Absence of hematological side effects in acute and subacute nasal dosing of erythropoietin with a low content of sialic acid.
The use of human recombinant erythropoietin (EPO) as a neuroprotective agent is limited due to its hematological side effects. An erythropoietin along with a low content of sialic acid (rhEPOb), similar to that produced in the brain during hypoxia, may be used as a neuroprotective agent without risk of thrombotic events. The objective of this investigation was to assess the toxicological potential of a nasal formulation with rhEPOb in acute, subacute and nasal irritation assays in rats. Healthy Wistar rats (Cenp:Wistar) were used for the assays. In an irritation test, animals received 15 μl of rhEPOb into the right nostril. Rats were sacrificed after 24 h and slides of the nasal mucosa tissues were examined. Control and treated groups showed signs of a minimal irritation consisting of week edema and vascular congestion in all animals. In the acute toxicity test, the dose of 47,143 UI/kg was administered by nasal route. Hematological patterns, body weight, relative organ weight, and organ integrity were not affected by single dosing with rhEPOb. In the subacute toxicity test, Wistar rats of both sexes received 6,600 UI/kg/day for 14 days. The toxicological endpoints examined included animal body weight, food consumption, hematological and biochemical patterns, selected tissue weights, and histopathological examinations. An increase of lymphocytes was observed in males that was considered to reflect an immune response to treatment. Histopathological examination of organs and tissues did not reveal treatment-induced changes. The administration of rhEPOb at daily doses of 6,600 UI/kg during 14 days did not produce hematological side effects. These results suggest that rhEPOb could offer the same neuroprotection as EPO, without hematological side effects.
Lagarto
Alicia
A
Drug Research and Development Center, CIDEM, 17 No. 6208 e/62 y 64, Playa, Código Postal 11300, Ciudad Habana, Cuba. alicialp@infomed.sld.cu
Bueno
Viviana
V
Guerra
Isbel
I
Valdés
Odalys
O
Couret
Micaela
M
López
Raisel
R
Vega
Yamile
Y
D000281:Administration, Intranasal; D000818:Animals; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000097:blood*; D004921:Erythropoietin / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D005260:Female; D008297:Male; D019158:N-Acetylneuraminic Acid / Q000032:analysis*; D009297:Nasal Mucosa / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D023382:Toxicity Tests, Acute; D059551:Toxicity Tests, Subacute
C554270:EPO protein, human; D018696:Neuroprotective Agents; D004921:Erythropoietin; D019158:N-Acetylneuraminic Acid