Safety, Tolerability, Pharmacokinetics and Initial Pharmacodynamics of a Subcommissural Organ-Spondin-Derived Peptide: A Randomized, Placebo-Controlled, Double-Blind, Single Ascending Dose First-in-Human Study.

INTRODUCTION: This randomized, double-blind, placebo-controlled study in healthy volunteers assessed the safety, tolerability, and pharmacokinetics of single ascending doses of intravenously administered NX210-a linear peptide derived from subcommissural organ-spondin-and explored the effects on blood/urine biomarkers and cerebral activity. METHODS: Participants in five cohorts (n = 8 each) were randomized to receive a single intravenous dose of NX210 (n = 6 each) (0.4, 1.25, 2.5, 5, and 10 mg/kg) or placebo (n = 2 each); in total, 10 and 29 participants received placebo and NX210, respectively. Blood samples were collected for pharmacokinetics within 180 min post dosing. Plasma and urine were collected from participants (cohorts: 2.5, 5, and 10 mg/kg) for biomarker analysis and electroencephalography (EEG) recordings within 48 h post dosing. Safety/tolerability and pharmacokinetic data were assessed before ascending to the next dose. RESULTS: The study included 39 participants. All dosages were safe and well tolerated. All treatment-emergent adverse events (n = 17) were of mild severity and resolved spontaneously (except one with unknown outcome). Twelve treatment-emergent adverse events (70.6%) were deemed drug related; seven of those (58.3%) concerned nervous system disorders (dizziness, headache, and somnolence). The pharmacokinetic analysis indicated a short half-life in plasma (6-20 min), high apparent volume of distribution (1870-4120 L), and rapid clearance (7440-16,400 L/h). In plasma, tryptophan and homocysteine showed dose-related increase and decrease, respectively. No drug dose effect was found for the glutamate or glutamine plasma biomarkers. Nevertheless, decreased blood glutamate and increased glutamine were observed in participants treated with NX210 versus placebo. EEG showed a statistically significant decrease in beta and gamma bands and a dose-dependent increasing trend in alpha bands. Pharmacodynamics effects were sustained for several hours (plasma) or 48 h (urine and EEG). CONCLUSION: NX210 is safe and well tolerated and may exert beneficial effects on the central nervous system, particularly in terms of cognitive processing.

Nitric oxide and sleep.

Nitric oxide (NO) is a biological messenger synthesized by three main isoforms of NO synthase (NOS): neuronal (nNOS, constitutive calcium dependent), endothelial (eNOS, constitutive, calcium dependent) and inducible (iNOS, calcium independent). NOS is distributed in the brain either in circumscribed neuronal sets or in sparse interneurons. Within the laterodorsal tegmentum (LDT), pedunculopontine tegmentum and dorsal raphe nucleus, NOS-containing neurons overlap neurons grouped according to their contribution to sleep mechanisms. The main target for NO is the soluble guanylate cyclase that triggers an overproduction of cyclic guanosine monophosphate. NO in neurons of the pontine tegmentum facilitates sleep (particularly rapid-eye-movement sleep), and NO contained within the LDT intervenes in modulating the discharge of the neurons through an auto-inhibitory process involving the co-synthesized neurotransmitters. Moreover, NO synthesized within cholinergic neurons of the basal forebrain, while under control of the LDT, may modulate the spectral components of the EEG instead of the amounts of different sleep states. Finally, impairment of NO production (e.g. neurodegeneration, iNOS induction) has identifiable effects, including ageing, neuropathologies and parasitaemia.

Hepatic ischemia is associated with an increase in liver parenchyma nitric oxide that is in part enzyme-independent.

BACKGROUND: Nitric oxide (NO) might be involved in liver response to local ischemia-reperfusion injury. METHODS: A specific NO-sensitive electrode was inserted into liver parenchyma of anesthetized rabbits. After a 45-min period of stable NO signal, the vascular pedicle of the caudal lobe of the liver was clamped for 45 min, then the clamp was removed. Perfusion of the right upper lobe was left unchanged. The same procedure was applied in other animals after administration of a long-acting nonspecific NO synthase inhibitor NAPNA. RESULTS: Occlusion of the caudal pedicle was associated with a mean threefold increase in NO signal measured in the caudal lobe. After unclamping, this signal returned within 8 min to baseline value and remained stable for the next 6 h. In the right upper lobe, NO signal was unaffected by caudal lobe ischemia. By the end of the 6-h reperfusion period, administration of the NO inhibitor l-NAME led to a suppression of the NO signal, thus demonstrating the specificity of the measurement. Plasma nitrate and nitrite concentrations remained almost unchanged during the study period in all groups. In animals whose NO synthases had been previously inhibited by NAPNA, clamping the caudal pedicle for 45 min was still associated with a significant increase in caudal lobe NO signal. CONCLUSION: Nitric oxide is present in liver parenchyma, and its generation is dramatically affected by an ischemia injury. The increased NO generation during local ischemia is, at least in part, independent of NO synthases.