Title:  Relieving symptoms of erectile dysfunction with proanthocyanidins

United States Patent:  6,565,851

Issued:  May 20, 2003

Inventors:  Rohdewald; Peter (Munster, DE); Ferrari; Victor (Feutersoey, CH)

Assignee:  Horphag Research Limited (Geneva, CH)

Appl. No.:  865189

Filed:  May 24, 2001

Use of proanthocyanidins as an active ingredient of a stimulator as a source of arginine and a source of nitric oxide in the treatment of erectile dysfunction. The active ingredient stimulates the endothelial NO-synthase enzyme, which acts as a catalyst for the synthesis of nitric oxide from its substrate L-arginine or its salts. The nitric oxide in turn activates theguanylyl cyclase, which leads to an increased development of cyclic guanosine monophosphate, which causes relaxation of smooth muscles. Blood vessel diameter may increase. The stimulator may also have Sildenafil or enzymes that inhibit an enzyme phosphodiesterase type5 from reducing an amount of the cyclic guanosine monophosphate. The substrate may be amino acid L-arginine, arginine salts or a dipeptide of arginine and aspartic acid.

DETAILED DESCRIPTION OF THE INVENTION

Due to its content of proanthocyanidins, Pycnogenol.RTM. food supplement--and other vegetable extracts containing proanthocyanidins--is often used as a preventive measure against atherosclerosis and venous insufficiency. Up until the publication on Apr. 6, 2000 of German Patent Application No. 19845 314.0, it was not predictable that this food supplement could also specifically be used for the treatment of erectile dysfunction. Surprisingly, it turned out that the proanthocyanidins have a stimulating effect on the endothelial NO-synthase enzyme and thus serves as a stimulator.

The remedy preferably contains a mixture of proanthocyanidins from 50 to 100%, preferably 70%. The effective dosage of proanthocyanidins is 100 to 300 mg, preferably 200 mg.

The dosage amount refers to the daily dose for a male patient weighing 70 kg. For a male patient weighing less than 70 kg, the dosage needed to be effective would be lower and may be as low as 40 mg.

The well known pine bark extract Pycnogenol.RTM. food supplement is used as a proanthocyanidins containing remedy for the treatment of erectile dysfunction. In this instance, an application of 125 to 375 mg of Pycnogenol.RTM. food supplement is recommended for a 70 kg male.

As mentioned above, nitric oxide and nitric oxide-synthase play and important part in the erectile physiology. Studies with NOS-inhibitors, such as e.g. L-NORAG or L-NAME, which have been injected intracarvenally, revealed that an erection induced by electro-stimulations was suppressed. Being afterwards injected intravenally, the natural substrate for NOS, i.e., L-arginine, was able to partly recover the erection (Jung et al., Yondei Med. J. 1997, 3 (5), 261-269). The simultaneous injection of NOS-inhibitors and L-arginine led to a suppression of the effect of the inhibitors. Although L-arginine as a natural substrate of the endothelial NO-synthase enzyme is--as mentioned previously--able to partly decrease the effect of the NOS-inhibitors, it yet has not been taken into account as a remedy to promote the erectility.

According to the invention, the preferred remedy in addition to the proanthocyanidins also contains L-arginine (or its salts) as an effective component in an amount of at least 0.5 to 2 g. According to the invention, the combination of proanthocyanidins with L-arginine (or its salts) is particularly efficient. The L-arginine (or its salts) is the natural substrate for the nitric oxide synthase.

The active ingredients proanthocyanidins and L-arginine (or its salts) may be taken simultaneously that for maximum effect and benefit in treating erectile dysfunction. In addition, additional ingredients may include further pharmaceutically acceptable auxiliary or carrier substances, so far as they are, for example, used to get the active substance into the shape suitable for the desired medication.

Surprisingly, proanthocyanidins have a selective and specific effect on the blood vessels in the erectile tissue so that a remedy containing proanthocyanidins can preferably be given orally. As such, the remedy according to the invention thus exists in a form suitable for oral medication.

When taken with a known oral treatment remedy for erectile dysfunction, i.e., sildenafil (Viagra), proanthocyanidins help stimulate the endothelial NO-synthase enzyme, which serves as a catalyst for synthesis of nitric oxide from the substrate L-arginine or its salts. The released nitric oxide activates the guanylyl cyclase, leading to an increase in cGMP, which causes relaxation of smooth muscles, which in turn is the condition needed for increased blood supply. Thus, taking proanthocyanidins and L-arginine or its salts would complement the taking of sildenafil (Viagra) in the treatment of erectile dysfunction.

In addition, there are other substances that are available that have the same, or substantially the same, mechanism of action as sildenafil. These other substances, which may be considered inhibitors, are formed to inhibit phosphodiesterase type 5 and/or prevent the decrease of cGMP. The taking of proanthocyanidins and L-arginine (or its salts) would complement these other substances by countering the persistent inability of a man with erectile dysfunction to get an erection and to maintain it long enough for satisfying sexual intercourse.

A clinical study was conducted on forty participants who had erectile dysfunction. The study involved the effect of taking arginine asparatate, which is a salt of arginine with aspartic acid. One gram of arginine asparatate contains 566.85 mg of arginine.

The participants were grouped according to their variant of disturbed erection. The variants are in five categories: weakened, delayed, hesitating, losing and normal. The "weakened" variant signifies that the penis increases in size and becomes hard to a certain extent, but it is not enough to enter the vagina. The "delayed" variant signifies that if it is possible for the penis to become hard enough to enter the vagina, but such may require additional time. The "hesitating" variant signifies that before or after sexual contact, the erection is unstable and thus makes the sexual intercourse more difficult. The `losing" variant signifies that during the love game there is good erection, but such is lost when trying to make contact or during intercourse. The "normal" variant signifies that no appreciable disturbed erection was present.

The clinical study was over three months. During the first month, only 3 doses of 1000 milligrams (mg) of arginine asparatate (Sargenor) were administered daily to each participant. By the end of the first month, there was improvement in erectile dysfunction in about 10% of the participants. During the second month, 2 doses of 40 mg of Pycnogenol.RTM. food supplement were administered daily to each participant, together with the 3 doses of 1000 mg of arginine asparatate. By the end of the second month, there was a statistically significant improvement of erectile dysfunction in 80% of the participants. During the third month, 3 doses of 40 mg of Pycnogenol.RTM. food supplement were administered daily to each participant, together with the 3 doses of 1000 mg of arginine asparatate. By the end of the third month, there was further improvement of the erectile dysfunction condition even for some of the participants who had not shown improvement during the second month. Overall, there was a statistically significant improvement of erectile dysfunction in 92% of the treated participants.

The following statistical analysis of the results from the clinical study calculate the probability of whether the observed differences between two treatments are statistically significant at a certain level.

NS=not significant, n=number of participants/patients, D=percent distribution, A=arginine asparatate (each month at 3 dosesx1000 mg daily), P=Pycnogenol.RTM. food supplement (2^nd month at 2 dosesx40 mg daily, 3^rd month at 3 dosesx40 mg daily), p=probability.

In view of the clinical trial results, a dosage between 200 mg and 2 g of arginine per day together with a dosage of 60-360 mg of Pycnogenol.RTM. food supplement per day would be a therapeutically effective amount to relieve erectile dysfunction. According to the clinical study, the amount of arginine administered per day was about 1.7 grams, which is computed on the basis that 3 doses were taken of arginine asparatate, with each dose containing 566.85 mg of arginine.

The clinical trial used Caucasian men as the participants and the results show that 80-120 mg of Pycnogenol.RTM. food supplement is effective. For men with a lower body weight as compared to Caucasians, such as some Asians, positive results would be expected with a lower dosage. A dosage as low as 40 mg Pycnogenol.RTM. food supplement would be expected to be effective. Also, turning to the higher dosage level, one must consider that a small portion of the population is of tall height and overweight, which is expected to need a higher dosage to be effective. The highest dosage of Pycnogenol.RTM. food supplement used so far in other clinical trials (against edema of the lower legs) was 360 mg daily. The dosage of 300 mg is within the dosage range which had been tested clinically and one can expect that men with overweight and oversize need such a higher dose. Therefore, a dosage range of 40 mg-300 mg of Pycnogenol.RTM. food supplement would be effective, with the amount of the dosage that would be effective within the range depending upon the body weight of the man taking it.

Of course the same arguments hold for L-arginine and its salts. For men of lower body weight, a dosage of L-arginine or its salts as low as 200 mg would be effective and for men of greater body weight, a dosage of L-arginine or its salts as high as 2 grams would be effective. Thus, a range of 200 mg to 2 grams of L-arginine or its salts is effective depending upon the body weight and size of the man taking it. The effects of arginine are also dependent on the dosage and on the time elapsed between intake and sexual activity. The clinical study was based on daily intake only and did not specify any particular dosing intervals or prescribe a dosage regimen instruction for the patient participants to take, such as taking a certain amount of arginine at a defined period of time before sexual activity. Such instruction would be expected to better optimize the effectiveness of treating erectile dysfunction with these substances.

The dosage of Pycnogenol.RTM. food supplement may be 1-1.5 mg/kg and the dosage of L-arginine may be 15-40 mg/kg, preferably taken simultaneously to maximize their effectiveness in treating erectile dysfunction.

The reference to NO-synthase in this application is with respect to endothelial nitric oxide synthase, as opposed to inducible nitric oxide. The inducible nitric oxide synthase acts in an entirely different way and on a different place as the endothelial nitric oxide synthase.

The inducible nitric oxide synthase is produced in macrophages, white blood cells, which use the produced nitric oxide as one of their weapons against virus or bacteria, it is an inflammatory response. The endothelial nitric oxide regulates physiologically the vascular diameter and it is this enzyme which regulates erectile function.

Various changes and modifications may be made to the embodiments without departing from the spirit and scope of the present invention.

Claim 1 of 17 Claims

We claim:

1. A method of relieving symptoms of erectile dysfunction by stimulating nitric oxide (NO) synthase enzyme and releasing nitric oxide, comprising administering both proanthocyanidins and a substrate, which is a source of arginine and, subsequently, of nitric oxide; stimulating an endothelial NO-synthase enzyme with the proanthocyanidins; and releasing the nitric oxide from the substrate in response to the stimulated endothelial NO-synthase enzyme acting as a catalyst for synthesis of the nitric oxide, the proanthocyanidins and the substrate each being in therapeutically effective amounts to cause a sufficient amount of the nitric oxide to be released from the synthesis to relieve symptoms of erectile dysfunction.
 

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