The influence of infusion rate on the acute intravenous toxicity of phytic acid, a calcium-binding agent

Efficacy of homologous inositol hexaphosphate‐loaded red blood cells in sickle transgenic mice

“…In extremely rare cases of a delayed haemolytic reaction following the transfusion, IHP concentrations released in the plasma of mice would be approximetely 2·8 mmol/l, which is insufficient to induce calcium chelation and is two times less than the LD 50 of IHP. In addition, it has been reported that the toxic manifestations of intravenous IHP could be significantly reduced by lowering the infusion rate (Gersonde & Weiner, ). Therefore, considering a therapeutic application in humans, potential toxicity associated with IHP could be avoided by reducing the transfusion rate of IHP‐RBCs to SCD patients and by oral supplementation with calcium to chelate free IHP.…”

“…Free IHP injected intravenously at massive dosage to mice induces rapid plasmatic calcium depletion, leading to convulsions and death of animals (Gersonde & Weiner, ). In order to investigate the safety profile of treatment, male OF1 mice were injected with control RBCs ( n = 12), IHP‐RBCs ( n = 12), and free IHP solutions: 2 mmol/l ( n = 12), 5 mmol/l ( n = 6), 10 mmol/l ( n = 6), 20 mmol/l ( n = 6) intravenously in the caudal vein at a dosage of 8 ml/kg body weight.…”

Efficacy of homologous inositol hexaphosphate‐loaded red blood cells in sickle transgenic mice

“…In extremely rare cases of a delayed haemolytic reaction following the transfusion, IHP concentrations released in the plasma of mice would be approximetely 2·8 mmol/l, which is insufficient to induce calcium chelation and is two times less than the LD 50 of IHP. In addition, it has been reported that the toxic manifestations of intravenous IHP could be significantly reduced by lowering the infusion rate (Gersonde & Weiner, ). Therefore, considering a therapeutic application in humans, potential toxicity associated with IHP could be avoided by reducing the transfusion rate of IHP‐RBCs to SCD patients and by oral supplementation with calcium to chelate free IHP.…”

“…Free IHP injected intravenously at massive dosage to mice induces rapid plasmatic calcium depletion, leading to convulsions and death of animals (Gersonde & Weiner, ). In order to investigate the safety profile of treatment, male OF1 mice were injected with control RBCs ( n = 12), IHP‐RBCs ( n = 12), and free IHP solutions: 2 mmol/l ( n = 12), 5 mmol/l ( n = 6), 10 mmol/l ( n = 6), 20 mmol/l ( n = 6) intravenously in the caudal vein at a dosage of 8 ml/kg body weight.…”

Safety Assessment of Polyol Phosphates as Used in Cosmetics

“…When the infusion rate was varied so that a range of doses was administered (to groups of 10 mice) within a fixed time of 7 minutes, a classical mortality rate distribution with dose was observed, yielding an LD 50 of ∼0.5 mg/g. 39 The lower doses (0.035 and 0.07 mg/g) administered to rats (mostly groups of 20) caused no detectable signs at any of the 3 injection rates. The 0.28 mg/g dose showed infusion raterelated mortality similar to the mouse, with 100% mortality when infused in 3 minutes or 5 minutes, and no mortality when infused at a rate of 40 minutes.…”

“…administration of Sodium Phytate to groups of 10 NMRI mice at doses up to 0.56 mg/g (range of doses administered within 7 minutes) yielded an LD 50 of ∼0.5 mg/g, and there were no detectable effects from infusion when the rate was not more than 0.02 mg/g/minute. 39 When Sodium Phytate was administered i.v. to rats at lower doses of 0.035 and 0.07 mg/g, there were no detectable signs when doses were administered at a rate requiring 40 minutes for administration of the total dose.…”

Identifying and Understanding Seizure Liability in Drug Development

“…A dosing schedule includes not only the dose(s) but also the pharmacological impact of the peak dose (maximum concentration [Cmax]) and/or total dose (area under the curve [AUC]), route of administration (RoA) and treatment duration, frequency (dosing interval), and rate. [63][64][65][66][67] Induction of seizures may be dictated by the RoA, particularly if exposure levels of a drug (and its metabolites) vary greatly in their bioavailability. For example, intravenous (IV) dosing typically results in a higher Cmax in blood compared to oral (PO) administration of the same drug and dose due to differing ADME kinetics.…”

Efficacy of homologous inositol hexaphosphate‐loaded red blood cells in sickle transgenic mice

“…In extremely rare cases of a delayed haemolytic reaction following the transfusion, IHP concentrations released in the plasma of mice would be approximetely 2·8 mmol/l, which is insufficient to induce calcium chelation and is two times less than the LD 50 of IHP. In addition, it has been reported that the toxic manifestations of intravenous IHP could be significantly reduced by lowering the infusion rate (Gersonde & Weiner, ). Therefore, considering a therapeutic application in humans, potential toxicity associated with IHP could be avoided by reducing the transfusion rate of IHP‐RBCs to SCD patients and by oral supplementation with calcium to chelate free IHP.…”

“…Free IHP injected intravenously at massive dosage to mice induces rapid plasmatic calcium depletion, leading to convulsions and death of animals (Gersonde & Weiner, ). In order to investigate the safety profile of treatment, male OF1 mice were injected with control RBCs ( n = 12), IHP‐RBCs ( n = 12), and free IHP solutions: 2 mmol/l ( n = 12), 5 mmol/l ( n = 6), 10 mmol/l ( n = 6), 20 mmol/l ( n = 6) intravenously in the caudal vein at a dosage of 8 ml/kg body weight.…”

Safety Assessment of Polyol Phosphates as Used in Cosmetics

“…When the infusion rate was varied so that a range of doses was administered (to groups of 10 mice) within a fixed time of 7 minutes, a classical mortality rate distribution with dose was observed, yielding an LD 50 of ∼0.5 mg/g. 39 The lower doses (0.035 and 0.07 mg/g) administered to rats (mostly groups of 20) caused no detectable signs at any of the 3 injection rates. The 0.28 mg/g dose showed infusion raterelated mortality similar to the mouse, with 100% mortality when infused in 3 minutes or 5 minutes, and no mortality when infused at a rate of 40 minutes.…”

“…administration of Sodium Phytate to groups of 10 NMRI mice at doses up to 0.56 mg/g (range of doses administered within 7 minutes) yielded an LD 50 of ∼0.5 mg/g, and there were no detectable effects from infusion when the rate was not more than 0.02 mg/g/minute. 39 When Sodium Phytate was administered i.v. to rats at lower doses of 0.035 and 0.07 mg/g, there were no detectable signs when doses were administered at a rate requiring 40 minutes for administration of the total dose.…”

Identifying and Understanding Seizure Liability in Drug Development

“…A dosing schedule includes not only the dose(s) but also the pharmacological impact of the peak dose (maximum concentration [Cmax]) and/or total dose (area under the curve [AUC]), route of administration (RoA) and treatment duration, frequency (dosing interval), and rate. [63][64][65][66][67] Induction of seizures may be dictated by the RoA, particularly if exposure levels of a drug (and its metabolites) vary greatly in their bioavailability. For example, intravenous (IV) dosing typically results in a higher Cmax in blood compared to oral (PO) administration of the same drug and dose due to differing ADME kinetics.…”

Efficacy of homologous inositol hexaphosphate‐loaded red blood cells in sickle transgenic mice

“…In extremely rare cases of a delayed haemolytic reaction following the transfusion, IHP concentrations released in the plasma of mice would be approximetely 2·8 mmol/l, which is insufficient to induce calcium chelation and is two times less than the LD 50 of IHP. In addition, it has been reported that the toxic manifestations of intravenous IHP could be significantly reduced by lowering the infusion rate (Gersonde & Weiner, ). Therefore, considering a therapeutic application in humans, potential toxicity associated with IHP could be avoided by reducing the transfusion rate of IHP‐RBCs to SCD patients and by oral supplementation with calcium to chelate free IHP.…”

“…Free IHP injected intravenously at massive dosage to mice induces rapid plasmatic calcium depletion, leading to convulsions and death of animals (Gersonde & Weiner, ). In order to investigate the safety profile of treatment, male OF1 mice were injected with control RBCs ( n = 12), IHP‐RBCs ( n = 12), and free IHP solutions: 2 mmol/l ( n = 12), 5 mmol/l ( n = 6), 10 mmol/l ( n = 6), 20 mmol/l ( n = 6) intravenously in the caudal vein at a dosage of 8 ml/kg body weight.…”

Safety Assessment of Polyol Phosphates as Used in Cosmetics

“…When the infusion rate was varied so that a range of doses was administered (to groups of 10 mice) within a fixed time of 7 minutes, a classical mortality rate distribution with dose was observed, yielding an LD 50 of ∼0.5 mg/g. 39 The lower doses (0.035 and 0.07 mg/g) administered to rats (mostly groups of 20) caused no detectable signs at any of the 3 injection rates. The 0.28 mg/g dose showed infusion raterelated mortality similar to the mouse, with 100% mortality when infused in 3 minutes or 5 minutes, and no mortality when infused at a rate of 40 minutes.…”

“…administration of Sodium Phytate to groups of 10 NMRI mice at doses up to 0.56 mg/g (range of doses administered within 7 minutes) yielded an LD 50 of ∼0.5 mg/g, and there were no detectable effects from infusion when the rate was not more than 0.02 mg/g/minute. 39 When Sodium Phytate was administered i.v. to rats at lower doses of 0.035 and 0.07 mg/g, there were no detectable signs when doses were administered at a rate requiring 40 minutes for administration of the total dose.…”

Identifying and Understanding Seizure Liability in Drug Development

“…A dosing schedule includes not only the dose(s) but also the pharmacological impact of the peak dose (maximum concentration [Cmax]) and/or total dose (area under the curve [AUC]), route of administration (RoA) and treatment duration, frequency (dosing interval), and rate. [63][64][65][66][67] Induction of seizures may be dictated by the RoA, particularly if exposure levels of a drug (and its metabolites) vary greatly in their bioavailability. For example, intravenous (IV) dosing typically results in a higher Cmax in blood compared to oral (PO) administration of the same drug and dose due to differing ADME kinetics.…”