Development of a Hypoparathyroid Male Rodent Model for Testing Delayed-Clearance PTH Molecules

Context Parathyroid hormone (PTH) replacement is a promising approach in the management of hypoparathyroidism but long-acting analogues need to be developed. To date, animal models for testing PTH required parathyroidectomy by surgery. We have developed a nonsurgical rodent hypoparathyroid model and tested a delayed-clearance PTH molecule (DC-PTH). Objective The aim of this study was to use cinacalcet to suppress calcium levels in normal rats and to reverse these effects with the administration of PTH or PTH analogues Methods Male Wistar rats were gavaged with either 30 mg/kg cinacalcet-HCl (cinacalcet) or vehicle only. Animals were then dosed with either single or repeated subcutaneous doses of PTH 1-34 or a DC-PTH at 20 nmol/kg. Control animals received vehicle only. Serum samples were analyzed for ionized calcium (iCa), phosphate, PTH, and DC-PTH. A pharmacokinetic-pharmacodynamic (PK-PD) model was built for cinacalcet, PTH 1-34, and DC-PTH using Phoenix64. Results Cinacalcet reduced iCa levels between 2 and 24 hours, returning to baseline by 72 hours post dose with nadir at 8 hours (analysis of variance P < .001), associated with a fall in rat PTH. For phosphate there was a variable biphasic response. Single-dose PTH abrogated the cinacalcet-induced fall in iCa for up to 2 hours. DC-PTH prevented the fall in iCa from 4 hours post dose and gave a prolonged response, with iCa levels quicker to return to baseline than controls. DC-PTH has a half-life of 11.5 hours, approximately 44 times longer than human PTH 1-34. The PK-PD models defined the reproducible effect of cinacalcet on iCa and that DC-PTH had prolonged biological activity. Conclusion The administration of cinacalcet provides a robust and reproducible nonsurgical animal model of hypoparathyroidism. DC-PTH holds promise for the treatment of hypoparathyroidism in the future.

Biphasic response of biological objects on variation of low deuterium concentration in water.

For the first time we study the effects of deuterium for various alive and model biological systems on a wide scale of deuterium concentration including water depleted of deuterium. All the data have statistical significance better than 0.05. Mechanisms of the observed phenomena are discussed.

Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B

As current interventions for chronic hepatitis B (CHB) rarely induce cure, more effective drugs are needed. Short-term treatment of woodchucks with the novel immunomodulator AIC649, a parapoxvirus-based stimulator of toll-like receptor 9 dependent and independent pathways, has been shown to reduce viral DNA and surface antigen via a unique, biphasic response pattern. The present study evaluated long-term AIC649 treatment in combination with Entecavir for potency and safety in woodchucks. AIC649 monotreatment induced modest reductions in serum viral DNA and surface and e antigens that were associated with the same biphasic response pattern previously observed. Entecavir monotreatment reduced transiently viremia but not antigenemia, while AIC649/Entecavir combination treatment mediated superior viral control. Undetectability of viral antigens and elicitation of antibodies in AIC649/Entecavir-treated woodchucks correlated with the expression of interferons and suppression of viral replication in liver. Combination treatment was well tolerated, and liver enzyme elevations were minor and transient. It was concluded that the AIC649-mediated effects were most likely based on an improvement and/or reconstitution of antiviral immune responses that are typically deficient in CHB. As a combination partner to Entecavir, the antiviral efficacy of AIC649 was markedly enhanced. This preclinical study supports future evaluation of AIC649 for treatment of human CHB.

Hormesis, screening and practical use of biostimulators in agriculture

The term hormesis describes the biphasic response of any biological system to increasing the dose of the stress factor of a different nature, characterized in that low doses have stimulating, beneficial effects. In contrast, high doses cause harmful, inhibitory effects. The hormonal response is practically universal, being stimulated by the action of toxic substances, heavy metal ions, hormones, including physical factors. The standard type of response to different factors suggests installing these evolving mechanisms, so they are of particular interest in elucidating plant adaptation mechanisms to various stressors, including developing screening methods and practical use of biostimulators. The practical use of hormesis principles was the theoretical basis for elaboration and rational use of the biostimulator Reglalg in agriculture.