Papers by Lawrence Bernstein
American Journal of Veterinary Research, Oct 1, 2007
APL Bioengineering, 2019
Chronic wounds are projected to reach epidemic proportions worldwide because of the aging populat... more Chronic wounds are projected to reach epidemic proportions worldwide because of the aging population and the increasing incidence of diabetes. Despite extensive research, infection remains one of the leading sources of complications in chronic wounds, resulting in improper healing, biofilm formation, and lower extremity amputation. To address the limitations of standard treatments, we have developed a hydrogel wound dressing with self-tuning moisture control that incorporates a novel antimicrobial agent to eliminate and prevent infection. 3D-printing of a hydrogel dressing with dual porosity resulted in a new dressing with greater flexibility, increased water uptake, and more rapid swelling than bulk hydrogel dressings. Additionally, gallium maltolate (GaM) was incorporated into the dressing to investigate the efficacy of this antimicrobial agent. Loading profiles, release kinetics, and the bactericidal activity against Staphylococcus aureus (including methicillin-resistant Staphylo...
U.S. GEOLOGICAL SURVEY BULLETIN 1577, 1986
The Apex Mine, in Washington County, southwestern Utah, is the first mine in the world to be oper... more The Apex Mine, in Washington County, southwestern Utah, is the first mine in the world to be operated primarily for germanium and gallium. The ore, consisting of goethite, limonite, hematite, jarosite, azurite, malachite, conichalcite, and several other metal oxides, carbonates, arsenates, and sulfates, is thoroughly oxidized to at least 42 5 m below the surface. Most of the copper-rich ore was removed during previous mining operations, leaving behind the iron-rich minerals that contain most of the germanium
and gallium. Germanium is concentrated chiefly in goethite (as much as 0.5 percent), hematite (as much as 0. 7 percent), and limonite (as much as 0. 5 percent), while gallium is concentrated mostly in jarosite (as much as 0. 7 percent) and in some limonite (as much as 2 percent). Copper minerals are concentrated in and adjacent to carbonate rock, apparently replacing it. The ore at the Apex Mine forms an irregular, branching, chimney-like body (or bodies) in fault breccia, gouge, and fissures associated with steeply dipping subparallel fault zones in the Pennsylvanian Callville Limestone. Within and immediately adjacent to the fault zones, limestone has been dolomitized and locally silicified. Only a few small pieces of unreplaced primary sulfide
ore have been found; these contain pyrite, galena, sphalerite, chalcopyrite, quartz, and traces of barite. The abundance of copper, germanium, gallium, and arsenic in the supergene ore implies the former presence of sulfides and sulfosalts containing these
metals in the primary ore, which would make it similar to dolomite-hosted ores at Kipushi, Zaire; Tsumeb, Namibia; and Ruby Creek, Alaska. High concentrations
of germanium and gallium should be looked for in gossans and other oxidized zones of copper-rich, arsenic-bearing sulfide deposits, particularly those in carbonate host rocks.
Journal of Veterinary Pharmacology and Therapeutics, 2014
Antimicrobial efficacy against Lawsonia intracellularis is difficult to evaluate in vitro, thus, ... more Antimicrobial efficacy against Lawsonia intracellularis is difficult to evaluate in vitro, thus, the effects of gallium maltolate's (GaM) were investigated in a rabbit model for equine proliferative enteropathy (EPE). Juvenile (5–6‐week‐old) does were infected with 3.0 × 108 L. intracellularis/rabbit and allocated into three groups (n = 8). One week postinfection, one group was treated with GaM, 50 mg/kg; one, with doxycycline, 5 mg/kg; and one with a sham‐treatment (control). Feces and blood were collected daily and weekly, respectively, to verify presence of L. intracellularis fecal shedding using qPCR, and seroconversion using immunoperoxidase monolayer assay. Rabbits were sacrificed after 1 week of treatment to collect intestinal tissues focusing on EPE‐affected sections. Intestinal lesions were confirmed via immunohistochemistry. No difference was noted between treatments regarding EPE‐lesions in jejunum (P = 0.51), ileum (P = 0.74), and cecum (P = 0.35), or in L. intracell...
Journal of Veterinary Pharmacology and Therapeutics, 2014
of gallium maltolate in Lawsonia intracellularis-infected and uninfected rabbits. J. vet. Pharmac... more of gallium maltolate in Lawsonia intracellularis-infected and uninfected rabbits. J. vet. Pharmacol. Therap.
PLOS Neglected Tropical Diseases, 2019
Background Gallium is a semi-metallic element known since the 1930s to have antimicrobial activit... more Background Gallium is a semi-metallic element known since the 1930s to have antimicrobial activity. This activity stems primarily from gallium's ability to mimic trivalent iron and disrupt specific Fe(III)-dependent pathways, particularly DNA synthesis (due to inhibition of ribonucleotide reductase). Because of its novel mechanism of action, gallium is currently being investigated as a new antibacterial agent, particularly in light of the increasing resistance of many pathogenic bacteria to existing antibiotics. Gallium maltolate (GaM) is being developed as an orally and topically administrable form of gallium. Yaws is a neglected tropical disease affecting mainly the skin and skeletal system of children in underprivileged settings. It is currently the object of a WHO-promoted eradication campaign using mass administration of the macrolide azithromycin, an antibiotic to which the yaws agent Treponema pallidum subsp. pertenue has slowly begun to develop genetic resistance. Methods Because yaws transmission is mainly due to direct skin contact with an infectious skin lesion, we evaluated the treponemicidal activity of GaM applied topically to skin lesions in a rabbit model of yaws. Treatment efficacy was evaluated by measuring lesion diameter, treponemal burden in lesion aspirates as determined by dark field microscopy and amplification of treponemal RNA, serology, and immunohistochemistry of biopsied tissue samples. Results Our results show that topical GaM was effective in reducing treponemal burden in yaws experimental lesions, particularly when applied at the first sign of lesion appearance but, as expected, did not prevent pathogen dissemination.
ACS Infectious Diseases, 2021
The decreasing efficacy of existing antibiotics against pulmonary pathogens that affect cystic fi... more The decreasing efficacy of existing antibiotics against pulmonary pathogens that affect cystic fibrosis (CF) patients calls for the development of novel antimicrobials. Iron uptake and metabolism are vital processes for bacteria, hence potential therapeutic targets. Gallium [Ga(III)] is a ferric ironmimetic that inhibits bacterial growth by disrupting iron uptake and metabolism. In this work we evaluate the efficacy of three Ga(III) compounds, namely, Ga(NO 3) 3 , (GaN), Ga(III)-maltolate (GaM), and Ga(III)-protoporphyrin IX (GaPPIX), against a collection of CF pathogens using both reference media and media mimicking biological fluids. All CF pathogens, except Streptococcus pneumoniae, were susceptible to at least one Ga(III) compound. Notably, Mycobacterium abscessus and Stenotrophomonas maltophilia were susceptible to all Ga(III) compounds. Achromobacter xylosoxidans, Burkholderia cepacia complex, and Pseudomonas aeruginosa were more susceptible to GaN and GaM, whereas Staphylococcus aureus and Haemophilus influenzae were more sensitive to GaPPIX. The results of this study support the development of Ga(III)-based therapy as a broad-spectrum strategy to treat CF lung infections.
Antiviral Chemistry and Chemotherapy, 2020
Background Gallium has demonstrated strong anti-inflammatory activity in numerous animal studies,... more Background Gallium has demonstrated strong anti-inflammatory activity in numerous animal studies, and has also demonstrated direct antiviral activity against the influenza A H1N1 virus and the human immunodeficiency virus (HIV). Gallium maltolate (GaM), a small metal-organic coordination complex, has been tested in several Phase 1 clinical trials, in which no dose-limiting or other serious toxicity was reported, even at high daily oral doses for several months at a time. For these reasons, GaM may be considered a potential candidate to treat coronavirus disease 2019 (COVID-19), which is caused by the SARS-CoV-2 virus and can result in severe, sometimes lethal, inflammatory reactions. In this study, we assessed the ability of GaM to inhibit the replication of SARS-CoV-2 in a culture of Vero E6 cells. Methods The efficacy of GaM in inhibiting the replication of SARS-CoV-2 was determined in a screening assay using cultured Vero E6 cells. The cytotoxicity of GaM in uninfected cells was ...
Journal of veterinary internal medicine / American College of Veterinary Internal Medicine, Jan 13, 2015
Macrolide-resistant isolates of Rhodococcus equi are emerging, prompting the search for clinicall... more Macrolide-resistant isolates of Rhodococcus equi are emerging, prompting the search for clinically effective alternative antimicrobials. The proportion of foals with ultrasonographic evidence of pneumonia presumed to be caused by R. equi that had a successful outcome when administered gallium maltolate (GaM) PO would not be more than 10% inferior (ie, lower) than that of foals receiving standard treatment. Fifty-four foals with subclinical pulmonary abscesses among 509 foals at 6 breeding farms in Kentucky. Controlled, randomized, prospective noninferiority study. Foals with ultrasonographic lesions >1 cm in diameter (n = 54) were randomly allocated to receive per os either clarithromycin combined with rifampin (CLR+R) or GaM, and followed up for 28 days by daily physical inspections and weekly (n = 1 farm) or biweekly (n = 4 farms) thoracic ultrasound examinations by individuals unaware of treatment-group assignments. Treatment success was defined as resolution of ultrasonograph...
Frontiers in Microbiology, 2015
Bacterial infection remains one of the leading causes of death worldwide, and the options for tre... more Bacterial infection remains one of the leading causes of death worldwide, and the options for treating such infections are decreasing, due the rise of antibiotic-resistant bacteria. The pharmaceutical industry has produced few new types of antibiotics in more than a decade. Researchers are taking several approaches toward developing new classes of antibiotics, including (1) focusing on new targets and processes, such as bacterial cell-cell communication that upregulates virulence; (2) designing inhibitors of bacterial resistance, such as blockers of multidrug efflux pumps; and (3) using alternative antimicrobials such as bacteriophages. In addition, the strategy of finding new uses for existing drugs is beginning to produce results: antibacterial properties have been discovered for existing anticancer, antifungal, anthelmintic, and anti-inflammatory drugs. In this review, we discuss the antimicrobial properties of gallium compounds, 5-fluorouracil, ciclopirox, diflunisal, and some other FDA-approved drugs and argue that their repurposing for the treatment of bacterial infections, including those that are multidrug resistant, is a feasible strategy.
Pharmacological reviews, 1998
Pain Medicine, 2012
Introduction. Postherpetic neuralgia is a common sequela of herpes zoster (shingles), in which ch... more Introduction. Postherpetic neuralgia is a common sequela of herpes zoster (shingles), in which chronic pain may last for weeks to years. Currently, available treatments include systemic opioid analgesics, tricyclic antidepressants, corticosteroids, and anticonvulsants, as well as topical capsaicin and lidocaine. These treatments are commonly unsatisfactory, with fewer than half of treated patients experiencing more than a 50% reduction in pain. Case. A 99-year-old woman had a 4-year history of severe postherpetic (trigeminal) neuralgia on the left side of her face. During those 4 years, numerous treatments were tried, including systemic opioid analgesics and anticonvulsants, and topical lidocaine and capsaicin, all with unsatisfactory results. The topical application of gallium maltolate, at a concentration of 0.5% in an emulsion of water and hydrophilic petrolatum, was found to relieve the severe pain within about 10 minutes, with the relief lasting for about 6-8 hours. The patient has been using this treatment for more than 5 years, with no adverse effects and a highly significant improvement in her quality of life. Discussion. Gallium has significant antiinflammatory activity, inhibiting the activation and proliferation of pro-inflammatory T cells. Because gallium is chemically similar to zinc, it can interfere with the activity of matrix metalloproteinases (zincbearing proteases), which have been implicated in the etiology of neuropathic pain, and it may suppress the secretion of substance P. Gallium may also inhibit viral replication and the inflammatory activity of viral proteins. This case provides rationale to study topical gallium maltolate in patients with refractory peripheral neuropathic pain.
Metal-Based Drugs, 2000
Gallium maltolate, tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium (GaM), is an orally active ga... more Gallium maltolate, tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium (GaM), is an orally active gallium compound for therapeutic use. It is moderately soluble in water (10.7 ± 0.9 mg/mL at 25C∘) with an octanol partition coefficient of 0.41±0.08. The molecule is electrically neutral in aqueous solution at neutral pH; a dilute aqueous solution (2.5 ×10−5 M) showed little dissociation at pH 5.5-8.0. Single crystal X-ray diffraction analysis found the GaM molecule to consist of three maltolate ligands bidentately bound to a central gallium atom in a propeller-like arrangement, with one of the ligands disordered in two possible orientations. The compound is orthorhombic, space group Pbca, unit cell a = 16.675(3), b = 12.034(2), c = 18.435(2) A∘ at 158K. GaM was administered to healthy human volunteers at single doses of 100, 200, 300, and 500 mg (three subjects per dose). GaM was very well tolerated. Oral absorption of Ga into plasma was fairly rapid (absorption half life = 0.8-2.0h), wi...
Geochimica et Cosmochimica Acta, 1987
At the Apex Mine in southwest Utah, fine-gin&d hematite contains as much as IO wt. percent Ge, an... more At the Apex Mine in southwest Utah, fine-gin&d hematite contains as much as IO wt. percent Ge, and fine-grained goethite contains as much as 0.7 wt. percent Ge. The mode of Ge incorporation in these minerals was investigated by high-resolution K-edge fluorescence spectroscopy using synchrotmn radiation. Analysis of extended fine structure (EXAFS) K-edge data for Ge and Fe shows that Ge substitutes for Fe in the octahedral metal sites of the studied hematite and goethite, with average Ge-ligand bond lengths of 1.88 A. The solid solution in hematite probably occurs through the coupled substitution 2Fe4III) = Ge(IV) + Fe(II), similar to the coupkd substitution 2Fe(III) = Ti(IV) + Fe(B) that occurs in the solid solution series hematite-ilmenite. The solid solution in goethite probably occurs by the loss of an H atom Tom an OH group, through the coupled substitution Fe(II1) f H(1) = Ge(IV). In related experiments, EXAFS data indicate. that in a neutral aqueous solution containing 790 ppm Ge, the Ge occurs predominately as Ge(OH), , with tetrah-Ge-OH bond lengths of 1.74 A. In stottite, FeGe(OHk, Fe(I1) and Ge(IV) occur in octahedral sites with average Fe-OH and Ge-OH bond lengths of about 2.20 A and 1.88 A.
Economic Geology, 1986
The Number One orebody is the largest and most sulfide-rich ore zone (at least 200,000 tons conta... more The Number One orebody is the largest and most sulfide-rich ore zone (at least 200,000 tons containing 8.4 wt % Cu) at the Ruby Creek copper deposit, in the southwestern Brooks Range of Alaska. Pyrite and copper-bearing sulfide minerals are concentrated within the matrix of a dolostone breccia body, which is enclosed by phyllite and calcic marble of Middle to Late Devonian age. The Number One orebody has three mineralogical zones that grade into each other: (1) an outer zone, widest toward the hanging wall, containing mostly pyrite with minor amounts of chalcopyrite and traces of carrollitc and sphalerite; (2) an intermediate zone containing major chalcopyrite and pyrite, minor tennantite-tetrahedrite, bornitc, carrollitc, and sphalerite, and traces of galena; and (3) a core zone containing major bornitc, chalcopyrite, pyrite, and chalcocite, minor carrollitc, digenite, and sphalerite, and traces of galena, covellite, and the germanium-bearing sulfides renierite and germanitc. Small clots of anthracitelike organic material (anthraxolite) are found throughout the ore. Much of the pyrite is fine grained and was deposited before the other sulfides, being increasingly replaced by Cu-bearing sulfides from the outer zone to the core. Some of this pyrite recrystallized into coarser grains having cobaltiferous rims, and these grains were generally not replaced. The sulfide minerals are commonly pseudomorphous after lath-shaped crystals within the dolomite clasts; no unreplaced examples were found, though the crystals closely resemble those of marcasite. The abundant fine-grained, porous pyrite also may represent replacement of marcasite. The origin and timing of brecciation and ore deposition remain unknown, though dolomitization and ore deposition appear to have occurred in preexisting carbonate breccia. Close mineralogical and geologic similarities are noted with the Kipushi Cu-Zn-Pb deposit in Zaire and with several other carbonate-hosted copper-rich organic-bearing deposits. The common concentration of the rare metals Co, Ge, and Ga in these structurally and mineralogically complex ores should increase their economic attractiveness.
Anti-Cancer Agents in Medicinal Chemistry, 2011
Gallium is antiproliferative to many types of cancer, due primarily to its ability to act as a no... more Gallium is antiproliferative to many types of cancer, due primarily to its ability to act as a non-functional mimic of ferric iron (Fe 3+). Because Fe 3+ is needed for ribonucleotide reductase activity-and thus DNA synthesis-gallium can inhibit DNA production and cell division. Diagnostic gallium scans have shown that hepatocellular carcinoma (HCC) is commonly avid for gallium. Furthermore, in vitro studies have found that gallium nitrate, and particularly gallium maltolate (GaM), have dose-dependent antiproliferative activity against HCC cell lines. Rationale thus exists to use GaM, an orally active compound that has been well tolerated in Phase I clinical trials, to treat patients whose HCC is gallium-avid in a gallium scan. Because gallium absorbed from orally administered GaM is bound predominately to serum transferrin, which travels to all tissues in the body, GaM has the potential to treat even distant metastases. A patient with advanced HCC (20 10 cm primary tumor, ascites around liver and spleen, resistant to sorafenib (Nexavar ®)), whose cancer was highly gallium-avid in a 67 Ga-scan, was treated with oral gallium maltolate at 1500 mg/day q.d. After four weeks of treatment, the patient had a large reduction in pain, with greatly increased mobility and quality of life, and significantly lowered serum bilirubin and inflammation-related liver enzymes. At eight weeks, CT scans showed apparent necrosis of the tumor.
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Papers by Lawrence Bernstein
and gallium. Germanium is concentrated chiefly in goethite (as much as 0.5 percent), hematite (as much as 0. 7 percent), and limonite (as much as 0. 5 percent), while gallium is concentrated mostly in jarosite (as much as 0. 7 percent) and in some limonite (as much as 2 percent). Copper minerals are concentrated in and adjacent to carbonate rock, apparently replacing it. The ore at the Apex Mine forms an irregular, branching, chimney-like body (or bodies) in fault breccia, gouge, and fissures associated with steeply dipping subparallel fault zones in the Pennsylvanian Callville Limestone. Within and immediately adjacent to the fault zones, limestone has been dolomitized and locally silicified. Only a few small pieces of unreplaced primary sulfide
ore have been found; these contain pyrite, galena, sphalerite, chalcopyrite, quartz, and traces of barite. The abundance of copper, germanium, gallium, and arsenic in the supergene ore implies the former presence of sulfides and sulfosalts containing these
metals in the primary ore, which would make it similar to dolomite-hosted ores at Kipushi, Zaire; Tsumeb, Namibia; and Ruby Creek, Alaska. High concentrations
of germanium and gallium should be looked for in gossans and other oxidized zones of copper-rich, arsenic-bearing sulfide deposits, particularly those in carbonate host rocks.
and gallium. Germanium is concentrated chiefly in goethite (as much as 0.5 percent), hematite (as much as 0. 7 percent), and limonite (as much as 0. 5 percent), while gallium is concentrated mostly in jarosite (as much as 0. 7 percent) and in some limonite (as much as 2 percent). Copper minerals are concentrated in and adjacent to carbonate rock, apparently replacing it. The ore at the Apex Mine forms an irregular, branching, chimney-like body (or bodies) in fault breccia, gouge, and fissures associated with steeply dipping subparallel fault zones in the Pennsylvanian Callville Limestone. Within and immediately adjacent to the fault zones, limestone has been dolomitized and locally silicified. Only a few small pieces of unreplaced primary sulfide
ore have been found; these contain pyrite, galena, sphalerite, chalcopyrite, quartz, and traces of barite. The abundance of copper, germanium, gallium, and arsenic in the supergene ore implies the former presence of sulfides and sulfosalts containing these
metals in the primary ore, which would make it similar to dolomite-hosted ores at Kipushi, Zaire; Tsumeb, Namibia; and Ruby Creek, Alaska. High concentrations
of germanium and gallium should be looked for in gossans and other oxidized zones of copper-rich, arsenic-bearing sulfide deposits, particularly those in carbonate host rocks.
southwestern Utah, is the first mine in the world to be
operated primarily for germanium and gallium. The
ore, consisting of goethite, limonite, hematite, jarosite,
azurite, malachite, conichalcite, and several other
metal oxides, carbonates, arsenates, and sulfates, is
thoroughly oxidized to at least 42 5 m below the
surface. Most of the copper-rich ore was removed
during previous mining operations, leaving behind the
iron-rich minerals that contain most of the germanium
and gallium. Germanium is concentrated chiefly in
goethite (as much as 0.5 percent), hematite (as much as
0. 7 percent), and limonite (as much as 0. 5 percent),
while gallium is concentrated mostly in jarosite (as
much as 0. 7 percent) and in some limonite (as much as 2
percent). Copper minerals are concentrated in and
adjacent to carbonate rock, apparently replacing it.
The ore at the Apex Mine forms an irregular, branching,
chimney-like body (or bodies) in fault breccia, gouge,
and fissures associated with steeply dipping subparallel
fault zones in the Pennsylvanian Callville Limestone.
Within and immediately adjacent to the fault zones,
limestone has been dolomitized and locally silicified.
Only a few small pieces of unreplaced primary sulfide
ore have been found; these contain pyrite, galena,
sphalerite, chalcopyrite, quartz, and traces of barite.
The abundance of copper, germanium, gallium, and
arsenic in the supergene ore implies the former
presence of sulfides and sulfosalts containing these
metals in the primary ore, which would make it similar
to dolomite-hosted ores at Kipushi, Zaire; Tsumeb,
Namibia; and Ruby Creek, Alaska. High concentrations
of germanium and gallium should be looked for in
gossans and other oxidized zones of copper-rich,
arsenic-bearing sulfide deposits, particularly those in
carbonate host rocks.
some metalloproteinases and neuropeptides, which rely on zinc for their activity (since gallium has chemical similarities to zinc, as well as to iron). Further laboratory and clinical studies are warranted to investigate the efficacy and mechanisms of activity of GaM; such research may lead to the discovery of new pain pathways.
effects. Because topical gallium maltolate has already been reported effective against refractory facial postherpetic neuralgia (in case studies) and refractory trigeminal neuralgia (in a pilot clinical trial of 14 subjects), controlled clinical trials of topical gallium
maltolate in orofacial pain are warranted.
the potential use of topical gallium maltolate as an alternative to opioids in the treatment of chronic pain.
maltolate, at a concentration of 0.5%, was effective in relieving refractory trigeminal neuralgia. Pain scores in all cases decreased by about 4-9 points on a 10-point scale. No adverse effects of any kind were reported. These results provide justification for topical GaM entering controlled clinical trials.