On The Mechanisms Of Toxicity Of Chlorine Oxides Against Malarial Parasites - An Overview

By Thomas Lee Hesselink, MD
Copyright September 6, 2007

ABSTRACT

Sodium chlorite (NaClO2) can be acidified as a convenient method to produce chlorine dioxide (ClO2) which is a strong oxidant and a potent disinfectant. A protocol has been developed whereby a solution of these compounds can be taken orally. This procedure rapidly eliminates malaria and other infectious agents in only one dose. Chlorine dioxide (ClO2) is highly reactive with thiols, polyamines, purines, certain amino acids and iron, all of which are necessary for the growth and survival of pathogenic microbes. Properly dosed this new treatment is tolerable orally with only transient side effects. More research to better document efficacy in malaria and in other infections is urgently called for.

DISCOVERY

Jim Humble, a modern gold prospecting geologist, needed to travel to malaria infested areas numerous times. He or his coworkers would on occassion contract malaria. At times access to modern medical treatment was absolutely unavailable. Under such dire circumstances it was found that a solution useful to sanitize drinking water was also effective to treat malaria if diluted and taken orally. [1a] Despite no formal medical training Mr. Humble had the innate wisdom to experiment with various dosage and administration techniques. Out of such necessity was invented an easy to use treatment for malaria which was found rapidly effective in almost all cases. [1b,1c]

References:

1a. Water disinfection for international and 
wilderness travelers. 
Backer H 
Clin Infect Dis. 2002 Feb 1;34(3):355-64 

1b. A Possible Solution to the Malaria Problem?
Humble J 
Libertarian Times, May 9, 2005 

1c. The Miracle Mineral Supplement of the 21st Century. 
Humble JV 
www.miraclemineral.org, 2nd Edition (2007)

MATERIALS AND METHODS

The procedure as used by Mr. Humble follows: A 28% stock solution of 80% (technical grade) sodium chlorite (NaClO2) is prepared. The remaining 20% is a mixture of the usual excipients necessary in the manufacture and stabilization of sodium chlorite powder or flake. Such are mostly sodium chloride (NaCl) ~19%, sodium hydroxide (NaOH) <1%, and sodium chlorate (NaClO3) <1%. The actual sodium chlorite present is therefore 22.4%. Using a medium caliber dropper (25 drops per cc), the usual administered dose per treatment is 6 to 15 drops. In terms of milligrams of sodium chlorite, this calculates out to 9mg per drop or 54mg to 135mg per treatment. Effectiveness is enhanced, if prior to administration the selected drops are premixed with 2.5 to 5 cc of table vinegar or lime juice or 5-10% citric acid and allowed to react for 3 minutes. The resultant solution is always mixed into a glass of water or apple juice and taken orally. The carboxylic acids neutralize the sodium hydroxide and at the same time convert a small portion of the chlorite (ClO2-) to its conjugate acid known as chlorous acid (HClO2). Under such conditions the chlorous acid will oxidize other chlorite anions and gradually produce chlorine dioxide (ClO2). Chlorine dioxide appears in solution as a yellow tint which smells exactly like elemental chlorine (Cl2). The above described procedure can be repeated a few hours later if necessary. Considerably lower dosing should be applied in children or in emaciated individuals scaled down according to size or weight. The diluted solution can be taken without food to enhance effectiveness but this often causes nausea. Drinking extra water usually relieves this. Nausea is less likely to occur if food is present in the stomach. Starchy food is preferable to protein as protein quenches chlorine dioxide. Significant amounts of vitamin C (ascorbic acid) must not be present at any point in the mixtures or else this will quench the chlorine dioxide (ClO2) and render it ineffective. For the same reason antioxidant supplements should not be taken on the day of treatment. Other side effects reported are transient vomiting, diarrhea, headache, dizziness, lethargy or malaise. [2a,2b]

References:

2a. The Miracle Mineral Supplement of the 21st Century. 
Humble JV 
www.miraclemineral.org, 2nd Edition (2007) 

2b. personal communications from Mr. Jim Humble 2007

EXPLORING BENEFITS

I first learned of Jim Humble's remarkable discovery in the fall of 2006. That sodium chlorite or chlorine dioxide could kill parasites in vivo seemed immediately reasonable to me at the onset. It is well known that many disease causing organisms are sensitive to oxidants. Various compounds classifiable as oxides of chlorine such as sodium hypochlorite and chlorine dioxide are already widely used as disinfectants. What is novel and exciting here is that Mr. Humble's technique seems: 1) easy to use, 2) rapidly acting, 3) successful, 4) apparently lacking in toxicity, and 5) affordable. If this treatment continues to prove effective, it could be used to help rid the world of one of the most devasting of all known plagues. [3a,3b,3c,3d,3e] Especially moving in me is the empathy I feel for anyone with a debilitating febrile illness. I cannot forget how horrible I feel whenever I have caught influenza. How much more miserable it must be to suffer like that again and again every 2 to 3 days as happens in malaria. Millions of people suffer this way year round. 1 to 3 million die from malaria every year mostly children. Thus motivated I sought to learn all I could about the chemistry of the oxides of chlorine. [4a-4hh] I wanted to understand their probable mechanisms of toxicity towards the causative agents of malaria (Plasmodium species). I wanted to check available literature pertaining to issues of safety or risk in human use.

References:

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4v. General-Acid-Catalyzed Reactions of Hypochlorous Acid 
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Zhongjiang Jia, Dale W. Margerum,* and Joseph S. Francisco 
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Indiana 47907 Received December 28, 1999 

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4bb. General-acid-catalyzed reactions of hypochlorous acid 
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OXIDANTS AS PHYSIOLOGIC AGENTS

Oxidants are atoms or molecules which take up electrons. Reductants are atoms or molecules which donate electrons to oxidants. I was already very familiar with most of the medicinally useful oxidants. I had taught at numerous seminars on their use and explained their mechanisms of action on the biochemical level. Examples are: hydrogen peroxide, zinc peroxide, various quinones, various glyoxals, ozone, ultraviolet light, hyperbaric oxygen, benzoyl peroxide, anodes, artemisinin, methylene blue, allicin, iodine and permanganate. Some work has been done using dilute solutions of sodium chlorite internally to treat fungal infections, chronic fatigue, and cancer; however, little has been published in that regard. [5a-5h]

Low dose oxidant exposure to living red blood cells induces a change in oxyhemoglobin (Hb-O2) activity so that more oxygen (O2) is released to tissues throughout the body. [6a-6d] Hyperbaric oxygenation (oxygen under pressure) is: 1) a powerful detoxifier against carbon monoxide; 2) a powerful support for natural healing in burns, crush injuries, and ischemic strokes; and 3) an effective aid to treat most bacterial infections. [7a-7d]

Taken internally, intermittently and in low doses many oxidants have been found to be powerful immune stimulants. Sodium chlorite acidified with lactic acid as in the product "WF10" has similarly been shown to modulate immune activation. Exposure of live blood to ultraviolet light also has immune enhancing effects. These treatments work through a natural physiologic trigger mechanism, which induces peripheral white blood cells to express and to release cytokines. These cytokines serve as a control system to down-regulate allergic reactions and as an alarm system to increase cellular attack against pathogens. [8a-8v]

Activated cells of the immune system naturally produce strong oxidants as part of the inflammatory process at sites of infection or cancer to rid the body of these diseases. Examples are: superoxide (*OO-), hydrogen peroxide (H2O2), hydroxyl radical (HO*), singlet oxygen (O=O) and ozone (O3). [9a-9v] Another is peroxynitrate (-OONO) the coupled product of superoxide (*OO-) and nitric oxide (*NO) radicals. [10a-10h] Yet another is hypochlorous acid (HOCl) the conjugate acid of sodium hypochlorite (NaClO). [11a,11b,11c] The immune system uses these oxidants to attack various parasites. [12a,12b,12c]

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Biochim Biophys Acta. 1968 Feb 1;156(1):168-78

OXIDES OF CHLORINE AS DISINFECTANTS

All bacteria have been shown to be incabable of growing in any medium in which the oxidants (electron grabbers) out- number the reductants (electron donors). [13a] Therefore, oxidants are at least bacteriostatic and at most are bacteriocidal. [13b] Many oxidants have been proven useful as antibacterial disinfectants. [13c,13d] Hypochlorites (ClO-) are commonly used as bleaching agents, as swimming pool sanitizers, and as disinfectants. At low concentrations chlorine dioxide (ClO2) has been shown to kill many types of bacteria [14a-14j], viruses [15a-15L] and protozoa [16a-16f]. Ozone (O3) or chlorine dioxide (ClO2) are often used to disinfect public water supplies or to sanitize and deodorize waste water. [17a-17L] Sodium chlorite (NaClO2) or chlorine dioxide (ClO2) solutions are used in certain mouth washes to clear mouth odors and oral bacteria. [18a-18i] Chlorine dioxide sanitizes food preparation facilities. [19a] Acidified sodium chlorite is FDA approved as a spray in the meat packing industry to sanitized meat. [20a-20g] This can also be used to sanitize vegetables and other foods. [21a,21b] Farmers use this to cleanse the udders of cows to prevent mastitis, [22a,22b,22c] or to rid eggs of pathogenic bacteria. Chlorine dioxide can be used to disinfect endoscopes. [23a] Oxidants such as iodine, various peroxides, permanganate and chlorine dioxide can be applied topically to the skin to treat infections caused by bacteria or fungi. [24a-24d]

References:

13a. Oxidation-Reduction Potentials In Bacteriology And 
Biochemistry. 
L F Hewitt, 6th Ed, E. & S. Livingston Ltd., 1950 

13b. Role of Oxidants in Microbial Pathophysiology. 
R A Miller, B E Britigan 
Clinical Microbiology Reviews, 10(1):1-18, Jan 1997 

13c. Antiseptics and Disinfectants: Activity, Action and Resistance. 
by G McDonnell & A D Russell 
Clinical Microbiology Reviews, pp 147-179, Jan 1999 

13d. Treatment with oxidizing agents damages the inner 
membrane of spores of Bacillus subtilis and sensitizes 
spores to subsequent stress.
Cortezzo DE, Koziol-Dube K, Setlow B, Setlow P 
J Appl Microbiol. 2004;97(4):838-52 

14a. Mechanisms of killing of Bacillus subtilis spores 
by hypochlorite and chlorine dioxide.
Young SB, Setlow P.
J Appl Microbiol. 2003;95(1):54-67

14b. Inactivation of bacteria by Purogene.
Harakeh S, Illescas A, Matin A.
J Appl Bacteriol. 1988 May;64(5):459-63

14c. The inhibitory effect of Alcide, an antimicrobial drug, 
on protein synthesis in Escherichia coli.
Scatina J, Abdel-Rahman MS, Goldman E.
J Appl Toxicol. 1985 Dec;5(6):388-94 

14d. Bactericidal properties of chlorine dioxide. 
Ridenour GM, Ingols RS 
J Am Water Works Assn, 1947 39:561-567 

14e. Bactericidal effects of chlorine dioxide. 
Ridenour GM, Armbruster EH 
J Am Water Works Assn, 1949 41:537-550 

14f. Sporicidal properties of chlorine dioxide. 
Ridenour GM, Ingols RS, Armbruster EH 
Water & Sewage Works, 1949 96(8):1 

14g. Efficacy of chlorine dioxide as a bacteriocide. 
Bernarde MA, Isreal BM, Olivieri VP, Granstrom ML 
Appl Microbiol, 1965, 13(5):776-780 

14h. Kinetics and mechanism of bacterial disinfection 
by chlorine dioxide. 
Bernarde MA, Snow WB, Olivieri VP, Davidson B 
Appl Microbiol, 1967, 15(2):257-265 

14i. Alternative Disinfectants and Oxidants 
EPA Guidance Manual, April 1999, 
4.4 Pathogen Inactivation and Disinfection Efficacy, 
pp 4-15 to 4-22 

14j. Evaluation of ultrasonic scaling unit waterline 
contamination after use of chlorine dioxide mouthrinse 
lavage. 
Wirthlin MR, Marshall GW JR 
J Periodontol. 2001 Mar;72(3):401-10 

15a. Degradation of the Poliovirus 1 genome 
by chlorine dioxide. 
Simonet J, Gantzer C 
J Appl Microbiol. 2006 Apr;100(4):862-70 

15b. Inactivation of enteric adenovirus and feline 
calicivirus by chlorine dioxide. 
Thurston-Enriquez JA, Haas CN, Jacangelo J, Gerba CP 
Appl Environ Microbiol. 2005 Jun;71(6):3100-5 

15c. Mechanisms of inactivation of hepatitis A virus 
in water by chlorine dioxide. 
Li JW, Xin ZT, Wang XW, Zheng JL, Chao FH 
Water Res. 2004 Mar;38(6):1514-9 

15d. Virucidal efficacy of four new disinfectants. 
Eleraky NZ, Potgieter LN, Kennedy MA 
J Am Anim Hosp Assoc. 2002 May-Jun;38(3):231-4 

15e. Chlorine dioxide sterilization of red blood cells 
for transfusion, additional studies. 
Rubinstein A, Chanh T, Rubinstein DB. 
Int Conf AIDS. 1994 Aug 7-12; 10: 235 (abstract no. PB0953). 
U.S.C. School of Medicine, Los Angeles 

15f. Inactivation of human immunodeficiency virus by a 
medical waste disposal process using chlorine dioxide. 
Farr RW, Walton C 
Infect Control Hosp Epidemiol. 1993 Sep;14(9):527-9 

15g. Inactivation of human and simian rotaviruses 
by chlorine dioxide. 
Chen YS, Vaughn JM 
Appl Environ Microbiol. 1990 May;56(5):1363-6 

15h. Disinfecting capabilities of oxychlorine compounds. 
Noss CI, Olivieri VP 
Appl Environ Microbiol. 1985 Nov;50(5):1162-4 

15i. Mechanisms of inactivation of poliovirus 
by chlorine dioxide and iodine. 
Alvarez ME, O'Brien RT 
Appl Environ Microbiol. 1982 Nov;44(5):1064-71 

15j. A comparison of the virucidal properties of chlorine, 
chlorine dioxide, bromine chloride and iodine. 
Taylor GR, Butler M 
J Hyg (Lond). 1982 Oct;89(2):321-8 

15k. Inactivation of Poliomyelitis Virus by "Free" Chlorine. 
Ridennour GM, Ingols RS 
Am J Pub Health, 1946, 36(6):639 

15L. Alternative Disinfectants and Oxidants 
EPA Guidance Manual, April 1999, 
4.4 Pathogen Inactivation and Disinfection Efficacy, 
pp 4-15 to 4-22 

16a. Alternative Disinfectants and Oxidants 
EPA Guidance Manual, April 1999, 
4.4 Pathogen Inactivation and Disinfection Efficacy, 
pp 4-15 to 4-22 

16b. Cysticidal effect of chlorine dioxide on Giardia 
intestinalis cysts.
Winiecka-Krusnell J, Linder E 
Acta Trop. 1998 Jul 30;70(3):369-72 

16c. Effects of ozone, chlorine dioxide, chlorine, and 
monochloramine on Cryptosporidium parvum oocyst viability.
Korich DG, Mead JR, Madore MS, Sinclair NA, Sterling CR 
Appl Environ Microbiol. 1990 May;56(5):1423-8 

16d. The effect of 'Alcide' on 4 strains of rodent 
coccidial oocysts. 
Owen DG 
Lab Anim. 1983 Oct;17(4):267-9 

16e. Water Treatment and Pathogen Control - 
Process Efficiency in Achieving Safe Drinking Water. 
LeChevallier MW, Au KK 
Section 3.3.3 Chlorine dioxide pp 52-54 
World Health Organization, IWA Publishing, 2004 

16f. Sequential inactivation of Cryptosporidium parvum 
oocysts with chlorine dioxide followed by free chlorine 
or monochloramine. 
Corona-Vasquez B, Rennecker JL, Driedger AM, Mariñas BJ 
Water Res. 2002 Jan;36(1):178-88

17a. Disinfectant efficacy of chlorite and 
chlorine dioxide in drinking water biofilms.
Gagnon GA, Rand JL, O'leary KC, Rygel AC, Chauret C, Andrews RC 
Water Research, 39(9):1809-17, May 2005 

17b. Pure Water Handbook. 
Osmonics, Inc. Minnetonka, Minnesota 

17c. Use Of Chlorine Dioxide In Water And Wastewater Treatment. 
Sussman S, Rauh JS pp 344-355 in: 
Ozone/Chlorine Dioxide Oxidation Products of Organic Materials. 
Rice RG, Cotruvo JA editors, 
International Ozone Institute & USEPA, 
Ozone Press International, 1978 

17d. Disinfection: Water and Wastewater. 
Johnson JD 
Ann Arbor Science Publishers, Inc. 1975 

17e. Chlorine dioxide in potable water treatment. 
Dowling LT 
Water Treat. & Exam. 1974, 23:190-204 

17f. Generation and use of chlorine dioxide in water treatment. 
Granstrom ML, Lee GF 
J Am Water Works Assn, 1958, 50:1453-1466 

17g. Use of chlorine dioxide to disinfect water supplies. 
Augenstein HW 
J Am Water Works Assn, 1974, 66(12):716-717 

17h. Water Treatment and Pathogen Control - 
Process Efficiency in Achieving Safe Drinking Water. 
LeChevallier MW, Au KK 
Section 3.3.3 Chlorine dioxide pp 52-54 
World Health Organization, IWA Publishing, 2004 

17i. Matching odour treatment processes to odour resources. 
Jeavons J, Hodgson P, Upton J 
Water Science and Technology, 2000, 41(9):227-232 

17j. The effect of predisinfection with chlorine dioxide 
on the formation of haloacetic acids and trihalomethanes 
in a drinking water supply. 
Harris CL 
Thesis submitted to Virginia Polytechnic Institute and 
State University, July 27,2001 

17k. Effect of pH and temperature on the kinetics 
of odor oxidation using chlorine dioxide. 
Kastner JR, Das KC, Hu C, McClendon R 
J Air Waste Manag Assoc. 2003 Oct;53(10):1218-24 

17L. Development of chlorine dioxide-related by-product 
models for drinking water treatment. 
Korn C, Andrew RC, Escobar MD 
Water Res. 2002 Jan;36(1):330-42 

18a. Cadaverine as a putative component of oral malodor. 
Goldberg S, Kozlovsky A, Gordon D, Gelernter I, 
Sintov A, Rosenberg M 
J Dent Res. 1994 Jun;73(6):1168-72 

18b. A multifactorial investigation of the ability of oral 
health care products (OHCPs) to alleviate oral malodour. 
Silwood CJ, Grootveld MC, Lynch E 
J Clin Periodontol. 2001 Jul;28(7):634-41 

18c. Use of 0.1% chlorine dioxide to inhibit the formation 
of morning volatile sulphur compounds (VSC). 
Peruzzo DC, Jandiroba PF, Nogueira Filho Gda R 
Braz Oral Res. 2007 Jan-Mar;21(1):70-4 

18d. Use of chlorine dioxide mouthrinse 
as the ultrasonic scaling lavage reduces 
the viable bacteria in the generated aerosols. 
Wirthlin MR, Choi JH, Kye SB 
J West Soc Periodontol Periodontal Abstr. 2006;54(2):35-44 

18e. Use of a novel group of oral malodor measurements 
to evaluate an anti-oral malodor mouthrinse (TriOralTM) 
in humans. 
Codipilly DP, Kaufman HW, Kleinberg I 
J Clin Dent. 2004;15(4):98-104 

18f. The clinical and microbiological effects of a novel 
acidified sodium chlorite mouthrinse on oral bacterial 
mucosal infections. 
Fernandes-Naglik L, Downes J, Shirlaw P, Wilson R, 
Challacombe SJ, Kemp GK, Wade WG 
Oral Dis. 2001 Sep;7(5):276-80 

18g. Efficacy of a chlorine dioxide-containing 
mouthrinse in oral malodor. 
Frascella J, Gilbert RD, Fernandez P, Hendler J 
Compend Contin Educ Dent. 2000 Mar;
21(3):241-4, 246, 248 passim; quiz 256 

18h. Odor reduction potential 
of a chlorine dioxide mouthrinse. 
Frascella J, Gilbert R, Fernandez P 
J Clin Dent. 1998;9(2):39-42 

18i. Use of a metastabilized chlorous acid/chlorine dioxide 
formulation as a mouthrinse for plaque reduction. 
Goultschin J, Green J, Machtei E, Stabholz A, Brayer L, 
Schwartz Z, Sela MN, Soskolne A 
Isr J Dent Sci. 1989 Oct;2(3):142-7 

19a. Use of chlorine dioxide for cannery sanitation and 
water conservation. 
Welch JL, Folinazzo JF 
Food Technology, 1959, 13(3):179-182 

20a. Effects of Carcass Washing Systems on Campylobacter 
Contamination in Large Broiler Processing Plants 
by M P Bashor, 
Masters Thesis, North Carolina State University, Dec 2002  

20b. Research Project Outline #4111, 
by C N Cutter, Penn State Univ, Nov 2005 

20c. Validation of the use of organic acids and acidified 
sodium chlorite to reduce Escherichia coli O157 and 
Salmonella typhimurium in beef trim and ground beef 
in a simulated processing environment.
by Harris K, Miller MF, Loneragan GH, Brashears MM.
J Food Prot. 69(8):1802-7, Aug 2006 
								
20d. Decreased dosage of acidified sodium chlorite reduces 
microbial contamination and maintains organoleptic 
qualities of ground beef products.
Bosilevac JM, Shackelford SD, Fahle R, Biela T, Koohmaraie M.
J Food Prot. 2004 Oct;67(10):2248-54

20e. The Evaluation of Antimicrobial Treatments for 
Poultry Carcasses 
European Commission Health & Consumer Protection Directorate-
General, April 2003 

20f. Determination of chlorate and chlorite and mutagenicity 
of seafood treated with aqueous chlorine dioxide. 
Kim J, Marshall MR, Du WX, Otwell WS, Wei CI 
J Agric Food Chem. 1999 Sep;47(9):3586-91 

20g. Acidified sodium chlorite solutions. 
Food and Drug Administration, HHS, pp143-144, 
Section 173.325, 21CFR Ch.1 (4-1-07 Edition) 

21a. Review - Application of Acidified Sodium Chlorite 
to Improve the Food Hygiene of Lightly Fermented Vegetables. 
by Y Inatsu, L Bari, S Kawamoto 
JARC 41(1 , pp 17-23, 2007 

21b. Reactions of aqueous chlorine and chlorine dioxide 
with model food compounds. 
Fukayama MY, Tan H, Wheeler WB, Wei CI 
Environ Health Perspect. 1986 Nov;69:267-74 

22a. Efficacy of Two Barrier Teat Dips Containing Chlorous 
Acid Germicides Against Experimental Challenge ... 
by R L Boddie, S C Nickerson, G K Kemp 
Journal of Dairy Science, 77 (10):3192-3197, 1994 

22b. Evaluation of a Chlorous Experimental and Natural Acid 
Chlorine Dioxide Teat Dip Under Experimental and Natural 
Exposure Conditions 
by P A Drechsler, E E Wildman, J W Pankey 
Journal of Dairy Science, 73 (8):2121, 1990 

22c. Preventing Bovine Mastitis by a Postmilking Teat 
Disinfectant Containing Acidified Sodium Chlorite
by J E Hillerton, J Cooper, J Morelli 
Journal of Dairy Science, 90:1201-1208, 2007 

23a. Endoscope disinfection using chlorine dioxide 
in an automated washer-disinfector. 
Isomoto H, Urata M, Kawazoe K, Matsuda J, Nishi Y, Wada 
A, Ohnita K, Hirakata Y, Matsuo N, Inoue K, Hirayama T, 
Kamihira S, Kohno S 
J Hosp Infect. 2006 Jul;63(3):298-305 

24a. Clinical and microbiological efficacy of chlorine dioxide 
in the management of chronic atrophic candidiasis: an open study.
Mohammad AR, Giannini PJ, Preshaw PM, Alliger H.
Int Dent J. 2004 Jun;54(3):154-8 

24b. Using a chlorine dioxide antibacterial gel 
for soft tissue healing. 
Babad MS 
Dent Today. 1999 Jun;18(6):88-9 

24c. Subchronic dermal toxicity studies 
of Alcide Allay gel and liquid in rabbits. 
Abdel-Rahman MS, Skowronski GA, Turkall RM, Gerges SE, 
Kadry AR, Abu-Hadeed AH 
J Appl Toxicol. 1987 Oct;7(5):327-33 

24d. Pharmacodynamics of alcide, a new antimicrobial 
compound, in rat and rabbit. 
Scatina J, Abdel-Rahman MS, Gerges SE, Khan MY, Gona O 
Fundam Appl Toxicol. 1984 Jun;4(3 Pt 1):479-84

MALARIA IS OXIDANT SENSITIVE

From November 2006 through May of 2007 I spent hundreds of hours searching biochemical literature and medical literature pertaining to the biochemistry of Plasmodia. Four species are commonly pathogenic in humans namely: Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale and Plasmodium malariae. What I found was an abundance of confirmation that, just like bacteria, Plasmodia are indeed quite sensitive to oxidants. [25a-25p]. Examples of oxidants toxic to Plasmodia include: artemisinin, artemether [26a-26n], t-butyl hydroperoxide [27a], xanthone [28a], various quinones [29a-29m] (e.g. atovaquone, lapachol, beta-lapachone, menadione) and methylene blue [30a-30i].

References:

25a. Double-drug development against antioxidant enzymes 
from Plasmodium falciparum. 
Biot C, Dessolin J, Grellier P, Davioud-Charvet E 
Redox Rep. 2003;8(5):280-3 

25b. Oxidative stress and antioxidant defenses: 
a target for the treatment of diseases caused 
by parasitic protozoa. 
Turrens JF 
Mol Aspects Med. 2004 Feb-Apr;25(1-2):211-20 

25c. Vampires, Pasteur and reactive oxygen species. 
Is the switch from aerobic to anaerobic metabolism 
a preventive antioxidant defence in blood-feeding 
parasites? 
Oliveira PL, Oliveira MF 
FEBS Lett. 2002 Aug 14;525(1-3):3-6 

25d. The role of cell-mediated immune responses 
in resistance to malaria, with special reference 
to oxidant stress. 
Allison AC, Eugui EM 
Annu Rev Immunol. 1983;1:361-92 

25e. Thalassaemia trait, red blood cell age and oxidant 
stress: effects on Plasmodium falciparum growth and 
sensitivity to artemisinin. 
Senok AC, Nelson EA, Li K, Oppenheimer SJ 
Trans R Soc Trop Med Hyg. 1997 Sep-Oct;91(5):585-9 

25f. Antiplasmodial activity of nitroaromatic and 
quinoidal compounds: redox potential vs. inhibition 
of erythrocyte glutathione reductase. 
Grellier P, Sarlauskas J, Anusevicius Z, Maroziene A, 
Houee-Levin C, Schrevel J, Cenas N 
Arch Biochem Biophys. 2001 Sep 15;393(2):199-206 

25g. Reactive oxygen and nitrogen intermediates and 
products from polyamine degradation are Babesiacidal 
in vitro.
Johnson WC, Cluff CW, Goff WL, Wyatt CR 
Ann N Y Acad Sci. 1996 Jul 23;791:136-47 

25h. Amine peroxides as potential antimalarials. 
Vennerstrom JL 
J Med Chem. 1989 Jan;32(1):64-7 

25i. Thalassaemia trait, red blood cell age and oxidant 
stress: effects on Plasmodium falciparum growth and 
sensitivity to artemisinin. 
Senok AC, Nelson EA, Li K, Oppenheimer SJ 
Trans R Soc Trop Med Hyg. 1997 Sep-Oct;91(5):585-9 

25j. Protection against murine cerebral malaria 
by dietary-induced oxidative stress. 
Levander OA, Fontela R, Morris VC, Ager AL Jr 
J Parasitol. 1995 Feb;81(1):99-103 

25k. Antioxidant defense mechanisms in parasitic protozoa. 
Mehlotra RK 
Crit Rev Microbiol. 1996;22(4):295-314 

25L. Killing of Plasmodium yoelii by enzyme-induced 
products of the oxidative burst. 
Dockrell HM, Playfair JH 
Infect Immun. 1984 Feb;43(2):451-6 

25m. Toxicity of certain products of lipid peroxidation 
to the human malaria parasite Plasmodium falciparum. 
Clark IA, Butcher GA, Buffinton GD, Hunt NH, Cowden WB 
Biochem Pharmacol. 1987 Feb 15;36(4):543-6 

25n. Oxidative stress and malaria-infected erythrocytes. 
Mishra NC, Kabilan L, Sharma A 
Indian J Malariol. 1994 Jun;31(2):77-87 

25o. Killing of blood-stage murine malaria parasites 
by hydrogen peroxide. 
Dockrell HM, Playfair JH 
Infect Immun. 1983 Jan;39(1):456-9 

25p. Evidence for reactive oxygen intermediates 
causing hemolysis and parasite death in malaria. 
Clark IA, Hunt NH 
Infect Immun. 1983 Jan;39(1):1-6 

26a. Mechanism-based design of parasite-targeted 
artemisinin derivatives: synthesis and antimalarial activity 
of new diamine containing analogues. 
Hindley S, Ward SA, Storr RC, Searle NL, Bray PG, Park BK, 
Davies J, O'Neill PM 
J Med Chem. 2002 Feb 28;45(5):1052-63 

26b. Proposed reductive metabolism of artemisinin 
by glutathione transferases in vitro. 
Mukanganyama S, Naik YS, Widersten M, Mannervik B, 
Hasler JA 
Free Radic Res. 2001 Oct;35(4):427-34 

26c. Effect of dihydroartemisinin on the antioxidant 
capacity of P. falciparum-infected erythrocytes. 
Ittarat W, Sreepian A, Srisarin A, Pathepchotivong K 
Southeast Asian J Trop Med Public Health. 2003 Dec;34(4):744-50 

26d. Evidence that haem iron in the malaria parasite is 
not needed for the antimalarial effects of artemisinin. 
Parapini S, Basilico N, Mondani M, Olliaro P, 
Taramelli D, Monti D 
FEBS Lett. 2004 Sep 24;575(1-3):91-4 

26e. Why artemisinin and certain synthetic peroxides are 
potent antimalarials. Implications for the mode of action. 
Jefford CW 
Curr Med Chem. 2001 Dec;8(15):1803-26 

26f. Redox reaction of artemisinin with ferrous 
and ferric ions in aqueous buffer. 
Sibmooh N, Udomsangpetch R, Kujoa A, Chantharaksri U, 
Mankhetkorn S 
Chem Pharm Bull (Tokyo). 2001 Dec;49(12):1541-6 

26g. Artemisinin and the antimalarial endoperoxides: 
from herbal remedy to targeted chemotherapy. 
Meshnick SR, Taylor TE, Kamchonwongpaisan S 
Microbiol Rev. 1996 Jun;60(2):301-15 

26h. The mode of action of antimalarial endoperoxides. 
Meshnick SR 
Trans R Soc Trop Med Hyg. 1994 Jun;88 Suppl 1:S31 

26i. Iron-dependent free radical generation from the 
antimalarial agent artemisinin (qinghaosu). 
Meshnick SR, Yang YZ, Lima V, Kuypers F, 
Kamchonwongpaisan S, Yuthavong Y 
Antimicrob Agents Chemother. 1993 May;37(5):1108-14 

26j. Effect of beta-arteether treatment on erythrocytic 
methemoglobin reductase system in Plasmodium yoelii 
nigeriensis infected mice. 
Srivastava S, Alhomida AS, Siddiqi NJ, Pandey VC, Puri SK 
Drug Chem Toxicol. 2001 May;24(2):181-90 

26k. In vitro assessment of methylene blue on chloroquine-
sensitive and -resistant Plasmodium falciparum strains 
reveals synergistic action with artemisinins. 
Akoachere M, Buchholz K, Fischer E, Burhenne J, 
Haefeli WE, Schirmer RH, Becker K 
Antimicrob Agents Chemother. 2005 Nov;49(11):4592-7 

26L. Studies on hepatic oxidative stress and antioxidant 
defence systems during arteether treatment of 
Plasmodium yoelii nigeriensis infected mice. 
Siddiqi NJ, Pandey VC 
Mol Cell Biochem. 1999 Jun;196(1-2):169-73 

26m. Effect of sodium artesunate on malaria infected human 
erythrocytes. 
Pan HZ, Lin FB, Zhang ZA 
Proc Chin Acad Med Sci Peking Union Med Coll. 1989;4(4):181-5 

26n. [Peroxidative antimalaria mechanism of sodium artesunate]
Li FB, Pan HZ [article in Chinese]
Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1989 Jun;11(3):180-4 

27a. Radical-mediated damage to parasites and erythrocytes 
in Plasmodium vinckei infected mice after injection 
of t-butyl hydroperoxide. 
Clark IA, Hunt NH, Cowden WB, Maxwell LE, Mackie EJ 
Clin Exp Immunol. 1984 Jun;56(3):524-30 

28a. Potentiation of an antimalarial oxidant drug. 
Winter RW, Ignatushchenko M, Ogundahunsi OA, 
Cornell KA, Oduola AM, Hinrichs DJ, Riscoe MK 
Antimicrob Agents Chemother. 1997 Jul;41(7):1449-54 

29a. The multiple roles of the mitochondrion 
of the malarial parasite. 
Krungkrai J 
Parasitology. 2004 Nov;129(Pt 5):511-24 

29b. Antimalarial quinones: redox potential dependence of 
methemoglobin formation and heme release in erythrocytes. 
Lopez-Shirley K, Zhang F, Gosser D, Scott M, Meshnick SR 
J Lab Clin Med. 1994 Jan;123(1):126-30 

29c. Antimalarial efficacy of methylene blue and 
menadione and their effect on glutathione metabolism 
of Plasmodium yoelii-infected albino mice. 
Arora K, Srivastava AK 
Parasitol Res. 2005 Dec;97(6):521-6 

29d. Antiplasmodial activity of nitroaromatic and 
quinoidal compounds: redox potential vs. inhibition 
of erythrocyte glutathione reductase. 
Grellier P, Sarlauskas J, Anusevicius Z, Maroziene A, 
Houee-Levin C, Schrevel J, Cenas N 
Arch Biochem Biophys. 2001 Sep 15;393(2):199-206 

29e. Antiplasmodial activity of naphthoquinones related 
to lapachol and beta-lapachone. 
Pérez-Sacau E, Estévez-Braun A, Ravelo AG, 
Gutiérrez Yapu D, Giménez Turba A 
Chem Biodivers. 2005 Feb;2(2):264-74 

29f. Newbouldiaquinone A: A naphthoquinone-anthraquinone 
ether coupled pigment, as a potential antimicrobial and 
antimalarial agent from Newbouldia laevis. 
Eyong KO, Folefoc GN, Kuete V, Beng VP, Krohn K, Hussain H, 
Nkengfack AE, Saeftel M, Sarite SR, Hoerauf A 
Phytochemistry. 2006 Mar;67(6):605-9;Epub 2006 Jan 26 

29g. Anthranoid compounds with antiprotozoal activity 
from Vismia orientalis. 
Mbwambo ZH, Apers S, Moshi MJ, Kapingu MC, Van Miert S, 
Claeys M, Brun R, Cos P, Pieters L, Vlietinck A 
Planta Med. 2004 Aug;70(8):706-10 

29h. Antimalarial activity of phenazines from lapachol, 
beta-lapachone and its derivatives against Plasmodium 
falciparum in vitro and Plasmodium berghei in vivo. 
de Andrade-Neto VF, Goulart MO, da Silva Filho JF, 
da Silva MJ, Pinto Mdo C, Pinto AV, Zalis MG, 
Carvalho LH, Krettli AU 
Bioorg Med Chem Lett. 2004 Mar 8;14(5):1145-9 

29i. In vitro antiprotozoal and cytotoxic activities 
of some alkaloids, quinones, flavonoids, and coumarins. 
del Rayo Camacho M, Phillipson JD, Croft SL, Yardley V, 
Solis PN 
Planta Med. 2004 Jan;70(1):70-2 

29j. Aminonaphthoquinones--a novel class of compounds 
with potent antimalarial activity against Plasmodium 
falciparum. 
Kapadia GJ, Azuine MA, Balasubramanian V, Sridhar R 
Pharmacol Res. 2001 Apr;43(4):363-7 

29k. In vitro response of Plasmodium falciparum to 
atovaquone and correlation with other antimalarials: 
comparison between African and Asian strains. 
Gay F, Bustos D, Traore B, Jardinel C, Southammavong M, 
Ciceron L, Danis MM 
Am J Trop Med Hyg. 1997 Mar;56(3):315-7 

29L. In vitro activity of natural and synthetic 
naphthoquinones against erythrocytic stages 
of Plasmodium falciparum. 
Carvalho LH, Rocha EM, Raslan DS, Oliveira AB, Krettli AU 
Braz J Med Biol Res. 1988;21(3):485-7 

29m. Antiplasmodial and antioxidant isofuranonaphthoquinones 
from the roots of Bulbine capitata. 
Bezabih M, Abegaz BM, Dufall K, Croft K, Skinner-Adams T, 
Davis TM 
Planta Med. 2001 Jun;67(4):340-4 

30a. Methylene blue as an antimalarial agent. 
Schirmer RH, Coulibaly B, Stich A, Scheiwein M, 
Merkle H, Eubel J, Becker K, Becher H, Müller O, 
Zich T, Schiek W, Kouyaté B 
Redox Rep. 2003;8(5):272-5 

30b. Recombinant Plasmodium falciparum glutathione reductase 
is inhibited by the antimalarial dye methylene blue. 
Färber PM, Arscott LD, Williams CH Jr, Becker K, 
Schirmer RH 
FEBS Lett. 1998 Feb 6;422(3):311-4 

30c. Antimalarial efficacy of methylene blue and 
menadione and their effect on glutathione metabolism 
of Plasmodium yoelii-infected albino mice. 
Arora K, Srivastava AK 
Parasitol Res. 2005 Dec;97(6):521-6 

30d. Methylene blue for malaria in Africa: results from 
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TARGETING THIOLS

Like bacteria, fungi and tumor cells, the ability of Plasmodia to live and grow depends heavily on an internal abundance of reductants. This is especially true regarding thiol compounds also known as sulfhydryl compounds (RSH). [31a,31b] Thiols as a class behave as reductants (electron donors). As such they are especially sensitive to oxidants (electron grabbers). Thiols (RSH) such as glutathione [32a-32L] and other sulfur compounds [33a,33b,33c] are reactive with sodium chlorite (NaClO2) and with chlorine dioxide (ClO2). These are the very agents present in Mr. Humble's solution. The products of oxidation of thiols (RSH) using various oxides of chlorine are: disulfides (RSSR), disulfide monoxides (RSSOR), sulfenic acids (RSOH), sulfinic acids (RSO2H), and sulfonic acids (RSO3H). None of these can support the life processes of the parasite. Upon sufficient removal of the parasite's life sustaining thiols by oxidation, the parasite rapidly dies. [34a-34e] A list of thiols (RSH) upon which survival of Plasmodium species heavily depend includes: lipoic acid and dihydrolipoic acid [35a-35h], coenzyme A and acyl carrier protein [36a-36f], glutathione [37a-37m], glutathione reductase [38a-38e], glutathione-S-transferase [39a-39g], peroxiredoxin [40a-40L], thioredoxin [41a-41g], glutaredoxin [42a,42b,42c], plasmoredoxin [43a], thioredoxin reductase [44a-44g], falcipain [45a-45i], and ornithine decarboxylase [46a-46e].

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40a. Roles of 1-Cys peroxiredoxin in haem detoxification 
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40h. Expression profiles of peroxiredoxin proteins 
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40i. Disruption of the Plasmodium falciparum 2-Cys 
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40k. Isolation and functional analysis of two thioredoxin 
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41f. The thioredoxin system of Plasmodium falciparum 
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41g. Thioredoxin, thioredoxin reductase, and thioredoxin 
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42a. Plasmodium falciparum thioredoxins and glutaredoxins 
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42b. Plasmodium falciparum possesses a classical 
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42c. Plasmodium falciparum glutaredoxin-like proteins. 
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43a. Plasmoredoxin, a novel redox-active protein 
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44a. Double-drug development against antioxidant enzymes 
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44b. Thioredoxin reductase and glutathione synthesis 
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44c. Specific inhibitors of Plasmodium falciparum 
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44d. Thioredoxin, thioredoxin reductase, and thioredoxin 
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44e. Thioredoxin reductase is essential for the survival 
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44f. Thioredoxin reductase as a pathophysiological 
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44g. Redox and antioxidant systems of the malaria parasite 
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45a. Gene disruption confirms a critical role for the 
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45b. Plasmodium falciparum cysteine protease falcipain-2 
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45c. Expression and characterization of the Plasmodium 
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45d. Characterization of native and recombinant falcipain-2, 
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45e. Reducing requirements for hemoglobin hydrolysis 
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45f. Cysteine proteases of malaria parasites. 
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45g. Responsiveness of parasite Cys His proteases 
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45h. Antimalarial activities of novel synthetic cysteine 
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45i. Responsiveness of parasite Cys His proteases to iron redox. 
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46a. Comparative properties of a three-dimensional model 
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46b. The Plasmodium falciparum bifunctional ornithine 
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J Biol Chem. 2001 Aug 10;276(32):29651-6 

46c. The ornithine decarboxylase domain of the 
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46d. In the human malaria parasite Plasmodium falciparum, 
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HEME IS AN OXIDANT SENSITIZER

Of particular relevance to treating malaria is the fact that Plasmodial trophozoites living inside red blood cells must digest hemoglobin as their preferred protein source. [47a,47b] They accomplish this by ingesting hemoglobin into an organelle known as the "acid food vacuole". [47c-47h] Incidently, the high concentration of acid in this organelle could serve as an additional site of conversion of chlorite (ClO2-) to the more active chlorine dioxide (ClO2) right inside the parasite. Furthermore, Plasmodia consume 50 to 100 times more glucose than noninfected red blood cells most of which is metabolized to lactic acid a known activator of chlorite. [48a-48b]

Next falcipain (a hemoglobin digesting enzyme) hydrolyzes hemoglobin protein to release its nutritional amino acids. [49a-49e] A necessary byproduct of this digestion is the release of 4 heme molecules from each hemoglobin molecule digested. Free heme (also known as ferriprotoporphyrin IX) is redox active and can react with ambient oxygen (O2), an abundance of which is always present in red blood cells. This produces superoxide radical (*OO-), hydrogen peroxide (H2O2) and other reactive oxidant toxic species (ROTS). [50a-50bb]. These can rapidly poison the parasite internally. To protect themselves against this dangerous side-effect of eating blood protein, Plasmodia must maintain a high reductant capacity (an abundance of reduced thiols and NADPH) to quench these ROTS. This is their main mechanism of antioxidant defense. [51a-51n]

Plasmodia must also rapidly and continuously eliminate heme , which is accomplished by two methods. 1) heme is polymerized producing hemozoin. [52a-52k] 2) heme is metabolized in a detoxification process that requires reduced glutathione (GSH). [53a,53b] Therefore any method (especially exposure to oxidants) which limits the availability of reduced glutathione (GSH) will cause a toxic build up of heme and of ROTS inside the parasite cells. Sodium chlorite and chlorine dioxide (the exact agents present in Mr. Humble's treatment) readily oxidize glutathione. [54a,54b] Therefore, a rapid killing of Plasmodia upon taking acidified sodium chlorite orally should be expected.

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OVERCOMING ANTIBIOTIC RESISTANCE WITH OXIDATION

Now the issue of resistance of Plasmodium species to commonly used antiprotozoal antibiotics must be addressed. Quinine, chloroquine, mefloquine, quinacrine, amodiaquine, primaquine and other quinoline-like antibiotics all work by blocking the heme detoxifying system inside the trophozoites. [55a-55gg] Many Plasmodial strains against which quinolines have repeatedly been used have found ways to adapt to these drugs and to acquire resistance. Research into the mechanisms of resistance has found that often resistance is accomplished by a meere upregulation of glutathione production and utilization. [56a-56j] Consequently oxidizing or otherwise depleting glutathione inside the parasite usually restores sensitivity to the quinoline antibiotics. [57a-57f] Therefore, protocols combining the use of oxidants with quinolines are under developement and already showing signs of success. [57g] In this context let us consider that no amount of intraplasmodial glutathione (GSH) could ever resist exposure to a suffient dose of chlorine dioxide (ClO2). Note that each molecule of ClO2 can disable 1 to 5 molecules of glutathione depending on the reaction mechanism.

2(GSH) + 2(ClO2) -> 1(GSSG) + 2(H+) + 2(ClO2-)
or 10(GSH) + 2(ClO2) -> 5(GSSG) + 2(H+) + 2(Cl-) + 4(H2O)

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Rojpibulstit P, Kangsadalampai S, Ratanavalachai T, 
Denduangboripant J, Chavalitshewinkoon-Petmitr P 
Southeast Asian J Trop Med Public Health. 2004 Jun;35(2):292-9 

56f. Plasmodium berghei: analysis of the gamma-glutamylcysteine 
synthetase gene in drug-resistant lines. 
Perez-Rosado J, Gervais GW, Ferrer-Rodriguez I, Peters W, 
Serrano AE, Pérez-Rosado J, Ferrer-Rodríguez I 
Exp Parasitol. 2002 Aug;101(4):175-82 

56g. Glutathione-S-transferase activity in malarial parasites. 
Srivastava P, Puri SK, Kamboj KK, Pandey VC 
Trop Med Int Health. 1999 Apr;4(4):251-4 

56h. Role of glutathione in the detoxification of 
ferriprotoporphyrin IX in chloroquine resistant 
Plasmodium berghei. 
Platel DF, Mangou F, Tribouley-Duret J 
Mol Biochem Parasitol. 1999 Jan 25;98(2):215-23 

56i. Plasmodium berghei: implication of intracellular 
glutathione and its related enzyme in chloroquine 
resistance in vivo. 
Dubois VL, Platel DF, Pauly G, Tribouley-Duret J 
Exp Parasitol. 1995 Aug;81(1):117-24 

56j. Amodiaquine failure associated with erythrocytic 
glutathione in Plasmodium falciparum malaria. 
Zuluaga L, Pabon A, Lopez C, Ochoa A, Blair S 
Malar J. 2007 Apr 23;6(1):47 

57a. A prodrug form of a Plasmodium falciparum glutathione 
reductase inhibitor conjugated with a 4-anilinoquinoline. 
Davioud-Charvet E, Delarue S, Biot C, Schwobel B, Boehme CC, 
Mussigbrodt A, Maes L, Sergheraert C, Grellier P, 
Schirmer RH, Becker K, Schwöbel B, Müssigbrodt A 
J Med Chem. 2001 Nov 22;44(24):4268-76 

57b. Deletion of the parasite-specific insertions and 
mutation of the catalytic triad in glutathione 
reductase from chloroquine-sensitive Plasmodium 
falciparum 3D7. 
Gilberger TW, Schirmer RH, Walter RD, Müller S 
Mol Biochem Parasitol. 2000 Apr 15;107(2):169-79 

57c. Potentiation of the antimalarial action of chloroquine 
in rodent malaria by drugs known to reduce cellular 
glutathione levels. 
Deharo E, Barkan D, Krugliak M, Golenser J, Ginsburg H 
Biochem Pharmacol. 2003 Sep 1;66(5):809-17 

57d. Glutathione is involved in the antimalarial action 
of chloroquine and its modulation affects drug 
sensitivity of human and murine species of Plasmodium. 
Ginsburg H, Golenser J 
Redox Rep. 2003;8(5):276-9 

57e. Double-drug development against antioxidant enzymes 
from Plasmodium falciparum. 
Biot C, Dessolin J, Grellier P, Davioud-Charvet E 
Redox Rep. 2003;8(5):280-3 

57f. Plasmodium falciparum: in vitro interactions 
of artemisinin with amodiaquine, pyronaridine, 
and chloroquine 
Gupta S, Thapar MM, Mariga ST, Wernsdorfer WH, Bjorkman A 
Exp Parasitol. 2002 Jan;100(1):28-35 

57g. Potentiation of chloroquine activity against Plasmodium 
falciparum by the peroxidase-hydrogen peroxide system. 
Malhotra K, Salmon D, Le Bras J, Vilde JL 
Antimicrob Agents Chemother. 1990 Oct;34(10):1981-5

SOME INCOMPATIBILITIES

Acidified sodium chlorite could provide a powerful new opportunity to improve or to restore sensitivity to quinolines by virtue of its oxidative power. However, quinolines contain secondary or tertiary amino groups which react with chlorine dioxide in such a way that both could destroy each other. Some possible strategies to resolve this incompatibility are suggested below.
  1. Acidified sodium chlorite could be used as explained above only as a solo therapy.
  2. Quinoline administration could be withheld until after the acidified sodium chorite has completed its action.
  3. Patients already preloaded with a quinoline could stop this, wait a suitable period of time for this to wash out, then administer the acidified sodium chlorite.
  4. The quinoline could remain in use and while the less active sodium chlorite is administered without acid. This should retain plenty of oxidant effectiveness without destroying any quinoline or wasting too much oxidant.
  5. Switch from a quinoline to an endoperoxide (such as artemisinin) or to a quinone (such as atovaquone) before using acidified sodium chlorite, as these may be less sensitive toward destruction by chlorine dioxide.
Similar problems apply to methylene blue and many other drugs if they have an unoxidized sulfur atom, a phenol group, a secondary amine or a tertiary amine. Such are also very reactive with the chlorine dioxide component. [58a]

References:

58a. Oxidation of pharmaceuticals during water treatment 
with chlorine dioxide. 
Huber MM, Korhonen S, Ternes TA, von Gunten U 
Water Res. 2005 Sep;39(15):3607-17

REDUCTANT RECOVERY SYSTEMS

Living things possess a recovery system to rescue oxidized sulfur compounds. It operates through donation of hydrogen atoms to these compounds and thereby restores their original condition as thiols. [59a,59b]

2 [H] + (GSSG) -> 2(GSH)

This system is known as the hexose monophophate shunt. [59c,59d] A key player in this system is the enzyme glucose- 6-phosphate-dehydrogenase (G6PDH). Patients with a genetic defect of G6PDH, known as glucose-6-phosphate-dehydrogenase deficiency disease, are especially sensitive to oxidants and to prooxidant drugs. However, this genetic disease has a benefit in that such individuals are naturally resistant to malaria. They can still catch malaria, but it is much less severe in them, since they permanently lack the enzyme necessary to assist the parasite in reactivating glutathione and other oxidized thiols. [60a-60i] Chlorine dioxide (ClO2) has been shown to oxidize and denature G6PDH by reaction with tyrosine and tryptophan residues inside the enzyme. [61a] Furthermore, G6PDH is sensitive to inhibition by sodium chlorate (NaClO3), another member of the chlorine oxide family of compounds. [61b,61c,61d] Sodium chlorate (NaClO3) is a trace ingredient present in Jim Humble's antimalarial solution. Some sodium chlorate (NaClO3) should also be produced in vivo by a slow reaction of chlorine dioxide (ClO2) with water under alkaline conditions [61e].

2(ClO2) + 2(OH-) -> (ClO2-) + (ClO3-) + H2O

The Plasmodia may attempt to restore any thiols (RSH) lost to oxidation. However, this becomes more difficult as G6PDH is inhibited by chlorine dioxide (ClO2) or by chlorate (ClO3-).

References:

59a. Malarial parasite hexokinase and hexokinase-dependent 
glutathione reduction in the Plasmodium falciparum 
infected human erythrocyte. 
Roth EF Jr 
J Biol Chem. 1987 Nov 15;262(32):15678-82 

59b. Double-drug development against antioxidant enzymes 
from Plasmodium falciparum. 
Biot C, Dessolin J, Grellier P, Davioud-Charvet E 
Redox Rep. 2003;8(5):280-3 

59c. Plasmodium falciparum carbohydrate metabolism: 
a connection between host cell and parasite. 
Roth E Jr. 
Blood Cells. 1990;16(2-3):453-60; discussion 461-6 

59d. Hexose-monophosphate shunt activity in intact 
Plasmodium falciparum-infected erythrocytes and 
in free parasites. 
Atamna H, Pascarmona G, Ginsburg H 
Mol Biochem Parasitol. 1994 Sep;67(1):79-89 

60a. Redox metabolism in glucose-6-phosphate dehydrogenase 
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chemotherapy. 
Ginsburg H, Golenser J 
Parassitologia. 1999 Sep;41(1-3):309-11 

60b. Plasmodium falciparum: thiol status and growth 
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deficient human erythrocytes. 
Miller J, Golenser J, Spira DT, Kosower NS 
Exp Parasitol. 1984 Jun;57(3):239-47 

60c. Plasmodium berghei: dehydroepiandrosterone sulfate 
reverses chloroquino-resistance in experimental malaria 
infection; correlation with glucose 6-phosphate 
dehydrogenase and glutathione synthesis pathway. 
Safeukui I, Mangou F, Malvy D, Vincendeau P, 
Mossalayi D, Haumont G, Vatan R, Olliaro P, Millet P 
Biochem Pharmacol. 2004 Nov 15;68(10):1903-10 

60d. Resistance of glucose-6-phosphate dehydrogenase 
deficiency to malaria: effects of fava bean hydroxypyrimidine 
glucosides on Plasmodium falciparum growth in culture and 
on the phagocytosis of infected cells. 
Ginsburg H, Atamna H, Shalmiev G, Kanaani J, Krugliak M 
Parasitology. 1996 Jul;113 ( Pt 1):7-18 

60e. Inhibition of the intraerythrocytic development 
of Plasmodium falciparum in glucose-6-phosphate 
dehydrogenase deficient erythrocytes is enhanced 
by oxidants and by crisis form factor. 
Golenser J, Miller J, Spira DT, Kosower NS, 
Vande Waa JA, Jensen JB 
Trop Med Parasitol. 1988 Dec;39(4):273-6 

60f. Ribose metabolism and nucleic acid synthesis in normal 
and glucose-6-phosphate dehydrogenase-deficient human 
erythrocytes infected with Plasmodium falciparum. 
Roth EF Jr, Ruprecht RM, Schulman S, Vanderberg J, Olson JA 
J Clin Invest. 1986 Apr;77(4):1129-35 

60g. The effect of X chromosome inactivation on the 
inhibition of Plasmodium falciparum malaria growth 
by glucose-6-phosphate-dehydrogenase-deficient red cells. 
Roth EF Jr, Raventos Suarez C, Rinaldi A, Nagel RL 
Blood. 1983 Oct;62(4):866-8 

60h. Excess release of ferriheme in G6PD-deficient 
erythrocytes: possible cause of hemolysis and 
resistance to malaria. 
Janney SK, Joist JJ, Fitch CD 
Blood. 1986 Feb;67(2):331-3 

60i. Susceptibility to hydrogen peroxide of Plasmodium falciparum 
infecting glucose-6-phosphate dehydrogenase-deficient erythrocytes. 
Kamchonwongpaisan S, Bunyaratvej A, Wanachiwanawin W, Yuthavong Y 
Parasitology. 1989 Oct;99 Pt 2:171-4 

61a. Denaturation of Protein by Chlorine Dioxide: 
Oxidative Modification of Tryptophan and Tyrosine Residues. 
Ogata N 
Biochemistry. 2007 Mar 31 

61b. Chlorate poisoning: mechanism of toxicity. 
Steffen C, Wetzel E 
Toxicology. 1993 Nov 12;84(1-3):217-31 

61c. Erythrocyte membrane alterations as the basis 
of chlorate toxicity. 
Singelmann E, Wetzel E, Adler G, Steffen C 
Toxicology. 1984 Mar;30(2):135-47 

61d. Chlorate poisoning: mechanism of toxicity.  
Steffen C, Wetzel E 
Toxicology. 1993 Nov 12;84(1-3):217-31 

61e. Inorganic Chemistry An Advanced Textbook. 
Moeller T 
p 440 
John Wiley & Sons, Inc.

TARGETING IRON

While most available literature refers to redox imbalances causing depletion of necessary thiols. Other mechanisms of toxicity of the oxides of chlorine against Plasmodia should also be considered. Oxides of chlorine are generally rapidly reactive with ferrous iron (Fe++) converting it to ferric (Fe+++). [62a-62d] This explains why in cases of overdosed exposures to oxides of chlorine such as sodium chlorite (NaClO2) there was a notable rise in methemoglobin levels. [63a,63b] Methemoglobin is a metabolically inactive form of hemoglobin in which its ferrous iron (Fe++) cofactor has been oxidized to ferric (Fe+++). In living things including parasites iron is a necessary cofactor for many enzymes. [64a-64f] Thus it is reasonable to expect that any damage to Plasmodia caused by oxides of chlorine is compounded by conversion of ferrous (Fe++) cofactors to ferric (Fe+++) or other alterations of iron compounds. [65a-65g] Superoxide dismutase (SOD) inside Plasmodial cells also utilizes iron in its active center. [66a-66m] Chlorine dioxide also oxidizes manganese. [67a]

References:

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on drinking water process performance. 
Henderson R, Carlson K, Gregory D 
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62b. Removal of chlorine dioxide disinfection 
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Katz A, Narkis N 
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62c. Chlorine dioxide reduction by aqueous iron(II) through 
outer-sphere and inner-sphere electron-transfer pathways. 
Wang L, Odeh IN, Margerum DW 
Inorg Chem. 2004 Nov 15;43(23):7545-51 

62d. Electrochemical metalloporphyrin-catalyzed reduction 
of chlorite. 
Collman JP, Boulatov R, Sunderland CJ, Shiryaeva IM, 
Berg KE 
J Am Chem Soc. 2002 Sep 11;124(36):10670-1 

63a. Potency ranking of methemoglobin-forming agents. 
French CL, Yaun SS, Baldwin LA, Leonard DA, Zhao XQ, 
Calabrese EJ 
J Appl Toxicol. 1995 May-Jun;15(3):167-74 

63b. Theoretical mechanistic basis of oxidants 
of methaemoglobin formation. 
Akintonwa DA 
Med Hypotheses. 2000 Feb;54(2):312-20 

64a. Design, synthesis and antimalarial activity 
of a new class of iron chelators. 
Solomon VR, Haq W, Puri SK, Srivastava K, Katti SB 
Med Chem. 2006 Mar;2(2):133-8 

64b. Heme biosynthesis by the malarial parasite. 
Import of delta-aminolevulinate dehydrase 
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J Biol Chem. 1997 Aug 29;272(35):21839-46 

64c. Hemoglobin catabolism and iron utilization 
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Rosenthal PJ, Meshnick SR 
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64d. Heme metabolism of Plasmodium is a major 
antimalarial target. 
Padmanaban G, Rangarajan PN 
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64e. Iron chelators: mode of action as antimalarials. 
Cabantchik ZI, Glickstein H, Golenser J, Loyevsky M, 
Tsafack A 
Acta Haematol. 1996;95(1):70-7 

64f. The reaction of chloroperoxidase with chlorite 
and chlorine dioxide. 
Shahangian S, Hager LP 
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65a. The plant-type ferredoxin-NADP+ reductase/ferredoxin 
redox system as a possible drug target against apicomplexan 
human parasites. 
Seeber F, Aliverti A, Zanetti G 
Curr Pharm Des. 2005;11(24):3159-72 

65b. Ferredoxin-NADP(+) Reductase from Plasmodium falciparum 
Undergoes NADP(+)-dependent Dimerization and Inactivation: 
Functional and Crystallographic Analysis. 
Milani M, Balconi E, Aliverti A, Mastrangelo E, Seeber F, 
Bolognesi M, Zanetti G 
J Mol Biol. 2007 Mar 23;367(2):501-13 

65c. Cloning and Characterization of Ferredoxin and 
Ferredoxin-NADP+ Reductase from Human Malaria Parasite. 
Kimata-Ariga Y, Kurisu G, Kusunoki M, Aoki S, Sato D, 
Kobayashi T, Kita K, Horii T, Hase T 
J Biochem (Tokyo). 2007 Mar;141(3):421-428;Epub 2007 Jan 23 

65d. Reconstitution of an apicoplast-localised electron 
transfer pathway involved in the isoprenoid 
biosynthesis of Plasmodium falciparum. 
Röhrich RC, Englert N, Troschke K, Reichenberg A, Hintz M, 
Seeber F, Balconi E, Aliverti A, Zanetti G, Köhler U, 
Pfeiffer M, Beck E, Jomaa H, Wiesner J 
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65e. The plant-type ferredoxin-NADP+ reductase/ferredoxin redox 
system as a possible drug target against apicomplexan human 
parasites. 
Seeber F, Aliverti A, Zanetti G 
Curr Pharm Des. 2005;11(24):3159-72 

65f. Biogenesis of iron-sulphur clusters 
in amitochondriate and apicomplexan protists. 
Seeber F 
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65g. Apicomplexan parasites possess distinct nuclear-encoded, 
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Vollmer M, Thomsen N, Wiek S, Seeber F 
J Biol Chem. 2001 Feb 23;276(8):5483-90;Epub 2000 Oct 30 

66a. Superoxide dismutase as a target enzyme 
for Fe-porphyrin-induced cell death. 
Asayama S, Kasugai N, Kubota S, Nagaoka S, Kawakami H 
J Inorg Biochem. 2007 Feb;101(2):261-6 

66b. The crystal structure of superoxide dismutase 
from Plasmodium falciparum. 
Boucher IW, Brzozowski AM, Brannigan JA, Schnick C, 
Smith DJ, Kyes SA, Wilkinson AJ 
BMC Struct Biol. 2006;6:20 

66c. Identification of a mitochondrial superoxide dismutase 
with an unusual targeting sequence in Plasmodium falciparum. 
Sienkiewicz N, Daher W, Dive D, Wrenger C, Viscogliosi E, 
Wintjens R, Jouin H, Capron M, Müller S, Khalife J 
Mol Biochem Parasitol. 2004 Sep;137(1):121-32 

66d. Oxidative stress and antioxidant defenses: 
a target for the treatment of diseases caused 
by parasitic protozoa. 
Turrens JF 
Mol Aspects Med. 2004 Feb-Apr;25(1-2):211-20 

66e. Screening of Plasmodium falciparum iron superoxide 
dismutase inhibitors and accuracy of the SOD-assays. 
Soulère L, Delplace P, Davioud-Charvet E, Py S, 
Sergheraert C, Périé J, Ricard I, Hoffmann P, Dive D 
Bioorg Med Chem. 2003 Nov 17;11(23):4941-4 

66f. Superoxide dismutase in Plasmodium: a current survey. 
Dive D, Gratepanche S, Yera H, Bécuwe P, Daher W, 
Delplace P, Odberg-Ferragut C, Capron M, Khalife J 
Redox Rep. 2003;8(5):265-7 

66g. Biochemical and electron paramagnetic resonance study 
of the iron superoxide dismutase from Plasmodium falciparum. 
Gratepanche S, Ménage S, Touati D, Wintjens R, Delplace P, 
Fontecave M, Masset A, Camus D, Dive D 
Mol Biochem Parasitol. 2002 Apr 9;120(2):237-46 

66h. Cloning and characterization of iron-containing 
superoxide dismutase from the human malaria species 
Plasmodium ovale, P. malariae and P. vivax. 
Baert CB, Deloron P, Viscogliosi E, Delgado-Viscogliosi P, 
Camus D, Dive D 
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66i. The role of superoxide dismutation in malaria parasites. 
Schwartz E, Samuni A, Friedman I, Hempelmann E, Golenser J 
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66j. Characterization of iron-dependent endogenous 
superoxide dismutase of Plasmodium falciparum. 
Bécuwe P, Gratepanche S, Fourmaux MN, Van Beeumen J, 
Samyn B, Mercereau-Puijalon O, Touzel JP, Slomianny C, 
Camus D, Dive D 
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66k. Subcellular distribution of superoxide dismutase and 
catalase in human malarial parasite Plasmodium vivax. 
Sharma A 
Indian J Exp Biol. 1993 Mar;31(3):275-7 

66L. Presence of an endogenous superoxide dismutase 
activity in three rodent malaria species. 
Bécuwe P, Slomianny C, Camus D, Dive D 
Parasitol Res. 1993;79(5):349-52 

66m. Oxidant defense enzymes of Plasmodium falciparum. 
Fairfield AS, Abosch A, Ranz A, Eaton JW, Meshnick SR 
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67a. Structural metal dependency of the arginase 
from the human malaria parasite Plasmodium falciparum. 
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TARGETING POLYAMINES

Other metabolites necessary for survival and growth in tumors, bacteria and parasites are the polyamines. [68a-68d] Plasmodia quit growing and die, when polyamines are lacking [69a-69k], or when their functions are blocked [70a-70L]. Polyamines are also sensitive to oxidation and can be eliminated by strong oxidants. When oxidized, polyamines are converted to aldehydes, which are deadly to parasites and to tumors. [71a-71e] Chlorine dioxide (ClO2) is known to be especially reactive against secondary amines. [72a] This includes spermine and spermidine the two main biologically important polyamines. Thus any procedure which is successful to oxidize both thiols and polyamines does quadruple damage to the pathogen: 1) oxidation of the thiol ornithine decarboxylase inhibits polyamine synthesis; 2) oxidation of the thiol S-adenosyl-L-methionine decarboxylase also inhibits polyamine synthesis; (see references below and in "Targeting Thiols" above) 3) oxidation of the secondary amines spermidine and spermine depletes polyamine supplies; 4) the products of polyamine oxidation are toxic aldehydes.

References:

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of parasitic protozoa--a possible new strategy 
for anti-parasitic treatment. 
Kaiser A, Gottwald A, Maier W, Seitz HM 
Parasitol Res. 2003 Dec;91(6):508-16 

68b. Cellular polyamine profile of the phyla Dinophyta, 
Apicomplexa, Ciliophora, Euglenozoa, Cercozoa and 
Heterokonta. 
Hamana K, Sakamoto A, Nishina M, Niitsu M 
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68c. Diamine derivatives with antiparasitic activities. 
Labadie GR, Choi SR, Avery MA 
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68d. Spermidine metabolism in parasitic protozoa--
a comparison to the situation in prokaryotes, viruses, 
plants and fungi. 
Kaiser AE, Gottwald AM, Wiersch CS, Maier WA, Seitz HM 
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69a. Polyamines in the cell cycle of the malarial parasite 
Plasmodium falciparum. 
Bachrach U, Abu-Elheiga L, Assaraf YG, Golenser J, Spira DT 
Adv Exp Med Biol. 1988;250:643-50 

69b. Polyamine synthesis and salvage pathways 
in the malaria parasite Plasmodium falciparum.
Ramya TN, Surolia N, Surolia A 
Biochem Biophys Res Commun. 2006 Sep 22;348(2):579-84 

69c. The spermidine synthase of the malaria parasite 
Plasmodium falciparum: molecular and biochemical 
characterisation of the polyamine synthesis enzyme. 
Haider N, Eschbach ML, Dias Sde S, Gilberger TW, Walter RD, 
Lüersen K 
Mol Biochem Parasitol. 2005 Aug;142(2):224-36 

69d. Targeting malaria with polyamines. 
Geall AJ, Baugh JA, Loyevsky M, Gordeuk VR, Al-Abed Y, 
Bucala R 
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69e. The Plasmodium falciparum bifunctional ornithine 
decarboxylase, S-adenosyl-L-methionine decarboxylase, 
enables a well balanced polyamine synthesis without 
domain-domain interaction. 
Wrenger C, Luersen K, Krause T, Muller S, Walter RD 
J Biol Chem. 2001 Aug 10;276(32):29651-6 

69f. Effect of polyamines on the activity of malarial 
alpha-like DNA polymerase. 
Bachrach U, Abu-Elheiga L 
Eur J Biochem. 1990 Aug 17;191(3):633-7 

69g. Plasmodium falciparum: purification, properties, 
and immunochemical study of ornithine decarboxylase, 
the key enzyme in polyamine biosynthesis. 
Assaraf YG, Kahana C, Spira DT, Bachrach U 
Exp Parasitol. 1988 Oct;67(1):20-30 

69h. Polyamines in the cell cycle of the malarial parasite 
Plasmodium falciparum. 
Bachrach U, Abu-Elheiga L, Assaraf YG, Golenser J, 
Spira DT 
Adv Exp Med Biol. 1988;250:643-50 

69i. Effect of polyamine depletion on macromolecular 
synthesis of the malarial parasite, Plasmodium 
falciparum, cultured in human erythrocytes. 
Assaraf YG, Abu-Elheiga L, Spira DT, Desser H, Bachrach U 
Biochem J. 1987 Feb 15;242(1):221-6 

69j. Polyamine levels and the activity of their 
biosynthetic enzymes in human erythrocytes infected 
with the malarial parasite, Plasmodium falciparum. 
Assaraf YG, Golenser J, Spira DT, Bachrach U 
Biochem J. 1984 Sep 15;222(3):815-9 

69k. Plasmodium berghei: inhibitors of ornithine 
decarboxylase block exoerythrocytic schizogony. 
Hollingdale MR, McCann PP, Sjoerdsma A 
Exp Parasitol. 1985 Aug;60(1):111-7 

70a. 3-Aminooxy-1-aminopropane and derivatives have an 
antiproliferative effect on cultured Plasmodium falciparum 
by decreasing intracellular polyamine concentrations. 
Das Gupta R, Krause-Ihle T, Bergmann B, Müller IB, 
Khomutov AR, Müller S, Walter RD, Lüersen K 
Antimicrob Agents Chemother. 2005 Jul;49(7):2857-64 

70b. Antimalarial effect of agmatine on Plasmodium 
berghei K173 strain. 
Su RB, Wei XL, Liu Y, Li J 
Acta Pharmacol Sin. 2003 Sep;24(9):918-22 

70c. Antiplasmodial activity of a series of 
1,3,5-triazine-substituted polyamines. 
Klenke B, Barrett MP, Brun R, Gilbert IH 
J Antimicrob Chemother. 2003 Aug;52(2):290-3 

70d. Effect of drugs inhibiting spermidine biosynthesis 
and metabolism on the in vitro development of Plasmodium 
falciparum. 
Kaiser A, Gottwald A, Wiersch C, Lindenthal B, Maier W, 
Seitz HM 
Parasitol Res. 2001 Nov;87(11):963-72 

70e. Polyamine metabolism in various tissues during 
pathogenesis of chloroquine-susceptible and resistant 
malaria. 
Mishra M, Chandra S, Pandey VC, Tekwani BL 
Cell Biochem Funct. 1997 Dec;15(4):229-35 

70f. Combined action of inhibitors of S-adenosylmethionine 
decarboxylase with an antimalarial drug, chloroquine, 
on Plasmodium falciparum. 
Das B, Gupta R, Madhubala R 
J Eukaryot Microbiol. 1997 Jan-Feb;44(1):12-7 

70g. Combined action of inhibitors of polyamine biosynthetic 
pathway with a known antimalarial drug chloroquine on 
Plasmodium falciparum. 
Das B, Gupta R, Madhubala R 
Pharmacol Res. 1995 Mar-Apr;31(3-4):189-93 

70h. Irreversible inhibition of S-adenosylmethionine 
decarboxylase in Plasmodium falciparum-infected 
erythrocytes: growth inhibition in vitro. 
Wright PS, Byers TL, Cross-Doersen DE, McCann PP, 
Bitonti AJ 
Biochem Pharmacol. 1991 Jun 1;41(11):1713-8 

70i. Antimalarial polyamine analogues. 
Edwards ML, Stemerick DM, Bitonti AJ, Dumont JA, 
McCann PP, Bey P, Sjoerdsma A 
J Med Chem. 1991 Feb;34(2):569-74 

70j. Plasmodium falciparum and Plasmodium berghei: 
effects of ornithine decarboxylase inhibitors 
on erythrocytic schizogony. 
Bitonti AJ, McCann PP, Sjoerdsma A 
Exp Parasitol. 1987 Oct;64(2):237-43 

70k. Ornithine decarboxylase of Plasmodium falciparum: 
a peak-function enzyme and its inhibition by chloroquine. 
Königk E, Putfarken B 
Trop Med Parasitol. 1985 Jun;36(2):81-4 

70L. Ornithine decarboxylase inhibition and 
the malaria-infected red cell: 
a model for polyamine metabolism and growth.
Whaun JM, Brown ND 
J Pharmacol Exp Ther. 1985 May;233(2):507-11 

71a. Polyamine oxidase in human retroplacental serum 
inhibits the growth of Plasmodium falciparum. 
Egan JE, Haynes JD, Brown ND, Eisemann CS 
Am J Trop Med Hyg. 1986 Sep;35(5):890-7 

71b. The effect of purified aminoaldehydes produced 
by polyamine oxidation on the development in vitro 
of Plasmodium falciparum in normal and 
glucose-6-phosphate-dehydrogenase-deficient erythrocytes. 
Morgan DM, Bachrach U, Assaraf YG, Harari E, Golenser J 
Biochem J. 1986 May 15;236(1):97-101 

71c. Polyamine oxidase-mediated intraerythrocytic 
killing of Plasmodium falciparum: evidence against 
the role of reactive oxygen metabolites. 
Rzepczyk CM, Saul AJ, Ferrante A 
Infect Immun. 1984 Jan;43(1):238-44 

71d. Polyamine oxidase mediates intra-erythrocytic 
death of Plasmodium falciparum. 
Ferrante A, Rzepczyk CM, Allison AC 
Trans R Soc Trop Med Hyg. 1983;77(6):789-91 

71e. Reactive oxygen and nitrogen intermediates and products 
from polyamine degradation are Babesiacidal in vitro. 
Johnson WC, Cluff CW, Goff WL, Wyatt CR 
Ann N Y Acad Sci. 1996 Jul 23;791:136-47 

72a. Chlorine Dioxide: Chemical and Physical Properties. 
Rosenblatt DH, pp 332-343, 338 
Products of Chlorine Dioxide Treatment of Organic Materials 
in Water. 
Stevens AA, pp 383-395, 388 
Ozone/Chlorine Dioxide Oxidation Products of Organic Materials. 
Rice RG, Cotruvo JA editors, 
International Ozone Institute & USEPA, 
Ozone Press International, 1978

TARGETING PURINES

Purines are essential to many life processes. These molecules have a double ring structure. The rings are heterocyclic being composed of both carbon and nitrogen. Their nitrogen atoms are vulnerable to reaction with chlorine dioxide. [73a] Examples of important biologic purines are xanthine, hypoxanthine, inosine, guanine and adenine. Guanine and adenine are essential components of DNA and RNA necessary for all genetic functions and for all protein syntheses. Adenine is an essential component of the cofactors NADH, NADPH, FAD and ATP, necessary for many metabolic functions including oxidation-reduction and energy metabolism. Any purines lost by chlorine dioxide exposure can be readily replaced by host cells. [74a] Plasmodia and other apicomplexae are uniquely vulnerable to purine deficiency as they lack the enzymes necessary to produce purines for themselves [75a,75b,75c]. Instead these must be scavenged from host cells and imported across the plasma membranes of the parasite cells. [76a-76i] Drugs are under development to inhibit purine utilization by Plasmodia and are already showing signs of success. [77a-77g] Temporarily destroying some of the purines in the blood as should occur upon brief exposure to chlorine dioxide in vivo is probably an additional stress that Plasmodia cannot tolerate.

References:

73a. Chlorine dioxide oxidation of guanosine 5'-monophosphate. 
Napolitano MJ, Stewart DJ, Margerum DW 
Chem Res Toxicol. 2006 Nov;19(11):1451-8 

74a. Transfer of purines from liver to erythrocytes. 
In vivo and in vitro studies. 
Konishi Y, Ichihara A 
J Biochem (Tokyo). 1979 Jan;85(1):295-301 

75a. Nucleoside transport as a potential target 
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Curr Pharm Des. 2007;13(6):569-80 

75b. Xanthine oxidase inhibits growth of Plasmodium 
falciparum in human erythrocytes in vitro. 
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J Clin Invest. 1991 Dec;88(6):1848-55 

75c. Hypoxanthine depletion induced by xanthine oxidase 
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76a. Molecules targeting the purine salvage pathway 
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Trends Parasitol. 2007 Aug;23(8):384-9 

76b. Nucleoside transport as a potential target 
for chemotherapy in malaria. 
Baldwin SA, McConkey GA, Cass CE, Young JD 
Curr Pharm Des. 2007;13(6):569-80 

76c. The plasma membrane permease PfNT1 is essential 
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Ben Mamoun C 
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9286-91 

76d. Purine metabolism by the avian malarial parasite 
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Yamada KA, Sherman IW 
Mol Biochem Parasitol. 1981 Aug;3(4):253-64 

76e. Purine metabolism during continuous erythrocyte 
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Webster HK, Whaun JM 
Prog Clin Biol Res. 1981;55:557-73 

76f. Purine base and nucleoside uptake 
in Plasmodium berghei and host erythrocytes. 
Hansen BD, Sleeman HK, Pappas PW 
J Parasitol. 1980 Apr;66(2):205-12 

76g. Comparison of tritiated hypoxanthine, adenine and 
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Van Dyke K 
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76h. Purine uptake and utilization by the avian malaria 
parasite Plasmodium lophurae. 
Tracy SM, Sherman IW 
J Protozool. 1972 Aug;19(3):541-9 

76i. [Incorporation of exogenous adenosine and 
hypoxanthine in the nucleic acids of malaria parasites 
(Plasmodium berghei and Plasmodium vinckei)] 
Büngener W 
Z Parasitenkd. 1968;31(1):1 [Article in German] 

77a. Targeting purine and pyrimidine metabolism in human 
apicomplexan parasites. 
Hyde JE 
Curr Drug Targets. 2007 Jan;8(1):31-47 

77b. Purine-less death in Plasmodium falciparum induced 
by immucillin-H, a transition state analogue 
of purine nucleoside phosphorylase. 
Kicska GA, Tyler PC, Evans GB, Furneaux RH, Schramm VL, 
Kim K 
J Biol Chem. 2002 Feb 1;277(5):3226-31 

77c. Structure-activity relationships and inhibitory effects 
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Plasmodium falciparum. 
Harmse L, van Zyl R, Gray N, Schultz P, Leclerc S, 
Meijer L, Doerig C, Havlik I 
Biochem Pharmacol. 2001 Aug 1;62(3):341-8 

77d. In vitro susceptibilities of Plasmodium falciparum 
to compounds which inhibit nucleotide metabolism. 
Queen SA, Jagt DL, Reyes P 
Antimicrob Agents Chemother. 1990 Jul;34(7):1393-8 

77e. Synthesis of adenosine nucleotides from hypoxanthine 
by human malaria parasites (Plasmodium falciparum) 
in continuous erythrocyte culture: 
inhibition by hadacidin but not alanosine. 
Webster HK, Whaun JM, Walker MD, Bean TL 
Biochem Pharmacol. 1984 May 1;33(9):1555-7 

77f. Hypoxanthine metabolism by human malaria 
infected erythrocytes: focus for the design 
of new antimalarial drugs. 
Webster HK, Wiesmann WP, Walker MD, Bean T, Whaun JM 
Adv Exp Med Biol. 1984;165 Pt A:219-23 

77g. Antimalarial properties of bredinin. 
Prediction based on identification of differences 
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Webster HK, Whaun JM 
J Clin Invest. 1982 Aug;70(2):461-9

TARGETING PROTEINS

Chlorine dioxide (ClO2) is highly reactive with thiols, phenols, secondary amines and tertiary amines. Therefore, proteins composed of amino acids which present these reactive groups are vulnerable to oxidation by this agent. Proteins which present residue(s) of the amino acid L-cysteine are discussed above under TARGETING THIOLS. L-tyrosine presents a phenol group and is therefore similarly vulnerable. L-tryptophan and L-histidine present secondary amino groups which are also especially reactive with chlorine dioxide. [78a-78d]

References:

78a. Denaturation of Protein by Chlorine Dioxide: 
Oxidative Modification of Tryptophan and Tyrosine Residues. 
Ogata N 
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78b. Chlorine dioxide oxidations of tyrosine, 
N-acetyltyrosine, and dopa. 
Napolitano MJ, Green BJ, Nicoson JS, Margerum DW 
Chem Res Toxicol. 2005 Mar;18(3):501-8 

78c. Reaction of chlorine dioxide with amino acids 
and peptides: kinetics and mutagenicity studies. 
Tan HK, Wheeler WB, Wei CI 
Mutat Res. 1987 Aug;188(4):259-66 

78d. Reactions of aqueous chlorine dioxide 
with amino acids found in water. 
Taymaz K, Williams DT, Benoit FF 
Bull Environ Contam Toxicol. 1979 Nov;23(4-5):456-63

SAFETY ISSUES

A remaining concern is safety. So far, at least anecdotally, the dosages of chlorine oxides as administered orally per Jim Humble's protocol have produced no definite toxicity. Some have taken this as often as 1 to 3 times weekly and on the surface seem to suffer no ill effects. To be certain if this is safe more research is warranted for such long term or repeated use. The concern is that too much or too frequent administration of oxidants could excessively deplete the body's reductants and promote oxidative stress. One useful way to monitor this may be to periodically check methemoglobin levels in frequent users. Sodium chlorite, as found in municipal water supplies after disinfection by chorine dioxide, has been studied and proven safe. [79a-79j] Animal studies using much higher oral or topical doses have proven relatively safe. [80a-80t] In a suicide attempt 10g of sodium chlorite taken orally caused nearly fatal kidney failure and refractory methemoglobinemia. [81a] Inhalation or aerosol exposure to chlorine dioxide gas is highly irritating and generally not recommended. [82a-82g] Special precautions must be employed in cases of glucose-6- phosphate-dehydrogenase deficiency disease, as these patients are especially sensitive to oxidants of all kinds. [83a-83g] Nevertheless, oral acidified sodium chlorite solutions might even be found safe [84a,84b] and effective in them, but probably will need to be administered at lower doses.

References:

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79f. Effect of chlorine dioxide water disinfection on 
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79g. The effects of chronic administration of chlorine dioxide, 
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J Environ Pathol Toxicol Oncol. 1984 Jul;5(4-5):229-38 

79h. Effects of the acute rising dose administration 
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Lubbers JR, Bianchine JR.
J Environ Pathol Toxicol Oncol. 1984 Jul;5(4-5):215-28 

79i. Controlled clinical evaluations of chlorine dioxide, 
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79j. Acute and chronic toxicity of chlorine dioxide (ClO2) 
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80a. The effects of chlorine dioxide and sodium chlorite 
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J Environ Pathol Toxicol. 1980 Sep;4(2-3):513-24 

80b. Subchronic toxicity of chlorine dioxide and related 
compounds in drinking water in the nonhuman primate. 
Bercz JP, Jones L, Garner L, Murray D, Ludwig DA, Boston J 
Environ Health Perspect. 1982 Dec;46:47-55 

80c. Oxidative damage to the erythrocyte induced 
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J Environ Pathol Toxicol. 1979 Jul-Aug;2(6):1487-99 

80d. Acute and chronic toxicity of chlorine dioxide (ClO2) 
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80e. The kinetics of chlorite and chlorate in rats. 
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80f. Teratologic evaluation of Alcide liquid 
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J Appl Toxicol. 1985 Apr;5(2):97-103 

80g. Effects of Alcide gel on fetal development 
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80h. Biochemical interactions of chlorine dioxide 
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80i. Pharmacokinetics of Alcide, a germicidal compound in rat. 
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80j. Effect of chlorine dioxide and its metabolites 
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J Appl Toxicol. 1983 Apr;3(2):75-9 

80k. Metabolism and pharmacokinetics 
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80L. Toxicological effects of chlorine dioxide, chlorite 
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80m. Toxicological effects of chlorite in the mouse. 
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80n. Chlorine dioxide metabolism in rat. 
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80o. Toxicity of chlorine dioxide in drinking water. 
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J Environ Pathol Toxicol Oncol. 1985 Sep-Oct;6(1):105-13 

80p. Sodium chlorite. IARC monographs on the evaluation 
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80q. Study on subchronic toxicity of chlorine dioxide 
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80s. Subchronic dermal toxicity studies of Alcide Allay gel 
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Abdel-Rahman MS, Skowronski GA, Turkall RM, Gerges SE, 
Kadry AR, Abu-Hadeed AH 
J Appl Toxicol. 1987 Oct;7(5):327-33 

80t. Effects of chlorine dioxide on thyroid function 
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Harrington RM, Shertzer HG, Bercz JP 
J Toxicol Environ Health. 1986;19(2):235-42 

81a. Acute sodium chlorite poisoning associated 
with renal failure. 
Lin JL, Lim PS 
Ren Fail. 1993;15(5):645-8 

82a. First-aid reports of acute chlorine gassing among 
pulpmill workers as predictors of lung health consequences. 
SALISBURY DA, ENARSON DA, CHAN-YEUNG M, KENNEDY SM 
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82b. Health Effects of Working in Pulp and Paper Mills: 
Exposure, Obstructive Airways Diseases, 
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Toren K, Hagberg S, Westberg H 
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82c. Reactive Airways Dysfunction Syndrome Due 
to Chlorine [Dioxide]: Sequential Bronchial Biopsies 
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Lemiere C, Malo J-L, Boutet M 
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83a. The effects of chronic administration of chlorite 
to glucose-6-phosphate dehydrogenase deficient healthy 
adult male volunteers. 
Lubbers JR, Chauhan S, Miller JK, Bianchine JR 
J Environ Pathol Toxicol Oncol. 1984 Jul;5(4-5):239-42 

83b. G6PD-deficiency: a potential high-risk group 
to copper and chlorite ingestion. 
Moore GS, Calabrese EJ 
J Environ Pathol Toxicol. 1980 Sep;4(2-3):271-9 

83c. Groups at potentially high risk from chlorine dioxide 
treated water. 
Moore GS, Calabrese EJ, Ho SC 
J Environ Pathol Toxicol. 1980 Sep;4(2-3):465-70 

83d. G6PD-deficiency: a potential high-risk group 
to copper and chlorite ingestion. 
Moore GS, Calabrese EJ 
J Environ Pathol Toxicol. 1980 Sep;4(2-3):271-9 

83e. Potential health effects of chlorine dioxide 
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Moore GS, Calabrese EJ, DiNardi SR, Tuthill RW 
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83f. [G6PD phenotype and red blood cell sensitivity 
to the oxidising action of chlorites in drinking water] 
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83g. Effects of environmental oxidant stressors 
on individuals with a G-6-PD deficiency with particular 
reference to an animal model. 
Calabrese EJ, Moore G, Brown R 
Environ Health Perspect. 1979 Apr;29:49-55 

84a. The effects of chronic administration of chlorite 
to glucose-6-phosphate dehydrogenase deficient healthy 
adult male volunteers. 
Lubbers JR, Chauhan S, Miller JK, Bianchine JR 
J Environ Pathol Toxicol Oncol. 1984 Jul;5(4-5):239-42 

84b. [G6PD phenotype and red blood cell sensitivity 
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Contu A, Bajorek M, Carlini M, Meloni P, Cocco P, Schintu M 
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MORE RESEARCH

It is hoped that this overview will spark a flurry of interest, and stimulate more research into the use of acidified sodium chlorite in the treatment of malaria. The above appreciated observations need to be proven more rigorously and published [85a]. The biochemistry most likely involved suggests that other members of the phylum Apicomplexa should also be sensitive to this treatment. [86a] This phylum includes: Plasmodium, Babesia, Toxoplasma [87a], Cryptosporidium [88a], Eimeria, Theileria, Sarcocystis, Cyclospora, Isospora and Neospora. These pathogens are responsible for widespread diseases in humans, pets and cattle. Other thiol dependent parasites should also be susceptible to acidified sodium chlorite. For example Trypanosoma and Leishmania extensively utilize and cannot survive without the cofactor known as trypanothione. Each molecule of trypanothione presents 2 sulfur atoms and 5 secondary amino groups all of which are vulnerable to oxidative destruction from chlorine dioxide (ClO2). [89a-89p]

Chlorine dioxide has been proven to be cidal to almost all known infectious agents in vitro using remarkably low concentrations. This includes parasites, fungi, bacteria and viruses. The experiences noted above imply that this compound is tolerable orally at effective concentrations. [90a,90b] Therefore extensive research is warranted to determine if acidified sodium chlorite is effective in treating other infections. We may be on the verge of discovering the most potent and broad spectrum antimicrobial agent yet known. Special thanks go to Jim Humble for his willingness to share his discovery with the world.

by Thomas Lee Hesselink, MD

References:

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89j. Phenotypic analysis of trypanothione synthetase 
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The End