Adaptation is one of the fundamental principles of physiology: it acts not only at species level, as Darwin suggested, but also at the levels of tissue, cells, molecules, and possibly genes. Almost every influence, which is able to damage a tissue or an organ, can activate endogenous defense mechanisms when applied at a low, subthreshold dose, countering thereby the damage from a subsequent strong exposure. This phenomenon is commonly referred to as preconditioning. One example is the well-known ischemic preconditioning (tolerance), where a non-critical drop in oxygen transport to the brain or to the myocardium improves resistance to subsequent ischemia and ameliorates ischemia-induced damage . Another common example is chemical preconditioning is delivering a subthreshold dose of a convulsant before administration of its high dose. This approach provides protection against severe epileptic state and improves brain cell survival . Preconditioning is a sort of “training” that initiates the endogenous mechanisms responsible for adaptation to damaging factors.
Roughly, co-administration of an ultrahigh dilution (UHD) and a standard dose of a substance can be regarded as an analogue of preconditioning. Findings of relevant studies enabled the formulation of a concept suggesting that a UHD of a preparation used in combination with the conventional dose of the same preparation can modify the effects of the latter. This phenomenon has been termed “bipathy” [3, 4], and it has been studied in various in vivo and in vitro biological models. For instance, in experiments to evaluate the effect exerted by UHD of anti-S100 antibodies on rat hippocampal slices (brain structures critical to learning, attention and memory), the suppression effect of long-term post-tetanic potentiation by anti-S100 antibodies was decreased and normal hippocampal synaptic activity was restored in slices pre-incubated with a UHD-containing medium . In another series of experiments performed in a neuronal cell line, long-term (3 days) pre-incubation of the cell culture with UHD of glutamate and UHD of cycloheximide resulted in better cell survival following subsequent exposure to high, toxic doses of these substances [20,21]. The authors assume that their findings might have potential in treating neurodegenerative diseases, such as Alzheimer’s or Parkinson’s diseases [20, 21].
In vivo experiments to study the bipathy effects were performed by testing various drugs. In particular, UHDs of morphine, a key opioid narcotic analgesic, were able to modulate the effects of toxic morphine doses when administered concomitantly with the latter. Oxygen consumption was reduced in the study animals, pointing to restored muscular tone, which is improved by morphine .
Other psychoactive substances have also been examined for the bipathy effect. Psychoactive drugs tend to have serious dose limitations and contraindications for use because of their significant undesirable effects. There has been continuous search for more specific analogues of those and for ways to reduce the therapeutic dose of a drug administered. Therefore, bipathy effect studies have been conducted for widely used drugs such as haloperidol and phenazepam [7, 8]. Both have pronounced side effects when used at high concentrations and/or as a long-term therapy. In vivo experiments demonstrated that UHD of these drugs administered before or concomitantly with their standard doses enhanced the drugs’ direct effect and, at the same time, reduced the severity of their side effects. In this way, phenazapam exhibited stronger anxiolytic and anticonvulsant effects following prior administration of or co-administration with its UHD . Furthermore, the combined use of phenazepam and UHD of phenazepam reduced the severity of the drug’s undesirable effects, i.e. muscle relaxant and sedative effects . As for haloperidol, the drug used at standard concentrations in combination with its UHD resulted in stronger antipsychotic effects along with a milder side effect exhibited as cataleptic action . That was characterized by a peculiar behavior of haloperidol: the drug’s psychotropic (neuroleptic) effect was increased for its standard dose preceded by administering UHD of haloperidol, whereas its cataleptic effect was less pronounced following co-administration of the two preparation types.
Another example of side effect reduction has been provided by combined use of standard-dose and UHD of acetylsalicylic acid (aspirin) [22, 23]. Aspirin is not only known as an effective antipyretic and analgesic but also as an anticoagulant and antiplatelet agent [22, 23], which, at the same time, constitutes its side effect, i.e. hemorrhagic complications. A team of researchers from France studied aspirin co-administered with UHD of aspirin in a rat model of thrombosis. It was found that this approach was able to reduce the time of experimentally-induced tail-tip bleeding [22, 23]. According to the authors, the obtained results could contribute to better safety of using aspirin in the treatment and prevention of cardiovascualr diseases.
There are studies of the UHD modifying effect on the activity of other drugs. For instance, bipathy effect of prednisolone and diclofenac tended to increase anti-inflammatory activity of these drugs in the models of artificially induced rat paw edema [9-11]. When administered simultaneously at ultralow and conventional doses, the nonsteroidal anti-inflammatory drug diclofenac demonstrated an anti-inflammatory effect similar to its high doses. Meanwhile, exposure to UHD of diclofenac before the use of conventional doses of the drug was shown to be at advantage compared to concomitant administration due to reducing inflammation by over 50% . However, prednisolone, a steroid hormone (glucocorticoids) was observed to suppress the progress of inflammatory rat paw edema when UHD of prednisolone was administered 1 hour after its conventional dose . Nonetheless, the experiments conducted clearly indicate that UHD of these drugs are effective in enhancing the anti-inflammatory action of the latter, which could help lower their standard dose, reducing thereby the side effects.
The strength and character of biological activity observed in bipathy probably depends on the drug being used. Indeed, the anti-inflammatory effect of dexamethasone, a synthetic glucocorticoid, was significantly decreased following co-administration of its conventional doses and UHD of dexamethasone in a similar model of artificially induced rat paw edema . Additionally, since dexamethasone influences many other physiopathalogical processes, including through suppressing tissue proliferation and restoration, as well as the immune response in carcinogenesis, its UHDs co-administered with its conventional doses have been examined for effects on cancer development and liver regeneration. This approach to dexamethasone use was shown to have no impact on normal liver regeneration but produced a detrimental effect in a hepatocancerogenesis model: the number of malignant preneoplastic (pretumor) and liver lesions overall was increased, with more severe bile congestion .
There are a number of research papers addressing the protective effect of arsenic UHD (the homeopathic preparation Arsenicum Album diluted to different potencies) on toxic doses of arsenic compounds, which has been investigated not only in mammalian in vivo experiments but also in in vitro studies with simplest eukaryotic cells (yeast)  and even procaryotes (Escherichia coli) . The addition of Arsenicum Album 30С to the medium decreased the magnitude of the toxic effect exerted by arsenic compounds on yeast, as well as the intensity of lipid peroxidation, protein carbonylation, DNA damage, ROS generation, etc. . This effect was demonstrated also in in vitro studies with Escherichia coli, where the above-mentioned approach also enhanced the expression of bacterial genes that promote cell growth and improve arsenic resistance .
In mouse in vivo models, Arsenicum Album (30С or 200С) was administered 2 hours or the next day after arsenic exposure and for the long term thereafter. In these experiments, the toxic effects of arsenic compounds were also mitigated [15-16, 26], and so were the cyto- [15,26] and genotoxic changes in liver  and bone marrow cells , abnormal sperm counts, and global degenerative changes in the liver . Thus, the authors have identified a positive effect for UHD of arsenic co-administered with arsenic proper.
According to a hypothesis suggested by Russian scientists, the bipathy phenomenon is not as much biological as it is physicochemical. This has been supported by experiments where UHD of mercury nitrate modified the effects of conventional-dose mercury in basic oxidation-reduction chemical reactions. That was expressed as enhanced or decreased activity of diluted mercury ions and atoms, depending on the potency of Hg(NO3)2 dilution . It is also worth mentioning a research paper which describes the effects of UHD of some salts used as the diluent on the structural properties of solutions of these salts (0.5 - 1 М), as compared with UHD of purified water or other salts. It was reported that the degree of water structuring in salt solutions where the diluent was represented by UHD of the initial salt was higher in solutions that contained ions with strong positive hydration (e.g., Ca2+). Oppositely, the structuring degree was lower in the presence of ions with strong negative hydration, such as Cs+ or I- .
Meanwhile, Indian scientists suggest the following: since the toxic effects of some substances were lowered by concomitant use with UHD of these substances in the studies of UHD effects on the simplest eukaryotic cells and small-genome prokaryotes, it seems reasonable to exclude the nervous system from any participation in this phenomenon. Thus, according to the hypothesis proposed by the scientists, UHD can directly influence gene expression in test organisms . Both Indian and Russian scientists believe that the modifying effects of UHD drugs do not directly depend on the concentration of the diluted substance. Instead, those are associated with the technology used to obtain extreme dilutions, i.e. the potentiation process “borrowed” by scientists from homeopathy. After processing, the carrier (e.g., water or an aqueous-alcoholic mixture) exhibits new properties, which are different from the properties of the diluted substance used at its conventional dose [12, 19].
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