the severity of an ED condition, said kit of parts comprising a VIP, an alpha-adrenergic blocker and an injecting device, typically a syringe.

Generally the VIP is buffered to a pH of from around 6 to 9, typically from around 6.5 to around 9, suitably from around 7 to around 9.

According to a further aspect of the present invention, there is provided a kit of parts for use in the diagnosis of the severity of an ED condition, said kit of parts comprising a VIP, an alpha-adrenergic blocker, one or more of testosterone and a PDE5i compound and an injecting device, typically a syringe. Definitions

The term "reversible" within the context of post radical prostatectomy erectile dysfunction is meant to refer to a condition wherein the cavernosal nerves have not been severed or resected by the surgeon during the radical prostatectomy surgery.

Ischaemia may generally be defined as a restriction in blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular metabolism (to keep tissue alive).[3] Vascular ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue. Ischaemia can result in local anaemia in a given part of a body sometimes resulting from congestion (such as vasoconstriction, thrombosis or embolism).

By an "effective" amount or "therapeutically effective amount" is meant an amount of one or more active substances which, within the scope of sound medical judgment, is sufficient to provide a desired effect without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein the term "compound" encompasses the pharmaceutically acceptable salts thereof.

A PDE5i compound is used to refer to a phosphodiesterase type 5 inhibitor. Such compounds block the degradative action of phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells lining blood vessels. Such compounds are known in the treatment of erectile dysfunction.

All numerical values provided incorporate 10% less than and 10% more than the numerical value provided. Erectile Dysfunction

According to an aspect of the present invention there is provided a method of providing an objective, repeatable measure of the severity of an erectile dysfunction (ED) condition comprising: 1. the administration in a therapeutically effective amount of a physiological mediator of penile erection, generally a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker;

2. measuring the time between administration of the physiological mediator of penile erection and erectile response, and/or measuring the strength of the erectile response erectile response;

Generally the method provides a diagnosis of the presence and/or severity of an ED condition.

Where the use of oral therapies such as Viagra^® and Cialis^® is not effective, or for patients who are unable to take such therapies due to their contra-indications, penile prostheses are generally considered to be the only appropriate remaining therapy. However, the ED condition of some of these patients may not be severe enough to properly consider such drastic action. The method of the present invention provides an objective, repeatable indication of the severity of the ED condition, allowing the patient and his medical advisors to make an informed choice regarding the appropriateness of surgical methods of treatment. Where the ED condition is mild or moderate, the severity of the ED condition may lessen in time resulting in the recovery of a spontaneous erectile function. In such cases, surgical intervention would be inappropriate and inadvisable. The method of the present invention provides a valuable tool in the diagnosis of the severity of the condition, allowing the advisability of surgical procedures such as penile prostheses to be judged more accurately. The method of the present invention may also provide an objective measure of any improvement in the ED condition over time. Where an improvement is measured, this can provide reassurance to the patient, lessening psychological factors in the ED condition, which in itself can lead to an improvement in the condition. Where no improvement is measured over time, further therapies can be investigated. The values obtained through the method of the present invention may be compared to mean values for these parameters obtained historically from men who do not suffer from an erectile dysfunction condition. According to one embodiment, the method includes measuring the time period from administration of the physiological mediator of penile erection and the erectile response.

Following administration of the physiological mediator of penile erection, the method may include a stimulation step through, for example vibratory stimulation. Generally the strength and duration of the stimulation step is the same for any repetitions of the method used to obtain measurements to be compared. For instance, where the stimulation step involves vibratory stimulation the intensity and timing of the vibratory stimulation is the same for any repetitions of the method used to obtain measurements to be compared.

The method may include the step of storing data generated, for instance amounts of physiological mediator of penile erection administered, time from administration to erectile response, strength of erectile response. Repeated measurements may be made to ensure reproducibility.

The method may include the step of comparing measurements over time to assess the progression or treatment of an ED condition. More than 50% of men who undergo radical prostatectomy surgery will suffer from post radical prostatectomy erectile dysfunction (ED RP). The severity of ED RP generally lessens in time resulting in the recovery of a spontaneous erectile function. The method of the present invention may also provide an objective measure of any improvement in the ED condition over time. Where an improvement is measured, this can provide reassurance to the patient, lessening psychological factors in the ED condition.

The method of the invention can be used to provide an indication of the presence and/or severity of any ED condition suffered by a patient prior to a medical intervention such as surgery. According to one embodiment, the steps of the method of the present invention are undertaken prior to surgery on or around the penis, in particular prior to radical prostatectomy surgery.

The method of the invention can be used to provide an indication of the presence and/or severity of any ED condition suffered by a patient prior to a medical intervention such as surgery. This is useful in enabling a medical practitioner to advise regarding the likelihood of recovery of spontaneous erectile function, and suitable methods of treatment.

The provision of an objective measure of the presence and severity of an ED condition prior to and after a medical intervention is useful in indicating whether the medical intervention is responsible for the ED condition. This can have implications in the treatment of the ED condition. This can also be of relevance in situations where a patient has attributed responsibility for the ED condition to the medical intervention. In particular, the objective measures provided by the method of the present invention can provide a useful defence to a medical practitioner where a patient is seeking to attribute the cause of a pre-existing ED condition to a medical intervention.

ED RP generally improves over time. The majority of men suffering from ED RP will experience a lessening in their symptoms within 12 months of their radical prostatectomy surgery. Where a patient is suffering from ED RP, penile tissue becomes unresponsive to oral ED treatments including phosphodiesterase type 5 inhibitors (PDE5i's) such as Viagra^®. Oral PDE5i's cannot modulate local blood flow if nerve-dependent generation of nitric oxide is compromised. As a result, PDE5i's fail to induce penile engorgement and erection in most patients with ED RP. Possible treatments of ED RP are thus greatly restricted. Where an ED condition is present following radical prostatectomy and was not present prior to radical prostatectomy, the patient is likely to be suffering from ED RP, and is thus not likely to be responsive to PDE5i's.

The present invention also provides a method of testing the efficacy of potentially therapeutic compounds in the treatment of ED. The methods of the present invention provide an objective measure of the efficacy of potential treatments.

Potentially therapeutic compositions are generally initially tested ex vivo or under controlled clinical conditions which may prove intimidating to a sufferer of ED. Such assays do not provide an environment similar to that in which the compositions will be used. In contrast, the method of the present invention provides an accurate reliable test of the potentially therapeutic compositions in conditions similar to which they would be used. It has been found that some compounds exhibit far higher efficacy in the method of the present invention, than would be expected from the results of ex vivo tests. The method of the present invention thus provides a useful, accurate indication of how a potentially therapeutic composition is likely to behave in vivo, in particular when compared to current assays.

The method of the present invention may provide an initial assessment of the severity of the erectile dysfunction condition, and this may be used as a baseline measurement. Novel therapeutic agents may then be administered to the patient, and the method of the present invention may be used to provide an intermediate or final assessment of the severity of the erectile dysfunction condition, providing an objective measure of the efficacy of the novel therapeutic agent.

A therapeutic agent should decrease the time between administration of the physiological mediator of penile erection and the erectile response, or should increase the strength of the erectile response when compared to the measurement. The potentially therapeutic composition may comprise one or more potentially therapeutic compound.

The potentially therapeutic composition may be compared to a control composition or placebo. The control composition may consist of the pharmaceutical excipients of the potentially therapeutic composition. Typically, the control composition consists of the same components as the potentially therapeutic composition, absent the potentially therapeutic compound.

Suitable pharmaceutical excipients include anti-adherents, binders, coatings, disintegrants, fillers and diluents, flavours, colours, glidants, lubricants, preservatives, sorbents, solvents, stabilisers, and sweeteners, such as polyethylene glycol and urea, and as described in the US Food and Drug Administration "Inactive Ingredient Approved Drug Products" database.

Vascular Ischaemia

It can be difficult to identify the location of an occlusion which may be resulting in vascular ischaemia.

Typical symptoms associated with vascular ischaemia include the absence or great reduction in a pulse in the area affected, a paleness in colour of the affected area, extreme cold to the touch, the presence of paraesthetic feeling such as burning or tingling and paralysis of the affected area.

However, such symptoms may be associated with other conditions. This is particularly true at the early stages of ischaemia. This leads to common misdiagnosis. Where misdiagnosed, ischaemia goes untreated. Over time, ischaemia can result in gangrene, limb loss and even death.

The methods of the present invention provide a simple and accurate way of both diagnosing and treating ischaemia, in particular vascular ischaemia such as large vessel ischaemia. Particular mention may be made of acute limb ischaemia.

Where vascular ischaemia is suspected, the area of the body which may be affected is identified. The method of the present invention typically involves the step of testing for one or more of the absence or great reduction in a pulse in the area affected, a paleness in colour of the affected area, extreme cold to the touch, the presence of paraesthetic feeling such as burning or tingling and paralysis of the affected area. Generally the method involves the step of testing for all of the symptoms noted above. Where the abovementioned symptom(s) are observed, a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha- adrenergic blocker are generally administered to the area of the body in question. Suitably the active agents are administered slightly upstream from the area of the body in question, that is slightly closer to the heart of the patient.

Where the symptoms of vascular ischaemia are alleviated, eliminated or relieved within a predetermined period from administration, (generally 1 to 15 minutes, suitably 1 to 5 minutes), the patient is likely to be suffering from vascular ischaemia. Typically, where the patient is suffering from vascular ischaemia, the symptoms are greatly relieved for at least 10 minutes, generally at least 30 minutes, suitably for at least 2 hours.

According to one embodiment, the pulse in the affected area returns or the strength of the pulse greatly increases. Generally one or more of the other symptoms are also alleviated. Methods of Treatment and Diagnosis

According to an aspect of the present invention there is provided a method of treating a patient suffering from vascular ischaemia comprising the administration of a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker. According to an aspect of the present invention there is provided a method of diagnosing a patient suffering from vascular ischaemia comprising:

identifying an area of the body (typically a limb) exhibiting symptoms of vascular ischaemia;

administering a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker;

wherein if the symptoms of vascular ischaemia are alleviated, eliminated or relieved within a predetermined period from administration, the patient is likely to be suffering from vascular ischaemia. Typically the method provides an indication of the location of the occlusion which is causing or contributing to the ischaemia.

According to one embodiment, the vascular ischaemia is due an embolism or thrombosis. The vascular ischaemia may be one or more of renal ischaemia, mesenteric ischaemia, cerebral ischaemia, cardiac ischaemia and critical limb ischaemia.

1) the administration in a therapeutically effective amount of a physiological mediator of penile erection, generally a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker;

2) measuring the erectile response;

3) grading the severity of the ED condition through the erectile response measurements. Generally the method provides a diagnosis of the severity of an ED condition.

b) identifying at least one potentially therapeutic compound;

c) administering the potentially therapeutic compound to the patient;

d) providing a measure of the severity of the ED condition during or after the administration of the potentially therapeutic compound using the method of step a);

e) comparing the severity of the ED condition as provided in steps a) and d) wherein a severity measurement in step d) less than the severity measurement in step a) is indicative of a compound likely to be effective in the treatment of the ED condition.

Typically the methods of the invention involve the sequential or combined administration in a therapeutically effective amount of a VIP and an alpha-adrenergic blocker, suitably phentolamine or phentolamine mesylate.

The method of the present invention involves the administration of a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and an alpha-adrenergic blocker. The active agents may be administered simultaneously or sequentially. According to one embodiment, the active agents are administered simultaneously.

Typically the method of the present invention involves the administration of a composition comprising a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker.

The composition is generally suitable for administration via injection.

The total volume administered is generally 0.1 to 0.5 ml. The method generally involves the administration of 10 to 25 μg of VIP and 200 μg to 2 mg of alpha adrenergic blocker. Typically the VIP is buffered to a pH of from around 6 to around 9, generally from around 6.5 to around 9, suitably from around 7 to around 9.

The active agents may be administered simultaneously or sequentially. Where the active agents are administered sequentially, the administration of all of the active agents is generally within 10 minutes, typically within 5 minutes.

Generally, the steps of the method(s) of the present invention may be repeated under the same or similar conditions to calculate an average response. Typically the steps of the method of the present invention may be repeated 5 to 10 times to calculate and average response, suitably 10 to 20 times, generally more than 50 times to calculate an average response.

The measurements may be taken over a prolonged time period ranging from several days to several months in order to provide an accurate indication of the severity of the condition. As noted above, the method of the present invention may be used to provide an indication of the severity of a condition before and after a medical intervention, in particular a surgical intervention such as radical prostatectomy. According to one embodiment, the method is used to provide an indication of the severity of the condition within one month prior to the medical intervention, generally within one week of the medical intervention.

The symptoms associated with ED RP are generally alleviated spontaneously, and the method of the present invention may be used to provide an indication of the severity of the ED condition at different time periods from the radical prostatectomy depending on the extent of the damage to the neurovascular bundles that supply the penis.

Typically the method is used to provide an indication of the severity of the condition within 2 years of the medical intervention, generally within 1 year, typically three to six months after the medical intervention, generally four to six months after the medical intervention. The method of the present invention may be undertaken whenever required. The active agents may be administered up to three times daily.

Identification of Therapeutic Agents for the treatment of Erectile Dysfunction

According to one embodiment, the steps of the method of providing an objective measure of the severity of an erectile dysfunction condition are repeated before and during or after a course of treatment. In such embodiments, the measurements can be used to assess the efficacy of the course of treatment.

According to one embodiment, the steps of the method of providing an objective measure of the severity of an erectile dysfunction condition are repeated following a non-treatment period. In such embodiments, the measurements can be used to assess whether the ED condition is improving without treatment.

According to one embodiment, the steps of the method of the present invention are performed before and after a medical intervention, in particular a surgical intervention such as a radical prostatectomy procedure. The active agents may be administered to the patient by injection to or around the penis, generally by intracavernosal injection.

During and/or following administration of the active agents, the penis is generally constricted at its base.

The method may include the steps of administering the active agents, during or prior to sexual stimulation.

Typically, the erectile response is measured within 1 to 15 minutes of administration of the active agents.

The erectile response may be measured using a number of different variables including: percentage increase in one or more of the circumference of the penis (in particular the base of the penis), the length of the penis, an increase in the rigidity of the penis, an increase in the angle between the penis and the legs in the standing position before and after administration of the active agents. Alternatively, the response may be measured as a change in a score obtained form a questionnaire such as the international index of erectile function (IIEF).

Generally a percentage increase in the circumference of the penis of more than 30% would be indicative of a high erectile response and generally a percentage increase in the circumference of the penis of less than 10% would be indicative of a low erectile response.

Generally a percentage increase in the length of the penis of more than 30% would be indicative of a high erectile response and generally a percentage increase in the length of the penis of less than 10% would be indicative of a low erectile response.

Generally a percentage increase in the rigidity of the penis of more than 30% would be indicative of a high erectile response and generally a percentage increase in the rigidity of the penis of less than 10% would be indicative of a low erectile response.

Generally where the angle between the penis and the legs of the man in the standing position is more than 90°, the erectile response may be considered to be high, and where the angle between the penis and the legs of the man in the standing position is less than 45°, the erectile response may be considered to be low.

Generally a change of 5 units or more in the International Index of Erectile Function (IIEF) would be indicative of a high erectile response and generally an increase of 3 or less would be considered a low erectile response.

Where the erectile response is high, the severity of the ED condition may be considered to be mild. Where the erectile response is low, the severity of the ED condition may be considered to be severe.

Where some of the factors measured in determining the erectile response indicate a high erectile response, and some of the factors measured in determining the erectile response indicate a low erectile response, the severity of the ED condition may be considered to be moderate. Generally, where the erectile response is high, the erectile response is sufficient for vaginal penetration. Where the erectile response is low, the erectile response is not generally sufficient for vaginal penetration. The patient is generally a human male although in some embodiments, an animal may be diagnosed.

Where the method of the present invention is for the diagnosis of an ED condition, the active agents are typically administered via injection to or around the penis, generally by intracavernosal injection.

The ED condition may have any cause including drugs (anti-depressants (SSRIs) and nicotine are most common); neurogenic disorders (spinal cord and brain injuries, nerve disorders such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, and stroke); cavernosal disorders (Peyronie's disease); psychological causes: performance anxiety, stress, mental disorders (clinical depression, schizophrenia, substance abuse, panic disorder, generalized anxiety disorder, personality disorders or traits), psychological problems; surgery (radiation therapy, surgery of the colon, prostate, bladder, or rectum may damage the nerves and blood vessels involved in erection. Prostate and bladder cancer surgery often require removing tissue and nerves surrounding a tumor, which increases the risk for impotence);

aging. It is four times higher in men in their 60s than in men in their 40s; kidney failure; diseases such as diabetes and multiple sclerosis (MS); lifestyle: smoking is a key cause of erectile dysfunction; iatrogenic (medically caused). Generally, systemic cardiovascular, metabolic and endocrine causes prevail.

Products

The method of the present invention involves the administration of a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker.

According to one embodiment, the VIP is buffered to a pH of from around 6 to around 9, generally from around 6.5 to around 9, suitably from around 7 to around 9. According to one embodiment, the method involves the administration of a composition comprising a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker. Generally the pH of the composition is neutral to alkali typically wherein the pH is above around 5.5, generally wherein the pH is between around 6 and around 9; typically from around 6.5 to around 9, suitably from around 7 to around 9.

Peptides are generally considered to be more stable in acidic solution that in alkali solution. The potential degradation pathways for peptides in alkali solution include base catalysed deamidation and base catalysed racemisation. In addition, oxidation of peptides is generally accelerated at higher pH. Surprisingly the composition of the present invention is more stable at neutral or alkali pH than at acidic pH.

VIP is an endogenous non-adrenergic non-cholinergic peptide neurotransmitter. It is a physiological mediator of penile erection. The VIP may have the formula Ci47H₂₃₇N₄₃0₄₃S (Aviptadil). According to one embodiment, VIP is administered in a dosage range of 1 to 60 &

The alpha adrenergic blocker is generally phentolamine mesylate or phentolamine. The alpha adrenergic blocker acts to increase arterial blood flow to the penis. According to one embodiment, the alpha adrenergic blocker is administered in a dosage range of 100 μg to 5 mg.

The ratio of the VIP to alpha-adrenergic blocker administered according to the invention may be at least 1:4 for example at least 1:6 or 1:8. Preferably the alpha-adrenergic blocker is phentolamine mesylate or phentolamine and the ratio of VIP to alpha-adrenergic blocker is 1:4 to 1:8.

Generally the composition comprises 1 to 50 μg VIP, typically 5 to 30 μg VIP, suitably 10 to 25 μg VIP.

The composition typically comprises 100 μg to 5 mg phentolamine or phentolamine mesylate, generally 200 μg to 3 mg phentolamine or phentolamine mesylate, suitably 200 g to 2 mg phentolamine or phentolamine mesylate. The composition may comprise 0.4 mg, 1 mg or 2 mg phentolamine or phentolamine mesylate.

According to one embodiment the composition comprises 25 μg VIP and 1 to 2 mg phentolamine or phentolamine mesylate.

Generally the ratio of VIP to alpha-adrenergic blocker is 1:4 to 1:8 in the product of the invention. The method of the present invention may include administering 0.1 to 0.5 ml of composition per administration.

The action associated with the composition for use in the present invention is generally independent of neuronal nitric oxide release and the generation of intracellular cGMP.

The abovementioned active agents may be administered as free or fixed combinations. Free combinations may be provided as combination packages containing all the active agents in free combinations. Fixed combinations are often injectable compositions, in particular compositions suitable for intracavernosal injection.

Generally, the active agents are administered as a fixed dose combination comprising VIP and an alpha-adrenergic blocker.

According to one embodiment, the method or use involves the administration of one or more of testosterone and a PDE5i compound.

Generally the method or use involves the administration of a VIP, an alpha-adrenergic blocker, testosterone and a PDE5i compound. According to one embodiment, the composition may comprise testosterone. The composition generally comprises 10 to 100 mg testosterone. Alternatively or additionally, the composition may comprise one or more PDE5i compounds such as sildenafil, avanafil, lodenafil, mirodenafil, tadalafil, vardenafil, udenafil and zaprinast. According to one embodiment, the composition of the present invention comprises 10 to 100 mg PDE5i compound.

The active agents may be administered simultaneously, sequentially or separately. The active agents may be provided as a combination package. The combination package may contain the product of the invention together with instructions for simultaneous, separate or sequential administration of each of the active agents. For sequential administration, the active agents can be administered in any order.

Where the active agents are administered sequentially or separately, the VIP is generally in the form of a composition having an associated pH of more than 5.5, typically from about 6 to about 9, generally from around 6.5 to around 9, suitably from around 7 to around 9.

Where the active agents are administered sequentially or separately each active agent may be in the form of a composition having an associated pH of more than 5.5, typically from about 6 to about 9, generally from around 6.5 to around 9, suitably from around 7 to around 9.

The active agents of the product of the invention may be provided as pharmaceutical compositions additionally containing one or more pharmaceutically acceptable diluents, excipients and/or carriers. This applies to both fixed and free combinations.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, and/or compositions which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or, as the case may be, an animal without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Such carriers are well known in the art and include buffers, fillers, extenders, binding agents, moisturizing agents, disintegrating agents, resorption accelerators, surface active agents, adsorptive carriers, lubricants and preservatives. The product of the invention is generally in the form of a liquid suitable for subcutaneous injection. Particular mention may be made of suspensions and solutions.

According to one embodiment, the composition is a solution. Solutions in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water- soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.

According to one embodiment the composition is a buffered aqueous solution.

The amount of therapeutically active compound that is administered and the dosage regimen for treating/diagnosing a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age and weight of the subject, the severity of the condition, the frequency of administration, and the particular compounds employed, as well as the pharmacokinetic properties of the individual treated, and thus may vary widely. One of skill in the art will appreciate that the dosage regime or therapeutically effective amount of the active agents to be administrated may need to be optimized for each individual. The pharmaceutical compositions may contain active ingredients in the range of about 0.01 to 200 mg, preferably in the range of about 0.05 to 50 mg and most preferably between about 1 and 5 mg. A daily dose of about 0.01 to 1 mg/kg body weight, preferably between about 0.01 and about 0.5 mg kg body weight and most preferably from about 0.01 to 0.2 mg kg body weight, may be appropriate. The product of the present invention may be administered up to three doses per day.

The agents of the invention may be administered in the form of pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., US, 1985, p. 1418, the disclosure of which is hereby incorporated by reference; see also Stahl et al, Eds, "Handbook of Pharmaceutical Salts Properties Selection and Use ", Verlag Helvetica Chimica Acta and Wiley- VCH, 2002. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or, as the case may be, an animal without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The invention thus includes pharmaceutically-acceptable salts of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof for example the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. The active agents mentioned in this specification can exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the invention includes all variant forms of the agents. Medical Use

According to a further aspect of the present invention there is provided a VIP and an alpha- adrenergic blocker for use in the treatment or diagnosis of vascular ischaemia. According to a further aspect of the present invention there is provided a VIP and an alpha- adrenergic blocker for use in the diagnosis of the severity of an ED condition, wherein the diagnosis generally involves providing an objective measure of the severity of the ED condition. Generally the VIP and the alpha-adrenergic blocker are as described above. Typically the active agents are in the form of a composition as described above.

There is also provided, a pharmaceutical product comprising at least a VIP and an alpha- adrenergic blocker for use in the diagnosis of the severity of an ED condition.

As described above, the composition is generally suitable for injection.

According to one embodiment, the composition is suitable for intracavernosal injection. Kit of Parts

According to a further aspect of the present invention, there is provided a kit of parts for use in the treatment or diagnosis of vascular ischaemia, said kit of parts comprising a VIP (generally at a pH of from 6 to 9, generally from around 6.5 to around 9, suitably from around 7 to around 9), an alpha-adrenergic blocker and an injecting device, typically a syringe. According to a further aspect of the present invention, there is provided a kit of parts for use in the diagnosis of the severity of an ED condition, said kit of parts comprising a VIP (generally at a pH of from 6 to 9, generally from around 6.5 to around 9, suitably from around 7 to around 9), an alpha-adrenergic blocker and an injecting device, generally a syringe. The kit of parts may comprise the active agents in dosage units containing a particular amount of the active agent, for example, one or more ampoules or capsules. The dosage units may comprise one or more of the active agents.

Generally the kit includes instructions for use, for example the nature of administration.

As described above, erectile dysfunction is a condition which remains difficult to treat as it is difficult to monitor the effectiveness of a treatment regime. The severity of an ED condition is generally judged subjectively, and the effectiveness of a treatment regime is also judged subjectively. The method of the present invention allows an objective measure of the severity of an ED condition to be made, meaning that it is easier to judge whether the severity of an ED condition has increased (as may be the case following a surgical intervention), or decreased (as may be the case following a course of treatment). The method of the present invention also allows the efficacy of potentially therapeutic compounds to be judged.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and are not intended to (and do not) exclude other moieties, additives, components, integers or steps. All documents referred to herein are incorporated by reference.

Example 1

Experiments relating to the present invention are in the process of being conducted. In these experiments, compositions comprising the VIP aviptadil and phentolamine or phentolamine mesylate are used to diagnose the severity of an erectile dysfunction condition. The method of diagnosis involves the administration of a composition is in the form of an aqueous buffered solution comprising 25 μg VIP and lmg or 2 mg phentolamine or phentolamine mesylate. 0.1 to 0.5 ml of the composition is administered to the patient via intracarveraosal injection. The severity of the erectile dysfunction condition is measured before and after a treatment regime. The measure of the severity of the erectile dysfunction condition provided by the method of the present invention has been found to be useful in assessing the efficacy of the treatment regime.

The results currently generated from these experiments indicate that the composition is effective in measuring the severity of an erectile dysfunction condition.

Example 2

The stability of compositions comprising the VIP aviptadil and phentolamine or phentolamine mesylate was tested at different pH. The composition is in the form of an aqueous buffered solution comprising 25 μg VIP and 2 mg phentolamine mesylate. The percentage degradation of the VIP aviptadil was tested after 30 days storage of the composition at standard room temperature and pressure. The results are summarized below in Table X. pH of the Composition Percentage Degradation of

the VIP component (%)

4.5 2.3

5.0 2.3

5.5 2.7

6.0 2.3

6.5 2.1

7.0 1.9

7.5 1.6

8.0 1.6

9.0 1.9

10.0 3.8 Surprisingly it was found that the stability of the VIP component of the composition increased at pH of from around 6 to 9. In general, the stability of peptides decreases with increasing pH and this effect was unexpected.

Further aspects and embodiments of the invention are set forth in the following claims.

Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

Claims

1. A method of providing an objective, repeatable measure of the severity of an erectile dysfunction condition comprising:

a) the administration in a therapeutically effective amount of a physiological mediator of penile erection, generally a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker;

b) measuring the erectile response;

c) grading the severity of the ED condition through the erectile response measurements.

2. A method of diagnosing a patient suffering from vascular ischaemia comprising:

• administering a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker; wherein if the symptoms of vascular ischaemia are alleviated, eliminated or relieved within a predetermined period from administration, the patient is likely to be suffering from vascular ischaemia.

3. A method of treating a patient suffering from vascular ischaemia comprising the administration of a therapeutically effective amount of a vasoactive intestinal peptide (VIP) and a therapeutically effective amount of an alpha-adrenergic blocker.

4. A method as claimed in any preceding claim wherein the VIP is in the form of a composition having a pH of from 6 to 9, generally from 6.5 to 9, suitably from 7 to 9.

5. The method as claimed in any preceding claim wherein the VIP and alpha-adrenergic blocker are administered simultaneously.

6. The method as claimed in any preceding claim wherein the VIP and alpha-adrenergic blocker are administered via injection, generally intracavernosal injection.

7. The method as claimed in any preceding claim wherein the alpha adrenergic blocker is phentolamine mesylate or phentolamine.

8. The method as claimed in any preceding claim wherein 100 μg to 5 mg, generally 200 μg to 2 mg, of the alpha adrenergic blocker is administered per dose.

9. The method as claimed in any preceding claim wherein 5 to 30 g VIP, suitably 10 to 25 μg VIP is administered per dose.

10. The method as claimed in any preceding claim including the step of administering a composition comprising 25 g VIP and 1 to 2 mg phentolamine or phentolamine mesylate.

11. The method as claimed in claim 10 wherein the composition has a pH of from 6 to 9, generally from 6.5 to 9, suitably from 7 to 9.

12. The method as claimed in either one of claims 10 and 11 wherein 0.1 to 0.5 ml of the composition is administered per dose.

13. The method as claimed in any one of claims 10 to 12 wherein the composition is in the form of a buffered aqueous solution.

14. The method as claimed in claim 1 wherein the steps of the method are repeated 5 to 10 times and an average erectile response is determined.

15. The method of claim 1 wherein the erectile response is measured by considering one or more of: the percentage increase in one or more of the circumference of the penis (in particular the base of the penis), the length of the penis, an increase in the rigidity of the penis and an increase in the angle between the penis and the legs in the standing position before and after administration of the active agents.

16. A method of assessing the efficacy of potentially therapeutic compounds in the treatment of an ED condition comprising the steps of: a) providing a measure of the severity of the ED condition using the method as described above;

b) identifying at least one potentially therapeutic compound;

17. A VIP and an alpha-adrenergic blocker for use in the treatment or diagnosis of vascular ischaemia.

18. A VIP and an alpha-adrenergic blocker for use in the diagnosis of the severity of an ED condition, wherein the diagnosis generally involves providing an objective, repeatable measure of the severity of the ED condition.

19. A pharmaceutical product comprising at least a VIP and an alpha-adrenergic blocker for use in the diagnosis of the severity of an ED condition.

20. A kit of parts for use in the diagnosis of the severity of an ED condition, or for use in the diagnosis or treatment of vascular ischaemia, said kit of parts comprising a VIP, an alpha-adrenergic blocker and an injecting device, generally a syringe.