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Pharmacokinetic study and evaluation of the safety of taurolidine for dogs with osteosarcoma.

Marley K, Helfand SC, Simpson J, Mata JE, Tracewell WG, Brownlee L, Bracha S, Séguin B - J. Exp. Clin. Cancer Res. (2013)

Bottom Line: Taurolidine infusion was safe in 6 healthy dogs and there were no significant side effects.Bone marrow and gastro-intestinal toxicity did not appear increased with taurolidine over doxorubicin or carboplatin alone.Taurolidine did not substantially exacerbate bone marrow or gastro-intestinal toxicity however, it is possible that taurolidine increased other toxicities of doxorubicin and carboplatin.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background: Osteosarcoma in dogs and humans share many similarities and the dog has been described as an excellent model to study this disease. The median survival in dogs has not improved in the last 25 years. Taurolidine has been shown to be cytotoxic to canine and human osteosarcoma in vitro. The goals of this study were to determine the pharmacokinetics and safety of taurolidine in healthy dogs and the safety of taurolidine in combination with doxorubicin or carboplatin in dogs with osteosarcoma.

Methods: Two percent taurolidine was infused into six healthy dogs (150 mg/kg) over a period of two hours and blood samples were taken periodically. One dog received taurolidine with polyvinylpyrrolidone (PVP) as its carrier and later received PVP-free taurolidine as did all other dogs in this study. Serum taurolidine concentrations were determined using high-performance liquid chromatography (HPLC) online coupled to ESI-MS/MS in the multiple reaction monitoring mode. Subsequently, the same dose of taurolidine was infused to seven dogs with osteosarcoma also treated with doxorubicin or carboplatin.

Results: Taurolidine infusion was safe in 6 healthy dogs and there were no significant side effects. Maximum taurolidine serum concentrations ranged between 229 to 646 μM. The dog that received taurolidine with PVP had an immediate allergic reaction but recovered fully after the infusion was stopped. Three additional dogs with osteosarcoma received doxorubicin and taurolidine without PVP. Toxicities included dilated cardiomyopathy, protein-losing nephropathy, renal insufficiency and vasculopathy at the injection site. One dog was switched to carboplatin instead of doxorubicin and an additional 4 dogs with osteosarcoma received taurolidine-carboplatin combination. One incidence of ototoxicity occurred with the taurolidine- carboplatin combination. Bone marrow and gastro-intestinal toxicity did not appear increased with taurolidine over doxorubicin or carboplatin alone.

Conclusions: Taurolidine did not substantially exacerbate bone marrow or gastro-intestinal toxicity however, it is possible that taurolidine increased other toxicities of doxorubicin and carboplatin. Administering taurolidine in combination with 30 mg/m2 doxorubicin in dogs is not recommended but taurolidine in combination with carboplatin (300 mg/m2) appears safe.

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Serum concentrations of taurolidine as calculated from the concentrations of taurultame and taurinamide (see Methods section) following a 150 mg/kg IV infusion of 2% taurolidine.
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Figure 1: Serum concentrations of taurolidine as calculated from the concentrations of taurultame and taurinamide (see Methods section) following a 150 mg/kg IV infusion of 2% taurolidine.

Mentions: Mean pharmacokinetic profiles of taurinamide, taurultame, and taurolidine are displayed in Figure 1. Plasma concentrations of taurolidine increased rapidly after the start of each infusion and continued to increase until the infusion was stopped, then declined rapidly and were not detectable at 18 hours post infusion. Pharmacokinetic parameters are presented in Table 3. An allergic reaction developed in healthy dog #1 within one minute of starting the infusion of taurolidine containing PVP and the infusion was stopped. The dog initially became very agitated, pawing at and shaking its head, looking disoriented, and then became sedated. Thirty-five minutes after the infusion, the dog vomited. The mucous membrane color was paler and the blood pressure dropped to a mean of 45 mm Hg 45 minutes after the infusion but the dog recovered fully after 90 minutes. All subsequent infusions used taurolidine without PVP and no such reaction was present in any dog, including healthy dog #1, when this solution was used.


Pharmacokinetic study and evaluation of the safety of taurolidine for dogs with osteosarcoma.

Marley K, Helfand SC, Simpson J, Mata JE, Tracewell WG, Brownlee L, Bracha S, Séguin B - J. Exp. Clin. Cancer Res. (2013)

Serum concentrations of taurolidine as calculated from the concentrations of taurultame and taurinamide (see Methods section) following a 150 mg/kg IV infusion of 2% taurolidine.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3852505&req=5

Figure 1: Serum concentrations of taurolidine as calculated from the concentrations of taurultame and taurinamide (see Methods section) following a 150 mg/kg IV infusion of 2% taurolidine.
Mentions: Mean pharmacokinetic profiles of taurinamide, taurultame, and taurolidine are displayed in Figure 1. Plasma concentrations of taurolidine increased rapidly after the start of each infusion and continued to increase until the infusion was stopped, then declined rapidly and were not detectable at 18 hours post infusion. Pharmacokinetic parameters are presented in Table 3. An allergic reaction developed in healthy dog #1 within one minute of starting the infusion of taurolidine containing PVP and the infusion was stopped. The dog initially became very agitated, pawing at and shaking its head, looking disoriented, and then became sedated. Thirty-five minutes after the infusion, the dog vomited. The mucous membrane color was paler and the blood pressure dropped to a mean of 45 mm Hg 45 minutes after the infusion but the dog recovered fully after 90 minutes. All subsequent infusions used taurolidine without PVP and no such reaction was present in any dog, including healthy dog #1, when this solution was used.

Bottom Line: Taurolidine infusion was safe in 6 healthy dogs and there were no significant side effects.Bone marrow and gastro-intestinal toxicity did not appear increased with taurolidine over doxorubicin or carboplatin alone.Taurolidine did not substantially exacerbate bone marrow or gastro-intestinal toxicity however, it is possible that taurolidine increased other toxicities of doxorubicin and carboplatin.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background: Osteosarcoma in dogs and humans share many similarities and the dog has been described as an excellent model to study this disease. The median survival in dogs has not improved in the last 25 years. Taurolidine has been shown to be cytotoxic to canine and human osteosarcoma in vitro. The goals of this study were to determine the pharmacokinetics and safety of taurolidine in healthy dogs and the safety of taurolidine in combination with doxorubicin or carboplatin in dogs with osteosarcoma.

Methods: Two percent taurolidine was infused into six healthy dogs (150 mg/kg) over a period of two hours and blood samples were taken periodically. One dog received taurolidine with polyvinylpyrrolidone (PVP) as its carrier and later received PVP-free taurolidine as did all other dogs in this study. Serum taurolidine concentrations were determined using high-performance liquid chromatography (HPLC) online coupled to ESI-MS/MS in the multiple reaction monitoring mode. Subsequently, the same dose of taurolidine was infused to seven dogs with osteosarcoma also treated with doxorubicin or carboplatin.

Results: Taurolidine infusion was safe in 6 healthy dogs and there were no significant side effects. Maximum taurolidine serum concentrations ranged between 229 to 646 μM. The dog that received taurolidine with PVP had an immediate allergic reaction but recovered fully after the infusion was stopped. Three additional dogs with osteosarcoma received doxorubicin and taurolidine without PVP. Toxicities included dilated cardiomyopathy, protein-losing nephropathy, renal insufficiency and vasculopathy at the injection site. One dog was switched to carboplatin instead of doxorubicin and an additional 4 dogs with osteosarcoma received taurolidine-carboplatin combination. One incidence of ototoxicity occurred with the taurolidine- carboplatin combination. Bone marrow and gastro-intestinal toxicity did not appear increased with taurolidine over doxorubicin or carboplatin alone.

Conclusions: Taurolidine did not substantially exacerbate bone marrow or gastro-intestinal toxicity however, it is possible that taurolidine increased other toxicities of doxorubicin and carboplatin. Administering taurolidine in combination with 30 mg/m2 doxorubicin in dogs is not recommended but taurolidine in combination with carboplatin (300 mg/m2) appears safe.

Show MeSH
Related in: MedlinePlus