Embolic or sclerosing agents for the treatment of erectile dysfunction

Abstract

This invention relates to a novel method for treating erectile dysfunction by injecting an embolic or sclerosing agent into the corpora cavernosa or corpus spongiosum of the penis. The invention also relates to a novel method for treating erectile dysfunction by injecting an embolic or sclerosing agent into one or more veins of the penis, wherein the embolic or sclerosing agent penetrates into the corpora cavernosa or corpus spongiosum.

Description

Technical Field

[0001] This invention relates to a novel method for treating erectile dysfunction by injecting an embolic or sclerosing agent into the bilateral corpora cavernosa or corpus spongiosum of the penis. The invention also relates to a novel method for treating erectile dysfunction by injecting an embolic or sclerosing agent into one or more veins of the penis, wherein the embolic or sclerosing agent penetrates into the bilateral corpora cavernosa or corpus spongiosum. Background Technology

[0002] Erectile dysfunction is a challenge in clinical treatment, and there is currently no universally accepted treatment. Treatment attempts include surgical and non-surgical methods. Kaba et al. (2020, Journal of Clinical Urology, Vol. 13(1), pp.33-39) described congenital venous leakage or venous occlusion as an important cause of vascular erectile dysfunction, posing a significant challenge to urologists.

[0003] Treatment for this pathology includes descriptions of techniques for embolizing draining veins and surgical options based on the resection or closure of incompetent veins. In catheter embolization, a liquid embolic agent is used to block the deep dorsal vein near the base of the penis through a catheter. To this day, erectile dysfunction, including that caused by venous occlusion, remains difficult to treat, and penile prostheses are often considered the only solution.

[0004] A common treatment for venous leakage is medication, such as phosphodiesterase type 5 inhibitors (like Viagra), which work by dilating blood vessels to allow blood to flow in faster than it leaks out. However, medication is only temporary and may not work for everyone (e.g., men with low blood pressure or men taking nitrates), and may cause side effects in some individuals.

[0005] Therefore, there is a need for new methods to effectively treat erectile dysfunction. This application addresses this need through the novel treatment method for erectile dysfunction provided herein. Summary of the Invention

[0006] This invention relates to a novel method for treating erectile dysfunction by injecting an embolic or sclerosing agent into the bilateral corpora cavernosa or corpus spongiosum of the penis. The invention also relates to a novel method for treating erectile dysfunction by injecting an embolic or sclerosing agent into one or more veins of the penis, wherein the embolic or sclerosing agent penetrates into the bilateral corpora cavernosa or corpus spongiosum.

[0007] This invention describes for the first time the treatment of erectile dysfunction, particularly venous occlusive erectile dysfunction, by targeting both corpora cavernosa or corpora spongiosum of the penis. Surprisingly, it has been found that targeting both corpora cavernosa or corpora spongiosum with embolic or sclerosing agents is effective in treating erectile dysfunction, particularly venous occlusive erectile dysfunction. This invention is based on the direct application of embolic or sclerosing agents to both corpora cavernosa or corpora spongiosum of the penis, or the application of embolic or sclerosing agents to one or more veins of the penis, particularly the draining veins of the penis. Surprisingly, it has been found that the embolic or sclerosing agents can penetrate from these draining veins into both corpora cavernosa or corpora spongiosum of the penis.

[0008] Aspects and embodiments of the present invention include: [1] A method of treating erectile dysfunction, comprising administering to a patient in need a composition comprising an embolic agent or a sclerosing agent, wherein the composition is administered by injection to... (a) One or more (draining) veins in the patient's penis; and / or (b) The corpus cavernosum or corpus spongiosum of the patient's penis.

[0009] [2] According to the method of [1(a)], the one or more (draining) veins are selected from any one of cavernous veins, deep dorsal veins, bulbourethral veins, para-arterial veins and circumflex veins.

[0010] [3] The method according to [1(a)] or [2], wherein the composition is forced into the corpus cavernosum or corpus spongiosum.

[0011] [4] The method according to any one of [1] to [3], wherein one or more veins of the penis are compressed at the proximal and / or distal sites of the injection site.

[0012] [5] The method according to any one of [1] to [4], wherein the composition is administered by directly puncturing one or more veins of the penis; or by puncturing the corpus cavernosum or corpus spongiosum.

[0013] [6] The method according to any one of [1] to [5], wherein the composition is injected into: (i) the sinusoidal spaces of the corpora cavernosa; and / or (ii) Sinusoidal space of the corpus spongiosum.

[0014] [7] The method according to any one of [1] to [6], wherein the erectile dysfunction is venous occlusive erectile dysfunction.

[0015] [8] According to the method described in [7], the venous leak associated with venous occlusive erectile dysfunction is determined by cavernosography, particularly dynamic infusion cavernosography (DIC), or ultrasound, particularly Doppler ultrasound.

[0016] [9] The method according to any one of [1] to [8] includes occluding venous leakage after administering a composition containing an embolic agent or a sclerosing agent.

[0017]

[10] The composition comprising an embolic agent according to any one of [1] to [9] is a liquid composition, preferably a liquid embolic agent.

[0018]

[11] The composition comprising a hardener according to any one of [1] to

[10] is a liquid composition, a foam or a microfoam, preferably a liquid hardener, a hardened foam or a hardened microfoam.

[0019]

[12] The method according to

[11] , wherein the hardener is polydextrose.

[0020]

[13] The method according to any one of [1] to

[12] further includes imaging the composition containing the embolic agent or sclerosing agent by ultrasound, or X-ray, or (CT-) cavernosography, preferably by ultrasound.

[0021]

[14] The method according to any one of [1] to

[13] , wherein the patient’s penis is in a non-erect state or in an erect state induced by (injection) (stimulating erection) drugs.

[0022] This description does not necessarily cover all features of the invention. Further aspects and embodiments of the invention will become clear from the following detailed description. Attached Figure Description

[0023] Figure 1: A cavernosography image showing a leak (arrow 1) from the corpus cavernosum to the pudendal vein. The corpus cavernosum was directly punctured near the leak (arrow 2) and contrast agent was injected to visualize the draining vein.

[0024] Figure 2 and Figure 3 The image shows the injection of a sclerosing agent (foam) into the corpus cavernosum and its distribution, demonstrating how the contrast agent disappears as the sclerosing agent (foam) replaces the contrast agent.

[0025] Arrow 1 (Figure 2): Injection begins.

[0026] Arrow 2 ( Figure 3 The contrast agent around the needle disappears as it is replaced by foam.

[0027] Arrow 3 ( Figure 3No contrast agent was found in the veins surrounding the prostate, thus proving the effectiveness of the treatment.

[0028] Figure 4: This shows the injection of contrast agent into the corpora cavernosa after treatment. The veins are spasmodic (arrow 1), and the contrast agent is visible in the corpora cavernosa (arrow 2), confirming the treatment effect.

[0029] Figures 5 and 6: Ultrasonic monitoring showing the entry of the hardener (foam) into the corpus cavernosum.

[0030] Arrow 1 (Figure 5) shows an ultrasound image of the corpus cavernosum without treatment.

[0031] Arrow 2 (Figure 6) shows an ultrasound image of the corpus cavernosum after the injection of the hardening agent (foam). The hardening agent appears as a hyperechoic line and shadow in the corpus cavernosum.

[0032] It has also been demonstrated that sclerosing agents can penetrate into the corpora cavernosa from the deep dorsal vein. The same effect (i.e., penetration into the corpora cavernosa) was also achieved by injecting sclerosing agents (foam) into the cavernous veins, bulbourethral veins, para-arterial veins, and circumflex veins.

[0033] Figure 7: Echo image showing a bulbourethral vein injection (puncture). The arrow indicates that the needle tip was located at the bulbourethral vein.

[0034] Figures 8 and 9: Showing the insertion of sclerosing agent into the deep dorsal vein under ultrasound monitoring. In each of Figures 8 and 9: the arrow indicates the insertion into the deep dorsal vein.

[0035] Figure 10: Sclerosing agent foam shown in the corpus cavernosum (arrow) after injection into the deep dorsal vein.

[0036] Figures 11 and 12: Showing the application of sclerosing agent to the bulbourethral vein. Figure 11: Direct puncture of the bulbourethral vein under ultrasound monitoring. Figure 12: Accompanying ultrasound monitoring (direct puncture).

[0037] Figures 13 and 14: Cavernosography before and after transurethral bulbovenous treatment. Figure 13: Cavernosography before treatment. Arrows indicate exposed veins. Figure 14: Post-treatment cavernosography. The leaking vein has disappeared.

[0038] definition As described herein, "corpus cavernosum" refers to the two chambers (sponge-like areas) of the penis that become engorged with blood and induce an erection. As further described herein, the terms "corpus cavernosum" and "corpora cavernosa" are used interchangeably. Specifically, in various embodiments of the invention, references to the singular term "corpus cavernosum" include both chambers, i.e., the plural term "corpora cavernosa." Therefore, in various embodiments of the invention, the application of an embolic agent or sclerosing agent as described herein includes application to both chambers, i.e., application to the "corpora cavernosa." The same consideration applies to the application of an embolic agent or sclerosing agent to the sinusoidal spaces of the corpus cavernosum according to the invention. Therefore, in various embodiments of the invention, the application of an embolic agent or sclerosing agent to the sinusoidal spaces of the corpus cavernosum as described herein includes application to both chambers, i.e., application to the "corpora cavernosa."

[0039] Furthermore, as described in this article, the terms "corpus spongiosum" and "corpus cavernosum urethrae" are used interchangeably.

[0040] The terms “sinusoid” and “sinusoid cavity”, or “sinusoids” and “sinusoid cavities”, are used interchangeably in this document.

[0041] As described herein, the terms "embolization agent" and "embolicagent" are used interchangeably. As further described herein, the terms "embolization agent" and "embolization substance" are used interchangeably.

[0042] As further described herein, the terms “sclerosing agent” and “sclerosing substance” are used interchangeably. As further described herein, “sclerosing agent” or “sclerosing substance” may be considered as “sclerosant”.

[0043] As used herein, the terms "composition comprising an embolic agent or a sclerosing agent" and "embolic agent or sclerosing agent" are used interchangeably. Specifically, aspects and embodiments in which "embolic agent or sclerosing agent" is referred to herein are considered to cover the same aspects and embodiments in which the "embolic agent or sclerosing agent" constitutes part of a "composition comprising an embolic agent or sclerosing agent." The terms "(wherein the composition) is delivered" and "(wherein the composition) is applied" are used interchangeably. Therefore, the terms "(wherein the composition) is delivered by injection" and "(wherein the composition) is applied by injection" are used interchangeably herein. In various embodiments, the terms "(wherein the composition) is applied by injection" and "(wherein the composition) is injected" are used interchangeably. Detailed Implementation

[0044] This invention relates to a novel method for treating erectile dysfunction by directly injecting an embolic or sclerosing agent into the bilateral corpora cavernosa or corpus spongiosum of the patient's penis or into one or more (draining) veins of the penis, wherein the embolic or sclerosing agent permeates into the bilateral corpora cavernosa or corpus spongiosum.

[0045] Surprisingly, the treatments requiring protection were found to be applicable to structural lesions that compensate for venous occlusive erectile dysfunction, affecting the closure mechanism of the draining venules in the sinusoidal spaces of the bilateral corpora cavernosa (and corpus spongiosum). Specifically, it was surprisingly found that direct injection of embolic or sclerosing agents into the bilateral corpora cavernosa or corpus spongiosum of the patient's penis did not result in serious side effects. For example, no thrombotic events were observed when treating erectile dysfunction by direct injection of embolic or sclerosing agents into the bilateral corpora cavernosa or corpus spongiosum of the patient's penis.

[0046] Furthermore, it was surprisingly found that when injected into one or more draining veins of the penis, the embolic or sclerosing agent could penetrate into both corpora cavernosa or corpora spongiosum, which in turn was found to be useful for treating erectile dysfunction. In particular, the penetration of the embolic or sclerosing agent into both corpora cavernosa or corpora spongiosum has not been associated with serious side effects; for example, as described above, no thrombotic events have been observed.

[0047] This invention describes for the first time the treatment of erectile dysfunction, particularly venous occlusive erectile dysfunction, by targeting both corpora cavernosa or corpora spongiosum of the penis. Surprisingly, it has been found that targeting both corpora cavernosa or corpora spongiosum with embolic or sclerosing agents is effective in treating erectile dysfunction, particularly venous occlusive erectile dysfunction. This invention is based on the direct application of embolic or sclerosing agents to both corpora cavernosa or corpora spongiosum of the penis, or the application of embolic or sclerosing agents to one or more draining veins of the penis. Unexpectedly, it has been found that the embolic or sclerosing agents can penetrate from these draining veins into both corpora cavernosa or corpora spongiosum of the penis, thereby achieving a therapeutic effect on erectile dysfunction.

[0048] Therefore, the treatments that require protection are particularly suitable for treating erectile dysfunction, especially venous occlusive erectile dysfunction, by directly treating the bilateral corpora cavernosa or by targeting the bilateral corpora cavernosa through one or more draining veins of the penis. Figure 2 and Figure 3 The injection of a sclerosing agent (foam) into the corpora cavernosa and its distribution are shown. No contrast agent was observed in the periprostatic veins. Figure 3 Arrow 3 in the middle of the image demonstrates the therapeutic effect. Figure 4 shows the injection of contrast agent into the corpora cavernosa after treatment. The veins are spasmodic (arrow 1 in Figure 4), and the contrast agent is visible in the corpora cavernosa (arrow 2), confirming the therapeutic effect. Figures 5 and 6 show ultrasound monitoring of the sclerosing agent foam in the corpora cavernosa. Arrow 1 (Figure 5) shows the ultrasound image of the corpora cavernosa without treatment. Arrow 2 (Figure 6) shows the ultrasound image of the corpora cavernosa after injection of the sclerosing agent. The sclerosing agent appears as a hyperechoic line and shadow in the corpora cavernosa.

[0049] It has also been demonstrated that sclerosing agents can penetrate into the corpora cavernosa from the deep dorsal vein. Figures 8 and 9 show the insertion of sclerosing agents into the deep dorsal vein under ultrasound monitoring. Figure 10 shows the sclerosing agent foam in the corpora cavernosa (arrows) after injection into the deep dorsal vein.

[0050] The same effect of penetrating into the corpora cavernosa was achieved by injecting sclerosing agents into the cavernous veins, bulbourethral veins, para-arterial veins, and circumflex veins. These draining veins have never been previously described as entry veins for injecting embolic or sclerosing agents. Figure 7 shows an echo-tracing image of bulbourethral vein injection (puncture) (arrows indicate the needle tip is located at the bulbourethral vein). Figures 11 and 12 show the application of sclerosing agents to the bulbourethral vein. Figure 11 shows an ultrasound image of direct puncture of the bulbourethral vein. Figure 12 shows the application (direct puncture) accompanied by ultrasound monitoring.

[0051] As described herein, the embolic or sclerosing agent that penetrates into both corpora cavernosa or corpora spongiosum preferably refers to the sinusoidal space of either corpora cavernosa or corpora spongiosum.

[0052] Therefore, the treatments that are to be protected are particularly suitable for treating erectile dysfunction, especially venous occlusive erectile dysfunction, by directly treating the sinusoidal spaces of the bilateral corpora cavernosa and / or the corpus spongiosum, or by targeting the sinusoidal spaces of the bilateral corpora cavernosa and / or the corpus spongiosum via one or more draining veins of the penis.

[0053] In various embodiments of the invention, when the penis is not erect (hard) or not fully erect (hard), an embolic agent or sclerosing agent is applied to one or more draining veins. This facilitates the penetration of the embolic agent or sclerosing agent into both corpora cavernosa or corpora spongiosum when applied to the draining veins of the penis. In particular, in the case of using a sclerosing agent, spasm of one or more draining veins is observed (immediately) after application / injection, which facilitates the entry of the sclerosing agent into both corpora cavernosa or corpora spongiosum. In the case of using an embolic agent (especially a liquid embolic agent), the agent acts as an embolizer, thereby facilitating the entry of the liquid embolic agent into both corpora cavernosa or corpora spongiosum. More specifically, a (liquid) embolic agent can be injected to form an embolus (at or near the leak point), and once the embolus is formed (observable / detectable by X-ray, cavernosography, especially DIC, or ultrasound, especially Doppler ultrasound), a subsequently injected (liquid) embolic agent can enter both corpora cavernosa (or corpora spongiosum). As described elsewhere in this document, applying pressure can further facilitate access to both corpora cavernosa (or corpus spongiosum). The embolic or sclerosing agent can be administered at a concentration of ≥10 mg / mL. In various embodiments, the embolic or sclerosing agent is applied to one or more draining veins when the penis is not erect (rigid) or not fully erect (rigid), and said one or more draining veins may be compressed at the proximal and / or distal sites of application (injection). In such embodiments, said one or more draining veins may be compressed at least at the proximal site of application (injection).

[0054] In various embodiments, the embolic agent or sclerosing agent is applied to one or more draining veins of the (venous) leak near the corresponding vein. This also (or further) facilitates the penetration of the embolic agent or sclerosing agent into both corpora cavernosa or corpora spongiosum when applied to one or more draining veins of the penis. In particular, in the case of using a sclerosing agent, spasm of one or more draining veins is observed (immediately) after application / injection, and (further) facilitates the penetration of the sclerosing agent into both corpora cavernosa or corpora spongiosum. In the case of using an embolic agent (especially a liquid embolic agent), the agent acts as an embolizer, thereby (further) facilitating the penetration of the (liquid) embolic agent into both corpora cavernosa or corpora spongiosum. The embolic agent or sclerosing agent can be applied to one or more draining veins proximal and / or distal to the (venous) leak near the corresponding vein. More specifically, a (liquid) embolic agent can be injected to form an embolism (at or near the leak point), and once the embolism is formed (observable / detectable by X-ray, cavernosography, particularly DIC, or ultrasound, particularly Doppler ultrasound), the subsequently injected (liquid) embolic agent can enter both corpora cavernosa (or corpus spongiosum). As described elsewhere herein, application of pressure can further facilitate entry into both corpora cavernosa (or corpus spongiosum). The embolic agent or sclerosing agent can be administered at a concentration of ≥10 mg / mL. In various embodiments, the embolic agent or sclerosing agent is applied to one or more draining veins (proximal and / or distal) of the (venous) leak near the corresponding vein, and said one or more draining veins can be compressed proximal and / or distal to the application (injection) site. In such embodiments, said one or more draining veins can be compressed at least proximal to the application (injection) site. Figure 1 is a cavernosography image showing a leak (arrow 1) from the corpora cavernosa to the pudendal vein. The corpus cavernosum was directly punctured near the leak (arrow 2) and contrast material was injected to visualize the draining vein.

[0055] In this invention, preferably when the penis is not erect (hard) or not fully erect (hard), the embolic agent or sclerosing agent is applied to one or more draining veins near the corresponding vein of the (venous) leak. The embolic agent or sclerosing agent can be applied to one or more draining veins proximal and / or distal to the corresponding vein of the (venous) leak. The embolic agent or sclerosing agent can be applied at a concentration of ≥10 mg / mL. In various embodiments, when the penis is not erect (hard) or not fully erect (hard), the embolic agent or sclerosing agent is applied to one or more draining veins (proximal and / or distal) near the corresponding vein of the (venous) leak, and said one or more draining veins can be compressed at the proximal and / or distal sites of application (injection). In such embodiments, said one or more draining veins can be compressed at least at the proximal site of application (injection).

[0056] In various embodiments of the invention, when the penis is in a (fully) erect (hard) state, an embolic agent or sclerosing agent is applied to one or more draining veins near the corresponding vein of the (venous) leak. In this case, it is preferable that the one or more draining veins are compressed at the proximal and / or distal sites of application (injection). Specifically, in this case, it is preferable that the one or more draining veins are compressed at least at the proximal site of application (injection). In this case, it is further preferable that the embolic agent or sclerosing agent is applied to one or more draining veins near the proximal and / or distal sites of the (venous) leak. The embolic agent or sclerosing agent may be applied at a concentration of ≥10 mg / mL.

[0057] Therefore, when applied to one or more (draining) veins of the penis, the embolic or sclerosing agent (composition) is forced into both corpora cavernosa or corpora spongiosum. The term "forced into both corpora cavernosa or corpora spongiosum" specifically refers to compression of the one or more draining veins at the proximal and / or distal sites of application (injection) to force the embolic or sclerosing agent into both corpora cavernosa or corpora spongiosum. Alternatively, in various aspects or embodiments, the effect of the embolic or sclerosing agent can be considered to provide (or cause) the embolic or sclerosing agent to be "forced into both corpora cavernosa or corpora spongiosum." The effect of the embolic or sclerosing agent includes or is based on the occlusion of venous leakage following application of the embolic or sclerosing agent (composition). Specifically, in the case of a sclerosing agent, the effect of the sclerosing agent includes or is based on spasm of one or more draining veins that can be observed (immediately) after application / injection. In the case of embolic agents, the effect includes or is based on the embolic effect of the embolic agent in one or more draining veins that can be observed after administration / injection. In various embodiments, occlusion of the venous leak after administration of (a) sclerosing agent (composition) means occlusion of the venous leak by spasm and endothelial damage of one or more draining veins. In various embodiments, occlusion of the venous leak after administration of (a) embolic agent (composition) means occlusion of the venous leak by embolic effect of the embolic agent in one or more draining veins. In a preferred embodiment, occlusion of the venous leak is induced and / or observed near the corresponding vein, more specifically at the proximal and / or distal end of the (venous) leak near the corresponding vein. In other preferred embodiments, spasm or embolism is induced and / or observed near the corresponding vein, more specifically at the proximal and / or distal end of the (venous) leak near the corresponding vein. The embolic agent or sclerosing agent can be administered at a concentration of ≥10 mg / mL.

[0058] The effects of the aforementioned embolic or sclerosing agents, particularly in cases of spasm or embolization, can be imaged or determined using X-rays, cavernosography, (CT-) cavernosography, dynamic infusion cavernosography (DIC), or ultrasound (especially Doppler ultrasound). In the case of embolic agents (especially liquid embolic agents), X-rays, cavernosography, (CT-) cavernosography, and dynamic infusion cavernosography (DIC) are preferred. In the case of sclerosing agents, ultrasound, especially Doppler ultrasound, is preferred.

[0059] In this invention, the embolic agent or sclerosing agent is preferably administered / injected via a direct puncture into the corpus cavernosum or corpus spongiosum of the penis. When administered to one or more draining veins, it is also preferred that the embolic agent or sclerosing agent be administered via a direct puncture into one or more draining veins of the penis.

[0060] In a particularly preferred embodiment, the embolic agent or sclerosing agent is applied / injected into the sinus cavities of both corpora cavernosa and / or the sinus cavities of the corpus spongiosum. Preferably, the embolic agent or sclerosing agent is applied / injected into the sinus cavities of both corpora cavernosa and / or the sinus cavities of the corpus spongiosum via direct puncture.

[0061] In this invention, both corpora cavernosa and corpus spongiosum are mentioned equally. In various embodiments, the bilateral corpora cavernosa are preferred for application compared to the corpus spongiosum. This preference is considered applicable to all aspects and embodiments disclosed herein. Therefore, in various embodiments, the sinusoidal space of the bilateral corpora cavernosa is preferred over the sinusoidal space of the corpus spongiosum.

[0062] In this invention, embolic agents and sclerosing agents are mentioned equally. In various embodiments, sclerosing agents are preferred over embolic agents. In particular, in various embodiments, (liquid) sclerosing agents are preferred over liquid embolic agents. This preference can be considered applicable to all aspects and embodiments disclosed herein. Therefore, in various embodiments, it is preferable to apply sclerosing agents to the bilateral corpora cavernosa or corpora spongiosum (sinusoidal spaces) of the penis compared to applying embolic agents. It can be considered that using X-rays makes embolization easier to control. Furthermore, it can be considered that sclerosing agents diffuse more easily.

[0063] In various preferred embodiments of the invention, the novel method is carried out by applying an embolic agent, particularly a liquid embolic agent, to both corpora cavernosa of the penis (preferably to one or more sinus cavities of both corpora cavernosa).

[0064] In a preferred embodiment of the invention, injection into both corpora cavernosa or corpora spongiosum is accompanied by / includes visual imaging of both corpora cavernosa or corpora spongiosum to assess the dynamic movement of the intercorpora cavernosa or intercorpora spongiosum. In a further preferred embodiment of the invention, injection into the sinusoidal cavities of both corpora cavernosa or corpora spongiosum is accompanied by / includes visual imaging of the sinusoidal cavities to assess the dynamic movement of the intercorpora cavernosa or intercorpora spongiosum.

[0065] The effects of the aforementioned embolic or sclerosing agents, particularly the occlusion of venous leaks after application (of a composition containing) an embolic or sclerosing agent, can be imaged or determined by X-ray, cavernosography, (CT-) cavernosography, dynamic infusion cavernosography (DIC), or ultrasound (especially Doppler ultrasound). The imaged or determined occlusion of the venous leak includes imaging or determination of spasm and endothelial injury (in the case of using sclerosing agents) or embolism (in the case of using embolic agents) by X-ray, cavernosography, (CT-) cavernosography, dynamic infusion cavernosography (DIC), or ultrasound (especially Doppler ultrasound). In the case of embolic agents (especially liquid embolic agents), X-ray, cavernosography, (CT-) cavernosography, and dynamic infusion cavernosography (DIC) are preferred. In the case of sclerosing agents, ultrasound, especially Doppler ultrasound, is preferred. Figures 13 and 14 show cavernosography before and after transurethral bulbovenous treatment. Figure 14 shows the disappearance of the leaking vein.

[0066] As described herein, treating or targeting both corpora cavernosa includes treating or targeting both chambers (both corpora cavernosa) or only one of them (corpora cavernosa), with a preferred embodiment being treating or targeting both chambers (simultaneously or within the same treatment window). Therefore, as used herein, reference to both corpora cavernosa encompasses embodiments that target or treat only one corpus cavernosum.

[0067] In a preferred embodiment of the invention, one or more veins of the penis are selected from any one of the cavernous veins, deep dorsal veins, bulbourethral veins, para-arterial veins, and circumflex veins. More preferably, one or more veins of the penis are selected from the deep dorsal vein and the bulbourethral vein. In various embodiments, the one or more veins are bulbourethral veins. Figure 7 shows bulbourethral vein injection (puncture). Figures 8 and 9 show deep dorsal vein injection (puncture). In various other preferred embodiments, the one or more veins are para-arterial veins and / or circumflex veins.

[0068] In some embodiments of the invention, one or more veins of the penis are deep dorsal veins. Preferably, an embolic or sclerosing agent is injected into the deep dorsal vein by puncture, particularly direct puncture. As described herein, direct puncture means direct puncture into one or more veins of the penis as described elsewhere herein.

[0069] Regarding the preferred type of draining vein: Application to the cavernous vein is preferable to application to the deep dorsal vein. Application to the bulbourethral vein, para-arterial vein, and / or circumflex vein is preferable to application to the deep dorsal vein or cavernous vein. Application to the bulbourethral vein is preferable to application to the para-arterial vein and / or circumflex vein.

[0070] As further described herein, a needle is preferred, more specifically an injection needle, and more preferably a sclerotherapy injection needle for direct puncture. In a preferred embodiment, direct puncture is performed under ultrasound examination or ultrasound guidance (using a needle as described elsewhere herein).

[0071] As described herein, the injected sclerosing agent dose is preferably no more than 2 mg / kg body weight / day. More specifically, the injected sclerosing agent dose is preferably no more than 2 mg / kg body weight / treatment. In a preferred embodiment, the injected sclerosing agent dose is preferably no more than 2 mg / kg body weight / day / treatment. The sclerosing agent is preferably polidocanol (polyoxyethylene lauryl ether). The polidocanol dose is preferably no more than 2 mg / kg body weight / treatment. In a preferred embodiment, the injected sclerosing agent dose is preferably no more than 2 mg / kg body weight / day / treatment. Preferred embolic agents are described elsewhere herein.

[0072] As further described herein, the dose of the embolic agent (particularly a liquid embolic agent) injected into the bilateral corpora cavernosa or corpus spongiosum can be very small. The dose of the injected embolic agent generally follows the manufacturer's recommendations. The volume of the (liquid) embolic agent administered according to the invention generally does not exceed 1 mL per administration, and preferably is less than 1 mL per administration.

[0073] The volume of the foam or microfoam of the hardener (e.g., polydextrose) applied according to the present invention is generally no more than 1.2 mL per application, and preferably less than 1.2 mL per application.

[0074] As described herein, the treatment of erectile dysfunction according to the present invention excludes treatment via or using a catheter. Therefore, in various preferred embodiments, the treatment of erectile dysfunction according to the present invention excludes catheter insertion or treatment using a catheter.

[0075] As discussed elsewhere herein, it has been surprisingly found that when injected into one or more draining veins of the penis, the embolic agent or sclerosing agent permeates into both corpora cavernosa or corpora spongiosum. In a preferred embodiment, the embolic agent or sclerosing agent, or a composition containing the embolic agent or sclerosing agent, is applied / injected into one (or a type of) draining vein of the penis. Preferred types of draining veins are described elsewhere herein.

[0076] As described elsewhere herein, an embolic agent or sclerosing agent, or a composition containing an embolic agent or sclerosing agent, can be forced into the corpus cavernosum or corpus spongiosum by compressing one or more of the draining veins. In this regard, the one or more veins can be compressed at the proximal site of injection. In a preferred embodiment, the compression occurs on the deep dorsal vein, more preferably anterior to the periprostatic venous plexus. In a further (preferred) embodiment, the one or more veins can be compressed at the distal site of injection. As described herein, the compression can be manual compression of one or more veins of the penis. The compression described herein should not be considered, in itself, a method of treating erectile dysfunction. Therefore, the compression described herein should not be considered a treatment or surgical method performed on a human or animal body.

[0077] In this invention, the treatment of erectile dysfunction is preferably the treatment of venous occlusive erectile dysfunction. As described herein, the terms venous occlusive erectile dysfunction and venous occlusive erectile disease are used interchangeably herein. As further described herein, the terms venous occlusive erectile dysfunction (or venous occlusive erectile disease) and venous-origin erectile dysfunction (or venous-origin erectile disease) are used interchangeably herein. Venous occlusive erectile dysfunction is due to venous occlusive dysfunction (or venous occlusive insufficiency), also known as "venous leakage," characterized by insufficient occlusion of the venous outflow pathway. Additionally or alternatively, venous-origin erectile dysfunction can be considered as insufficient penile blood retention during erection due to venous leakage. In any case, in this invention, venous occlusive erectile dysfunction is characterized by (or related to) venous leakage, particularly leakage of the venous outflow pathway (of the patient's penis). More specifically, venous leakage means leakage of the venous outflow pathway in the bilateral corpora cavernosa (or cavernous tissue) of the penis.

[0078] As further described herein, venous leakage can be additionally or alternatively considered as the inability to maintain an erection despite sufficient arterial blood flow through the cavernous body arteries. As mentioned above, this defect is based on excessive venous drainage primarily within the cavernous body tissue, which impairs normal erectile function. This defect persists due to excessive venous drainage around the outer walls of the bilateral corpora cavernosa. These veins include the deep dorsal vein, bulbourethral vein, para-arterial vein, and circumflex vein. Therefore, in various embodiments of the invention, venous leakage refers to venous leakage around the outer walls of the bilateral corpora cavernosa (or cavernous body tissue). These veins include the deep dorsal vein, bulbourethral vein, para-arterial vein, and circumflex vein. In various embodiments, the vein may be a pudendal vein. Pudendal veins can be treated by injection into the corpora cavernosa.

[0079] As described herein, the novel treatment method provided by the present invention provides occlusion of venous leakage after application of an embolic agent or sclerosing agent, or after application of a composition containing an embolic agent or sclerosing agent.

[0080] As further described herein, venous occlusive erectile dysfunction can be definitively confirmed and visualized by CT cavernosography. In a preferred embodiment, the treatment of the present invention may include the step of performing cavernosography (particularly CT cavernosography) prior to the administration of a composition comprising an embolic agent or sclerosing agent to confirm venous occlusive erectile dysfunction and / or visualize the one or more venous leaks. In a preferred embodiment of the invention, venous leaks associated with venous occlusive erectile dysfunction can be determined by cavernosography, particularly dynamic infusion cavernosography (DIC), or ultrasound, particularly Doppler ultrasound. Cavernosography is preferred, and therefore DIC is also preferred.

[0081] As described in this article, one or more veins used to administer (inject) embolic or sclerosing agents can be any draining vein that can be visualized using ultrasound or X-ray (using contrast material).

[0082] In a preferred embodiment, the treatment of the present invention includes injecting (a combination of) an embolic agent or a sclerosing agent at a site near the one or more venous leaks.

[0083] In a preferred embodiment of the invention, the composition comprising the embolic agent is a liquid composition, preferably a liquid embolic agent. In various preferred embodiments, the embolic agent is a liquid and fills a vein, thereby blocking the vein (“glue embolization”). Therefore, the embolic agent does not necessarily damage the vein. In a preferred embodiment, the embolic agent is typically based on cyanoacrylate. The invention covers cyanoacrylate liquid embolic agents, or cyanoacrylate glues, or cyanoacrylate liquid glues. The invention particularly covers (liquid) embolic agents based on n-alkyl cyanoacrylates, including (liquid) embolic agents based on n-hexyl cyanoacrylate and n-butyl cyanoacrylate. The invention also covers mixtures of n-alkyl cyanoacrylates and metacryloxysulfolane as (liquid) embolic agents, including n-hexyl cyanoacrylate or mixtures of n-butyl cyanoacrylate and metacryloxysulfolane as (liquid) embolic agents. The present invention also covers mixtures of n-alkyl cyanoacrylate and 2-octyl cyanoacrylate as (liquid) embolic agents, including mixtures of n-hexyl cyanoacrylate or n-butyl cyanoacrylate and 2-octyl cyanoacrylate as (liquid) embolic agents.

[0084] Liquid embolic agents typically harden upon entering the bloodstream. Therefore, in cases where embolic agents (especially liquid embolic agents) are used, the agent can be considered to act as an embolic agent, as described elsewhere in this document.

[0085] The liquid embolizing agent used in this invention may include, but is not limited to, ethanol, butyl cyanoacrylate (NBCA) gel, and Lipiodol. ® Ethylene-iodized oil (Guerbet LLC) and embolic agents based on ethylene-iodized (poppy seed) oil, as well as Onyx™ (Medtronic). Onyx™ is an embolic agent (fluid) made from EVOH (ethylene-vinyl alcohol copolymer), DMSO (dimethyl sulfoxide), and TA (micronized tantalum powder). Therefore, the present invention covers EVOH-based (liquid) embolic agents, preferably (liquid) embolic agents based on EVOH dissolved in DMSO, and more preferably (liquid) embolic agents based on EVOH dissolved in DMSO with micronized tantalum powder suspended in it.

[0086] The liquid embolic agents disclosed herein encompass suitable combinations, such as mixtures of ethanol and ethyl iodized oil, which may be a 1:1 mixture of ethanol and ethyl iodized (poppy seed) oil. The terms "ethyl iodized oil" and "ethiodol" are used interchangeably herein.

[0087] As described herein, the terms “embolization agent” and “embolicagent” are used interchangeably.

[0088] Furthermore, in a preferred embodiment of the invention, the composition containing the hardening agent is a liquid composition, foam, or microfoam, preferably a liquid hardening agent, a hardened foam, or a hardened microfoam. The hardening agent can be a nonionic detergent, particularly a synthetic nonionic detergent, such as sodium tetradecyl sulfate (STS). In a preferred embodiment, the hardening agent can be a long-chain fatty alcohol, particularly a synthetic long-chain fatty alcohol. In a more preferred embodiment, the hardening agent can be polydocalol (hydroxyl polyethoxylate; polyoxyethylene lauryl ether). As described herein, hardening agents may damage the inner wall of veins. In this invention, foam, particularly microfoam, is preferred. Such (micro)foam can be prepared from any hardening substance with oxygen or a mixture of oxygen and carbon dioxide gas.

[0089] As described elsewhere herein, in a preferred embodiment, the treatment method of the present invention includes the step of imaging a composition comprising an embolic agent or sclerosing agent by ultrasound, or X-ray or (CT-) cavernosography, preferably by ultrasound.

[0090] In a preferred embodiment, the treatment method of the present invention includes injecting a composition comprising an embolic agent or a sclerosing agent into a non-erect (non-rigid) penis or an erect (rigid) penis, wherein an erect (rigid) state can be induced by injecting a drug that stimulates erection.

[0091] In various preferred embodiments of the invention, patients receiving the treatment according to the invention do not need to take a PDE5 (phosphodiesterase-5) inhibitor (in addition to or simultaneously with the erectile dysfunction treatment). Surprisingly, it has been found that erectile dysfunction is completely resolved by the treatment of the invention, thus patients do not need to use any PDE5 inhibitors at all. In various embodiments, erection occurs when a PDE5 inhibitor is supplemented following the treatment according to the invention, i.e., the two treatments complement each other. Therefore, in various embodiments, the treatment of the invention may include the administration of a PDE5 inhibitor to further support or achieve an erection.

[0092] This invention further covers: [1] A composition comprising an embolic agent or a sclerosing agent for treating erectile dysfunction (in a method), comprising administering the composition to a patient in need, wherein the composition is administered by injection to the following site (in the patient in need): (a) One or more (draining) veins in the patient's penis; and / or (b) The corpus cavernosum or corpus spongiosum of the patient's penis.

[0093] [2] The composition for treating erectile dysfunction according to [1(a)], wherein the one or more (draining) veins are selected from any one of the cavernous veins, deep dorsal veins, bulbourethral veins, para-arterial veins and circumflex veins.

[0094] [3] The composition for treating erectile dysfunction according to [1(a)] or [2], wherein the composition is forced into the corpus cavernosum or corpus spongiosum.

[0095] [4] The composition for treating erectile dysfunction according to any one of [1] to [3], wherein one or more veins of the penis are compressed at the proximal part of the injection site.

[0096] [5] The composition for treating erectile dysfunction according to any one of [1] to [4], wherein one or more veins of the penis are compressed at a distal portion of the injection site.

[0097] [6] A composition for treating erectile dysfunction according to any one of [1] to [5], wherein the composition is administered by direct puncture into one or more veins; or by puncture into the corpus cavernosum or corpus spongiosum, respectively.

[0098] [7] The composition for treating erectile dysfunction according to any one of [1] to [6], wherein the composition is injected into: (i) the sinusoidal spaces of the corpora cavernosa; and / or (ii) Sinusoidal space of the corpus spongiosum.

[0099] [8] The composition for treating erectile dysfunction according to any one of [1] to [7], wherein the erectile dysfunction is venous occlusive erectile dysfunction.

[0100] [9] The composition for treating erectile dysfunction according to [8] wherein the venous leakage associated with venous occlusive erectile dysfunction is determined by cavernosography (especially dynamic infusion cavernosography (DIC)) or ultrasound (especially Doppler ultrasound).

[0101]

[10] The composition for treating erectile dysfunction according to any one of [1] to [9] includes occlusion of venous leakage after administration of a composition comprising an embolic agent or a sclerosing agent.

[0102]

[11] The composition for treating erectile dysfunction according to any one of [1] to

[10] , wherein the composition comprising an embolic agent is a liquid composition, preferably a liquid embolic agent.

[0103]

[12] The composition for treating erectile dysfunction according to any one of [1] to

[10] , wherein the composition comprising a sclerosing agent is a liquid composition, a foam or a microfoam, preferably a liquid sclerosing agent, a sclerosing foam or a sclerosing microfoam.

[0104]

[13] A composition for treating erectile dysfunction according to any one of [1] to

[10] and

[12] , wherein the sclerosing agent is polydextrose.

[0105]

[14] The composition for treating erectile dysfunction according to any one of [1] to

[13] further includes imaging of the composition containing the embolic agent or sclerosing agent by ultrasound, X-ray or (CT-) cavernosography, preferably by ultrasound.

[0106]

[15] A composition for treating erectile dysfunction according to any one of [1] to

[14] , wherein the patient’s penis is in a non-erect state or in an erect state induced by (injection) (stimulating erection) medication.

[0107] The embodiments of the method of the present invention are illustrated in the following examples. These examples are provided for illustrative purposes and are not intended to limit the scope of the method and its uses.

[0108] Example Example 1: Cavernosography to determine venous occlusive erectile dysfunction A male patient with erectile dysfunction underwent cavernosography to identify a venous leak. Figure 1 shows a cavernosography image and illustrates a leak from the corpus cavernosum to the pudendal vein (arrow 1). Direct puncture of the corpus cavernosum near the leak (arrow 2) and injection of contrast material revealed the draining vein. The patient had venous occlusive erectile dysfunction.

[0109] Example 2: Proof of concept for intracavernosal therapy Patients with erectile dysfunction (male, human) underwent intracavernosal injection of a sclerosing agent (foam). Prior to the sclerosing agent injection, all patients received a contrast agent injection to verify the therapeutic effect of the subsequently injected sclerosing agent. Figure 2 and Figure 3 The image shows the injection of a sclerosing agent (foam) into the corpus cavernosum and its distribution, illustrating how the contrast agent disappears as the sclerosing agent (foam) replaces it. Arrow 1 in Figure 2 indicates the start of the sclerosing agent injection. Figure 3 Arrow 2 in the image shows that the contrast agent around the needle disappeared as it was replaced by foam. Figure 3 Arrow 3 in the image shows the absence of contrast agent in the veins surrounding the prostate, thus demonstrating the effectiveness of the treatment.

[0110] Figures 5 and 6 show ultrasound images demonstrating the entry of the sclerosing agent (foam) into the corpora cavernosa. Arrow 1 (Figure 5) shows an ultrasound image of the corpora cavernosa without treatment. Arrow 2 (Figure 6) shows an ultrasound image of the corpora cavernosa after the injection of the sclerosing agent (foam). The sclerosing agent appears as a hyperechoic line and shadow in the corpora cavernosa.

[0111] Example 2 illustrates the treatment according to the invention, wherein an embolic agent or sclerosing agent is injected into both corpora cavernosa of the penis. Erections were achieved after treatment in all treated patients. Erections occurred normally in time and were of normal rigidity. Erections were sustained over time (“prolonged”) because the treated leaking veins (did not reappear).

[0112] Example 3: Patients who had their erections induced before treatment In an independent trial with the same setup as in Example 2, patients (male, human) were induced to have an erection before treatment. Erections were maintained after treatment in all treated patients. Erections were shown to occur normally in time and to be of normal rigidity. Erections were shown to be maintained over time (“prolonged”) because the treated leaking veins (did not reappear).

[0113] Example 4: Injected into the bulbourethral vein, para-arterial vein, and circumflex vein. In an experiment with the same setup as in Example 2, the sclerosing agent was injected into any of the bulbourethral vein, para-arterial vein, and circumflex vein. Figure 7 shows an echo-tracing image of the injection (puncture) into the bulbourethral vein. The arrow indicates that the needle tip was located at the bulbourethral vein.

[0114] The same effect as demonstrated in Example 2 was achieved by injecting a sclerosing agent (foam) into the bulbourethral vein, para-arterial vein, and circumflex vein. Figures 11 and 12 are images showing the application of the sclerosing agent foam to the bulbourethral vein. Figure 11 shows an ultrasound image of direct puncture of the bulbourethral vein. Figure 12 shows the application (direct puncture) accompanied by ultrasound monitoring. Figures 13 and 14 are cavernosography images before and after treatment via the bulbourethral vein. In Figure 13, the arrows indicate leaking veins. Figure 14 shows the disappearance of the leaking veins after treatment. Figures 13 and 14 verify that the sclerosing agent entered both corpora cavernosa of the penis, thus verifying that the treatment was correct.

[0115] Therefore, Example 4 further confirms the treatment according to the invention, wherein an embolic or sclerosing agent is injected into one or more draining veins of the patient's penis. Erections were achieved after treatment in all patients treated in Example 4. Erections occurred normally in time and were of normal rigidity. Erections were sustained over time ("prolonged") because the treated draining veins (did not reappear).

[0116] Example 5: Injected into the deep dorsal vein and into both corpora cavernosa of the penis. In experiments with the same setup as in Examples 2 or 4, a sclerosing agent was injected into the deep dorsal vein. Figures 8 and 9 show ultrasound images of the sclerosing agent being punctured into the deep dorsal vein. In each of Figures 8 and 9, the arrows indicate puncture into the deep dorsal vein. Figure 10 shows sclerosing agent foam in the corpora cavernosa (arrows) after injection into the deep dorsal vein, thus demonstrating the sclerosing agent entering both corpora cavernosa of the penis.

[0117] Therefore, the same effect as demonstrated in Example 4 was achieved by injecting the sclerosing agent (foam) into the deep dorsal vein.

[0118] Therefore, Example 5 further confirms the treatment according to the invention, wherein an embolic agent or sclerosing agent is injected into one or more draining veins of the patient's penis. Erections were achieved after treatment in all patients treated in Example 5. The erections were durable.

[0119] Example 6: Further validation of the treatment The treatment effect was further verified by injecting contrast agent after treatment. Figure 4 shows the injection of contrast agent into the corpora cavernosa after treatment. Arrow 1 in Figure 4 shows the spasmodic vein, and the contrast agent is visible in the corpora cavernosa (arrow 2), confirming the treatment effect.

Claims

1. A method of treating venous occlusive erectile dysfunction with a composition comprising an embolic agent or a sclerosing agent, comprising administering the composition to a patient in need, wherein, The composition is administered by injection into the corpus cavernosum or corpus spongiosum of the patient's penis.

2. The composition according to claim 1, wherein, The composition is administered by direct puncture into the corpus cavernosum or the corpus spongiosum.

3. The composition used according to claim 1 or 2, wherein the composition is injected into: (i) the sinusoidal space of the corpus cavernosum; and / or (ii) The sinusoidal space of the corpus spongiosum.

4. The composition used according to any one of claims 1 to 3, wherein, Venous leaks associated with the aforementioned venous occlusive erectile dysfunction are identified by cavernosography, particularly dynamic infusion cavernosography (DIC), or ultrasound, particularly Doppler ultrasound.

5. The composition used according to any one of claims 1 to 4, comprising occluding venous leakage after administration of the composition comprising the embolic agent or the sclerosing agent.

6. The composition used according to any one of claims 1 to 5, wherein, The composition containing the embolic agent is a liquid composition, preferably a liquid embolic agent.

7. The composition used according to any one of claims 1 to 5, wherein, The composition containing the hardener is a liquid composition, foam, or microfoam, preferably a liquid hardener, hardened foam, or hardened microfoam.

8. The composition used according to any one of claims 1 to 5 and 7, wherein, The hardener is polydextrose.

9. The composition used according to any one of claims 1 to 8 further comprises imaging the composition containing the embolic agent or the sclerosing agent by ultrasound, X-ray or (CT) cavernosography, preferably by ultrasound.

10. The composition used according to any one of claims 1 to 9, wherein, The patient's penis is either in a non-erect state or in an erect state induced by (injection) (stimulating erection) drugs.

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