How can Cont®aFlu work?
How can Cont®aFlu modulate the TLR3?
There is no brief and at the same time correct answer to this question. Similar is true for the actual mechanisms underlying the effects of any other existing medication, especially one based on a small molecule.That’s why, for those who is really interested in reply, below is description of important context.
Problems of today’s pharmacology: a brief summary
Medications are designed to interfere with the body’s regulation and “correct” it to obtain the desired result. In other words, medications are used to control regulation in a living system, even more briefly – to control a living system.
To control a living system, one needs an adequate concept of what mechanisms, what “programming language” the system itself uses.
Does today’s pharmacology have such a concept? At the level of a model? At the level of practical solutions (effective and safe treatment for diseases)? – Alas, the answer is negative.
Below is an incomplete list of supporting facts (details and references are available on demand).
Over the last few decades pharmacology has failed in providing cardinal solutions (breakthrough treatments) for all the major chronic diseases.
Even the most effective solutions: a) only give a temporary relief; b) help only a part of patients; c) have to be taken lifelong.
The real costs the largest pharmaceutical companies spend to bring a new product from idea to the market have exceeded $ 2 billion.
Development of new medications for the most important ACUTE diseases (primarily, bacterial and virus infections) has actually been suspended due to their too low profitability.
Drug side effects have entered the list of top causes of mortality in developed economies.
What might be the reason for such a miserable situation with effectiveness and safety of today’s medicines? Insufficient finances spent on drug development? PRINCIPAL insolubility of the task of controlling a living system? Or an INADEQUATE MODEL of regulation in living systems that today’s pharmacology uses?
What is the model of regulation in the body that today’s pharmacology applies in development of new medications? This model can be expressed as a list of the following points (summarized according to a review in British Journal of Pharmacology):
The whole regulation in the body is mediated only by molecular (chemical) interactions - chemical signals. Regulation of any physiological process involves a stage of binding a signal molecule (ligand) to a specific receptor.
In any disease, an underlying impairment of chemical signaling can be revealed: it can be either down-regulated or up-regulated.
Development of any disease can be influenced by stimulation of the corresponding chemical signal, if the signal is down-regulated, or by suppression of the signal, if it is up-regulated. For this purpose, a chemical stimulator (agonist) or blocker (antagonist) of the corresponding receptor should be introduced.
The described model logically implies that if a substantial dose of a chemical or biological agent, an agonist or antagonist of some receptor, is not introduced in the body, it is impossible to influence regulation changed due to a disease.
Inadequacy of this model results in the following serious technical limitations for development of new drugs that today’s pharmacology is facing:
Many promising drug targets are located inside the cell.
Small molecule products can reach the intracellular targets, but their binding specificity is limited, hence high probability of off-target effects, including adverse effects.
Large molecule products (antibodies, etc.) provide high specificity, however, they usually cannot reach targets inside the cell.
In a disease, most of molecular systems rather require modulation, whereas standard pharmacological instruments offer either inhibition (more often) or stimulation. Hence a narrow therapeutic window of pharmaceuticals and, more importantly, inability to provide a complete and stable therapeutic effect.
The mechanisms underlying chronic diseases involve dysregulation of multiple molecular systems – that is, requires use of multiple pharmaceuticals; on the other hand, polypharmacy reduces predictability and safety of the treatment.
Calls to development of individualized medications are held back by very high cost of new drug development without any warranty that it will provide a stable therapeutic effect.
What innovation do Cont®aFlu authors propose?
We use a fundamentally different model of regulation in the body – and, correspondingly, fundamentally different tools to control this regulation.
Our model is based on two key theories: 1) Theory of functional systems (Pyotr Anokhin, USSR), and
2) Perceptual Control Theory (William Powers, USA).
Brief description of the model:
Human body is a hierarchy of multiple nested and closely associated functional systems (FS).
Activity of each FS is organized around a goal provided by a FS of a higher hierarchy.
The goal of a particular FS is maintenance of a specific controlled internal or external variable (parameter) within limits set by the “higher” FS. The limits are set through tuning the FS with a special reference signal provided by the “higher” FS.
The FS perceives the current value of the controlled variable, compares it with the reference signal, and in case of difference employs all the available means (primarily, nested subordinate FSs) to bring the controlled variable to the reference value.
To work effectively, the FS uses the following key mechanism: Synchronization (harmonization) across different elements of the FS through biophysical communications based on resonance interactions. Chemical signals as slower and more energy-consuming rather play the role of “documenting” and “long-term archiving” of the interactions mediated by biophysical signals.
From theory to development of Cont®aFlu
One of Cont®aFlu inventors (A.Martyushev-Poklad) took an active part in development of new medications for the Russian market. These studies revealed that the reference signals regulating molecular functional systems can be reproduced artificially, with the use of antibodies. In particular, this was found for angiotensin II receptor, for endothelial NO synthase (product sold under brand name Impaza), for interferon gamma (product sold under brand name Anaferon), TNF alpha, etc.
Antibodies to a particular fragment of the target molecular FS after exposure to special technological processing turn into the source of highly specific reference signal. Such a reference signal carries information on the optimum mode of functioning for this molecular system. If the mechanisms underlying a particular disease involve impaired activity of the given molecular FS, then introduction of the reference signal (as an oral dosage form of antibodies) results in correction of the molecular FS towards the optimum state.
Such a pharmacological activity is most close to MODULATION: insufficient baseline activity of the molecular FS is up-regulated, while excessive baseline activity is down-regulated. The dependence of Cont®aFlu effect on baseline activity of the molecular FS was proven in a placebo-controlled clinical trial.
Brief review of the role TLR3 plays in influenza and other viral infections
1) This is one of the key receptors in innate immunity responsible for detection of actively replicating virus in the cell and in the body in general (double strand RNA).
2) Its activation launches two lines of events: rapid suppression of virus replication (through induction of interferons) + induction of adaptive immune response.
3) Over the first 5 days from disease onset, the severity of influenza symptoms is determined by the adequacy of innate host response
4) Excessive activation of TLR3 mediates severe forms of influenza; however, complete TLR3 inhibition blocks virus clearance from the body – that is, TLR3 needs modulation.
Findings of Cont®aFlu development
1) Oral Cont®aFlu formulation used in a mouse model of moderate influenza reduced severity and duration of clinical infection.
2) In patients with very mild and mild forms of common cold Cont®aFlu increased duration and severity of the symptoms.
3) In patients with moderate to severe forms of common cold Cont®aFlu reduced duration and severity of the symptoms.
Since the starting substance of Cont®aFlu is highly specific to a small peptide fragment of TLR3 cytoplasmic domain, the above effects can only be attributed to MODULATION of TLR3.
The discovery of the exact MOLECULAR MECHANISM of TLR3 modulation by Cont®aFlu is impeded by certain technical and financial hurdles. This task lies outside the scope of drug development and registration.
There is also an ideological prejudice in a major part of expert community that considers the model of “chemical regulation” as the doubtless axiom, whereas it is only a model.
This psychological barrier can be overcome with systemic approach to the human body as a living system, and not an aggregate of chemical systems.