Inside the body with DSIP (delta sleep-inducing peptide)

In Caco-2 human intestinal epithelial monolayers, DSIP applied to the apical side was extensively metabolised (about 8% remaining after 2 hours), with Trp as the main metabolite and Trp-Ala as a minor one. Even with aminopeptidase, dipeptidylpeptidase IV and peptidyl dipeptidase A inhibitors, which raised stability to about 95%, no intact DSIP was detected on the basolateral side. This is an in-vitro finding only.[src]

After intravenous injection, plasma half-life was about 4.0 min in dogs, 2.9 min in a monkey and 2.0 min in rats (Kato 1984, enzyme immunoassay). FDA's review cites human serum half-lives of about 5 to 10 min in vitro, with N-terminal peptidases starting the breakdown, and notes that peptidyl dipeptidase A also cleaves it, so ACE-inhibitor-type drugs could in principle slow its degradation (nonclinical data only). No pharmacokinetic data exist for subcutaneous dosing.[src][src]

FDA's review summarises transport data: in dogs, CSF concentrations peaked about 30 min after an intravenous bolus; in rats, brain tissue concentrations were higher than in controls seconds after a high intravenous dose; and in perfused sheep choroid plexus, radiolabelled DSIP crossed from blood to CSF by a saturable process. Human blood-brain-barrier penetration was not measured in the studies FDA identified.[src]

Intraventricular infusion of synthetic DSIP in rabbits increased EEG delta and spindle activity, by about 35% in neocortex and limbic cortex versus control (Schoenenberger and Monnier 1977; 1978). Similar effects were reported after intravenous, intraperitoneal or subcutaneous dosing in rabbits, rats and cats. Results are inconsistent: some studies show selective non-REM prolongation, others also REM prolongation, and one group found no delta increase in rats. No DSIP gene, precursor or receptor has been isolated, and a 2006 review described the sleep-factor hypothesis as poorly documented.[src][src][src][src]

In rats, naloxone prevented the sleep-prolonging effect of intracerebroventricular DSIP, and naloxone also reduced DSIP-induced analgesia in rodents. In vitro, DSIP did not displace [3H]diprenorphine from rat brain or human placental membranes, but it was reported to promote calcium-dependent enkephalin release from several brain regions. FDA notes that this mechanism could theoretically carry reinforcing or abuse potential, which has not been studied.[src]

Bes 1992 (n = 16, double-blind, matched-pairs parallel groups, intravenous DSIP versus glucose over three nights) found higher sleep efficiency and shorter sleep latency versus placebo but judged the effects weak, partly due to a chance change in the placebo group, and concluded DSIP is unlikely to be of major therapeutic benefit. FDA's review also describes a second double-blind, placebo-controlled crossover study in 6 patients (Monti 1987) with no significant differences from placebo, a 6-person crossover study reporting only tendencies, and small Schneider-Helmert studies without a placebo arm that reported improvements against baseline or external control groups; FDA judged that these could not show clinically meaningful benefit and concluded there was insufficient evidence of effectiveness.[src][src]

Dick et al. 1984 reported an uncontrolled study in 107 inpatients (47 alcohol, 60 opiate withdrawal), with clinical signs improving markedly in 87% and 97% of evaluable alcohol and opiate patients respectively; anxiety improved more slowly, and headaches were reported by a few. FDA judged the design (no blinding or comparison group, ill-defined population, subjective assessments) unable to support effectiveness, and reported that anxiety and marked insomnia often returned within 24 to 72 hours of stopping.[src][src]