Dosage research on Semax

Preclinical research dose ranges

In published preclinical research on Semax, administered dose ranges in rodent studies have most commonly fallen in the 50 to 600 microgram per kilogram range delivered intranasally or intraperitoneally. The cognitive-endpoint literature in rats and mice has used doses in this span across acute and sub-chronic dosing protocols in active-avoidance learning, passive-avoidance learning, and Morris water-maze designs.

The neuroprotection-endpoint literature has used a comparable dose range in cerebral-ischaemia and middle-cerebral-artery-occlusion rodent models. Doses in the microgram-per-kilogram range delivered intranasally or intraperitoneally have been used across multi-day post-stroke dosing protocols, with the protocol design optimised to maximise central-nervous-system exposure through the nose-to-brain delivery route.

The Levitskaya and colleagues line of work characterised the gene-expression and neurotrophic-factor effects of Semax in rat hippocampus and cortex tissue across this dose range. Investigators reading the Semax literature should note the Russian-laboratory tradition of per-animal versus per-kilogram dose reporting and translate to per-kilogram equivalents using the reported animal body weights when comparing across literatures.

Dose-response considerations from the published literature

The published Semax literature has reported dose-response characteristics in cognitive and neuroprotection endpoints across the 50 to 600 microgram per kilogram range in rodent models. Effects on learning, memory, neurotrophic-factor expression, and post-ischaemic outcomes scaled with administered dose across the tested range. Higher doses in some protocols produce mixed-profile effects that the published work attributes to broader-spectrum neuropeptide pathway engagement.

A small number of Russian clinical-pilot reports exist in the cognitive and post-stroke neuropeptide literature using doses in the microgram-per-day range intranasally in adult subjects. These reports do not constitute Phase 1 dose-ranging trials, and the research community continues to rely on the rodent literature and these pilots for dose-design inference.

Reconstitution math and per-vial dose calculation

A 10 mg lyophilised Semax vial reconstituted with 2 mL of bacteriostatic water yields a stock concentration of 5 mg per mL. From this stock, a research aliquot of 0.1 mL contains 500 micrograms; an aliquot of 0.02 mL contains 100 micrograms. Researchers working with the microgram-per-kilogram dose ranges in published rodent studies further dilute the stock to a working concentration appropriate to the model and the body weight of the animal subject. For intranasal administration, the working concentration is typically further diluted to the small-volume delivery range appropriate to per-nostril dosing. Refrigerated storage at 2 to 8 degrees Celsius, protected from light, is the standard handling practice.

Research-protocol design considerations

Protocol-design choices in the published Semax literature reflect several recurring considerations. Dose selection in rodent cognitive studies anchors at the 50 to 600 microgram per kilogram range. Acute single-dose protocols predominate in pharmacology and acute-effect designs; sub-chronic multi-day protocols appear in cognitive-training, neuroprotection, and gene-expression time-course studies.

Route of administration in the published rodent work uses both intranasal and intraperitoneal injection. Intranasal administration matches the delivery route used in the Russian clinical-pilot reports and exploits the nose-to-brain delivery considerations relevant to central-nervous-system endpoints. Intraperitoneal administration appears in systemic-endpoint and pharmacokinetic studies.

The ACTH-fragment origin is a protocol-design consideration for investigators interested in melanocortin-receptor-related effects. Semax reproduces some of the cognitive and neurotrophic profile attributed to the ACTH(4-7) fragment without engaging the adrenocortical axis at the same magnitude as intact ACTH; protocol designs interested in distinguishing melanocortin-receptor-mediated from melanocortin-receptor-independent neurotrophic effects use this distinction in comparator-arm experimental design.

References

1. Levitskaya NG et al. ACTH(4-10) analog Semax produces neuroprotective and behavioral effects in rats. Behavioural Brain Research, 2010. [PMID 20211211]
2. Asmarin IP et al. The development of biological active heptapeptide Semax: synthesis, pharmacology, mechanism. Russian Journal of Bioorganic Chemistry, 2010. [PMID 21381335]
3. Kolomin TA et al. Comparison of the transcriptome response to Semax and Selank in rat hippocampus and spleen cells. Molecular Biology, 2013. [PMID 23808162]
4. Dolotov OV et al. Semax, an analog of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain. Journal of Neurochemistry, 2006. [PMID 16524382]
5. Bashkatova V et al. Neurochemical mechanism of action of synthetic ACTH(4-7)-Pro-Gly-Pro (Semax) in the central nervous system. Bulletin of Experimental Biology and Medicine, 2012. [PMID 22708331]
6. Dolotov OV et al. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Research, 2006. [PMID 16996037]