Hema-Plus Mechanism of Action

PHARMACOLOGY: Endothelioid cells of the cortex of the kidney and the outer medulla seem to be responsible for Erythropoietin synthesis (Lacombe, 1988). After it is synthesized in the kidney and released into the circulation erythropoietin develops its hormonal action in the bone marrow by stimulating the development of erythroid progenitor cells into mature erythrocytes. The product stimulates not only the proliferation of erythropoietic progenitor cells, but also their differentiation.
During the maturation phase, hemoglobin values increase together with an acceleration of the erythroblast maturing process and an increase of reticulocytes, which are direct producers of erythrocytes.
At the cell level, it works as a polypeptidic hormone on the receptors of the progenitor erythroid cells. It can also work through a second messenger and internalize.
Various groups, among which Miller (1988), have studied erythropoietin's biochemical action upon its ligand at the cell level. Reports indicate that it can notably increase intracellular calcium levels.
Recombinant human erythropoietin stimulates proliferation and differentiation of erythroid progenitors which is clearly dependent on dose and duration of administration. The increase in reticulocyte count is followed by rises in hematocrit and hemoglobin levels. Tissue iron stores are mobilized during recombinant human erythropoietin therapy, and iron supplement to maintain erythropoiesis is recommended when serum ferritin <100 - 150 ng/mL and/or transferrin saturation is < 20%.
The therapy is not associated with any effects on the peripheral leukocyte or platelets counts.
Blood pressure may increase, particularly during induction therapy. Improvements in left ventricular function and cardiac output appear to be less likely in patients with preexisting hypertension or in those who develop hypertension during the therapy. The treatment with recombinant human erythropoietin has been successful with improvements in exercise capacity. It is also demonstrated that this treatment does not produce the progression of the chronic renal failure.
Chronic renal failure patients: The level of tissue oxygenation normally regulates production of endogenous serum of erythropoietin. Hypoxia and anemia generally increase the production of erythropoietin, which in turn stimulates erythropoiesis.
In normal subjects, plasma erythropoietin levels range from 0.01 to 0.03 mIU/mL and may increase up to 1000-fold during hypoxia or anemia. In contrast, in-patients suffering from chronic renal failure, production of erythropoietin is impaired, and this erythropoietin deficiency is the primary cause of their anemia.
Chronic renal failure is the clinical situation in which there is a progressive and usually irreversible decline in kidney function. Such patients may manifest the sequel of renal dysfunction; including anemia. Patients with end-stage renal disease are those patients with chronic renal failure who require regular dialysis or kidney transplantation for survival.
Erythropoietin has been shown to stimulate erythropoiesis in anemic patients with chronic renal failure, including both patients on dialysis and those who do not require regular dialysis.
The first evidence of a response to the three times weekly administration of erythropoietin is an increase in the reticulocyte count within 10 days, followed by increases in the red cell count, hemoglobin and hematocrit, usually within 2-6 weeks. Once the proposal target hematocrit (30-36%) is reached this level should be maintained provided there is no iron deficiency or other concomitant disease.
Cancer patients: Anemia in cancer patients may be related to the disease itself or the effect of concomitantly administered chemotherapeutic agents.
It is recommended that the endogenous serum erythropoietin level be evaluated prior to treatment, since available evidence suggests that patients with endogenous serum erythropoietin levels greater than 200 mIU/mL do not respond to the treatment.
Pharmacokinetics: Intravenous route: Research works conducted on patients after administration of multiple intravenous erythropoietin doses have revealed a half-life of approximately 4 hours in volunteers and a slightly longer half-life (approximately 5 hours) in patients with chronic renal failure. For the time being, a half-life of 6 hours is reported in children.
Subcutaneous route: Serum concentrations following subcutaneous injection are much lower than those following intravenous injection. Serum levels increase slowly and reach a peak 8 to 12 hours after subcutaneous dosing. The maximum concentration is always lower than the obtained with intravenous administration.