Pharmacology and toxicology of phosphorothioate oligonucleotides in the mouse, rat, monkey and man

Iversen, Patrick L.; Copple, Bryan L.; Tewary, Hemant K.

doi:10.1016/0378-4274(95)03572-9

Cited by 26 publications

(11 citation statements)

References 26 publications

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“…Over the years, there have been a number of reports describing the toxicity of phosphorothioate oligodeoxy¬ nucleotides in experimental animals or preclinical trials (Agrawal et al, 1988(Agrawal et al, , 1991(Agrawal et al, , 1996bGalbraith et al, 1994;Sarmiento et al, 1994;Iverson et al, 1995;Wallace et al, 1996;Henry et al, 1997). Toxicity associated with phospho¬ rothioate oligodeoxynucleotides in mice and rats is generally manifested as thrombocytopenia, elevation of liver enzymes, and enlargement of liver and spleen.…”

Section: Discussionmentioning

confidence: 99%

Toxicologic Effects of an Oligodeoxynucleotide Phosphorothioate and Its Analogs Following Intravenous Administration in Rats

Agrawal¹,

Zhao²,

Jiang³

et al. 1997

Antisense and Nucleic Acid Drug Development

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The aim of the present study is to evaluate the in vivo toxicologic effects of a phosphorothioate oligodeoxynucleotide (PS oligo) and three of its analogs [PS oligo containing four methylphosphonate linkages at the 3' and 5'-ends (MBO 1), PS oligo containing four 2'-O-methylribonucleosides at both the 3'- and 5'-ends (MBO 2), and PS oligo containing an 8 bp loop region at the 3'-end (self-stabilized oligo)]. Oligodeoxynucleotides were administrated intravenously to male and female rats at doses of 3, 10, and 30 mg/kg/day for 14 days. Rats were killed on day 15, blood samples were collected for hematology and clinical chemistry determinations, and tissues, including lymph nodes, spleens, livers, and kidneys, were subjected to pathologic examinations. The toxicity profiles of the four oligodeoxynucleotides were very similar, but differed in magnitude. In terms of the severity of the abnormalities caused by the oligodeoxynucleotides, the order was MBO 2> PS oligo > self-stabilized oligo > MBO 1. Alterations in hematology parameters included thrombocytopenia, anemia, and neutropenia. Abnormalities in clinical chemistry parameters observed with PS oligo or MBO 2 were dose-dependent elevation of liver transaminases and reduction of the levels of alkaline phosphatase, albumin, and total protein. In addition, MBO 2 caused elevation of the total bilirubin level in male rats at the 30 mg/kg dose. No major alterations in hematology or clinical chemistry were observed in rats receiving MBO 1 or self-stabilized oligo. Dose-dependent enlargements of spleen, liver, and kidney were observed, especially in rats receiving PS oligo and MBO 2. Pathologic studies showed a generalized hyperplasia of the reticuloendothelial (RE) system in the tissues examined. Alterations in the spleen were mainly RE cell hyperplasia and hematopoietic cell proliferation. In addition to RE cell hyperplasia, lymph nodes showed necrosis, hepatocytes showed cytologic alterations and necrosis, and kidneys showed renal tubule regeneration. The severity of pathologic changes observed was oligodeoxynucleotide dependent, in the order of MBO 2 > PS oligo > self-stabilized oligo > MBO 1.

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Section: Discussionmentioning

confidence: 99%

Toxicologic Effects of an Oligodeoxynucleotide Phosphorothioate and Its Analogs Following Intravenous Administration in Rats

Agrawal¹,

Zhao²,

Jiang³

et al. 1997

Antisense and Nucleic Acid Drug Development

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“…Furthermore, aside from the acute toxicity after rapid administration of 1 mM Randomer 1 into the brain, no in vivo toxicity was observed with any of the effective in vivo doses described here. In fact, PS-ONs (as antisense agents) have been shown to be generally well tolerated when they are administered parenterally to humans in several clinical trials (10,21,31). Thus, degenerate PS-ONs represent an attractive new type of anti-TSE compound that should be considered for clinical trials of treatments for CJD.…”

Section: Discussionmentioning

confidence: 99%

Potent Antiscrapie Activities of Degenerate Phosphorothioate Oligonucleotides

Kocisko

Vaillant²,

Lee

et al. 2006

Antimicrob Agents Chemother

123

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“…5,8 These studies have demonstrated that PS-ODN can be administered systemically without complications by slow intravenous infusion allowing doses sufficient to reach therapeutic concentrations. Further, we have shown that PS-ODNs have a t 1/2 of 24.4 hours at a dose of 0.05 mg/kg/h.…”

Section: Discussionmentioning

confidence: 97%

Evidence of Enhanced Iron Excretion During Systemic Phosphorothioate Oligodeoxynucleotide Treatment

Mata

Bishop

Tarantolo

et al. 2000

Journal of Toxicology: Clinical Toxicology

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Pharmacology and toxicology of phosphorothioate oligonucleotides in the mouse, rat, monkey and man

Cited by 26 publications

References 26 publications

Toxicologic Effects of an Oligodeoxynucleotide Phosphorothioate and Its Analogs Following Intravenous Administration in Rats

Toxicologic Effects of an Oligodeoxynucleotide Phosphorothioate and Its Analogs Following Intravenous Administration in Rats

Potent Antiscrapie Activities of Degenerate Phosphorothioate Oligonucleotides

Evidence of Enhanced Iron Excretion During Systemic Phosphorothioate Oligodeoxynucleotide Treatment

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