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Animal Research Context: Scaling from Rodents Preclinical studies with Dihexa and angiotensin IV analogues employed doses that ranged considerably depending on species, route, and outcome measured: Intravenous (IV) Administration Animal studies using intravenous dosing (which bypasses absorption barriers and achieves near-complete bioavailability) reported cognitive and neuroprotective effects at: 0.1 to 2.0 mg/kg in rodent studies (McCoy et al., 2013) Doses at the higher end of this range (12 mg/kg IV) produced robust behavioral effects For a 70 kg human, equivalent to 70140 mg total IV dose (crude extrapolation) However, direct extrapolation from rodents to humans is unreliable due to differences in metabolism, brain penetration, and receptor sensitivity Intraperitoneal (IP) Administration IP dosing (injection into the abdominal cavity, with slower absorption than IV) showed effects at: Up to 10 mg/kg in some studies Lower bioavailability than IV, requiring higher nominal doses for similar effects This route is not practical for human use Why Rodent Dosing Doesn't Directly Translate Rodent pharmacokinetics differ substantially from humans

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1 Effect of semaglutide treatment or placebo on waist circumference from baseline to week 104 by subgroups