Biological disposition of antibilharzial antimony drugs. II. Antimony fate and uptake by Schistosoma haematobium eggs in man

Schulert, Arthur R.; Rassoul, A. A. Abdel; Mansour, Moustafa; Girgis, Nabil I.; McConnell, E.; Farid, Z.

doi:10.1016/0014-4894(66)90040-3

Cited by 12 publications

(9 citation statements)

References 9 publications

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“…In fact, 0.3 M PAT/Sb(III) was sufficient to increase cardiac calcium currents by approximately 50%. This provides the rationale for proarrhythmic events reported in the past with therapeutic concentrations of PAT/ Sb(III) during therapy of schistosomiasis, another tropical parasitic infection (Schulert et al, 1966). PAT/Sb(III) induced increases in calcium currents could be blunted by the antioxidant NAC consistent with the well known property of trivalent antimony to produce oxidative stress via an increase in ROS production (Mueller at al., 1998).…”

Section: Discussionmentioning

confidence: 66%

“…Because better tolerated pentavalent antimony compounds such as SSG have supplanted the more toxic trivalent PAT/Sb(III), which is tolerated in patients only up to a serum concentration of approximately 1 M (Schulert et al, 1966;Doenges, 1968), we sought to determine whether our findings with PAT/Sb(III) could be extended to SSG/Sb(V). In cultures of Leishmania donovani parasites in human macrophages, 10 to 15 g/ml SSG/Sb(V) was able to eliminate 80 to 90% of the parasite load.…”

Section: Resultsmentioning

confidence: 99%

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Antimony-Based Antileishmanial Compounds Prolong the Cardiac Action Potential by an Increase in Cardiac Calcium Currents

Kuryshev¹,

Wang²,

Wible³

et al. 2006

Molecular Pharmacology

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Antimonial agents are a mainstay for the treatment of leishmaniasis, a group of protozoal diseases that includes visceral leishmaniasis, or Kala Azar. Chemotherapy with trivalent potassium antimony tartrate (PAT) and, more importantly, pentavalent antimony-carbohydrate complexes, such as sodium stibogluconate (SSG), has been reported to prolong the QT interval and produce life-threatening arrhythmias. PAT is chemically related to As 2 O 3 , which alters cardiac excitability by inhibition of human ether a-go-go related gene (hERG) trafficking and an increase of cardiac calcium currents. In this study, we report that PAT does not block hERG currents on short-term exposure but reduces current density on long-term exposure (IC 50 , 11.8 M) and inhibits hERG maturation on Western blots (IC 50 , 62 M). Therapeutic concentrations of 0.3 M PAT increase cardiac calcium currents from Ϫ4.8 Ϯ 0.7 to Ϫ7.3 Ϯ 0.5 pA/pF at 10 mV. In marked contrast, pentavalent SSG, the drug of choice for the treatment of leishmaniasis, did not affect hERG/I Kr or any other cardiac potassium current at therapeutic concentrations. However, both cardiac sodium and calcium currents were significantly increased on long-term exposure to 30 M SSG in isolated guinea pig ventricular myocytes. We propose that the increase in calcium currents from Ϫ3.2 Ϯ 0.3 to Ϫ5.1 Ϯ 0.3 pA/pF at 10 mV prolongs APD 90 from 464 Ϯ 35 to 892 Ϯ 64 ms. Our data suggest that conversion of Sb(V) into active Sb(III) in patients produces a common mode of action for antimonial drugs, which define a novel compound class that increases cardiac risk not by a reduction of hERG/I Kr currents but-for the first time-by an increase in cardiac calcium currents.

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Section: Discussionmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Antimony-Based Antileishmanial Compounds Prolong the Cardiac Action Potential by an Increase in Cardiac Calcium Currents

Kuryshev¹,

Wang²,

Wible³

et al. 2006

Molecular Pharmacology

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“…Lecureur et al (2002b) pointed out that the cytotoxic potassium antimonyl tartrate concentrations action on human lymphoma Daudi cells and on B lymphocytes from leukemia patients were in micromolar concentrations; concentrations that are likely to be achievable in vivo in humans (Schulert et al 1966). …”

Section: Discussionmentioning

confidence: 99%

Urinary antimony and leukocyte telomere length: An analysis of NHANES 1999–2002

Scinicariello

Buser

2016

Environmental Research

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Telomeres are repetitive DNA sequences (TTAGGG) at the end of chromosomes. Cells with critically short telomeres enter replicative senescence and apoptosis. Several in vitro studies report that antimony causes cell apoptosis in human leukocyte cell lines. The goal of this analysis was to investigate whether there is an association between antimony exposure and leukocyte telomere length (LTL) among US adults aged 20 and older based on the National Health and Nutrition Examination Survey (NHANES) 1999–2002. We used multivariate linear regression to analyze the association of urinary antimony with LTL. LTL was log-natural transformed and the results were re-transformed and presented as percent differences. After adjustment for potential confounders, individuals in the 3rd and 4th quartiles of urinary antimony had statistically significantly shorter LTL (−4.78%, 95% CI: −8.42, −0.90; and −6.11%, 95% CI: −11.04, −1.00, respectively) compared to the lowest referent quartile, with evidence of a dose-response relationship (p-value for trend = 0.03). Shorter LTL with antimony was driven by middle aged (40–59 years) and older (60–85 years) adult groups. The association may be biologically plausible because of reported oxidative stress and apoptosis effects of antimony on blood cells, effects known to shorten telomere length.

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“…PAT interferes with phosphofructokinase and the thiol redox potential of the parasite (Schulert et al, 1966). Initially reported by Lecureur et al (2002a,b), PAT, which is similar to As 2 O 3 , was found to be cytotoxic toward acute promyelocytic leukemia.…”

Section: Introductionmentioning

confidence: 97%

The Antiparasitic Drug, Potassium Antimony Tartrate, Inhibits Tumor Angiogenesis and Tumor Growth in Nonsmall-Cell Lung Cancer

Wang

Guo

et al. 2015

The Journal of Pharmacology and Experimental Therapeutics

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Repurposing existing drugs not only accelerates drug discovery but rapidly advances clinical therapeutic strategies. In this article, we identified potassium antimonyl tartrate (PAT), an antiparasitic drug, as a novel agent to block angiogenesis by screening US Food and Drug Administration-approved chemical drugs. By comparing the cytotoxicity of PAT in various nonsmallcell lung cancer (NSCLC) cells with that observed in primary cultured human umbilical vein endothelial cells (HUVECs), we found that HUVECs were much more sensitive to the PAT treatment. In in vivo tumor xenograft mouse models established either by PAT-resistant A549 cells or by patient primary tumors, PAT significantly decreased the tumor volume and tumor weight of NSCLC xenografts at dosage of 40 mg/kg (i.p., daily) and, more importantly, augmented the antitumor efficacy of cisplatin chemotherapy. Remarkable loss of vascularization in the treated xenografts indicated the in vivo antiangiogenesis property of PAT, which was well correlated with its tumor growth inhibition in NSCLC cells. Furthermore, in the in vitro angiogenic assays, PAT exhibited dose-dependent inhibition of HUVEC proliferation, migration, and tube formation in response to different stimuli. Consistently, PAT also abolished the vascular endothelial cell growth factor-induced angiogenesis in the Matrigel plugs assay. Mechanistically, we found that PAT inhibited the activities of several receptor tyrosine kinases and specifically blocked the activation of downstream Src and focal adhesion kinases in HUVECs. Taken together, our results characterized the novel antiangiogenic and antitumor function of PAT in NSCLC cells. Further study of PAT in anticancer clinical trials may be warranted.

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Biological disposition of antibilharzial antimony drugs. II. Antimony fate and uptake by Schistosoma haematobium eggs in man

Cited by 12 publications

References 9 publications

Antimony-Based Antileishmanial Compounds Prolong the Cardiac Action Potential by an Increase in Cardiac Calcium Currents

Antimony-Based Antileishmanial Compounds Prolong the Cardiac Action Potential by an Increase in Cardiac Calcium Currents

Urinary antimony and leukocyte telomere length: An analysis of NHANES 1999–2002

The Antiparasitic Drug, Potassium Antimony Tartrate, Inhibits Tumor Angiogenesis and Tumor Growth in Nonsmall-Cell Lung Cancer

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