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(2) Patent Application Publication (10) Pub. No.: US 2011/0008471 A1 Ean (43) Pub US 2011 0008471A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2011/0008471 A1 Ean (43) Pub. Date: Jan. 13, 2011 (54) SYNERGISTIC ANTIPARASITIC Related U.S. Application Data COMPOSITIONS AND SCREENING METHODS (60) Provisional application No. 61/017,145, filed on Dec. 27, 2007, provisional application No. 61/017,157, (75) Inventor: Essam Ean, Nashville, CA (US) filed on Dec. 27, 2007, provisional application No. 61/018,879, filed on Jan. 3, 2008. Correspondence Address: DAVIS WRIGHT TREMAINE LLP - San Fran- Publication Classification cisco 505 MONTGOMERYSTREET, SUITE 800 (51) Int. Cl. SAN FRANCISCO, CA 94111 (US) AðIN 65/16 (2009.01) A0IP 5/06) (2006.01) (73) Assignee: TyraTech, Inc., Melbourne, FL A0IP 7/00 (2006.01) (US) A0IP 15/06) (2006.01) (21) Appl. No.: 12/810,811 (52) U.S. Cl. ........................................................ 424/725 (22) PCT Filed: Dec. 24, 2008 (57) ABSTRACT (86) PCT No.: PCT/US08/88342 Compositions for treating parasitic infections and methods of using the compositions to treat subjects with parasitic infec § 371 (c)(1), tions are provided. Methods of selecting compositions foruse (2), (4) Date: Sep. 29, 2010 in treating parasitic infections are further provided. 5 O 1 In Vivo Treatment Patent Application Publication Jan. 13, 2011 Sheet 1 of 14 US 2011/0008471 A1 100 3 90 5 80 C) > 70 9 KD 60 Cl 8: 50 8 J. 40 É 30 * 20 S$ 10 O In Vivo Treatment FIGURE 1 Patent Application Publication Jan. 13, 2011 Sheet 2 of 14 US 2011/0008471 A1 160 460 or . C. c 140 - 140 120 120 # 100 # 100 ". 3 g 80 • Sº E E 60 ~ - ~ 40 - `s 20 e ºss r 0 *===> m 1250 0 250 500 750 1000 1250 Concentration, ppm Concentration, ppm 160 160 140 140 - 120 120 F 109 | # 100 —s— Rx3 d 80 3 80 Y ... C. RX4 $2 HT \ -v- praziquantel E. 60 – 60 \ \ 40 40 20 20 0 T I I —r- i O r== 3 O 250 500 750 4000 1250 O 250 500 750 1000 1250 Concentration, ppm Concentration, ppm FIGURE 2 Patent Application Publication Jan. 13, 2011 Sheet 3 of 14 US 2011/0008471 A1 Compounds FIGURE 3 Patent Application Publication Jan. 13, 2011 Sheet 4 of 14 US 2011/0008471 A1 400 400 # control —º–~ control o Rx4 | 300 300 --~~~~~ Rx5 RX6 200 200 100 100 \ `s-s 0 | ----------------------> 0.0 0, f {}.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 (). 1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Concentration (%) Concentration (%) 400 300 200 1 OO 0.0 0 1 0.2 0.3 0.4 0.5 C.6 0.7 0.8 0.9 1.0 Concentration (%) FIGURE 4 Patent Application Publication Jan. 13, 2011 Sheet 6 of 14 US 2011/0008471 A1 Freshly slaughtered pig The compressorium Encysted T. spiralis larva in the muscle FIGURE 6 Patent Application Publication Jan. 13, 2011 Sheet 7 of 14 US 2011/0008471 A1 Relaxed T. spiralis larva FIGURE 7 Patent Application Publication Jan. 13, 2011 Sheet 8 of 14 US 2011/0008471 A1 Contracted T. spiralis larva with both anterior and posterior ends Contracted anterior end of T. spiralis larva FIGURE 8 Patent Application Publication Jan. 13, 2011 Sheet 9 of 14 US 2011/0008471 A1 250 200 150 | 100 50 - 1 ppm 10ppm 25ppm 50ppm 100ppm Concentration FIGURE 9 Patent Application Publication Jan. 13, 2011 Sheet 10 of 14 US 2011/0008471 A1 Small intestine full of A. suum FIGURE 10 Patent Application Publication Jan. 13, 2011 Sheet 11 of 14 US 2011/0008471 A1 Free A . Still Fºº Female worm w ith straight and tapering poster ior end FIGURE 11 Patent Application Publication Jan. 13, 2011 Sheet 12 of 14 US 2011/0008471 A1 The worms varies from 20-40 cm in length FIGURE 12 Patent Application Publication Jan. 13, 2011 Sheet 13 of 14 US 2011/0008471 A1 Relaxed adult worm FIGURE 13 Patent Application Publication Jan. 13, 2011 Sheet 14 of 14 US 2011/0008471 A1 | 1 ppm 10ppm 25ppm 50ppm 100ppm FHGURE 14 US 2011/0008471 A1 Jan. 13, 2011 SYNERGISTIC ANTIPARASITIC tures of a given embodiment is likewise exemplary. Such an COMPOSITIONS AND SCREENING embodiment can typically exist with or without the feature(s) METHODS mentioned; likewise, those features can be applied to other embodiments of the presently-disclosed subject matter, FIELD OF THE INVENTION whether listed in this Summary or not. To avoid excessive repetition, this Summary does not list or suggest all possible [0001] The presently-disclosed subject matter relates to combinations of such features. methods for treating parasitic infections and compositions [0008] The presently-disclosed subject matter includes useful for treating parasitic infections. It also relates to compositions and methods for treating parasitic infections, screening systems and methods for developing agents and and methods of screening for and selecting compositions compositions useful for treating parasitic infections useful for treating a parasitic infection. [0009] In some embodiments, the parasitic infections are BACKGROUND caused by parasites classified as endoparasites, ectoparasites, [0002] Parasitic infections of plants, humans, and other human parasites, animal parasites, or agricultural parasites. animals pose a worldwide problem. For example, more than [0010] In some embodiments, the composition for treating 650 million people are at risk for gastrointestinal parasitic a parasitic infection in a subject includes two or more com infection, and about 200 million are actually infected. Various pounds selected from: trans-anethole, para-cymene, linalool, conditions contribute to the development and spread of para Cº-pinene, and thymol. sitic infections, including poor sanitary conditions; low host [0011] In some embodiments, the composition includes resistance; population expansion; and inadequate control of two more compounds selected from: para-cymene, linalool, vectors and infection reservoirs. Cº-pinene, and thymol. In some embodiments, the composi [0003] Such parasitic infections present an abundance of tion includes three or more compounds selected from: para medical and social problems. For example, parasiticinfection cymene, linalool, Cº-pinene, and thymol. In some embodi can undermine child development, educational achievement, ments, the composition includes para-cymene, linalool, reproductive health, and social and economic development. Cº-pinene, and thymol. In some embodiments, the composi Indeed, some parasitic infections can cause morbidity and tion further includes soybean oil. mortality. Notwithstanding the severe impact that parasitic [0012] In some embodiments, the composition includes infections can have, relatively few treatment options are 25-35% by weight para-cymene, 1-10% by weight linalool, available. 1-10% by weight Cº-pinene, 35-45% by weight thymol, and [0004] Available treatments are limited, and treatments for 20-30% by weight soybean oil. In some embodiments, the some parasitic infections are non-existent. In the 1960s, composition includes 28.39% by weight para-cymene, 6.6%0 niclosamide (also known as yomesan) was identified for use by weight linalool, 3.8% by weight Cº-pinene, 37.2% by in treating certain helminthic parasitic infections; however, weight thymol, and 24% by weight soybean oil. niclosamide has certain drawbacks. For example, in many [0013] In some embodiments, the composition includes cases a single dose of niclosamide does not provide a curative 25-35% by volume para-cymene, 1-10% by volume linalool, effect, rather, a relapse ensues because the compound has 1-10% by volume o-pinene, 35-45% by volume thymol and difficulty accessing cysticercoids buried deeply within the 20-30% by volume soybean oil. In some embodiments, the mucosal villi. As such, satisfactory results require an composition includes 30% by volume para-cymene, 7% by extended treatment with niclosamide for approximately 7 volume linalool, 4%-by volume o-pinene, 35% by volume days. See Davis, Drug treatment of intestinal helminthiasis, thymol, and 24% by volume soybean oil. World Health Organization (WHO), Geneva, 1973. [0014] In some embodiments, the composition includes [0005] Another drug that has been used to treat helminthic three or more compounds selected from: trans-anethole, para parasitic infections is Praziquantel (2-(cyclohexylcarbonyl) cymene, linalool, Cº-pinene, and thymol. In some embodi 1,2,3,6,7,11b-hexahydro-4H-pyrazino(2,1-a)isoquinolin-4 ments, the composition includes four or more compounds one; also known as Biltracide). See Pearson and Gurrant, selected from: trans-anethole, para-cymene, linalool, Praziquantel: a major advance in anthelminthic therapy. Cº-pinene, and thymol. In some embodiments, the composi Annals of Internal Medicine, 99:195-198, 1983. Praziquantel tion includes trans-anethole, para-cymene, linalool, can be administered in a single dose; however, treatment Cº-pinene, and thymol. strategies making use of Praziquantel are at risk because of [0015] In some embodiments, the composition includes the possibility of the development of resistance to Praziquan 15-25% by weight trans-anethole, 30-40% by weight para tel. Accordingly, there remains a need in the art for non cymene, 1-10% by weight linalool, 1-10% by weight harmful compositions that are effective for treating parasitic o-pinene, and 35-45% by weight thymol. In some embodi infections. ments, the composition includes 18.2% by weight trans-anet hole, 34.4% by weight para-cymene, 4.7% by weightlinalool, SUMMARY 1.9% by weight o-pinene, and 40.8% by weight thymol. [0006] The presently-disclosed subject matter meets some [0016] In some embodiments, the composition includes or all of the above-identified needs, as will become evident to 10-20% by volume trans-anethole, 30-40% by volume para those of ordinary skill in the art after a study of the informa cymene, 1-10% by volume linalool, 1-10% by volume tion provided in this document.
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