GUNA aplicado en procesos inflamatorios

PHYSIOLOGICAL REGULATING MEDIC INE 1/2007

INFLAMMATION ANDPHYSIOLOGICAL REGULATINGMEDICINE– NEW IDEAS AND INNOVATIVE MEDICALPRODUCTS

Cytokines (CKs) are proteins secreted by cellsof both the innate Immune System (true mobi-le Nervous System) and the acquired ImmuneSystem in response to antigens that induce va-rious responses according to the cell types in-volved in the mechanisms of stress-immunity-inflammation.

Due to their peculiarities as biological motors-messengers-modifiers-modulators - orientedtoward coherent (homeostatic-homeodynamic)equilibrium - and consequently to preservationof the individual - CKs appear in the early sta-ges of the history of life: the Epstein-Barr vi-rus contains a homologous gene to IL-10; thetransduction mechanism of IL-1 is Toll type,from the name of the same transduction me-chanism discovered in Drosophila. The evolu-tion of the species is nothing more than theevolution of the Immune System. CKs have adirect general mechanism of action on activa-tion (differentiation + lymphocyte growth) andimplementation (elimination of the stressor).CKs secretion is: 1) a brief and self-limitingevent; 2) pleiotropic, redundant, synergic, an-tagonist. CKs influence the synthesis and ac-tion of other CKs (immune cascade confirmedby natural selection as the hormonal, coagu-lation, and nervous cascade) requiring specifictarget receptors boosted by external signalsto the target cells, which react by modifying ge-ne expression (start-up of silent genes).

- A complete and effective targeted biologicalresponse is achieved with the occupation of aminimal quantity of receptors (e.g. no morethan 1% - 2% for IL-1) and with characteristi-cally low-dose and low titred physiological di-lutions all below Avogadro's Number. Molecu-lar intelligence, coherence domains and elec-tromagnetic superdomains are topics verifiedand accepted by the international scientificcommunity. Together with the physiological di-lutions (the same that operate in living orga-nisms) they are administered with dedicatedand innovative medical products characteristicof Physiological Regulating Medicine. They re-present a major advance in homeopathy andhomotoxicology, by endorsing them as an ad-vanced objective in progress workshops for fu-ture developments of low-dose sciences.- Immune Physiological Regulating Medicine -resetting, promotion and coordination of the al-tered immune language - includes the use ofPRM complex remedies. In particular, the characteristics of Guna®-Arth-ro drops, Guna®-Flam drops and Guna injecta-ble ampoules for pain therapy are highlighted.

INFLAMMATION,CYTOKINES, HOMEOPATHISED CYTOKINES,PHYSIOLOGICAL REGULATING MEDICINE

SUMMARY

L. Milani

CLI

NIC

AL

19

KEY WORDS

INTRODUCTION

Inflammation is useful to the body as itis aimed at the limitation, destructionand elimination of etiologic agents orcellular detritus produced following tis-sue damage. The final effect is the re-storation of the pre-existing state priorto the stressor with repair of the dama-ge. Peripheral memory traces of theevent remain at the dendritic level, atthe central level and in the macropha-ges in the form of an electromagnetictemplate.- Inflammation is an essential defensi-ve phenomenon whose developmentand conditions are articulated by mo-lecular events programmed accordingto an encoded procedure through me-chanisms of convergent evolution: 1)the Epstein-Barr virus contains a homo-logous gene to that of human IL-10 thatencodes a product with similar activityto that of the natural cytokine. This ma-kes it possible to see that the acquisitionby the virus of the IL-10 gene duringevolution has conferred on the virus thecapacity to inhibit the immune respon-se of the host and, consequently, a se-lective benefit for its own survival; 2) theIL-1 transduction mechanism is Tolltype, named after the one found in Dro-sophila melanogaster, the fruit fly;

3) IL-1 α and IL-1 ß share the same rib-bon-like structure folded at 12 points li-ke the growth bonds of heparin and theKunitz-type inhibitors of trypsin; 4) re-ceptor similarity of a number of che-mokines with the Duffy AG that media-tes the penetration of Plasmodium vivaxinto erythrocytes. These examples of"molecular archaeology" demonstratehow the phylogenetic continuum is ac-complished through progressive, im-perceptible transformations of the ar-chaic genomes, but only for the essen-tial functions - among them moleculardefense and protection - the base-mo-del (pattern) has remained essentiallyunchanged in comparison to the onethat was active millions of years ago.This type of “immune reductionism” ne-vertheless had to be put to the test, notonly by external transformations, but al-so in man by transformations inducedby his “reading” of the world, by the in-terpretation of phenomena, logical andanalogical abilities, the awareness of in-tellectual superiority in comparison toother animal creatures, the sensation ofbeing different and conscious, the un-conscious feeling of carrying an effi-cient and effective frontal neocortex.- Tissue stress (infection, nonself, exo-/endogenous toxicosis) of the inferiorPhyla turns into somatic stress involvingcomplex apparatuses and systems in

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fish, reptiles and birds leaving the fieldopen to the emotional stress specific tomammals that turns into a typicalpsychic and spiritual stress - real be-cause it is at the highest point of theevolutionary pyramid - in man.The alerting of the non-specific and spe-cific, local and systemic ImmuneSystem (I.S.) through neuro-endocrinemediation creates the basis for the sur-vival of the individual and the species,the condicio sine qua non for shaping -by adapting it -the appropriate indivi-dual response to internal and external

requirements (TAB. 1). The relationshipsbetween the human Nervous Systemand I.S. are numerous (Milani, 2006):

- Structural polyphormism- Immaturity at birth- Short- and long-term memory- Amplification mechanisms of the

afferent stimuli- Control of the stressors in excess- Auto-inhibition- Local and remote effects- Various stereotyped responses.

The I.S. can be interpreted as a true mo-bile Nervous System.The junction where stress, immunityand pain are sorted is represented by thelimbic brain which influences reactivebehaviour with the memory-affective-emotional dimension (TAB. 2).

ä Thus, the same, with an almost iden-tical genome; but different, therefore,due to the individuality of the culturaland emotional experience.Purposes that are, so to speak, “histori-cal”, “phyletic”, almost mechanically

Synoptic table

illustrating the

different bonds,

correlations and

influences that the

single elements of

the P.N.E.I develop

in response to a

stressor in the

genesis of

inflammation.

Below: role of

Physiological

Regulating

Medicine that

unifies selected

concepts from

Homeopathy,

Homotoxicology and

basic and applied

scientific research,

promoting an

innovative,

preventive and

therapeutic method,

responding to the

needs of modern

biological medicine.

TAB. 1

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predetermined emerge in the N.E.I. re-sponses of every individual into a com-mon file; but it is really the P. theacronym header that informs the subse-quent N.E.I cascade by making eachone - in the biological sense - uniqueand unrepeatable. This difference isgreatly valued by Physiological Regula-ting Medicine: a standardized medicaltherapy must always be integrated fromindividualized therapeutic approaches,which are varying, dynamic and dedi-cated in accordance with the evolutionof the clinical condition. In such a con-text, the concept of homeopathic simil-limum fits perfectly with this statement,demonstrating its puzzling modernity.

CYTOKINES AND INFLAMMATION

Cytokines (CKs) are peptides producedby different lines of cells of both the in-nate and specific I.S. in response to awide variety of inducing stimuli, mainlygerms and antigens that produce va-

rious responses depending on the celltypes involved in inflammation and im-munity. In some ways, they are similarto the peptide hormones though theseare secreted by specific endocrinestructures: they partially share the cha-racteristic of highly informative mole-cules on target cells and tissues due totheir telecrine function, acting on tar-gets at a site different to the one inwhich they were produced (the CKs au-tocrine action on the cell that has se-creted it and paracrine action on va-rious neighbouring cells are specific tothe CKs). This is a para-endocrine func-tion as it is transported by the blood inorder to interact with the cells that ha-ve the receptors they can bind with.

The functional characteristics of theCKs are illustrated schematically, but inessence, in TAB. 3. The second functioncombines 4 effects: pleiotropism, thecapacity to affect more target cells, asin the case of IL-4 (the response to thestimulation varies according to thecytotype with which they have reacted

through specific high-affinity receptorsexpressed on the surface of the targetcells); antagonism as with IFN g acti-vating and IL-4 inhibiting macrophagefunction; redundancy as with IL-2, IL-4, IL-5 which induce the proliferationof B lymphocytes; synergy as with IFNg and TNF a by activating the major hi-stocompatibility complex (MHC) onmany cell types. An effect not suffi-ciently exploited is the synergy of ac-tion of the CKs (explosion of effects) insequence (cascade of CKs). One hourafter the inoculation of LPS (endotoxinfrom Gram- bacteria) a peak TNF a

concentration is obtained experimen-tally. While the TNF a activity is beco-ming exhausted, the activity of IL-1 isboosted; as this declines, the activity ofIL-12 increases. The three CKs are se-creted only by macrophages and NKcells. The whole proinflammatory phe-nomenon lasts 6 hours on average, en-suring that a suitable status is maintai-ned. The organic response is therebyoptimized by a steady, secure and ef-fective plateau so that the host can ade-

TAB. 2

A stressor of

similar intensity

and duration

produces different

(sometimes

opposing) effects in

individuals differing

by the peculiarity of

the biological

unicum expressed

by each person.

To this is added a

common basic

stereotyped

response not

depending on

individual need but

on the behaviour of

the species.

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quately neutralize the cytolytic effect ofthe LPS. Individually, none of the threeCKs is able to neutralize the LPS, evenin greater than physiological concen-trations. On the contrary, they triggerreceptor down-regulation with inhibi-tion of the specific goals. Physiologically, CKs are not stored inthe cells; their synthesis requires thetranscription of genes that have been si-lent until now and are activated afterstimulation of the cell. Such transcrip-tion activation is transitory. The RNAmthat encode the CKs are unstable. Con-sequently, the secretion of cytokines isbrief and self-limiting so the interven-tion of more CKs “in relay” is necessaryto support a biologically targeted effect(telenomy of the natural phenomena).

These 4 effects are responsible for theSiedeck ternary rhythm: after a firstphase of activation in which lymphocy-te differentiation and growth occur(Phase A of Hoff's vegetative commu-tation - proinflammation = Selye's

shock phase) follows the implementa-tion phase through the attempt to eli-minate the stressor (anti-inflammatoryPhase B of Hoff's vegetative commuta-tion = Selye's counter-shock phase).Acute inflammation includes three ma-jor phenomena: 1) vascular alterations- neurogenic inflammation (initial va-soconstriction, active hyperemia, pas-sive hyperemia and stasis) which invol-ve the caliber and blood flow in arte-rioles, venules and capillaries; 2) for-mation of exudate; 3) migration of leu-cocytes in the extracellular matrix(ECM). The vasoconstriction induced byadrenaline and the subsequent vasodi-latation in which histamine, serotoninand prostaglandins E2 and G2 are in-volved, are equivalent to Selye's fightphase. The allopathic use of antihista-mines and COX-2 inhibitors (cyclooxy-genase - lipoxygenase) inhibits the va-sodilatation by stopping passive hype-remia, diapedesis, formation of exuda-te and phagocytosis, with a resultingstand-by state and toxicosis of the ECM

due to the accumulation of antigen de-tritus. The prolonged use of these drugsmay result in chronic and autoimmu-ne pathologies. The angioinflammationturns into histoinflammation. - The Biological Division in the Recke-weg Six Phases Table is nothing morethan the watershed between angio- andhistoinflammation. The sudden inter-ruption of the phenomena following onPhase A can indicate temporary aboli-tion of the symptoms, resetting thephysiological course that is articulatedby a strict and predetermined timeta-ble: a tissue that is not completely hea-led (end of Phase B) represents - evenafter years - a tissue of less resistance,serious irritation for the CNS, a prodro-me for various diseases, even involvingorgans derived from different embryo-nic germ layers from those from whichthe organ originates that is the site ofthe earlier pathology. In actual fact, therecovery process is achieved when abalance is established between Th1and Th2 immunity regulated by Th3 im-munity, immune tolerance - memorythat fights the plus-inflammation andthat becomes established as a result ofa functional deficit of the Th3 system. - Terms such as “relapse”, “slow anddifficult recovery”, “chronification”,“progressive vicariation” are differentexpressions highlighting a single con-cept: non-physiological recovery. No therapy is really effective if it doesnot respect the clock that million ofyears have standardized.

KEY-LOCK - STEREOSCOPIC COMPLEMENTARITY

CKs receptors are transmembrane pro-tein structures with an external part andan internal part that triggers the casca-de of signals (transduction).Two molecules are attracted only if theyresonate at the same frequency of oscil-lation. CKs receptors are divisible into 5families in accordance with their three-dimensional morphology; each of theminduces a different mode of transduc-

TAB. 3

The “motors”

of the CKs.

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tion (TAB. 4). Several receptors are co-upled to others control the amount ofinformation: an interesting analogy iswith the inhibitory corticospinal ner-vous tract blocking an excess of peri-pheral information, a type of protectiverelay that interrupts the circuit so as notto damage the apparatus.A paradigmatic example is provided byIL-1 R2 (IL-1 Ra, IL-1 ra), present onlyon the B lymphocytes, which does nottranslate any activation signal; it is a realmolecular trap, a decoy or false recep-tor that blocks the excess IL-1 in orderto limit and circumscribe the inflam-mation and prevent the B lymphocytefrom immediately producing IgGs, thusallowing the inflammation to becomeactivated. This inhibitory receptor,which is competitive-antagonist of thereal IL-1 receptor (IL-1R1) seems to ha-ve evolved before the division of IL-1 in-to the two subclasses IL-1 a and IL-1 b.- Anakinra, a recombinant IL-R2, eta-nercept and infliximab which block theTNF a receptors have recently been in-troduced in the conventional therapy ofrheumatoid arthritis.These drugs have opened up interestingtherapeutic perspectives although thenegative side effects are particularly im-pressive. For anakinra: pain, bruises,bleeding at the injection site, which fre-quently force the patients to discontinuetreatment (Cohen, 2002). Other adverse reactions are headacheand abdominal pain (Cohen, 2002). Foretanercept and infliximab: neutropenia,increased incidence of serious infec-tions.The receptors bind the CKs with high affinity and a constant dissociation of10-10-10-12 M. Consequently, to make a receptor per-form its function, very low cytokineconcentrations are sufficient becausethe number of receptors per cell is re-latively low (≈ from 100 to 1000). Besi-des the intrinsic characteristics, the con-centrations of CKs are very important fortherapeutic purposes as different con-centrations induce different effects. For example, low plasma concentra-tions of TNF and IL-1 (10-9 M) induce:

1) leucocyte activation, 2) secretion ofIL-1, chemokines and adhesion mole-cules [local proinflammatory effects]; inmoderate concentration: 1) fever (hypo-thalamic centre for temperature regula-tion); 2) acute-phase proteins (liver); 3)production of leucocytes (bone mar-row); at plasma concentrations (≥ 10-7

M): septic shock with hypoglycaemia,low endothelial resistance and forma-tion of thrombosis, low cardiac output.The similarities between the actions ofTNF and IL-1 depend on the commontransduction of the signal using similarproteins, though they are structurallydifferent. The effect of the different con-centrations of a biological active prin-ciple had already been experimentally

highlighted (Pennec and Aubin, 1984): 10-5 M aconitine causes heart fibrilla-tion; 10-7 M bradycardia; 10-18 M has noeffect on a healthy heart and there is anormalization of the rhythm in thepreintoxicated, isolated and infused eelheart (Anguilla anguilla Linn.). In a re-cent micro-auto radiographic receptorstudy (Stumpf, 2005) it was shown thatlow-dose and low-titred substances in-teract with the cell nucleus, while hi-gher concentrations trigger a cellular re-sponse at cytoplasmic level.

Chronologically, the effects of low-doseimmuno-modulants have been reportedby Poitevin et al. (1983), Wagner et al.(1986), Poitevin et al. (1986), Wagner et

TAB. 4

The five family

types of CKs

receptors.

Some salient

characteristics

of the receptor of

the CKs are shown.

24


al. (1988), Davenas et al. (1988), Poite-vin et al. (1988), Daurat (1988), Enbergsand Arndt (1993), Enbergs (1998), Belonet al. (2004), Jäggi et al. (2005), Amadoriet al. (2007).- There is no receptor turnover since thereceptor synthesis is regulated by ap-propriate external signals to the cell: the ligand CK and the specific receptorare neosynthesised only if required andsimply do not exist when they are notneeded, complying closely with the na-tural principle of parsimony.

CONTROL OF INFLAMMATION -FROM PHYSIOLOGY TO THERAPY-HOMEOPATHISED CYTOKINES

The control and the specific sequenceof the activator or suppressor stages ofthe immune response are mediated bycells through the release of proinflam-matory and anti-inflammatory CKs:- Th1 or proinflammatory: TNF a, IL-1

a, IL-1 b, IL-2, IL-6, etc. (accepted to-day: 13),

- Th2 or anti-inflammatory: IL-4, IL-10,etc. (accepted today: 4).

The classic proinflammatory CK and thefirst to be discovered is IL-1 (a and b va-riants). Once bound to the membranereceptor - the a barrel (12-stranded be-ta-sheet structure) so-called from thedistinctive form of overlapped circlesspaced out by linear structures, a re-ceptor shared with the M-CSF-Mono-nuclear phagocyte colony stimulatingfactor, of the cells of the endothelium,epithelial keratinocytes, platelets, neu-trophils and microglia, it enters the cyto-plasm and binds to the NF-kb transcrip-tion factor: this complex stimulates se-veral signal molecules which can relea-se several silent genes at nuclear levelallowing them to encode proinflamma-tory proteins operating at the level of thesurrounding tissues. The message also reaches the CNS byinducing fever (endogenous pyrogen)and alerting of the system (TAB. 5).All the main functions of IL-1 a and bare illustrated synoptically in TAB. 6.- On the whole, IL-1 (a; b) activates type2 cyclooxygenase (COX2) (effect 1),prostaglandin E2 (effect 2), nitric oxide(effect 3), activating and acceleratingthe inflammatory process.ä Consequently, the Anti IL-1 (Anti IL-1 a, Anti IL-1 b) inhibits effect 1 (like theNSAIDs), effect 2 (like the corticoste-roids) and effect 3 (like the salicylates),without the negative side effects indu-ced by these synthetic drugs. The homeopathised Anti IL-1 a and bare therefore used successfully in thetherapy of the osteo-arthro-myofascialpain (inflammation of joints and myofa-scial structures) as according to the con-cepts specific to Physiological Regula-ting Medicine (PRM).

PRM IN INFLAMMATION ANDPAIN CONTROL

Patients suffering from painful and in-flammatory diseases of orthopaedic,rheumatologic and traumatologic natu-re account for 25-35% of all patientsconsulting a general practitioner. A great resource for a general practitioneris to be able to use effective medical pro-ducts acting rapidly and with no negative

TAB. 5

Synoptic table

illustrating how

IL-1a and b bind

to the IL-1 R1

receptor.

-This is the prime

mover of the

coding of proteins

and inflammatory

peptides.

25


nor recurrent side effects. PRM is basedon a wide range of medical products ha-ving all the above characteristics besidesbeing innovative in some respects.

E GUNA®-ARTHRO dropsGUNA®-ARTHRO is a PRM productcomposed of 5 therapeutical cores: Anti-inflammatory, Antidegenerative,

TAB. 6 Activity, phenomena, epiphenomena and proinflammatory effects of IL-1αα and ββ.

Metabolic, Trophic and PNEI core.- Uses: Osteoarticular degenerative pro-cess of small joints (e.g.: in combinationwith Guna®-Polyarthritis + Guna®-HandFoot) and large joints (e.g.: in co-xarthrosis or gonarthrosis in combina-tion with Guna®-Hip + Guna®-Muscle),inflammatory disease of the joints (in as-sociation with Guna®-Flam), osteoporo-

sis (in association with Osteobios®).

E GUNA®-FLAM dropsGUNA®-FLAM is a PRM product com-posed of 4 therapeutic cores: Antiseptic,Antalgic, Neuro-endocrine and Anti-in-flammatory core. The Anti-inflammatory core includes 1 nosode (Pyrogenium), 4 single reme-

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dies of plant origin (Aconitum, Bella-donna, Bryonia, Phytolacca), 3 single re-medies of mineral origin (Ferrumphosph., Hepar sulph. calc., Coppergluconate), 2 metabolites of Krebs cycle(Natrium pyr., Citricum ac.), 1 single re-medy of animal origin (Apis) and 4 spe-cific PRM remedies (Anti IL-1α 4C, TGF1β 4C, IL-10 4C, Melatonin 4C).- Uses: acute and chronic inflamma-tions, pain of inflammatory origin.

E GUNA INJECTABLE AMPOULESFOR PAIN THERAPYThe 10 Guna injectable ampoules forPain Management are specific and se-lective for osteo-arthro-myofascial painand pathologies of every single soma-tic anatomic part: Guna®-Neck, Guna®-Thoracic, Guna®-Lumbar, Guna®-Shoul-der (shoulder and elbow), Guna®-Hip(hip and knee), Guna®-HandFoot, Gu-na®-Ischial, Guna®-Polyarthritis, Guna®-Muscle and Guna®-Neural. Nine out of 10 contain Beta Endorphin4C; 8 out of 10 contain Anti IL-1α 4Cand Anti IL-1β 4C, having a great pain-killing and anti-inflammatory effect.The homeopathic physiological micro-doses involve no negative side-effects,and help avoid any trouble concerningtolerance as well as pharmacologicalcatabolite overload in ECM and organs.

E Guna®-Arthro, Guna®-Flam and the10 Guna injectable ampoules for PainManagement may be used in combi-nation in an outpatient or home treat-ment according to the needs of everysingle clinical case.

CONCLUSIONS

For more than 150 years, due to the in-trinsic characteristic of symptomaticmedicine, even with the integration ofnew pathogenesis, classic Homeopathyhas remained closely and structurallyanchored to its historical roots (Milani,2007). Medicine of symptoms, if not adequa-tely integrated with the new advance-ment of the low dose - low titred ho-meopathic immunobiotherapy, is desti-

ned to disappear: it does not have achance of progressing.

By means of an ambitious project,Physiological Regulating Medicine (PRM)has fully achieved the theoretical propo-sals of Prof. H. Wagner.

In the 3rd Italian National Congress of Ho-meopathy: “Physics, biology, medicine. Aunifying approach” organized by A.I.O.T(Italian Medical Association of Homoto-xicology) in 1988, he pointed out (I quo-te) the “characteristics of the immuno-therapies to achieve the strengthening ofthe non-specific defenses” which musthave:1) Normative or modulating property2) Similarity with the "biological

response modifiers"3) Results achieved through

microdoses4) Therapeutic results depending on:

a) dosageb) administration typec) administration timed) immune status.

E Moreover, PRM does not use units thathave “similarity with the modifiers of thebiological response” [point 2)]. It uses the real modifiers of the biologi-cal response - those that work physiolo-gically at those concentrations!- The rational inclusion in therapeuticpractice of homeopathised CKs, hor-mones, neurotransmitters and homeo-pathised peptides at the same dilutionin which they are physiologically pre-sent and active in the human body andthe formulation of innovative medicalproducts containing unitaries of whichwe know the active principles and theiraction in the healthy and sick person,define and are inherent to PRM, whichdoes not deny the past but faces the fu-ture strong in the consciousness that itcan always be updated and adapt to thenew ideas and new solutions that scien-ce will provide. n

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ä Tables 1, 2, 5, 6 are original by the Author;Tables 3, 4, are adapted explanations by the Author in relation to the updated bibliography.

Author's address

Prof. Leonello Milani, MD, PhD- Vice President of A.I.O.T.- Scientific director of

“La Medicina Biologica” and “Physiological RegulatingMedicine”

- Professor h.c. of the HigherInstitute of Health Studies,Rome; a collaborative Centre for the WHO

- Lecturer and tutor in the Schoolof Homeopathy, Homotoxicologyand Integrated Disciplines -Academy of BiologicalMedicine.

Via Vanvitelli 6I - 20129 Milano

GUNA aplicado en procesos inflamatorios

Health & Medicine