COMBINATIONS OF VANILLOID COMPOUNDS AND NUCLEOSIDE ANTIVIRAL COMPOUNDS FOR TREATMENT OF HERPES INFECTIONS

Abstract: The subject invention involves methods of treating or preventing lesion epidodes in humans, due to Herpes infections, comprising administering to such human a combination of a vanilloid compound and a nucleoside antiviral compound.

Description: COMBINATIONS OF VANILLOID COMPOUNDS AND NUCLEOSIDE ANTIVIRAL COMPOUNDS FOR TREATMENT OF HERPES INFECTIONS TECHNICAL FIELD The subject invention relates to a novel method for the treatment of Heroes infections. BACKGROUND OF THE INVENTION The subject invention involves natural and synthetic vanil- loid compounds. The following references disclose vanilloid compounds and are incorporated herein by reference: U.S. Patent No. 4,313,958 issued to LaHann on February 2, 1982; U.S. Patent No. 4,401,663 issued to Buckwalter & LaHann on August 30, 1983; U.S. Patent 4,424,205 issued to LaHann & Buckwalter on January 3, 1984; U.S. Patent No. 4,443,473 issued to Buckwalter & LaHann on April 17, 1984; U.S. Patent No. 4,460,602 issued to Buckwalter & LaHann on July 17, 1984; U.S. Patent No. 4,493,848 issued to LaHann & Buckwalter on January 15, 1985; U.S. Patent No. 4,532,139 issued to Janusz & LaHann on July 30, 1985; U.S. Patent No. 4,544,668 issued to Janusz, Buckwalter & LaHann on October 1, 1985; U.S. Patent No. 4,544,669 issued to LaHann, Janusz & Buckwalter on October 1, 1985; U.S. Patent No. 4,564,633 issued to LaHann & Buckwalter on January 14, 1986; U.S. Patent 4,898,887 issued to Janusz, Loomans, LaHann & Kasting, on February 6, 1990; U.S. Patent Application Serial No. 473,122 of Berman, Buckwalter, Cupps & Gardner, filed January 31, 1990; U.S. Patent Application Serial No. 404,924 of Gardner, Kasting, Cupps, Echler, Gibson & Shulman, filed September 8, 1989; U.S. Patent No. 4,810,716 issued to Connor & Flynn on March 7, 1989; U.K. Patent Applica¬ tion No. 2,168,974A of Loomans & Buckwalter, published July 2, 1986; U.K. Patent Application No. 2,168,975A of Janusz & Loomans, published July 2, 1986; and U.K. Patent Application No. 2,168,976 A of Loomans, Janusz & Buckwalter, published July 2, 1986; U.K. Patent Application No. 2,206,347A of Masdin, Walpole & rigglesworth, published January 5, 1989; and PCT Patent Applica¬ tion No. WO 89/04297 of Johnson & Rafferty published May 18, 1989. Vanilloid compounds have been generally disclosed in the above references to have analgesic, anti-irritant and anti-in¬ flammatory activity. Vanilloid compounds have been disclosed to be useful in the treatment of Heroes simplex infections in European Patent Application No. 0,347,000 of O'Neill, Kasting & Cupps, pub ished December 20, 1989. The subject invention also involves nucleoside antiviral compounds. Certain nucleoside antiviral compounds have been disclosed to have anti-herpetic activity. Nucleoside antiviral compounds are disclosed in the following references which are incorporated herein by reference: U.S. Patent No. 3,201,387 issued to Heidelberger on August 17, 1965; U.S. Patent No. 3,616,208 issued to Howells, Woods & Ryder on October 26, 1971; U.S. Patent No. 3,642,771 issued to Gauri on February 15, 1972; U.S. Patent No. 3,651,045 issued to Haskell & Hanessian on March 21, 1972; U.S. Patent No. 3,666,771 issued to Hoefle & Holmes on May 30, 1972; U.S. Patent No. 3,687,808 issued to Merigan, Eckstein & deClercq on August 29, 1972; U.S. Patent No. 3,708,469 issued to Vorbruggen & Strehike on January 2, 1973; U.S. Patent No. 3,709,874 issued to Moffatt & Russell on January 9, 1973; U.S. Patent No. 3,728,450 issued to Gordon on April 17, 1973; U.S. Patent No. 3,792,040 issued to Moffatt & Russell on February 12, 1974; U.S. Patent No. 3,798,209 issued to itkowski, Niguel & Robins on March 19, 1974; U.S. Patent No. 3,804,826 issued to Scheit & Faerber on April 16, 1974; U.S. Patent No. 3,804,827 issued to Robins & Long on April 16, 1974; U.S. Patent No. 3,812,098 issued to Moffatt & Russell on May 21, 1974; U.S. Patent No. 3,817,982 issued to Verheyden & Moffatt on June 18, 1974; M.S. Patent No. 3,826,803 issued to Tolman & Smith on July 30, 1974; U.S. Patent No. 3,847,898 issued to Kelly, Wechter & Gish on November 12, 1974; U.S. Patent No. 3,849,397 issued to Robins & Khwaja on November 19, 1974; U.S. Patent No. 3,853,845 issued to Rousseau, Robins & Ivanovics on December 10, 1974; U.S. Patent No. 3,870,700 issued to Kotick & Polazzi on March 11, 1975; U.S. Patent No. 3,897,415 issued to Robins & Witkowski on July 29, 1975; U.S. Patent No. 3,910,885 issued to Moffatt & Verheyden on October 7, 1975; U.S. Patent No. 3,915,958 issued to Shuman & Meyer on October 28, 1975; U.S. Patent No. 3,923,785 issued to Ryder, Dion, Woo & Howells on December 2, 1975; U.S. Patent No. 3,948,885 issued to Witkowski, Robins & Leh kuhl on April 6, 1976; U.S. Patent No. 3,948,886 issued to Shuman, Meyer & Robins on April 6, 1976; U.S. Patent No. 3,956,277 issued to Elion, Litster & Beacham on May 11, 1976; U.S. Patent No. 3,975,367 issued to Gish, Gray & Wechter on August 17, 1976; U.S. Patent No. 3,976,545 issued to Witkowski & Robins on August 24, 1976; U.S. Patent No. 3,984,396 issued to Witkowski & Robins on October 5, 1976; U.S. Patent No. 3,988,314 issued to Argoudelis & Mizsak on October 26, 1976; U.S. Patent No. 3,991,078 issued to Witkowski & Robins on November 9, 1976; U.S. Patent No. 3,998,807 issued to Moffatt on December 21, 1976; U.S. Patent No. 4,000,260 issued to Prusoff, Cheng, Ward & Neenan on December 28, 1976 U.S. Patent No. 4,006,159 issued to Newman on February 1, 1977 U.S. Patent No. 4,007,198 issued to Newman on February 8, 1977 U.S. Patent No. 4,010,269 issued to Renis & Skaletzky on March 1, 1977; U.S. Patent No. 4,017,606 issued to Hanze & Camiener on April 12, 1977; U.S. Patent No. 4,038,479 issued to Elion & Strelitz on July 26, 1977; U.S. Patent No. 4,048,432 issued to Baker on September 13, 1977; U.S. Patent No. 4,055,717 issued to Baker & Haskell on October 25, 1977; U.S. Patent No. 4,055,718 issued to Baker on October 25, 1977; U.S. Patent No. 4,056,673 issued to Heimer & Nussbaum on November 1, 1977; U.S. Patent No. 4,066,696 issued to Kraska & Schnur on January 3, 1978; U.S. Patent No. 4,069,382 issued to Baker & Haskell on January 17, 1978; U.S. Patent No. 4,092,472 issued to Townsend, Wise & Earl on May 30, 1978; U.S. Patent No. 4,093,714 issued to Tolman, Sidwell & Revankar on June 6, 1978; U.S. Patent No. 4,093,715 issued to Lin, Prusoff & Ward on June 6, 1978; U.S. Patent No. 4,093,716 issued to Lin, Prusoff & Ward on June 6, 1978; U.S. Patent No. 4,096,324 issued to Kelly & Wechter on June 20, 1978; U.S. Patent No. 4,097,525 issued to Kraska & Schnur on June 27, 1978; U.S. Patent No. Re 29,835, of Witkowski & Robins reissued on November 14, 1978; U.S. Patent No. 4,136,175 issued to Rideout, Miller & Elion on January 23, 1979; U.S. Patent No. 4,138,562 issued to Vince on February 6, 1979; U.S. Patent No. 4,145,414 issued to Kelly & Wechter on March 20, 1979; U.S. Patent No. 4,146,715 issued to Schaeffer on March 27, 1979; U.S. Patent No. 4,148,888 issued to Cantoni & Chiang on April 10, 1979; U.S. Patent No. 4,156,778 issued to Rosner, Loewe & Raether on May 29, 1979; U.S. Patent No. 4,158,056 issued to Nagarajan on June 12, 1979; U.S. Patent No. 4,177,348 issued to Shealy on December 4, 1979; U.S. Patent No. 4,188,378 issued to Montgomery on February 12, 1980; U.S. Patent No. 4,190,656 issued to Matsumura, Miyashita, Shimadzu & Hashimoto on February 26, 1980; U.S. Patent No. 4,199,574 issued to Schaeffer on April 22, 1980; U.S. Patent No. 4,210,638 issued to Greer on July 1, 1980; U.S. Patent No. 4,211,711 issued to aus der Fόnten & Vogt on July 8, 1980; U.S. Patent No. 4,211,771 issued to Witkowski & Robins on July 8, 1980; U.S. Patent No. 4,211,773 issued to Lopez, Watanabe, Reichman & Fox on July 8, 1980; U.S. Patent No. 4,221,909 issued to Yoshida & Taga on July 8, 1980; U.S. Patent No. ' 4,221,910 issued to Kusunoki & Tanaka on July 8, 1980; U.S. Patent No. 4,223,156 issued to Vince on September 16, 1980; U.S. Patent No. 4,230,708 issued to DeClercq & Holy on October 28, 1980; U.S. Patent No. 4,247,544 issued to Bergstrom & Ruth on January 27, 1981; U.S. Patent No. 4,267,171 issued to Bergstron & Ruth on May 12, 1981; U.S. Patent No. 4,271,153 issued to Gauri on June 2, 1981; U.S. Patent No. 4,287,188 issued to Schaeffer on September 1, 1981; U.S. Patent No. 4,294,831 issued to Schaeffer on October 13, 1981; U.S. Patent No. 4,315,920 issued to Schaeffer, DeMiranda, Elion &. Hitchings on February 16, 1982; U.S. Patent No. 4,323,573 issued to Schaeffer on April 6, 1982; U.S. Patent No. 4,328,336 issued to Robins & Rousseau on May 4, 1982; U.S. Patent No. 4,329,460 issued to Miyashita, Matsumura, Shimadzu & Hashimoto on May 11, 1982; U.S. Patent No. 4,338,310 issued to Vince on July 6, 1982; U.S. Patent No. 4,340,726 issued to Simon, Giner-Sorolla & Guttag on July 20, 1982; U.S. Patent No. 4,344,937 issued to Machida on August 17, 1982; U.S. Patent No. 4,347,360 issued to Ogilvie on August 31, 1982; U.S. Patent No. 4,355,032 issued to Verheyden & Martin on October 19, 1982; U.S. Patent No. 4,360,522 issued to Schaeffer on November 23, 1982; U.S. Patent No. 4,363,909 issued to Malcolm & Binninger on December 7, 1982; U.S. Patent No. 4,382,925 issued to deClercq, Verhelst, Jones & Walker on May 10, 1983; U.S. Patent No. 4,383,114 issued to Vince on May 10, 1983; U.S. Patent No. 4,383,990 issued to Coe, Jones, Noble & Walker on May 17, 1983; U.S. Patent No. 4,386,076 issued to Machida & Sakata on May 31, 1983; U.S. Patent No. 4,396,623 issued to Shealy, O'Dell & Shannon on August 2, 1983; U.S. Patent No. 4,423,050 issued to Verheyden & Martin on December 27, 1983; U.S. Patent No. 4,424,211 issued to Jones, Walker, deClercq & Barr on January 3, 1984; U.S. Patent No. 4,461,757 issued to Ogilvie on July 24, 1984; U.S. Patent No. 4,469,863 issued to Ts'o & Miller on September 4, 1984; U.S. Patent No. 4,495,190 issued to Hagberg, Johansson, Kovacs & Stening on January 22, 1985; U.S. Patent No. 4,507,305 issued to Verheyden & Martin on March 26, 1985; U.S. Patent No. 4,508,898 issued to Ogilvie on April 2, 1985; U.S. Patent No. 4,526,988 issued to Hertel on July 2, 1985; U.S. Patent No. 4,536,504 issued to Okutani on August 20, 1985; U.S. Patent No. 4,537,899 issued to Horvath, Lang, Pongo, Reiter, Somorai & Szilέgyi on August 27, 1985; U.S. Patent No. 4,539,313 issued to Suhadolnik, Wu, Doetsch & Henderson on September 3, 1985; U.S. Patent No. 4,542,210 issued to Sakata & Machida on September 17, 1985; U.S. Patent No. 4,544,741 issued to Robins & Revankar on October 1, 1985; U.S. Patent No. 4,548,819 issued to DeClercq, VanderHaeghe & Busson on October 22, 1985; U.S. Patent No. 4,556,659 issued to Verheyden & Martin on December 3, 1985; U.S. Patent No. 4,564,618 issued to Scopes, Newton & Cookson on January 14, 1986; U.S. Patent No. 4,564,622 issued to Streissle, Plempel, Paessens, Hol wood & Bϋchel on January 14, 1986; U.S. Patent No. 4,594,350 issued to Vince on June 10, 1986; U.S. Patent No. 4,594,415 issued to Robins & Revankar on June 10, 1986; U.S. Patent No. 4,595,780 issued to Ogata, Sato & Konishi on June 17, 1986; U.S. Patent No. 4,605,658 issued to Holy & deClercq on August 12, 1986; U.S. Patent No. 4,605,659 issued to Verheyden, Martin, Madhaven & McGee on August 12, 1986; U.S. Patent No. 4,606,917 issued to Eppstein on August 19, 1986; U.S. Patent No. 4,609,661 issued to Verheyden & Martin on September 2, 1986; U.S. Patent No. 4,609,662 issued to Krenitsky on September 2, 1986; U.S. Patent No. 4,612,314 issued to Verheyden & Martin on September 16, 1986; U.S. Patent No. 4,617,304 issued to Ashton, Walton & Tolman on October 14, 1986; U.S. Patent No. 4,629,729 issued to Gatti on December 16, 1986; U.S. Patent No. 4,642,346 issued to Chan & Nguyen on February 10, 1987; U.S. Patent No. 4,649,140 issued to Schaeffer on March 10, 1987; U.S. Patent No. 4,652,580 issued to Janssen, Karbach, Meyer & Laur on March 24, 1987; U.S. Patent No. 4,659,698 issued to Imbach, Gosselin & DeRudder on April 21, 1987; U.S. Patent No. 4,663,338 issued to Hanssen, Koenig & Scharwaechter on May 5, 1987; U.S. Patent No. 4,663,446 issued to Wright on May 5, 1987; U.S. Patent No. 4,666,892 issued to Fox, Watanabe & Lopez on May 19, 1987; U.S. Patent No. 4,668,660 issued to Paessens, Streissle, Plempel, Bϋchel, Elbe, Holmwood, Kraatz & Regel on May 26, 1987; U.S. Patent No. 4,668,778 issued to Morozumi & Sakata on May 26, 1987; U.S. Patent No. 4,670,424 issued to MacCross & Tolman on June 2, 1987; U.S. Patent No, 4,681,933 issued to Chu & Schinaizi on July 21, 1987; U.S. Patent No. 4,690,917 issued to Knight, Scopes, Storer & Hoi an on September 1, 1987; U.S. Patent No. 4,692,434 issued to Hertel on September 8, 1987; U.S. Patent No. 4,695,570 issued to Krenitsky on September 22, 1987; U.S. Patent No. 4,710,492 issued to Lin & Prusoff on December 1, 1987; U.S. Patent No. 4,719,214 issued to Shealy & O'Dell on January 12, 1988; U.S. Patent No. 4,719,295 issued to Cook, Robins & McNamara on January 12, 1988; U.S. Patent No. 4,724,232 issued to Rideout, Barry, Lehrman, St. Clair & Furman on February 9, 1988; U.S. Patent No. 4,724,233 issued to DeClercq, Hoi & Rosenberg on February 9, 1988; U.S. Patent No. 4,728,736 issued to Shealy & Clayton on March 1, 1988; U.S. Patent No. 4,742,064 issued to Vince on May 3, 1988; U.S. Patent No. 4,743,689 issued to Shimada, Hasegawa, Harada, Tomizawa & Fujii on May 10, 1988; U.S. Patent No. 4,745,119 issued to Krenitsky on May 17, 1988; U.S. Patent No. 4,755,516 issued to Tolman & Ashton on July 5, 1988; U.S. Patent No. 4,758,572 issued to Spector, Averett & Nelson on July 19, 1988; U.S. Patent No. 4,762,823 issued to Watanabe, Matulic-Adamic, Price & Fox on August 9, 1988; U.S. Patent No. 4,772,609 issued to Higa & Sakai on September 20, 1988; U.S. Patent No. 4,780,453 issued to Rideout, Barry, Lehrman, St. Clair & Fur an on October 25, 1988; U.S. Patent No. 4,782,142 issued to Bardos, Cheng, Schroeder & Efange on November 1, 1988; 4,788,181 issued to Driscoll, Marquez, Kim & Kelly on November 29, 1988; U.S. Patent No. 4,794,174 issued to Secrist on December 27, 1988; U.S. Patent No. 4,798,833 issued to Kohansson, Lindborg & Norέn on January 17, 1989; U.S. Patent No. 4,806,542 issued to Stoss & Kaes on February 21, 1989; U.S. Patent No. 4,806,642 issued to Sircar, Schwender & Suto on February 21, 1989; U.S. Patent No. 4,808,716 issued to Hoi & Rosenberg on February 28, 1989; U.S. Patent No. 4,816,447 issued to Ashton, Field, Karkas & Tolman on March 28, 1989; U.S. Patent No. 4,826,823 issued to Cook, Robins & McNamara on May 2, 1989; U.S. Patent No. 4,833,130 issued to Rideout, Barry, Lehrman, St. Clair & Furman on May 23, 1989; U.S. Patent No. 4,837,311 issued to Tarn, Weigele, Broder & Mitsuya on June 6, 1989; U.S. Patent No. 4,841,039 issued to Chu & Schinazi on June 20, 1989; U.S. Patent No. 4,845,084 issued to Hannah & Tolman on July 4, 1989; U.S. Patent No. 4,845,215 issued to Shi ada, Tomizawa, Hasegawa, Matsuo, Fujii & Hoshino on July 4, 1989; U.S. Patent No. 4,849,412 issued to Albrecht, Lee & Steinsland on July 18, 1989; U.S. Patent No. 4,851,391 issued to Hempel & Kaul on July 25, 1989; U.S. Patent No. 4,851,519 issued to Lambert, Martin & Thomas on July 25, 1989; U.S. Patent No. 4,855,304 issued to Devash on August 8, 1989; U.S. Patent No. 4,857,316 issued to Eppstein on August 15, 1989; U.S. Patent No. 4,857,531 issued to Borthwick, Kirk, Evans, Biggadike & Stephenson on August 15, 1989; U.S. Patent No. 4,857,539 issued to Diana & Carabateas on August 15, 1989; U.S. Patent No. 4,859,677 issued to Borchardt & Borcherding on August 22, 1989; U.S. Patent No. 4,859,680 issued to Ashton, Walton & Tolman on August 22, 1989; U.S. Patent No. 4,859,768 issued to Suhadolnik & Pfleiderer on August 22, 1989; U.S. Patent No. 4,861,759 issued to Mitsuya & Broder on August 29, 1989; U.S. Patent No. 4,863,906 issued to Rahim & Selway on September 5, 1989; U.S. Patent No. 4,863,927 issued to Tolman & Ashton on September 5, 1989; U.S. Patent No. 4,868,162 issued to Kawaguchi, Fujinaga & Suzuki on September 19, 1989; U.S. Patent No. 4,868,187 issued to Ogilvie on September 19, 1989; U.S. Patent No. 4,874,609 issued to Rideout, Barry, Lehrman, St.Clair & Furman on October 17, 1989; U.S. Patent No. 4,879,277 issued to Mitsuya, Broder & Yarchoan on November 7, 1989; U.S. Patent No. 4,880,782 issued to Echstein, Hunsmann & Hartman on November 14, 1989; U.S. Patent No. 4,880,785 issued to Borbas, Otvδs, Sagi, Feuer, Szemzδ, Veres, Szinai, Vajda, Csernus, Marossy, Janscό, Lukέcs & Bacsa on November 14, 1989; U.S. Patent No. 4,882,316 issued to Lambert, Martin & Thomas on November 21, 1989; U.S. Patent No. 4,886,785 issued to Lambert, Martin & Thomas on December 12, 1989; U.S. Patent No. 4,927,830 issued to Townsend & Drach on May 22, 1990; Focher, F., C. Hildebrand, S. Freese, G. Ciarrocchi, T. Noonan, S. Sangall , N. Brown, S. Spadari & G. Wright, "N 2 -Phenyldeoxy- guanosine: A Novel Selective Inhibitor of Herpes Simplex Thymi- dine Kinase", Journal of Medicinal Chemistry, Vol. 31 (1988), pp. 1496-1500; Martin, J.A., I.B. Duncan, M.J. Hall, P. Wong-Kai-In, R.W. ' Lambert & G.J. Thomas, "New Potent and Selective Inhibitors of Herpes Simplex Virus Thy idine Kinase", Nucleosides & Nucleo- tides. Vol. 8, Nos. 5&6 (1989), pp. 753-764; Norbeck, D.W., E. Kern, S. Hayashi, W. Rosenbrook, H. Sham, T. Herrin, J.J. Plattner, J. Erickson, J. Clement, R. Swanson, N. Shipkowitz, D. Hardy, K. Marsh, G. Arnett, W. Shannon, S. Broder & H. Mitsuya, "Cyclobut-A and Cyclobut-G: Broad Spectrum Antiviral Agents with Potential Utility for the Therapy of AIDS", Journal of Medicinal Chemistry. Vol. 33 (1990), pp. 1281-1285. Herpes Zoster Infections Herpes zoster infections are caused by the varicella-zoster virus (VZV), the etiologic agent of the conditions commonly known as shingles, zona and acute posterior ganglionitis. VZV lesion episodes usually cause severe pain and exhibit large groups of lesions distributed along the course of a sensory nerve. The vesicular eruptions of Heroes zoster are often activated by systemic diseases such as Hodgkins, and i muno- suppressive therapy. VZV is also the causative agent in chicken pox. Later Herpes zoster infections (or shingles outbreaks) are most common after the age of fifty. Crops of vesicles form on an erythema- teous base and follow the sensory distribution of one or more posterior root ganglia. The sensory zone on the skin that is affected is usually hyperalgesic with associated severe pain. Herpes zoster lesion episodes rarely recur in a patient (recurrence rate is less than 2%); one attack, generally associ¬ ated with an outbreak of lesions in any one of numerous areas of the skin surface, usually confers immunity thereafter. Herpes Simplex Infections Clinically, Herpes zoster infections may have some similari- ty to Herpes simplex virus (HSV) infections, but several impor¬ tant differences between the two exist. Herpes simplex lesion episodes are characterized by general¬ ized or localized cutaneous and mucosal lesions, often with associated severe constitutional (general, not local) symptoms. The virus spreads along sensory nerves and becomes established in the regional sensory ganglia, or area of neuron cell bodies. HSV usually present with latent infections in the trigeminal or presacral ganglia (Type I) or dorsal root ganglia (Type II). Although VZV infections generally produce latent infections, these occur mainly in the dorsal root ganglia. HSV infections are generally of two types, Type I or Type II. Type I HSV infections are mainly implicated in oral or ocular Herpes infections. HSV Type II infections are usually genital and transmitted primarily through direct contact with Herpes lesions. While Heroes simplex lesions may appear anywhere on the skin or mucosa, they most frequently appear on the mouth, the lips, the conjunctiva and cornea and the genitalia. Unlike the 2% recurrence rate of VZV lesion episodes, the likelihood of Type I HSV recurrence is 80%, while the likelihood of Type II HSV recurrence is 50%. Reinfection with different strains of Type II HSV may also occur. Recurrent herpetic eruptions can be precipitated by conditions as broad as over exposure to sunlight, febrile illness, physical or emotional stress, or certain foods or drugs. The primary lesions of HSV (vesicular eruptions) are the most painful, prolonged and widespread. During periods of vesi¬ cular eruption, patients often experience pain in the region of viral infection. This pain, though it may be severe, resolves upon healing of the herpetic lesions, and leaves the patient basically asymptomatic between recurrent herpetic episodes. OBJECTS OF THE PRESENT INVENTION It is an object of the present invention to provide new methods which are effective for treating or preventing lesion episodes due to Herpes infections. It is a further object of the present invention to provide methods for preventing or reducing the severity of recurrent lesion episodes due to Heroes simplex infections. SUMMARY OF THE INVENTION The subject invention involves methods of treating or preventing lesion epidodes in humans, due to Herpes infections, comprising administering to the humans combinations of vanilloid compounds and nucleoside antiviral compounds. DETAILED DESCRIPTION OF THE INVENTION The term "alkyl", as used herein, means carbon-con¬ taining chains which may be straight, branched, or cyclic; substituted or unsubstituted; and which may be saturated, mono- unsaturated (i.e., one double or triple bond in the chain), or polyunsaturated (e.g., two or more double bonds in the chain; two or more triple bonds in the chain; one or more double and one or more triple bonds in the chain). Unless indicated otherwise, alkyl preferences, alone and/or collectively, are as follows. Preferred alkyl are straight or branched chain, especially straight chain. Preferred alkyl are unsubstituted. Preferred alkyl are monounsaturated, or especially saturated. Preferred alkyl are about C x -C 2 o » more preferably about Cj-Cj,,. Preferred alkyl are lower alkyl, about x-Ce, more preferably about C x -C 4 , more preferably still C x -C 2 , especially C x . Substituted alkyl groups can be mono- or polysubstituted. Preferred is mono-, di- or trisubstituted; more preferred is monosubstituted. Preferred • substitutents are selected from the group consisting of halogen, hydroxy, alkoxy, aryloxy, amino, nitro, cyano, trifluoromethyl, thiol, aryl, heteroaryl and carboxylate; more preferred are halogen, hydroxy, amino, thiol, aryl and carboxylate; most preferred are hydroxy or amino, and also aryl. As used herein, saturated alkyl groups are referred to as "alkanyl"; unsaturated alkyl groups comprising double bonds in the chain are referred to as "alkenyl" (preferred are chains having the double bonds in the "Z" or "cis" geometric configura¬ tion); and unsaturated alkyl groups comprising triple bonds in the chain are referred to as "alkynyl". The designation of geometric configurations for any double bonds present in com¬ pounds of the present invention utilizes the art-known nomencla- ture "Z" and "E", and is fully described in Morrison and Boyd, Organic Chemistry. Third Edition (Allyn and Bacon, Inc., Boston; 1973), pp. 131-133 and 148-151; and March, Advanced Organic Chemistry. Second Edition (McGraw-Hill Book Company, New York; 1977), pp. 86-124; the disclosures of both these references being incorporated herein by reference in their entirety. • The terms "aryl" and "heteroaryl", as used herein, mean aryl or heteroaryl rings which may be mono-, di-, or tri-substituted or unsubstituted, preferably monosubstituted or unsubstituted. Additionally, heteroaryl rings comprise at least one heteroatom in the ring structure. As used herein, "heteroatom" means an atom other than carbon that can covalently bond to at least two other atoms and become part of a stable chemical structure. Preferred heteroatoms are nitrogen, oxygen and sulfur. Preferred aryls and heteroaryls include substituted or unsubstituted phenyl, naphthyl, pyridyl, pyrimidyl, i idazolyl, furanyl, thiophenyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, tri- azinyl, pyrrolyl, indolyl and purinyl. More preferred aryls and heteroaryls include unsubstituted and substituted phenyl, pyri¬ dyl, imidazolyl, furanyl and thiophenyl. Most preferred aryl is unsubstituted or substituted phenyl. Substituted aryls and heteroaryls can be mono- or polysubstituted. Preferred is mono-, di- or trisubstituted; more preferred is monosubstituted. Preferred substituents include halogen, hydroxy, alkoxy, amino, nitro, cyano, phenyl, benzyl, benzyloxy, trifluoromethyl, formyl- amino, carboxylate and alkyl; more preferred substituents include alkyl, alkoxy, halogen, hydroxy, amino and carboxy; most pre- ferred are halogen, and especially lower alkyl. More preferred aryl or heteroaryl is unsubstituted. The term "carboxylate", as used herein, means an organic carboxylic acid moiety (i.e., COOH), and the salts (e.g., sodium, potassium, calcium, tetraethylammonium) and esters (e.g., methyl ester, ethyl ester) and amides (e.g., unsubstituted amide, N-methyl amide, N,N-dimethyl amide) thereof. The term "pharmaceutically-acceptable salts, esters and/or amides", as used herein, means the compounds referred to in their salt or ester or amide form which have the same general pharmaco- logical properties as the basic amino form from which they are derived, and which are acceptable from a toxicity viewpoint. Pharmaceutically-acceptable salts include ammonium salts derived from inorganic acids (e.g., HC1, HBr, NaHS0 4 , H 2 C0 3 ), and ammoni¬ um carboxylic acid salts derived from organic carboxylic acids (e.g., acetic acid; lactic acid; gluconic acid; citric acid; glucuronic acid; galacturonic acid; fu aric acid; gentisic acid; lactobionic acid; benzoic acid). Pharmaceutically-acceptable amides include those derived from organic carboxylic acids (e.g., acetic acid amides) including amino acids (e.g., glycine amides). The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal. The term "compat¬ ible", as used herein, means that the components of a pharma- ceutical carrier are capable of being commingled with the vanil¬ loid compounds and with each other, in a manner such that there is no interaction which would substantially reduce the pharma¬ ceutical efficacy of the pharmaceutical composition under ordi¬ nary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated. Vanilloid Compounds and Compositions The vanilloid compounds useful in the present invention are natural and synthetic vanilloid compounds, and the pharmaceuti¬ cally-acceptable salts thereof, having the general structure: [R l xi --CCHH]]„ n - W - X - R (1) Z Y - V In structure (1) n = 0 or 1. In structure (1), the -W-X- moiety is selected from -C(0)NH-, -C(S)NH-, -S(0) 2 NH-, -NHC(0)0-, -NHC(S)0-, -NHC(0)NH-, and -NHC(S)NH-. Preferred -W-X- is selected from -C(0)NH-, -C(S)NH-, -NHC(0)NH-, -NHC(S)NH- and -S(0) 2 NH-. More preferred -W-X- is selected from -C(0)NH-, -C(S)NH-, and -NHC(0)NH-. Most preferred -W-X- is -C(0)NH-. Either available bond of the -W-X- moiety may be bonded to the -R moiety, with the other bond being attached to the benzyl carbon atom, or directly attached to the benzene ring. In structure (1), the -R 1 moiety is selected from hydrogen, hydroxy, lower alkyl esters of hydroxy, lower alkyl, and lower alkoxy. Preferred -R 1 is selected from hydrogen, hydroxy, and methyl; most preferred -R 1 is hydrogen. In structure (1), the -Z moiety is selected from hydrogen, hydroxy and ethoxy; preferred -Z is selected from hydroxy and methoxy. Most preferred -Z is methoxy. In structure (1), the -Y- moiety is selected from -0-, -S-, -NR 4 -, -0C(0)-, -OSO 3 --, and -OPO 3 "-, where -R 4 is selected from hydrogen and Cj-C 4 alkanyl; preferred -Y- is selected from -0- , -S- and -NH-. More preferred -Y- is selected from -0- and -S-; most preferred -Y- is -0-. In structure (1) the -V moiety is selected from hydrogen, short chain alkyl, and -CR 2 2 -CR 2 2 -NH 2 . Preferred -V is selected from C x to C 3 alkyl and hydrogen. Even more preferred -V is selected from hydrogen and methyl, especially hydrogen. Also more preferred is -V being -CR 2 2 -CR 2 2 -NH 2 . The -R 2 moieties are each independently selected from hydro¬ gen; halogen; unsubstituted or substituted alkyl, the alkyl portion having from about 1 to about 6 carbon atoms; substituted or unsubstituted aryl or heteroaryl; and carboxylate; or two -R 2 moieties are covalently bonded to form a substituted or unsub¬ stituted alkyl, heteroalkyl, aryl or heteroaryl ring having from 5 about 3 to about 8 atoms, preferably 3-6 atoms, in the ring, including from 0 to about 3 heteroatoms. It is preferred that no more than two -R 2 are other than hydrogen. Preferred -R 2 substi¬ tuents other than hydrogen include unsubstituted and substituted lower alkyl (preferred substituents being hydroxy, amino and 10 phenyl) and unsubstituted and substituted phenyl. It is pre¬ ferred that at least one -R 2 on the alpha carbon atom (the carbon atom bonded directly to the Y moiety) be a hydrogen. Also pre¬ ferred is at most only one -R 2 being other than hydrogen. Also preferred is all -R 2 being hydrogen. 15 Also preferred is where both -R 2 on the alpha carbon atom are hydrogen and both -R 2 on the beta carbon atom (the carbon atom bonded directly to the alpha carbon atom) are unsubstituted or substituted alkyl or are covalently bonded to form a sub¬ stituted or unsubstituted alkyl or heteroalkyl ring having from 0 about 3 to about 8 atoms, including from 0 to about 3 hetero¬ atoms, in the ring. Preferred is a substituted or unsubstituted alkyl ring having from about 3 to about 6 carbon atoms, more preferably 3 or 4 or 5 carbon atoms in the ring. Preferred -R 2 alkyl moieties on the beta carbon atom are saturated or unsatur- ^ ated having a single double or triple bond, more preferred is that both -R 2 on the beta carbon be unsubstituted or substituted alkanyl or covalently bonded to form an unsubstituted or sub¬ stituted alkanyl ring. More preferred still is that both -R 2 on the beta carbon atom are methyl or ethyl, especially methyl. 0 Also preferred is where both -R 2 on the alpha carbon atom are hydrogen, one -R 2 on the beta carbon atom is hydrogen and the other is arylalkyl or heteroarylalkyl, preferably having the structure -(CH 2 ) n -Ar, wherein -Ar is aryl or heteroaryl and n is an integer from 1 to about 6; preferably n is 1 or 2, especially ° 1. Preferred aryl and heteroaryl moieties of this structure include unsubstituted and substituted phenyl, pyridyl, or fura¬ nyl, especially unsubstituted and substituted phenyl. Preferred substitutents on the aryl or heteroaryl moiety include chloro, methyl, methoxy, nitro, fluoro, and C x -C 6 alkyl. Most pre¬ ferred aryl is phenyl, especially unsubstituted phenyl. In such compounds, the beta carbon is a chiral center; preferred co - pounds have the S-enantiomer structure: -V being NH 2 - CH 2 —C-« 2 H In structure (1) the -R moiety is a C x -C 24 alkyl moiety which may be straight, branched or cyclic chain and may be saturated, monounsaturated, or polyunsaturated, substituted or unsubstituted. Preferred -R moieties are straight and branched chain alkanyl, straight and branched chain monounsaturated alkyl, straight and branched chain diunsaturated alkyl, and straight and branched chain triunsaturated alkyl. More preferred -R moieties are mono or diunsaturated or saturated, C 6 -C 24 straight or branched chain alkyls. Also more preferred are C 6 -C X straight chain alkyls, especially C 7 -C xo straight chain .alkanyls. Even more preferred are mono or diunsaturated alkenyls, or C 6 -C 24 straight chain alkenyls. Further preferred are monounsaturated cis-double bond C 6 -C 18 straight or branched chain alkenyls. Even further preferred is mono-unsaturated cis-double bond C β -C x straight chain alkenyls. Such preferred -R moieties are prefera- bly unsubstituted. Other preferred -R moieties are arylalkyls having a C X -C X2 , more preferably C x -C 6 , most preferably C x -C 2 , alkyl portion which is preferably straight chain and also preferably alkanyl. The aryl portion is preferably unsubstituted or substituted phenyl. Preferred - groups are selected from n-hexanyl, n-heptanyl, n-octanyl, n-nonanyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tri- decanyl, n-tetradecanyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, octadienyl, nonadienyl, decadienyl, undecadienyl, dodecadienyl, tridecadienyl and tetra- decadienyl. More preferred -R groups are selected from n-octa¬ nyl, n-nonanyl, n-decanyl, 7-methyl-5E- or 5Z-octenyl, 9-decenyl, 8Z-undecenyl, 9Z-dodecnyl, 8Z-tridecnyl, and 9Z-tetradecenyl. Preferred compounds useful in the subject invention include 8-methyl-N-vanillyl-6-nonenamide; N-vanillylnonanamide; N-van- illyl-9-octadecenamide; N-((4-(2-aminoethoxy)-3-methoxyphenyl)- methyl)-9Z-octadecenamide; N-((4-(2-aminoethoxy)-3-methoxyphe- nyl)-methyl)nonanamide; N-((4-(2-methyl-2-aminopropoxy)3-methoxy- phenyl)-methyl)-nonanamide; N-((4-(2-methyl2-aminopropoxy)-3- methoxyphenyl)methyl)-9Z-octadecenamide; N-((4(2amino-3methyl- butoxy)-3methoxyphenyl)-methyl)-9Z-octadecenamide; N-((4-(1-ami- no-l-cyclopropylmethoxy)-3-methoxyphenyl)methyl)9Z-octadecena- mide; N-((4-(l-amino-l-cyclopentylmethoxy)-3-methoxy)phenyl)me- thyl)-9Z-octadecenamide; N-(9Z-octadecenyl)-4-(2-amino-2-methyl- propoxy)-3-methoxyphenylacetamide; N-(9Z-octadecenyl)-4-(2-amino- ethoxy)-3-methoxyphenylacetamide; N-octanyl-4-(2-aminoethoxy)- 3-methoxyphenylacetamide; N-((4-(2-amino-3-hydroxypropoxy)- 3-methoxyphenyl)-methyl)-9Z-octadecenamide; N-((4-(2-amino-2-car- boxyethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide; N-(9- decenyl)-4-hydroxy-3-methoxyphenylacetamide; N-(9Z-dodecenyI)-4- hydroxy-3-methoxyphenylacetamide; N-(9Z-tetradecenyl)-4-hydroxy- 3-methoxyphenylacetamide; N-((4-hydroxy-3-methoxyphenyl)-methyl)- 9-decenamide; N-((4-hydroxy-3-methoxyphenyl)-methyl)-9Z-dodecena- πride; N-((4-hydroxy-3-methoxyphenyl)-methyl)-9Z-tetradecenamide; N-((4-(3-phenyl-2(S)-2-amino-l-propoxy)-3-methoxyphenyl)-methyl)- nonanamide; and the pharmaceutically-acceptable salts and amides thereof. More preferred compounds useful in the methods of the present invention include 8-methyl-N-vanillyl-6-nonenamide-; N-vanillylnonanamide; N-(9-decenyl)-4-hydroxy-3-methoxyphenyl- acetamide; N-(9Z-dodecenyl)-4-hydroxy-3-methoxyphenylacetamide; N-(9Z-tetradecenyl)-4-hydroxy-3-methoxyphenylacetamide; N-((4- hydroxy-3-methoxyphenyl)-methyl)-9-decenamide; N-((4-hydroxy-3- methoxyphenyl)-methyl)-9Z-dodecenamide; N-((4-hydroxy-3-methoxy- phenyl)-methyl)-9Z-tetradecenamide; N-((4-(3-phenyl-2(S)-2-ami- no-l-propoxy)-3-methoxyphenyl)-methyl)-nonanamide; and the pharmaceutically-acceptable salts and amides thereof. Preferred pharmaceutically-acceptable salts for the vanil- loid compounds are the ammonium carboxylic acid salts derived from organic carboxylic acids, especially the acetate and lactate salts. Specific vanilloid pharmaceutical compositions useful in this invention are described in the following U.S. Patents, all incorporated by reference herein: U.S. Patent No. 4,401,663, Buckwalter, et al, issued August 30, 1983; U.S. Patent No. 4,424,205, LaHann, et al, issued January 31, 1984; U.S. Patent No. 4,443,473, Buckwalter, et al, issued April 12, 1984; U.S. Patent No. 4,493,848, LaHann, et al, issued January 15, 1985. Vanilloid pharmaceutical compositions preferably comprise one or more of the vanilloid compounds and a pharmaceutically-acceptable carrier. Total single dosages of the vanilloid compounds present in pharmaceutical compositions useful herein are generally from about 1 ug to about 1 g. Preferred single dosages are from about 10 ug to about 100 mg; more preferred are from about 100 ug to about 50 mg; and most preferred are from about 1 mg to about 10 mg. The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the vanilloid compounds in the subject invention is largely determined by the way the compound is to be administered. Such methods include parenteral (especially subcu¬ taneous), peroral and topical. Nucleoside Antiviral Compounds and Compositions As used herein, "nucleoside antiviral compounds" include antiviral compounds which are derivatives of purine nucleosides, preferably adenosine, guanosine and inosine, more preferably guanosine, and especially adenosine. Examples of "purine nucleo¬ side antiviral compounds" are disclosed in U.S. Patent Nos. 3,651,045 3,728,450 3,817,982 3,826,803 3,849,397 3,910,885 3,915,958 3,923,785 3,948,886 3,956,277 4,038,479 4,048,432 4,055,717 4,055,718 4,056,673 4,069,382 4,093,714 4,136,175 4,138,562 4,146,715 4,148,888 4,158,056 4,188,378 4,199,574 4,221,909 4,221,910 4,223,156 4,230,708 4,287,188 4,294,831 4,315,920 4,323,573 4,328,336 4,338,310 4,340,726 4,347,360 4,355,032 4,360,522 4,383,114 4,423,050 4,461,757 4,469,863 4,495,190 4,507,305 4,526,988 4,539,313 4,544,741 4,548,819 4,556,659 4,594,350 4,594,415 4,605,658 4,605,659 4,606,917 4,609,661 4,609,662 4,612,314 4,617,304 4,642,346 4,649,140 4,659,698 4,663,446 4,668,778 4,670,424 4,692,434 4,695,570 4,719,295; 4,724,233; 4,728,736; 4,742,064; 4,743,689; 4,745,119 4,755,516; 4,758,572; 4,794,174; 4,798,833; 4,806,642; 4,808,716 4,816,447; 4,826,823; 4,837,311; 4,845,084; 4,845,215; 4,849,412 4,855,304; 4,857,316; 4,857,531; 4,859,677, 4,859,768; 4,861,759 4,880,782; and 4,927,830; which have been incorporated herein by reference. Preferred purine nucleoside antiviral compounds are those in which purine or a purine derivative is linked through the nitrogen of position 9 to a sugar or sugar derivative. The purine nucleoside antiviral compounds useful in the subject invention include those disclosed in U.S. Patent Nos. 4,199,574 and 4,287,188 issued to Schaeffer on April 22, 1980 and September 1, 1981, respectively, having the general structure: R 1 In Structure (2), X is sulphur or oxygen, R 1 is hydrogen, halogen, hydroxy, alkoxy, azide, thio, alkylthio, amino, alkyl- amino or dialkylamino; R 2 is hydrogen, halogen, alkylthio, acylamino, amino or azide; R 3 is hydrogen, straight or branch chain or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl; R* is hydrogen, hydroxy or alkyl; R 5 is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzyloxy, aroyloxy (e.g., benzoyloxy), benzoyloxymethyl, sul ha oyloxy, phosphate, carboxyacyloxy containing 4 to 6 carbon atoms (e.g., 3-carboxypropionyloxy, 4-carboxybutyryloxy and 5-carboxyvaleryloxy), straight chain or cyclic acyloxy having from 1 to 8 carbon atoms, or substituted carbamoyl group of formula -NHCO-Z wherein Z is alkyl, aryl or aralkyl optionally substituted by one or more of sulphonyl, amino, carbamoyl or halogen; R 6 is hydrogen, alkyl or hydroxy- alkyl; or a pharmaceutically-acceptable salt thereof. Compounds of Structure (2) as defined above wherein X is oxygen; R 1 is halogen, hydroxy, alkylthio or amino; R 2 is hydro¬ gen, halogen, amino or azide; R 3 is hydrogen, straight or branched chain or cyclic alkyl, hydroxyalkyl or phenyl; R 4 is hydrogen, lower alkyl or hydroxy; R 5 is hydrogen, hydroxy, benzoyloxy, hydroxyalkyl, amino, acyloxy containing 1 to 5 carbon atoms (e.g., formyloxy, acetyloxy, propionyloxy, and pivaloyloxy), carboxyacyloxy with 4 to 6 carbon atoms, benzyloxy, benzoyloxy ethyl, phosphate, sulphamoyloxy, substituted carbamoyl group of the formula -NHCO-Z where Z is aryl or aralkyl optional¬ ly substituted by one or more of sulphonyl, amino, carbamoyl or halogen; R 6 is hydrogen or alkyl; or a pharmaceutically-accept- able salt are preferred. In particular compounds of Structure (2), as hereinbefore defined, where X is oxygen; R 1 is amino or hydroxy; R 2 is amino; R 5 is hydrogen, phosphate, hydroxy, benzoyloxy, 3-carboxypro- pionyloxy, acetyloxy or hydroxyalkyl; and R 3 , R 4 and R 6 are hydrogen; are more preferred. Compounds where X is sulphur; R 1 is halogen, amino or alkylamino; and R 2 , R 3 , R 4 and R 6 are hydrogen are also preferred. Additionally, the compounds where X is oxygen; R 1 is hydroxy; R 2 is amino; R 3 , R 4 and R 6 are hydro¬ gen; are particularly preferred. Especially preferred is when R 5 is hydroxy or hydroxymethyl or benzoyloxy or 3-carboxy-propionyl- oxy or monophosphate. Salts which are especially convenient for therapeutic use are salts of pharmaceutically-acceptable organic acids such as lactic, acetic, malic, or p-toluenesulfonic acid as well as salts of pharmaceutically-acceptable mineral acids such as hydrochloric or sulfuric acid. Where R 5 is phosphate (may also be mono- or dihydrogen phosphate), sodium, potassium, ammonium, calcium, magnesium and aluminum, especially sodium and ammonium, salts of the phosphate (or monohydrogen phosphate) are preferred. The most preferred compound of Structure (2) is acyclovir wherein R 1 and R 5 are hydroxy, R 2 is amino, X is oxygen, and R 3 , R 4 and R 6 are hydrogen. Also preferred are derivatives of acyclovir disclosed in Schaeffer '188 wherein R 5 is phosphory- lated and the specific salts thereof. Another preferred compound of Structure (2) is ganciclovir wherein R 1 and R 2 are amino, X is oxygen, R 3 is hydroxymethyl, R 4 is hydroxy and R 5 is hydrogen. Another preferred compound of Structure (2) is 9-(l,3-di- hydroxy-2-propoxymethyl)guanine and pharmaceutically-acceptable salts thereof, disclosed in U.S. Patent No. 4,355,032 issued to Verheyden & Martin on October 19, 1982; and active antiviral analogs thereof. The purine nucleoside antiviral compounds also include vidarabine, 9-(,β-D-arabinofuranosyl)adenine, as disclosed in U.S. Patent No. 3,616,208 issued to Howells & Ryder on October 26, 1971, pharmaceutically-acceptable salts thereof, and active antiviral analogs thereof. The purine nucleoside antiviral compounds of Structure (2) also include HOE-602, 2-amino-9-(l,3-bis(isopropoxy)-2-propoxy- methyl)purine, as disclosed in Winkelmann, E., I. Winkler, H. Roily, M. Rosner, & G. Jahne, "New Prodrugs of Acyclic Nucleo- sides with Antiviral Activity", Arzneimittelforschung. Vol. 38, No. 11 (1988), pp. 1545-1548, and active antiviral analogs thereof. The purine nucleoside antiviral compounds also include VSA-671, 9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine, and buciclovir: (R)-9-(3,4-dihydroxybutyl)guanine, as disclosed in Larsson, A., K. Stenberg, A.C. Ericson, U. Haglund, W.A. Yisak, N.G. Johansson, B. Oberg & R. Datema, "Mode of Action, Toxicity, Pharmacokinetics, and Efficacy of Some New Antiherpesvirus Guanosine Analogs Related to Buciclovir", Antimicrobial Agents Chemotherapy. Vol. 30, No. 4 (1986), pp. 598-605, and active antiviral analogs thereof. The purine nucleoside antiviral compounds also include fa ciclovir: 9-(4-acetoxy-3-hydroxymethylbut-l-yl)guanine, and penciclovir: 9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine, as disclosed in Vere Hodge, R.A., D. Sutton, M.R. Boyd, M.R. Harnden & R.L. Jarvest, "Selection of an Oral Prodrug (BRL 42810; Famci¬ clovir) for the Antiherpesvirus Agent BRL 39123", Antimicrobial Agents Chemotherapy. Vol. 33, No. 10 (1989), pp. 1765-1773, and active antiviral analogs thereof. The purine nucleoside antiviral compounds also include HPMPA, (S)-9-(3-hydroxy-2-phosphonyl-methoxypropyl)adenine, as disclosed in DeClercq, E., T. Sakuma, M. Baba, R. Pauwels, J. Balzarini, I. Rosenberg & A. Holy, "Antiviral Activity of Phos- phonylmethoxyalkyl Derivatives of Purine and Pyri idines", Antiviral Research. Vol. 8, Nos. 5-6 (1987), pp. 261-272, and active antiviral analogs thereof. The purine nucleoside antiviral compounds also include PMEG, 9-(2-phosphonylmethoxyethyl)guanine, as disclosed in DeClercq, E., T. Sakuma, M. Baba, R. Pauwels, J. Balzarini, I. Rosenberg & A. Holy, Antiviral Research. Vol. 8, Nos. 5-6 (1987), pp. 261 -272, and active antiviral analogs thereof. The purine nucleoside antiviral compounds also include N 2 -phenyl guanine derivatives disclosed in Focher, F., C. Hilde- brand, S. Freese, G. Ciarrocchi, T. Noonan, S. Sangalli, N. Brown, S. Spadari & G. Wright, "N 2 -Phenyldeoxyguanosine: A Novel Selective Inhibitor of Herpes Simplex Thymidine Kinase", Journal of Medicinal Chemistry. Vol. 31 (1988), pp. 1496-1500, having the general structure: and active antiviral analogs thereof. In Structure (3), -X and -Y are independently selected from hydrogen and lower alkyl or -X and -Y are connected to form a cyclic alkyl; more preferably -X is methyl, or especially hydro¬ gen, and -Y is ethyl or methyl, or especially hydrogen. In Structure (3), -Z is preferably selected from the group consisting of hydrogen, 2-deoxy-?-D-ribofuranosyl, ø-D-ribofuran- osyl, 2-deoxy-5-phospho-^-D-ribofuranosyl, and -CH 2 0CH 2 CH 2 0H; more preferably from hydrogen, 2-deoxy-^-D-ribufuranosyl and 2-deoxy-5-phospho-^-D-ribofuranosyl . The purine nucleoside antiviral compounds also include cyclobut-A, 9-((1,5,2a, Zβ)-2,3-bis(hydroxymethyl)-l-cyclobutyl)- adenine, and cyclobut-G, 9-((l^,2α,3,3)-2,3-bis(hydroxymethyl)-l- cyclobutyl)guanine, as disclosed in Norbeck, D.W., E. Kern, S. Hayashi, W. Rosenbrook, H. Sham, T. Herrin, J.J. Plattner, J. Erickson, J. Clement, R. Swanson, M. Shipkowitz, D. Hardy, K. Marsh, G. Arnett, W. Shannon, S. Broder and H. Mitsuya, "Cyclobut-A and Cyclobut-G: Broad-Spectrum Antiviral Agents with Potential Utility for the Therapy of AIDS", Journal of Medicinal Chemistry. Vol. 33 (1990), pp. 1281-1285, and active antiviral analogs thereof. As used herein, "nucleoside antiviral compounds" include antiviral compounds which are derivatives of pyrimidine nucleo- sides, preferably cytidine, uridine and thymidine. Examples of "pyrimidine nucleoside antiviral compounds" are disclosed in U.S. Patent Nos. 3,642,771; 3,708,469; 3,709,874; 3,792,040 3,804,826; 3,804,827; 3,812,098; 3,817,982; 3,847,898; 3,853,845 3,870,700; 3,910,885; 3,975,367; 3,988,314; 3,998,807; 4,000,260 4,010,269; 4,017,606; 4,056,673; 4,066,696; 4,092,472; 4,093,715 4,093,716; 4,096,324; 4,097,525; 4,145,414; 4,156,778; 4,177,348 4,190,656; 4,210,638; 4,211,773; 4,247,544; 4,267,171; 4,271,153 4,329,460; 4,344,937; 4,363,909; 4,382,925; 4,383,990; 4,386,076 4,396,623; 4,424,211; 4,469,863; 4,526,988; 4,536,504; 4,542,210 4,564,618; 4,595,780; 4,605,659; 4,629,729; 4,659,698; 4,666,892 5,668,778; 4,670,424; 4,681,933; 4,690,917; 4,692,434; 4,710,492 4,719,214; 4,755,516; 4,762,823; 4,772,609; 4,780,453; 4,782,142 4,788,181; 4,806,542; 4,833,130; 4,837,311; 4,841,039; 4,849,412 4,851,391; 4,851,519; 4,855,304; 4,859,680; 4,863,906; 4,863,927 4,868,162; 4,868,187; 4,874,609; 4,879,277; 4,880,785; 4,882,316 4,886,785 and 4,927,830; which have been incorporated herein by reference. Preferred pyrimidine nucleoside antiviral compounds are those in which pyrimidine or a pyrimidine derivative is linked through the nitrogen of position 1 to a sugar or sugar derivative. The pyrimidine nucleoside antiviral compounds useful in the subject invention include trifluridine, 5-trifluoromethyl-2'- deoxyuridine, and 5-trifluoromethyl uracil as disclosed in U.S. Patent No. 3,201,387 issued to Heidelberger on August 17, 1965, and active antiviral analogs thereof. The pyrimidine nucleoside antiviral compounds also include zidovudine, 3'-azido-3'-deoxythymidine (AZT), and its mono-, di- and triphosphates as disclosed in U.S. Patent No. 4,724,232 issued to Rideout, Barry, Lehrman, St. Clair & Furman on February 9, 1988, and active antiviral analogs thereof. The pyrimidine nucleoside antiviral compounds also include analogs of 5-ethyl-2'-deoxyuridine as disclosed in Martin, J.A., I.B. Duncan, M.J. Hall, P. Wong-Kai-In, R. W. Lambert & G.J. Thomas, "New Potent and Selective Inhibitors of Herpes Simplex Virus Thymidine Kinase", Nucleosides & Nucleotides. Vol. 8 (1989), pp. 753-764, having the general structure: and active antiviral analogs thereof. In Structure (4), R is selected from the group consisting of halo and lower alkyl, preferably from iodo, trifluoromethyl, ethyl, ethenyl and n-butyl. In Structure (4), R' is selected from the group consisting of hydroxy, phosphate, alkylphosphate, methylsulfonate, tosyl, phenylsulfonamide, amino, and R"C0NH, where R" is selected from aryl, aryl lower alkyl, and aryloxy lower alkyl; R' is preferably hydroxy. A preferred compounds of Structure (4) is idoxuridine wherein R is iodo and R' is hydroxy. Another preferred compound of Structure (4) is edoxudine wherein R is ethyl and R' is hydroxy. The pyrimidine nucleoside antiviral compounds include BVRU, E-5-(2-bromovinyl)-ribouridine, as disclosed in DeClercq, E., C. Desgranges, P. Herdewijn, I.S. Sim, A.S. Jones, M.J. McLean, & R.T. Walker, "Synthesis and Antiviral Activity of (E)-5-(2-brom- ovinyl)uracil and (E)-5-(2-bromovinyl)uridine", Journal of Medicinal Chemistry. Vol. 29, No. 2 (1986), pp. 213-217, and active antiviral analogs thereof. The pyrimidine nucleoside antiviral compounds also include BVDU, E-5-(2-bromoethenyl)-2'-deoxyuridine, as disclosed in DeClercq, E., "The Antiviral Spectrum of (E)-5-(2-bromovinyl)-2'- deoxyuridine", Journal of Antimocrobial Chemotherapy. Vol. 14, Supplement A (1984), pp. 85-95, and active antiviral analogs thereof. The pyrimidine nucleoside antiviral compounds also include YN-72, l-,5-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil, as disclosed in Machida, H., S. Sakata, A. Kuninaka & H. Yoshino, "Antiherpesviral and Anticellular Effects of 1-beta-D-arabino- furanosyl-E-5-(2-halogenovinyl)uraciIs", Antimicrobial Agents Chemotherapy. Vol. 20, No. 1 (1981), pp. 47-52, and active antiviral analogs thereof. The pyrimidine nucleoside antiviral compounds also include FEAU, l-(2'-deoxy-2'-fluoro- l β-D-arabinofuranosyl)-5-ethyluracil, as disclosed in Mansuri, M.M., I. Ghazzouli, M.S. Chen, H.G. Howell, P.R. Brodfuehrer, D.A. Benigni & J.C. Martin, "l-(2- deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil . A Highly Selective Antiherpes Simplex Agent", Journal of Medicinal Che is- try, Vol. 30, No. 5 (1987), pp. 867-871, and active antiviral analogs thereof. The pyrimidine nucleoside antiviral compounds also include FIAU, 2'-fluoro-5-iodo-1-0-D-arabinofuranosyluraci1, as disclosed in Mansuri, M.M., I. Ghazzouli, M.S. Chen, H.G. Howell, P.R. Brodfuehrer, D.A. Benigni & J.C. Martin, "l-(2-deoxy-2-fluoro- beta-D-arabinofuranosyl)-5-ethyluraci1. A Highly Selective Antiherpes Simplex Agent", Journal of Medicinal Chemistry. Vol. 30, No. 5 (1987), pp. 867-871, and active antiviral analogs thereof. The pyrimidine nucleoside antiviral compounds also include BW-41117U, l-((l,3-dihydroxy-2-propoxy)methyl)cytosine, as disclosed in Beauchamp, L.M., B.L. Serling, J.E. Kelsey, K.K. Biron, P. Collins, J. Selway, J.-C. Lin & H.J. Schaeffer, "Effect of Acyclic Pyrimidines Related to 9-((l,3-dihydroxy-2-propoxy)- methyl)guanine on Herpes Viruses", Journal of Medicinal Chemistry. Vol. 31 (1988), pp. 144-149, and active antiviral analogs thereof. The pyrimidine nucleoside antiviral compounds also include HPMPC, (S)-l-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, as disclosed in Bronson, J.J., I. Ghazzouli, M.J. Hitchcock, R.R. Webb & J.C. Martin, "Synthesis and Antiviral Activity of the Nucleotide Analog (S)-l-(3-hydroxy-2-(ρhosphonylmethoxy)propyl)- cytosine", Journal of Medicinal Chemistry. Vol. 32, No. 7 (1989), pp. 1457-1463, and active antiviral analogs thereof. The pyrimidine nucleoside antiviral compounds include amino- pyrimidopyrimidine, 4-amino-8-(J-D-ribofuranosylamino)-pyrimido- (5,4-d)pyrimidine, as disclosed in Abstracts of the 85th American Society of Microbiologists Meeting. Las Vegas (1985), Abstract A33, and active antiviral analogs thereof. As used herein, "nucleoside antiviral compounds" include antiviral compounds which are derivatives of triazole nucleo- sides. Examples of "triazole nucleoside antiviral compounds" are disclosed in U.S. Patent Nos. Re 29,835; 3,666,771; 3,798,209 3,897,415; 3,948,885; 3,976,545; 3,984,396; 3,991,078; 4,006,159 4,007,198; 4,211,711; 4,537,899; 4,544,741; 4,564,622; 4,594,415 4,652,580; 4,663,338; 4,668,660; 4,806,542; 4,857,539; which have been incorporated herein by reference. Preferred triazole nucleoside antiviral compounds are those in which triazole or a triazole derivative is linked through the nitrogen of position 1 to a sugar or sugar derivative. The triazole nucleoside antiviral compounds useful in the subject invention include those disclosed in U.S. Patent No. 3,798,209 issued to Witkowski, Niguel & Robins on March 19, 1974, having the general structure: and active antiviral analogs thereof. In Structure (5), G is a pentofuranosyl moiety, preferably characterized by 2'-oxygen trans to the triazole aglycon, R x being cyano-, carboxamido-, thiocarboxamido-, -methylcarboxylate, carboxamidoxime, -carboxamidine, or a physiologically-acceptable acid addition salt of the latter group. Compounds of Structure (5) also embrace the O-acylated analogs of the foregoing com¬ pounds and the 5'-phosphates and 3',5'-cyclic phosphates thereof as well as the ammonium and alkali metal salts of the phosphates. 5 Preferred embodiments include compounds of the structure: 5 and active antiviral analogs thereof. In Structure (6), R x is as previously defined for Structure (5) and one of R 2 or R 3 is hydrogen, the other being hydroxyl, as well as 5'-phosphates and 3',5'-cyclic phosphates thereof. The preferred compound of structure (6) is ribavirin, l-(?-D-ribo- 0 furanosyl)-1,2, -triazole-3-carboxamide. Nucleoside antiviral compositions useful in the subject invention preferably comprise one or more of the nucleoside antiviral . compounds in a pharmaceutically-acceptable carrier. Total single doses of the nucleoside antiviral compounds present 5 in the pharmaceutical compositions useful herein are generally from about 1 μg to about 1 g. Preferred single doses are from about 10 μg to about 600 mg; more preferred are from about 0.1 mg to about 400; and most preferred are from about 1 mg to about 200 mg. 0 The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the nucleoside antiviral compounds in the methods of the subject invention is largely determined by the way the compound is to be administered. Such methods include oral, topical, and parenteral, e.g., intravenous. Examples of ^ typical nucleoside antiviral compositions, which are generally useful for such compounds, are disclosed in the Physicians' Desk Reference. 44th Edition (1990), E.R. Barnhart, Pub., which is incorporated herein by reference: acyclovir on pp. 816-820, zidorudine on pp. 799-801, vidarabine on pp. 1657-1659, ribavirin on pp. 1075-1077, trifluridine on pp. 812-813, and ganciclovir on pp. 2195-2197. Methods of Treating Herpes Simplex Infections The subject invention involves methods of treating Heroes infections, particularly methods of alleviating signs and symptoms associated with herpetic vesicular eruptions and the attendant pain of Herpes lesions by administering to a person a safe and effective amount of a combination of a vanilloid com¬ pound and a nucleoside antiviral compound. The methods of the subject invention include the prevention of recurrent Herpes simplex lesion episodes and/or the reduction in number and/or severity of Heroes simplex or Herpes zoster vesicular eruptions that manifest in a lesion episode. The phrase a "safe and effective amount", as used herein, means an amount of compounds or compositions high enough to significantly positively modify the condition to be treated, but low enough to avoid serious side effects (at a reasonable bene- fit/risk ratio), within the scope of sound medical judgment. The safe and effective amount of compounds or compositions will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concur- rent therapy, the specific compounds or compositions employed, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician. The vanilloid compounds and the nucleoside antiviral com- pounds useful in the subject invention may be administered to a person together in a single composition or separately in differ¬ ent compositions. When administered separately in different compositions, the compounds may be administered by the same or different routes of administration, and may be administered at about the same time or at different times. Daily dosages of vanilloid compounds preferably range from about 0.01 mg/kg of body weight to about 200 mg/kg of body weight. More preferred daily dosages are from about 0.1 mg/kg to about 10 mg/kg of body weight; still more preferred daily dosages are from about 0.2 mg/kg to about 1 mg/kg of body weight. Up to about 6, preferably from about 1 to about 4, single dosages per day may be administered. Preferred routes of administration of vanilloid compounds include topical, peroral, and parenteral; more preferred are topical and peroral; most preferred is topical. Topical admini¬ stration can be used by directly laying on or spreading a safe and effective amount of a vanilloid composition on epidermal or epithelial tissue, including outer skin and oral, anal, vaginal and gingival tissue. The amount of the pharmaceutical composi¬ tion to be topically administered may vary from about 1 mg/cm 2 to about 20 mg/cm 2 , and if a patch is worn over the affected area possibly higher amounts, depending upon such factors as the sensitivity, type and location of tissue to be treated, the composition and carrier to be administered, and the particular compound to be administered. When administered topically, the vanilloid compound is preferably administered between lesion episodes to tissue in areas ' where lesions previously occurred and/or are likely to occur, especially on the face or in the .genital region. The vanilloid compound is preferably administered topically for from about 1 to about 60 days at a frequency of about weekly to about yearly, more preferably for from about 2 days to about 30 days at a frequency of from about biweekly to about twice yearly, more preferably still for from about 3 days to about 15 days at a frequency of from about monthly to about thrice yearly, most preferably from about 4 days to about 7 days at a frequency of from about bimonthly to about trimonthly. On days when the vanilloid compound is administered topically, it is preferably administered from about once to about six times daily, more preferably from about twice to about 4 times daily. Preferred routes of administration of nucleoside antiviral compounds are peroral, topical, and parenteral (especially intra¬ venous); preferred routes of administration are peroral and topical, especially peroral . Daily dosages of nucleoside antiviral compounds preferably range from about 0.01 mg/kg of body weight to about 20 mg/kg of body weight. More preferred daily dosages are from about 0.1 mg/kg to about 15 mg/kg of body weight; still more preferred daily dosages are from about 1 mg/kg to about 10 mg/kg of body weight; more preferred still is from about 5 mg/kg to about 8 mg/kg of body weight. Up to about 8, preferably from about 1 to about 6, more preferably from about 2 to about 4, single dosages per day may be administered. The nucleoside antiviral compound is preferably administered everyday, although less frequent administration is also often effective. An animal model which can be used to demonstrate the use of combinations of vanilloid compounds and nucleoside antiviral compounds for the prevention or treatment of lesion episodes of Herpes simplex infections is disclosed in Stanberry, L.R., R. L. Burke and M. G. Myers, "Herpes Simplex Virus Glycoprotein Treat¬ ment of Recurrent Genital Herpes", The Journal of Infectious Diseases. Vol. 157, (1988), pp. 156-163; and Stanberry, L. R., S. Kit and M. G. Myers, "Thy idine Kinase-deficient Herpes Simplex Virus Type 2 Genital Infection in Guinea Pigs", Journal of Virology. Vol. 55, (1985), pp.322-328. Combination Compositions The subject invention also includes pharmaceutical composi¬ tions comprising one or more vanilloid compounds, one or more nucleoside antiviral compounds, and a pharamaceutically-accept- able carrier. Preferred combination compositions of the subject invention comprise one vanilloid compound, one nucleoside anti¬ viral compound and a carrier formulated for topical, peroral or parenteral administration. Preferred combination compositions of the subject invention are for topical administration. As used herein, "administered topically" means placing the compounds, whether vanilloid, nucleoside antiviral, or combina¬ tions thereof, in contact with the skin, mucous membrane, or body cavity. It thus includes epidermal, intraoral, intravaginal, intraanal, and intraaural administration. Preferred methods of the subject invention involve topical administration of one or both of the active compounds. Suitable pharmaceutically- acceptable carriers for topical application include those suited for use in lotions, creams, solutions, gels, ointments, tapes and the l ke. Suitable carriers for topical administration preferably 5 remain in place on the skin as a continuous film and resist being washed off easily by perspiration or by immersion in water. Generally, the carrier is either organic in nature or an aqueous emulsion and capable of having the vanilloid compound dispersed or dissolved therein. The carrier may include pharmaceutically- 0 acceptable emollients, skin penetration enhancers, coloring agents, fragrances, emulsifiers, thickening agents, and solvents. A more detailed description of such forms follows: 1. Lotions The lotions can comprise an effective amount (preferably 5 from about 0.001% to about 5%, more preferably from about 0.1% to about 1%) of a vanilloid compound; from 1% to 50%, preferably from 3% to 15%, of an emollient; the balance being water, a C 2 or C 3 alcohol, or a mixture of water and the alcohol. Several emollients are known. Examples of such emollients are as fol- lows: a. Hydrocarbon oils and waxes. Examples are mineral oil, petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, and perhydrosqualene. b. Silicone oils, such as dimethylpolysiloxanes, methyl- ^ phenylpolysiloxanes, water-soluble and alcohol-soluble silcone- glycol copolymers. c. Triglyceride fats and oils such as those derived from vegetable, animal and marine sources. Examples include castor oil, safflower oil, cotton seed oil, corn oil, olive oil, cod 0 liver oil, almond oil, avocado oil, palm oil, sesame oil, and soybean oil. d. Acetoglyceride esters, such as acetylated onoglycer- ides. e. Ethoxylated glycerides, such as ethoxylated glyceryl monostearate. f. Alkyl esters of fatty acids having 10 to 20 carbon atoms. Methyl, isopropyl and butyl esters of fatty acids are useful herein. Examples include hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate, isopropyl myristate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stear- ate, isopropyl isostearate, diisopropyl adipate, diisohexyl adipate, dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate, myristyl lactate, and cetyl lactate. g. Alkenyl esters of fatty acids having 10 to 20 carbon atoms. Examples thereof include oleyl myristate, oleyl stearate, and oleyl oleate. h. Fatty acids having 9 to 22 carbon atoms. Suitable examples include pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachi- donic, behenic, and erucic acids. i. Fatty alcohols having 10 to 22 carbon atoms. Lauryl, myristyl, cetyl, hexadecyl, stearyl, isostearyl, hydroxystearyl , oleyl, ricinoleyl, behenyl, erucyl, and 2-octyl dodecyl alcohols are examples of satisfactory fatty alcohols. j. Fatty alcohol ethers. Ethoxylated fatty alcohols of 10 to 20 carbon atoms include the lauryl, cetyl, stearyl, isostear- yl, oleyl, and cholesterol alcohols having attached thereto from 1 to 50 ethylene oxide groups or 1 to 50 propylene oxide groups, or a mixture thereof. k. Ether-esters such as fatty acid esters of ethoxylated fatty alcohols. 1. Lanolin and derivatives. Lanolin, lanolin oil, lanolin wax, lanolin alcohols, lanolin fatty acids, isopropyl lanolate, ethoxylated lanolin, ethoxylated lanolin alcohols, ethoxylated cholesterol, propoxylated lanolin alcohols, acetylated lanolin, acetylated lanolin alcohols, lanolin alcohols linoleate, lanolin alcohols ricinoleate, acetate of lanolin alcohols ricinoleate, acetate of ethoxylated alcohols-esters, hydrogenolysis of lano¬ lin, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and semisolid lanolin absorption bases are illustrative of emollients derived from lanolin. m. Polyhydric alcohols and polyether derivatives. Pro¬ pylene glycol, dipropylene glycol, polypropylene glycol (M.W. 2000-4000), polyoxyethylene polyoxypropylene glycols, polyoxypropylene polyoxyethylene glycols, glycerol, ethoxylated glycerol, propoxylated glycerol, sorbitol, ethoxylated sorbitol, hydroxypropyl sorbitol, polyethylene glycol (M.W. 200-6000), methoxy polyethylene glycols 350, 550,750, 2000, 5000, poly[ethylene oxide] homopolymers (M.W. 100,000-5,000,000), polyalkylene glycols and derivatives, hexylene glycol (2-methyl-2,4-pentanediol), 1,3-butylene glycol, 1,2,6-hexane- triol, ethohexadiol USP (2-ethyl-l,3-hexanediol) C X5 -C X8 vicinal glycol, and polyoxypropylene derivates of trimethylolpropane are examples thereof. n. Polyhydric alcohol esters. Ethylene glycol mono- and di-fatty acid esters, diethylene glycol mono- and di-fatty acid esters, polyethylene glycol (M.W. 200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty acid esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol poly-fatty acid esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty acid esters, and polyoxy¬ ethylene sorbitan fatty acid esters are satisfactory polyhydric alcohol esters. o. Wax esters such as beeswax, spermaceti, myristyl myrist¬ ate, stearyl stearate. p. Beeswax derivatives, e.g., polyoxyethylene sorbitol beeswax. These are reaction products of beeswax with ethoxylated sorbitol of varying ethylene oxide content, forming a mixture of ether-esters. q. Vegetable waxes including carnauba and candelilla waxes. r. Phospholipids such as lecithin and derivatives. s. Sterols. Cholesterol, cholesterol fatty acid esters are examples thereof. t. Amides such as fatty acid amides, ethoxylated fatty acid amides, solid fatty acid alkanolamides. The lotions further preferably comprise from 1% to 10%, more preferably from 2% to 5%, of an emulsifier. The emulsifiers can be nonionic, anionic or cationic. Examples of satisfactory - 33 - nonionic emulsifiers include fatty alcohols having 10 to 20 carbon atoms, fatty alcohols having 10 to 20 carbon atoms con¬ densed with 2 to 20 moles of ethylene oxide or propylene oxide, alkyl phenols with 6 to 12 carbon atoms in the alkyl chain condensed with 2 to 20 moles of ethylene oxide, mono- and di-fat¬ ty acid esters of ethylene oxide, mono- and di-fatty acid esters of ethylene glycol wherein the fatty acid moiety contains from 10 to 20 carbon atoms, diethylene glycol, polyethylene glycols of molecular weight 200 to 6000, propylene glycols of molecular weight 200 to 3000, glycerol, sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and hydrophilic wax esters. Suitable anionic emulsifiers include the fatty acid soaps, e.g. sodium, potassium and triethanolamine soaps, wherein the fatty acid moiety contains from 10 to 20 carbon atoms. Other suitable anionic emulsifiers include the alkali metal, ammonium or substi¬ tuted ammonium alkyl sulfates, alkyl arylsulfonates, an alkyl ethoxy ether sulfonates having 10 to 30 carbon atoms in the alkyl moiety. The alkyl ethoxy ether sulfonates contain from 1 to 50 ethylene oxide units. Satisfactory cationic emulsifiers are the quaternary ammonium, morpholinium and pyridinium compounds. Certain of the emollients described in preceding paragraphs also have emulsifying properties. When a lotion is formulated con¬ taining such an emollient, an additional emulsifier is not needed, though it can be included in the composition. The balance of the lotion is water or a C 2 or C 3 alcohol, or a mixture of water and the alcohol. The lotions are formulated by simply admixing all of the components together. Preferably the compound of the present invention is dissolved in the mix¬ ture. Conventional optional components can be included. One such additive is a thickening agent at a level from 1% to 10% of the composition. Examples of suitable thickening agents include: cross-linked carboxypolymethylene polymers, ethyl cellulose, polyethylene glycols, gum tragacanth, gum kharaya, xanthan gums and bentonite, hydroxyethyl cellulose, and hydroxypropyl cellu¬ lose. 2. Creams The creams comprise an effective amount (preferably from about 0.001% to about 5%, more preferably from about 0.1% to about 1%) of a vanilloid compound; from 5% to 50%, preferably from 10% to 25%, of an emollient; the balance being water. The emollients above described can also be used in the cream composi- tions. Optionally the cream form contains a suitable emulsifier, as previously described. When an emulsifier is included, it is in the composition at a level from 3% to 50%, preferably from 5% to 20%. 3. Solutions The solution form comprises an effective amount (preferably from about 0.001% to about 5%, more preferably from about 0.1% to about 1%) of a vanilloid compound; the balance being water and/or a suitable organic solvent. Suitable organic materials useful as the solvent or a part of a solvent system are as follows: propyl- ene glycol, polyethylene glycol (M.W. 200-600), polypropylene glycol (M.W. 425-2025), glycerine, sorbitol esters, 1,2,6-hexa- netriol, ethanol, isopropanol, diethyl tart ate, butanediol, and mixtures thereof. Such solvent systems can also contain water. These compositions in solution form can be applied to the skin as is, or else can be formulated into an aerosol and applied to the skin as a spray-on. The aerosol compositions further com¬ prise from 25% to 80%, preferably from 30% to 50%, of a suitable propel1ant. Examples of such propel1ants are the- chlorinated, fluorinated and chlorofluorinated lower molecular weight hydro- • carbons. Nitrous oxide, carbon dioxide, butane, and propane are also used as propel1ant gases. These propel1ants are used at a level sufficient to expel the contents of the container. 4. Gels Gel compositions can be formulated by simply admixing a suitable thickening agent to the previously described solution compositions. Examples of suitable thickening agents have been previously described with respect to the lotions. The gelled compositions comprise an effective amount (pref¬ erably from about 0.001% to about 5%, more preferably from about 0.1% to about 1%) of a vanilloid compound; from 5% to 75%, preferably from 10% to 50%, of an organic solvent as previously described; from 0.5% to 20%, preferably from 1% to 10% of the thickening agent; the balance being water. 5. Solids Compositions of solid forms have use as stick-type composi- 5 tions intended for application to the lips or other parts of the body. Such compositions comprise an effective amount (preferably from about 0.001% to about 5%, more preferably from about 0.1% to about 1%) of a vanilloid compound, and from 50% to 98%, prefer¬ ably from 60% to 90%, of the previously described emollients. 10 This composition can further comprise from 1% to 20%, preferably from 5% to 15%, of a suitable thickening agent, and optionally emulsifiers and water. Thickening agents previously described with respect to lotions are suitable herein. Compositions used in the subject invention can be ad inis- 15 tered in a wide variety of vehicles, especially in the genital region. In addition to general skin treatment, infections in the genital area can be treated using vaginal, anal or uretheral suppositories; vaginal pessaries; vaginal or rectal tablets or inserts; catamenial and non-catamenial tampons; ointments; 20 enemas; cones; emulsions; and douches. Additives commonly found in topical compositions such as preservatives, e.g., methyl and ethyl-paraben, dyes and perfume can be included in any of the previously described topical compo¬ sitions. 25 Topical compositions of the subject invention preferably comprise from about 0.1% to about 5%, more preferably from about 0.2% to about 2%, more preferably still from about 0.5% to about 1% of a vanilloid compound, and from 0% to about 10%, more preferably from about 0.2% to about 5%, more preferably still 30 from about 0.5% to about 2% of a nucleoside antiviral compound. EXAMPLES The following non-limiting examples provide illustrations of various aspects of the subject invention. Topical compositions are formulated according to Examples " 1-14 by blending the listed ingredients according to conventional processes for making such compositions. 36 - 100 100 100 100 Example 15 After a lesion episode has subsided in a person having a genital Herpes simplex infection, one gram of the topical compo¬ sition of any of Examples 1, 3, 5, 7, 9, 11 or 13 is applied to the skin of the genital region for five consecutive days at the beginning of each month. The person also ingests a 500 mg capsule of acyclovir twice daily. The person remains free of the recurrence of Heroes simplex lesions. Example 16 After a lesion episode has subsided in a person having a genital Herpes simplex infection, two grams of the topical composition of any of Examples 2, 4, 6, 8, 10, 12 or 14 is applied to the skin of the genital region for three consecutive days every two weeks. The person remains free of the recurrence of Herpes simplex lesions. Example 17 After a lesion episode has subsided in a person having an oral Herpes simplex infection, one-half gram of the topical composition of any of Examples 1, 3, 5, 7, 9, 11 or 13 is applied to the skin of the oral region once a week. The person also ingests one 500 mg capsule of acyclovir daily. The person remains free of the recurrence of Heroes simplex lesions. Example 18 In addition to the post lesion episode dosing of Examples 15-17, the same dosage of each composition is applied or ingested during the lesion episode, resulting in a lesion episode of less severity and shorter duration. While particular embodiments of the subject invention have been described, it will be obvious to those skilled in the art that various changes and modifications to the methods and compo¬ sitions disclosed herein can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention. WHAT IS CLAIMED IS:

Claims: 1. The use of a vanilloid compound and the use of a nucleoside antiviral compound for the manufacture of separate or combined medicaments for treating or preventing lesion episodes due to Heroes infections in a human. 2. The use of Claim 1 characterized in that the vanilloid compound has the general structure: wherein: (a) n is 1; (b) -W-X- is selected from -C(0)NH- and -C(S)NH-, preferably -C(0)NH-, where either available bond of -W-X- is bonded to -R, the other being bonded to the benzyl carbom atom; (c) -R 1 is selected from -H,-0H and -CH 3 ; preferably -R 1 is -H; (d) -Z is selected from -H, -OH and -0CH 3 ; preferably from -OH and -0CH 3 ; more preferably -Z is -0CH 3 ; (e) -Y- is selected from -0-, -S- and -NH-; preferably -Y- is -0-; (f) -V is selected from -H, -CH 3 , and -CR 2 2 -CR 2 2 -NH 2 ; preferably from -H and -CH 2 -CHR 2 -NH 2 ; (g) -R 2 moieties are independently selected from hydrogen, halogen, lower alkyl, aryl, and carboxylate; or two -R 2 moieties are covalently bonded to form a substituted or unsubstituted alkyl, heteroalkyl, aryl, or heteroaryl ring having from about 3 to about 8 atoms in the ring including from 0 to about 3 heteroatoms; preferably from hydrogen and benzyl; and (h) -R is saturated or mono-, di- or tri- unsaturated C 6 -C 2 straight or branched chain alkyl; preferably unsubstituted, saturated C 6 -C X , especially C 7 -C X0 , or mono- or di-unsaturated with double bonds C 6 -C 24 , especially mono-unsaturated cis double bond C 8 -C X4 , straight chain alkyl. 3. The use of Claim 1 or 2 characterized in that the vanilloid compound is selected from 8-methyl-N-vanillyl-6-non- enamide; N-vanillylnonanamide; N-(9-decenyl)-4-hydroxy-3-methoxy- phenylacetamide; N-(9Z-dodecenyl)-4-hydroxy-3-methoxyphenylacet¬ amide; N-(9Z-tetradecenyl)-4-hydroxy-3-methoxyphenylacetamide; N-((4-hydroxy-3-methoxyphenyl)-methyl)-9-decenamide; N-((4-hy- droxy-3-methoxyphenyl)-methyl)-9Z-dodecenamide; N-((4-hydroxy- 3-methoxyphenyl)-methyl)-9Z-tetradecenamide and N-((4-(3-phenyl- 2(S)-2-amino-1-propoxy)-3-methoxyphenyl)-methyl)-nonanamide. 4. The use of Claim 1, 2 or 3 characterized in that the nucleoside antiviral compound is selected from acyclovir, ganciclovir, vidarabine, HOE-602, VSA-671, buciclovir, famci- clovir, penciclovir, HPMPA, PMEG, cyclobut-A, cyclobut-G, trifluridine, zidovudine, idoxuridine, edoxudine, BVRU, BVDU, YN-72, FEAU, FIAU, BW-41117U, HPMPC, aminopyrimidopyrimidine, and ribavirin; preferably from acyclovir, ganciclovir, vidarabine, trifluridine, zidovudine, idoxuridine, and ribavirin; more pre¬ ferably the nucleoside antiviral compound is acyclovir or ganci¬ clovi . 5. The use of Claim 1 characterized in that the nucleoside antiviral compound is acyclovir and the vanilloid compound is N-((4-hydroxy-3-methoxyphenyl)-methyl)-9Z-dodecenamide or N-(9Z- tetradecenyl)-4-hydroxy-3-methoxyphenylacetamide. 6. The use of Claim 1, 2, 3, 4 or 5 characterized in that from about 0.1 mg/kg/day to about 5 mg/kg/day of the vanilloid compound is administered, preferably topically, to the human between lesion episodes for from about 2 days to about 7 days, fro about weekly to about trimonthly, and from about 0.1 mg/kg/day to about 10 mg/kg/day of the nucleoside antiviral compound is administered, preferably orally, to the human daily. 7. A topical composition comprising a safe and effective amount of a vanilloid compound, a safe and effective amount of a nucleoside antiviral compound, and a pharmaceutically-acceptable topical carrier. 8. The composition of Claim 7 wherein the composition comprises: (a) from about 0.1% to about 5% of a vanilloid compound having the structure CH 2 -W-X-R & 0-V wherein -W-X- is -C(0)NH- or -NHC(O)-, -V is -H or -CH 3 or -CH 2 -CHR 2 -NH 2 , -R 2 is -H or benzyl, -Z is -0CH 3 or -OH, and -R is unsubstituted, saturated C 6 -C X4 or mono- or di-unsaturated with double bonds C 6 -C 24 straight chain alkyl ; and (b) from about 0.1% to about 10% of a nucleoside antiviral compound selected from acyclovir, ganciclovir, vidarabine, HOE-602, VSA-671, buciclovir, famciclovir, penciclovir, HPMPA, PMEG, cyclobut-A, cyclobut-G, trifluridine, zidovudine, idoxuridine, edoxudine, BVRU, BVDU, YN-72, FEAU, FIAU, BW-41117U, HPMPC, aminopyrimid¬ opyrimidine, and ribavirin, preferably from acyclovir and ganciclovir. 9. The composition of Claim 8 wherein the nucleoside antiviral compound is acyclovir and the vanilloid compound is N-((4-hydroxy-3-methoxyphenyl)-methyl)-9Z-dodecenamide or N-(9Z- tetradecenyl)-4-hydroxy-3-methoxyphenylacetamide or N-((4-(3- phenyl-2(S)-2-amino-l-propoxy)-3-methoxyphenyl)-methyl)-non- anamide. 10. A method of treating or preventing lesion episodes due to Herpes infections in a human comprising administering to the human a combination of a safe and effective amount of a vanilloid compound and a safe and effective amount of a nucleoside anti¬ viral compound. 11. The method of Claim 1 wherein the vanilloid compound has the general structure: wherein: (a) n is 1; (b) -W-X- is selected from the group consisting of -C(0)NH- and -C(S)NH-, where either available bond of -W-X- is bonded to -R, the other being bonded to the benzyl carbom atom; (c) -R 1 is selected from the group consisting of -H,-0H and -CH 3 ; (d) -Z is selected from the group consisting of -H, -OH and -0CH 3 ; (e) -Y- is selected from the group consisting of -0-, -S- and -NH-; (f) -V is selected from the group consisting of -H, -CH 3 , and -CR 2 2 -CR 2 2 -NH 2 ; (g) -R 2 moieties are independently selected from the group consisting of hydrogen, halogen, lower alkyl, aryl, and carboxylate; or two -R 2 moieties are covalently bonded to form a substituted or unsubstituted alkyl, hetero¬ alkyl, aryl, or heteroaryl ring having from about 3 to about 8 atoms in the ring including from 0 to about 3 heteroatoms; and (h) -R is saturated or mono-, di- or tri- unsaturated C 6 -C 2 straight or branched chain alkyl. 12. The method of Claim 2 wherein -R 1 is -H, -W-X- is -C(0)NH-, -Y- is -0-, -V is -H or -CH 3 or -CH 2 -CHR 2 -NH 2 , -R 2 is benzyl, -Z is -0CH 3 or -OH, and -R is unsubstituted, saturated C 6 -C 14 or mono- or di- unsaturated with double bonds C 6 -C 24 straight chain alkyl. 13. The method of Claim 3 wherein -V is -H or -CH 2 -CHR 2 -NH 2 , -R 2 is benzyl, -Z is -0CH 3 , and -R is saturated C 7 -C xo or mono-unsaturated, cis double bond, C 8 -C X4 . 14. The method of Claim 4 wherein the vanilloid compound is selected from the group consisting of 8-methyl-N-vanillyl-6-non- enamide; N-vanillylnonanamide; N-(9-decenyl)-4-hydroxy-3-methoxy- phenylacetamide; N-(9Z-dodecenyl)-4-hydroxy-3-methoxyphenylacet¬ amide; N-(9Z-tetradecenyl)-4-hydroxy-3-methoxyphenylacetamide; N-((4-hydroxy-3-methoxyphenyl)-methyl)-9-decenamide; N-((4- hydroxy-3-methoxyphenyl)-methyl)-9Z-dodecenamide; N-((4-hydroxy- 3-methoxyphenyl)-methyl)-9Z-tetradecenamide and N-((4-(3-phenyl- 2(S)-2-amino-l-propoxy)-3-methoxyphenyl)-methyl)-nonanamide. 15. The method of Claim 3 wherein the nucleoside antiviral compound is selected from the group consisting of acyclovir, ganciclovir, vidarabine, HOE-602, VSA-671, buciclovir, famci- clovir, penciclovir, HPMPA, PMEG, cyclobut-A, cyclobut-G, trifluridine, zidovudine, idoxuridine, edoxudine, BVRU, BVDU, YN-72, FEAU, FIAU, BW-41117U, HPMPC, aminopyrimidopyrimidine, and ribavirin. 16. The method of Claim 4 wherein the nucleoside antiviral compound is selected from the group consisting of acyclovir, ganciclovir, vidarabine, HOE-602, VSA-671, buciclovir, famci- clovir, penciclovir, HPMPA, PMEG, cyclobut-A, cyclobut-G, tri¬ fluridine, zidovudine, idoxuridine, edoxudine, BVRU, BVDU, YN-72, FEAU, FIAU, BW-41117U, HPMPC, aminopyrimidopyrimidine, and ribavirin. 17. The method of Claim 5 wherein the nucleoside antiviral compound is selected from the group consisting of acyclovir, ganciclovir, vidarabine, trifluridine, zidovudine, idoxuridine, and ribavirin. 18. The method of Claim 8 wherein the nucleoside antiviral compound is a acyclovir or ganciclovir. 19. The method of Claim 9 wherein the nucleoside antiviral compound is acyclovir and the vanilloid compound is N-((4-hydro- xy-3-methoxyphenyl)-methyl)-9Z-dodecenamide or N-(9Z-tetra- decenyl)-4-hydroxy-3-methoxyphenylacetamide. 20. The method of Claim 1, 3, 7, 8 or 10 wherein from about 0.1 mg/kg/day to about 5 mg/kg/day of the vanilloid compound is administered to the human between lesion episodes for from about 2 days to about 7 days, from about weekly to about trimonthly, and from about 0.1 mg/kg/day to about 10 mg/kg/day of the nucleo¬ side antiviral compound is administered to the human daily. 21. The method of Claim 1, 3, 7, 8 or 10 wherein from about 0.1 mg/kg/day to about 5 mg/kg/day of the vanilloid compound is administered topically to the human between lesion episodes to tissues where lesions are likely .to occur for from about 2 days to about 7 days at a frequency of from about weekly to about trimonthly, and from about 0.1 mg/kg/day to about 10 mg/kg/day of the nucleoside antiviral compound is administered perorally to the human daily.

Inventors: BRAND LARRY MILTON, FLOYD BENJAMIN FRANKLIN, O'NEILL TIMOTHY PETER, STANBERRY LAWRENCE RAYMOND, BRAND, LARRY, MILTON, FLOYD, BENJAMIN, FRANKLIN, O'NEILL, TIMOTHY, PETER, STANBERRY, LAWRENCE, RAYMOND
Applicants: PROCTER & GAMBLE, THE PROCTER & GAMBLE COMPANY
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P31