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Updated patent references; briefly updated information on chemical properties and on topical gallium maltolate
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'''Gallium maltolate''' is a [[coordination complex]] consisting of a trivalent [[gallium]] cation coordinated to three [[maltol]]ate [[ligand]]s. The compound is undergoing clinical and preclinical testing as a potential therapeutic agent for cancer, infectious disease, and inflammatory disease.<ref name="MBD">{{cite journal |last=Bernstein |first=L.R.|coauthors=Tanner, T.; Godfrey, C.; Noll, B. | title = Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability | journal = Metal Based Drugs | year = 2000 | volume = 7 | pages = 33–48 | doi = 10.1155/MBD.2000.33 |pmid=18475921 |issue=1 |pmc=2365198}}</ref><ref name="Metallotherapeutics">{{cite book |last=Bernstein |first=L.R. |editor=Gielen, M.; Tiekink, E.R.T. |title=Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine|publisher=Wiley |location=New York |isbn=978-0-470-86403-6 |pages=259–277 |chapter=Therapeutic gallium compounds
'''Gallium maltolate''' is a [[coordination complex]] consisting of a trivalent [[gallium]] cation coordinated to three [[maltol]]ate [[ligand]]s. The compound is undergoing clinical and preclinical testing as a potential therapeutic agent for cancer, infectious disease, and inflammatory disease.<ref name="MBD">{{cite journal |last=Bernstein |first=L.R.|coauthors=Tanner, T.; Godfrey, C.; Noll, B. | title = Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability | journal = Metal Based Drugs | year = 2000 | volume = 7 | pages = 33–48 | doi = 10.1155/MBD.2000.33 |pmid=18475921 |issue=1 |pmc=2365198}}</ref><ref name="Metallotherapeutics">{{cite book |last=Bernstein |first=L.R. |editor=Gielen, M.; Tiekink, E.R.T. |title=Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine|publisher=Wiley |location=New York |isbn=978-0-470-86403-6 |pages=259–277 |chapter=Therapeutic gallium compounds
|chapterurl=http://home.earthlink.net/~alixapharm/GAMReferences/MetallotherapeuticsChapter14.pdf |year=2005}}</ref><ref name="Chitambar">{{cite journal | author = Chitambar, C.R.; Purpi, D.P.; Woodliff, J.; Yang, M.; Wereley J.P. | title = Development of Gallium Compounds for Treatment of Lymphoma: Gallium Maltolate, a Novel Hydroxypyrone Gallium Compound, Induces Apoptosis and Circumvents Lymphoma Cell Resistance to Gallium Nitrate | journal = J. Pharmacol. Exp. Ther. | year = 2007 | volume = 322 | pages = 1228–1236 |url=http://home.earthlink.net/~alixapharm/GAMReferences/Chitambar_GaM_2007.pdf|doi = 10.1124/jpet.107.126342 | pmid = 17600139 | issue = 3}}</ref><ref name="Chua">{{cite journal | author = Chua, M.-Z.; Bernstein, L.R.; Li, R.; So, S.K. | title = Gallium maltolate is a promising chemotherapeutic agent for the treatment of hepatocellular carcinoma| journal = Anticancer Research | year = 2006 | volume = 26 | pages = 1739–1743 | url = http://home.earthlink.net/~alixapharm/GAMReferences/6910CHUA.pdf | pmid = 16827101 | issue = 3A}}</ref> It appears to
|chapterurl=http://home.earthlink.net/~alixapharm/GAMReferences/MetallotherapeuticsChapter14.pdf |year=2005}}</ref><ref name="Chitambar">{{cite journal | author = Chitambar, C.R.; Purpi, D.P.; Woodliff, J.; Yang, M.; Wereley J.P. | title = Development of Gallium Compounds for Treatment of Lymphoma: Gallium Maltolate, a Novel Hydroxypyrone Gallium Compound, Induces Apoptosis and Circumvents Lymphoma Cell Resistance to Gallium Nitrate | journal = J. Pharmacol. Exp. Ther. | year = 2007 | volume = 322 | pages = 1228–1236 |url=http://home.earthlink.net/~alixapharm/GAMReferences/Chitambar_GaM_2007.pdf|doi = 10.1124/jpet.107.126342 | pmid = 17600139 | issue = 3}}</ref><ref name="Chua">{{cite journal | author = Chua, M.-Z.; Bernstein, L.R.; Li, R.; So, S.K. | title = Gallium maltolate is a promising chemotherapeutic agent for the treatment of hepatocellular carcinoma| journal = Anticancer Research | year = 2006 | volume = 26 | pages = 1739–1743 | url = http://home.earthlink.net/~alixapharm/GAMReferences/6910CHUA.pdf | pmid = 16827101 | issue = 3A}}</ref> It appears to
have low toxicity when administered orally, without the renal toxicity observed for intravenously administered gallium nitrate. The lower toxicity probably results because gallium absorbed into the body from oral gallium maltolate becomes nearly entirely protein bound, whereas gallium from intravenous gallium nitrate tends to form anionic gallium hydroxide (Ga(OH)<sub>4</sub><sup>-</sup>; gallate) in the blood, which is rapidly excreted in the urine and may be renally toxic.<ref name = "MBD"/>
have low toxicity when administered orally, without the renal toxicity observed for intravenously administered gallium nitrate. The lower toxicity probably results because gallium absorbed into the body from oral gallium maltolate becomes nearly entirely protein bound, whereas gallium from intravenous gallium nitrate tends to form anionic gallium hydroxide (Ga(OH)<sub>4</sub><sup>-</sup>; gallate) in the blood, which is rapidly excreted in the urine and may be renally toxic.<ref name = "MBD"/> Topical gallium maltolate, administered to the skin at a dose of approximately one-thousandth that of the safe oral dose, has had no reported adverse effects.<ref name="PHN"/>


==Chemical properties==
==Chemical properties==
Gallium maltolate is stable in aqueous solutions between about pH 5 and 8, and it has significant solubility in both water and lipids (octanol:water partition coefficient = 0.41).<ref name = "MBD"/>
In aqueous solutions, gallium maltolate has neutral charge and pH, and is stable between about pH 5 and 8. It has significant solubility in both water and lipids (octanol:water partition coefficient = 0.41).<ref name = "MBD"/>


==Therapeutic activity==
==Therapeutic activity==
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The anti-inflammatory activity of gallium appears to involve the down-regulation of inflammatory [[T cell]]s and [[macrophage]]s, as well as possible interference with [[matrix metalloproteinase]]s.<ref name="Metallotherapeutics"/><ref name="PharmRev"/> Because many iron compounds are pro-inflammatory, the ability of gallium to act as a non-functional iron mimic may contribute to its anti-inflammatory activity.<ref name="Metallotherapeutics"/>
The anti-inflammatory activity of gallium appears to involve the down-regulation of inflammatory [[T cell]]s and [[macrophage]]s, as well as possible interference with [[matrix metalloproteinase]]s.<ref name="Metallotherapeutics"/><ref name="PharmRev"/> Because many iron compounds are pro-inflammatory, the ability of gallium to act as a non-functional iron mimic may contribute to its anti-inflammatory activity.<ref name="Metallotherapeutics"/>


Analgesic activity has also been reported for gallium maltolate. Orally administered gallium maltolate has alleviated cancer-related pain, and topically applied gallium maltolate has been effective against refractory [[neuropathic pain]] (severe [[postherpetic neuralgia]]).<ref name="PHN">{{cite journal |last=Bernstein |first=L.R.| title = Successful treatment of refractory postherpetic neuralgia with topical gallium maltolate: case report | journal = Pain Medicine | year = 2012 | volume = 13 | pages = 915-918 | url = http://home.earthlink.net/~alixapharm/GAMReferences/BernsteinPainMedicine2012.pdf | doi = 10.1111/j.1526-4637.2012.01404.x | pmid = 22680305 }}</ref> The analgesic activity likely derives from gallium's observed anti-inflammatory mechanisms, and possibly from its interactions with certain [[matrix metalloproteinase]]s and [[substance P]], whose activities are zinc-mediated and which have been implicated in the etiology of pain.<ref name="PHN"/>
Analgesic activity has also been reported for gallium maltolate. Orally administered gallium maltolate has alleviated cancer-related pain, and topically applied gallium maltolate, at doses one-thousandth those of the safe oral doses, has been effective against refractory [[neuropathic pain]] (severe [[postherpetic neuralgia]]).<ref name="PHN">{{cite journal |last=Bernstein |first=L.R.| title = Successful treatment of refractory postherpetic neuralgia with topical gallium maltolate: case report | journal = Pain Medicine | year = 2012 | volume = 13 | pages = 915-918 | url = http://home.earthlink.net/~alixapharm/GAMReferences/BernsteinPainMedicine2012.pdf | doi = 10.1111/j.1526-4637.2012.01404.x | pmid = 22680305 }}</ref> The analgesic activity likely derives from gallium's observed anti-inflammatory mechanisms, and possibly from its interactions with certain [[matrix metalloproteinase]]s and [[substance P]], whose activities are zinc-mediated and which have been implicated in the etiology of pain.<ref name="PHN"/>


==Pharmaceutical development==
==Pharmaceutical development==
Pharmaceutical compositions and uses of gallium maltolate were first patented by Lawrence R. Bernstein.<ref>{{US patent|src=uspto|5574027}}</ref><ref>{{US patent|src=uspto|5747482}}</ref><ref>{{US patent|src=uspto|6048851}}</ref><ref>{{US patent|src=uspto|6087354}}</ref><ref>{{US patent|src=uspto|8076371}}</ref><ref>{{US patent|src=uspto|8168214}}</ref>
Pharmaceutical compositions and uses of gallium maltolate were first patented by Lawrence R. Bernstein.<ref>{{US patent|src=uspto|5574027}}</ref><ref>{{US patent|src=uspto|5747482}}</ref><ref>{{US patent|src=uspto|6048851}}</ref><ref>{{US patent|src=uspto|6087354}}</ref><ref>{{US patent|src=uspto|8293268}}</ref><ref>{{US patent|src=uspto|8293787}}</ref>


Christopher Chitambar and his associates at the [[Medical College of Wisconsin]] have found that gallium maltolate is active against several [[lymphoma]] cell lines, including those resistant to gallium nitrate.<ref name = "Chitambar"/>
Christopher Chitambar and his associates at the [[Medical College of Wisconsin]] have found that gallium maltolate is active against several [[lymphoma]] cell lines, including those resistant to gallium nitrate.<ref name = "Chitambar"/>

Revision as of 15:51, 3 November 2012

Gallium maltolate
Gallium maltolate
Names
IUPAC name
Tris(3-hydroxy-2-methyl-4H-pyran-4-one)gallium
Identifiers
Properties
Ga(C6H5O3)3
Molar mass 445.03 g/mol
Appearance White to pale beige crystalline solid or powder
Density 1.56 g/cm3, solid
Melting point 220 °C (decomposes)
24(2) mM; 10.7(9) mg/mL (25 °C)
Structure
Orthorhombic; space group Pbca
Distorted octahedral
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Gallium maltolate is a coordination complex consisting of a trivalent gallium cation coordinated to three maltolate ligands. The compound is undergoing clinical and preclinical testing as a potential therapeutic agent for cancer, infectious disease, and inflammatory disease.[1][2][3][4] It appears to have low toxicity when administered orally, without the renal toxicity observed for intravenously administered gallium nitrate. The lower toxicity probably results because gallium absorbed into the body from oral gallium maltolate becomes nearly entirely protein bound, whereas gallium from intravenous gallium nitrate tends to form anionic gallium hydroxide (Ga(OH)4-; gallate) in the blood, which is rapidly excreted in the urine and may be renally toxic.[1] Topical gallium maltolate, administered to the skin at a dose of approximately one-thousandth that of the safe oral dose, has had no reported adverse effects.[5]

Chemical properties

In aqueous solutions, gallium maltolate has neutral charge and pH, and is stable between about pH 5 and 8. It has significant solubility in both water and lipids (octanol:water partition coefficient = 0.41).[1]

Therapeutic activity

Gallium maltolate is able to deliver gallium with high oral bioavailability: the bioavailability is several times higher than that of gallium salts such as gallium nitrate and gallium trichloride.[1] Gallium is antiproliferative to pathologically proliferating cells, particularly cancer cells and some bacteria, due primarily to its ability to mimic ferric iron (Fe3+). Ferric iron is essential for DNA synthesis, as it is present in the active site of the enzyme ribonucleotide reductase, which catalyzes the conversion of ribonucleotides to the deoxyribonucleotides required for DNA. Gallium is taken up by the rapidly proliferating cells, but it is not functional for DNA synthesis, so the cells cannot reproduce and they ultimately die by apoptosis. Normally reproducing cells take up little gallium (as is known from gallium scans), and gallium is not incorporated into hemoglobin, accounting for the relatively low toxicity of gallium.[6]

The anti-inflammatory activity of gallium appears to involve the down-regulation of inflammatory T cells and macrophages, as well as possible interference with matrix metalloproteinases.[2][6] Because many iron compounds are pro-inflammatory, the ability of gallium to act as a non-functional iron mimic may contribute to its anti-inflammatory activity.[2]

Analgesic activity has also been reported for gallium maltolate. Orally administered gallium maltolate has alleviated cancer-related pain, and topically applied gallium maltolate, at doses one-thousandth those of the safe oral doses, has been effective against refractory neuropathic pain (severe postherpetic neuralgia).[5] The analgesic activity likely derives from gallium's observed anti-inflammatory mechanisms, and possibly from its interactions with certain matrix metalloproteinases and substance P, whose activities are zinc-mediated and which have been implicated in the etiology of pain.[5]

Pharmaceutical development

Pharmaceutical compositions and uses of gallium maltolate were first patented by Lawrence R. Bernstein.[7][8][9][10][11][12]

Christopher Chitambar and his associates at the Medical College of Wisconsin have found that gallium maltolate is active against several lymphoma cell lines, including those resistant to gallium nitrate.[3]

Gallium maltolate is being studied as a potential treatment for primary liver cancer (hepatocellular carcinoma; HCC). In vitro experiments demonstrated efficacy against all HCC cell lines tested [4] and a clinical case study produced very encouraging results in a patient with advanced HCC who had not responded to therapy with sorafenib [13]

The activity of gallium against infection-related biofilms, particularly those caused by Pseudomonas aeruginosa, is being studied by Pradeep Singh at the University of Washington, and by others, who have reported encouraging results in mice.[14][15] Pulmonary P. aeruginosa biofilms are responsible for many fatalities in cystic fibrosis and immunocompromised patients; in general, bacterial biofilms are responsible for significant morbidity and mortality.[16] In related research, locally administered gallium maltolate has shown potent efficacy against P. aeruginosa in a mouse burn/infection model.[17]

Oral gallium maltolate is also being investigated as a treatment for Rhodococcus equi foal pneumonia, a common and often fatal disease of newborn horses. R. equi can also infect humans with AIDS or who are otherwise immunocompromized. The veterinary studies are being conducted by researchers at Texas A&M University, led by Ronald Martens, Noah Cohen, and M. Keith Chaffin.[18][19]

References

  1. ^ a b c d Bernstein, L.R. (2000). "Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability". Metal Based Drugs. 7 (1): 33–48. doi:10.1155/MBD.2000.33. PMC 2365198. PMID 18475921. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: unflagged free DOI (link)
  2. ^ a b c Bernstein, L.R. (2005). "Therapeutic gallium compounds". In Gielen, M.; Tiekink, E.R.T. (ed.). Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine. New York: Wiley. pp. 259–277. ISBN 978-0-470-86403-6. {{cite book}}: External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help)CS1 maint: multiple names: editors list (link)
  3. ^ a b Chitambar, C.R.; Purpi, D.P.; Woodliff, J.; Yang, M.; Wereley J.P. (2007). "Development of Gallium Compounds for Treatment of Lymphoma: Gallium Maltolate, a Novel Hydroxypyrone Gallium Compound, Induces Apoptosis and Circumvents Lymphoma Cell Resistance to Gallium Nitrate" (PDF). J. Pharmacol. Exp. Ther. 322 (3): 1228–1236. doi:10.1124/jpet.107.126342. PMID 17600139.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ a b Chua, M.-Z.; Bernstein, L.R.; Li, R.; So, S.K. (2006). "Gallium maltolate is a promising chemotherapeutic agent for the treatment of hepatocellular carcinoma" (PDF). Anticancer Research. 26 (3A): 1739–1743. PMID 16827101.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ a b c Bernstein, L.R. (2012). "Successful treatment of refractory postherpetic neuralgia with topical gallium maltolate: case report" (PDF). Pain Medicine. 13: 915–918. doi:10.1111/j.1526-4637.2012.01404.x. PMID 22680305.
  6. ^ a b Bernstein, L.R. (1998). "Mechanisms of therapeutic activity for gallium" (PDF). Pharmacol. Rev. 50 (4): 665–682. PMID 9860806.
  7. ^ U.S. patent 5,574,027
  8. ^ U.S. patent 5,747,482
  9. ^ U.S. patent 6,048,851
  10. ^ U.S. patent 6,087,354
  11. ^ U.S. patent 8,293,268
  12. ^ U.S. patent 8,293,787
  13. ^ Bernstein, L.R.; van der Hoeven, J.J.; Boer, R.O. (2011). "Hepatocellular carcinoma detection by gallium scan and subsequent treatment with gallium maltolate: rationale and case study" (PDF). Anti-Cancer Agents in Medicinal Chemistry. 11 (6): 585–590. PMID 21554205.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Kaneko, Y.; Thoendel, M.; Olakanmi, O.; Britigan, B.E.; Singh, P.K. (2007). "The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity". J. Clin. Invest. 117 (4): 877–888. doi:10.1172/JCI30783. PMC 1810576. PMID 17364024.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Wirtz, U.F.; Kadurugamuwa, J.; Bucalo, L.R.; Sreedharan, S.P. (2006). "Efficacy of gallium maltolate in a mouse model for Pseudomonas aeruginosa chronic urinary tract infection" (PDF). American Society for Microbiology 106th general meeting. Orlando, Florida. pp. poster A-074. {{cite conference}}: Unknown parameter |booktitle= ignored (|book-title= suggested) (help)CS1 maint: multiple names: authors list (link)
  16. ^ Parsek, M.; Singh, P. (2003). "Bacterial biofilms: an emerging link to disease pathogenesis". Annu. Rev. Microbiol. 57: 677–701. doi:10.1146/annurev.micro.57.030502.090720. PMID 14527295.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ DeLeon K.; Balldin F.; Watters C.; Hamood A.; Griswold J.; Sreedharan S.; Rumbaugh K.P. (2009). "Gallium maltolate treatment eradicates Pseudomonas aeruginosa infection in thermally injured mice". Antimicrobial Agents and Chemotherapy. 53 (4): 1331–1337. doi:10.1128/AAC.01330-08. PMC 2663094. PMID 19188381.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Harrington, J.R.; Martens, R.J.; Cohen, N.D.; Bernstein, L.R. (2006). "Antimicrobial activity of gallium against virulent Rhodococcus equi in vitro and in vivo". J. Vet. Pharmacol. Ther. 29 (2): 121–127. doi:10.1111/j.1365-2885.2006.00723.x. PMID 16515666.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Martens, R.J.; Mealey, K.; Cohen, N.D.; Harrington, J.R.; Chaffin, M.K.; Taylor, R.J.; Bernstein, L.R. (2007). "Pharmacokinetics of gallium maltolate after intragastric administration in neonatal foals". Am. J. Vet. Res. 68 (10): 1041–1044. doi:10.2460/ajvr.68.10.1041. PMID 17916007.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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