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Possible new way to fight lung infections
- Thread starter Chaggie
- Start date
This was the first and second clinical trials proposal for Univ. of Iowa. I believe these are finished and they are trying to get 3rd phase clinical trials going but I've heard it's slow going. We need more people to ask about this and help inform others. Gallium, a Potential New Therapeutic for CF Airway Infections
University of Washington School of Medicine
Principal Investigator:
Peter Thorne
Occupational & Environmental Health
College of Public Health
Professor
Funding:* $76,088
Many chronic infections are caused by bacteria living in biofilms, and the biofilm mode of growth is a major factor in the persistence of these infections. In biofilms, bacteria live in matrix-encased groups, and exhibit different physiology and gene expression than free-living (planktonic) organisms. Biofilm growth provides many benefits to infecting organisms, most notably, marked resistance to killing. Pseudomonas aeruginosa live in biofilms in the airway infections that afflict cystic fibrosis (CF) and other bronchiectasis patients, the endotracheal tube colonization leading to ventilator associated pneumonia; and in infections of medical devices.
Currently, no therapies exist that target biofilms, and new anti-biofilm treatments are sorely needed. Work from several laboratories suggests that iron (Fe) is a key environmental signal that promotes biofilm development, and that disrupting bacterial iron metabolism can block biofilm formation at early and late stages of development. Iron is also essential for planktonic growth. Gallium (Ga), a group IIIA transition metal, can substitute for Fe in biomolecular processes. Ga enters cells via the same mechanism used to acquire Fe.
However, substitution of Ga for Fe renders some enzymes inactive since Ga is not able to undergo redox cycling required for activity.
In preliminary studies, we have found that low concentrations of Ga block P. aeruginosa biofilm formation and inhibit planktonic growth. At higher concentrations, Ga kills planktonic and biofilm bacteria. Ga is not toxic to airway epithelia, is well tolerated by humans (administered systemically) and mice (systemic and inhaled dosing), and does not interfere with the host defense actions of native iron chelators like lactoferrin. Ga may also have anti-inflammatory activity. Importantly, we found that Ga is effective in two different murine lung infection models. Ga decreased bacterial counts by ~1000 fold in an airway biofilm infection model. Ga also completely protected mice from a lethal inoculum of planktonic P. aeruginosa in an acute pneumonia model. These preliminary data, the fact that gallium nitrate is FDA approved (for IV administration), and the dearth of new antibiotics in development make Ga a promising new therapeutic for the airway infections of cystic fibrosis and other infections. Here we will investigate whether inhaled gallium nitrate is a safe and potentially effective treatment.
In Years one and two of the proposal, Dr. Peter Thorne will perform comparison animal experiments in his laboratory. Dr. Thorne will be responsible for the characterization and optimization of the Ga nitrate aerosol generation system. He will conduct experiments to define Ga\'s dose-limiting adverse effects, pulmonary pharmacokinetics and the safety of prolonged Ga inhalation in mice.
University of Washington School of Medicine
Principal Investigator:
Peter Thorne
Occupational & Environmental Health
College of Public Health
Professor
Funding:* $76,088
Many chronic infections are caused by bacteria living in biofilms, and the biofilm mode of growth is a major factor in the persistence of these infections. In biofilms, bacteria live in matrix-encased groups, and exhibit different physiology and gene expression than free-living (planktonic) organisms. Biofilm growth provides many benefits to infecting organisms, most notably, marked resistance to killing. Pseudomonas aeruginosa live in biofilms in the airway infections that afflict cystic fibrosis (CF) and other bronchiectasis patients, the endotracheal tube colonization leading to ventilator associated pneumonia; and in infections of medical devices.
Currently, no therapies exist that target biofilms, and new anti-biofilm treatments are sorely needed. Work from several laboratories suggests that iron (Fe) is a key environmental signal that promotes biofilm development, and that disrupting bacterial iron metabolism can block biofilm formation at early and late stages of development. Iron is also essential for planktonic growth. Gallium (Ga), a group IIIA transition metal, can substitute for Fe in biomolecular processes. Ga enters cells via the same mechanism used to acquire Fe.
However, substitution of Ga for Fe renders some enzymes inactive since Ga is not able to undergo redox cycling required for activity.
In preliminary studies, we have found that low concentrations of Ga block P. aeruginosa biofilm formation and inhibit planktonic growth. At higher concentrations, Ga kills planktonic and biofilm bacteria. Ga is not toxic to airway epithelia, is well tolerated by humans (administered systemically) and mice (systemic and inhaled dosing), and does not interfere with the host defense actions of native iron chelators like lactoferrin. Ga may also have anti-inflammatory activity. Importantly, we found that Ga is effective in two different murine lung infection models. Ga decreased bacterial counts by ~1000 fold in an airway biofilm infection model. Ga also completely protected mice from a lethal inoculum of planktonic P. aeruginosa in an acute pneumonia model. These preliminary data, the fact that gallium nitrate is FDA approved (for IV administration), and the dearth of new antibiotics in development make Ga a promising new therapeutic for the airway infections of cystic fibrosis and other infections. Here we will investigate whether inhaled gallium nitrate is a safe and potentially effective treatment.
In Years one and two of the proposal, Dr. Peter Thorne will perform comparison animal experiments in his laboratory. Dr. Thorne will be responsible for the characterization and optimization of the Ga nitrate aerosol generation system. He will conduct experiments to define Ga\'s dose-limiting adverse effects, pulmonary pharmacokinetics and the safety of prolonged Ga inhalation in mice.
This is a long but informative article about an oral form of Gallium that sounds promising. Take a look.
http://www.surechem.org/index.php?A...27:BNRNXUUZRGQAQC-UHFFFAOYSA-N:7:5:inchi:2:0:
http://www.surechem.org/index.php?A...27:BNRNXUUZRGQAQC-UHFFFAOYSA-N:7:5:inchi:2:0:
http://www.ncbi.nlm.nih.gov/pubmed/22964249
[h=1]In vitro and in vivo antimicrobial activity of gallium nitrate against multidrug resistant Acinetobacter baumannii.[/h]Antunes LC, Imperi F, Minandri F, Visca P.
[h=3]Source[/h]Department of Biology, University "Roma Tre", Viale G. Marconi 446, 00146 Roma, Italy.
[h=3]Abstract[/h]Multidrug resistant Acinetobacter baumannii poses a tremendous challenge to traditional antibiotic therapy. Due to the crucial role of iron in bacterial physiology and pathogenicity, we investigated iron metabolism as a possible target for anti-A. baumannii chemotherapy using gallium as an iron-mimetic. Due to chemical similarity, gallium competes with iron for binding to several redox enzymes, thereby interfering with a number of essential biological reactions. We found that Ga(NO(3))(3), the active component of the FDA-approved drug Ganite®, inhibits the growth of a collection of 58 A. baumannii strains in both chemically-defined medium and human serum, at concentrations ranging from 2 to 80 μM and from 4 to 64 μM, respectively. Ga(NO(3))(3) delayed the entry of A. baumannii into the exponential phase and drastically reduced bacterial growth rates. Ga(NO(3))(3) activity was strongly dependent on iron availability in the culture medium, though the mechanism of growth inhibition was independent of dysregulation of gene expression controlled by the ferric uptake regulator Fur. Ga(NO(3))(3) also protected Galleria mellonella larvae from lethal A. baumannii infection, with survival rates ≥75%. At therapeutic concentrations for humans (28 μM plasma levels), Ga(NO(3))(3) inhibited the growth in human serum of 76% of the multidrug resistant A. baumannii isolates tested by ≥90%, raising expectations on the therapeutic potential of gallium for the treatment of A. baumannii bloodstream infections. Ga(NO(3))(3) also showed strong synergism with colistin, suggesting that a colistin-gallium combination holds promise as a last-resort therapy for infections caused by pan-resistant A. baumannii.
[h=1]In vitro and in vivo antimicrobial activity of gallium nitrate against multidrug resistant Acinetobacter baumannii.[/h]Antunes LC, Imperi F, Minandri F, Visca P.
[h=3]Source[/h]Department of Biology, University "Roma Tre", Viale G. Marconi 446, 00146 Roma, Italy.
[h=3]Abstract[/h]Multidrug resistant Acinetobacter baumannii poses a tremendous challenge to traditional antibiotic therapy. Due to the crucial role of iron in bacterial physiology and pathogenicity, we investigated iron metabolism as a possible target for anti-A. baumannii chemotherapy using gallium as an iron-mimetic. Due to chemical similarity, gallium competes with iron for binding to several redox enzymes, thereby interfering with a number of essential biological reactions. We found that Ga(NO(3))(3), the active component of the FDA-approved drug Ganite®, inhibits the growth of a collection of 58 A. baumannii strains in both chemically-defined medium and human serum, at concentrations ranging from 2 to 80 μM and from 4 to 64 μM, respectively. Ga(NO(3))(3) delayed the entry of A. baumannii into the exponential phase and drastically reduced bacterial growth rates. Ga(NO(3))(3) activity was strongly dependent on iron availability in the culture medium, though the mechanism of growth inhibition was independent of dysregulation of gene expression controlled by the ferric uptake regulator Fur. Ga(NO(3))(3) also protected Galleria mellonella larvae from lethal A. baumannii infection, with survival rates ≥75%. At therapeutic concentrations for humans (28 μM plasma levels), Ga(NO(3))(3) inhibited the growth in human serum of 76% of the multidrug resistant A. baumannii isolates tested by ≥90%, raising expectations on the therapeutic potential of gallium for the treatment of A. baumannii bloodstream infections. Ga(NO(3))(3) also showed strong synergism with colistin, suggesting that a colistin-gallium combination holds promise as a last-resort therapy for infections caused by pan-resistant A. baumannii.
[h=2]Ganite Description[/h]Gallium nitrate injection is a clear, colorless, odorless, sterile solution of gallium nitrate, a hydrated nitrate salt of the group IIIa element, gallium. Gallium nitrate is formed by the reaction of elemental gallium with nitric acid, followed by crystallization of the drug from the solution. The stable, nonahydrate, Ga(N03)3•9H2O is a white, slightly hygroscopic, crystalline powder of molecular weight 417.87, that is readily soluble in water. Each mL of Ganite (gallium nitrate injection) contains gallium nitrate 25 mg (on an anhydrous basis) and sodium citrate dihydrate 28.75 mg. The solution may contain sodium hydroxide or hydrochloric acid for pH adjustment to 6.0-7.0.
[h=2]Ganite - Clinical Pharmacology[/h]Mechanism of Action Ganite exerts a hypocalcemic effect by inhibiting calcium resorption from bone, possibly by reducing increased bone turnover. Although in vitro and animal studies have been performed to investigate the mechanism of action of gallium nitrate, the precise mechanism for inhibiting calcium resorption has not been determined. No cytotoxic effects were observed on bone cells in drug-treated animals.
Pharmacokinetics Gallium nitrate was infused at a daily dose of 200 mg/m2 for 5 (n=2) or 7 (n=10) consecutive days to 12 cancer patients. In most patients apparent steady-state is achieved by 24 to 48 hours. The range of average steady-state plasma levels of gallium observed among 7 fully evaluable patients was between 1134 and 2399 ng/mL. The average plasma clearance of gallium (n=7) following daily infusion of gallium nitrate at a dose of 200 mg/m2 for 5 or 7 days was 0.15 L/hr/kg (range: 0.12 to 0.20 L/hr/kg). In one patient who received daily infusion doses of 100, 150 and 200 mg/m2 the apparent steady-state levels of gallium did not increase proportionally with an increase in dose. Gallium nitrate is not metabolized either by the liver or the kidney and appears to be significantly excreted via the kidney. Urinary excretion data for a dose of 200 mg/m2 has not been determined.
[h=2]Ganite - Clinical Pharmacology[/h]Mechanism of Action Ganite exerts a hypocalcemic effect by inhibiting calcium resorption from bone, possibly by reducing increased bone turnover. Although in vitro and animal studies have been performed to investigate the mechanism of action of gallium nitrate, the precise mechanism for inhibiting calcium resorption has not been determined. No cytotoxic effects were observed on bone cells in drug-treated animals.
Pharmacokinetics Gallium nitrate was infused at a daily dose of 200 mg/m2 for 5 (n=2) or 7 (n=10) consecutive days to 12 cancer patients. In most patients apparent steady-state is achieved by 24 to 48 hours. The range of average steady-state plasma levels of gallium observed among 7 fully evaluable patients was between 1134 and 2399 ng/mL. The average plasma clearance of gallium (n=7) following daily infusion of gallium nitrate at a dose of 200 mg/m2 for 5 or 7 days was 0.15 L/hr/kg (range: 0.12 to 0.20 L/hr/kg). In one patient who received daily infusion doses of 100, 150 and 200 mg/m2 the apparent steady-state levels of gallium did not increase proportionally with an increase in dose. Gallium nitrate is not metabolized either by the liver or the kidney and appears to be significantly excreted via the kidney. Urinary excretion data for a dose of 200 mg/m2 has not been determined.
[h=1]Gallium maltolate treatment eradicates Pseudomonas aeruginosa infection in thermally injured mice.[/h]DeLeon K, Balldin F, Watters C, Hamood A, Griswold J, Sreedharan S, Rumbaugh KP.
[h=3]Source[/h]Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
[h=3]Abstract[/h]Gallium (Ga) is a semimetallic element that has demonstrated therapeutic and diagnostic-imaging potential in a number of disease settings, including cancer and infectious diseases. Gallium's biological actions stem from its ionic radius being almost the same as that of ferric iron (Fe(3+)), whereby it can replace iron (Fe) in Fe(3+)-dependent biological systems, such as bacterial and mammalian Fe transporters and Fe(3+)-containing enzymes. Unlike Fe(3+), ionic gallium (Ga(3+)) cannot be reduced, and when incorporated, it inactivates Fe(3+)-dependent reduction and oxidation processes that are necessary for bacterial and mammalian cell proliferation. Most pathogenic bacteria require Fe for growth and function, and the availability of Fe in the host or environment can greatly enhance virulence. We examined whether gallium maltolate (GaM), a novel formulation of Ga, had antibacterial activity in a thermally injured acute infection mouse model. Dose-response studies indicated that a GaM dose as low as 25 mg/kg of body weight delivered subcutaneously was sufficient to provide 100% survival in a lethal P. aeruginosa-infected thermally injured mouse model. Mice treated with 100 mg/kg GaM had undetectable levels of Pseudomonas aeruginosa in their wounds, livers, and spleens, while the wounds of untreated mice were colonized with over 10(8) P. aeruginosa CFU/g of tissue and their livers and spleens were colonized with over 10(5) P. aeruginosa CFU/g of tissue. GaM also significantly reduced the colonization of Staphylococcus aureus and Acinetobacter baumannii in the wounds of thermally injured mice. Furthermore, GaM was also therapeutically effective in preventing preestablished P. aeruginosa infections at the site of the injury from spreading systemically. Taken together, our data suggest that GaM is potentially a novel antibacterial agent for the prevention and treatment of wound infections following thermal injury.
[h=3]Source[/h]Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
[h=3]Abstract[/h]Gallium (Ga) is a semimetallic element that has demonstrated therapeutic and diagnostic-imaging potential in a number of disease settings, including cancer and infectious diseases. Gallium's biological actions stem from its ionic radius being almost the same as that of ferric iron (Fe(3+)), whereby it can replace iron (Fe) in Fe(3+)-dependent biological systems, such as bacterial and mammalian Fe transporters and Fe(3+)-containing enzymes. Unlike Fe(3+), ionic gallium (Ga(3+)) cannot be reduced, and when incorporated, it inactivates Fe(3+)-dependent reduction and oxidation processes that are necessary for bacterial and mammalian cell proliferation. Most pathogenic bacteria require Fe for growth and function, and the availability of Fe in the host or environment can greatly enhance virulence. We examined whether gallium maltolate (GaM), a novel formulation of Ga, had antibacterial activity in a thermally injured acute infection mouse model. Dose-response studies indicated that a GaM dose as low as 25 mg/kg of body weight delivered subcutaneously was sufficient to provide 100% survival in a lethal P. aeruginosa-infected thermally injured mouse model. Mice treated with 100 mg/kg GaM had undetectable levels of Pseudomonas aeruginosa in their wounds, livers, and spleens, while the wounds of untreated mice were colonized with over 10(8) P. aeruginosa CFU/g of tissue and their livers and spleens were colonized with over 10(5) P. aeruginosa CFU/g of tissue. GaM also significantly reduced the colonization of Staphylococcus aureus and Acinetobacter baumannii in the wounds of thermally injured mice. Furthermore, GaM was also therapeutically effective in preventing preestablished P. aeruginosa infections at the site of the injury from spreading systemically. Taken together, our data suggest that GaM is potentially a novel antibacterial agent for the prevention and treatment of wound infections following thermal injury.
This is exciting news. I will research this topic further. Check out my blog for other ways to beat the bacteria: http://cfandhealthy.blogspot.com.au/
litteni,
Thanks so much for bringing back this old post and drawing light on gallium!
I just wanted to tell you (and everyone else interested) that I asked my doctor about this at clinic yesterday. I thought there was a decent chance he would have no clue what I was even talking about and/or think I was a little wacky. Much to my surprise, he said my center is going to be doing a study on it!! He said the the head of the research dept is VERY interested in using gallium to treat cystic fibrosis. They are still in the development stage of the study, so not ready to recruit or anything yet. I told him to keep me in the loop and that I'd be interested in participating.
So I can also keep you posted when I hear more. Sounds like it could be a little while. These things seem to move at a snails pace.
Thanks again,
Autumn
Thanks so much for bringing back this old post and drawing light on gallium!
I just wanted to tell you (and everyone else interested) that I asked my doctor about this at clinic yesterday. I thought there was a decent chance he would have no clue what I was even talking about and/or think I was a little wacky. Much to my surprise, he said my center is going to be doing a study on it!! He said the the head of the research dept is VERY interested in using gallium to treat cystic fibrosis. They are still in the development stage of the study, so not ready to recruit or anything yet. I told him to keep me in the loop and that I'd be interested in participating.
So I can also keep you posted when I hear more. Sounds like it could be a little while. These things seem to move at a snails pace.
Thanks again,
Autumn
T
terypowel
Guest
Now a days, most of the people face lung infection around the whole world. People should avoid smoking and take precautions for minor illnesses that results in lung infection. One should take proper sleep and food in order to stay healthy. Most importantly, people should wash their hands very well.