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Artemisia afra cures Buruli ulcer with high efficacy. Possible role of gallium

July 6, 2017 - 11:24 -- Pierre Lutgen

         Abstract.

Following up on same encouraging earlier trials, we launched with our African partners and the French association M4L larger scale clinical trials. The results obtained in these trials are extraordinary. The trials were run in the Maniema province of RDC and were coordinated by Dr Jerome Munyangi who has alrready run the very successfull clinical trials with Artemisia plants against malaria, tuberculosis and bilharzia. The treatment consisted in the administration per os of an Artemisia afra decoction during 14 days and the application of a poultice containing an Artemisia afra extract during 28 days. These produces were from » Mother Nature » in Burundi. 21 patients completed the full treatment, some others were lost from sight. Those who took the complete treatment were totally cured, without any need for surgical intervention. No remanent limitation in movements or other sequelae were noticed as it often happens after antibiotic treatment. Mycobacteria were counted under the microscope by the Ziehl-Neelsen method. No remaining mycobacteria could be detected after the treatment.

           Résumé

Suite à quelques essais préliminaires en 2015 nous avons décidé avec nos partenaires africains et français (M4L) de conduire des essais cliniques pilote. Les résultats qu’on vient de nous communiquer sont fort encourageants. Nos essais ont été menés au Maniema RDC et ont été coordonnées par le Dr Jerôme Munyangi et son équipe, comme cela avait été le cas précédemment pour les essais cliniques contre le paludisme et la bilharziose. Le traitement consistait dans la consommation d’une tisane d’Artemisia afra pendant 14 jours et l’application cutanée d’une pommade contenant un extrait de la même plante pendant 28 jours. Les produits provenaient de Mother Nature au Burundi. 21 jeunes patients ont suivi le traitement complet, d’autres ont été perdus de vue. Chez ceux qui ont suivi le traitement complet, la guérison était totale, sans qu’une intervention chirurgicale soit nécessaire et sans rémanence d’une limitation de mouvement comme c’est souvent le cas après guérison. L’identification des mycobactéries sous microscope par la méthode de Ziehl-Neelsen était positive et très marquée avant traitement et était indétectable après.

Un énorme espoir.

Buruli ulcer is an infectious disease caused by Mycobacterium ulcerans. The early stage of the infection is characterised by a painless nodule or area of swelling. This nodule can turn into an ulcer. The ulcer may be larger inside than at the surface of the skin, and can be surrounded by swelling. As the disease worsens, bone can be infected. Buruli ulcers most commonly affect the arms or legs. Healing may occur spontaneously but more often the disease is slowly progressive with further ulceration, granulation, scarring, and contractures. Satellite infection may occur with other nodules developing and infection may occur into bone causing osteomyelitis. Although seldom fatal, the disease results in considerable morbidity and deformity.

The treatment recommended by WHO consists of a combination of antibiotics given for 8 weeks and complementary treatments. Interventions such as wound management and surgery (mainly debridement and skin grafting) are used to speed up the healing thereby shortening the duration of hospitalization. In addition, physiotherapy is needed in severe cases to prevent disability. Those who are left with disability require long-term rehabilitation.

        WHO publication "Treatment of mycobacterium ulcerans disease .

Mycobacterium ulcerans releases a toxin known as mycolactone, which decreases immune system function and results in tissue death. Bacteria from the same family also cause tuberculosis and leprosy (Mycobacterium tuberculosis and M. leprae, respectively). The first trials against Buruli were run with the antibiotics dofazimine or corrimoxazole, but the results of these monotherapies were disappointing.

According to recommendations of the 6th WHO Advisory Committee on Buruli ulcer, directly observed treatment with the combination of rifampin and streptomycin, administered daily for 8 weeks, was recommended to 310 patients diagnosed with Buruli ulcer in Pobè, Bénin. Among the 224 (72%) eligible patients for whom treatment was initiated, 215 (96%) were categorized as treatment successes. Of the 215 successfully treated patients, 102 (47%) were treated exclusively with antibiotics and 113 (53%) were treated with antibiotics plus surgical excision and skin grafting.

        Annick Chauty, Marie-Françoise Ardant, Ambroise Adeye, Hélène Euverte,Augustin Guédénon, Promising Clinical Efficacy of Streptomycin-Rifampin Combination for Treatment of Buruli Ulcer (Mycobacterium ulcerans Disease). Antimicrob Agents Chemother. 2007 Nov; 51(11): 4029–4035.

In a treatment with antibiotics in Togo the lesions of 84.5% of the patients were healed without complications, 3.9% had secondary lesions, and 11.6%, a lower proportion than in other studies, had functional limitations. Hereby, edema, category II Iulcers, healing times >180 days, and limitation of movement at discharge constituted the main risk factor. Sometimes delayed paradoxical reactions in the form of new ulcer skin lesions emerged several months after completion of chemotherapy.

        Beissner M, Aren sN, Wiedemann F, Piten E, Kobara B, Bauer M (2015) Treatment Outcome of Patients with Buruli Ulcer Diseasein Togo . PLoSNeglTropDis 9(10):e0004170. doi:10.1371/journal.pntd.0004170

Similar paradoxical reactions were seen in French Guinea after antibiotic treatment. Four patients presented apparent worsening of their lesions during treatment. It was concluded that the symptoms were caused by a paradoxical response or a reaction, a phenomenon already described in tuberculosis and leprosy. The most plausible pathophysiological hypothesis involves the re-emergence of potentially necrotizing cellular immunity secondary to the loss of mycolactone, a necrotizing and immunosuppressive toxin produced by M. ulcerans, resulting from the action of the antibiotics.

         Sambourg E, Dufour J, Edouard S, Paradoxical reactions and responses during antibiotic treatment for Mycobacterium ulcerans infection (Buruli ulcer). Four cases from French Guiana. Ann Dermatol Venereol. 2014 Jun-Jul;141(6-7):413-8. doi: 10.1016/j.annder.2014.01.010. Epub 2014 Feb 24.

The province of Bas-Congo in RDC contains one of the most important Buruli ulcer foci of the country. In a study using a combination of rifamicin and streptomycin and surgery the median duration of hospitalization was 90 days. 21.0, % were healed with complications and sequelae. 6 out of 190 died due to Buruli ulcer.

         Phanzu DM, Suykerbuyk P, Imposo DBB, Lukanu PN, Minuku J-BM, et al. (2011) Effect of a Control Project on Clinical Profiles and Outcomes in Buruli Ulcer: A Before/After Study in Bas-Congo, Democratic Republic of Congo. PLoS Negl Trop Dis 5(12): e1402. doi:10.1371/journal.pntd.0001402

Another study in Benin gave similar results. 1 year after treatment, 229 (22% )of 1043 patients presented with permanent functional sequelae. Presentation with oedema, osteomyelitis, or large (≥15 cm in diameter), or multifocal lesions was significantly associated with occurrence of permanent functional sequelae.

        Vincent QB, Ardant MF, Adeye A,, Alcaïs A. Clinical epidemiology of laboratory-confirmed Buruli ulcer in Benin: a cohort study. Lancet Glob Health. 2014 Jul;2(7):e422-30. doi: 10.1016/S2214-109X(14)70223-2. Epub 2014 Jun 17.

In a more recent clinical trial in Nigeria 35 patients, who consented to treatment, completed chemotherapy as prescribed. Of the treated cases, 29 (82.9 %) needed and received surgery. All cases healed, but 29 (82.9 %) kept some limitations in movement. The median duration of treatment was 130 (87–164) days for children and 98 (56–134) days for adults.

         Kingsley N. Ukwaja, , Anthony O. Meka, Alphonsus Chukwuka, Kingsley B. Asiedu, Kristina L. Huber, Miriam Eddyani, Joseph N. Chukwu, Moses C. Anyim, Charles C. Nwafor, Daniel C. Oshi, Nelson O. Madichie, Buruli ulcer in Nigeria: results of a pilot case study in three rural districts. Infectious Diseases of Poverty20165:39 DOI: 10.1186/s40249-016-0119-8

Another review was conducted by authors from Cameroon on 115 patients. The duration of treatment ranged from 8 to 48 weeks depending on the severity. The "dual" mode of treatment (surgery + chemotherapy) reduced hospital admission period from 90 to 39.8 days, that's to 44.2%. Oral chemotherapy alone obtained a curative rate of 50% only.

          Vouking MZ, Tamo VC, Tadenfok CN. Clinical efficacy of Rifampicin and Streptomycin in combination against Mycobacterium ulcerans infection: a systematic review. Pan Afr Med J. 2013 Aug 29;15:155. doi: 10.11604/pamj.2013.15.155.2341.

The objective of a recent systematic review was to examine the clinical effectiveness of various antibiotic regimens for the treatment of Buruli ulcers. Although several antibiotics have demonstrated bactericidal activity against Mycobacterium ulcerans in vitro, no consensus on their clinical efficacy against M. ulcerans in humans has been reached. Seven studies involving a total of 712 patients were included in the final review. The average treatment success was reported to be 92%, at the 12 months follow-up. Evidence obtained from this systematic review indicates that surgery will remain necessary for some ulcers; however, detection of early lesions and treatment with antibiotics would have a greater impact on the control of M. ulcerans disease.

       Tanywe A, Fernandez RS. Effectiveness of rifampicin-streptomycin for treatment of Buruli ulcer: a systematic review. JBI Database System Rev Implement Rep. 2017 Jan;15(1):119-139. doi: 10.11124/JBISRIR-2016-003235.

A Cochrane interview is also underway. They highlight the concern that development of resistance against the present antibiotic treatment, might also render rifampicin and streptomycin resistant against tuberculoisis and leprosy.

       Rie Yotsu, Marty Richardson, Norihisa Ishii. Drugs for treating Buruli ulcer (Mycobacterium ulcerans disease) [Cochrane Protocol]. 2016:CRD42016045564 Available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016045564

The risk of resistance had already been described by the team of Dr T Efferth in 2010.

       Denise Bamberger, Nora Jantzer Thomas Efferth. Fighting mycobacterial infections by antibiotics, phytochemicals and vaccines.Microbes and Infection Volume 13, Issue 7, July 2011, Pages 613-623

Compliance with antimicrobial therapy for Buruli ulcer is a frequent problem. For several reasons. Intramuscular injections of antibiotics are painful and administration is logistically complicated in a rural African setting, sometimees forcing patients to travel several hours daily for 8 weeks to the nearest healt care facility. In addition streptomycin carries a considerable risk of toxicity, especially the ototoxic adverse effects.

       S. Klis, R.Kingma, W Tuah. Compliance with antimicrobial therapy for Buruli ulcer. Antimicrob Agents Chemother, 2014 58, 6340.

Direct costs of Buruli ulcer diagnosis and treatment are catastrophic to a substantial proportion of patients and their families. In a survey in Nigeria it was found that the overall direct costs per patient was US$135 (58-327), which corresponded to 162% of median monthly household income.. The direct costs of Buruli ulcer care were catastrophic for 50% of all patients/households - the rates of catastrophic costs for Buruli ulcer care was 66% and 19% for patients belonging to the lowest and highest income quartiles, respectively.

       Chukwu JN, Meka Ao, Nwafor CC, Ukwaja J Financial burden of healt care for Buruli ulcer patients in Nigeria. Int Health, 2017, 9, 36-43.

The mode of transmission of Mycobacterium ulcerans remains poorly understood. It is more frequent in marshy areas where arthropods may be the vector. The current working hypothesis is that humans with active, openly discharging Buruli lesions may play a pivotal role in the spread of the bacterium. The possible role of humans as potential reservoir to sustain new Buruli infections suggests that interventions aimed at reducing the human Buruli burden will at the same time break the transmission chains in the same region.

        Silva MT, Portaels F, Pedrosa J. Aquatic insects and Mycobacterium ulcerans: an association relevant to Buruli ulcer control? PLoS Med. 2007 Feb;4(2):e63.

The WHO recommended duration of the antibiotic treatment against Buruli ulcer is 8 weeks. If the treatment as used in this clinical trial with Artemisia afra infusion and poultice is of much shorter duration, this is a major advantage.

A review made in 2011 lists for Artemisia afra all the diseases and literature references for the following ailments : cardiovascular disease, parasitic diseases, cancers, respiratory infections, digestive diseases, diabetes mellitus, gynecological problems, gout, malaria, asthma, measles but fails to find any reference to the treatment of Buruli ulcer.

        Patil GV, Dass SK, Chandra R (2011) Artemisia afra and Modern Diseases. J Pharmacogenom Pharmacoproteomics 2:105. doi:10.4172/2153-0645.1000105

The potential efficacy of Artemisia afra against mycobacteria is well documented in several research papers from South Africa. They showed that the aqueous extract regulated pulmonary inflammation during early infection of tuberculosis. Their study clearly demonstrates that Artemisia afra contains in vitro antimycobacterial activity. It is often suggested that the flavone luteolin is a key molecule.

        Ntulela S, Smith P, Jacobs M. Efficacy of Artemisia afra phytotherapy in experimental tuberculosis. Tuberculosis 2009. 89, S 33-40

        Peter Masoko, Kulani Nxumalo, Validation of antycobacterial plants used by traditional healser of the Limpopo province. Evid Based Complement Alternat Med. 2013, ID 586247.

Luteolin present in other plants also has a strong effect against mycobacteria.

        Rafaele CP Araujo, Francisco AR Neves, Anelise SN Formagio. Evaluation of the anti-mycobacterium tuberculosis activity and in vivo acute toxicity of Annona sylvatica. BMC Complement Altern Med. 2014; 14: 209.

The bioavailability of luteolin in peanut hull extract form is significantly greater than that of pure luteolin. A pharmacokinetics study showed that following oral administration of a single dose of pure luteolin (14.3 mg/kg) or peanut hull extract(= 14.3 mg/kg of luteolin) in rats, the peak concentration of luteolin in plasma ( C max) and the area under the concentration curve (AUC) for pure luteolin were 10 times lower than for the extract.

        Zhou P, Li LP, Luo SQ, Jiang HD, Zeng S. Intestinal absorption of luteolin from peanut hull extract is more efficient than that from individual pure luteolin. J Agric Food Chem. 2008 Jan 9;56(1):296-300. Epub 2007 Dec 5.

The efficiency of Artemisia afra against Mycobacteria might also be related to its ability to raise the CD4+ count as we have demonstrated in Katanga.

        Constant Kansango Tchandema, Pierre Lutgen. In Vivo Trials on The Therapeutic Effects of Encapsulated Artemisia Annua and Artemisia Afra. GJRA Global Journal for Research analysis 2016 June, ISSN No2277-8160

CD4 T cells are essential for the control of infection. Mice with impaired CD4 and CD8 T-cell responses have a markedly weakened control of infection agains Mycobacterium bovis. Buruli ulcer was found to be more than double in patients with a CD4 cell count below 500cell/mm3.

        AM Green, R diFazio, J Flynn. IFN-gamma from CD4 T celles is essential for host survival during Mycobacterium tuberculosis infection. J Immunol 2013, 190, 270-277

        Zhou Xing, Jun Wang, J Wakeham. Protection by CD4 and CD8 cells against pulmonary Mycobacterium bovis. Infection and Immunity. 1998, 5537-5542.

        V Christnet, E Comte, A Calmy. Impact of human immunodeficiency virus on the severity of buruli ulcer disease in Cameroon. Open Forum Infect Dis 2014 May 21.

Worrisome is the antagonism between rifampicin and antimalarial drugs. In a clinical trial artemether and dihydroartemisinin area under the concentration-time curve were significantly lower by 89% during rifampicin-based treatment The authors conclude that artemether-lumefantrine should not be co-administered with rifampicin.

        Lamorde M, Byakika-Kibwika P, Mayito J, Nabukeera L, Ryan M, Hanpithakpong W, Lefèvre G, Back DJ, Khoo SH, Merry C. Lower artemether, dihydroartemisinin and lumefantrine concentrations during rifampicin-based tuberculosis treatment. AIDS. 2013 Mar 27;27(6):961-5. doi: 10.1097/QAD.0b013e32835cae3b.

Selenium levels are very low in people infected by Mycobacterium ulcerans et tuberculosis. In Malawi lower plasma levels of selenium were found in smear-positive tuberculosis patients

         Shor-Posner G, Miguez MJ, Pineda LM. Impact of selenium status on pathogenesis. .J Acquir Immune Defic Syndr 2002;29:169–173. 140.

         Arntsen A, Sakhi AK, Kalfoss T, Maleta K, Blomhoff R, Duttaroy AK, Bjune A. Lower plasma levels of selenium and glutathione in smear-positive tuberculosis patients in Malawi. Ethiopian J Health Dev 2011, 25 230-232

This was confirmed by another study: low selenium concentrations, high HIV load and high IL-6 concentrations are associated with anemia in adults with pulmonary tuberculosis

         M van Lettow, C E West, J W M van der Meer, F T Wieringa and R D Semba. Low plasma selenium concentrations, high plasma human immunodeficiency virus load and high interleukin-6 concentrations are risk factors associated with anemia in adults presenting with pulmonary tuberculosis in Zomba district, Malawi, European Journal of Clinical Nutrition 2005, 59, 526–532. doi:10.1038/sj.ejcn. 1602116

A clinical trial was run in Ghana studying the effect of topical application nitric oxide on Buruli ulcer wounds. Creams containing sodium nitrite and citric acid were applied, a mixture which generates nitric oxide. These creams significantly increased the healing rate and reduced the ulcer size.

       R Phillips, O Adjei, S Lucas. Pilot randomized double-blind trial of treatment of Mycobacterium ulcerans with topical nitrogen oxides. Antimicrob Ag and Chemotherapy. 2004 286-2870

In another assay, Buruli ulcer, was exposed to acidified nitrite or to acid alone for 10 or 20 min. Killing was rapid, and viable counts were reduced below detectable limits within 10 min of exposure to 40 mM acidified nitrite. M. ulcerans is highly susceptible to acidified nitrite in vitro.

       Phillips R, Kuijper S, Benjamin N, Wansbrough-Jones M, Wilks M, Kolk AH. In vitro killing of Mycobacterium ulcerans by acidified nitrite. Antimicrob Agents Chemother. 2004 Aug;48(8):3130-2

The results of a Portuguese study show that NO production is required for the control of M. ulcerans. Mycolactone plays a key inhibitory role in this process

       Egıdio Torrado, Alexandra G. Fraga, Elsa Logarinho, IFN-g–Dependent Activation of Macrophages during Experimental Infections by Mycobacterium ulcerans Is Impaired by the Toxin Mycolactone The Journal of Immunology. J Immunol 2010; 184:947-955;

All Artemisia plants are rich in arginine, the only amino acid which produces nitric oxide enhancing the defense mechanism of animals against bacteria and the killer potential of the immune system. Medicinal plants in general are richer in nitrates and nitro-compounds than common vegetables.

THE BATTLEFIELD BETWEEN IRON AND GALLIUM

Iron is a prerequisite for in vitro growth of mycobacteria. Several studies also suggest that an excess of iron may enhance the growth of M tuberculosis and worsen the outcome of human tuberculosis. Iron sequestration represents a challenge to in vivo growth of pathogenic mycobacteria. Artemisia plants contain several chelating agents and they may play a critical role.

      Lounis N, Truffot-Pernot C, Grosset J, Iron and Mycobacterium tuberculosis infection. J Clin Virol 2001, 20, 123-6.

      J De Vos, K Rutter, B Schroeder. Iron acquisition and metabolism of mycobacteria. J of Bacteriology, 1999, 4443-4451.

This also may explain the efficiency of clay poultices on open Buruli ulcer wounds. Clay absorbs excess iron and other minerals. (Mission Anti-Ulcère de Buruli. Mission catholique italienne des Frères capucins. Zouan-Hounien, Côte-d’Ivoire). Limitation of Fe availability is utilized by many animal species as a means to host defense. Clays are rich in gallium up to 55 ppm versus 16 ppm in the earth crust. Some clays in Niger and Ethiopia go up to 130 ppm gallium.

        Amin N, Andi Y, Mineralogie et physicochimie des argiles de traitement de l’ulcère de Buruli en Côte-d’Ivoire J. sci. pharm. biol., Vol.10, n°1 - 2009, pp. 21-30

        Lynda B. Williams, Rossman F. Giese, Jr., and Dennis D. Eberl. Shelley E. Haydel, Chemical and mineralogical caracteristics of French green clays used for healing. Clays Clay Miner. 2008 Aug; 56(4): 437–452.

        O Alakanmi, B Britigan, L Schlesinger. Gallium disrupts iron metabolism of mycobacteria residing within human macrophages.Infection and Immunity, 2000, 5619-27.

Gallium acts like an Trojan horse. The bacteria have to steal some iron from the host if they are to survive. Feeding them gallium which they mistake for iron, kills them. Many biological systems cannot distinguish Ga3+ from Fe3+ because they have virtually identical ionic radii. But gallium lacks iron’s vital redox chemistry driving cells’ metabolic processes. Mistaking gallium for iron is fatal for bacteria. Mycobacterium abscessus comprises a group of rapidly growing, multidrug-resistant, nontuberculous mycobacteria that are responsible for a wide spectrum of skin and soft tissue diseases, central nervous system infections, bacteremia, and ocular and other infections. Treatment options are limited because the organism’s resistance to currently available antibiotics. In a study in the US the growth inhibitory activity of different Ga compounds against an American type strain was studied. Gallium nitrate and all other Gallium compounds inhibited the growth of these mycobacteria. Inhibition was mediated by disrupting iron uptake, as the addition of exogenous iron restored basal growth. Ga-propoprphyrin completely and significantly inhibited the mycobacteria at much lower concentrations than gallium nitrate. Both act at µM concentrations.

        M Y Abdalla, B L Switzer, C H Goss, B E Britigan. Gallium compounds exhibit potential as new therapeutic agents against Mycobacterium abscessus. , Antimicrob Ag and Chemotherapy, 2015, 59, 4826-4834

In Pseudomonas aeruginosa gallium is preferably taken up over iron and gallium nitrate inhibits growth of this bacteria in vitro.

       The Group 13 Metals Aluminium, Gallium, Indium and Thallium; Simon Aldridge Anthony Downs, 2011

Protoporphyrin IX is a carrier molecule for divalent cations. Together with iron (Fe 2+) the body of the heme- group of hemoglobin, myoglobin and many other heme-containing enzymes like cytochrome and catalase are formed. Complexed with magnesium-ions (Mg 2+) the main part of the chlorophylls are formed. Complexed with zinc-ions (Zn 2+) it forms zinc protoporphyrin. But protoporphyrin may also form complexes with gallium, interfering strongly with hemoglobin. Gallium [Ga(III)] is an iron mimetic metal which inhibits P. aeruginosa growth by interfering with iron-dependent metabolism. The Ga(III) complex of the heme precursor protoporphyrin IX (GaPPIX) showed enhanced antibacterial activity against several bacterial species.

       Sarah Hijazi, Paolo Visca, and Emanuela Frangipani. Gallium-Protoporphyrin IX Inhibits Pseudomonas aeruginosa Growth by Targeting Cytochromes. Front Cell Infect Microbiol. 2017; 7: 12.

It is difficult to find data on gallium concentration in plants. But this trace metal has the highest uptake compared to a series of other metals B 100-fold higher than the MIC for sensitive bacteria.

It is difficult to find data on gallium concentration in plants. But this trace metal has the highest uptake compared to a series of other metals B<Mn<Fe<Zn<La<Cu<Ga.

     Wheeler DM, Power IL, Comparison of plant uptake of various ions in wheat. Plant and Soil 1995, 172, 167-173.

There is a selective uptake of gallium by plants: a higher ratio of Ga to Al is found in plants than in soils. The gallium concentration is around 1-10 ppm, 100 times higher than for other trace metals like As, Pb, Sr, Hg, Cd. In wheat gallium concentrations can go up to 2mg/g DM. Gallium also inhibits iron uptake, and Fe deficiency can be found in plants treated with gallium salts. Rice (Oryza sativa) also accumulates gallium.

      Johnson GV, Barton LL. Inhibition of iron deficiency stress response in cucumber by rare earth elements. Plant Physiol Biochem. 2007 May;45(5):302-8.

       Syu CH, Chien PH, Lee Dy The growth and uptake of Ga and In of rice, Ecotoxocol Environ Saf 2o17 135, 32-93

Organic wastes from plant material, citrus peels, tea waste, olive pomace are used to remove gallium from aqueous solutions

      Chou, W.L., Wang, C.T. and Huang, Y.H. 2010, Removal of Gallium Ions from Aqueous Solutions ... Fresenius Environmental Bulletin, 19 (12), 2848-2856

Many plants of the Artemisia family are accumulators of metals and heavy metals. The concentration of certain metals may exceed the concentration which is toxic to other plants

      E Alirzayeva, Heavy metal accumulation in Artemisia and foliaceous lichen species from the Azerbaijan flora. Forest Snow and Landscape Research 2006. 80, 3, 339-348 

In Italy Artemisia absinthium and Artemisia campestris are often found on industrial sites contaminated by metals.

      Massa N, Andreucci F, Poli M, Aceto M, Barbato R, Berta G. Screening for heavy metal accumulators amongst autochtonous plants in a polluted site in Italy. Ecotoxicol Environ Saf. 2010 Nov;73(8):1988-97. doi: 10.1016/j.ecoenv.2010.08.032. Epub 2010 Sep 29.

The stems and leaves of Artemisia tridentata are uranium acccumulators and indicators of uraniferous deposits in the western USA. Artemisia persia is a gold accumulator. Artemisia diffusa can carry remarkably high zinc levels.

Gallium salts, mainly nitrate, are well known as wound healing agents. It significantly enhances epidermal reepithelization.

There is even an US patent which claims that gallium containing medicaments enhance wound healing, skin, connective and support tisssue repair. They can be administered per os or topically applied. To this effect about 50 µM is required in the blood. However if gallium containing compounds are applied proximate to the site of injury a higher efficacy may be obtained. Administration of the compounds would cease once wound healing has occurred. Topical application of gallium containing ointments may also be useful to promote healing of skin grafts.

       Goncalves J, Wasif N, Esposito D. Gallium nitrate accelerates partial thickness wound repair. J Surg Res 2002, 103, 134-40.

        Patent EP0970700. Gallium containing medicaments enhancing wound healing and tissue repair

There are 0,7 mg gallium in the human body. The plasma concentration is around 30 µM. It is known since 40 years that gallium accumulates in inflammatory lesions. Permeability indices for inflammatory tissue are much greater than for normal tissues. Gallium nitrates inhibit the release of inflammatory mediators like IL-6, reducing pain and injury. This explains why this metal is used in the gallium scan, which looks for swelling (inflammation), infection, or cancer in the body.

      Min-Fu Tsan, Mechanism of Gallium-67. Accumulation in Inflammatory Lesions. The Journal of Nuclear Medicine, 26, 88-92. 1985.

      S Menon, H Wagner, Min-Fu Tsan, Studies on Gallium accumulation in inflammatory lesions. J Nucl Med. 1978. 19, 44-47.

When injected at tracer levels into the blood, radiogallium binds to plasma transferrin and is transported to the tumor tissue. The mechanism, however, by which this transferrin-bound gallium is converted to tumor-bound gallium is not clearly understood. There are some interferences with bicarbonate.  The stability of gallium-transferrin complex is pH-dependent and suggest that acidic pH at the tumor site may be one of the factors involved in gallium localization in tumors. The role of wound bed pH has proven to be of fundamental importance during the healing of chronic wounds, with prolonged chemical acidification of the wound bed having been shown to increase the healing rate in chronic venous leg ulcers.

       S.R. Vallabhajosula, J.F. Harwig, W. Wolf. The mechanism of tumor localization of gallium-67 citrate: Role of transferrin binding and effect of tumor pH. Science direct, 1981, 8, 363-70 DOI: http://dx.doi.org/10.1016/0047-0740(81)90044-9

In addition to binding to transferrin, gallium binds even more avidly to the related protein lactoferrin. A third iron-binding protein to which gallium can bind is ferritin, a very large nearly spherical protein. Ferritin is used for iron storage, is present in most cells, and is particularly concentrated in Kuppfer cells of the liver. Gallium is not, however, able to enter hemoglobin. This behaviour is important because gallium does not interfer with oxygen transport.

      E Peremiakov, Metalloproteomics, Wiley 2009

Already in 1994 it as suspected that Kuppfer cells have a supportive role in the homing of sporozoites.

      Vreden SG, The role of Kuppfer cells in the clearance of malaria sporozoites from the circulation. Parasitol Today 1994, 10, 304-8

It is now recognized that Kuppfer cells function as portals for malaria sporozoites to the liver. They are the resident macrophages of the liver and should phagocytose sporozoites. These traverse Kuppfer cells yet suffer no harm. It seems plausible that Plasmodium evolution produced sporozoites with the ability to manipulate Kuppfer cell function. They have learned to use Kuppfer cells as an affable portal and hepatocytes as a relatively secure niche and nutritional Schlaraffenland (land of plenty), thereby providing a jump start towards a successful blood infection.

       Ute Frevert, Ivan Usynin, Kerstin Baer. Kuppfer cells function as portals for malaria sporozoites to the liver. Cellular Microbiology 2006, 8, 1537-1546.

In our opinion, if so, and as Kuppfer cells are a reservoir of iron, any perturbation of this reservoir by sizeable quantities of gallium, may act as a prophylactic tool against sporozoite invasion. The liver is a major organ of gallium accumulation and iron deficiency markedly enhances this uptake.

       U Scheffel, H Wagner, J Frazier, Min-fu Tsan. Gallium-67 uptake by the liver. J Nucl Med 1984, 25, 1094-1100.

Several studies show that an acidic environment created by use of acid helps in wound healing by controlling wound infection, increasing antimicrobial activity, altering protease activity, releasing oxygen, reducing toxicity of bacterial end products, and enhancing epithelization and angiogenesis.

      Basavraj S. Nagoba, PhD; Namdev M. Suryawanshi, MD; Bharat Wadher, PhD; Sohan Selkar, MPhT . Acidic environment in wound healing.   Wounds . 2015;27(1):5-11.

Preclinical studies also indicate a role for gallium in autoimmune disorders, suggesting that gallium is able to modulate T-cell immune reactivity. Since gallium binds to transferrin in vivo, in vitro studies evaluated the effect of transferrin-gallium (Tf-Ga) on human T cells. Collectively, these data demonstrate that, at clinically achievable concentrations, Tf-Ga potently inhibits T-cell activation. This may explain why Artemisia annua from Cameroon which is growing on a gallium rich soil might inhibit lymphocyte activation whilst Artemisia annua from Luxembourg does not.

       Drobyski WR; Ul-Haq R; Majewski D; Chitambar CR Modulation of in vitro and in vivo T-cell responses by transferrin-gallium and gallium nitrate. Blood, 88(8):3056-64 1996 Oct 15

Gallium accumulates in plasma and bones. The process of absorption and desorption is slow, not hours but days and even weeks.

        Bockman RS; Boskey AL; Blumenthal NC; Alcock NW; Warrell RP Jr. Gallium increases bone calcium and crystallite perfection of hydroxyapatite Calcif Tissue Int, 39(6):376-81 1986

        Rubow S, Klopper J, Scholtz P. Excretion of gallium 67 in human breast milk Eur J Nucl Med. 1991;18(10):829-33.

The in vitro antimalarial activity against Plasmodium falciparum and heme polymerization (hemozoin) were evaluated for ten metalloporphyrins: gallium protoporphyrin IX (GaPPIX), sodium salt of gallium protoporphyrin IX, silver protoporphyrin IX, palladium protoporphyrin IX, cobalt protoporphyrin IX, manganese protoporphyrin IX, tin protoporphyrin IX (SnPPIX), chromium protoporphyrin IX, and gallium hematoporphyrin IX. Metalloporphyrins inhibited parasite growth with 50% inhibitory concentrations (IC50) ranging from 15.5 microM to 190 microM. In trophozoite lysate-mediated heme polymerization assays, SnPPIX, GaPPIX exerted potent inhibitory activity similar to that of artemisinin and chloroquine.

        Begum K, Kim HS, Kumar V, Stojiljkovic I, Wataya Y. In vitro antimalarial activity of metalloporphyrins against Plasmodium falciparum.

Gallium salts also appear to have a prophylactic action. This is claimed in several patents.

       Procédés de prévention ou de traitement de maladies infectueuses au moyen de composés de gallium. EP 2141996 B1

       Contrôle de la croissance des microorganismes oraux et superficiels à l’aide de composés de gallium EP 1962774 B1

This prophylactic activity is described against Mycobacterium avium in calves.

       Monk CS, Sweeney, Bernstein LR, Fecteau ME, Serum and tissue concentrations of gallium after oral administration of gallium nitrate and gallium maltolate to neonatal calves. Am J Vet Res, 2016, 77, 151-155.

Synergism between gallium(III) and antibiotics holds promise as a last resort therapy for infections sustained by pandrug-resistant bacteria. Particularly Rhodococcus equi in foals or immunodeficient people. Gallium maltonate has a higher efficiency than gallium nitrate. Macrophage cells were incubated with gallium maltonate and than infected with virulent R equi. Gallium pretreatment resulted in significant reductions of intracellular R equi and a dose-dependant effect was evident.

        RJ Martens, NA Miller, J Harrington, LR Bernstein. Chemprophylactic antimicrobial activity of gallium maltolate against intracellular Rhodococcus equi. J Equine Veterinary Science, 2007, 27, 341-345

        Adrián Rangel-Vega, Lawrence R. Bernstein, Edna Ayerim Mandujano-Tinoco, Drug repurposing as an alternative for the treatment of recalcitrant bacterial infections. Front Microbiol. 2015; 6: 282.

        Minandri F, Bonchi C, Visca P. Promises and failures of gallium as antibacterial agent. Future Microbiol 2014, 9, 379-97

        Arthur Baca. Gallium targets mycobacterial iron-uptake mechanisms: A potential treatment for Buruli ulcer? WHO Meeting on Buruli ulcer Control and Research (20–22 March 2017

Gallium nitrate stems blood flow from an open wound. A substantial reduction in bleeding time was observed in punctures in the forearm when a solution of gallium nitrate was applied.

       PH Goodley, M Rogosnitzky, The effect of gallium nitrate on arresting blood flow from a wound. Hindawi. Case reports in Medicine, 2011, article 819710

Gallium nitrate is FDA approved. Ga-protoporphyrin is not toxic to primary human fibroblasts, several established cell lines and experimental animals at concentrations > 100-fold higher than the MIC for sensitive bacteria.

        Stojiljkovic , Kumar V, Srinivasan N. Non-iron metalloporphyrins: potent antibacterial compounds that exploit haem/Hb uptake systems of pathogenic bacteria. Gallium nitrate is FDA approved. Mol Microbiol. 1999 Jan;31(2):429-42.