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3. Two out of four studies on larger animals (dog, sheep and two
studies with pig) reported the lack of effect of EPO, even if
EPO was administered before ischemia and/or right before
reperfusion (
23, 26, 29, 33
); one study in the pig showed bet-
ter left ventricular function than controls, in the presence of
unchanged size of infarct.
Pharmacokinetics and pharmacodynamics of erythropoietin in
healthy volunteers have been well established (
51
). A single subcu-
taneous dose of erythropoietin as high as 2,400 IU/kg is well tol-
erated by healthy people (higher dose was not tested), and while
with respect to erythropoiesis the effect of EPO is dose-dependent,
the dose higher than 1,800 IU/kg not followed by further increase
of reticulocytes in blood. However, the safety and tolerance of
erythropoietin in patients, especially patients with developing MI
needed to be tested. 33,000 IU of rhEPO (about 450 IU/kg) had
been well tolerated by patients when injected during the first 3
days after stroke (
52
). 200 U/kg had been also injected intrave-
nously to 29 patients during the first 3 days of acute MI with
ST-segment elevation additionally to PCI and standard therapy
(
53
). EPO treatment did not result in any complications. The
bleeding time, platelet function assay closure time and plasma lev-
els of von Willebrand factor were not altered by the EPO treat-
ment. Safety of EPO in patients in acute stage of MI was also
evaluated in the safety arms of clinical trials described below and it
was found mostly safe.
Published to date results of completed phase I and II clinical
trials are summarized in the Table
3
. The first small study
(20 patients with first acute ST-segment elevation MI and indica-
tions for PCI) was concluded in 2006 in the Netherlands (
54
).
60,000 IU of Darbepoetin-alfa (long-acting EPO with half-life of
21 h), which is approximately equivalent to 800 IU/kg in the aver-
age patient, or placebo were injected intravenously immediately
before PCI. Time between PCI and symptom onset was not
reported. The serum EPO level was significantly increased 24 h
and the progenitor endothelial cells were significantly increased
72 h after treatment in EPO treated vs. placebo cohorts. EPO
treatment was well tolerated and no adverse effect of EPO treat-
ment had been noted during 30 days after treatment. However,
the LV function measured 4 months after intervention by radionu-
clide ventriculography showed no differences in LVEF between
two groups.
A pilot study involving 51 patients with non-STEMI was also
conducted in the Netherlands (
55
). Single intravenous dose of
40,000 IU of Epoetin-alfa was given within 8 h from elevated tro-
ponin level to 26 patients. Enzymatic MI size measured at non-
STEMI was not different between experimental and placebo groups.
Elevation of BP was noted among patients treated with EPO.
1.2
Clinical trials
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