Thomas Lee Hesselink博士によるＭＭＳの参考文献です。英文ではありますが、資料の元となっている情報などが記載されています。
1.On The Mechanisms of Oxidation of Chlorine Oxides
– An Overview
DISCOVERY
Jim Humble, a modern gold prospecting geologist, needed to travel to malaria infested areas
numerous times. He or his coworkers would on occasion 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. 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. [1]
References:
1. A Possible Solution to the Malaria Problem? Humble J Libertarian Times, May 9, 2005
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 large 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
and allowed to react for 3 minutes. The acidified solution is then mixed into a glass of water or
apple juice and taken orally. This can be taken on an empty stomach to enhance effectiveness
but this often causes nausea. Nausea is less likely to occur if food is present such as one hour
after meals. The vinegar (5% acetic acid) or lime juice (6 to 9% citric acid) neutralizes the
sodium hydroxide and at the same time converts a small portion of the chlorite (ClO2-) to its
conjugate acid known as chlorous acid (HClO2). Under such conditions some of 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 chlorine.
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 devastating of all known plagues. [1,2]
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
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
Copyright 2007-2008 Thomas Lee Hesselink. Published with permission
on web site http://MMS-medicalresearch.com
2
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. I wanted to understand their probable mechanisms of toxicity towards the
causative agents of malaria (Plasmodium species). [3] I wanted to check available literature
pertaining to issues of safety or risk in human use.
References: 1. Current status of malaria control. Tripathi RP, Mishra RC, Dwivedi N, Tewari N,
Verma SS Curr Med Chem. 2005;12(22):2643-59
2. Current status and progresses made in malaria chemotherapy. Linares GE, Rodriguez JB Curr
Med Chem. 2007; 14(3):289-314
3. An overview of chemotherapeutic targets for antimalarial drug discovery. Olliaro PL,
Yuthavong Y Pharmacol Ther. 1999 Feb; 81(2):91-110
OXIDANTS AS PHYSIOLOGIC AGENTS
I was already very familiar with most of the other known medicinally useful oxidants.
Examples are: hydrogen peroxide, zinc peroxide, various quinones, various glyoxals, ozone,
ultraviolet light, hyperbaric oxygen, benzoyl peroxide, artemisinin, methylene blue, allicin,
iodine and permanganate. I had taught at numerous seminars on their use and explained
their mechanisms of action on the biochemical level. Oxidants are atoms or molecules
which take up electrons. Reductants are atoms or molecules which donate electrons to oxidants.
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.
[1] Hyperbaric oxygenation (oxygen under pressure): 1) is a powerful detoxifier against
carbon monoxide; 2) is a powerful support for natural healing in burns, crush injuries, and
ischemic strokes; and 3) is an effective aid to treat most bacterial infections.
Taken internally, intermittently and in low doses many oxidants have been found to be powerful
immune stimulants. Exposure of live blood to ultraviolet light has similar 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 an alarm system to increase cellular attack against pathogens and to
down-regulate allergic reactions.
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. One such
natural defense oxidant is hydrogen peroxide (H2O2). Another is peroxynitrate (-
OONO) the coupled product of superoxide (*OO-) and nitric oxide (*NO) radicals. Yet
another is hypochlorous acid (HOCl) the conjugate acid of sodium hypochlorite (NaClO).
References:
Decreased level of 2,3-diphosphoglycerate and alteration of structural integrity in erythrocytes
infected with Plasmodium falciparum invitro.Dubey ML, Hegde R, Ganguly NK, Mahajan
RC Mol Cell Biochem. 2003 Apr; 246(1-2):137-41
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
Copyright 2007-2008 Thomas Lee Hesselink. Published with permission
on web site http://MMS-medicalresearch.com
3
OXIDANTS AS DISINFECTANTS
Various strong oxidants are widely used as disinfectants. [4, 11, 12, 13, 28] All bacteria have
been shown to be incapable of growing in any medium in which the oxidants (electron grabbers)
out-number the reductants (electron donors). [29] Thus oxidants are at least
bacteriostatic and at most are bactericidal. [27] Some oxidants such as iodine, various peroxides,
or permanganate are applied topically to the skin to treat or to prevent infections caused
by bacteria or fungi. Chlorine dioxide has been similarly used. [15]
Hypochlorites (ClO-) are commonly used as bleaching agents, as swimming pool
sanitizers, and as disinfectants. Chlorine dioxide (ClO2) as well as ozone (O3) are
effective disinfectants for public water supplies and are often used for that purpose. [9,14]
Sodium chlorite (NaClO2) solutions have long been used as mouth washes to rapidly clear
mouth odors and oral bacteria. Acidified sodium chlorite is FDA approved as a spray in the meat
packing industry to sanitized meat. [1, 2, 8, 10, 26] Farmers use this to cleanse the udders of
cows
to prevent mastitis, [5, 6, 7] and to rid eggs of pathogenic bacteria. Chlorine dioxide kills many
viruses. [16, 17, 18, 19, 20, 21, 22, 23, 24, 25] Acidified sodium chlorite is even useful to
sanitize vegetables. [3] Some work has been done using dilute solutions of sodium
chlorite internally to treat fungal infections, chronic fatigue, and cancer. Little
however has been published in that regard.
References:
1. 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
2. Research Project Outline #4111, by C N Cutter, Penn State Univ, Nov 2005
3. 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
4. Antiseptics and Disinfectants: Activity, Action and Resistance. by G McDonnell
& A D Russell Clinical Microbiology Reviews, pp 147-179, Jan 1999
5. 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
6. 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
7. 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
8. 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
9. Disinfectant efficacy of chlorite and chlorine dioxide in drinking water biofilms. Gagnon GA, Rand
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
Copyright 2007-2008 Thomas Lee Hesselink. Published with permission
on web site http://MMS-medicalresearch.com
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JL, O’leary KC, Rygel AC, Chauret C, Andrews RC Water Research, 39(9):1809-17, May 2005
10. 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
11. 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
12. Mechanisms of killing of Bacillus subtilis spores by hypochlorite and chlorine dioxide. Young SB,
Setlow P. J Appl Microbiol. 2003; 95(1):54-67
13. Inactivation of bacteria by Purogene. Harakeh S, Illescas A, Matin A. J Appl Bacteriol. 1988
May;64(5):459-63
14. 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
15. 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
16. Degradation of the Poliovirus 1 genome by chlorine dioxide. Simonet J, Gantzer C J Appl Microbiol.
2006 Apr; 100(4):862-70
17. 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
18. 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
19. Virucidal efficacy of four new disinfectants. Eleraky NZ, Potgieter LN, Kennedy MA J Am Anim
Hosp Assoc. 2002 May-Jun; 38(3):231-4
20. 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
21. 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
22. Inactivation of human and simian rotaviruses by chlorine dioxide. Chen YS, Vaughn JM Appl
Environ Microbiol. 1990 May;56(5):1363-6
23. Disinfecting capabilities of oxychlorine compounds. Noss CI, Olivieri VP Appl Environ
Microbiol. 1985 Nov;50(5):1162-4
24. Mechanisms of inactivation of poliovirus by chlorine dioxide and iodine. Alvarez ME,
O’Brien RT Appl Environ Microbiol. 1982 Nov; 44(5):1064-71
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
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25. 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
26. The Evaluation of Antimicrobial Treatments for Poultry Carcasses European Commission
Health & Consumer Protection Directorate- General, April 2003
27. Role of Oxidants in Microbial Pathophysiology. R A Miller, B E Britigan Clinical Microbiology
Reviews, 10(1):1-18, Jan 1997
28. PURE WATER HANDBOOK Osmonics, Inc. Minnetonka, Minnesota
29. OXIDATION-REDUCTION POTENTIALS IN BACTERIOLOGY AND BIOCHEMISTRY L F
Hewitt, 6th Ed, E. & S. Livingston Ltd., 1950
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. [15] Examples of oxidants toxic to Plasmodia include: artemisinin
[16, 27, 36, 41], atovaquone [48], menadione, and methylene blue [29,47]. Also like bacteria
and tumor cells, the ability of Plasmodia to live and grow depends heavily on an internal
abundance of thiol compounds [38,55]. Thiols are also known as sulfhydryl compounds
(RSH). Thiols as a class behave as reductants (electron donors). Thus they are notoriously
sensitive to oxidation and they are rapidly reactive with oxides of chlorine.
This includes sodium chlorite (NaClO2) and chlorine dioxide (ClO2) the very agents
present in Mr. Humble’s solution. The products of oxidation of thiols 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. A list of thiols (RSH) upon which
survival of Plasmodium species heavily depend includes: lipoic acid & dihydrolipoic acid [1, 2,
3, 5, 7, 8, 10, 11], coenzyme A & acyl carrier protein [6, 9, 12, 39, 43], glutathione [4, 19, 26,
32, 35, 37], glutathione reductase [33, 34, 42], glutathione-S-transferase [24, 30, 49, 50, 52, 53],
peroxiredoxin [40, 56, 57, 58, 59, 60, 61, 62, 63, 65, 66, 67], thioredoxin [20, 21, 22, 25, 44,
64], glutaredoxin [31,45], plasmoredoxin [28], thioredoxin reductase [23, 46],
ornithine decarboxylase and falcipain [13,14,17,18,51,54].
References:
1. The plasmodial apicoplast was retained under evolutionary selective pressure to assuage
blood stage oxidative stress. Toler S Med Hypotheses. 2005; 65(4):683-90
2. Scavenging of the cofactor lipoate is essential for the survival of the malaria parasite
Plasmodium falciparum Allary M, Lu JZ, Zhu L, Prigge ST Mol Microbiol. 2007 Mar; 63(5):1331-
44;Epub 2007 Jan 22
3. Plasmodium falciparum possesses organelle-specific alpha- keto acid dehydrogenase complexes and
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
Copyright 2007-2008 Thomas Lee Hesselink. Published with permission
on web site http://MMS-medicalresearch.com
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lipoylation pathways. Günther S, McMillan PJ, Wallace LJ, Müller S Biochem Soc Trans. 2005
Nov;33(Pt 5):977-80
4. Characterization of the glyoxalases of the malarial parasite Plasmodium falciparum and comparison
with their human counterparts Akoachere M, Iozef R, Rahlfs S, Deponte M, Mannervik B, Creighton
DJ, Schirmer H, Becker K Biol Chem. 2005 Jan;386(1):41-52
5. The malaria parasite Plasmodium falciparum has only one pyruvate dehydrogenase
complex, which is located in the apicoplast. Foth BJ, Stimmler LM, Handman E, Crabb
BS, Hodder AN, McFadden GI Mol Microbiol. 2005 Jan; 55(1):39-53 Comment in: Mol
Microbiol. 2005 Jan; 55(1):1-4
6. Fatty acid biosynthesis as a drug target in apicomplexan parasites. Goodman CD,
McFadden GI Curr Drug Targets. 2007 Jan;8(1):15-30
7. The human malaria parasite Plasmodium falciparum possesses two distinct
dihydrolipoamide dehydrogenases. McMillan PJ, Stimmler LM,
Foth BJ, McFadden GI, Müller S Mol Microbiol. 2005 Jan;55(1):27-38 Comment in: Mol
Microbiol. 2005 Jan; 55(1):1-4
8. The human malaria parasite Plasmodium falciparum has distinct organelle-specific
lipoylation pathways. Wrenger C, Müller S Mol Microbiol.
2004 Jul; 53(1):103-13
9. Apicoplast fatty acid biosynthesis as a target for medical intervention in apicomplexan parasites.
Gornicki P Int J Parasitol. 2003 Aug; 33(9):885-96
10. Apicomplexan parasites contain a single lipoic acid synthase located in the plastid. Thomsen-Zieger
N, Schachtner J, Seeber F FEBS Lett. 2003 Jul 17; 547(1-3):80-6
11. Biosynthetic pathways of plastid-derived organelles as potential drug targets against parasitic
apicomplexa. Seeber F Curr Drug Targets Immune Endocr Metabol Disord. 2003 Jun; 3(2):99-109
12. A type II pathway for fatty acid biosynthesis presents drug targets in Plasmodium falciparum. Waller
RF, Ralph SA, Reed MB, Su V, Douglas JD, Minnikin DE, Cowman AF, Besra GS, McFadden GI
Antimicrob Agents Chemother. 2003 Jan; 47(1):297-301
13. Gene disruption confirms a critical role for the cysteine protease falcipain-2 in
hemoglobin hydrolysis by Plasmodium falciparum. Sijwali PS, Rosenthal PJ Proc Natl Acad Sci U S A.
2004 Mar 30;101(13):4384-9
14. Plasmodium falciparum cysteine protease falcipain-2 cleaves erythrocyte membrane
skeletal proteins at late stages of parasite development. Hanspal M, Dua M, Takakuwa Y,
Chishti AH, Mizuno A Blood. 2002 Aug 1;100(3):1048-54
15. 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
16. 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
17. Expression and characterization of the Plasmodium falciparum haemoglobinase falcipain-3.
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
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on web site http://MMS-medicalresearch.com
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Sijwali PS, Shenai BR, Gut J, Singh A, Rosenthal PJ Biochem J. 2001 Dec 1; 360(Pt 2):481-9
18. Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine
protease and essential hemoglobinase of Plasmodium falciparum. Shenai BR, Sijwali PS, Singh A,
Rosenthal PJ J Biol Chem. 2000 Sep 15; 275(37):29000-10
19. Glutathione–functions and metabolism in the malarial parasite Plasmodium falciparum.
Becker K, Rahlfs S, Nickel C, Schirmer RH Biol Chem. 2003 Apr; 384(4):551-66
20. The thioredoxin system of the malaria parasite Plasmodium falciparum. Glutathione reduction
revisited. Kanzok SM, Schirmer RH, Turbachova I, Iozef R, Becker K J Biol Chem. 2000 Dec
22;275(51):40180-6
21. Thioredoxin networks in the malarial parasite Plasmodium falciparum. Nickel C, Rahlfs S, Deponte
M, Koncarevic S, Becker K Antioxid Redox Signal. 2006 Jul-Aug;8(7-8):1227-39
22. Thioredoxin and glutathione system of malaria parasite Plasmodium falciparum. Muller S, Gilberger
TW, Krnajski Z, Luersen K, Meierjohann S, Walter RD, Müller S, Lüersen K Protoplasma.
2001;217(1-3):43-9
23. Thioredoxin reductase and glutathione synthesis in Plasmodium falciparum. Muller S,
Müller S Redox Rep. 2003;8(5):251-5
24. Glutathione S-transferase of the malarial parasite Plasmodium falciparum: characterization
of a potential drug target. Harwaldt P, Rahlfs S, Becker K Biol Chem. 2002 May; 383(5):821-30
25. Plasmodium falciparum thioredoxins and glutaredoxins as central players in redox
metabolism. Rahlfs S, Nickel C, Deponte M, Schirmer RH, Becker K Redox Rep. 2003;8(5):246-50
26. Plasmodium falciparum-infected red blood cells depend on a functional glutathione de novo
synthesis attributable to an enhanced loss of glutathione. Luersen K, Walter RD, Muller S,
Lüersen K, Müller S Biochem J. 2000 Mar 1;346 Pt 2:545-52
27. 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
28. Plasmoredoxin, a novel redox-active protein unique for malarial parasites. Becker K,
Kanzok SM, Iozef R, Fischer M, Schirmer RH, Rahlfs S
Eur J Biochem. 2003 Mar; 270(6):1057-64
29. 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
30. Glutathione S-transferase from malarial parasites: structural and functional aspects.
Deponte M, Becker K Methods Enzymol. 2005;401: 241-53
31. Plasmodium falciparum possesses a classical glutaredoxin and a second, glutaredoxin-like
protein with a PICOT homology domain. Rahlfs S, Fischer M, Becker K J Biol Chem. 2001 Oct 5;
276(40):37133-40
32. Characterization of the glyoxalases of the malarial parasite Plasmodium falciparum and comparison
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
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on web site http://MMS-medicalresearch.com
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with their human counterparts. Akoachere M, Iozef R, Rahlfs S, Deponte M, Mannervik B, Creighton
DJ, Schirmer H, Becker K Biol Chem. 2005 Jan;386(1):41-52
33. Glutathione reductase-deficient erythrocytes as host cells of malarial parasites. Zhang Y,
König I, Schirmer RH Biochem Pharmacol. 1988 Mar 1;37(5):861-5
34. Glutathione reductase of the malarial parasite Plasmodium falciparum: crystal structure and
inhibitor development. Sarma GN, Savvides SN, Becker K, Schirmer M, Schirmer RH, Karplus
PA J Mol Biol. 2003 May 9;328(4):893-907
35. Glutathione synthetase from Plasmodium falciparum. Meierjohann S, Walter RD, Müller S
Biochem J. 2002 May 1; 63(Pt 3):833-8
36. 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
37. Ceramide mediates growth inhibition of the Plasmodium falciparum parasite. Pankova-
Kholmyansky I, Dagan A, Gold D, Zaslavsky Z, Skutelsky E, Gatt S, Flescher E Cell Mol Life Sci. 2003
Mar;60(3):577-87
38. Thiol-based redox metabolism of protozoan parasites. Müller S, Liebau E, Walter
RD, Krauth-Siegel RL Trends Parasitol. 2003 Jul;19(7):320-8 Comment in: Trends Parasitol.
2004 Feb; 20(2):58-9
39. Recombinant expression and biochemical characterization of the unique elongating betaketoacyl-
acyl carrier protein synthase involved in fatty acid biosynthesis of Plasmodium falciparum
using natural and artificial substrates Lack G, Homberger-Zizzari E, Folkers G, Scapozza L, Perozzo R J
Biol Chem. 2006 Apr 7;281(14):9538-46
40. Roles of 1-Cys peroxiredoxin in haem detoxification in the human malaria parasite
Plasmodium falciparum. Kawazu S, Ikenoue N, Takemae H, Komaki-Yasuda K, Kano S FEBS J. 2005
Apr;272(7):1784-91
41. 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
42. Kinetic characterization of glutathione reductase from the malarial parasite Plasmodium
falciparum. Comparison with the human enzyme. Bohme CC, Arscott LD, Becker K, Schirmer
RH, Williams CH Jr J Biol Chem. 2000 Dec 1;275(48):37317-23
43. Identification, characterization, and inhibition of Plasmodium falciparum beta-hydroxyacylacyl
carrier protein dehydratase (FabZ). Sharma SK, Kapoor M, Ramya TN, Kumar S, Kumar G,
Modak R, Sharma S, Surolia N, Surolia A J Biol Chem. 2003 Nov 14;278(46):45661-71
44. The thioredoxin system of Plasmodium falciparum and other parasites. Rahlfs S, Schirmer RH,
Becker K Cell Mol Life Sci. 2002 Jun; 59(6):1024- 41
45. Plasmodium falciparum glutaredoxin-like proteins. Deponte M, Becker K, Rahlfs S Biol Chem. 2005
Jan;386(1):33-40
46. Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents.
Andricopulo AD, Akoachere MB, Krogh R, Nickel C, McLeish MJ, Kenyon GL, Arscott LD, Williams
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
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on web site http://MMS-medicalresearch.com
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CH Jr, Davioud-Charvet E, Becker K Bioorg Med Chem Lett. 2006 Apr 15;16(8):2283-92
47. 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
48. The multiple roles of the mitochondrion of the malarial parasite. Krungkrai J
Parasitology. 2004 Nov; 129(Pt 5):511-24
49. The glutathione S-transferase from Plasmodium falciparum. Liebau E, Bergmann B, Campbell AM,
Teesdale-Spittle P, Brophy PM, Lüersen K, Walter RD Mol Biochem Parasitol. 2002 Sep-
Oct;124(1-2):85-90
50. Glutathione S-transferases and related proteins from pathogenic human parasites behave as
immunomodulatory factors. Ouaissi A, Ouaissi M, Sereno D Immunol Lett. 2002 May 1;
81(3):159-64
51. Reducing requirements for hemoglobin hydrolysis by Plasmodium falciparum cysteine proteases.
Shenai BR, Rosenthal PJ Mol Biochem Parasitol. 2002 Jun;122(1):99-104
52. Plasmodium falciparum glutathione S-transferase– structural and mechanistic studies on
ligand binding and enzyme inhibition. Hiller N, Fritz-Wolf K, Deponte M, Wende W, Zimmermann H,
Becker K Protein Sci. 2006 Feb;15(2):281-9;Epub 2005 Dec 29.
53. Cooperativity and pseudo-cooperativity in the glutathione S-transferase from Plasmodium
falciparum. Liebau E, De Maria F, Burmeister C,
Perbandt M, Turella P, Antonini G, Federici G, Giansanti F, Stella L, Lo Bello M, Caccuri AM,
Ricci G J Biol Chem. 2005 Jul 15;280(28):26121-8
54. Cysteine proteases of malaria parasites. Rosenthal PJ Int J Parasitol. 2004 Dec;34(13-14):1489-99
55. The thiol-based redox networks of pathogens: unexploited targets in the search for new drugs.
Jaeger T, Flohe L, Flohé L Biofactors. 2006; 27(1-4):109-20
56. Structural and biochemical characterization of a mitochondrial peroxiredoxin from
Plasmodium falciparum. Boucher IW, McMillan PJ, Gabrielsen M, Akerman SE, Brannigan JA,
Schnick C, Brzozowski AM, Wilkinson AJ, Muller S, Müller S Mol Microbiol. 2006 Aug; 61(4):948-59
57. 2-Cys Peroxiredoxin TPx-1 is involved in gametocyte development in Plasmodium berghei. Yano K,
Komaki-Yasuda K, Tsuboi T, Torii M, Kano S, Kawazu S Mol Biochem Parasitol. 2006
Jul;148(1):44-51
58. Plasmodium falciparum 2-Cys peroxiredoxin reacts with plasmoredoxin and peroxynitrite. Nickel
C, Trujillo M, Rahlfs S, Deponte M, Radi R, Becker K Biol Chem. 2005
Nov;386(11):1129-36
59. Expression of mRNAs and proteins for peroxiredoxins in Plasmodium falciparum erythrocytic stage.
Yano K, Komaki-Yasuda K, Kobayashi T, Takemae H, Kita K, Kano S, Kawazu S Parasitol Int. 2005
Mar;54(1):35-41
60. Crystal structure of a novel Plasmodium falciparum 1-Cys peroxiredoxin. Sarma GN,
Nickel C, Rahlfs S, Fischer M, Becker K, Karplus PA J Mol Biol. 2005 Mar 4;346(4):1021-34
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
Copyright 2007-2008 Thomas Lee Hesselink. Published with permission
on web site http://MMS-medicalresearch.com
10
61. 2-Cys peroxiredoxin PfTrx-Px1 is involved in the antioxidant defence of Plasmodium
falciparum. Akerman SE, Muller S, Müller S Mol Biochem Parasitol. 2003 Aug 31; 130(2):75-81
62. Expression profiles of peroxiredoxin proteins of the rodent malaria parasite Plasmodium yoelii.
Kawazu S, Nozaki T, Tsuboi T, Nakano Y, Komaki-Yasuda K, Ikenoue N, Torii M, Kano S Int
J Parasitol. 2003 Nov;33(13):1455-61
63. Disruption of the Plasmodium falciparum 2-Cys peroxiredoxin gene renders parasites
hypersensitive to reactive oxygen and nitrogen species. Komaki-Yasuda K, Kawazu S, Kano S FEBS
Lett. 2003 Jul 17;547(1-3):140-4
64. Thioredoxin, thioredoxin reductase, and thioredoxin peroxidase of malaria parasite
Plasmodium falciparum. Kanzok SM, Rahlfs S, Becker K, Schirmer RH Methods Enzymol. 2002;
347:370-81
65. Molecular characterization of a 2-Cys peroxiredoxin from the human malaria parasite Plasmodium
falciparum. Kawazu S, Komaki K, Tsuji N, Kawai S, Ikenoue N, Hatabu T, Ishikawa H,
Matsumoto Y, Himeno K, Kano S Mol Biochem Parasitol. 2001 Aug; 116(1):73-9
66. Isolation and functional analysis of two thioredoxin peroxidases (peroxiredoxins) from
Plasmodium falciparum. Krnajski Z, Walter RD, Muller S, Müller S Mol Biochem Parasitol. 2001
Apr 6;113(2):303-8
67. Thioredoxin peroxidases of the malarial parasite Plasmodium falciparum. Rahlfs S, Becker
K Eur J Biochem. 2001 Mar; 268(5):1404-9
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. [8, 13] They
accomplish this by ingesting hemoglobin into an organelle known as the “acid
food vacuole”. [3, 16] 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.
Next falcipain (a hemoglobin digesting enzyme) hydrolyzes hemoglobin protein to
release its nutritional amino acids. [4, 5, 6, 26, 27] A necessary byproduct of this digestion is the
release of 4 heme molecules from each hemoglobin molecule digested. [1] Free heme (also
known as ferriprotoporphyrin) 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.
[2, 7, 9, 10, 11, 12, 14, 15, 20] These can rapidly poison the parasite internally.
To protect itself against this dangerous side-effect of eating blood protein,
Plasmodia must continuously and rapidly eliminate heme. [18, 22] This is accomplished
by two methods. Firstly, heme is polymerized producing hemozoin. [19, 21, 23, 24]
Secondly, heme is metabolized in a detoxification process that requires reduced
glutathione (GSH). [17, 25] Therefore any method (including exposure to oxidants)
which limits the availability of reduced glutathione will cause a toxic build up of heme
inside the parasite cells. Since sodium chlorite and chlorine dioxide readily oxidize
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
Copyright 2007-2008 Thomas Lee Hesselink. Published with permission
on web site http://MMS-medicalresearch.com
11
glutathione heme detoxification is inhibited. As these are the exact agents used in Mr. Humble’s
treatment, the observed effect of killing Plasmodia should be expected.
References:
1. In vitro activity of riboflavin against the human malaria parasite Plasmodium falciparum.
Akompong T, Ghori N, Haldar K Antimicrob Agents Chemother. 2000 Ja ; 44(1):88-96
2. 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
3. Hemoglobin degradation. Goldberg DE Curr Top Microbiol Immunol. 2005; 295:275-91
4. Development of cysteine protease inhibitors as chemotherapy for parasitic diseases: insights
on safety, target validation, and mechanism of action. McKerrow JH Int J Parasitol. 1999 Jun; 29(6):833-
7
5. Cysteine proteases of malaria parasites: targets for chemotherapy. Rosenthal PJ, Sijwali
PS, Singh A, Shenai BR Curr Pharm Des. 2002; 8(18):1659-72
6. Proteases of malaria parasites: new targets for chemotherapy. Rosenthal PJ Emerg Infect Dis. 1998
Jan-Mar;4(1):49-57 7. Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. Francis
SE, Sullivan DJ Jr, Goldberg DE Annu Rev Microbiol. 1997; 51:97-123
8. Plasmodium falciparum: inhibitors of lysosomal cysteine proteinases inhibit a trophozoite
proteinase and block parasite development. Rosenthal PJ, McKerrow JH, Rasnick D, Leech JH Mol
Biochem Parasitol. 1989 Jun 15;35(2):177-83
9. Identification and characterization of heme-interacting proteins in the malaria parasite,
Plasmodium falciparum. Campanale N, Nickel C, Daubenberger CA, Wehlan DA, Gorman JJ,
Klonis N, Becker K, Tilley L J Biol Chem. 2003 Jul 25;278(30):27354-61
10. The redox status of malaria-infected erythrocytes: an overview with an emphasis on unresolved
problems. Ginsburg H, Atamna H Parasite. 1994 Mar; 1(1):5-13
11. Redox and antioxidant systems of the malaria parasite Plasmodium falciparum. Muller S
Mol Microbiol. 2004 Sep;53(5):1291-305
12. Origin of reactive oxygen species in erythrocytes infected with Plasmodium falciparum.
Atamna H, Ginsburg H Mol Biochem Parasitol. 1993 Oct; 61(2):231-41 Erratum in: Mol
Biochem Parasitol 1994 Feb;63(2):312
13. Intraerythrocytic Plasmodium falciparum utilizes only a fraction of the amino acids derived from
the digestion of host cell cytosol for the biosynthesis of its proteins. Krugliak M, Zhang J,
Ginsburg H Mol Biochem Parasitol. 2002 Feb;119(2):249-56
14. Oxidative stress in malaria parasite-infected erythrocytes: host-parasite interactions. Becker K, Tilley
L, Vennerstrom JL, Roberts D, Rogerson S, Ginsburg H Int J Parasitol. 2004 Feb; 34(2):163-89
15. Clotrimazole binds to heme and enhances heme-dependent hemolysis: proposed antimalarial
mechanism of clotrimazole. Huy NT, Kamei K, Yamamoto T, Kondo Y, Kanaori K, Takano R,
Tajima K, Hara S J Biol Chem. 2002 Feb 8;277(6):4152-8 16. Acidification of the malaria
parasite’s digestive vacuole by a H+-ATPase and a H+-pyrophosphatase. Saliba KJ, Allen RJ,
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
Copyright 2007-2008 Thomas Lee Hesselink. Published with permission
on web site http://MMS-medicalresearch.com
12
Zissis S, Bray PG, Ward SA, Kirk K J Biol Chem. 2003 Feb 21; 278(8):5605-12
17. A non-radiolabeled heme-GSH interaction test for the screening of antimalarial
compounds. Garavito G, Monje MC, Maurel S, Valentin A, Nepveu F, Deharo E Exp Parasitol.
2007 Jan 23
18. Effect of antifungal azoles on the heme detoxification system of malarial parasite. Huy NT, Kamei K,
Kondo Y, Serada S, Kanaori K, Takano R, Tajima K, Hara S J Biochem (Tokyo). 2002 Mar; 131(3):437-
44
19. Malarial haemozoin/beta-haematin supports haem polymerization in the absence of protein.
Dorn A, Stoffel R, Matile H, Bubendorf A, Ridley RG Nature. 1995 Mar 16;374(6519):269-71
20. Illumination of the malaria parasite Plasmodium falciparum alters intracellular pH.
Implications for live cell imaging. Wissing F, Sanchez CP,
Rohrbach P, Ricken S, Lanzer M J Biol Chem. 2002 Oct 4;277(40):37747-55
21. Plasmodium falciparum histidine-rich protein-2 (PfHRP2) modulates the redox activity of
ferri-protoporphyrin IX (FePPIX): peroxidase-like activity of the PfHRP2-FePPIX complex.
Mashima R, Tilley L, Siomos MA, Papalexis V, Raftery MJ, Stocker R J Biol Chem. 2002
Apr 26;277(17):14514-20
22. Chloroquine - some open questions on its antimalarial mode of action and resistance. Ginsburg H,
Krugliak M Drug Resist Updat. 1999 Jun; 2(3):180-187
23. A physiochemical mechanism of hemozoin (beta-hematin) synthesis by malaria parasite. Tripathi
AK, Garg SK, Tekwani BL Biochem Biophys Res Commun. 2002 Jan 11;290(1):595-601
24. Histidine-rich protein 2 of the malaria parasite, Plasmodium falciparum, is involved in detoxification
of the by-products of hemoglobin degradation. Papalexis V, Siomos MA, Campanale N,
Guo X, Kocak G, Foley M, Tilley L Mol Biochem Parasitol. 2001 Jun; 115(1):77-86
25. Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine
as a possible basis for their antimalarial mode of action. Ginsburg H, Famin O, Zhang J,
Krugliak M Biochem Pharmacol. 1998 Nov 15; 56(10):1305-13
26. Hydrolysis of erythrocyte proteins by proteases of malaria parasites. Rosenthal PJ Curr Opin
Hematol. 2002 Mar; 9(2):140-5
27. Cysteine protease inhibitors as chemotherapy for parasitic infections. McKerrow JH, Engel JC,
Caffrey CR Bioorg Med Chem. 1999 Apr; 7(4):639-44
OVERCOMING ANTIBIOTIC RESISTANCE WITH OXIDATION
Now the issue of resistance of Plasmodium species to commonly used antiprotozoal
antibiotics must be addressed. Quinine, chloroquine, mefloquine and other quinoline
antibiotics all work by blocking the heme detoxifying system inside the trophozoites. [1, 2, 3,
4, 5] Many Plasmodial strains against which quinolines have repeatedly been used
have found a way to adjust to this treatment and to acquire resistance. Recent research has
shown, however, that the mechanism of this acquired resistance amounts to a mere
upregulation of glutathione production and utilization. [6, 7, 8, 11, 19, 21, 22, 23] Recent
research has also shown that oxidizing or otherwise depleting glutathione inside the
parasite restores sensitivity to the quinoline antibiotics. [10, 12, 13, 15, 16, 18, 20] Therefore,
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
Copyright 2007-2008 Thomas Lee Hesselink. Published with permission
on web site http://MMS-medicalresearch.com
13
some protocols combining the use of oxidants with quinolines are already showing signs of
success. In this regard let us consider that no amount of intraplasmodial glutathione (GSH)
could ever resist exposure to a sufficient dose of chlorine dioxide (ClO2). Note that each
molecule of ClO2 can disable 5 molecules of glutathione. 10 GSH + 2 ClO2 -> 5 GSSG + 4
H2O + 2 HCl . 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. [9] 2 [H] + GSSG -> 2 GSH 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. [14, 17]
Furthermore, G6PDH is profoundly sensitive to inhibition by sodium chlorate (NaClO3),
another member of the chlorine oxide family of compounds. Sodium chlorate (NaClO3) is a
lesser ingredient present in Jim Humble’s antimalarial solution. Some sodium chlorate should
also be produced in vivo by a slow reaction of chorine dioxide with water under slightly alkaline
conditions. The Plasmodia may attempt to restore its glutathione that is lost to oxidation.
However, this will be difficult or impossible if G6PDH is inhibited by chlorate.
References:
1. Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other
quinoline antimalarials. Loria P, Miller S, Foley M, Tilley L Biochem J. 1999 Apr 15; 339 ( Pt
2):363- 70
2. Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents. Foley M,
Tilley L Pharmacol Ther. 1998 Jul; 79(1):55-87
3. Quinoline antimalarials: mechanisms of action and resistance. Foley M, illey L Int J Parasitol.
1997 Feb; 27(2):231-40
4. Inhibition by anti-malarial drugs of haemoglobin denaturation and iron release in acidified red blood
cell lysates–a possible mechanism of their anti-malarial effect? Gabay T, Krugliak M,
Shalmiev G, Ginsburg H Parasitology. 1994 May; 108 ( Pt 4):371-81
5. Chloroquine: mechanism of drug action and resistance in Plasmodium falciparum. Slater
AF Pharmacol Ther. 1993 Feb-Mar;57(2-3):203-35
6. Regulation of intracellular glutathione levels in erythrocytes infected with chloroquinesensitive
and chloroquine-resistant Plasmodium falciparum. Meierjohann S, Walter RD, Muller S,
Müller S Biochem J. 2002 Dec 15; 368(Pt 3):761-8
7. The malaria parasite supplies glutathione to its host cell-investigation of glutathione
transport and metabolism in human erythrocytes infected with Plasmodium falciparum.
Atamna H, Ginsburg H Eur J Biochem. 1997 Dec 15; 250(3):670-9
8. Is the expression of genes encoding enzymes of glutathione (GSH) metabolism involved in
chloroquine resistance in Plasmodium chabaudi parasites? Ferreira ID, Nogueira F, Borges ST, do
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
Copyright 2007-2008 Thomas Lee Hesselink. Published with permission
on web site http://MMS-medicalresearch.com
14
Rosario VE, Cravo P, do Rosyo VE Mol Biochem Parasitol. 2004 Jul; 136(1):43-50
9. 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
10. 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
11. Plasmodium falciparum glutathione metabolism and growth are independent of glutathione
system of host erythrocyte. Ayi K, Cappadoro M, Branca M, Turrini F, Arese P FEBS Lett. 1998
Mar 13;424(3):257-61
12. The treatment of Plasmodium falciparum-infected erythrocytes with chloroquine leads to
accumulation of ferriprotoporphyrin IX bound to particular parasite proteins and to the
inhibition of the parasite’s 6-phosphogluconate dehydrogenase. Famin O, Ginsburg H Parasite.
2003 Mar;10(1):39-50
13. 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
14. Redox metabolism in glucose-6-phosphate dehydrogenase deficient erythrocytes and its
relation to antimalarial chemotherapy. Ginsburg H, Golenser J Parassitologia. 1999 Sep;41(1-3):309-11
15. 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
16. 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
17. Plasmodium falciparum: thiol status and growth in normal and glucose-6-phosphate dehydrogenase
deficient human erythrocytes.Miller J, Golenser J, Spira DT, Kosower NS Exp Parasitol.
1984 Jun;57(3):239-47
18. 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
19. Glutathione-S-transferases from chloroquine-resistant and -sensitive strains of Plasmodium
falciparum: what are their differences? Rojpibulstit P, Kangsadalampai S, Ratanavalachai T,
Denduangboripant J, Chavalitshewinkoon-Petmitr P Southeast Asian J Trop Med Public Health. 2004
Jun; 35(2):292-9
20. 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
21. Plasmodium berghei: analysis of the gamma-glutamylcysteine synthetase gene in drugMMS
Overview and Bibliography by Thomas Lee Hesselink, MD
Copyright 2007-2008 Thomas Lee Hesselink. Published with permission
on web site http://MMS-medicalresearch.com
15
resistant lines. Perez-Rosado J, Gervais GW, Ferrer-Rodriguez I, Peters W, Serrano AE, Pérez-Rosado
J, Ferrer- RodrÃguez I Exp Parasitol. 2002 Aug;101(4):175-82
22. 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
23. 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
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++). 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. Methemoglobin is a metabolically inactive form of
hemoglobin in which its ferrous iron (Fe++) cofactor has been oxidized to ferric (Fe+++).
Many enzymes in living things employ iron as a cofactor including those in parasites. [8, 9, 10] Thus it
is reasonable to expect that any damage to Plasmodia caused by oxides of chlorine is
compounded by conversion of ferrous cofactors to ferric. [1, 2, 3, 4, 5, 6, 7]
References:
1. 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
2. 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;Epub 2007 Jan 09
3. 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
4. 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.
FEBS Lett. 2005 Nov 21; 579(28):6433-8;Epub 2005 Nov 02
5. 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
6. Biogenesis of iron-sulphur clusters in amitochondriate and apicomplexan protists. Seeber
F Int J Parasitol. 2002 Sep; 32(10):1207-17
7. Apicomplexan parasites possess distinct nuclear-encoded, but apicoplast-localized, plant-type
ferredoxin-NADP+ reductase and ferredoxin. Vollmer M, Thomsen N, Wiek S, Seeber F J Biol Chem.
2001 Feb 23;276(8):5483-90;Epub 2000 Oct 30
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
Copyright 2007-2008 Thomas Lee Hesselink. Published with permission
on web site http://MMS-medicalresearch.com
16
8. 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
9. Heme biosynthesis by the malarial parasite. Import of delta-aminolevulinate dehydrase
from the host red cell. Bonday ZQ, Taketani S, Gupta PD, Padmanaban G J Biol Chem. 1997
Aug 29; 272(35):21839-46
10. Hemoglobin catabolism and iron utilization by malaria parasites. Rosenthal PJ, Meshnick SR Mol
Biochem Parasitol. 1996 Dec 20; 83(2):131-9
TARGETING POLYAMINES
Other metabolites necessary for survival and growth in tumors, bacteria and parasites are
the polyamines. [2] When these are lacking pathogens quit growing and die. [1]
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.
Thus any procedure which is successful to oxidize polyamines does double damage to the
pathogen. Chlorine dioxide (ClO2) is known to be especially reactive against secondary amines. This
includes spermine and spermidine, the two main biologically important polyamines.
References:
1. Targeting enzymes involved in spermidine metabolism 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
2. 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
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. Animal studies using yet higher oral doses have also proven safe.
One case of extreme overdose in a suicide attempt caused nearly fatal kidney
failure and refractory methemoglobinemia. 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. Nevertheless, oral sodium chlorite (NaClO2)
solutions may yet be found safe and effective in them, but probably will need to be administered
at lower doses.
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 [8]. The biochemistry
most likely involved suggests that other members of the phylum Apicomplexa should
also be sensitive to this treatment. This phylum includes: Plasmodium, Babesia, Toxoplasma
[2], Cryptosporidium [3], Eimeria [4], Theileria, Sarcocystis, Cyclospora, Isospora
MMS Overview and Bibliography by Thomas Lee Hesselink, MD
Copyright 2007-2008 Thomas Lee Hesselink. Published with permission
on web site http://MMS-medicalresearch.com
17
and Neospora. These agents are responsible for widespread diseases in humans, pets and cattle.
Chlorine dioxide has been proven to be cidal to almost all known infectious agents in vitro using
remarkably low concentrations. This includes parasites [1, 6, 7, 9, 10], fungi [5], bacteria and
viruses. The experiences noted above imply that this compound is tolerable orally at effective
concentrations. Therefore extensive research is warranted to determine if acidified sodium
chlorite is effective in many other infections. We may be on the verge of discovering the most
potent and broad spectrum antibiotic yet known. Special thanks go to Jim Humble for his
willingness to share his discovery with the world.
References:
1. Cysticidal effect of chlorine dioxide on Giardia intestinalis cysts. Winiecka-Krusnell J, Linder E Acta
Trop. 1998 Jul 30;70(3):369-72
2. Toxoplasma gondii: the model apicomplexan. Kim K, Weiss LM Int J Parasitol. 2004 Mar 9;
34(3):423-32
3. 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
4. The effect of ‘Alcide’ on 4 strains of rodent coccidial oocysts. Owen DG Lab Anim. 1983
Oct;17(4):267-9
5. Glutathione, altruistic metabolite in fungi. Pócsi I, Prade RA, Penninckx MJ Adv Microb
Physiol. 2004; 49:1-76
6. Characterization of an omega-class glutathione- S-transferase from Schistosoma mansoni with
glutaredoxin-like dehydroascorbate reductase and thiol transferase activities. Girardini J,
Amirante A, Zemzoumi K, Serra E Eur J Biochem. 2002 Nov; 269(22):5512-21
7. Thiol-based redox metabolism of protozoan parasites.Müller S, Liebau E, Walter RD, Krauth-Siegel
RL Trends Parasitol. 2003 Jul;19(7):320-8 Comment in: Trends Parasitol. 2004 Feb;20(2):58-9
8. Estimation of the total parasite biomass in acute falciparum malaria from plasma
PfHRP2. Dondorp AM, Desakorn V, Pongtavornpinyo W, Sahassananda D, Silamut K,
Chotivanich K, Newton PN, Pitisuttithum P, Smithyman AM, White NJ, Day NP PLoS
Med. 2005 Aug;2(8):e204;Epub 2005 Aug 23 Erratum in: PLoS Med. 2005 Oct;2(10):390
Comment in: PLoS Med. 2006 Jan;3(1):e68; Author reply e69.
9. The parasite-specific trypanothione metabolism of trypanosome and leishmania. Krauth-
Siegel RL, Meiering SK, Schmidt H Biol Chem. 2003 Apr; 384(4):539-49
10. The synthesis of parasitic cysteine protease and trypanothione reductase inhibitors. Chibale K,
Musonda CC Curr Med Chem. 2003 Sep; 10(18):1863-89
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or made available upon request. Thomas Lee Hesselink, MD
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二酸化塩素は病原菌を殺し、重金属や毒性物質を破壊する、地球上で最も強力な殺菌・消毒成分です。同時に大変に優れた選択性を持つ酸化剤ですから、健康な細胞や有益な微生物や天然成分を傷つけません。生体の免疫系が二酸化塩素を使って生体にとって有害な病原菌と毒性化学物質、および重金属を破壊して、後は免疫系がそれらの残滓を体外へと排出します。
