Gallium Nitrate for Acute Treatment of Cancer-Related Hypercalcemia

Warrell, Raymond P.; Israel, Robert J.; Frisone, Marianne; Snyder, Teresa E. Kelly; Gaynor, Jeffrey J.; Bockman, Richard S.

doi:10.7326/0003-4819-108-5-669

Cited by 146 publications

(61 citation statements)

References 21 publications

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“…6; see Table S3 in the supplemental material). At these serum concentrations of Ga(III), serum creatinine remains in the normal concentration range and there are no adverse reactions (62). Clinical studies are therefore needed to confirm the promising potential of Ga(III) as an antibacterial agent.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Antimicrobial Activities of Gallium Nitrate against Multidrug-Resistant Acinetobacter baumannii

Antunes

Imperi

Minandri

et al. 2012

Antimicrob Agents Chemother

127

144

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b 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 an 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 M and from 4 to 64 M, 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 of >75%. At therapeutic concentrations for humans (28 M 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.

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Antimicrobial Activities of Gallium Nitrate against Multidrug-Resistant Acinetobacter baumannii

Antunes

Imperi

Minandri

et al. 2012

Antimicrob Agents Chemother

127

144

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“…It has been found that in some cases, such relapses may be partly prevented by the co-administration of corticosteroids (e.g. prednisolone 40 mg day-') (Binstock & Mundy, 1980), although in many patients with cancer-associated hypercalcaemia, the addition of steroids makes little difference to the response (Warrell et al, 1988). In the longer term, this combination of drugs provides less complete control of hypercalcaemia than the bisphosphonates or mithramycin (Ralston et al, 1985).…”

Section: Calcitoninmentioning

confidence: 99%

“…Although the drug may cause renal impairment, the risk of this is relatively low, provided the patient is kept well hydrated and other nephrotoxic drugs (e.g. aminoglycosides) are avoided (Warrell et al, 1988). It is not yet available in the UK for routine clinical use.…”

Section: Other Treatmentsmentioning

confidence: 99%

“…It acts by inhibiting osteoclastic bone resorption and like the bisphosphonates, has a slow onset of action (2-3 days) with a maximal effect between days 6-8 post treatment (Warrell et al, 1983(Warrell et al, , 1984(Warrell et al, , 1988(Warrell et al, , 1990. Although the drug may cause renal impairment, the risk of this is relatively low, provided the patient is kept well hydrated and other nephrotoxic drugs (e.g.…”

Section: Other Treatmentsmentioning

confidence: 99%

See 1 more Smart Citation

Medical management of hypercalcaemia.

Ralston¹

1992

Brit J Clinical Pharma

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1. Hypercalcaemia is a common disorder, which frequently requires specific treatment either to control symptoms, or to prevent the development of irreversible organ damage or death. Although the best and most effective way of controlling hypercalcaemia in the long‐term is to treat the underlying cause, medical antihypercalcaemic therapy is often required in clinical practice, either as a holding measure, or because the primary disease cannot itself be treated. 2. The mainstays of medical antihypercalcaemic therapy are firstly, to promote calcium excretion by the kidney by restoring extracellular volume with intravenous saline and secondly, to administer pharmacological agents which inhibit bone resorption. Measures which seek to reduce intestinal calcium absorption are seldom effective. 3. Intravenous bisphosphonates are the treatment of first choice for the initial management of hypercalcaemia, followed by continued oral, or repeated intravenous bisphosphonates to prevent relapse. These drugs have a relatively slow onset of action (1‐3 days) but have potent and sustained inhibitory effects on bone resorption, resulting in a long duration of action (12‐ 30 days). 4. Of the other agents available, calcitonin has an important place in the management of severe hypercalcaemia where a rapid effect is desirable; calcitonin is best used in conjunction with a bisphosphonate however, because of its short duration of action. Intravenous phosphate also has a place in the emergency management of severe hypercalcaemia, but is probably best reserved for patients in whom other less toxic therapies have failed. Corticosteroids are generally ineffective except in certain specific instances and are best avoided in the routine treatment of undiagnosed hypercalcaemia.

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“…Clinically, gallium nitrate is administered by a continuous infusion at a dosage of 200 mg/m 2 per day over 5 consecutive days. Reports comparing gallium to bisphosphonates (73,74) and calcitonin (75) have shown equal or perhaps even superior efficacy in decreasing calcium levels. Adverse effects from treatment include hypocalcemia and hypophosphatemia, the latter being observed in nearly 80% of patients.…”

Section: Gallium Nitratementioning

confidence: 99%

Onco-Nephrology

Rosner

Dalkin

2012

Clinical Journal of the American Society of Nephrology

134

108

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SummaryHypercalcemia complicates the course of 10%-30% of all patients with malignancies and can be a sign of very poor prognosis and advanced malignancy. Prompt recognition of the nonspecific signs and symptoms of hypercalcemia and institution of therapy can be lifesaving, affording the opportunity to address the underlying etiology. The mechanisms of malignancy-associated hypercalcemia generally fall into three categories: humoral hypercalcemia due to secreted factors (such as parathyroid-related hormone), local osteolysis due to tumor invasion of bone, and absorptive hypercalcemia due to excess vitamin D produced by malignancies. The mainstays of therapy for hypercalcemia are aggressive intravenous volume expansion with saline, bisphosphonate therapy, and perhaps loop diuretics. Adjunctive therapy may include calcitonin and corticosteroids. In refractory cases, gallium nitrate and perhaps denosumab are alternatives. In patients presenting with severe AKI, hemodialysis with a low-calcium bath can be effective. In most cases, therapy normalizes calcium levels and allows for palliation or curative therapy of the malignancy.

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Gallium Nitrate for Acute Treatment of Cancer-Related Hypercalcemia

Abstract: Gallium nitrate therapy is highly effective and superior to maximally approved doses of calcitonin for acute control of cancer-related hypercalcemia.

Cited by 146 publications

References 21 publications

In Vitro and In Vivo Antimicrobial Activities of Gallium Nitrate against Multidrug-Resistant Acinetobacter baumannii

In Vitro and In Vivo Antimicrobial Activities of Gallium Nitrate against Multidrug-Resistant Acinetobacter baumannii

Medical management of hypercalcaemia.

Onco-Nephrology

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