Semi-Mechanistic Modeling of HY-021068 Based on Irreversible Inhibition of Thromboxane Synthetase

Background: HY-021068 [4-(2-(1H-imidazol-1-yl) ethoxy)-3-methoxybenzoate], developed by Hefei Industrial Pharmaceutical Institute Co., Ltd. (Anhui, China), is a potential thromboxane synthetase inhibitor under development as an anti-platelet agent for the treatment of stroke. A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the PK of HY-021068 and its platelet aggregation inhibitory effect in beagle dogs.Method: Beagle dogs received single oral administration of 2.5 mg/kg HY-021068 or consecutively oral administration of 5 mg/kg HY-021068 once daily for 7 days. The plasma concentration of HY-021068 and the platelet aggregation rate (PAR) were determined by liquid chromatography tandem-mass spectrometry (LC‐MS/MS) assay and a photometric method, respectively. The PK/PD data was sequentially fitted by Phoenix NLME. The PK/PD parameters of HY-021068 in beagle dogs were estimated by 2.5 and 5 mg/kg dosing on the 1st day, and then used to simulate the PAR of HY-021068 on the 7th day after 5 mg/kg dosing daily.Result: A one-compartment model with saturable Michaelis-Menten elimination was best fitted to the PK of HY-021068. A mechanistic PD model based on irreversible inhibition of thromboxane synthetase was constructed to describe the relationship between plasma concentration of HY-021068 and PAR. Diagnostic plots showed no obvious bias. Visual predictive check confirmed the stability and reliability of the model. Most of PK/PD observed data on the 7th day after 5 mg/kg dosing fell in the 90% prediction interval.Conclusion: We established a semi-mechanistic PK/PD model for characterizing the PK of HY-021068 and its anti-platelet effect in beagle dogs. The model can be used to predict the concentration and PAR under different dosage regimen of HY-021068, and might be served as a reference for dose design in the future clinical studies.

Functional properties of platelets in piglets when changing methods of nutrition

A functionally significant element in ensuring homeostasis of the internal environment of an animal organism is platelets. The state of their activity greatly influences the rheology of blood in small vessels and, thus, the metabolism in tissues. It becomes clear that the process of growth and development of piglets at any age substantially depends on the level of their activity. In this regard, the assessment of agerelated changes in platelet activity in piglets during their early ontogenesis is of great importance. In the work performed, it was found that in piglets during the dairy and vegetable nutrition phase there is an increase in the adhesive, aggregation and secretory properties of platelets. The leading cause of these changes can be the enhancement of receptor processes and activation of the work of post-receptor mechanisms of information transfer in platelets. This is noted in piglets during the milk-plant nutrition phase simultaneously for both strong and weak aggregation inducers. The growth of platelet activity in piglets found during the observation period apparently was due to the intensification of thromboxane generation in platelets as a result of the increased activity of their cyclooxygenase and thromboxane synthetase, as well as an increase in the secretion of ADP molecules from them. The increase in the severity of the hemostatic properties of platelets in piglets during the milk-plant nutrition phase seems to be a serious regulator of their microcirculation and metabolism processes in any environmental conditions.

Platelet function activity in black-motley calves during the dairy phase

Platelet activity in cattle can change under the influence of many factors. Their assessment in the second phase of their early ontogenesis is of great interest, taking into account the breed of calves. The purpose of the work is to evaluate platelet activity in black-and-white breed dairy calves. The study was conducted on 41 calf of black-motley breed, which was obtained from healthy cows as a result of 2–3 pregnancies. The calves were examined on the 11th, 15th, 20th, 25th and 30th day of ontogenesis. The study used biochemical, hematological and statistical methods. In animals, an increase in platelet aggregation with all tested inductors was detected during the milk feeding phase. The number of discoid platelets in the blood of calves observed during the second phase of early ontogenesis decreased by 10.5 %. Moreover, the total number of active platelets increased by 24.0 %. The levels of small, as well as medium and large aggregates of platelets present in the blood also increased during the milk feeding phase by 28.6 and 27.3 %, respectively. This was achieved in the observed calves by an increase of 9.6 % in the synthesis of thromboxane in platelets due to an increase in the activity of cyclooxygenase in them by 9.4 % and thromboxane synthetase by 9.3 %. This was also influenced by the increase in the platelet content of adenosine phosphates and the increase in their secretion. The levels of actin and myosin in inactive calf platelets increased during the milk feeding phase by 9.7 and 13.2 %, respectively. In animals, an increase in the additional generation of actin and myosin was revealed during platelet aggregation by 11.1 and 9.8 %, respectively. It is clear that calves of the black-motley breed of dairy food are characterized by a certain increase in the activity of platelet aggregation and secretion. This provides them with a high degree of preservation of blood volume in case of damage to blood vessels. The growth of intravascular platelet activity in these calves also contributes to the creation of the necessary conditions to minimize blood loss and ensure homeostasis.

Physiological parameters of thrombocytes in piglets during phase of plant nutrition early ontogeny

A very important mechanism for maintaining homeostasis in the animal body is platelet hemostasis. The level of his activity very strongly determines the rheology of blood in the capillaries and due to this the state of metabolism in the tissues. There is reason to believe that the growth and development of piglets depends on the level of functional activity of platelets. For this reason, studies of the age-related dynamics of platelet activity in piglets at the end of early ontogenesis are of great importance. In the study, it was found that the piglets of plant nutrition showed an increase in the aggregation capacity of platelets (aggregation of their platelets was accelerated by ADP from 34.10.12 s to 27.60.12 s, with collagen from 24.70.08 s to 17.50.10 s, with thrombin from 36.50.08 s to 28.40.12 s). The main reason for this may be an intensification of the work of receptor and postreceptor mechanisms of platelets. This was characteristic of piglets during the phase of plant nutrition of early ontogenesis to the same extent with respect to strong and weak inducers of platelet aggregation. The increase in thromboxane synthesis in platelets (from 48.50.05% to 59.80.09%) was largely due to an increase in the activity of cyclooxygenase in them (from 78,40.06% to 89.80.12%) and thromboxane synthetase (from 69.20.07% to 81.50.07%) and activation of ADP secretion from them (from 46.00.13% to 56.90.15%). The increase in hemostatic activity of platelets in piglets during the phase of plant nutrition of early ontogeny should be considered an important regulator of their microcirculation and metabolism in tissues under existing conditions of existence.

Physiological Features of Platelets in Milk and Vegetable Nutrition Piglets

A very important mechanism for maintaining homeostasis in the animal body is platelet hemostasis. The level of his activity very strongly determines the rheology of blood in the capillaries and due to this the state of metabolism in the tissues. There is reason to believe that the growth and development of piglets depends on the level of functional activity of platelets. For this reason, studies of the age-related dynamics of platelet activity in piglets during early ontogeny are of great importance. In the study, it was established that piglets of milk and vegetal nutrition showed an increase in the adhesive, aggregation and secretory capacity of platelets. The main reason for this may be an intensification of the work of receptor and postreceptor mechanisms of platelets. This was characteristic of piglets during dairy and plant nutrition in the same degree with respect to strong and weak inducers of platelet aggregation. At the base of the revealed increase in the activity of platelets in piglets throughout the course of the observation, the increase in the synthesis of thromboxane in platelets was largely due to the increase in the activity of cyclooxygenase and thromboxane synthetase in them and activation of the secretion of ADP from them. The increase in hemostatic activity of platelets in piglets during the phase of milk and plant nutrition should be considered an important regulator of their microcirculation and metabolism in tissues under changing conditions of existence.