eCAM 2007 4(2):149-163; doi:10.1093/ecam/nel117

(c) 2007 The Author(s)

Immunology and Homeopathy. 5. The Rationale of the 'Simile'
Paolo Bellavite1, Riccardo Ortolani2, Francesco Pontarollo1,
Giuseppina Pitari3 and Anita Conforti4
1Department of Scienze Morfologico-Biomediche, University of Verona,
Piazza L. A. Scuro, 37134 Verona, 2Association for Integrative
Medicine 'Giovanni Scolaro', 3Department of Basic and Applied Biology,
University of L'Aquila and 4Department of Medicina e Sanità Pubblica,
University of Verona, Italy

   Abstract

The foundation of homeopathic medicine is the 'Similia Principle',
also known as the 'Principle of Similarity' or also as the 'Simile',
which reflects the inversion of pharmacological effects in healthy
subjects as compared with sick ones. This article describes the
inversion of effects, a widespread medical phenomenon, through three
possible mechanisms: non-linearity of dose-response relationship,
different initial pathophysiological states of the organism, and
pharmacodynamics of body response to the medicine. Based on the
systemic networks which play an important role in response to stress,
a unitary and general model is designed: homeopathic medicines could
interact with sensitive (primed) regulation systems through complex
information, which simulate the disorders of natural disease.
Reorganization of regulation systems, through a coherent response to
the medicine, could pave the way to the healing of the cellular,
tissue and neuro-immuno-endocrine homeodynamics. Preliminary evidence
is suggesting that even ultra-low doses and high-dilutions of drugs
may incorporate structural or frequency information and interact with
chaotic dynamics and physical-electromagnetic levels of regulation.
From the clinical standpoint, the 'simile' can be regarded as a
heuristic principle, according to which the detailed knowledge of
pathogenic effects of drugs, associated with careful analysis of signs
and symptoms of the ill subject, could assist in identifying
homeopathic remedies with high grade of specificity for the individual
case.

Keywords: action - reaction principle - biologic networks -
homeopathic medicine - hormesis - inverse effects - paradoxical
pharmacology - response to stress - self-organization - Similia
principle - Wilder's rule

   Introduction

The cardinal principle on which the theory of homeopathic medicine is
based is that of 'similarity', according to which a homeopathic remedy
in a healthy subject will produce certain sets of symptoms, while the
same remedy will cure similar sets of symptoms in unhealthy (sick)
subjects (1-3). Hahnemann's theory withstands the test of time, and
has been supported by scientific findings in an array of fields,
including that of immuno-allergology, as described in previous
lectures on the subject (4-7). This principle can now be integrated
into a broad theory of the homeodynamics of living systems (Table 1).

  Table 1. The homeopathic simile and regulation of body
homeodynamics

Indeed, there is a need for viable hypotheses of homeopathy mechanism
of action. One of the earliest systematic reviews of homeopathic
clinical trials concludes: '... The amount of positive evidence even
among the best studies came as a surprise to us. Based on this
evidence we would readily accept that homeopathy can be efficacious,
if only the mechanism of action were more plausible' (8).
Another controversial principle of homeopathy is that the strength of
a remedy would be increased through its dilution, which is a process
known as dynamization, or potentization. At the end of this report, we
will briefly discuss this issue. In any event, there is the need to
clarify a preliminary assumption: both molecular and non-molecular
information (i.e. mechanic, acoustic, electromagnetic, quantum
electrodynamic) operate biologically, and regulation through the
'simile' could work in both cases, since they are not conflicting one
with the other.

The purpose of this lecture is to re-evaluate the principle of
similarity through up-to-date scientific knowledge concerning many
phenomena, from cell behavior to clinical practice (9-11). This will
allow us to extrapolate a general working hypothesis according to
which biologically active compounds (including highly diluted
solutions) could have inverse or paradoxical effects, based on one or
a combination of the following factors:

non-linearity of response to different doses of the compound/signal,

pathophysiological state of the treated organism and

pharmacodynamics of the drug, particularly with regard to the rebound
effects and long-term adaptation.

   Non-linearity of the Dose-Response

In biological systems, non-linearity between dose and effect is the
rule, rather than the exception. Even if this phenomenon does not
clarify all the clinical effectiveness of homeopathy, the following
controlled experimental models examine the similia principle.

Hormoligosis

The terms 'hormoligosis' and 'hormesis' refer to stimulation of
biological systems by low-dose toxins and inhibitors, as shown in a
number of experimental models (12-20). Early attempts to describe
hormesis date back to 1877 when Schulz, while studying yeast
metabolism, proved that almost all poisons have a weak stimulus effect
at low doses (21,22). Together with R. Arndt, he then developed a
principle, the so-called 'Arndt-Schulz law': 'weak stimuli slightly
increase biological responses, medium-strong stimuli markedly raise
them, strong ones suppress them and very strong ones arrest
them' (23).

In general, these hormetic effects can be documented by reverse-U dose-
response plots or even more complex dose-response curves. In Fig. 1A,
a typical hormetic (reverse-U shaped) curve is shown. Figure 1B shows
the kinetic of low-dose and high-dose effects of inhibitors on a
biological system: an overcompensatory response follows the initial
decrease in activity due to inhibitor low doses. This may optimize the
ability of an organism to meet challenges beyond the limits of normal
(unexercised) adaptation.

  Figure 1. Examples of biphasic or polyphasic dose-response curves.

Inhibition by Low Doses
A wide variety of substances exert opposing effects (inhibitory or
stimulating) at low or high doses; this phenomenon is well documented
in immunology. Figure 1C shows how specific antibody levels can change
in mice inoculated with different antigen (bovine serum albumin)
doses. At low or high antigen doses, the murine immune response is
depressed (immune-tolerance), while there is a positive antibody-
production response at intermediate doses.

Various factors contribute to the result, in conjunction with specific
lymphocyte subset activation, different receptor sensitivities and the
role of the tissue environment on the cell activation/suppression. At
least two different mechanisms are responsible for T-cell auto-
reactivity: high concentration of self-antigens causes cell depletion,
while low doses cause a specific inhibition, known as bystander
suppression. This low-dose regulation could be used to explain the
effects of some homeopathic medicines (24). However, even with much
scientific evidence, the concept of hormetic dose-response
relationship is not integrated by mainstream schools of thought in
toxicology (25).

Inverse Effects in a Leukocyte Model

The activation of human neutrophils shows a dose-dependence on
bacterial peptides (Fig. 1D) (26,27). High doses (10-6-10-7 M) of
bacterial peptides formyl-Methionyl-Leucyl-Phenylalanine (fMLP) were
able to induce a marked increase in adhesiveness of human leukocytes,
whereas 100 times lower doses (10-8-10-9 M) inhibited and reversed the
adhesion induced by bacterial endotoxin (LPS) (28) or by migration
into the inflammatory exudate (29).

This paradoxical effect of low-dose fMLP models is probably due to the
'gating' exerted by cyclicAMP (cAMP) at the level of intracellular
signal transduction pathways (26). Figure 2 shows a schematic
representation of a LPS-treated cell, with no fMLP (A), and low (B)
and high (C) doses of fMLP. The latter bacterial peptide at low doses
does not stimulate adhesion, whereas the intracellular cAMP increases,
through activation of adenylate cyclase. cAMP is an intracellular
messenger for many enzymes, including protein kinase A which, in turn,
can inhibit the LPS-activated transduction machinery of adhesion
(gating pathway). fMLP at high doses obtains full activation, using a
different transduction pathway (represented in Fig. 2 by squares),
thus by-passing the gating by cAMP.

    Figure 2. Schematic representation of the inverse effects of
different doses of fMLP on LPS-treated human neutrophils.

The importance of cAMP has also been invoked in explaining other
phenomena which recall the 'simile': interleukin-2 has opposite
effects on B lymphocytes depending on intracellular cAMP levels (30);
the inhibition of basophil responses by low doses (31) or high
dilutions (32) of natural compounds may have a similar explanation at
the level of signal transduction.
Furthermore, not only the gating theory explains the occurrence of
inverse effects at a cell level: the presence of various receptors
with both different affinities and different coupling capabilities to
effector systems, or the induction of detoxification enzymes (gene
expression and enzyme activation) should also be considered (33).
Other authors (34-39) have elaborated different theories, based on the
heat-shock protein system activation, or on the metabolism regulation
and on toxicology. Those theories do not conflict with each other, but
concern different levels of cell organization.

   The Role of Pathophysiological State

The role of inflammatory processes is to control the structural
integrity of organs and tissues, while the immune system controls the
specific identity, or biological 'selfness', of molecules within the
organism. Those systems are integrated with the peripheral and central
nervous systems (40): mood and behavior disorders are associated with
immunopathological disorders, with susceptibility to recurring
infection, hypersensitivity, allergies, autoimmune diseases and
diabetes. Homeopathic therapy should act by regulating the
inflammatory and immune systems, both directly through molecular
similarity, as seen in isopathic therapies, and indirectly through
systemic interconnections, as shown in Fig. 3.

  Figure 3. Typical neuroimmunoendocrine networks involved in the
response to any type of stress (A) and possible dysfunction in chronic
inflammatory diseases (B). 1. Cognitive functions, 2. neural networks,
3. hypothalamus, 4. locus ceruleus, 5. hypophysis, 6. sympathetic
nervous system (adrenergic), 7. adrenals, 8. cardiovascular system, 9.
immune system and inflammatory processes. ACTH, adrenocorticotropic
hormone; CRH, corticotropin-releasing hormone; IL-1, interleukin-1;
IL-6, interleukin-6; TNF, tumor-necrosis factor;  stimulation,
inhibition.

The Response To Stress
Figure 3A shows a typical sequence of physiological mechanisms which
maintain homeodynamics in the immune and endocrine systems.
Psychosocial stressors activate the neuroendocrine pathways which,
eventually, can lead to higher corticosteroid levels; uninterrupted
strong stimulation can suppress the immune system, thus increasing
susceptibility to infection (41,42). On the other hand, peripheral
inflammatory cells are recruited and activated to counteract chemical
or biological stress, producing molecular messages (cytokines) toward
the central nervous system to build up a neuroendocrine response to
stress. Increased steroid production, in conjunction with adrenergic
stimulation, is important in a wide variety of adaptive responses,
including regulation of inflammatory processes.

Repeated biological or physiological stress can cause internal
communication failures, leading to the adaptation to a pathological
state, more specifically, to chronic disease. Figure 3B depicts a
typical loss of sensitivity to cytokines or to steroids. A variety of
diseases are based on the lack of adaptability to environmental change
through system or sub-system derangement. Immunodeficiency syndrome,
atopic dermatitis, encephalomyelitis, coronary artery disease, chronic
heart failure, anxiety and depression all exhibit an altered
coordination or disruption of neuro-endocrine signaling. For example,
glucocorticoid overproduction, combined with depression and chronic
stress, cause destabilization in the glucocorticoid receptors to the
feedback inhibition of the hypothalamus-pituitary-adrenal (HPA) axis
and to an increase of inflammatory cytokines (43). Some chronic
diseases, such as asthma, are considered as a type of pathologic
adaptation of complex networks, which behave like semi-stable
'attractors' within the organism (11,44). This self-maintenance of
disease, as organization of pathologic attractors in complex systems,
can be regarded as an update to the 'miasm' concept of classic
homeopathy (11,45-47).

The above theoretical background suggests that homeopathic medicine
can regulate inflammatory and immunopathological processes as well as
the neuroendocrine network and peripheral receptors. Homeopathic
information mimics a pathophysiological stress, because it is able to
induce symptoms of pathology, and, in the 'already-stressed' and
inefficient organism, would re-activate a coherent response. In fact,
homeopathy could have a positive effect on stress-induced behavior and
on gastric and immunologic alterations in mice (48). Highly diluted
histamine shows to be active on blood basophils, on skin inflammation
reactions and on sleep patterns in rats (5,49).

The 'Initial Value' Rule

Biological responses strictly depend on the 'starting conditions' of
any tissue or organ, and different starting conditions yield peculiar
reverse responses to a drug. An example of different effects due to
different cellular conditions can be found in macrophages--these cells
are known to be activated, for example, by cytokines in a number of
biological events including chronic inflammatory reactions, tumor
defense, repair phenomena, atherosclerosis and so on. Interferons,
endotoxins and tumor-necrosis factors (TNFs) increase resting
macrophage functional capability, whereas they suppress previously
activated macrophages (50). A related phenomenon was described by
Wilder in the first decades of the past century in experimental
settings (2,51,52). A typical report of Wilder's findings is shown in
Fig. 4. He recorded heart frequency and blood pressure (not shown in
the figure) in dogs before and after the administration of 1 mg
adrenalin.

   Figure 4. Diagram of the effects of adrenaline (epinephrine) on
the cardiovascular system (the 'initial value' rule of Wilder). For
explanation, see text.

Under normal conditions (Fig. 4, line 1) the drug causes an increase
in both heart rate and blood pressure; these then plateau and finally
revert to the resting state. This kinetic is due to the activation
threshold of homeodynamic feedback response, conceivably due to vagus
stimulation and to the inactivation of the stimulant. However, when
the initial heart rate is elevated (high sympathetic tone of the test
animal), the exogenous adrenaline response is different--the initial
increase is less, prior to returning to the resting state (line 2).
Thus, the net effect of the drug is the decrease in heart rate when
compared with the initial rate. Starting with very low heart rate
(vagotonic state, line 3), the response to adrenaline is higher than
in normal animals, due to the system's higher sensitivity to the drug
and to a slower homeodynamic feedback threshold.
In humans, bronchial asthma is characterized by the increase of vagus
activity on smooth bronchial musculature; under these conditions,
adrenaline supports breathing, thanks to its dilating and relaxing
effects. On the other hand, in normal subjects, adrenalin has little
or no effects. In conclusion, the same treatment or similar treatments
can cause different, if not opposite, effects, depending on the
initial state of the system. This typical behavior has been described
in different physiological systems (cardiovascular, hormonal,
respiratory, nervous, etc.) and using various drugs (53,54).

More recently, a preliminary mathematical model of the action-reaction
principles was developed looking at the 'weak quantum theory' and the
'patient-practitioner entanglement', based on the metaphor of a
hypothetical gyroscope as physical representation of the vital force
(55). Briefly, increase or decrease in the rate of spin of a
hypothetical gyroscope (namely the 'vital force') was described in
terms of quantized 'shift operators' constructed mathematically from
the 'complementarity' of a remedy's primary and secondary symptoms.
Therefore, the vital force was studied as a 'wave function' able to
illustrate the biphasal action of remedies encapsulated in the Arndt-
Schulz law, Wilder's law of initial value and some of the results of
homeopathic provings.

   Rebound Effects and Paradoxical Pharmacology

Inverse drug effects are evident by changing their schedule or
treatment duration, or the observation period of the therapy: short
treatment can be stimulating, whereas longer treatment can be
inhibitory (or opposite, based on the experimental model). This area
includes the so-called 'paradoxical pharmacology' (56): chronic and
acute treatments produce opposite effects, similar to those of a
single physical exercise, which will increase blood pressure, whereas
ongoing training will regulate it. Obvious evidence of these phenomena
is observed in receptor-mediated events and in heart failure
progression: the time-course of ß-blocker treatment during heart
failure can be described as an immediate worsening of the patient,
whose condition then improves, with a net result of a decrease in
death by heart failure in the long term. This paradox can be described
in terms of beta-receptor protection from overexposure, which is a
phenomenon generally associated with desensitization and decreased
signaling.

In addition to analgesia, opioids cause hyperalgesic effects,
depending on whether treatment is acute or chronic, which have many
clinical implications (57). Antiepileptic drugs can frequently
aggravate epilepsy by way of an inverse pharmacodynamic effect (58).
The same secondary reaction of the organism can be described for
hundreds of modern drugs, including antiinflammatory agents (59), and
can be referred to as the rebound effect. The drug's primary effect
forces the organism toward a reaction against its own upsets by way of
a vital (paradoxical, secondary or compensating) reaction.

If acute and chronic responses are often opposite in nature, and if
the drug's counter-indications are based on its acute effects, it is
possible to find scientific input to study paradoxical pharmacology--
the list of drug contra-indications, since 'the opposite of
contraindicated is indicated ...' (56). A rapid initial decline may
produce long-term beneficial effects (60,61). Therefore, paradoxical
and rebound effects could be considered curative, thus allowing a
connection between homeopathic 'simile' and traditional pharmacology
(62).

   General Model of the 'Simile'

Having analyzed a few possible applications of the 'similarity' in
biological systems, we will now describe a general model of this core
principle of homeopathy. In previous studies (10,11,27,63), the
concept of 'regulation of stressed homeodynamic networks' was
introduced, based on how the networks react to stress, and on the
possible role of homeopathic self-recovery regulation. Here we
summarize and update this conceptual model, which can help rationalize
the basic mechanisms of homeopathic simile on different levels of
biological organization (molecular, cellular, organic and systemic).

Homeodynamics of Biological Systems

The concept of homeostasis (more correctly referred to as
'homeodynamics'), introduced by physiologist W. B. Cannon (64), refers
to those activities which tend to maintain the variables of a vital
system constant, or within acceptable limits. Hahnemann himself based
his medical system on the action and reaction principle. In paragraph
3 of the 'Organon', he describes this fundamental principle: 'Every
agent that acts upon vitality, every medicine, deranges more or less
the vital force, and causes a certain alteration in the health of the
individual for a longer or a shorter period. This is termed primary
action. To its action our vital force endeavours to oppose its own
energy. This resistant action is a property, it is indeed an automatic
action of our life-preserving power, which goes by the name of
secondary action or counteraction'.

The Feed-back is the Core of Homeodynamics

To illustrate homeodynamic concepts, it is best to refer to the simple
model in Fig. 5A. We will consider the variable A-A' in a state of
imbalance and in reversible conditions due to the actions of two
operator or effector mechanisms, which can move A towards A' and vice
versa. We refer to A as the normal condition and A' as a far-from-
equilibrium (stressed, or diseased) condition. No homeodynamic
variable can properly function without a form of control, represented
by one or more regulatory systems which receive information from A' in
the form of signal 'a', which is associated with its specific state
(for example, an enzyme reaction product proportional to how much of
A' is present or to how much of A' is functioning). Having received
the 'a' signals (for which it has specific receptors), the control
system is activated and produces the 'r' signal, which inhibits the A-
A' conversion, or activates the A'-A conversion. Figure 5A illustrates
that the signals are considered capable of affecting other systems or
other effector mechanisms, in the same way as the regulatory system
can have different receptors which bind different active signals.
Therefore, all homeodynamic systems are included in a broad network
built on multiple elements. The model in this figure is simplified; in
fact, it only shows the central feed-back structure of the complex
biological homeodynamics.

  Figure 5. Schematic description of the feedback in biological
systems (A), of normal homeodynamic reaction to stress and to
pathogenic factors (B) and of the effect of 'simile' signal on healthy
and sensitive systems (homeopathic 'proving') (C).

The Reaction Phase
When a perturbing factor comes into play, the balance shifts to
A' (Fig. 5B) and an increase of the 'a' signal occurs. The regulatory
system, in turn, enhances its own activity, thus producing a higher
quantity of the 'r' signal. For example, if 'a' is a signal molecule
(e.g. interleukin-1, cytokines, interferons) released from
inflammatory exudate, the immune system produces more 'r' signal (e.g.
antibodies, interleukin-2), thus bringing the effector system
(phagocytes or complement) back to its normal homeodynamic, by
eliminating A' excess and re-establishing A condition (healing). In
the initial phase of disease, the system reacts logically and
efficiently in the direction of balance and health. Of course, if 'a'
signal was an inhibitor, the A-A' perturbation would be followed by
decrease of regulatory system's function (not described in the
figure).

As shown in Fig. 5B, symptoms will appear when physiologic systems are
under stress, far from the equilibrium. Symptoms are associated with
endogenous regulatory system activation (or inhibition), more than
with the direct damage due to the stressor/pathogenic factor. In
infectious diseases, for example, fever, fatigue, loss of appetite,
tachycardia and skin rashes are the product of the organism's
reaction, primarily due to molecular signals, such as complement
factors, kinins, interleukin-6, adrenalin and TNF.

Generally speaking, the initial response of a regulatory system is
associated with the priming of its own sensitivity with respect to the
signal, represented in Fig. 5B as an increase in the number of surface
receptors within the system. This pre-activation was described by us
in leukocytes as 'homologous priming' (65) and may also involve
increase of receptor sensitivity or of signal transduction. However,
priming is usually not specific, owing to the increase of sensitivity
also to other stimuli (heterologous priming), here represented as the
exposure of new receptors by the regulatory system for substances
other than 'a'. This event is functional to adapting to new
environmental conditions and to reinforcing network communications.
For example, when a cell, such as a lymphocyte (a primary component of
host defenses), becomes stimulated by a cytokine or another specific
antigen, it becomes 'primed' to express a higher number of receptors
to more compounds. Other examples of priming are bronchial reactivity
in asthmatics following antigenic stimulation, liver induction of
detoxifying enzymes following alcohol or drug ingestion, cardiac
hypertrophy following physical exercise and increase of synaptic
strength in neurons (memory).

Homeopathic Proving

Figure 5C shows a schematic view of homeopathic proving: in a
'healthy' regulating system network, an exogenous pharmacological
signal could trigger many activities which mimic the reaction to
stress. In accordance with homeopathic principles, because most
symptoms derive from homeodynamic system activation, it should somehow
be possible to reproduce their activation with a compound capable of
provoking symptoms in healthy and sensitive subjects. Theoretically,
symptoms similar to natural reaction can be reproduced by
administering an activating (or inhibiting) substance through
homologous or heterologous receptors. The resulting pattern of
characteristic signs is the 'portrait' of a disease involving the same
regulatory systems in reaction to a natural stressor.

Homeopathic Regulation

The traditional approach of mainstream medicine is essentially
reductionistic and mechanistic--it is based on the identification and
elimination of pathogenic factors (for example, antibiotic therapy),
on the antagonism toward endogenous signals (such as anti-TNF
antibodies) or on inhibition of hyperactive control systems (such as
anti-inflammatory agents), or on their stimulation if assuming they
are inefficient (such as immunostimulatory agents) or, finally, on
substitutive therapies (such as insulin for diabetics or bone marrow
transplantation for severe immunodeficiency). This approach works in a
number of circumstances, but when homeodynamic loss is due to many
factors or to ambiguous causes, it becomes difficult to identify all
the specific biochemical blocks or the specific molecules that would
be required. For example, it is well documented that the psychological
profile or subtle functional disorders negatively impact long-term
health (40,66-68).

Taking into account its fundamental complexity, regulation can be
obtained through the similia principle, starting with a new and
holistic view of what constitutes the vital force and its possible
dynamic alterations. To quote Hahnemann (Organon, para 29) 'every
disease (not entirely surgical) consists only in a special, morbid,
dynamic alteration of our vital energy'. The 'dynamic alteration of
vital energy' can be translated in today's terms as both homeodynamic
and communication disorders. By reference to our basic model we should
distinguish two modes of action of the simile, the first one related
to acute diseases, the second one to chronic diseases.

Acute Diseases

An acute disease (Fig. 6A) occurs when an external pathogen damages
the organism, which in turn generates an excessive reaction, thus
causing more damage--classic examples include rhinoconjunctivitis,
abscess, thrombosis, panic attack, pneumonia, anaphylaxis, influenza
and shock. Apart from any necessary attempt to eliminate or at least
to reduce the pathogen, here the homeopathic intervention (Fig. 6B)
could assist in decreasing the risk of excessive reaction.

  Figure 6. Schematic representation of the acute disease (A) and of
the regulatory action of the homeopathic 'simile' (B).

This outcome could be obtained by using a remedy which, in healthy
subjects, mimics the actual symptoms of the disease which are produced
by the regulating system. In the diseased organism, which is already
activated by the disease, the effect of 'similar' medicine is not an
increase of symptoms, but, on the contrary, has the opposite effect as
previously described (e.g.: non-linearity, hormesis, initial value
rule). Consequently, the acute condition would continue its
physiological course toward healing without the risk of excessive
reactions and with fewer symptoms.
Other regulatory systems can become depressed in the course of acute
disease (not shown in the figure), causing, for example, fatigue,
anorexia, loss of concentration, etc. In such cases, the inversion of
effects of the 'simile' drug would be associated with the stimulation
of the affected regulatory systems.

Chronic Diseases

When the homeodynamic upset is continuous, following an initial
reactive phase, the regulatory system may undergo a significant change
of status--it will adapt to its altered conditions and will
progressively suppress its own sensitivity to the persistent and
stronger signal (Fig. 7A). The adaptation thus enables the system to
survive the disease in question, which would otherwise require an
excessive expenditure of energy (continual activation of regulatory
systems and of both the A-A' and A'-A mechanisms). This phase can be
considered the major factor of disease chronicization, as previously
described in the HPA axis (Fig. 3B). The homeodynamic displacement is
self-maintained by the suboptimal network response, through
desensitization of one or more regulatory systems.

  Figure 7. Schematic representation of the chronic disease (A) and
of the regulatory action of the homeopathic 'simile' (B).

From a molecular point of view, cells can down-regulate specific
receptors for 'a' to the point of complete elimination, or can reduce
their affinity, or diminish signal transduction to the effector
systems (in our case, the production of 'r'). This phenomenon is quite
specific on the receptor level--in other words, the occupied receptors
disappear, while others either persist or at least increase
quantitatively; desensitization tends to be agonist-specific. How
different receptors behave in cells exposed to a change of functional
state is clearly shown by our experiments comparing human neutrophils
isolated either from blood or from skin inflammatory exudate of the
same subjects (69). Inflammatory cells exhibited a respiratory burst
in response to fMLP and to substance P that was 2- to 3-fold higher
than the burst exhibited by blood cells (priming). On the contrary,
the response to other stimulants such as concanavalin A was not primed
and the response to TNF- was decreased in exudate versus blood cells
by about 50% (desensitization). Therefore, the inflammatory cells,
compared with blood cells, appear to be at the same time primed,
unmodified and desensitized, according to the different receptors
involved.
Because the regulatory system conserves other sensitivities in the
diseased state and, in all probability, also accentuates these
sensitivities (see heterologous priming), the system can be
reactivated. This is where we see the fundamental contribution of
homeopathic tradition--in chronic disease (Fig. 7B), the homeopathic
remedy, identified as the remedy which produces symptoms similar to
those of the disease (considering its overall course, including 'old'
symptoms and constitutional symptoms), would activate the regulatory
system through receptors and sensitivities other than those for 'a',
but which would produce the same outcome, by restoring the 'r' signal.
This phenomenon would activate the counterbalance mechanism A'-A. The
homeopathic drug is thus considered a functional substitute of 'a' to
which the system is no longer sensitive because it has adapted.

The homeopathic remedy will stimulate homeodynamic feedback by
latching onto perfectly efficient sensitivities that are not blocked
by the disease. By recalling the medicinal effects on the healthy
subjects (proving), one can assume that in the diseased subject these
medicines will assist in re-establishing the introduction of specific
information. With the stress factor removed, the network will find its
way (attractor) back to a healthy state.

   The Homeopathic 'Potencies'

The second major challenge of homeopathy is the use of ultra-low doses
(more precisely termed high dilutions, or high potencies according to
classic homeopathic parlance), i.e. those which contain virtually no
molecules of the active compound. Even if the present study is
committed to the similia principle, a brief mention of the theories
and evidence regarding how ultra-diluted homeopathic could act is
warranted. Two basic questions need to be answered:

Can a solvent, such as water or water-containing various percentages
of ethanol, incorporate and maintain some information from the
original solute?

Admitting that some pharmacological information is endowed by
homeopathic solutions, how could it be transmitted to the body and
have therapeutic effects?

Briefly, most of the findings converge on a non-molecular (or 'meta-
molecular') intelligence carried by solvent molecules (being water or
a water/alcohol mixture), which could interact within the organism by
way of resonance with biophysical regulatory systems (10,70-75).

The Physical Nature of the Remedy

Many studies have been conducted to offer an in-depth explanation of
the physiochemical nature of homeopathic drugs which have been highly
diluted. A number of experimental findings and physical theories
support the possibility that water and ethanol molecules, which are
typical solvents of homeopathic drugs, are somehow 'connected' in a
type of dynamic, self-organizing networks, described as 'water
clusters' (73,76-78). These physical states of the solvent could then
encode the information necessary to activate the biological processes,
possibly on the cell membrane level.

In the process of serial dilution and succussion, a homeopathic
solution could undergo an increase of its physical structure, similar
to geometrically grand and branched fractal images resulting from
iterative mathematical algorithm (10,79,80). Although today such a
hypothesis is strictly speculative, recent scientific evidence directs
us to study this elusive phenomenon. It is worth noting that
laboratory models of homeopathic dilutions show alternating activity
peaks (5,32). Homeopathic solutions, when compared with the control
solvent samples, show increased electrical conductivity (81,82),
distinct NMR signals (83), optical emissions (84) and characteristic
thermo-luminescent patterns when undergoing electromagnetic impulses
(85).

Furthermore, the concept of self-developing 'coherent domains' (CD) in
liquid crystals and water, has been proposed to follow the quantum
electrodynamic (QED) theories concerning condensed matter (86-89). The
theory rests on the different behavior between the macroscopical
assemblies of identical microscopical systems and classical
microscopic interaction due to weak forces; the differences are
exalted below the so-called critical temperature or above the
'critical' density. CDs are taking shape as the 'fundamental blocks'
for condensed matter: atoms, molecules, electrons and nuclei tune
inside blocks to a macroscopic (classical) electromagnetic field, thus
allowing the efficient frequency exchange between different system's
CDs. Some evidence suggests the effects of low-frequency
electromagnetic fields on water (90) and on biological structures
through changes in solvent structuring: microwave irradiated solutions
modify the opening capability of cell membrane ionic channels even if
irradiation stopped (91-93). The authors referred the phenomenon as
'electromagnetic memory of water'.

Sensitivity, Complexity and Resonance

According to the dynamic systems theory, the whole organism and each
cell can be described as complex systems where the 'equilibrium' is a
special case of attractor, the integration of a number of attractors
(94-99). As a consequence, healthy and pathological states become
interpretable as different types of attractors, which may be converted
from each other by bifurcations or critical perturbations. An
important characteristic of those attractors are their chaotic
dynamics, referred to as 'sensitive dependence on initial conditions
and on perturbations'. Small differences of the starting conditions or
perturbations of trajectories in the space-states produce important
differences in the final phenomena (100-102).

Future studies on fractals and deterministic chaos will influence
knowledge on physiology and pathology, enabling the characterization
of the therapeutic effects of periodic stimuli (including
physiological stress, acupuncture, electric pacing, psychotherapy and
so on), different pharmacological compounds (103) and highly diluted
homeopathic remedies (11,104-108). Very slight and highly specific
signals could act at unison with the resonant recipient system (s)
thus becoming 'regulators' of its (their) dysregulation and unbalance,
where the choice, at the bifurcation point, depends upon minor
fluctuations between order and chaos.

In this connection, the possible effect of ultra-diluted and succussed
medicines has a chance for a scientific explanation. The disease could
be regarded both as functional or molecular-structural abnormality and
as disturbance of the overall network of electromagnetic
communications: long-range interactions act between oscillating
elements (molecules, nerve centers, organs, to mention but a few),
whose frequencies are coherent and specific, in other words, resonant.
Therefore, disease is the disturbance of internal oscillators and
their communications. Thus, a homeopathic drug might be regarded as a
small quantity of matter in which phase oscillating elements could
coherently transmit oscillatory frequencies, via resonance, to both
oscillating and non-linear biological fluids or complex 'metastable'
structures (macromolecules, protein different conformations,
membranes, filamentous structures, receptors).

In synthesis, the homeopathic simile can be re-evaluated as a
heuristic (finding) principle, a principle of biological and clinical
research which assists in finding therapeutic strategies: in classic
homeopathy, the 'similars' are those compounds which generate symptoms
akin to those of the disease in all of its pathological, psychological
and physiological complexity. The administration of the remedy to a
sick organism would restore synchronism and cooperativity in cell
enzymes, metabolic cycles, molecular feed-back loops, bioelectric
potentials, with the consequence of higher cooperativity and more
efficient energy handling.

The two approaches to system regulation--scientific/reductionistic and
homeopathic/holistic--are not conflicting, but use different
approaches: mainstream pharmacology applies a 'structural' analog,
which is identified as the molecule binding to specific receptors or
enzymes of the target system (if known). Classic homeopathy applies a
'functional' analogue, which is identified as the diluted compound
that is able to regulate and/or to trigger homeodynamic systems. This
kind of functional analogy, based on the similarity of symptoms, can
be exploited even if the details of the receptors or the effector
enzymes are unknown within the complex homeodynamic networks.

Mainstream pharmacology is much more precise when the exact mechanism
of the disease is known, and specific drugs can therefore be
administered. Homeopathy could be more effective when considering the
complexity of the disease and subtle regulations. The homeopathic
approach may be useful specifically because it does not focus on the
cause of the disease, but on the teleonomy of the patient's reaction.
It is therefore not to be considered an alternative approach, but
complementary to effective drug use.

For example, some people frequently become infected (primarily upper-
respiratory infections) due to climatic change, cold weather, stress
or contact with an infected person (in schools or hospitals). It is
known that often there is no molecular or genetic explanation which
fully justifies such an increase of susceptibility to infection. It is
obvious that the immediate cause of the infection could be microbial,
but it is also true that the whole 'terrain' plays an important role.
Therefore, a more logical and effective approach is one where the
focus is placed on complex response stimulation, a homeopathic
cornerstone (6,7).

  Footnotes

For reprints and all correspondence: Prof. Paolo Bellavite, Department
of Scienze Morfologico-Biomediche, University of Verona, Piazza L. A.
Scuro, 37134 Verona, Italy. Tel: +39 045 8202978; Fax: +39 045 820
2978; E-mail: paolo.bellavite@univr.it

   References

Hahnemann CFS. Versuch über ein neues Princip zur Auffindung der
Heilkrafte der Arzneisubstanzen (Essay on a new principle for
ascertaining the curative powers of drugs). Hufeland's J ( 1796;) 2::
391-439.
Boyd LJ. A Study of the Simile in Medicine ( 1936;) Philadelphia:
Boericke and Tafel.
Bellavite P, Conforti A, Piasere V, Ortolani R. Immunology and
homeopathy. 1. Historical background. Evid Based Complement Alternat
Med ( 2005;) 2:: 441-52.[Abstract/Free Full Text]
Bellavite P, Conforti A, Pontarollo F, Ortolani R. Immunology and
homeopathy. 2. Cells of the immune system and inflammation. Evid Based
Complement Alternat Med ( 2006;) 3:: 13-24.[Abstract/Free Full Text]
Bellavite P, Conforti A, Ortolani R. Immunology and homeopathy. 3.
Experimental studies on animal models. Evid Based Complement Alternat
Med ( 2006;) 3:: 171-86.[Abstract/Free Full Text]
Bellavite P, Ortolani R, Pontarollo F, Piasere V, Benato G, Conforti
A. Immunology and homeopathy. 4. Clinical studies - part 1. Evid Based
Complement Alternat Med ( 2006;) 3:: 293-301.[Abstract/Free Full Text]
Bellavite P, Ortolani R, Pontarollo F, Piasere V, Benato G, Conforti
A. Immunology and homeopathy. 4. Clinical studies - part 2. Evid.
Based. Complement Alternat. Med ( 2006;) 3:: 397-409.[Abstract/Free
Full Text]
Kleijnen J, Knipschild P, ter Riet G. Clinical trials of homoeopathy.
Br Med J ( 1991;) 302:: 316-23.[ISI][Medline]
Bellavite P, Signorini A. Physiopathological models of the similia
principle. ( 1996;) Proceedings of the 51st L. M. H. I. International
Congress Capri, 2-6 October 1996. 98-106.
Bellavite P, Signorini A. The Emerging Science of Homeopathy ( 2002;)
Berkeley (CA): North Atlantic.
Bellavite P. Complexity science and homeopathy. A synthetic overview.
Homeopathy ( 2003;) 92:: 203-12.[CrossRef][Medline]
Townsend JF, Luckey TD. Hormoligosis in pharmacology. J Am Med a.s
( 1960;) 173:: 44-8.[ISI][Medline]
Sagan LA. On radiation, paradigms and hormesis. Science ( 1989;) 245::
574.[Free Full Text]
Macklis RM, Beresford B. Radiation hormesis. J Nucl Med ( 1991;) 32::
350-9.[Abstract/Free Full Text]
Von Zglinicki T, Edwall C, Ostlund E, Lind B, Nordberg M, Ringertz NR,
et al. Very low cadmium concentrations stimulate DNA synthesis cell
growth. J Cell Sci ( 1992;) 103:: 1073-81.[Abstract/Free Full Text]
Stebbing AR. A theory for growth hormesis. Mutat Res ( 1998;) 403::
249-58.[ISI][Medline]
Olivieri G. Adaptive response and its relationship to hormesis and low
dose cancer risk estimation. Hum Exp Toxicol ( 1999;) 18:: 440-2.[Free
Full Text]
Calabrese EJ, Baldwin LA. Hormesis as a biological hypothesis. Environ
Health Perspect ( 1998;) 106:(Suppl 1): 357-62.[CrossRef][ISI]
[Medline]
Renn O. Implications of the hormesis hypothesis for risk perception
and communication. Hum Exp Toxicol ( 1998;) 17:: 431-8.[Free Full
Text]
Rozman KK, Doull J. Scientific foundations of hormesis. Part 2.
Maturation, strengths, limitations, and possible applications in
toxicology, pharmacology, and epidemiology. Crit Rev Toxicol ( 2003;)
33:: 451-62.[ISI][Medline]
Schulz H. Uber die Theorie der Arzneimittelwirkung. Virchow's Archiv
( 1877;) 108:: 423-34.
Schulz H. Uber Hefegifte. Arch Fuer Physiol ( 1888;) 42:: 517-41.
[CrossRef]
Martius F. Das Arndt-Schulz Grundgesetz. Muench Med Wschr ( 1923;)
70:: 1005-6.
Heine H, Schmolz M. Immunoregulation via 'bystander suppression' needs
minute amounts of substances - a basis for homeopathic therapy? Med
Hypotheses ( 2000;) 54:: 392-3.[CrossRef][ISI][Medline]
Calabrese EJ, Baldwin LA. The marginalization of hormesis. Hum Exp
Toxicol ( 2000;) 19:: 32-40.[Abstract/Free Full Text]
Bellavite P, Chirumbolo S, Santonastaso C, Biasi D, Lussignoli S,
Andrioli G. Dose-dependence of the various functional responses of
neutrophils to formylpeptides. Activation, regulation, and inverse
effects according to the agonist dose and cell condition. In: Signals
and Images --Bastide M, ed. ( 1997;) Dordrecht: Kluwer Academic
Publishers. 111-9.
Bellavite P, Lussignoli S, Semizzi M, Ortolani R, Signorini A. The
similia principle. From cellular models to regulation of homeostasis.
Brit Hom J ( 1997;) 86:: 73-85.[CrossRef]
Bellavite P, Chirumbolo S, Lippi G, Andrioli G, Bonazzi L, Ferro I.
Dual effects of formylpeptides on the adhesion of endotoxin-primed
human neutrophils. Cell Biochem Funct ( 1993;) 11:: 231-9.[CrossRef]
[ISI][Medline]
Bellavite P, Carletto A, Biasi D, Caramaschi P, Poli F, Suttora F, et
al. Studies of skin-window exudate human neutrophils: complex patterns
of adherence to serum-coated surfaces in dependence on FMLP doses.
Inflammation ( 1994;) 18:: 575-87.[CrossRef][ISI][Medline]
Dennig D, Mecheri S, Bourhis JH, Hoffman MK. Interleukin-2 may enhance
or inhibit antibody production by B cells depending on intracellular
cAMP concentration. Immunology ( 1992;) 77:: 251-5.[ISI][Medline]
Masini E, Blandina P, Brunelleschi S, Mannaioni PF. Evidence for H2-
receptor-mediated inhibition of histamine release from isolated rat
mast cells. Agents Actions ( 1982;) 12:: 85-8.[CrossRef][ISI][Medline]
Belon P, Cumps J, Ennis M, Mannaioni P, Roberfroid M, Sainte-Laudy J,
et al. Histamine dilutions modulate basophil activation. Inflamm Res
( 2004;) 53:: 181-8.[CrossRef][ISI][Medline]
Widakowich J. Pharmacodynamic principles of homeopathy. Med Hypotheses
( 2000;) 54:: 721-2.[CrossRef][ISI][Medline]
Oberbaum M, Cambar J. Hormesis: dose-dependent reverse effects of low
and very low doses. In: Ultra High Dilution --Endler PC, Schulte J,
eds. ( 1994;) Dordrecht: Kluwer Academic Publishers. 5-18.
Van Wijk R, Wiegant FA. The similia principle as a therapeutic
strategy: a research program on stimulation of self-defense in
disordered mammalian cells. Altern Ther Health Med ( 1997;) 3:: 33-8.
[Medline]
Van Wijk R, Wiegant FAC, Souren JEM, Ovelgonne JH, van Aken JM, Bol
AWJM. A molecular basis for understanding the benefits from subharmful
doses of toxicants. Biomed Ther ( 1997;) 15:: 4-13.
Wiegant FA, Souren JEM, Van Wijk R. Stimulation of survival capacity
in heat shocked cells by subsequent exposure to minute amounts of
chemical stressors; role of similarity in hsp-inducing effects. Hum
Exp Toxicol ( 1999;) 18:: 460-70.[Abstract/Free Full Text]
Chattopadhyay S. Proposition of a new system of medicine based on
tolerance principle. Med Hypotheses ( 2002;) 59:: 191-203.[CrossRef]
[ISI][Medline]
Bernardini S, Dei A. Hormesis may provide a central concept for
homeopathy development. Toxicol Appl Pharmacol ( 2006;) 211:: 84.
[CrossRef][ISI][Medline]
Solomon GF. Stress, hormones, immunity, the complexity of interwined
systems, and the simplicity of humanism. J Intensive Care Med ( 1997;)
12:: 219-22.[ISI]
Cohen S, Tyrrel DAJ, Smith AP. Psychological stress and the
susceptibility to the common cold. New Engl J Med ( 1991;) 325:: 606-
12.[Abstract]
Ader R, Cohen N, Felten D. Psychoneuroimmunology: interactions between
the nervous system and the immune system. Lancet ( 1995;) 345:: 99-103.
[CrossRef][ISI][Medline]
Leonard BE. The HPA and immune axes in stress: the involvement of the
serotonergic system. Eur Psychiatry ( 2005;) 20:: S302-6.[CrossRef]
[ISI][Medline]
Hyland ME, Lewith GT. Oscillatory effects in a homeopathic clinical
trial: an explanation using complexity theory, and implications for
clinical practice. Brit Hom J ( 2002;) 91:: 145-9.
Guajardo G, Bellavite P, Wynn S, Searcy R, Fernandez R, Kayne S.
Homeopathic terminology: a consensus quest. Brit Hom J ( 1999;) 88::
135-41.[CrossRef]
Bellavite P, Pettigrew A. Miasms and modern pathology. Homeopathy
( 2004;) 93:: 65-6.[CrossRef][Medline]
Milgrom LR. Patient-practitioner-remedy (PPR) entanglement. Part 6.
Miasms revisited: non-linear quantum theory as a model for the
homeopathic process. Homeopathy ( 2004;) 93:: 154-8.[CrossRef]
[Medline]
Bousta D, Soulimani R, Jarmouni I, Belon P, Falla J, Foment N, et al.
Neurotropic, immunological and gastric effects of low doses of Atropa
belladonna L. Gelsemium sempervirens L. and Poumon histamine in
stressed mice. J Ethnopharmacol ( 2001;) 74:: 205-15.[CrossRef][ISI]
[Medline]
Ruiz-Vega G, Poitevin B, Perez-Ordaz L. Histamine at high dilution
reduces spectral density in delta band in sleeping rats. Homeopathy
( 2005;) 94:: 86-91.[CrossRef][Medline]
Adams DO, Hamilton TA. Macrophages as destructive cells in host
defense. In: Inflammation --Gallin JI, ed. ( 1992;) 2nd. New York:
Raven Press. 637-62.
Wilder J. Das 'Ausgangswert-Gesetz', ein unbeachtes biologisches
Gesetz und seine Bedeutung fur Forschung und Praxis. Zeit d Gesamte
Neur u Psych ( 1931;) 137:: 317.
Wilder J. Stimulus and Response: The Law Of Initial Value ( 1967;)
Bristol: Wright.
Eskinazi D. Homeopathy re-revisited: is homeopathy compatible with
biomedical observations? Arch Intern Med ( 1999;) 159:: 1981-7.[Free
Full Text]
Teixeira MZ. Similitude in modern pharmacology. Brit Hom J ( 1999;)
88:: 112-20.[CrossRef]
Milgrom LR. Patient-Practitioner-Remedy (PPR) entanglement, Part 7: a
gyroscopic metaphor for the vital force and its use to illustrate some
of the empirical laws of homeopathy. Forsch Komplementarmed Klass
Naturheilkd ( 2004;) 11:: 212-23.[CrossRef][Medline]
Bond RA. Is paradoxical pharmacology a strategy worth pursuing? Trends
Pharmacol Sci ( 2001;) 22:: 273-6.[CrossRef][Medline]
Xu XJ, Colpaert F, Wiesenfeld-Hallin Z. Paradoxical opioid
hyperalgesia and inverse tolerance. Trends Pharmacol Sci ( 2003;) 24::
634-9.[CrossRef][Medline]
Genton P. When antiepileptic drugs aggravate epilepsy. Brain Dev
( 2000;) 22:: 75-80.[CrossRef][ISI][Medline]
Doux JD, Bazar KA, Lee PY, Yun AJ. Can chronic use of anti-
inflammatory agents paradoxically promote chronic inflammation through
compensatory host response? Med Hypotheses ( 2005;) 65:: 389-91.
[CrossRef][ISI][Medline]
Yun AJ, Lee PY, Bazar KA. Paradoxical strategy for treating chronic
diseases where the therapeutic effect is derived from compensatory
response rather than drug effect. Med Hypotheses ( 2005;) 64:: 1050-9.
[CrossRef][ISI][Medline]
Yun AJ. The intellectual lineage of paradoxical pharmacology strategy.
Med Hypotheses ( 2005;) 65:: 815.[Medline]
Teixeira MZ. Homeopathic use of modern medicines: utilisation of the
curative rebound effect. Med Hypotheses ( 2003;) 60:: 276-83.[CrossRef]
[ISI][Medline]
Bellavite P, Andrioli G, Lussignoli S, Signorini A, Ortolani R,
Conforti A. Scientific reappraisal of the 'Principle of Similarity'.
Med Hypotheses ( 1997;) 49:: 203-12.[CrossRef][ISI][Medline]
Cannon WB. Stresses and strains of homeostasis. Am J Med Sci ( 1935;)
1-14.
Bellavite P, Chirumbolo S, Lippi G, Guzzo P, Santonastaso C.
Homologous priming in chemotactic peptide-stimulated neutrophils. Cell
Biochem Funct ( 1993;) 11:: 93-100.[CrossRef][ISI][Medline]
Stroebel CF. Somatization and alexithymia as aspects of mind-body
intelligence. Advances-J. Body-Mind Health ( 1998;) 14:: 113-7.
[Medline]
Denollet J. Type D personality. A potential risk factor refined. J
Psychosom Res ( 2000;) 49:: 255-66.[CrossRef][ISI][Medline]
Duncko R, Makatsori A, Fickova E, Selko D, Jezova D. Altered
coordination of the neuroendocrine response during psychosocial stress
in subjects with high trait anxiety. Prog ( 2006;) 30:: 1058-66.
Biasi D, Bambara LM, Carletto A, Caraffi M, Serra MC, Chirumbolo S, et
al. Factor-specific changes of the oxidative metabolism of exudate
human neutrophils. Inflammation ( 1993;) 17:: 13-23.[CrossRef][ISI]
[Medline]
Bastide M. Information and communication in living organisms. In:
Fundamental Research in Ultra High Dilution and Homeopathy --Schulte J,
Endler PC, eds. ( 1998;) Dordrecht: Kluwer Academic Publishers. 229-
39.
Schulte J. Effects of potentization in aqueous solutions. Brit Hom J
( 1999;) 88:: 155-60.[CrossRef]
Endler PC, Schulte J. Homoopathie und Bioresonanztherapie. In. In:
Physiologiche und Physikalische Voraussetzungen Grundlagenforchung
( 1997;) Wien: Medizinverlag Maudrich.
Smith CW. Quanta and coherence effects in water and living systems. J
Altern Complement Med ( 2004;) 10:: 69-78.[CrossRef][ISI][Medline]
Bonamin LV. Experimental illustrations of body signifiers theory. In:
Les Médecines Non-conventionelles: une nouvelle approche de la santé --
Halm RP, ed. ( 2005;) Monaco: Les Entretiens Internationaux. 195-207.
Tschulakow AV, Yan Y, Klimek W. A new approach to the memory of water.
Homeopathy ( 2005;) 94:: 241-7.[CrossRef][Medline]
Anagnostatos GS. Small water clusters clathrates in the preparation
process of homoeopathy. In: Ultra High Dilution --Endler PC, Schulte J,
eds. ( 1994;) Dordrecht: Kluwer Acadermic Publishsers. 121-8.
Sukul NC, Sukul A. High Dilution Effects: Physical and Biochemical
Basis ( 2003;) Dordrecht: Kluwer.
Roy R, Tiller W, Bell IR, Hoover MR. The structure of liquid water.
Novel insights from materials research; potential relevance to
homeopathy. Mat Res Innovat ( 2005;) 9:: 98-103.
Garner C, Hock N. Chaos theory and homoeopathy. Berlin J Res Hom
( 1991;) 1:: 236-42.
Shepperd J. Chaos theory: implications for homeopathy. J Am Inst
Homeopathy ( 1994;) 87:: 22-9.
Elia V, Napoli E, Niccoli M, Nonatelli L, Ramaglia A, Ventimiglia E.
New physico-chemical properties of extremely diluted aqueous
solutions. A calorimetric and conductivity study at 25°C. J Thermal
Anal Calorim ( 2004;) 78:: 331-42.[CrossRef]
Elia V, Niccoli M. New physico-chemical properties of extremely
diluted aqueous solutions. J Thermal Anal Calorim ( 2004;) 75:: 815-36.
[CrossRef]
Demangeat JL, Gries P, Poitevin B, Droesbeke JJ, Zahaf T, Maton F, et
al. Low-field NMR water proton longitudinal relaxation in ultrahighly
diluted aqueous solutions of silica-lactose prepared in glass material
for pharmaceutical use. Appl Magn Reson ( 2004;) 26:: 465-81.
Bell IR, Lewis DA, Brooks AJ, Lewis SE, Schwartz GE. Gas discharge
visualization evaluation of ultramolecular doses of homeopathic
medicines under blinded, controlled conditions. J Altern Complement
Med ( 2003;) 9:: 25-38.[CrossRef][ISI][Medline]
Rey LR. Thermoluminescence of ultra-high dilutions of lithium chloride
and sodium chloride. Physica ( 2003;) A323:: 67-74.[CrossRef]
Preparata G. Quantum Electrodynamic Coherence in Matter ( 1995;)
Singapore: World Scientific.
Preparata G. Regimi coerenti in Fisica e Biologia. Il problema della
forma. Biology Forum. Biologv Forum ( 1997;) 90:: 434-6.
Del Giudice E, Preparata G. Coherence electrodynamics in water. In:
Fundamental Research in Ultrahigh Dilution and Homeopathy --Schulte J,
Endler C, eds. ( 1998;) Dordrecht: Kluwer. 89-100.
Ho MW, Popp FA, Warnke U. Bioelectrodynamics and Biocommunication
( 1994;) Singapore: World Scientific.
Vallee P, Lafait J, Mentre P, Monod MO, Thomas Y. Effects of pulsed
low frequency electromagnetic fields on water using photoluminescence
spectroscopy: role of bubble/water interface. J Chem Phys ( 2005;)
122:: 114513.[CrossRef][Medline]
Fesenko EE, Gluvstein AY. Changes in the state of water, induced by
radiofrequency electromagnetic fields. FEBS Lett ( 1995;) 367:: 53-5.
[CrossRef][ISI][Medline]
Fesenko EE, Geletyuk VI, Kazachenko VN, Chemeris NK. Preliminary
microwave irradiation of water solutions changes their channel-
modifying activity. FEBS Lett ( 1995;) 366:: 49-52.[CrossRef][ISI]
[Medline]
Fesenko EE, Popov VI, Novikov VV, Khutsian SS. Water structure
formation by weak magnetic fields and xenon. Electron microscopic
analysis. Biofizika ( 2002;) 47:: 389-94.[Medline]
Elbert T, Ray WJ, Kowalik ZJ, Skinner JE, Graf KE, Birbaumer N. Chaos
and physiology: deterministic chaos in excitable cell assemblies.
Physiol Rev ( 1994;) 74:: 1-47.[Abstract/Free Full Text]
Bellavite P. Disease as information disorder. Advances-J. Body-Mind
Health ( 1997;) 13:: 4-7.
Bellavite P, Semizzi M, Lussignoli S, Andrioli G, Bartocci U. A
computer model of the five elements theory of traditional Chinese
medicine. Complem Ther Med ( 1998;) 6:: 133-40.[Medline]
Callard R, George AJ, Stark J. Cytokines, chaos, and complexity.
Immunity ( 1999;) 11:: 507-13.[ISI][Medline]
Mainzer K. Thinking in Complexity. In. In: The Complex Dynamics of
Matter, Mind, and Mankind ( 1994;) Berlin-Heidelberg: Springer-Verlag.
Holland JH. Emergence. From Chaos to Order ( 2000;) Reading (MA):
Addison-Wesley.
Shinbrot T, Grebogi C, Ott E, Yorke JA. Using small perturbations to
control chaos. Nature ( 1993;) 363:: 411-7.[CrossRef]
Garfinkel A, Spano ML, Ditto WL, Weiss JN. Controlling cardiac chaos.
Science ( 1992;) 257:: 1230-5.[Abstract/Free Full Text]
Germain RN. The art of probable: system control in the adaptive immune
system. Science ( 2001;) 293:: 240-5.[Abstract/Free Full Text]
van Rossum JM, de Bie JEGM. Chaos and illusion. Trends Pharmacol Sci
( 1991;) 12:: 379-83.[CrossRef][Medline]
Ruiz G, Torres JL, Michel O, Navarro R. Homeopathic effect on heart
rate variability. Brit Hom J ( 1999;) 88:: 106-11.[CrossRef]
Torres JL, Ruiz G. Stochastic resonance and the homoeopathic effect.
Brit Hom J ( 1996;) 85:: 134-40.[CrossRef]
Schwartz GE, Russek LG, Bell IR, Riley D. Plausibility of homeopathy
and conventional chemical therapy: the systemic memory resonance
hypothesis. Med Hypotheses ( 2000;) 54:: 634-7.[CrossRef][ISI]
[Medline]
Bell IR, Baldwin CM, Schwartz GE. Translating a nonlinear systems
theory model for homeopathy into empirical tests. Altern Ther Health
Med ( 2002;) 8:: 58-66.[ISI][Medline]
Bell IR, Koithan M, Gorman MM, Baldwin CM. Homeopathic practitioner
views of changes in patients undergoing constitutional treatment for
chronic disease. J Altern Complement Med ( 2003;) 9:: 39-50.[CrossRef]
[ISI][Medline]
Received July 3, 2006; accepted January 4, 2007

This article has been cited by other articles:

A. Hielm-Bjorkman, R.-M. Tulamo, H. Salonen, and M. Raekallio
Evaluating Complementary Therapies for Canine Osteoarthritis Part II:
A Homeopathic Combination Preparation (Zeel(R))
Evid. Based Complement. Altern. Med., October 29, 2007; (2007)
nem143v2.
[Abstract] [Full Text] [PDF]

Online ISSN 1741-4288 - Print ISSN 1741-427X Copyright (c) 2005 Oxford
Journals Oxford University Press