Inside the body with Semax

After intranasal administration of tritium-labelled semax to rats, about 0.093% of the administered radioactivity per gram of brain was found at 2 minutes, of which about 80% was intact semax (Russian-language paper; FDA's summary of the English version reports about 0.072% of the dose and a peak brain-to-blood ratio of about 0.67). In the studies FDA reviewed, intranasal delivery gave a higher brain fraction and brain-to-blood ratio than intravenous delivery. Direct olfactory-pathway transport is the proposed route. FDA found no human pharmacokinetic study by any route.[src][src]

In rat blood, brain tissue and basal forebrain cell cultures semax is hydrolysed rapidly, with removal of N-terminal residues (Met-Glu) and Gly-Pro; in rat serum the main enzymes are aminopeptidases and angiotensin-converting enzyme, and Pro-Gly-Pro is the main metabolite in rat blood and brain. The C-terminal Pro-Gly-Pro segment is thought to improve peptidase resistance. Semax itself and Pro-Gly-Pro have partly different effects in ischemia models, so metabolites may contribute to activity. All of these data are from rats or rat-derived material.[src][src][src][src]

Tritium-labelled semax showed time-dependent, specific, reversible, calcium-dependent binding to rat basal forebrain membranes (Kd 2.4 +/- 1.0 nM; Bmax 33.5 +/- 7.9 fmol/mg protein). The binding protein has not been identified. FDA describes semax, like ACTH(4-10), as lacking the hormonal corticotropic and melanotropic properties of full-length ACTH while keeping neurobehavioural effects. Binding data are from rat tissue only.[src][src]

A single intranasal semax application in rats raised hippocampal BDNF protein up to 1.4-fold and TrkB tyrosine phosphorylation 1.6-fold, with 3-fold and 2-fold increases in exon III Bdnf and TrkB mRNA. In rats with permanent middle cerebral artery occlusion, semax increased transcription of Bdnf, TrkC and TrkA at 3 h and of Nt-3 and Ngf at later times, and affected neurotrophin genes selectively in ischemic cortex. The molecular route by which semax regulates gene expression is unknown. All findings are animal-only.[src][src][src]

In rodents, systemically injected semax increased striatal 5-HIAA (extracellular up to 180% within 1-4 h) without changing dopamine on its own, but strongly potentiated D-amphetamine-induced striatal dopamine release and locomotion. Rat analgesia was blocked by cyproheptadine (5-HT antagonist) but not naloxone, and in vitro semax inhibited enkephalin-degrading enzymes in human serum (IC50 about 10 micromolar). FDA noted that potentiation of amphetamine-induced dopamine release is a concern and that abuse potential has not been studied. Animal and in vitro findings only.[src][src][src]

Repeated intranasal semax and Pro-Gly-Pro enhanced plasma anticoagulant and fibrinolytic activity (total fibrinolytic activity, plasmin, plasminogen activator), lowered antiplasmin, and reduced thrombus weight in a rat thrombosis model; other rat work reported reduced platelet aggregation. Semax lacked anticoagulant effect in vitro, suggesting metabolites may mediate it. FDA highlighted a possible bleeding risk in people at risk of bleeding or taking drugs that raise bleeding risk; the only human-related report it found was a meeting abstract that did not give full clotting results or make clear whether they were measured in rats or people.[src][src]

In 110 post-ischemic-stroke patients, subgroups receiving semax showed higher and sustained plasma BDNF and faster Barthel index improvement than those not receiving it (Russian-language journal; the English abstract does not describe randomisation or blinding). In 24 healthy volunteers, resting-state fMRI after intranasal 1% semax (n=14) versus placebo (n=10) showed a larger rostral default-mode-network subcomponent. A retrospective analysis in acute stroke reported changes in blood immune markers (interleukin-10, TNF-alpha, interleukin-8, C-reactive protein) that the authors interpreted as an anti-inflammatory shift; only a brief Russian abstract is available. FDA judged the clinical evidence insufficient.[src][src][src][src]