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(12) Patent Application Publication (10) Pub. No.: US 2010/0056643 A1 Bachynsky Et Al US 2010.0056643A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0056643 A1 Bachynsky et al. (43) Pub. Date: Mar. 4, 2010 (54) CHEMICALLY INDUCED INTRACELLULAR (60) Provisional application No. 60/094.286, filed on Jul. HYPERTHERMA 27, 1998. (75) Inventors: Nicholas Bachynsky, Parkland, FL Publication Classification (US); Woodie Roy, Parkland, FL (US) (51) Int. Cl. A63L/045 (2006.01) Correspondence Address: (52) U.S. Cl. S14/728 FULBRIGHT & JAWORSKI, LLP ' ' " ' " 1301 MCKINNEY, SUITE 5100 HOUSTON, TX 77010-3095 (US) (57) ABSTRACT An invention relating to therapeutic pharmacological agents (73) Assignee: STUDE and methods to chemically induce intracellular hyperthermia PHARMACEUTICALS, INC. and/or free radicals for the diagnosis and treatment of infec tions, malignancy and other medical conditions. The inven (21) Appl. No.: 12/613,189 tion relates to a process and composition for the diagnosis or 1-1. killing of cancer cells and inactivation of Susceptible bacte (22) Filed: Nov. 5, 2009 rial, parasitic, fungal, and viral pathogens by chemically gen O O erating heat, and/or free radicals and/or hyperthermia-induc Related U.S. Application Data ible immunogenic determinants by using mitochondrial (63) Continuation of application No. 09/744,622, filed on uncoupling agents, especially 2,4 dinitrophenol and, their May 7, 2002, now Pat. No. 7,635,722, filed as appli conjugates, either alone or in combination with other drugs, cation No. PCT/US99/16940 on Jul. 27, 1999. hormones, cytokines and radiation. Patent Application Publication Mar. 4, 2010 Sheet 1 of 33 US 2010/0056643 A1 Glucose ATP-> A --> ADP Glucose 6-phosphate Fructose 6-phosphate ATP-O- v A --> ADP Fructose 1,6-phosphate Dihydroxyacetone phosphate 2 (Glyceraldehyde 3-phosphate) A -->4H 2 (1,3-Diphosphoylceric acid) 2ADP-- -> +2ATP 2 (3-Phosphoglyceric acid) 2 (2-Phosphoglyceric acid) A 2 (Phosphoenolpyruvic acid) 2ADP-> v A -> 2ATP 2 (Pyruvic acid) NET REACTION PER MOLECULE OF GLUCOSE: Glucose--2ADP+2PO4- 2 Pyruvic acid+2ATP+4H+HEAT FIG, Patent Application Publication Mar. 4, 2010 Sheet 2 of 33 US 2010/0056643 A1 O O CH3-C-COOH + CoA-SH -> CH3-C-S-CoA + CO2+2H+ (Pyruvic Acid) (Coenzyme A) (acetyl CoA) COAN NAD CO2 u \NADH Acetyl CoA Oxolocetote cis-Aconitote Iso-citrote Oxolosuccinote CO2 ox-Ketoglutarote Patent Application Publication Mar. 4, 2010 Sheet 3 of 33 US 2010/0056643 A1 +HZ+ZOZ/1 \deH+OZH AIxe|duoO oeuouoo?KOesop?xo 204 xe|duu00HOWNI Patent Application Publication Mar. 4, 2010 Sheet 4 of 33 US 2010/0056643 A1 (uo?oppo)4qwM-HOZH4H+Ø0%+HGYN(1) Patent Application Publication Mar. 4, 2010 Sheet 5 of 33 US 2010/0056643 A1 ELECTRIC POTENTIAL -------------- RESPIRATION LOW PROTON NADH 2H CONCENTRATION 2H H HIGH PROTON CONCENTRATION PHOSPHORYLATION FIG, 5 Patent Application Publication Mar. 4, 2010 Sheet 6 of 33 US 2010/0056643 A1 +HZ+ZOZ/1 ?uodsudu!9 [H]+H \Ompold Patent Application Publication Mar. 4, 2010 Sheet 7 of 33 US 2010/0056643 A1 pe?dnooun pe?dnoO OZH Patent Application Publication Mar. 4, 2010 Sheet 9 of 33 US 2010/0056643 A1 J9uuI euDuquueW Patent Application Publication Mar. 4, 2010 Sheet 10 of 33 US 2010/0056643 A1 a 4. 12 .9 On 2 1o F 5 's t 8 E 5 2 6 O S. 4 N 1 3 2 o O D 36 .38 40 4-2 4-4 4-6 48 5O f Temperature (C) FG, 8C O 20 40 60 80 1 OO Uncoupling (%) FIG. 8b. Patent Application Publication Mar. 4, 2010 Sheet 11 of 33 US 2010/0056643 A1 2 O O 1 5 O Stimulation 1 O O 5 O O O 3O 6O 9 O Time (min) FIG, 9 Patent Application Publication Mar. 4, 2010 Sheet 12 of 33 US 2010/0056643 A1 ZOO HOWN air - He ?soon19 Patent Application Publication Mar. 4, 2010 Sheet 13 of 33 US 2010/0056643 A1 10100109so 10 167 1d 16 1615: 162 Minimal uncoupler M} which stimulates swelling FIG. I Patent Application Publication Mar. 4, 2010 Sheet 14 of 33 US 2010/0056643 A1 eby goddeW Patent Application Publication Mar. 4, 2010 Sheet 15 of 33 US 2010/0056643 A1 Patent Application Publication Mar. 4, 2010 Sheet 16 of 33 US 2010/0056643 A1 O 15 3O 45 - 6O Patent Application Publication Mar. 4, 2010 Sheet 19 of 33 US 2010/0056643 A1 N Ch P O O3 - 9 at as a ro o2. 2a 2.a c CSas SCN, CNS CNS SC ) 3 O) to EO CO / .E CO W1 g L K;N * () N - O O O. O. O. O. O. eqoA Seo ueoue Patent Application Publication Mar. 4, 2010 Sheet 20 of 33 US 2010/0056643 A1 Patent Appl US 2010/0056643 A1 Patent Application Publication Mar. 4, 2010 Sheet 22 of 33 US 2010/0056643 A1 Patent Application Publication Mar. 4, 2010 Sheet 23 of 33 US 2010/0056643 A1 OO 8O SO 4O 2O O SO 6O 9 O 1 OO Days following tumor implantation FIG, 2O Patent Application Publication Mar. 4, 2010 Sheet 25 of 33 US 2010/0056643 A1 an 9, %O NC CN 9 p CO rt Ca O C O O O ? 9 N t) CN |DAlmuns upiS dol. 24 CN CN U2 l N O O y Dmlauns Aueoued Patent Application Publication Mar. 4, 2010 Sheet 26 of 33 US 2010/0056643 A1 s Patent Application Publication Mar. 4, 2010 Sheet 27 of 33 US 2010/0056643 A1 Patent Application Publication Mar. 4, 2010 Sheet 28 of 33 US 2010/0056643 A1 Patent Application Publication US 2010/0056643 A1 Patent Application Publication Mar. 4, 2010 Sheet 30 of 33 US 2010/0056643 A1 .S. E CNg o o sa CJ s vo2 S .S. C 2. O 2 Patent Application Publication Mar. 4, 2010 Sheet 31 of 33 US 2010/0056643 A1 Period copies/ml U/ (IU/L) o sex to 7s as "HCV-RNA - Roche polymerase chain reaction methodology "AST - aspartate aminotransferase *ALT-alanine aminotransferase FG, 29 Patent Application Publication Mar. 4, 2010 Sheet 33 of 33 US 2010/0056643 A1 US 2010/0056643 A1 Mar. 4, 2010 CHEMICALLY INDUCED INTRACELLULAR above the hypothalamic thermoregulatory set point and the HYPERTHERMIA physiologically intact body attempts to lower it's core tem perature back to the set point baseline. CROSS-REFERENCE TO RELATED 0005 Renewed clinical interest in hyperthermia has APPLICATIONS occurred over the past 35 years due to continued failure of 0001. This application claims benefit of priority to U.S. standard therapies to treat various forms of cancer and emerg provisional patent application Ser. No. 60/094.286, filed Jul. ing infections. Except for a few exceedingly rare forms of 27, 1998, which is hereby incorporated by reference in its cancer like childhood leukemias and testicular cancer or entirety. immune responsive infections, chemotherapy, radiation or drug therapy often do very little except briefly extend Sur FIELD OF INVENTION vival. One of the major obstacles to “cure” disseminated cancer and infections has been the innate or acquired resis 0002. This invention relates to therapeutic pharmacologi tance of tumor cells and emerging microbes to antibiotics, cal agents and methods to chemically induce intracellular drugs and treatments given in tolerable doses. Escalation of hyperthermia and/or free radicals for the diagnosis and treat treatments, or use of multiple drugs to overcome resistance is ment of infections, malignancy and other medical conditions. invariably prevented by concomitant toxicities or develop This invention further relates to a process and composition for ment of multi-drug resistance. Further, in contrast to drugs, the diagnosis or killing of cancer cells and inactivation of which represent a single molecular species that biochemi susceptible bacterial, parasitic, fungal, and viral pathogens by cally interact with specific enzymes or receptors of viruses, chemically generating heat, free radicals and hyperthermia prokaryotes and eukaryotes, the action of hyperthermia is inducible immunogenic determinants. Such pathogens, biophysical and global. Hyperthermia has no specific heat infected or transformed cells are inactivated or killed without receptors. Therefore, the possibility of a point mutation caus irreparable injury to non-transformed, uninfected, normal ing a functional change in a receptor and conferring resis cells. More specifically, this invention relates to the diagnosis tance to hyperthermia is unlikely, and would be equivalent to and treatment of cancer; treatment of AIDS; and, other dis the development of resistance to the in vitro process of Pas eases and conditions using mitochondrial uncoupling agents, teurization. Among pathogenic bacteria, it has been reported especially 2,4 dinitrophenol and, their conjugates, either that only one variant in 1x10° cells of an original population alone or in combination with other drugs, hormones, cytok is resistant to hyperthermia. ines and radiation. 0006 Hyperthermia has been used alone or in conjunction with radiation and chemotherapy in the treatment of a variety GENERAL BACKGROUND ofmalignancies. Overgaard et al., reported that a combination 0003. Local heat, systemic hyperthermia and fever of heat and radiation results in complete control of twice as therapy have been empirically used as effective treatments for many melanoma lesions compared to radiation alone. Maeda, malignant, infectious and other diseases since antiquity. M. Watanabe, N. et al., published in Gastroenterologia Therapeutic hyperthermia was first documented in the Edwin Japonica, that hyperthermia with tumor necrosis factor Smith surgical papyrus in the 17th century B.C. Coley's toxin resulted in successful treatment of hepatocellular carcinoma. extracts of Streptococcus erysipelatis (group A streptococ Prospective randomized studies of hyperthermia combined cus) and Bacillus prodigiosus (Serratia marcescens) were with chemoradiotherapy for esophageal carcinoma demon used to induce fever for the treatment of patients with strated the cumulative three year survival rates to be more advanced cancer.
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