Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity

Formaldehyde has been previously shown to play a dominant role in promoting synergy between doxorubicin (Dox) and formaldehyde-releasing butyric acid (BA) prodrugs in killing cancer cells. In this work, we report that these prodrugs also protect neonatal rat cardiomyocytes and adult mice against toxicity elicited by Dox. In cardiomyocytes treated with Dox, the formaldehyde releasing prodrugs butyroyloxymethyl diethylphosphate (AN-7) and butyroyloxymethyl butyrate (AN-1), but not the corresponding acetaldehyde-releasing butyroyloxydiethyl phosphate (AN-88) or butyroyloxyethyl butyrate (AN-11), reduced lactate dehydrogenase leakage, prevented loss of mitochondrial membrane potential (ΔΨm) and attenuated upregulation of the proapoptotic gene Bax. In Dox-treated mice, AN-7 but not AN-88 attenuated weight-loss and mortality, and increase in serum lactate dehydrogenase. These findings show that BA prodrugs that release formaldehyde and augment Dox anticancer activity also protect against Dox cardiotoxicity. Based on these observations, clinical applications of these prodrugs for patients treated with Dox warrant further investigation

Recent Progress in the Use of Glucagon and Glucagon Receptor Antagonists in the Treatment of Diabetes Mellitus

Glucagon is an important pancreatic hormone, released into blood circulation by alpha cells of the islet of Langerhans. Glucagon induces gluconeogenesis and glycogenolysis in hepatocytes, leading to an increase in hepatic glucose production and subsequently hyperglycemia in susceptible individuals. Hyperglucagonemia is a constant feature in patients with T2DM. A number of bioactive agents that can block glucagon receptor have been identified. These glucagon receptor antagonists can reduce the hyperglycemia associated with exogenous glucagon administration in normal as well as diabetic subjects. Glucagon receptor antagonists include isoserine and beta-alanine derivatives, bicyclic 19-residue peptide BI-32169, Des-His1-[Glu9] glucagon amide and related compounds, 5-hydroxyalkyl-4-phenylpyridines, N-[3-cano-6- (1,1 dimethylpropyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]-2-ethylbutamide, Skyrin and NNC 250926. The absorption, dosage, catabolism, excretion and medicinal chemistry of these agents are the subject of this review. It emphasizes the role of glucagon in glucose homeostasis and how it could be applied as a novel tool for the management of diabetes mellitus by blocking its receptors with either monoclonal antibodies, peptide and non-peptide antagonists or gene knockout techniques

Data for: Pharmacokinetics of two Bis-pyridinium Aldoximes

Aims: K117 and K127 are bis-pyridinium aldoximes. Both K117 and K127 are developed as potential antidotes in the case of poisoning both acetylcholinesterase and butyrylcholinesterese in terrorist attacks or intoxication with other organophosphorous compounds. Their distribution has been scouted in the body of rats. Main methods: White male Wistar rats were intramuscularly injected. The animals were sacrificed, tissue samples were homogenized, and either K117 or K127 concentrartions were determined using reversed-phase high-performance liquid chromatography.Key findings: Both K117 and K127 were present in all tissues that were analyzed including blood (serum), the brains, cerebrospinal fluid, the eyes, livers, kidneys, lungs and testes. Two novel proper names should be conceptualized in the practice of these antidotes, t1/10 (instead of t1/2) and maximal blood-brain penetration cmaxBBP.(instead of the individual cmax values for blood and also for the brain).Significance: Either K117 or K127 meets the essential requirements for antidotes. Dose dependence and kinetics of their distribution were compared to that of other pyridinium aldoximes

Data for: Pharmacokinetics of two Bis-pyridinium Aldoximes

Aims: K117 and K127 are bis-pyridinium aldoximes. Both K117 and K127 are developed as potential antidotes in the case of poisoning both acetylcholinesterase and butyrylcholinesterese in terrorist attacks or intoxication with other organophosphorous compounds. Their distribution has been scouted in the body of rats. Main methods: White male Wistar rats were intramuscularly injected. The animals were sacrificed, tissue samples were homogenized, and either K117 or K127 concentrartions were determined using reversed-phase high-performance liquid chromatography.Key findings: Both K117 and K127 were present in all tissues that were analyzed including blood (serum), the brains, cerebrospinal fluid, the eyes, livers, kidneys, lungs and testes. Two novel proper names should be conceptualized in the practice of these antidotes, t1/10 (instead of t1/2) and maximal blood-brain penetration cmaxBBP.(instead of the individual cmax values for blood and also for the brain).Significance: Either K117 or K127 meets the essential requirements for antidotes. Dose dependence and kinetics of their distribution were compared to that of other pyridinium aldoximes.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV

Data for: Pharmacokinetics of two Bis-pyridinium Aldoximes

Aims: K117 and K127 are bis-pyridinium aldoximes. Both K117 and K127 are developed as potential antidotes in the case of poisoning both acetylcholinesterase and butyrylcholinesterese in terrorist attacks or intoxication with other organophosphorous compounds. Their distribution has been scouted in the body of rats. Main methods: White male Wistar rats were intramuscularly injected. The animals were sacrificed, tissue samples were homogenized, and either K117 or K127 concentrartions were determined using reversed-phase high-performance liquid chromatography.Key findings: Both K117 and K127 were present in all tissues that were analyzed including blood (serum), the brains, cerebrospinal fluid, the eyes, livers, kidneys, lungs and testes. Two novel proper names should be conceptualized in the practice of these antidotes, t1/10 (instead of t1/2) and maximal blood-brain penetration cmaxBBP.(instead of the individual cmax values for blood and also for the brain).Significance: Either K117 or K127 meets the essential requirements for antidotes. Dose dependence and kinetics of their distribution were compared to that of other pyridinium aldoximes

Data for: Pharmacokinetics of two Bis-pyridinium Aldoximes

Aims: K117 and K127 are bis-pyridinium aldoximes. Both K117 and K127 are developed as potential antidotes in the case of poisoning both acetylcholinesterase and butyrylcholinesterese in terrorist attacks or intoxication with other organophosphorous compounds. Their distribution has been scouted in the body of rats. Main methods: White male Wistar rats were intramuscularly injected. The animals were sacrificed, tissue samples were homogenized, and either K117 or K127 concentrartions were determined using reversed-phase high-performance liquid chromatography.Key findings: Both K117 and K127 were present in all tissues that were analyzed including blood (serum), the brains, cerebrospinal fluid, the eyes, livers, kidneys, lungs and testes. Two novel proper names should be conceptualized in the practice of these antidotes, t1/10 (instead of t1/2) and maximal blood-brain penetration cmaxBBP.(instead of the individual cmax values for blood and also for the brain).Significance: Either K117 or K127 meets the essential requirements for antidotes. Dose dependence and kinetics of their distribution were compared to that of other pyridinium aldoximes.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV