Clinical Applications of System Regulation Medicine

Abstract

Increasing incidence and poor outcome of chronic non-communicable diseases in western population would require a paradigm shift in the treatments. Guidelines-based medical approaches continue to be the standard rule in clinical practice, although only less than 15% of them are based on high-quality research. For each person who benefits from the 10 best-selling drugs in the USA, a number between 4 and 25 has no one beneficial effect.

The reductionist linear medicine method does not offer solutions in the non-manifest preclinical stage of the disease when it would still be possible to reverse the pathological progression and the axiom "a drug, a target, a symptom" are still inconclusive. Needs additional tools to address these challenges.

System Medicine considers the disease as a dysregulation of the biological networks that changes throughout the evolution of the pathological process and with the comorbidities development. The strength of the networks indicates their ability to withstand dysregulations during the perturbation phases, returning to the state of stability. The treatment of dysregulated networks before the symptomatological manifestation emerges offers the possibility of treating and preventing pathologies in the preclinical phase and potentially reversing the pathological process, stopping it or preventing comorbidities. Furthermore, treating shared networks instead of individual phenotypic symptoms can reduce drug use, offering a solution to the problem of ineffective drug use.

Full text

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Open Access Maced J Med Sci. 2019 Sep 30; 7(18):3053-3060. 3053
ID Design Press, Skopje, Republic of Macedonia
Open Access Macedonian Journal of Medical Sciences. 2019 Sep 30; 7(18):3053-3060.
https://doi.org/10.3889/oamjms.2019.775
eISSN: 1857-9655
Global Dermatology
Clinical Applications of System Regulation Medicine
Massimo Fioranelli1*, Alireza Sepehri1, Maria Grazia Roccia1, Cota Linda1, Chiara Rossi1, Amos Dawodo1, Petar Vojvodic2,
Jacopo Lotti1, Victoria Barygina3, Aleksandra Vojvodic4, Uwe Wollina5, Michael Tirant6, Thuong Nguyen Van7, Torello Lotti8
1Department of Nuclear Physics, Sub-nuclear and Radiation, G. Marconi University, Rome, Italy; 2Clinic for Psychiatric
Disorders “Dr. Laza Lazarevic”, Belgrade, Serbia; 3Department of Biomedical Experimental and Clinical Sciences, University
of Florence, Florence, Italy; 4Department of Dermatology and Venereology, Military Medical Academy, Belgrade, Serbia;
5Department of Dermatology and Allergology, Städtisches Klinikum Dresden, Dresden, Germany; 6G. Marconi University,
Rome, Italy; 7Vietnam National Hospital of Dermatology and Venereology, Hanoi, Vietnam; 8Department of Dermatology,
University of G. Marconi, Rome, Italy
Citation: Fioranelli M, Sepehri A, Roccia MG, Linda C,
Rossi C, Dawodo A, Vojvodic P, Lotti J, Barygina V,
Vojvodic A, Wollina U, Tirant M, Nguyen Van T, Lotti T .
Clinical Applications of System Regulation Medicine.
Open Access Maced J Med Sci. 2019 Sep 30;
7(18):3053-3060.
https://doi.org/10.3889/oamjms.2019.775
Keywords: Bioregulatory Systems Medicine; Preclinical;
Networks
*Correspondence: Massimo F ioranelli. Department of
Nuclear Physics, Sub-nuclear and Radiation, G. Marconi
University, Rome, Italy. E-mail:
massimo.fioranelli@gmail.com
Received: 16-Jul-2019; Revised: 04-Aug-2019;
Accepted: 05-Aug-2019; Online first: 14-Sep-2019
Copyright: © 2019 Massimo Fioranelli, Alireza Sepehri,
Maria Grazia Roccia, Cota Linda, Chiara Rossi, Amos
Dawodo, Petar Vojvodic, Jacopo Lotti, Victoria Barygina,
Aleksandra Vojvodic, Uwe Wollina, Michael Tirant,
Thuong Nguyen Van, Torello Lotti. This is an open-access
article distributed under the terms of the Creative
Commons Attribution-NonCommercial 4.0 International
License (CC BY-NC 4.0)
Funding: This research did not receive any fi nancial
support
Competing Interests: The authors have declared that no
competing interests exist
Abstract
Increasing incidence and poor outcome of chronic non-communicable diseases in western population would
require a paradigm shift in the treatments. Guidelines-based medical approaches continue to be the standard rule
in clinical practice, although only less than 15% of them are based on high-quality research. For each person who
benefits from the 10 best-selling drugs in the USA, a number between 4 and 25 has no one beneficial effect.
The reductionist linear medicine method does not offer solutions in the non-manifest preclinical stage of the
disease when it would still be possible to reverse the pathological progression and the axiom "a drug, a target, a
symptom" are still inconclusive. Needs additional tools to address these challenges.
System Medicine considers the disease as a dysregulation of the biological networks that changes throughout the
evolution of the pathological process and with the comorbidities development. The strength of the networks
indicates their ability to withstand dysregulations during the perturbation phases, returning to the state of stability.
The treatment of dysregulated networks before the symptomatological manifestation emerges offers the possibility
of treating and preventing pathologies in the preclinical phase and potentially reversing the pathological process,
stopping it or preventing comorbidities. Furthermore, treating shared networks instead of individual phenotypic
symptoms can reduce drug use, offering a solution to the problem of ineffective drug use.
Introduction
The reductionist linear medicine has
undoubtedly contributed to the prolongation of the life
expectancy of the western population, but, as far as
chronic non-communicable diseases are concerned, it
presents some problems that require a paradigm shift
in the treatments currently in use.
The progressive ageing of the population and
the increase in environmental pollution are conditions
capable to profoundly influencing the health status of
the population.
The management of non-communicable
diseases, the ageing of the population and the
progressive environmental pollution, pose new and
complex problems, difficult to be solved by the current
health organisation, also due to the economic
sustainability of the care [1], [2], [3].
The incidence of complex non-communicable
diseases, such as type II diabetes, cardiovascular
diseases (growing exponentially), atopic dermatitis
and cancer, increases with age, but the most worrying
fact is that it is also increasing in the pediatric
population [4], [5], [6], [7], [8].
Also, regarding transmissible pathologies,
there are new challenges related to the increasing
resistance of microbes to antibiotics and to the limited
number of new drugs being developed [9], [10], [11].
Guidelines-based medical approaches
continue to be the rule in clinical practice, although
only less than 15% of them are based on high-quality

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research. Although this type of (statistical) approach
can be profitable in the general population, it becomes
unsuccessful when compared to the genetic,
epigenetic and environmental characteristics of the
individual subject [4]. The result is excessive
healthcare spending compared to poor results. The
annual cost of ineffective treatments in the US would
be $ 350 billion, while the development of new linear
drugs costs $ 1 billion for each formulation, with an
additional impact on the cost of health care [12].
In research on the 10 best-selling drugs in the
USA, it was found that, for each person who benefits
from one of these treatments, a number between 4
and 25 has none [13].
Another study showed that the use of
prescription drugs has drastically increased among
the elderly population during an observation period of
12 years and, in particular, the number of patients
taking more than 5 drugs has increased from 12.8% at
39.0% from 1988 to 2010, identifying a population
considered particularly fragile [14].
Usually, in chronic conditions, Western
Medicine treats the symptomatic manifestations of the
disease (e.g. hypertension or hypercholesterolemia)
and often can identify patients at risk in advance.
However, this method does not offer solutions in the
non-manifest preclinical stage of the disease, when it
would still be possible to reverse the pathological
progression, correcting underlying causes [12], [13],
[14], [15].
It, therefore, appears clear that the need for
additional tools to address these challenges. For this
reason, more and more frequently, System Medicine
is proposed as a useful tool [16], [17], [18], [19], in
particular in terms of different view and approach to
the disease, unfortunately even more in theory than in
practice, because the alternatives to the axiom "a
drug, a target, a symptom" are still struggling to get
ahead.
The Bioregulatory System Medicine (BrSM),
the subsequent evolution of Systems Medicine, aims
to bridge this gap through the use of low dose
medicines with precise, targeted and synergistic
bioregulatory capacities. These are medicines
composed of different therapeutic nuclei (multi-
component) with an effect on as many different
targets (multi-target) and a favourable safety profile
[20], [82]. Based on a correct evaluation of the
patient's clinical history, recognition of its
characteristics specific and at the stage of progression
of the pathology, the BrSM directs the choices of
therapeutic strategy, allowing a more complete and
systematic approach to the patient.
Systems Medicine
Biological systems have some aspects in
common, including self-organisation, intrinsic stability,
robustness and resilience [12], [15], [21].
Self-organisation is one of the fundamental
characteristics of Systems Medicine and takes up the
so-called autopoiesis of the school of Santiago de
Francisco Varela and Humberto Maturana [21], [22].
The complexity of the human body is
considered as a set of interconnected networks,
composed of genome, molecules, cells, organs, going
beyond, up to the environment surrounding the
organism and to the networks created by individuals in
societies [4], [12].
The disease is considered a dysregulation of
the networks, linked to different perturbations or
disturbances that act by jeopardising stability and
functionality [23], [24], [25].
The networks go through phases of
dysregulation long before the recognisable pathology
divides, and before any structural symptoms or
alterations appear.
Stability is another intrinsic characteristic of
complex systems, and in living organisms, it is
ensured by self-regulation to maintain homeostasis.
The networks are organised in functional
modules to protect the system from global collapse,
and robustness (i.e. the ability of systems to resist,
without modification, to perturbations) allows the
system to defend itself against elements of
disturbance and destabilisation [15], [26].
Finally, resilience indicates the ability of the
system to withstand disturbances by adapting to it to
guarantee the function of the system itself.
These characteristics can be exploited in the
clinical approach and the BrSM aims at this goal,
placing as the main goal of the therapy the support to
the organism self-regulation system to re-establish a
normal state of homeostasis or, if this is not possible,
a state of optimal compensation, reducing the use of
drugs as much as possible [20].
In practice, numerous distinctive aspects
differentiate the Systems Medicine from the linear
reductionist approach [4], [16], [81].
The use of targeted drug therapies that target
only one point of the network, as happens in
reductionist medicine, has been questioned. If the
interrelations of the target are not taken into account,
in fact, one risks unintentionally causing the opposite
effect. For example, the use of statins could increase
atherosclerosis due to the depletion of coenzyme Q10
and vitamin K2, 25 or the use of non-steroidal anti-
inflammatory drugs in acute inflammation has an anti-
inflammatory effect, but also tends to block the

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production of prostaglandins (PG) E2, necessary for
the activation of lipid mediators responsible for
resolving inflammation and triggering the repair and
restoration processes of tissue physiology [28], [29],
[30].
The recognition of the role of the
dysregulation of biological networks in the evolution of
pathologies not only offers opportunities for their
management but also questions the current diagnostic
procedure, based on a fixed number of biomarkers
that are interpreted only after the onset of clinical
symptoms [31], [32]. This different approach to the
patient, called Network Medicine, has many
advantages [12].
According to this more current reference
model, in the diagnosis phase we tend to recognize
dynamic patterns in network dysregulations rather
than resort to isolated and immutable biomarkers over
time and, in particular, in the approach to the
progressive evolution of the pathology, such patterns
contribute to the definition of an individualized vision
for each patient [17], [33], [34].
In 2008 Fuite et al., showed him that, through
the analysis of a genomic network in patients with
chronic fatigue syndrome, it was possible to identify
an alteration in the interrelation of the immune system,
adrenocorticotropic hormone, and thyroid [35].
More recently, recognition of specific patterns
in patients with systemic sclerosis has allowed
physicians to predict prognosis and contributed to the
definition of therapy [36].
To examine and visualise these complex
networks to define their patterns, the so-called "-
omics" technologies are used: genomics,
epigenomics, proteomics, metabolomics and
microbiomics, up to the most recent exposomics [10],
[19], [37]. It appears very promising, in this panorama,
also the alterations of the parameters of bio-
impedance metre that involve the analysis of the
systems [38].
The reductionist approach tends largely to
ignore environmental influences, but starting from the
revolutionary article by Christopher Wild, who
introduced the term esposoma in 2005, this concept
has taken on a prominent role in the systems
approach [10], [39], [40], [41].
The concept of exposome indicates the list of
all the chemical substances to which a subject has
been and including environmental, food or work-
related, endogenous biochemical substances formed
by normal metabolic processes, and by inflammation,
oxidative stress, lipid peroxidation and infections, as
well as other natural metabolic processes, such as
alteration of the intestinal microbiome [41]. These
exhibits affect all networks and in particular the
epigenetic one.
The omics technologies are also ideally useful
for investigating the effects of multicomponent /
multitarget drugs with bioregulation properties, as they
would allow clarifying the effects effects [42] better.
In summary, System Medicine considers the
disease as a dysregulation of the biological networks
that changes throughout the evolution of the
pathological process and with the development of
comorbidities. The strength of the networks indicates
their ability to withstand dysregulations during the
perturbation phases, returning to the state of stability
or guaranteeing the best possible stability through
compensation mechanisms [5], [24], [43], [44].
The treatment of dysregulated networks
before the symptomatological manifestation emerges
offers the possibility of treating and preventing
pathologies in the preclinical phase and potentially
reversing the pathological process, stopping it or
preventing comorbidities [15].
Furthermore, treating shared networks
instead of individual phenotypic symptoms can reduce
drug use, offering a solution to the problem of
ineffective drug use [4].
Systems Bioregulation Medicine
The conceptual pillar of BrSM is a therapeutic
approach that aims to treat the networks
dysregulations of underlying pathology by supporting
self-regulation networks, to promote the restoration of
physiological homeostatic conditions of networks or
the achievement of a state of equilibrium [20].
The dysregulation of the networks is the initial
phase of the pathological evolution, preceding the
symptomatological manifestation; it follows an
advantageous overall therapeutic intervention and
directed to the dysregulation as a whole, instead of on
the single symptomatological manifestations of each
disease.
Complex non-communicable diseases often
share dysregulations of the inflammatory and
metabolic networks. During evolution, these same
networks have evolved to address a wide variety of
circumstances. At the same time, however, it must be
considered that this characteristic of flexibility also
makes them more vulnerable to dysregulation. The
regulation of these networks is based on relatively
primitive self-regulation processes and is often
overwhelmed by incongruous lifestyles and by
increasingly unfavourable conditions of environmental
pollution to which modern man is exposed [45], [46].
The Nervous and Endocrine Systems
maintain a systemic homeostatic state, while the local
homeostatic circuits regulate the state and integrity of
cell and tissue networks. However, when homeostatic
mechanisms are not sufficient, the inflammatory

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process is triggered in order to maintain or restore
balance. Several authors define this process as
homeostatic inflammation (or physiological
inflammation [47], [48].
The inflammatory response of the organism
and its effects on it in the acute phase play a
fundamental role in the model of BrSM. The
inflammations that persist can potentially cause
alterations of the cellular microenvironment and
progressively lead to structural tissue damage, up to
their degeneration [45], [49]. In BrSM the inflammatory
response is used as a substitute in clinical decision
making.
The vision of inflammation as a static process
that ends with the elimination of its mediators has
changed a lot in recent years. Today inflammation is
considered an active process. As is often observed in
homeostatic mechanisms, it is the initial mechanism
itself that also determines its end. Among the main
protagonists is PGE2, which is not only responsible
for most of the symptoms associated with acute
inflammation, but also plays a fundamental role in the
activation of the so-called mediators favouring the
resolution of the inflammatory process [26], [27].
Drugs developed linearly, such as non-
steroidal anti-inflammatory drugs, whose main target
is cyclo-oxygenase 2, have an anti-inflammatory
action, but can at the same time prevent the resolution
of the problem by forcibly suppressing PGE2 [28].
It has recently been shown that the multi-
component drug Traumeel has a different mechanism
of action in the context of the inflamed tissue and a
modulation effect on PGE2 and on specialised
prorisolutive mediators that can favour a more
physiological resolution of the process [50], [51].
Individualised treatments
In their pioneering article, Ahn et al., they also
outlined the future of System Medicine in clinical
practice [52].
The applications-omics bode well for a
revolution in the approach to the diagnosis and
individualisation of patients based on risk, stage of the
disease and possible response to treatment.
However, the costs and degree of innovation currently
prevent the use of these tools as a routine medical
practice. This means that doctors must continue to
rely on classical methods to selectively choose the
therapy of their patients.
The path starts from the collection of the
anamnesis, in which the aspects related to genetics
and exposome deserve special attention. The
patient's prenatal history has the same importance as
post-birth events, as many stress factors, such as
maternal psychological stress and exposure to
environmental xenobiotics, have a fundamental
impact on the patient's responses in the later stages
of life. This is often mediated by epigenetic alterations
[53], [54], [55].
Work and leisure activities can be indicative of
possible exposures and stress factors.
Genetic and genomic markers are often
suggestive of possible risks; by way of example,
single nucleotide polymorphisms may represent a risk
factor, for example in the known association between
homocysteine metabolism disorders and
cardiovascular diseases [56]; another example is the
risk assessment tests for breast cancer [57].
Genomics and metabolomics are also used in clinical
practice to predict treatment responses [58].
This is also useful for the probabilistic
forecasts cited by Ahn.
The biomarkers and algorithms currently used
to diagnose pathologies in terms of phenotypic results
(e.g. erythrocyte sedimentation rate, high-sensitivity
C-reactive protein and complete blood count) should
be used appropriately for clinical decisions.
The treatment based on the progression of
the disease and in particular on the recognition of
preclinical stages will remain difficult to apply until the
sciences-omics and Networks Medicine become part
of the common practice.
In BrSM, the effect of the inflammatory
response on the microenvironment is used as a
substitute / in addition to the sciences-omics available
for the interpretation of clinical decisions. Unlike what
was thought in the past, the microenvironment has the
possibility to reverse the structural alterations,
provided that the cell membrane has not been
damaged.
In the BrSM there is, therefore, a dynamic
attitude in the prescription, which will be based on the
degree of progression of the patient's pathology.
To further individualize the treatment, the
patient's exposure and microbiome are considered
and, consequently, the use of appropriate draining
and detoxifying medicines and the insertion of certain
probiotic strains, often specific for each pathological
process (eg Bifidobacterium PBL1 in the metabolic
syndrome or Bifidobacterium lactis CECT 8145,
Bifidobacterium longum CECT 7347, and
Lactobacillus casei CECT 9104 in atopic dermatitis)
[59], [80].

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Change in therapy paradigm
In the "one drug, one target, one symptom"
approach, pharmacological treatment is often
symptomatic or aimed at treating phenotypic results
secondary to dysregulation. These are static
treatments, and patients often take the same
therapies for long periods.
Supporting the self-regulation system, the
BrSM aims to re-establish a state of health or
compensation, and this means that often, once this
result is achieved, the patient no longer needs drugs
or needs only in limited quantities. This requires
careful assessments of disease progression and good
monitoring. In the case of advanced phenotypic
alterations, drug treatment is frequently the only
option available. Obviously, this also applies to
diseases in which there is no possibility of regulation,
for example in the case of ablation of an organ, and,
in these cases, replacement therapy must be taken for
life.
Low dose drugs effects
This characteristic does not exclusively refer
to the attempt to reduce the use of drugs to the
minimum necessary, which can be the result of better
individualisation of the patient or improvement of the
state of health through the achievement of optimal
self-regulation.
The hormetic effects of the substances are
the subject of constant research [60]. The hormesis
seems to have positive consequences on the
resilience of the organism, in particular through the
so-called mitormesis [slight mitochondrial damage can
induce a hormetic response (mitormesis) that
promotes compensatory adaptive processes] [61],
[62], [63].
Some authors have specifically cited the
hormetic effects that increase adaptive responses
through the exposure of natural phytotherapeutic
substances (xenormes) [64].
This is a concept that requires further
research but could be a plausible hypothesis to
explain how some substances in reduced
concentrations exert bioregulation effects.
The low naltrexone dose, which has been
discussed earlier, is a good example of how a drug to
conventional doses, developed with a specific
purpose, can also be used for other purposes. It is
able, at this lower dosage, to generate bioregulatory
effects. This also happens for other preparations with
bioregulation properties: for example, the medicinal
product Lymphomyosot, originally developed for
lymphatic pathology, has subsequently shown that it
can also be usefully used for wound healing [65].
Since-omic technologies allow the analysis of
large groups of data on multitarget actions; the
identification of alternative applications of drugs is
destined to grow over time.
Synergistic treatments
To achieve bioregulation in dysregulations
involving more than one network or different functional
modules of a network, it may be necessary to resort to
a combination of several drugs (treatments).
This is a common approach in the BrSM, in
particular for chronic diseases, in which with the
development of comorbidities we are witnessing the
subsequent dysregulation of further networks.
Chronic diseases seem to have in common
the main dysregulation of certain networks [66], [67],
[83]. These include the network inflammatory, the
network metabolic, the network energy-mobile, and
network neuroendocrine.
The chronic dysregulation of the networks
also puts a strain on the processes of self-regulation.
It is, therefore, necessary to add cofactors to optimise
the efficient operation of enzymes, for example, since
they can run out if they are not reintegrated over time.
The patient's nutritional status must be carefully
considered and, about it, deficient cofactors will be
established according to specific needs.
As mentioned above, some pharmacological
therapies also lead to the depletion of cofactors that
are fundamental for self-regulation (e.g. coenzyme Q
10 and vitamin K2 in statin-based therapies) [25].
Missing cofactors must be adequately replenished
and, if bioregulation allows it, the patient must
gradually reduce and then stop therapy.
Recently the efficacy of a combination of two
drugs with bioregulatory properties and their
synergistic effects in the treatment of knee
osteoarthritis (Arnica comp. + Zeel T) has been
demonstrated [68], [69], [70].
"Space - sensitive" treatments:
administration of drugs in specific
locations
As can be seen from the bioregulation model,
the microenvironment plays a fundamental role in the
therapeutic approach of the BrSM. In numerous

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publications, it is argued that connective tissue is an
organ with interconnecting properties [71], [72]. A
recent publication in Nature even speaks of interstitial
spaces containing fluidly plastic structures previously
not characterised, emphasising the fundamental
function of this important tissue and introducing for it
the most correct classification of the organ [73].
Drugs can be administered directly in this
organ through infiltration techniques at specific points.
In fact, injection into the acupuncture points is
frequent in the BrSM approach [74], [75], [76], [77].
Intradermal injections are also used in Aesthetic
Medicine, similarly to infiltration in the corresponding
dermatomes to act on the internal organs [78], [79].
Conclusions
In the current context, medical personnel are
exposed to numerous challenges, which require new
tools to respond to patients' needs.
The Systems Medicine approach is making
headway in clinical practice as a solution for improving
patient management; however, the reference
paradigm of conventional therapies "a target, a drug"
is proving not entirely suitable.
System Medicine applications, such as BrSM,
aim to remedy the shortcomings of the conventional
approach, using complex multicomponent drugs, to
obtain regulatory effects on multiple targets.
The BrSM complies with the fundamental
criteria that distinguish the Systems Medicine
approach, but the clear therapeutic objective is the
support of patient self-regulation networks. This
approach can be associated with "linear drugs" based
on the specific needs of patients. Applying these
different approaches at the same time, we will witness
the birth of a single Medicine: the one that responds to
the specific patient's needs at a specific time.
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