Original article:

Released-activity is a term that describes new physico-chemical and biological properties differing from those of the original substance during the preparation process of ultrahigh dilutions (UHD) of various substances. In practical terms, the ability of UHD substances to exert a modifying effect on the initial substance is of the greatest interest.

Traditionally, high dilutions of biologically active substances are studied by biologists and doctors. For a long time, UHD was a little-studied subject, almost isolated from modern research methods. The first rational studies of UHD date back to the 1970s and 1980s. In Russia, UHD have been studied by a number of eminent scientists. For example, Academician I.P. Ashmarin and Prof. E.B. Burlakova, who showed that UHDs of various biologically active substances can elicit an aphysiological response at the molecular level [Ashmarin et al., 1999; Ashmarin et al., 2005; Burlakova, 2003]. Prof. Burlakova noted that UHD reproduce only part of the full spectrum of the biological effects of the initial substance [Burlakova, 2003].

However, subsequent work on UHD has not been supported by pharmacologists, for which there may be two reasons. Firstly, in an era of rapid successes in molecular biology, medicine simply did not need new approaches. Secondly, scientists were held back by prejudice towards homeopathy, which has used UHD for individual therapy since the 18th century in order to minimise the severity of undesirable effects.

Homeopathy is based on the empirically discovered ability of UHD to cause weakened symptoms of intoxication by the original substance if patients have a high innate sensitivity to this substance. UHD are selected for each patient according to a complex technique that takes into account their phenotypic features or 'markers' in order to enhance the physiological action of the drug. Similar effects are classified in immunology as hypersensitivity reactions. In other words, in homeopathy it is not a physiological but an atypical response to the administration of UHD. If the patient does not have sensitivity to the prescribed drug, the physiological effect it causes is insufficient to provide a therapeutic effect.

As I have noted on many occasions it is extremely difficult, if not impossible, to conduct randomised, placebo-controlled clinical trials on the effectiveness of UHDs among the entire population of patients with a particular disease in accordance with homeopathic doctrine. [Walach H. et al., 1997; Vithoulkas G., 2017]. Therefore, homeopathy cannot be part of evidence-based medicine a priori. Homeopathy is an alternative individual therapy in its ideology and it is precisely as an individual therapy that homeopathy is unrivalled. The homeopathic approach allows one to eliminate various non-life-threatening psychosomatic symptoms when the possibilities of other methods have been exhausted. It is in this that I see the secret of homeopathy's longevity. Homeopathy should not oppose modern medicine, but complement it.

At the same time, the UHD preparation technology itself opens up new possibilities for both modern evidence-based medicine and other fields of science.

Despite the fact that homeopathy has been known for a long time, the properties of UHD, as well as the process of their preparation, have barely been studied within the field to which they actually belong – physics.
On 12^th December 2018, the first public discussion of this subject in our country by physicists took place as part of the Physics of Aqueous Solutions conference, held at the Russian Academy of Sciences Prokhorov General Physics Institute under the chairmanship of I.A. Shcherbakova, Academician-Secretary of the Russian Academy of Sciences Physical Sciences Division. During the scientific discussion, as noted by the press, an 'unspoken taboo' was broken in respect of studying UHDs. [Conference of Russian Academy of Sciences Physicists remove unspoken taboo from high dilutions. Komsomolskaya Pravda, 14^th December 2018].

It is well known that the physics of solutions is a difficult field of research which has had mixed results, since many processes in water are non-linear in nature. It was noted at the conference that the main solvent, water, is a poorly studied substance containing nanoinhomogeneities, and has a large number of rapidly changing characteristics and state transitions: “... the presence of nano-objects in a medium that was previously considered homogeneous can significantly affect the properties of solutions, including their chemical and biological activity ...».

Therefore, one cannot apply a simple mathematical calculation of molarity based on the Avogadro number in relation to such a complex system as the water used as a solvent in the preparation of UHD. Thus, some scientists have shown that the initial substance can be stored in the UHD and have suggested it is possible that the mechanisms of this phenomenon are physical. For example, as Chikramane writes in the American Chemical Society's journal Langmuir: "...physicochemical studies of these solutions have unequivocally established the presence of the initial material in nanoparticulate form, even in these extreme (super-Avogadro, >10²³) dilutions. In this article, we propose and confirm a hypothesis to explain how nanoparticles are retained even at such enormous dilution levels.” [Chikramane P.S. et al., 2012].

My twenty-five years of experience in experimental and clinical studies of UHDs has allowed me to form my own view of the UHD problem [Epstein, 2008; Epstein, 2013; Epstein, 2017; Epstein O., 2018]. The most unexpected and even paradoxical conclusion that I have come to is that UHDs are not in fact dilutions, but should be considered products of technological processing that acquire new properties in the process of their preparation.

What appears to be an extremely simple procedure of sequential repeated dilution is, in fact, a complex technological process from a physical point of view. In any method of preparing UHDs, whether manual or automated, including using a flow microchannel system, a decrease in concentration is accompanied by an external effect, which leads to a change in the characteristics of the complex 'water-soluble substance' system.

The key role of technology is underlined by the fact that the initial ordinary purified water, when subjected to the technological processing of multiple sequential dilutions with the same purified water in combination with external influences, differs from the initial 'intact' water in a number of electrochemical, optical and mechanical properties, as well as in its chemical reaction behaviour. The change in the properties of aqueous solutions under the influence of external effects has long been known. The modification of a liquid's physical characteristics by external effects was known as far back as 1963, when the 'light-hydraulic effect' (the phenomenon of hydraulic shock pulses appearing when a liquid absorbs light from a quantum generator) was discovered [Askaryan et al., 1963].

The role of technology is also important in chemistry. It is well known that multistage chemical synthesis includes a sequence of steps that use certain reaction components and observe the necessary conditions for their interaction. It is not possible to create the desired product by simply mixing the components. The same principle applies when obtaining UHDs: when a small part of the initial substance is introduced into a gigantic volume of solvent (even if technically feasible), a UHD with long-lasting activity cannot be obtained. In order for this to happen, studies show that multiple sequential dilution - an artificial process that is not found in nature - is a critical requirement.

The demonstrated features of a technologically processed solvent are the basis of a newly discovered phenomenon: UHDs of various substances can have an effect on the initial substance, leading to a modification of its properties [Epstein, 2017]. This effect is specific: a UHD of one substance does not affect others. It is of utmost importance to note that UHDs modify the initial substance both in vitro and in vivo. For example, a UHD of the well-known anti-inflammatory drug diclofenac increases the activity of the normal dose of diclofenac in experimental animals [Sakat SS et al., 2014], and changes the characteristics of diclofenac's interaction with antibodies to it in vitro [Pschenitza M. et al., 2014].

Assessing the ability of diclofenac UHDs to influence the anti-inflammatory activity of diclofenac [Sakat SS et al. Inflammation, 2014]. * p<0.05 compared with rats treated with diclofenac (5 mg/kg) + control.

Assessing the ability of diclofenac UHDs to influence the effectiveness of diclofenac interaction with antibodies [Pschenitza M. et al., International immunopharmacology, 2014].
* p<0.05 compared with control.

UHDs are capable of affecting only a limited quantity of the initial substance (as seen in Figure 2: the effect of the UHD increases as the ratio of UHD to target molecules increases) and their contact with the external environment does not pose any danger.

The modifying effect of UHDs is based on their ability to change the spatial (conformational) structure of the initial substance or its biological target [Epstein O., 2018]. The demonstrated ex vivo modifying effect of UHDs [Epstein O.I., 2017] allows their potential use in technology, for example, to obtain new materials.

In the course of our research we came to the conclusion that the most promising targets for UHDs of drugs are endogenous regulatory biological molecules that are involved in the pathogenetic mechanisms of disease development. We initially studied UHDs of various regulatory antigens: proteins or polypeptides, however, when later working together with the famous Russian neuroscientist Academician M.B. Stark, it was demonstrated that UHDs of antibodies modify antigen activity, rather than inhibit it like antibodies in normal doses [Epstein et al., 1999]. Later, an experimental study into the therapeutic possibilities of antibody UHDs was carried out, led by another well-known scientist - the pharmacologist and member of the Russian Academy of Sciences E.D. Goldberg. Based on the study, a new group of drugs was created, whose developers were awarded the Russian Federal Government Prize in 2005.

The main idea behind developing these drugs is that instead of a biological substance, a modifier of a particular endogenous regulatory molecule is introduced into the body in the form of a UHD of antibodies to this molecule. The use of antibodies provides high selectivity of action in UHD drugs.

For instance, in changing the conformational characteristics of interferon-gamma in the body, UHD of antibodies to interferon-gamma lead to an increased number of interferon-gamma molecules that bind to their receptors and to the activation of the classical interferon pathway. As a result, a drug based on a UHD of antibodies to interferon-gamma has a similar effect to interferon-gamma.

Schematic representation of interferon-gamma (IFN-γ) signal pathway activation under the influence of a UHD of antibodies.

UHDs of antibodies to the insulin receptor sensitise the receptor, increasing the ratio of phosphorylated to general forms of the receptor, which leads to insulin-dependent signalling pathway activation and, ultimately, to plasma glucose level normalisation and a decrease in glycated haemoglobin [Gorbunov et al., 2015; Mkrtumyan et al., 2018].

Drugs based on UHDs of antibodies have several advantages, the first and foremost being high safety, which is especially important in an era of polypharmacy and mass complications of pharmacotherapy.

Practically any molecules in the body, including those inaccessible to other drugs due to biological barriers, can be targets for UHD-based drugs.

Studies have shown that with targeted use of UHD of antibodies (that is, aimed at the molecules involved in the pathogenesis of the disease), their physiological action is sufficient to provide a therapeutic effect.

The effectiveness, safety and molecular mechanisms of antibody UHD drugs' action were studied as part of a comprehensive program of pre-clinical and toxicological studies in accordance with modern principles of evidence-based medicine. The studies were carried out in independent research centres and research institutes in Russia, the USA, and Europe. In the studies conducted, data were obtained on the specific activity of the drugs, as well as the dependence of effect severity on the volume of the administered drug [for example, Don et al., 2017; E.V. Kardash et al., 2018; J. Nicoll et al., 2013]. The lack of general or specific toxic properties was confirmed in studies subject to the requirements of Russian and foreign registration authorities.

Evaluation of the anti-anxiety activity of three doses of UHDs of antibodies by the number of visits to the light compartment in a light-dark box test [E.V. Kardash et al., Dose-Response, 2018]. The dose-response curve was constructed using the following equation: y=e^3.540+0.499*log(x)

Over the past ten years, more than 40 randomised clinical trials (RCTs) of drugs containing UHD of antibodies have been conducted. More than 500 medical centres were involved in the studies and about 10,000 patients participated. Numerous clinical trials are underway in Russia and abroad, with 4,500 patients participating. The research was designed considering current scientific and regulatory requirements, with a predominance of double-blinded, placebo-controlled randomised trials.

As part of post-registration observation, nine observational clinical trials were conducted with almost 68,000 patients. NPF Materia Medica Holding LLC, a company conducting clinical trials of UHD of antibodies, is one of the leaders among Russian companies in the number of registered clinical trials and is ahead of foreign companies conducting research in Russia in terms of the number of RCT participants.

The designs and results of the RCTs (both positive and negative) are posted on the US National Institutes of Health website clinicaltrials.gov despite the lengthy technical review process and the priority of research conducted in the USA. At present, this website contains abstracts of 23 RCTs, of which five are completed RCTs with results, and the results of another five completed RCTs are awaiting verification and posting.

I shall provide some examples. The results of an international multicentre double-blinded, placebo-controlled, randomised clinical trial of the safety and efficacy of a drug based on a UHD of antibodies to a prostate-specific antigen reliably showed that the drug reduces the severity of periuria, restricts prostate growth, and reduces the risk of benign prostatic hyperplasia (BPH) progression in patients with symptoms of BPH at risk of progression [Pushkar D. et al., 20 18]. In a double-blinded, placebo-controlled study of a drug based on a UHD of antibodies to the insulin receptor beta subunit in patients with type 1 diabetes, supplementing the drug to baseline bolus insulin therapy resulted in a statistically significant decrease in glycated haemoglobin (the main indicator of diabetes compensation). In other words, glycemic control is optimised without increasing insulin doses or increasing the risk of hypoglycaemic conditions [A. Mkrtumyan et al., 2018].

The dynamics of HbA1c over the course of 36 weeks of treatment of type 1 diabetes [A. Mkrtumyan et al., Diabetes Research and clinical practice, 2018]. The analysis was performed using Student's t-test, and the p-value is Holm-adjusted in order to take into account the multiplicity of comparisons.

After obtaining results in a placebo-controlled clinical trial, further study of new drugs can be carried out in comparative randomised trials using reference drugs whose efficacy has been proven. For example, in a multicenter, open, comparative, randomised clinical trial, the efficacy of an anti-influenza drug based on a UHD of antibodies to interferon-gamma and CD4 receptor was studied in comparison with oseltamivir (branded Tamiflu, F. Hoffmann La Roche Ltd.). The need to use oseltamivir in the treatment of influenza has been confirmed by numerous RCTs, meta-analyses, and systematic reviews [T. Jefferson et al., 2014; K.G. Nicholson et al., 2014; S.G. Muthuri et al. 2014]; The US FDA recommends oseltamivir for the treatment and prevention of influenza in adults and children.

It has been shown that this drug has a similar effect to oseltamivir: the number of patients with a normalised temperature was comparable in both groups throughout the observation [V. Rafalsky et al., 2016].

More than 1000 scientific articles on the findings of experimental and clinical studies have been published not only in leading Russian specialist journals, but also in foreign journals such as The International Journal of Infectious Diseases, Nutrition & Diabetes, The International Journal of Endocrinology, The Journal of Pharmacy and Pharmacology, Pharmacology Biochemistry & Behaviour, Inflammation, The Journal of Diabetes Research, The Journal of Sexual Medicine, Sensors, Symmetry, Antiviral Therapy, Dose-Response, The Central European Journal of Urology, Diabetes Research and Clinical Practice, The Journal of Immunoassay and Immunochemistry, The Journal of Medical Virology and Drug Discovery.

The results and, above all, data on clinical testing have been presented during scientific consultations at the world's leading medical agencies - the FDA (USA), EMA (Europe), and MHRA (Great Britain). As a result of the analysis and discussion, expert opinions have been given stating that drugs based on UHDs of antibodies are not homeopathic. As an example, I cite an excerpt from a document based on the results of scientific consultations with experts from the UK's MHRA on the drug Anaferon (which contains a UHD of antibodies to interferon-gamma): “Anaferon should not be registered in accordance with UK government requirements for homeopathic medicines, since at present the drug is outside the framework of British homeopathic traditions according to the given indications."

On 21^st February 2019, an international conference named “The phenomenon of release activity: prospects for use in medicine and technology” was held in the European Parliament in Brussels. It was attended by scholars from Russia, Norway, France, Britain, and the United States, as well as European politicians and deputies of the European Parliament. During the conference, the results of both pre-clinical and clinical studies of release-active drugs were presented. Conference participants praised the level of work performed, expressed confidence in the need to support further developments in the field of UHD [European Parliament supports medical developments in the field of release activity. Pharmaceutical Bulletin, 22^nd February 2019; EP deputies supported joint Russian and European scientific studies of the released-activity phenomenon. The London Weekly, 22^nd February 2019].

Thus, to date, the presence of physiological or biological effects of UHDs has been repeatedly demonstrated, and the modifying nature of their action has been identified. It was found that this activity is due to the technology used in UHD preparation. The perspectives for their therapeutic application has also been shown. The unusual aspect of the current state of the 'high dilutions' problem is that the research methods available in biology and medicine have exhausted themselves. The baton is therefore passed on to experimental and theoretical physics. Only after understanding the physical nature of UHD can the phenomenon itself be explained. For our part, we are contributing to physical research in every way possible. For instance, in 2018 a competition of research implementation projects took place under the title Fundamental and applied features of the physical properties of ultra-high dilutions of substances. After analysing the projects submitted by the entrants, the expert council announced the winners, who received three-year grants to study the physical properties of UHD.

In conclusion, I wish to note that UHD deserve the right to be a completely ordinary area of research, and not a taboo. The current findings on the experimental and clinical effects of UHD allow us to take a fundamental step from "it can't ever be" to "it is worthy of deep scientific study and explanation".

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