US20120093950A1 - Compositions and methods for treating, inhibiting the onset, and slowing the progression of erectile dysfunction including naturally occuring age related erectile dysfunction - Google Patents
Compositions and methods for treating, inhibiting the onset, and slowing the progression of erectile dysfunction including naturally occuring age related erectile dysfunction Download PDFInfo
- Publication number
- US20120093950A1 US20120093950A1 US12/907,113 US90711310A US2012093950A1 US 20120093950 A1 US20120093950 A1 US 20120093950A1 US 90711310 A US90711310 A US 90711310A US 2012093950 A1 US2012093950 A1 US 2012093950A1
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- United States
- Prior art keywords
- composition
- ginger
- erectile dysfunction
- arginine
- citrulline
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- Abandoned
Links
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Classifications
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Definitions
- the present inventions relate to compositions and methods for treating, inhibiting the onset, and/or slowing the rate of development of erectile dysfunction (“ED”), and in particular relate to compositions and methods for treating, inhibiting the onset, and slowing age related erectile dysfunction (“ARED”).
- ED erectile dysfunction
- ADAD age related erectile dysfunction
- Impotence or erectile dysfunction is a problem that most men will face at some time in their life. In fact, by the time a man reaches 50 years of age, he has about a 1 in 2 chance of having some problem with his erection; the problem could be either attaining and/or maintaining his erection long enough to complete the sexual act. As men get older, the chance of getting ED increases such that a 60 year old man has approximately a 60% chance of having ED, a 70 year old man has about a 70% chance, etc.
- CSM corporal cavernosal smooth muscle
- the function of the CSM in the erectile process is to receive and trap blood entering the corporal bodies. This is accomplished when the CSM undergoes relaxation that allows it to open up and create spaces or sinusoids into which the entering blood pools. The pooling of this blood in sinusoidal spaces increases the pressure within the corporal bodies and when a certain intracorporeal pressure is reached, the pressure closes off the veins that drain the blood out of the corporal bodies, essentially trapping it within the corporal bodies. Clinically, this is how the CSM tissue is able to attain (by creating spaces for the blood to pool into) and maintain (by closing off the veins) an erection.
- flaccidity can be considered as the baseline state. Flaccidity is due to corpus cavernosum smooth-muscle cells (“CSM”) being contracted and helicine arterioles being sufficiently contracted to limit blood flow to corpus covernosal sinuses; the sympathetic nervous system and tonic adrenergic discharge maintain baseline contraction of smooth muscle cells and arteriole blood supply (e.g., adrenergic, cholinergic, and nonadrenergic-noncholinergic pathways). So, a combination of metabolic pathways are involved in inducing the erectile processes involving smooth muscle relaxation, arterial dilation, and venous occlusion.
- CSM corpus cavernosum smooth-muscle cells
- helicine arterioles being sufficiently contracted to limit blood flow to corpus covernosal sinuses
- tonic adrenergic discharge maintain baseline contraction of smooth muscle cells and arteriole blood supply (e.g., adrenergic, cholinergic, and nonadrenergic-noncholinergic pathways
- the impact on erectile function becomes noticeable.
- the first recognition that one's erectile mechanism is worsening is the increase in time that it takes for one to achieve subsequent erections. This time in between subsequent erections is called the refractory period and it is the first indication that the CSM tissue is changing for the worse.
- nNOS neuronal nitric oxide synthase
- nNOS This NO from nNOS is the major chemical that is involved in the relaxation of the CSM cells and hence is required for the initiation and maintenance of a normal erection. Therefore, while nNOS is normally present in the nerves innervating the penis, iNOS is normally not present in the CSM cells of the penis and is only induced by the CSM cells themselves when the cells experience oxidative stress. However, when iNOS is induced as seen in U.S. Pat. No. 5,594,032, human erectile dysfunction can be ameliorated by treatment with iNOS, inducers of iNOS or iNOS cDNA. Further background on sexual dysfunction, urogenital disease, and ED and related treatments can be found in U.S. Pat. No.
- fibrotic disease is linked to reproductive disorders and cardiovascular disease, which are both prevalent in aging males.
- the ubiquitous and long felt need to treat sexual dysfunction has led to surgical and pharmacological treatment approaches.
- the ongoing commercial success of prescription medications under the trademarks VIAGRA®, LEVITRA® and CIALIS® for treatment of ED demonstrates the long felt and widespread need for effective treatments for ED, particularly for patients that present with ED symptoms advanced sufficiently that erections of satisfactory duration at the desired time can only be reliably accomplished by taking the prescription drug.
- PDE5 Type 5 phosphodiesterase
- Viagra Cialis and Levitra prevent the cGMP from breaking down so the effect of the cGMP on the tissues is enhanced.
- cGMP is formed within the CSM from a reaction that is initiated by the NO that is released from the cavernosal nerve following sexual stimulation.
- the NO that begins the erectile response comes from the enzyme nNOS that is located in the nerve endings.
- the NO goes into the CSM cells and causes a reaction to occur in these CSM cells.
- NO activates the enzyme soluble guanylyl cyclase (sGC) in the cytoplasm of the CSM and this enzyme in turn converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP).
- sGC soluble guanylyl cyclase
- GTP guanosine triphosphate
- cGMP cyclic guanosine monophosphate
- cGMP stimulates protein kinase G to phosphorylate potassium and calcium channels causing a decrease in cytosolic calcium, dilation of the helicine arterioles, and the relaxation of the trebecular smooth muscle where all the CSM cells are located.
- the relaxation of the smooth muscle leads to an increase in the intracavernosal volume, initiating the erectile process.
- endogenous PDE5 enzyme degrades cGMP which reverses the relaxation of the smooth muscle cells and leads to loss of erection whereas the ingestion of these PDE5 inhibitors prior to sexual stimulation prevent the degradation of the cGMP that is formed thereby prolonging any CSM relaxation and enhancing any erectile response.
- PDE5 inhibitors like Viagra, Cialis and Levitra depend on the specificity of the compound. While PDE5 inhibitors are considered the “first line treatment of ED,” there are notable side effects (headache, flushing, dyspepsia, rhinitis, visual disturbances, back pain, etc.) and adverse interactions that can limit or bar their use (e.g., patients taking nitrates with a PDE5i can experience hypotension and syncope.
- ED can be arrested, inhibited, or even reversed by use of a composition of the present inventions and methods of treatment utilizing same.
- in vitro experiments have established that when inducible nitric oxide synthase (“iNOS”) is stimulated on a daily basis when the penile musculature is deteriorating (e.g., from oxidative stress), penile muscle loss can be inhibited and in some instances new penile muscle tissue forms to replace lost muscle (Ferrini et al. Biol Reprod 76:915-923,2007).
- iNOS stimulation is utilized to treat and/or prevent ED.
- compositions of the present inventions should be varied depending on the age of the patient or on the onset of ED symptoms.
- the compositions of the present inventions are particularly useful in the treatment of ARED.
- the present inventor has surprisingly discovered that dosages of ginger small enough to be useful and practicable in routine, even daily, administration over an extended period of time can be used in compositions of the present invention for treating and inhibiting ED.
- compositions include ginger, and L-arginine or a compound that induces production of L-arginine in vivo.
- a composition for the treatment and prevention of ED comprises ginger and L-citrulline, the latter inducing L-arginine in vivo.
- Treatment for ED includes repeated administration of the compositions of the present inventions to a patient over a period of time sufficient to obtain the desired result.
- Preferred compositions of the present inventions may not contain compounds that require a prescription and/or avoid side effects of current “first line” treatments for ED. More details of exemplary embodiments of the present inventions follow.
- ginger also known as Zingiber officinale roscoe (ZOR)
- ZOR Zingiber officinale roscoe
- the present inventor made the surprising discovery that at higher dosages of ZOR, e.g. 500 mg/L, in the presence of LPS stimulates iNOS.
- the present inventor also surprisingly discovered that ginger, without separating its ingredients and without the presence of LPS, can cause sufficient stimulation of iNOS to enable much lower dosages of ginger to be used effectively in compositions of the present inventions to treat and prevent ED.
- Table 1 are presented nitrite production data from in vitro experiments with cells incubated with varying amounts of ginger without LPS.
- compositions of the present inventions are administered in a pharmaceutically effective amount to treat erectile dysfunction.
- Treatments can consist of either short term self administered oral dosages taken periodically, e.g. at least once a day or other period of time in between dosages until the desired effect is reached or as part of one's long term, even life time, daily nutrition.
- the present inventor found with in vitro experiments that dosages of ginger low enough to be practicable for routine administration are capable of use to treat ED when used in the compositions and methods of the present inventions. Also, by varying the ratio of ginger to other ingredients, the formulations and dosing schedule can be optimized for specific patients and/or patient profiles.
- One method to determine patient profiles is by obtaining a biopsy of the penile tissue to evaluate the integrity of the CSM cells. Obtaining biopsy specimens of penile tissue can be performed in a relatively painless manner, either during the performance of other surgical procedures e.g. during prostate surgery or even an office visit at which an analgesic/local anesthetic can be used prior to the biopsy.
- a composition for the treatment of erectile dysfunction comprises cortex magnoliae officinalis and/or fructus aurantil immaturus (also referred to hereinafter as “CMO” and “FAI” respectively; while not wishing to be limited to a particular theory of pharmacologic action, these compounds stimulate nitric oxide).
- CMO cortex magnoliae officinalis
- FAI fructus aurantil immaturus
- Ginger is a complex natural composition having numerous purported properties when used alone and/or combination with other compounds.
- traditional Chinese medicines have used or included ginger in compositions to treat or prevent various maladies based on a variety of metaphysical reasons.
- scientific methods have shown that many traditional Chinese medicines do not produce the purported effects and/or may even make the target maladies worse.
- some traditional Chinese medicines have been found to contain active agents that may be of medical use, even if not effective or safe for the use purported by traditional Chinese medicine.
- the complexity of ginger and its myriad properties is reflected, for example by certain constituent compounds which have the following structure:
- 6-gingerol (also called gingerol) is (S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone and has the following structure:
- ginger contains multiple compounds, of varying complexity and chemical activity, there are multiple biochemical pathways involved in erectile function and dysfunction, and there are conflicting teachings in the prior art about the biological activity of compounds that might be useful in inducing NO production or otherwise having a potential role in treatment, there remains considerable unpredictability about how to understand, much less control, the relevant metabolic pathways.
- compositions that contain ginger for example Danzhixiaoyao Wan
- Danzhixiaoyao Wan actually inhibit nitric oxide production, i.e., could cause erectile dysfunction
- erectile dysfunction see Liao, Hui et al., “Elucidation of Danzhixiaoyao Wan and its Constituent Herbs on Antioxidant Activity and Inhibition of Nitric Oxide Production,” eCam, Advanced Access publication Jan. 9, 2007.
- ZOR ginger
- the present inventor has surprisingly discovered that ginger at low doses in compositions of the present invention can be effectively used to treat ED.
- Preferred amounts of ginger in compositions of the present inventions comprise between about 1 mg and about 2 grams.
- the compositions further comprise about 10 mg to about 2 grams L-citrulline.
- About 10 mg to about 2 grams L-arginine can be used in place of and/or in addition to L-citrulline.
- preferred compositions of the present invention include L-citrulline in place of and/or in addition to L-arginine (see Schwedhelm et al., British Journal of Clinical Pharmacology, 65: pp 51-59, (2007)).
- compositions of the present inventions are believed to be surprisingly beneficial for the cardiovascular system, and can also be utilized in the treatment of cardiovascular disease.
- compositions and methods of the present inventions can be used for treating cardiovascular disease manifesting in hypertension.
- a preferred composition for treatment of penile muscle degradation in men that do not exhibit substantial or noticeable symptoms of ED contains about 100 milligrams to about 2 grams ginger and about 500 milligrams to about 3 grams of L-citrulline.
- An alternative composition comprises about 100 milligrams to about 2 grams ginger and about 500 milligrams to about 3 grams of L-arginine. While the present inventor has found a composition using 210 milligrams of 6-gingerol (85%) to about 1 gram of L-arginine to be effective, as noted above the use of ginger is preferred as it has been found to be effective at surprisingly low dosages in compositions of the present invention. Compositions of the present inventions are also useful in treatment of men of any age whether or not ED symptoms are noticeable.
- treatment includes slowing or inhibition of further deterioration of the penile corporal cavernosal smooth muscle even when symptoms of ED are not noticeable.
- Repeated dosages of compositions of the present inventions can be provided over extended periods of time until the desired effect is obtained.
- Repeated administration of the compositions of the present inventions to patients demonstrating ED symptoms can be made until desired ED treatment results are obtained, and may be continued thereafter as a prophylactic.
- the compositions can also be used as a prophylactic against eventual ED symptom manifestation in patients likely to demonstrate same.
- compositions of the present invention may begin at any age.
- Administration of the compositions of the present invention to a patient that has not noticed an increase in the refractory period, decrease in duration of erection, and/or insufficient tumescence of erection may also be referred to as preventing ED.
- prevention is likely a treatment that slows or stops further progression of the causes of ED.
- a pharmaceutically effective amount of compositions of the present invention are taken regularly, if not daily, by males between the age of 20 and 40 (if not sooner).
- nutraceutical composition For patients that have noticeable symptoms of ED, regardless of age, or for older males, whether or not symptomatic, a preferred nutraceutical composition comprises ginger, L-arginine or L-citrulline, FAI, CMO,. Paullinia cupana, and Muira puama. Since certain preferred compositions of the present inventions comprise compounds found in foods or extracted from foods, they may be referred to as “nutraceuticals.” While nutraceutical compositions have traditionally been found in a medicinal format, such as capsules or tablets, an increasing number of foods have been fortified with nutraceuticals.
- Analogs and/or homologs of ginger constituents that have activity in promoting iNOS sufficient to ameliorate, stop or reverse fibrotic events associated with ED may also be used in combination with L-arginine and/or L-citrulline.
- the present inventions can therefore be administered in a wide variety of ways and forms matching the lifestyle and dietary preferences of the users. Further, predicate studies of sildenafil have been performed (i.e., Schwartz et al) to show beneficial impact on smooth muscle cells, making it more practical and/or feasible to conduct such studies.
- natural products that the present inventor found that can enhance the effectiveness of and prolong the effects of ED treatment include Muira Puama, which is derived from shrubs and trees found in Brazil, and Paullinia cupana (also known as guarana), which is derived from a climbing shrub that grows wild in the Amazon regions of Brazil and Brazil. Muira Puama and Paullinia cupana appear to enhance sexual desire.
- compositions for the treatment of ED comprise from about 100 mg to about 2 grams ginger, about 1 g to about 3 g L-arginine or an amount of L-citrulline sufficient to produce the same amount of L-arginine endogenously as about 1 gram to about 3 grams L-arginine and/or that have the same effect on NO production in vivo as L-arginine.
- a composition of the present inventions comprises about 250 mg to 2 grams L-arginine (and/or L-citrulline equivalent), about 500 mg Paullinia cupana, and about 100 mg to about 3 g Muira Puama, preferably about 500 mg to about 1.5 g Muira Puama.
- the forgoing formulation above may additionally or in place of ginger contain about 20 mg to about 1000 mg 6-gingerol, preferably about 220 mg 6-gingerol, although the present inventor has found it preferable to use ginger.
- a preferred composition for the treatment of ED, particularly ARED comprises about 100 mg to about 3 grams ginger, preferably about 2 grams ginger, about 1 g L-arginine, or an amount of L-citrulline sufficient to produce the same amount of L-arginine endogenously, about 500 mg Paullinia cupana, and about 500 mg to about 1.5 g Muira Puama.
- the foregoing compositions may also contain CMO and/or FAI, preferably in small amounts from 10 mg to 1 gm and preferably in equal amounts.
- the formulation above may additionally or in place of ginger contain about 20 mg to about 1000 mg 6-gingerol, preferably about 220 mg 6-gingerol, although the present inventors have found it preferable to use ginger.
- any man who is beginning to develop symptoms of ED may also be a candidate for this regimen with the hope that the compositions of the present inventions, taken once daily, will halt or at least slow the progression of the deterioration of the CSM and not further exacerbate preexisting ED treatment and evaluation.
- testing for ED is performed with a questionnaire called the IIEF (International index of erectile function or similar terminology).
- a treatment for preventing deterioration of one's erectile function men treated with daily ginger (500 mg) and L-citrulline (1500 mg) in two divided doses would show no deterioration or less deterioration of their erectile function over time.
- the addition of paullina cupana (500 mg/day) and muira puama (500 mg /day) to daily ginger (500 mg) and L-citrulline (1500 mg) would not only prevent deterioration of erectile function as in the first study but would have an excellent chance of improving one's erectile function.
- Exemplary formulations include at least ginger and at least one compound selected from the group consisting of L-arginine or L-citrulline.
- the first two ingredients are ginger and L-arginine
- L-arginine can be partially or completely replaced by L-citrulline, so collectively L-citrulline and L-arginine may be referred to as L-arginine since L-citrulline is converted to L-arginine in vivo.
- Formulation G-C (“Ginger-L-Citrulline), which comprises ginger and L-citrulline (preferably consists of about 100 mg to about 2 grams ginger and from about 500 mg to about 3 grams L-citrulline.
- compositions of the present inventions include ginger and L-arginine (or L-citrulline).
- compositions of the present inventions can contain about 50 or 100 mg to about 2 grams Muira puama, about 5 mg to about 500 mg of cortex magnoliae officinalis (CMO), and about 5 mg to about 500 mg fructus aurantil immaturus.(FAI).
- DIAGNOSTIC AND PROPHYLAXIS Substantial barriers exist to conducting routine biopsies on corpus cavernosal (“CC”) tissue, e.g., pain, embarrassment, need to avoid erection until the biopsy wound heals, etc. Further, such biopsies must be repeated periodically. Patients must give informed consent before agreeing to the biopsies. Even a patient that has had a radical prostatectomy procedure that included a biopsy of the corporal tissue while under anesthesia may not be willing to have a follow up biopsy, even with assurances of provision of adequate pain relief and the promise that such biopsies can advance the field.
- CC corpus cavernosal
- IRB Institutional Review Board
- a significant problem confronting scientists and Institutional Review Board (IRB) panels is the need to conduct studies of the drug formulations on a double blind basis. So, half of the patients may receive a placebo in place of the drug formulation being tabulated; thus, there is a considerable difficulty in recruiting sufficient patients to provide biopsies, particularly when there is a considerable chance that a placebo will be administered instead of the drug formulation being tested.
- IRBs may also desire that another study be performed in vitro and/or that animal studies could be used in place of some human studies. In some instances, such study designs may provide substantially the same and/or better data. Financial incentives to trial participants may not draw in a statistically representative group of subjects, and may not reflect a suitable sampling of the relevant population.
- patient histories are collected and evaluated for the occurrence of ED.
- Patients that have prostate problems, urogenital disorders, and/or cancers in the genital area may be biopsied while under anesthesia for treatment (with prior written informed consent). Some patients may agree to give subsequent biopsy samples, while others will permit a sample to be taken at the time of death.
- Family histories of ED may also be useful in evaluating ED potential.
- compositions of the present invention can be given to candidates while others will receive a placebo. Patients receiving compositions of the present invention that slow or halt ED symptom development, could then qualify for further studies to optimize ingredients, dosages, and period between dosages, etc. Patients that received the placebo and did not improve may be given the other formulation if statistically significant benefits are demonstrated. With sufficient patient data and DNA analysis, it will be possible to identify genetic predisposition to ED symptoms, and prophylaxis treatment can start at the expected age and/or when ED symptoms appear.
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TW100137976A TWI538681B (zh) | 2010-10-19 | 2011-10-19 | 用於包含與自然發生年齡有關之勃起功能障礙的治療、抑制其開始及減緩勃起功能障礙之病程的組成物及方法 |
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HK18104341.8A HK1244706A1 (zh) | 2010-10-19 | 2014-02-22 | 用於治療勃起功能障礙的組成物及方法 |
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US20180078602A1 (en) * | 2015-03-04 | 2018-03-22 | K.L.R.M., Llc | Methods and compositions for extending the efficacy of phosphodiesterase inhibitors for treating erectile dysfunction, and compositions for inhibiting the onset and slowing the progression of erectile dysfunction |
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Cited By (1)
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CN113543649A (zh) * | 2019-02-06 | 2021-10-22 | K.L.R.M.有限公司 | 治疗便秘和其他胃肠系统疾病的组合物和方法 |
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ES2549193T3 (es) | 2015-10-23 |
EP2637505A1 (en) | 2013-09-18 |
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KR20180049149A (ko) | 2018-05-10 |
US20190307829A1 (en) | 2019-10-10 |
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CA2815340A1 (en) | 2012-05-24 |
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HK1244706A1 (zh) | 2018-08-17 |
US10406196B2 (en) | 2019-09-10 |
KR101975729B1 (ko) | 2019-05-07 |
CA2815340C (en) | 2022-07-05 |
KR20140020232A (ko) | 2014-02-18 |
MX347021B (es) | 2017-04-07 |
CN103402530B (zh) | 2017-07-28 |
WO2012067745A1 (en) | 2012-05-24 |
EP2637505B1 (en) | 2015-08-05 |
KR101853851B1 (ko) | 2018-05-02 |
TWI538681B (zh) | 2016-06-21 |
US10973866B2 (en) | 2021-04-13 |
CN107537013A (zh) | 2018-01-05 |
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