Program randomization for cyber-attack resilient control in programmable logic controllers

A method of treatment of a disorder selected from the group consisting of Tourette syndrome, developmental coordination disorder, stereotypic movement disorder, autism spectrum disorders, bacterial-induced repetitive behavior, NMDA antibody-related encephalitis, autoimmune antibody-mediated mental disorder, autoimmune antibody-mediated psychosis, pediatric autoimmune neuropsychiatric disorders-associated with streptococcal infections (PANDAS), chorea (Sydenham's chorea (SC), chorea minor, chorea gravidarum, drug-induced chorea), drug-induced repetitive behaviors, akathisia, dyskinesias, dystonias, cramps and spasms, tremors, restless leg syndrome, moving toes/fingers syndrome, involuntary movement, stereotypic movement disorder, extrapyramidal movement disorders, Wernicke-Korsakoff syndrome and a combination thereof wherein acute, transient or chronic, comprising administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a mixed CB2/SERM ligand in a pharmaceutically acceptable carrier, wherein the mixed CB2/SERM ligand has formula II:

• wherein
• X is a bond, CH2, or CH2CH2;
• R and R1, independently, are hydrogen, hydroxyl, C1-C6 alkoxy, C1-C6-acyloxy, C1-C6-alkoxy-C2-C6-acyloxy, R3-substituted aryloxy, R3-substituted aroyloxy, R4-substituted carbonyloxy, chloro, or bromo;
• R2 is a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, or hexamethyleneimino;
• R3 is C1-C3-alkyl, C1-C3-alkoxy, hydrogen, or halo;
• and
• R4 is C1-C6-alkoxy or aryloxy;
• or a pharmaceutically acceptable salt thereof.

A method of treatment of a disorder, wherein the disorder is selected from the group consisting of ADHD (Attention-deficit hyperactivity disorder), Tourette syndrome (TS), tic disorder, vocal disorder, developmental coordination disorder, stereotypic movement disorder, autism spectrum disorders, obsessive-compulsive disorder (OCD), bacterial-induced repetitive behavior, NMDA antibody-related encephalitis, autoimmune antibody-mediated mental disorder, autoimmune antibody-mediated psychosis, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), chorea (Sydenham's chorea (SC), chorea minor, chorea gravidarum, drug-induced chorea), drug-induced repetitive behaviors, akathisia, dyskinesias, dystonias, cramps and spasms, tremors, restless leg syndrome, moving toes/fingers syndrome, involuntary movement, stereotypic movement disorder, extrapyramidal movement disorders, Wernicke-Korsakoff syndrome and combinations thereof, wherein acute, transient or chronic, comprising administering to a subject in need thereof a pharmaceutical fixed drug combination composition, comprising therapeutically effective amounts of at least two therapeutic agents selected from the group consisting of an agent according to formula I, an agent according to formula II, phytocannabinoids, cannabidiol (CBD) and its analogues cannabidivarin (CBDV), cannabiodiolic acid (CBDA), cannabigerol (CBG) and its analogues CBGA and CBGV, Δ9-tetrahydrocannabinol (Δ9-THC) and its analogue THCV, cannabinol (CBN), N-acylethanolamines, palmitoylethanolamide (PEA), omega-3 fatty acids, phosphatidylserine, rosmarinic acid, guanfacine, a noradrenaline agonist, clonidine, antipsychotic drugs, HU-308, BCP, pimozide, haloperidol, aripiprazole, a dopamine-depleting agent tetrabenazine, an acetylcholine release blocker, botulinum toxin, a benzodiazepine, a stimulant and a dopamine/norepinephrine reuptake inhibitor, methylphenidate, amphetamine and its analogues, lisdexamfetamine, atomoxetine, an SSRI, wherein the SSRI is selected from the group consisting of fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine and paroxetine and combinations thereof.

A method of screening for a candidate active agent for the treatment of a mental disease selected from any of the above claims, comprising

• operatively linking a reporter gene which expresses a detectable protein to a regulatory sequence for a gene selected from the group consisting of genes encoding CB1 receptor, CB2 receptor, GPR55, GPR18, GPR119, GABAA receptors, GABAB receptors, COX-1, COX-2, COX-3 enzymes and combinations thereof, to produce a reporter construct;
• transfecting a cell with the reporter construct;
• exposing the transfected cell to a candidate active agent;
• and
• comparing the level of expression or function of the receptor before vs. after exposure to the candidate active agent, wherein an alteration in the level of expression after exposure is indicative of the candidate active agent being useful for the treatment of a mental disease.