This defensive publication discloses agmatine-containing and agmatine-adjacent compositions, salt forms, delivery architectures, dosage forms, release profiles, gastrointestinal tolerability systems, co-localised mast-cell support systems, multi-component regimens, formulation technologies, clinical service models, companion diagnostics, outcome measures, kit architectures and product models for neurodevelopmental, psychiatric, autonomic, sensory, cognitive, emotional, social-functioning, fatigue-associated, gastrointestinal, immune, inflammatory, mitochondrial, microbiome, purinergic, endocrine, sleep, stress-recovery and transdiagnostic state-regulation applications. The disclosed compositions, formulations, kits, regimens, protocols and diagnostic systems are expressly disclosed for use in preventing, treating, reducing, ameliorating, modulating, managing or supporting state-regulation impairments occurring in subjects with, diagnosed with, presenting traits of, or at risk of autism spectrum condition/autism spectrum disorder, ADHD, anxiety disorders, obsessive-compulsive disorder, major depressive disorder, persistent depressive disorder, treatment-resistant depression, depression with psychomotor retardation, bipolar depressive or mixed episodes, post-traumatic stress disorder, complex PTSD, acute stress disorder, adjustment disorders, autistic burnout, occupational burnout, caregiver burnout, academic burnout, sensory processing disorder, executive dysfunction, ME/CFS, fibromyalgia, long-COVID cognitive or autonomic dysfunction, perimenopause-associated or menopause-associated cognitive/autonomic dysfunction, PMDD, substance-withdrawal-associated dysregulation, traumatic-brain-injury-associated state-regulation difficulty, pathological demand avoidance/PDA profile, Tourette syndrome or tic disorders, eating disorders with interoceptive or state-regulation features, personality disorders with emotional-dysregulation features, intellectual disability or Down syndrome with co-occurring state-regulation difficulty, IBS-associated neurobehavioural dysregulation, mast-cell-activation-syndrome or histamine-intolerance-associated sensory/autonomic dysregulation, chronic pain with fatigue, shutdown, autonomic or sensory dysregulation, sleep-restoration impairment with daytime state-regulation impairment, and subclinical, subthreshold, mixed or multi-diagnosis presentations. The disclosure is centred on a state-regulation framework in which functional impairment is defined by disruption of a demand-response-recovery cycle rather than by a single diagnostic label. Disclosed phenotypes include impaired action initiation, autistic inertia, executive state-transition difficulty, task paralysis, sensory overload, reduced sensory tolerance, shutdown vulnerability, meltdown vulnerability, autonomic dysregulation, chronic hyperarousal, cognitive rigidity, perseverative state-locking, depression-linked inertia, trauma-related hyperarousal, social functioning impairment, impaired social initiation, reduced social reciprocity, social communication impairment, social fatigue, impaired recovery after social demand, impaired recovery after sensory or cognitive demand, stress-recovery failure and burnout-associated loss of adaptive capacity. A principal disclosed system is a four-component regimen comprising: (1) an agmatine-pathway component, (2) a palmitoylethanolamide-class component, (3) an acylcarnitine component and (4) a citicoline or choline-cytidine donor component. In preferred embodiments, the regimen is physically separated into: a first enterically protected dosage unit comprising agmatine and PEA with a hydrophilic matrix-forming polymer such as HPMC that hydrates after enteric opening to moderate intestinal agmatine exposure; and a physically separate immediate-release second dosage unit comprising ALCAR and citicoline. The same four-component system is also expressly disclosed as an all-in-one or single-product-unit system in which the components, salts, derivatives, analogues, prodrugs, complexes or functional substitutes are contained in one capsule, tablet, caplet, MUPS tablet, gummy, chewable, ODT, sachet, liquid unit, film, spray, patch, suppository, injection, infusion container, implantable depot or other administrable unit while using internal particles, pellets, layers, coatings, reservoirs, compartments, matrices or encapsulated subunits to provide different release sites, release rates, stability environments or sensory profiles. The separated and all-in-one architectures are disclosed for any agmatine salt or form, including agmatine sulfate as a principal commercial embodiment and agmatine dihydrochloride as an optimisation, and for all technically feasible combinations, routes, dose ranges, excipients, packaging systems and clinical protocols described herein. The disclosure further covers: agmatine sulfate retained with delivery-based GI tolerability improvement; agmatine dihydrochloride or other non-sulfate salts for counterion optimisation; co-localised PEA for local mast-cell/histamine support at the intestinal site of agmatine release; ALCAR upper-intestinal release to reduce lower-intestinal TMA/TMAO formation; citicoline moisture-management architectures; taste- and odour-masked acylcarnitines; intranasal, buccal, sublingual, transdermal, injectable and other non-oral agmatine delivery; loading, maintenance and rescue protocols; paediatric, geriatric and sensory-sensitive formats; product kits; support stacks; microbiome/ecology products; outcome measures; companion diagnostic systems; and publication evidence practices. All ingredients, ingredient classes, salt forms, routes, release profiles, dosage forms, excipients, technologies, indications, populations, outcome measures, product architectures and protocols disclosed herein are disclosed both individually and in all technically feasible combinations, including open, partially closed and closed compositions. Specific examples, ranges, combinations and embodiments are provided to avoid relying solely on generic genus language. Keywords: agmatine; agmatine sulfate; agmatine dihydrochloride; agmatine hydrochloride; enteric release; HPMC; hydrophilic matrix; palmitoylethanolamide; PEA; mast cells; histamine; diamine oxidase; acetyl-L-carnitine; ALCAR; trimethylamine; TMAO; citicoline; CDP-choline; moisture management; autism; autism spectrum disorder; ADHD; OCD; depression; treatment-resistant depression; PTSD; complex PTSD; anxiety; autistic inertia; sensory overload; shutdown; meltdown; burnout; state regulation; demand-response-recovery; intranasal agmatine; companion diagnostics; defensive publication.
Offmap LTD (Wed,) studied this question.