WO1992015315A1

WO1992015315A1 - Method for the treatment of herpes

Info

Publication number: WO1992015315A1
Application number: PCT/US1991/001381
Authority: WO
Inventors: Alfred H. B. Wilkinson
Original assignee: Wilkinson Alfred H B
Priority date: 1991-03-06
Filing date: 1991-03-06
Publication date: 1992-09-17

Abstract

The present invention relates to a method of treating a herpes infection comprising administering to an infected individual a therapeutically effective amount of a formulation that includes lysine, vitamin C and hesperidin, and to a pharmaceutical composition suitable for use in such a method.

Description

METHOD FOR THE TREATMENT OF HERPES

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates, in general, to a method of treating a herpes infection and, more particularly, to a method of treatment, referred to as chronic suppressive therapy, which comprises administering lysine, vitamin C, and hesperidin to a herpes-infected individual. The invention further relates to a composition suitable for use in such a • method.

Background Information

The family of viruses classified as Herpesviridae comprises a large group of closely related viruses that infect a broad range of animal hosts. There are six herpes viruses that cause herpes-type infections in humans: two types of herpes simplex viruses (HSV-1 and HSV-2) ; varicella- zoster virus; cytomegalovirus; Epstein-Barr virus and human B-lymphotrophic virus. The first two of these herpes simplex virus types are best known because of the widespread existence of infections that they cause. Herpes simplex viruses may be isolated from nearly all visceral and muco-cutaneous sites; however, HSV-1 is most frequently associated with oral/facial lesions while HSV-2 most commonly infects the genitalia.

Herpes simplex viruses are now recognized as a^' serious national health problem, owing in large part to the epidemic of sexually transmitted HSV-2 infections occurring during the last two decades. For example, office visits and consultations for HSV-2 infections and cases of HSV-2 neonatal herpes increased approximately ten-fold during the period from the late 1960's to the early 1980's [N. Engl. J. Med. Vol. 314, pp. 686-691 (1986)]. A recent seroepidemiological study of the prevalence of HSV- 2 infections showed that 16.4 percent of the U.S. population 15 to 74 years of age (approximately 25 million people) was infected during the period from 1976 to 1980 [N. Engl. J. Med. Vol. 321, pp. 7-12 (1989)].

The most remarkable as well as troublesome aspect of herpes virus infections (both HSV-1 and HSV-2) is the ability of the virus to remain latent in humans for life and reactivate periodically (with or without lesions) . The frequency of recurrence of HSV-2 genital lesions is highly variable, and has been difficult to estimate. However, in a retrospective study of 375 private patients with genital herpes simplex infections seen between 1973 and 1980, about one-half of the respondents (49.6 percent) experienced between six and twelve episodes per year [Cutis, Vol. 31 (1983)]. The individuals profiled in this study were predominantly well- educated, white, heterosexual, affluent and between the ages of 18 and 35. The sexual mode of transmission, the presence of recurrent genital symptoms and the lack of a definite cure can result in severe psychosocial morbidity.

There is no known cure for any of the herpes virus infections. Acyclovir (9-[2-hydroxyethoxy__ethyl]guanosine) is the indicated drug for the treatment of initial herpes episodes and for the management of recurrent episodes. Acyclovir accelerates healing but does not eradicate the infection or affect the subsequent risk, frequency or severity of recurrence after a patient stops taking the drug. Acyclovir is administered orally for primary and recurrent episodes. For severe disease or complications necessitating hospitalization, Acyclovir is administered intravenously. Most recurrent episodes of herpes are not significantly affected by therapy with Acyclovir. Daily treatment with 200 mg orally two to five times daily or 400 mg twice daily (chronic suppressive therapy) , however, does reduce the frequency of recurrences by 45% to 87% among patients with frequent (more than six per year) recurrences. These dosages have proven safe and effective among persons receiving daily therapy for up to two years [Am. J. Med., Vol. 85 (2A) , pp. 14- 19 (1988); Obstet. Gynecol., Vol. 73(1), pp. 84-87 (1988)].

The only usages of Acyclovir that are successful and non-controversial are those for treatment of primary genital herpes and suppression of recurrences in immunocompetent patients. Other usages for genital herpes (HSV-2) infections are controversial, and efficacy has not been established [MMWR, Vol. 38, pp. 5-8 (1989)]. For example, the indications, need and proper higher-than-standard doses of oral Acyclovir for three large groups of patients - those who are HIV-infected but immunocompetent, those who have immunodeficiency (AIDS) , and those who are immunocompromised but need suppressive therapy - have not been established.

Suppressive treatment with oral Acyclovir to prevent reactivation among infected pregnant women near term remains controversial and is not recommended. Genital herpes has been associated with an increased risk of contracting HIV infections. Suppressive or prophylactic therapy could likely decrease this risk; however, there are no data to support this presumed benefit.

The use of Acyclovir for treatment of HSV- 2 infections other than for primary genital episodes and especially for suppression of recurrent infections is likely to increase substantially. Limited clinical trials have shown Acyclovir to be effective in treating infections caused by varicella-zoster and Epstein-Barr viruses. This will in addition cause an increase in the use of Acyclovir. On the other hand, concerns have been raised about the long-term use of Acyclovir, clearly indicating that alternative forms of therapy are needed for HSV-2 infections. First, clinically important viruses that are resistant to Acyclovir have been noted [N. Engl. J. Med. Vol. 320, pp. 293- 296 (1989)]. Second, Acyclovir has not been shown to be effective for the treatment of a variety of HSV infections. Third, questions of safety, including concern about opportunity for drug misuse, have been raised concerning long-term administration of Acyclovir for suppressive therapy, as well as doubts about the treatment's cost-effectiveness. Alternative methods of treating HSV-2 infections may also have application for infections caused by other herpes viruses.

The amino acid lysine, a component of the proteins occurring in natural foodstuffs, has been described in the literature as having an inhibitory effect against both genital and nongenital herpes. (Dermatologia, Vol. 175, pp. 183-190 (1987) , Gen. Dent., Vol. 32, pp. 490-493 (1984), Oral. Surg. , Vol. 58, pp. 659-666 (1984), and J. Antimicrob. Chemother., Vol. 12, pp. 489-496 (1983). However, Milman and his associates (Lancet. Oct. 28, 1978, Vol. 2, p. 942) have reported on the failure of lysine hydrochloride treatment in patients with recurrent herpes simplex labialis. Specifically, in the Milman study, it was concluded that a dose of 500 mg of lysine hydrochloride given orally in a tablet twice a day was inadequate to register a positive therapeutic effect. In a subsequent study, Milman reported that on the whole, lysine prophylaxis had no effect on the recurrence rate of herpes simplex. However, in that study, more patients were recurrence-free during lysine- treatment than during placebo-treatment, suggesting that certain patients may benefit from prophylactic lysine administration. In the herpes lesions described, lysine had no effect on the rate of healing or on the appearance of the lesions when at their worst (Acta. Derm. Venereol. Vol. 60, pp. 85- 87 (1980)). Studies by DiGiovanna et al (Arc.

Dermatol., Vol. 120 pp. 48-51 (1984)) and Armstrong et al (Drug. Intell, Clin. Pharm. , Vol. 17, p. 186 (1983)) indicated that there was no substantial benefit of lysine therapy as a- treatment for genital and nongenital forms of herpes simplex nor was there benefit as a prophylactic drug for the prevention of recurrences. However, McCune et al (Cutis, Vol. 34, pp. 366-373 (1984)), using genital and nongenital herpes patients, reported that oral ingestion of 1,248 mg a day of L-lysine monochloride decreased the recurrence rate of herpes simplex attacks in non-immunocompromised hosts. The administration of 624 mg L-lysine had no effect. Neither dosage showed any evidence of shortening the healing time compared to placebo.

Griffith, Norris, and Kagan (Dermatologica, Vol. 156, 257-267, 1978) reported on a multiσentered study of oral lysine monohydrochloride in treating patients with recurring herpes simplex infections (both genital and nongenital) . Some degree of acceleration of recovery was observed, as well as suppression of recurrences. Doses given ranged from 312 mg of lysine hydrochloride daily to 1,200 mg daily in single or multiple doses. As patients often experienced return of lesions within one to four weeks after stopping medication, it was concluded that the results should be interpreted as suppressive rather than curative.

In a follow-up study by Griffith et al. (Der atologia, Vol. 175, pp. 183-190, 1987) a double-blind, placebo-controlled trial of oral lysine for the treatment and prevention of recurrent herpes infections (both genital and nongenital) was conducted. The treatment group was given 1000 mg of lysine 3 times per day for 6 months. Patients on this regimen showed on an average, 2.4 less HSV infections, diminished symptoms and reduced healing times. It appears, therefore, that lysine, as heretofore employed, offers at least some encouraging signs in the treatment of herpes infections, but it does not provide the whole answer.

Compositions which include L-lysine have also been described as a treatment of herpes simplex. U.S. Patent No. 4,415,590 discloses a composition for the treatment of herpes simplex-1 and -2 comprising the L-glutamic acid salt of L- lysine. U.S. Patent No. 4,424,232 discloses the topical application of an effective amount of a composition comprising L-lysine, gibberellic acid and urea. The composition may also contain L- ascorbic acid and methyl paraben, propyl paraben or mixtures thereof.

Water-soluble bioflavonoid-ascorbic acid complexes have also been used in the treatment of recurrent herpes simplex labialis. Terezhalmy, Bottomley and Pelleu (Oral Surg., Vol, 45, No. 1, pp. 56-62 (1978)) reported that a water-soluble bioflavonoid-ascorbic acid complex was observed to reduce vesiculation and prevent disruption of the vesicular membrane. Further, Bottomley (U.S. Patent No. 4,049,798) reported that optimum results were obtained when the patient was treated as soon as the first symptoms of a herpes attack were observed. In cases where therapy was initiated during the prodromal stage, the vesicle stage was completely aborted. However, the treatment is proportionally less effective when time has elapsed between the detection of the first symptoms of the herpes attack and the beginning of treatment. After the herpes simplex has reached the blister stage, the administration of an ascorbic acid and bioflavanoids composition appears to reduce both the period of tenderness and the time of healing. Hesperidin, a flavonoid occurring in orange rind was reported by Kaul et al (J. Med. Virol. Vol. 15, pp. 71-79 (1985)) to have no effect on infectivity of herpes simplex type-1 in tissue culture but did reduce intracellular replication of the virus.

The present invention provides a significant advance in the treatment of herpes, particularly, in the suppression of recurrent lesions associated with genital herpes.

SUMMARY OF THE INVENTION

It is one object of the present invention to provide a method of treating a herpes infection.

The method provided comprises administering to an individual infected with herpes virus a formulation comprising lysine, vitamin C and hesperidin.

It is a further object of the invention to provide, in dosage unit form, a composition suitable for use in the above method. Other objects and advantages of the present invention will be apparent to one skilled in the art from a reading of the description that follows. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of treating a herpes-type infection. The method comprises administering to an infected individual an amount of a formulation comprising lysine, vitamin C and hesperidin sufficient to suppress the recurrent lesions associated with the infection. The invention further relates to a composition suitable for use in such a method, which composition comprises, in dosage unit form, lysine and hesperidin in an amount sufficient, when administered in .combination with vitamin C, to suppress the recurrence of herpes lesions in infected patients. The method of the present invention can be used as chronic suppressive therapy in the_^ treatment of herpes infection (e.g., herpes simplex infection (HSV-1 or HSV-2)). In a preferred embodiment, the present method is used to suppress the recurrence of lesions in patients suffering from genital herpes.

The lysine component of the formulation is, advantageously, in the form of L-lysine, preferably a water soluble salt thereof, for example L-lysine monohydrochloride. DL-lysine can be used so long as the dosage level is adjusted appropriately. While the amount of lysine to be administered will vary with the individual, a dose of about 2 grams of L-lysine three to four times per day can be expected to prove adequate for an average adult male. The vitamin C component of the formulation can be administered in any form that is convenient. The amount to be administered to obtain the suppressive effect will vary with the individual but 200 mg three to four times a day can be expected to prove adequate for an average adult male. The hesperidin component of the formulation is, advantageously, administered as hesperidin complex (HC) . A portion (for example, about 25%) of the required dose of HC can be administered as hesperidin methylchalcone. Alternatively, the required dose of hesperidin can be administered, in whole or in part, in the form of orange juice (fresh or prepared from concentrate) , although, it will be appreciated that large volumes of orange juice will necessarily be consumed in order to achieve appropriate levels of hesperidin. Regardless of the form in which this compound is administered, levels of about 200 mg three to four times per day are likely to be required by a typical adult male.

The compounds of the above-described formulation can be administered separately (e.g., as individual tablets (containing a pharmaceutically acceptable binder)) and at different points in time (so long as the time points are selected such that the suppressive effect is observed) . Alternatively, the compounds can be administered in combination. In a preferred embodiment, the compounds of the formulation are administered orally in a single dosage unit form, for example as a tablet, containing a pharmaceutically acceptable binder. The three ingredients can be also provided in alternative forms suitable for oral administration, including as a capsule or powder. When the hesperidin component of the formulation is administered in the form of orange juice, the lysine and vitamin C components can be provided separately or in a single dosage unit form.

One skilled in the art will appreciate that the above-described preferred formulation can be varied depending, not only on the individual, but also on the frequency and tenaciousness of the lesions. Required dosage levels of each component of the formulation can readily be determined by one skilled in the art.

The following non-limiting Example illustrates the invention in more detail:

EXAMPLE

A white male, age 48, 185 pounds, was diagnosed in 1977 by a physician as having genital herpes. The subject was experiencing recurrent lesions on the average of once every four weeks. The subject began taking various medications available on the market at that time and gained no relief.

In 1979, the subject started taking capsules of Lactobacillus acidophilus culture.

Initially there was some relief from recurrences during the first three months. However thereafter, the lesions began to recur at approximately the same frequency as in the absence of therapy. The acidophilus regimen was continued for several months with only limited success. In the spring-summer of 1980, the subject started taking one 500 mg tablet of lysine 4 times per day, then increased to six 500 mg tablets 4 times per day for several months with poor results. In August of 1980, the subject started taking 2-3 g of lysine with 500-1000 mg of vitamin C, 4 times per day, again with poor results.

In October 1980, the subject started taking 2-3 g of lysine with 1000 mg of vitamin C, mixed and/or administered with 1 pint of orange juice four times per day before meals. The orange juice was frozen concentrated orange juice and it was prepared in accordance with the producers instructions. Initially, the subject took the tablets with water, but eventually left out the water completely when taking the tablets. The orange juice intake was increased to 3-4 quarts per day afterwards. The results proved good with no eruption of lesions in the following months. This formulation continued to show good results in the following months. Sometimes 500 mg rosehips vitamin C complex was added.

In the summer of 1981, the subject started taking 100 μg of vitamin B-12, 2-3 g of lysine and 500 mg of rosehips vitamin C complex with 1 quart of orange juice, with no water, 4 times per day. In addition 50-100 mg of vitamin B-15 was added occasionally, with very good results, no lesions erupting. The results continued to be good through

1986. Occasionally 10,000 IU of vitamin A, 50 mg of vitamin B-15 and 100 μg of vitamin B-12 were added, but proved to be too expensive and were omitted from the formulation. Even without the presence of vitamins A, B-15 and B-12, the formulation of lysine, vitamin C and orange juice gave good results and no eruptions occurred. The subject continued in 1987 with 2-3 g of lysine, 1000 mg of vitamin C and almost one quart of orange juice, all taken four times per day.

In the winter of 1988-89 the subject began to substitute 800 mg of the citrus bioflavonoid hesperidin for the orange juice and to reduce the intake of vitamin C from 4 g to 800 mg per day. This formulation proved to be as effective as the formulation used during 1987. The subject is presently taking 4 tablets of lysine (500 mg) , one tablet containing 200 mg of vitamin C, 150 mg of hesperidin complex and 50 mg of hesperidin methylchalcone with 6-8 ounces of orange juice 4 times daily.

While the present invention has been illustrated by detailed descriptions of preferred embodiments thereof, it will be obvious to those skilled in the art that various changes in form and detail can be made therein without departing from the true scope of the invention. For that reason, the invention must be measured by the claims appended hereto.

Claims

WHAT IS CLAIMED IS:

1. A method for treating a herpes infection which comprises administering to a patient suffering from such an infection an amount of a formulation comprising lysine, vitamin C, and hesperidin sufficient to treat said infection.

2. The method according to claim 1 wherein said lysine is L-lysine.

3. The method according to claim 1 wherein said hesperidin is hesperidin complex.

4. The method according to claim 1 wherein about 2 g of L-lysine, about 200 mg vitamin C, about 150 mg of hesperidin complex, about 50 mg of hesperidin methylchalcone and about 6 to 8 ounces of orange juice per day is administered to the said patient four times.

5. The method according to claim 1, wherein said herpes infection is a herpes simplex infection.

6. The method according to claim 5 wherein said herpes simplex infection is a genital herpes simplex infection.

7. A pharmaceutical composition comprising, in dosage unit form, lysine and hesperidin in an amount sufficient, when administered to a patient receiving vitamin C, to suppress recurrence of herpes lesions in said patient, together with a pharmaceutically acceptable carrier.

8. The composition according to claim 7 further comprising vitamin C.

9. The composition according to claim 7 wherein lysine is present as L-lysine.

10. The composition according to claim 7 wherein hesperidin is present as hesperidin complex.

11. A method of preventing the appearance of herpes virus-induced lesions in a patient infected with said virus, or reducing the number of outbreaks of such lesions, comprising administering to said patient an amount of a formulation comprising lysine, vitamin C, and hesperidin, sufficient to effect said prevention or said reduction.

12. • The method according to claim 11 wherein said herpes virus is genital herpes simplex virus.

13. The method according to claim 11 wherein said formulation is administered orally.

14. The method according to claim 11 wherein said formulation is administered essentially daily.