Scientific Research

Basic and clinical research has underpinned the thesis of Physiological Regulating Medicine: in November 2009, in fact, the journal Pulmonary Pharmacology & Therapeutics published the first paper on the effects of low dose SKA cytokines in an animal model of allergic asthma (Gariboldi et al. Low dose oral administration of cytokines for treatment of allergic asthma. Pulmonary Pharmacology & Therapeutics 22 (2009) 497-510).

Since 2009, new publications have followed the paper published by Pulmonary Pharmacology & Therapeutics.

Low Dose Pharmacology

Year

Authors

Journal

Research type

Title

Molecules or compounds

2007Müller-Krampe B. et alPediatrics InternationalClinical researchEffects of Spascupreel versus hyoscine butylbromide for gastrointestinal cramps in childrenSpascupreel
2007Claussen CFInternational Tinnitus JournalClinical researchThe Slow-Brainstem Syndrome: Tinnitus and Dyssynchrony in the Central Nervous SystemVertigoheel®

2009

Gariboldi S. et al.

Pulmonary Pharmacology & Therapeutics

In vivo basic research

Low Dose oral administration of cytokines for treatment of allergic asthma.

IL-12

IFN-γ

2009

Gebhardt R.Environmental Toxicology and PharmacologyIn vitro basic researchPrevention of cadmium-induced toxicity in liver-derived cells by the combination preparation Hepeel®

Heepel®

2009van den Meerschaut L. and Sunder A.eCAMClinical researchThe Homeopathic Preparation Nervoheel N can Offer an Alternative to Lorazepam Therapy for Mild Nervous DisordersNervoheel N
2010Roeska K and Seilheimer B.Journal of Immune Based Therapies and VaccinesIn vitro basic researchAntiviral activity of Engystol® and Gripp-Heel®: an in-vitro assessment

Engystol®

Gripp-Heel®

2010Heinle H. et al.Clinical Hemorheology and MicrocirculationEx vivo basic researchThe low-dose combination preparation Vertigoheel activates cyclic nucleotide pathways and stimulates vasorelaxation

Vertigoheel

2011Schneider C.International Journal of General MedicineClinical researchTraumeel – an emerging option to nonsteroidal anti-inflammatory drugs in the management of acute musculoskeletal injuriesTraumeel

2012

D’amico L. et al.

Journal of Cancer Therapy

Ex vivo basic research

Low Dose of IL-12 stimulates T Cell response in cultures of PBMCs derived from Non Small Cell Lung Cancer Patients.

IL-12

2013

Cardani D. et al.

Gastroenterology Research

In vivo basic research

Oral administration of Interleukin-10 and Anti-IL-1 Antibody ameliorates experimental intestinal inflammation.

IL-10

ANTI IL-1

2013Keim AP. et alLymphatic Research and BiologyIn vivo basic researchThe Multicomponent Medication Lymphomyosot Improves the Outcome of Experimental Lymphedema.

Lymphomyosot

2013Gonzalez de Vega C. et al.International Journal of Clinical PracticeClinical researchTraumeel vs. diclofenac for reducing pain and improving ankle mobility after acute ankle sprain: A multicentre,
randomised, blinded, controlled and non-inferiority trial
Traumeel

2014

Roberti M. L. et al.

Journal of Biological Regulatory & Homeostatic Agents

Clinial Trial

Immunomodulating treatment with Low Dose interleukin-4, interleukin-10 and interleukin-11 in psoriasis vulgaris

IL-4

IL-10

IL-11

2014

Radice E. et al.

International Immunopharmacology

Ex vivo basic research

Low Doses of sequential-kinetic-activated interferon-gamma enhance the ex vivo cytotoxicity of peripheral blood natural killer cells from patients with early-stage colorectal cancer. A preliminary study.

IFN-γ

2015

Luchetti P.

Minerva Medica Oftalmologica

Observational retrospective study

Increasing of visual function in patients with retinal atrophy treated with drugs of Low Dose Medicine.

NT3

NT4

NGF

2015

Barygina V. et al

Journal of Dermatological Science

In vitro basic research

Treatment with cytokines reduces oxidative-mediated injury in perilesional keratinocytes from vitiligo skin.

IL-4

IL-10

FGF-b

β-endorphin

2015

Lotti T. et al

Journal of Biological Regulatory & Homeostatic Agents

Clinical Trial

Vitiligo: successful combination treatment based on oral Low Dose cytokines and di­fferent topical treatments.

IL-4

IL-10

ANTI IL-1

FGF-b

2015

Radice E. et al

Translational oncology

Ex vivo basic research

Enhancement of the immunomodulatory functions of ex vivo-generated dendritic cells from early-stage colon cancer patients by consecutive exposure to Low Doses of sequential kinetic activated IL-4 and IL-12. A preliminary study.

IL-4

IL-12

2015

Lotti T. et al

Der Hautarzt

Observational retrospective study

Successful combination treatment for Psoriasis with phototherapy and Low Dose Cytokines.

IL-4

IL-10

ANTI IL-1

2015

Tessaro et al.

Journal of Ovarian Research

In vivo basic research

Effect of oral administration of Low Dose follicle stimulating hormone on hyperandrogenized mice as amodel of polycystic ovary syndrome

FSH

2015Pilat C. et alScandinavian Journal of medicine and science in sportsClinical researchExploring effects of a natural combination medicine on
exercise-induced inflammatory immune response: A double-blind RCT
Traumeel
2015Vanden Bossche L. and Vanderstraeten G.BMC Musculoskeletal DisordersClinical researchA multi-center, double-blind, randomized, placebocontrolled
trial protocol to assess Traumeel injection vs dexamethasone injection in rotator cuff syndrome: the TRAumeel in ROtator cuff syndrome
(TRARO) study protocol
Traumeel

2016

Barygina V. et al.

Journal of Dermatological Science

In vivo basic research

Low Dose cytokines reduce oxidative stress in primary lesional fibroblasts obtained from psoriatic patients.

IL-4

IL-10

FGF-b

β-ENDORPHIN

2016

Fiorito F. et al.

Comparative Immunology, Microbiology and Infectious Diseases

Veterinary study

Clinical improvement in feline herpesvirus 1 infected cats by oral Low Dose of interleukin-12 plus interferon-gamma.

IL-12

IFN-γ

2016

Uberti F. et al

Cells Tissues Organs

In vitro basic research

Stimulation of the Non-neuronal Cholinergic System by Highly Diluted Acetylcholine in Keratinocytes.

ACh
2016Mayer J. et al.International ImmunopharmacologyIn vivo basic researchThe immunomodulatory effects of a commercial antiviral homeopathic compound in C57BL/6 mice, pre and post vaccine challenge

Engystol®

2016Fioranelli M, et al.Minerva CardioangiologicaClinical researchEffects of Arnica comp.-Heel® on reducing cardiovascular events in patients with stable coronary disease.Arnica comp. -Heel
2016Genazzani A.
et al.
Frontiers in Gynecological Endocrinology
(Bollettino di Ginecologia Endocrinologica)
Observational pilot studyPharmacological and Integrative Treatment of Stress-Induced Hypothalamic AmenorrheaBeta-Estradiol

2017

Tessaro I. et al.

J Reprod Infertil.

In vivo basic research

Ultra Low Dose of Follicle Stimulating Hormone and Progesterone attenuate the Severity of Polycystic Ovary Syndrome Features in a Hyperandrogenized Mouse Model.

FSH

PROGESTERON

2017

Martin Martin L. S. et al.Drud Design, Development and TherapyClinical TrialAn open randomized active-controlled clinical trial with Low Dose SKA cytokines versus DMARDs evaluating low disease activity maintenance in patients with rheumatoid arthritis.

ANTI IL-1

IL-4

IL-10

2017

Castiglioni S. et al.

International Journal of Molecular Sciences

In vitro basic research

Femtograms of Interferon-gamma Suffice to Modulate the Behavior of Jurkat Cells: A New Light in Immunomodulation.

IFN-γ
2017St. Laurent III G. et alFrontiers in Molecular BiosciencesIn vivo basic researchDeep Sequencing Transcriptome Analysis of Murine Wound Healing: Effects of a Multicomponent, Multitarget Natural Product Therapy-Tr14.

Traumeel

2017Carello R,
et al
Italian Journal of PediatricsClinical trialLong-term treatment with low-dose medicine in chronic childhood eczema: a double-blind two-stage randomized control trial

Galium-Heel®

IL-12

IFN-γ

2017Muders K. et alEur J Appl PhysiolClinical researchEffects of Traumeel (Tr14) on recovery and inflammatory
immune response after repeated bouts of exercise: a double-blind RCT
Traumeel
2017Lozada JC. et al.European Journal of Integrative MedicineClinical researchA double-blind, randomized, saline-controlled study of the efficacy and safety of co-administered intra-articular injections of Tr14 and Ze14 for treatment of painful osteoarthritis of the knee: The MOZArT trial

Traumeel

Zeel

2018Wronski S.
et al
PLOS oneIn vivo basic researchEngystol reduces onset of experimental respiratory syncytial virus-induced respiratory inflammation in mice by modulating macrophage phagocytic capacity.

Engystol®

2018

Mancini F. et al.

International Immunopharmacology

In vitro basic research

Low Dose SKA progesterone and Interleukin-10 modulate inflammatory pathway cytokines in endometriotic cell lines.

IL-10

PROGESTERON

2018

Uberti F. et al.

Wound

In vivo basic research

Highly Diluited Acetylcholine Promotes Wound Repair in an In Vivo Model

ACh

2018

Tagliacarne S. C. et al.

Immunology Letters

Ex vivo basic research

Low Dose multicomponent medication modulates humoral and cellular immune response in an ex-vivo study on children subjected to adenoid surgery.

CITOMIX

Collagen Medical Devices

Year

Authors

Journal

Research type

Title

Medical Device

2016

Martin-Martin L. S. et al.

BMC Musculoskeletal Disorders

Clinical Trial

A double blind randomized active-controlled clinical trial on the intra-articular use of Md-Knee versus sodium hyaluronate in patients with knee osteoarthritis (“Joint”).

MD-KNEE

2018

Randelli F. et al.

Cells

Ex vivo basic research

Effect of a Collagen-Based Compound on Morpho-Functional Properties of Cultured Human Tenocytes.

MD-TISSUE

2018

Nitecka-Buchta A. et al.

Pain Research and Management

Clinical Study

Comparison between Collagen and Lidocaine Intramuscular Injections in Terms of Their Efficiency in Decreasing Myofascial Pain within Masseter Muscles: A Randomized, Single-Blind Controlled Trial.

MD-MUSCLE

Physiological Nutraceutical

Year

Authors

Journal

Research type

Title

Food Supplement

2012

Roncuzzi A. et al.

Giornale Italiano di Ostetricia e Ginecologia

Clinical Trial

Efficacia e tollerabilità di Ferroguna versus ferro solfato nel trattamento dell’anemia sideropenica in gravidanza. Studio controllato di non inferiorità.

FERROGUNA

2014

Cardani D.

Minerva Gastroenterol Dietol

In vitro basic research

COLOSTRO NONI administration effects on epithelial cells turn-over, inflammatory events and integrity of intestinal mucosa junctional systems.

COLOSTRONONI

2014

Cardani D.

Inflammation & Cell Signaling 

Review

New perspective in dietary supplementation: bovine colostrum and noni juice synergic protective effects on intestinal epithelium and microbiota

COLOSTRONONI

2014

Lozzi A.

Minerva Cardioangiol

Observational retrospective study

Overview sulle strategie di trattamento farmacologico e nutraceutico della dislipidemia border-line.

OMEGA-FORMULA

2016

Chisari G. et al.

Minerva Oftalmol

Observational study

La cosomministrazione dei ceppi batterici Lactobacillus e Bifidobacterium in associazione con frutto-oligosaccaridi a corta catena riduce il danno alla superficie oculare causato dalla sindrome dell’occhio secco.

PROFLORA

2019

Duranti S. et al.

Plos One

In vitro basic research

Exploring the effects of Colostrononi on the mammalian gut microbiota composition.

COLOSTRONONI

Synopsis of research on Physiological Regulating Medicine

The analyzed articles report the experimental evidence of the effectiveness of PRM approach on diseases involving the immune system. All the papers show the ability of the signaling molecules to modulate the responses of immune cells in a highly selective fashion; especially, the immunostimulatory and immunomodulatory skills of the tested cytokines are clearly described.

The ability to act in a refined manner on the Th1/Th2 balance is crucial for the management of diseases with diametrically opposed cytokine imbalances such as Bronchial Allergic Asthma (which shows a Th2 predominance), Crohn’s disease and Psoriasis Vulgaris (Th1-driven diseases).

One of the key issues emerging from the analyzed scientific works is the effectiveness of treatment with low dose molecules in spite of the fact that they operate at lower concentrations than those generally considered pharmacologically effective.

The use of cytokines and other signaling molecules has often collided with the need of high dosages, realizing concentrations which show a wide range of side effects in addition to the proper pharmacological effects.

The classical minimum active dose is generally found between the lowest pharmacological one (10-5) and the highest physiological one (10-6) (Figure 4); low dose pharmacology moves within the range of physiological concentrations of signaling molecules acting below the concentrations at which adverse effects appear but equally reaching appreciable therapeutic results.The ligand-receptor binding properties are crucial to explain how low dose SKA signaling molecules can be effective. Receptor affinity for its specific ligand is fundamental for the activation of postreceptorial downstream, in fact ligand saturation generally induces the receptor freezing and/or its down-regulation. Low dose molecules are able to induce a direct physiological receptorial stimulation of immune cells (as described by Gariboldi S. and colleagues) modulating the responses within the homeostatic range; PRM realizes one of the cardinal points of P.N.E.I. approach to the disease: to restore physiological panel of signaling molecules.

From a pharmacological point of view the revised works highlight the importance of the activation of low dose molecules through the process of drug delivery known as SKA (Sequential Kinetic Activation): low dose molecules not processed with this activation procedure are totally ineffective as described by Gariboldi Set al. SKA activation is fundamental in order to overcome the conceptual wall represented by the minimum pharmacologically effective dose inducing an activity release effect exerted by low dose molecules by interaction with the aqueous vehicle.

Conclusions on Physiological Regulating Medicine and related research

Five years of scientific research on Physiological Regulating Medicine have allowed researchers to provide data of a different nature, scientifically relevant, able to demonstrate:

  1. The validity of the theoretical concepts underlying the PRM;
  2. The centrality of the pharmaceutical technological process called SKA (Sequential Kinetic Activation);
  3. The experimental and clinical effectiveness of low dose SKA signaling molecules.
  4. The immunomodulatory and immunostimulant ability of cytokines and the trophic activity of  growth factors;
  5. The safety of the preparations tested.