T r a n s E u r o p e a n S t e m C e l l T h e r a p y S o c i e t y

Dr. Marco Traub, Director TESCT-Society, Bern Switzerland,London,UK.

Our commitment(s) recently submitted within the call for commitments launched by the EIP on AHA has/have been accepted as part of the Action Group (AG) A1 on “Prescription and Adherence to Medical Plans”.

"Patient and citizen Empowerment across the EIP Action”

Do illegal pharmaceutically active compounds pave the way for advanced therapies?

Many thanks to Marco Cappato, Marco Perduca, Filiomena Gallo and the team of the 5th Meeting of the World Congress forFreedom of Scientific Research in the European Parliament-Brusselsforthehonortoattendthattoplevelmeeting.

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11-12-13April2018EuropeanParliament,Brussels

I am greatful to my family and the friends and colleagues from the TransEuropeanStemCell-Society. Dr. M. Baker, MBE Management Board of the European Medicines Agency (EMEA) Chair of the Working Group on Parkinson’s Disease Marco Cappato Segretariodell“AssociazioneLucaCoscioni“perlalibertadiricercascientifica,Italia,MemberoftheCityCouncilMilan,Italy. Prof. T.J. Ekström Dept. of Clinical Neuroscience, Karolinska Institutet, Sweden Prof. Miomir Knezevic National Institute of Biology University of Ljubljana, Slovenia Dr. Stephen Minger Senior Consultant in Cellular Sciences and Regenerative for GE Healthcare Life Sciences, Director of SLM Blue Skies Innovations Ltd, United Kingdom Dr. Colin Natali Consultant Spine Surgeon, Department of Trauma and Orthopaedics, The Royal London Hospital Whitechapel, London Marco Perduca Former Senator in Italy, serving on the Foreign Affairs and Jus9ce commiEees and as secretary of the Special Commission on Human Rights of the Senate and UN Representa9ve. Founder of the“ Associazione Luca Coscioni and board member. Dr. J. Prakash Age Management Consultant, Harley Street, London, United Kingdom Dr Srividya Seshadri Consultant Gynaecologist & Specialist in Reproductive Medicine & Surgery. Head of Clinical Research and Development The Centre for Reproductive & Genetic Health, London UK. Dr. Alagapan Sivaram Consultant Orthopaedic Spinal Surgeon The Princess Grace Hospital, The London Independent Hospital and Spire Hartswood Hospital , London. Prof. Dr. Elke Smits Manager Research & Innovation Policy, Division of Medical Director, Antwerp University Hospital, Belgium.Prof. R. R. Tönjes Paul-Ehrlich-Institut Federal Institute for Vaccines and Biomedicines, Head of Section Xenogeneic Cell Therapeutics“, Goethe University, Frankfurt; Germany.

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T r a n s E u r o p e a n S t e m C e l l T h e r a p y S o c i e t y

Major Goal of the TESCT-Society: To generate an evidence guided scientific base for the society and clinical research and health economy to understand, treat and prevent age related neurological diseases with advanced stem cell technology and gene editing.

Recalling Prof. Dame Julia Pollak TESCT Meeting 2006: “Regenerative medicine is an emerging field that approaches the repair or replacement of tissues and organs by incorporating the use of cells, genes or other biological building blocks along with bioengineered materials and technologies. Advances in stem cell biology, including the isolation and characterization of embryonic and post-natal somatic stem cells, have made the prospect of tissue regeneration a potential clinical reality.”

CH-3066 Berne Switzerland drmarcotraub@transeuropeanstemcelltherapyconsortium.ch Phone: +41 78 834 6262

8th Workmeeting of the TransEuropeanStemCellTherapy Society Venue: Florence 10th-12th of November 2017 Program: “European Innovation Partnership on Active and HealthyAgeing“. EU-Proposals e.g. Premature Ovarian Failure (POF) Stem Cell tracking with nano particles. Stem Cell application in spinal chord injuries and back paine. Crispr, fashion or substantial? “Right of Science Education“ the prerequiste for “Right of Science“

Dr. M. Baker, MBE Management Board of the European Medicines Agency (EMEA) Chair of the Working Group on Parkinson’s Disease M. Perduca Former Senator in Italy, serving on the Foreign Affairs and Justice committees and as secretary of the Special Commission on Human Rights of the Senate and UN Representative. Founder of the“ Associazione Luca Coscioni „and board member. Prof. T.J. Ekström Dept. of Clinical Neuroscience, Karolinska Institutet, Sweden Prof. M. Knezevic National Institute of Biology University of Ljubljana, Slovenia Dr. Marisa Jaconi Faculty of medicine,Department of Pathology and Immunology University of Geneva, CMU,Geneva, Switzerland Dr. S. Minger Senior Consultant in Cellular Sciences and Regenerative for GE Healthcare Life Sciences, Director of SLM Blue Skies Innovations Ltd, United Kingdom Dr. Colin Natali Consultant Spine Surgeon Department of Trauma and Orthopaedics, The Royal London Hospital Whitechapel, London Dr. J. Prakash AgeManagementConsultant, Harley Street, London, United Kingdom Dr. Srividya Seshadri Consultant Gynaecologist & Specialist in Reproductive Medicine & Surgery. Head of Clinical Research and Development The Centre for Reproductive & Genetic Health, London UK. Dr. Alagapan Sivaram Consultant Orthopaedic Spinal Surgeon The Princess Grace Hospital, The London Independent Hospital and Spire Hartswood Hospital , London. Project Coordinator/CEO: Dr. M. Traub TransEropeanStemCellTherapy Society, Bern; London

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TransEuropeanStemCellTherapy Society's public ID number in the EU-Transparency Register: 355746725153-85

Why is a legal drug frequently prescribed for the treatment of children and young adults displaying the evidence for significant side effects such as Ritalin?

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“In the United States, the use of Ritalin and other stimulants to treat ADHD* steadily increased in the 1970s and early 80s, but between 1991 and 1999, Ritalin sales in the United States increased 500 percent.6,7 The United Nations reports that the United States produces and consumes as much as 85 percent of the worlds production of Ritalin.“8

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*Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children).

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UPDATE [10-17-2016 and 11-4-16] FDA proposes to withdraw approval of two generic versions of Concerta (methylphenidate hydrochloride) The FDA is proposing to withdraw approval of two generic versions of Concerta (methylphenidate hydrochloride) extended-release (ER) capsules, used to treat attention-deficit hyperactivity disorder. Mallinckrodt Pharmaceuticals and UCB/Kremers Urban (formerly Kudco) the companies that make the generic products, have failed to demonstrate that their products provide the same therapeutic effect as (are bioequivalent to) the brand-name drug they reference.

U.S.FoodandDrugAdminist2016

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Handbook of Medical Sociology Chloe E. Bird,Peter Conrad,Allen M. Fremont,Stefan Timmermans. 2010, 6th ed. Vanderbilt University Press, Nashville Tenesse, USA.

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Cannabis, LSD, MDMA, Ketamin, Methadon: Do illegal drugs turn out to be better medicines?

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Methadone as a “TumorTheralgesic” against Cancer Marta Michalska, Arndt Katzenwadel, and Philipp Wolf*. Front Pharmacol. 2017; 8: 733.

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“Methadone has beneficial characteristics as an analgesic against cancer pain, including high bioavailability, multiple receptor affinities, and lack of active metabolites that might induce adverse side effects“. “There is evidence from preclinical studies that methadone could also elicit antitumor activity by downregulating the threshold of apoptosis and to enhance the effects of different chemotherapeutic agents“ Marta Michalska, Arndt Katzenwadel, and Philipp Wolf*. Front Pharmacol. 2017; 8: 733.

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It was more than eight years ago, when molecular biologist Dr. Claudia Friesen from the University of Ulm in Germany first found signs that the opioid D,L-methadone could help fight leukemia-cells and certain types of solic cancer cells. The leukemia cells died when methadone was added to an in-vitro cell culture.

Now the researcher spoke to Bavarian public broadcaster Bayerischer Rundfunk (BR) - a member of Germany's national public broadcasting system ARD - about remarkable successes in treating cancer patients. For some years, the doctor had treated 80 patients with potentially fatal, advanced tumors with a combination of the chemotherapeutic drug temozolomide and methadone. All of the patients had previously received a very grim prognosis from their doctors, with a predicted life-expectancy not beyond summer 2015.

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Magic Mushrooms but no magic in science. Knowledge of scientific principles and bas i c pharmaco log ica l methodology are revealing the pharmaceutical properties of chemical compounds.

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Prerequisite for the informed citizien is the start of early science education: Scientific Literacy

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R e c o m m e n d a t i o n t o t h e stakeholders from politics, from patient organisations, from the pharma industry and from medical centers:

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Support the freedom of Scientific Research! The translation into clinics of currently illegal drugs and more support for stem cell research is the essential step forward to informed and healthy citizens.

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Molecu lar mechan i sms and epigenetics with strict correlation of the drug action to patients is the key to the transition to clinics and to a legal level.

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Selective rather than specific?

What is the impact towards drug efficacy?

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!

JohnLangley

•  Langleyconcludedthataprotoplasmic"receptivesubstance"mustexistwhichthetwodrugscompetefordirectly.Hefurtheraddedthattheeffectofcombinationofthereceptivesubstancewithcompetingdrugswasdeterminedbytheircomparativechemicalaffinitiesforthesubstanceandrelativedose.Levy2003

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The Key Lock Mechanism proposed by Emil Fischer in 1889, explains the receptor ligand interaction.

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Short comming of the Key Lock Mechanism Theory: The key can fit many locks but open a few. Formation of supramolecular complexes depends not only, and often not even primarily on an optimal geometric fit between host and guest. Induced fit and allosteric interactions have long been known as important modifications. Different binding mechanisms, the medium used and pH effects can exert a major influence on the affinity. Limitations and Extensions of the Lock-and-Key Principle: Differences between Gas State, Solution and Solid State Structures, Hans-Jörg Schneider Int. J. Mol. Sci. 2015, 16, 6694-6717

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IG-Farben (Bayer, Boehringer...)

Principles of Pharmacodynamics and Pharmokinetics, 1934.

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Receptortheoryandreceptorbinding.

MustobeytheLawofMassActionandfollowbasiclawsofthermodynamics.• Primaryassumption–asingleligandisbindingtoahomogeneouspopulationofreceptors

NH+3

COO-

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Assumptionsofthelawofmassaction.

•  Allreceptorsareequallyaccessibletoligand.•  Nopartialbindingoccurs;receptorsareeitherfreeofligandorboundwithligand.

•  Ligandisnoralteredbybinding•  Bindingisreversible•  Differentaffinitystates?????

Levy2003

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Ligand: Any molecule that binds to another, in normal usage a soluble molecule such as a hormone or neurotransmitter, that binds to a receptor.

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Receptor:

A specialized molecule that receives information from the environment and conveys it to other parts of the cell; the information is transmitted by a specific chemical that must fit the receptor, like a key in a lock.

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Drug receptor interactions may involve many different types of chemical bonds, but usually weak non-comvalent interactions that are reversible. Drug associates and the dissociates.

Drug Receptor interaction:

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•  kon=#ofbindingevents/time(Rateofassociation)=[ligand]•[receptor]kon=M-1min-1

•  koff=#ofdissociationevents/time(Rateofdissociation)=[ligand•receptor]koff=min-1

•  Bindingoccurswhenligandandreceptorcollidewiththeproperorientationandenergy.

•  Interactionisreversible.•  Rateofformation[L]+[R]ordissociation[LR]depends

solelyonthenumberofreceptors,theconcentrationofligand,andtherateconstantskonandkoff.

kon/k1

[ligand] + [receptor] [ligand • receptor]

koff/k2

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• Atequilibrium,therateofformationequalsthatofdissociationsothat: [L]•[R]kon=[LR]koff

KD=k2/k1=[L][R] [LR]

*thisratioistheequilibriumdissociationconstantorKD.KDisexpressedinmolarunits(M/L)andexpressestheaffinityofadrugforaparticularreceptor.• KDisaninversemeasureofreceptoraffinity.• KD=[L]whichproduces50%receptoroccupancy

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Scatchardtransformation

•  Y-axisisBound/Free(totalradioligand-bound)•  X-axisBound(fmol/mgprotein)•  Straightlinesareeasiertointerpret.

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Partialagonistscanactasfunctionalantagonistswhenincompetitionwithhigherefficacyagonists.

•  Methadoneforheroinabusetreatment.–  Usedto“weanoff”abuseddrugs.

•  Basicallycompetitionbetweenthefullandpartialagonist.

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Predictingwhetheradrugwillcausearesponseinaparticulartissue

Factorsinvolvingtheequilibriumofadrugatareceptor.• Limiteddiffusion• Metabolism• Entrapmentinproteins,fat,orblood.Responsedependsofwhatthereceptorisconnectedto.• Effectortype• Needforanyallostericco-factors–THBontyrosinehydroxylase.• Directreceptormodification–phosphorylation

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•  Affinity:Thetenacitybywhichadrugbindstoitsreceptor.–  Discussion:averylipidsolubledrugmayhaveirreversibleeffects;

isthishigh-affinityormerelyanon-specificeffect?

•  Intrinsicactivity:Relativemaximaleffectofadruginaparticulartissuepreparationwhencomparedtothenatural,endogenousligand.–  Fullagonist–IA=1(*equaltotheendogenousligand)–  Antagonist–IA=0–  Partialagonist–IA=0~1(*produceslessthanthemaximal

response,butwithmaximalbindingtoreceptors.)

•  Intrinsicefficacy:adrugsabilitytobindareceptorandelicitafunctionalresponse–  Ameasureoftheformationofadrug-receptorcomplex.

•  Potency:abilityofadrugtocauseameasuredfunctionalchange.

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Receptorshavetwomajorproperties:RecognitionandTransductionRecognition:Thereceptorproteinmustexistinaconformationalstatethatallowsforrecognitionandbindingofacompoundandmustsatisfythefollowingcriteria:• Saturability–receptorsexistsinfinitenumbers.• Reversibility–bindingmustoccurnon-covalentlyduetoweakintermolecularforces(H-bonding,vanderWaalforces).• Stereoselectivity–receptorsshouldrecognizeonlyoneofthenaturallyoccurringopticalisomers(+or-,dorl,orSorR).• Agonistspecificity–structurallyrelateddrugsshouldbindwell,whilephysicallydissimilarcompoundsshouldbindpoorly.• Tissuespecificity–bindingshouldoccurintissuesknowntobesensitivetotheendogenousligand.Bindingshouldoccuratphysiologicallyrelevantconcentrations.

Levy2003

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Receptor/Subtype Function and Correlation with Physiological Phenotypes

Opiate specific Receptors/Suptypes

Analgesia

Respiratory Depression

Addiction

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Bayer Company started the production of heroin in 1898 on a commercial scale.

ActaPharmHung.2001Aug;71(2):233-42.

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The first clinical results were so p r om i s i n g t h a t h e r o i n wa s considered a wonder drug.

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It has turned out, however, that repeated administration of heroin results in the development of tolerance and the patients become heroin-addicts soon.

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In the early 1910s morphine addicts "discovered" the euphorising properties of heroin and this effect was enhanced by intravenous administration.

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Restrictions on its production, use and d i s t r i bu t i o n were regu la t ed by international treties. The total ban on heroin production was also proposed. As a result of the strict regulations the production and cosumption of heroin showed a significant decrease after 1931.

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The actions of endogenous opioid peptides are mediated by 3 main classes of opioid receptors; mu (MOR), kappa (KOR), and delta (DOR).

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Opioidreceptorsubtypes

Receptortype

µ-Receptorµ1,µ2,µ3??

δ-Receptorδ1,δ2??

κ-Receptorκ1,κ2??

Selectiveagonists

endomorphin-1endomorphin-2DAMGO

[D-Ala2]-deltorphinI[D-Ala2]-deltorphinIIDPDPESNC80DSLET

enadolineU-50488U-69593

Selectiveantagonists

CTAP

naltrindoleTIPP-ψICI174864

nor-binaltorphimine

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Fig.X.RadiolabelledcompoundsestablishedforclinicalPET-investigationsoftheopioidreceptors.

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Fig.3Hypotheticalsequenceofeventsleadingtochangesinthereceptorstatusandthuschangestothebaseline(A)receptorbindingofatracerduetoincreasedoccupancy(B)ofendogenousorexogenousopioidligandsleadingpotentiallyalsototheinductionofloweraffinitystatesofthereceptor(C)(decoupling/inactivation)anddownregulationandreducedreceptorexpression(D).

Imaging of opioid receptors in the central nervous system, Brain 2008 131(5):1171-1196.

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The failure of a drug to satisfy any of these conditions indicates non-specific binding to proteins or phospholipids in places like blood or plasma membrane components.

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•  Oncebound,ligandandreceptorremainboundforarandomtimeinterval.

•  Theprobabilityofdissociationisthesameatanypointafterassociation.

•  Oncedissociated,ligandandreceptorshouldbeunchanged.

•  Ifeitherisphysicallymodified,thelawofmassactiondoesnotapply(receptorphosphorylation)

•  Ligandsshouldberecyclable.

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Receptoroccupancy,activationoftargetcellresponses,kineticsofbinding

• Activationofmembranereceptorsandtargetcellresponsesisproportionaltothedegreeofreceptoroccupancy.

• However,theligandconcentrationatwhichhalfofthereceptorsisoccupiedbyaligand(Kd)isoftenlowerthantheconcentrationrequiredtoelicitahalf-maximalbiologicalresponse(ED50)

Levy2003

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Technical conclusion: Combination of receptor binding assays e.g. with SAR (Structure Ac t i v i t y Re l a t i o n sh i p ) w i th compound l ibrar i e s , pept ide libraries and chip technology (DNA/Protein) are not solving the major problem of drug side effects.

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Selected References: El Khamlichi A ( 2001): African neurosurgery: Current situation, priorities and needs. Neurosurgery 48:1344–1347. Freye,E.,M.SchnitzlerandM.Traub(1989):Opioidinducedrespiratorydepressionandantinociceptionaremediatedbydifferentsubreceptors,Adv.Biosciences75,463-466.Pasi, A., P. Mehraein, A. Jehle, M. Traub, G. Morniroli, W. Bär and N. Kopp. (1992): b-Endorphin: Regional levels profile in the brain of the human infant, Neurochem. Int. 20, 93-95. Traub,M.,K.-D.SpindlerandA.Pasi(1989):Bindingstudieswith[3H]sufentanilandantagonistsindifferentbrainareas.In:Newleadsinopioidresearch,VanRee,J.M.,Mulder,A.H.,Wiegant,V.M.,WimersmaGreidanus,T.B.,eds.,Amsterdam-NewYork-Oxford,ExcerptaMedica,347-349.

Traub,M.,K.-D.Spindler,H.P.Schmitt,F.S.Messiah,W.BärandA.Pasi.(1991):Opioidreceptorsinhumanbrain.Detectionwithmonoclonalanti-idiotypicantibodies,J.Medicine22,311-326. Traub, M. (2009): Impact of Extending Knowledge in Stem Cell Biology on Vintage Concepts in Molecular Pharmacology. Symposion sur la Biotechnologie et la regeneration cellulaire. XVII Journees Medicale, Pharmaceutique, Odontologique et Veterinaires. University of Dakar, Senegal. Traub, M. (2009): Potential impact of advances in stem cell based therapies for Africa in the course of knowledge transfer and affordable medicine. Proceedings of the Second Meeting of the WORLD CONGRESS FOR FREEDOM OF SCIENTIFIC RESEARCH (European Parliament – Brussels, March 5-7, 2009) Associazione Luca Coscioni, European Parliament, Brussels, pp 246-249.

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Traub M. (2017), : “European Innovation Partnership on Active and HealthyAgeing“. Gene Editing in Parkinson and Heart Disease. European Health Care Systems and Co-Morbidity Paradigm change: Shifting from Patient centricity to Society and Pharma Industry as a holistic view. 7th work meeting, Champéry, Switzerland: TransEuropeanStemCellTherapy-Society. Traub M. (2017), : CRISPR, fashion or substantial? Stem Cell application: Premature Ovarian Failure (POF), Stem Cell tracking with nano particles, spinal chord injuries and back paine. 8th workmeeting, Florence, Italy: TransEuropeanStemCellTherapy-Society. Traub, M. (2017): Right to participate scientific progress and science education. Patient and citizen empowerment across Europe. Side Event on the Right to Science at UNOG, Geneva, Switzerland. R. G. M. Morris, W. Oertel, W. Gaebel, G. M. Goodwin, A. Little, P. Montellano, M. Westphal, D. J. Nutt and M. Di Luca (2016): Consensus Statement on European Brain Research: the need to expand brain researc in Europe 2015, European Journal of Neuroscience, Vol. 44, pp. 1919–1926.

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