Erythropoietin plasma concentrations

To date, three pharmaceutical companies have entered clinical trials with PHD inhibitors for the treatment of anemia with the most advanced being FG-2216. In clinical studies, compound 2 (likely FG-2216) showed a dose- and time-dependent elevation of plasma erythropoietin after oral administration [66]. Healthy volunteers were orally administered various doses of compound 2 and serum erythropoietin (EPO) concentrations were measured at various times. Compound 2 increased serum EPO levels in a dose-dependent manner and, following administration of the 20 mg/kg dose, a 5-fold increase of EPO levels was observed after 12 h. In the same patent application, the effect of 2 on anemic predialysis patients with no previous rh-EPO exposure was also disclosed. Patients were treated with 2 three times/week for 4 weeks (no dose reported) and the hemoglobin levels were assessed on day 42. The patients who received treatment showed a mean increase in hemoglobin of 1.9 g/dL from baseline values, whereas subjects who received placebo showed a mean decrease of 0.35 g/dL from baseline levels. These data suggest for the first time that an oral PHD inhibitor could be effective for the treatment of anemia. 

Opatmy Jr, K, Krouzecky, A., Wiith, J., Vit, L., Eiselt, J. The effects of a polyacrylonitrile membrane and a membrane made of regenerated cellulose on the plasma concentrations of erythropoietin during hemodialysis. Artif. Organs 22, 816-820 (1998)... 

Changes in catecholamines and 3-O-methyl metabolite concentrations in human plasma Erythropoietin in pharmaceutical products 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, amphetamine, and methamphetamine in rat urine Azoxystrobin, kresoxim-methyl, and trifloxystrobin fungiddes ... 

Anemia in hemodialysis (10) and mainly in renal transplant patients has been reported (11-13). The suggested mechanism is by an action on erythropoietin, similar to that of ACE inhibitors, which produce the same adverse effect. However, in a small uncontrolled but prospective study, losartan given for 3 months to 15 patients on chronic hemodialysis with anemia, neither altered plasma erythropoietin concentrations nor aggravated the anemia (14). In those taking losartan there was no need for higher doses of co-administered r-Hu Epo in order to correct anemia, in contrast to controls. 

A mathematical model of the control system for erythropoiesis is presented. It is postulated that the rate of erythropoiesis is controlled by a hormone, erythropoietin, which is released from the kidney in response to reduced renal oxygen supply. Equations are developed relating erythropoietin release to arterial oxyhemoglobin concentration, and hemoglobin production to plasma erythropoietin concentration, with appropriate time delays. Effects of plasma volume changes during hypoxia are included. The model simulates the dynamic response of the erythropoietic system to a step decrease in the pOt of inspired air. Contributions of the parameters and relationships to the predicted response are analyzed. The model response compares favorably with experimental data obtained from mice subjected to different degrees of hypoxia. 

Figure 1. Block diagram of a model for the control of erythropoiesis (HbO), oxyhemoglobin concentration Vi, viscosity factor (HbO), effective oxyhemoglobin concentration R, rate of erythropoietin release (E), plasma erythropoietin concentration E0, normal plasma erythropoietin concentration V , distribution volume for erythropoietin P, rate of hemoglobin production MT, erythrocyte maturation time L, rate of hemoglobin loss TH, total circulating hemoglobin (Hb), blood hemoglobin concentration Vb, blood volume Vp, plasma volume Vp0, normal plasma volume Vpf, steady-state hypoxic plasma volume MCV, mean corpuscular volume MCH, mean corpuscular hemoglobin k, constant...

A delay of 4 hours (Ti) was incorporated into the model between changes in oxyhemoglobin concentration and subsequent erythropoietin release to account for the time required from release of the renal erythropoietic factor to the development of active erythroproietin in the blood stream (3). Values for Ki and K2 were estimated for the mouse by scaling a relationship derived from data in rats, relating oxyhemoglobin concentration to erythropoietin release (I). It was assumed that the released erythroproietin mixes instantly in a volume equal to twice the plasma volume and that the disappearance rate of erythropoietin is proportional to the plasma erythropoietin concentration with a disappearance constant of. 130 day (4). 

In the model, plasma erythropoietin concentration was used to determine the amount of hemoglobin produced and the time delay before new red blood cells (hemoglobin) are released into the blood stream. Equation 2 shows the postulated relationship between the rate of hemoglobin production and plasma erythropoietin concentration. 

P(t) = rate of hemoglobin production at time t Pm = maximum rate of hemoglobin production [E( t)] = plasma erythropoietin concentration at time t K3 and K4 are constants... 

Two relationships were used to determine the time delay (maturation time) between the stimulation of red blood cell production by erythropoietin and the release of mature red blood cells (hemoglobin) into the blood stream. Normally cells are assumed to mature and enter the blood stream 3.75 days after stimulation by erythropoietin. However, this maturation time can vary from 2.5 to approximately 4.0 days, depending on the plasma erythropoietin concentration at the time of stimulation. This relationship is shown in Equation 3. 

In response to sustained hypoxia, the model predicts a sudden increase in plasma erythropoietin concentration followed by a rapid decrease with the maximum at approximately 12 hours. This type of response has been reported for man and animals (9, 10, II, 12). However, in contrast to the reported experimental data, the erythropoietin levels predicted by the original model did not return to baseline levels after a few days of hypoxia. It appears that some mechanism not included in the model allows a continuing high level of erythropoiesis even after the plasma erythropoietin concentration has returned to near baseline levels. Such a mechanism has been proposed by Kretchmar in a model for the action of erythropoietin (13). His model predicts that the sensitivity of erythropoietin depends on the preceding level of stem cell differentiation. Increased erythropoietin concentration causes an immediate increase in stem cell differentiation as well as an increase in the effectiveness of erythropoietin during a subsequent period. His model also predicts a temporary reduction in the effectiveness of erythropoietin between an initial increase in erythropoietin concentration and the subsequent increase in erythropoietin effectiveness. 

With the relationship between oxyhemoglobin concentration and erythropoietin production selected to provide good agreement of erythropoietin concentration changes and experimental data, the constants in Equation 2 (hemoglobin production) were modified to produce a better total hemoglobin response. The conditions were that (1) normal plasma... 

Figure 8. Model predictions for plasma erythropoietin concentration as a function of duration of hypoxic exposure at 360 mm Hg total pressure. The model responses were obtained with the parameter values listed in Table 1. The solid line was generated with the changes in plasma volume and arterial p0 as described in the text and included in the model. The broken lines were obtained with either the plasma volume held constant or arterial p02 held at the acute level for the duration of hypoxic exposure.

Progress in our knowledge of erythropoietin has been hindered by the fact that it is present in plasma only in small quantities and cannot easily be concentrated and purified from plasma. Furthermore, avail-... 

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