Abstract:
:The objective was to determine the respiratory toxicity of MAP0004, orally inhaled dihydroergotamine (DHE), via inhalation for six months. Forty beagle dogs (twenty females, twenty males) were treated by nose-only inhalation for 182 days. Groups 2 through 5 received MAP0004 (mean doses: 0.045, 0.154, 0.44, 0.825 mg/kg); Group 1 received vehicle only. Groups 1 through 4 received single thirty-minute exposures, whereas Group 5 was exposed twice daily for thirty minutes. Toxicity was assessed from clinical observations, objective evaluations, and clinical and anatomical pathology. Systemic effects were scabbing of ear tips in Groups 3, 4, and 5 and excessive salivation and emesis, observed in Group 5. No changes were observed in the lungs in any dose group. Minimal treatment-related microscopic changes were observed in the respiratory nasal epithelium only in Group 5. No plexiform, vascular media, or fibroproliferative changes in any heart valves were observed in any group. Expected systemic pharmacologic effects were observed only at MAP0004 target doses ≥ 0.224 mg/kg (achieved doses > 0.154 mg/kg), which was more than five times the maximum daily intravenous (IV) human clinical dose of DHE, and more than twenty times the systemic equivalent dose of MAP0004. The no-observed adverse effect level (NOAEL) was the achieved inhaled dose of 0.045 mg/kg, or four times the human clinical dose of MAP0004.
journal_name
Toxicol Patholjournal_title
Toxicologic pathologyauthors
Armer TA,Lynch M,Moutvic R,Singer Adoi
10.1177/0192623311399786subject
Has Abstractpub_date
2011-04-01 00:00:00pages
544-52issue
3eissn
0192-6233issn
1533-1601pii
0192623311399786journal_volume
39pub_type
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