Problems of pharmacology, pharmacogenetics, and...

Problems of pharmacology, pharmacogenetics, and personalized medicine



Most modern pharmacological drugs are xenobiotics - artificially created organic compounds. The possibilities of organic synthesis are limited by the laws of nature only. A variety of homologous series can be represented by a multidimensional space. Mathematicians calculated that for synthesizes one molecule of each of all possible organic structures with a molecular weight not exceeding 1000 g / mol in the universe there is not enough matter [1].

Thus, simply try all possible structures for specific medical purposes will not be possible. To narrow the search of compounds-leaders, various databases and special software have been created, the development of which are actively ongoing. Long time, the concept of Similarity was used for choosing compounds-leader (similar structures should have similar biological activity). However, in any homologous series, even the chemical properties of the compounds often change quite sharply, and as for biological activity, sometimes the introduction of only one methyl group into the initial structure can reduce toxicity or deprive the compound of useful activity [2].

This became especially noticeable during the development of combinatorial chemistry, at large homologous libraries. In addition, the concept of Similarity collapsed after the tragedy with Talidomide, when it became clear that optical isomers can have fundamentally different biological activities. Gradually, the concept of Similarity was replaced by QSAR models - a mathematical apparatus that allows making correlations between the structures of chemical compounds and their biological activity [3].

The main disadvantage of the method is the need to assemble a new set of pharmacophores and compose a new QSAR model for each individual target and even for each individual binding site, i.e. this approach is not universal and in some cases has a high error [2].

In addition, any results obtained in silico require laboratory verification and experimental confirmation. And as the practice of 2019 - 2020 has shown, such data can mislead the whole world, as was in case with an attempt to identify the causative agent of atypical pneumonia in Wuhan. Sequencing of several millions of RNA sequences from bronchoalveolar lavage and compiling hundreds of thousands of contigs from them using special software and a database of various pathogens was mistaken for the "isolating" of SARS-CoV-2 [4].


An equally laborious task is the search of disease markers that can be used as targets, as well as for the development of diagnostic methods. With the development of molecular biology, developers turned their attention to the search of special signaling pathways and molecular cascades. Successes in this direction have demonstrated that the classification of subtypes of some diseases can occur in three main directions: according to clinical data, by molecular objects (primarily defects in some genes), and according to signaling cellular pathways. The search of genetic features and different gene variants allowed to study hereditary diseases, and to identify some factors of genetic predisposition or resistance and led to the emergence of a section such as pharmacogenetics. As it turned out, the presence of specific polymorphisms can affect to the pharmacological effect of medicinal and biologically active compounds, reduce or enhance it, and even redirect it in some cases. Genetics has given answer to the question: why pharmaceuticals do not work for everyone or work differently for different groups of people.

The understanding that without taking into account genetic factors, pharmacological intervention will not be effective sufficiently, and in some cases, it could cause serious harm, led to the concept of personalized medicine. In general, for the effective and safe use of drugs, it is necessary to have clear understanding of the following link: substance - target - cascade pathway (considering genetic variants) - cellular process - physiological response.

It should be remembered that all xenobiotics have toxicity, therefore it is necessary to establish of the optimal dosage. In addition, these compounds rarely affect to the trigger of the pathological process. Often, the toxicity of drugs is because of the therapeutic target. Chemicals are investigated for cellular toxicity also: the ability to cause cell death/apoptosis, affect the integrity of the cytoplasmic membrane, reduce the potential of the mitochondrial membrane, or exhibit other mitochondrial toxicity, increase the number of reactive oxygen species, reduce the concentration of glutathione, affect the cell cycle. Toxicology studies are often conducted in healthy volunteers.

The question arises, to what extent is it justified to damage conditionally 1 healthy person for the sake of potential recovery of 10 patients? Where the researchers typed the thousands of healthy volunteers for Phase III clinical trials? Do these people understand the danger they are putting their health at? If there is not enough matter in the universe to create just one molecule of all possible structures, will there really be enough healthy people in the world to test all pharmaceutical products? In addition, the discovery of new features and patterns in this direction leads to the fact that previously obtained results in experiments on humans often cannot be used due to the lack of critical data.

There are areas of application of hard drugs that do not raise doubts about the appropriateness. These are resuscitation, surgical anesthesia, acute infectious diseases, etc. As for metabolic disorders, chronic processes, neurological and psychiatric disorders, not all currently used substances meet safety and efficacy criteria. Some of these drugs have unjustified side effects or questionable therapeutic possibilities. A separate group should be selected the drugs used for relieving symptoms, maintenance therapy, applicable in the field of services (contraception, weight loss, rejuvenation, smoking cessation, etc.), as well as for diagnosis and prevention.

Strictly speaking, these drugs should not be called medicinal at all, since they do not solve the problem, but only allow you to get a "momentary" effect. Currently, such drugs have led society to the false concept of a "magic" pill. The commercialization of the pharmacological field allowed to use of marketing technologies for the sale of these products. In fact, it creates false hope and negatively effects on health and quality of life people. It was this concept that encouraged people to line up to receive immunoprophylactic drugs against a new coronavirus infection, which in the classical sense cannot even be called vaccines. Thus, true health care is supplanted by a high-tech surrogate whose side effects are hidden behind by colorful commercials.

The actively developing personalized medicine involves genetic screening, the possibility of which exists in many diagnostic centers. Already at this stage, two serious problems arise: the security of such data and the processing of the results. Currently, there are not enough such specialists. Incomplete genetic screening without interpreting the data leads to delocalization of responsibility for the results of use of these data by the attending physician. The collection of genetic information can take place, regardless of the wishes of people, under the guise of PCR testing, for example, or during clinical examination (blood test, smears, biopsy). In addition, the question arises whether the introduction of genetic passports will lead to eugenics? A separate niche in this business is prenatal diagnosis, based on which a decision is made about the fate of the embryo. At the same time, few of the future parents understand that the presence of some mutations is only probabilistic in nature. Even gross genetic damage associated with hereditary syndromes never give a 100% result. This is due to the fact that the concept: one mutation - one gene - one trait or disease - is an extremely simplified scheme. In this case it is more correct to speak about the haplotype and mutation threshold. Mutations can reinforce each other, or they can offset. Moreover, one mutation can carry both a negative and a protective effect. For example, mutations responsible for the development of cystic fibrosis prevent the onset of intestinal diseases caused by the bacteria salmonella. And mutations that lead to sickle cell anemia prevent human from contracting malaria. In addition to this, there is epigenetics, the laws of which are not fully understood.

However, a change in the epigenetic landscape can both block a pathogenic mutation and mimic it on a healthy gene. With the discovery of the CRISPR/CAS9 system, it became possible to edit the genome, including the human genome. Previously, adenoviral vectors were used for these purposes, allowing the transfer of entire genes. The easiest way to carry out such manipulations is at the cellular level. And this is either IVF or the introduction of edited stem cells. The IVF procedure itself was originally developed to create of knockout mice. Now there are more subtle technologies, and given to attention Murphy's law, we get the threat of genetic experiments in humans. Using edited stem cells will lead to mosaicism and chimerization of tissue. Thus, a moratorium on human genomic editing is necessary, at least until a full understanding of the phenomenon of life comes. In addition, there is an ethical question, what is better, to allow to live a short life for children with severe congenital genetic diseases (for example, progeria syndromes that cause premature aging) or to give them up for experiments, including genomic editing?

As can be seen from the above, scientific progress has led to considerable detail of research in the pharmaceutical industry, but could not facilitate the development of new drugs, but, rather, complicated it. Since such developments are long-term projects that require huge investments and efforts of many specialists, while the results cannot guarantee 100% success, and only ill people feel the need of drugs, the attention of pharmaceutical companies has been redirected to the development of vaccines, which are currently quite aggressively imposed for all people on the planet (both healthy and not so).
Immunoprophylactic drugs requiring regular revaccination, for example, against influenza, caused special economic interest. In a panic environment around a well-planned "pandemic," this interest led to the rapid creation of series of drugs for immunization against a new coronavirus infection. However, attempts to create such vaccines against various strains of coronaviruses have been going on since the 70s, and all of them have been failed because all such vaccines lead to Antibody-Dependent Enhancement.

As shown in animal experiments, after infection with the corresponding serotype the control group carries a fairly mild disease without fatalities, while in the group of immunized animals, autoimmune lung pathologies develop during subsequent infection, which in the absence of treatment can lead to 100% death [5].

This effect was demonstrated at the cellular level using the MERS strain [6].
After the outbreak of SARS-CoV in 2002, 4 vaccine variants were tested [7]:
1) Whole virus vaccine prepared in tissue cultures Vero, zonal centrifuged and twice inactivated by formalin and UV irradiation (with and without alum adjuvant);
2) Whole virus vaccine purified, inactivated with beta-propiolactone and irradiation (with alum adjuvant);
3) Vaccine based on recombinant DNA S-protein, produced in insect cells and purified using column chromatography (with and without alum adjuvant);
4) The vaccine containing virus-like particles, S-proteins of SARS-CoV and other components.

All of them showed antibody-dependent enhancement of infection. At the same time, the principles of creating modern currently offered to the population of the whole world vaccines for covid 19 are not different from principles of creating previous vaccines:
1) "CoviVak": a whole virus vaccine (which of 3-4 thousand gene variants?);
2) Pfizer and Moderna: based on mRNA particles that are capable of performing the functions of epigenetic modulators and participate in cellular reprogramming;
3) Sputnik V , AstraZeneca: GMO products that are consisting of recombinant adenoviruses, in which the gene of S-protein of the SARS-CoV-2 virus is inserted; 4) "EpiVacCorona": contains three different protein conjugates with S-proteins SARS-CoV-2 and adjuvant - aluminum hydroxide.

All these modern vaccines, like their precursors, are aimed at producing antibodies to the S-proteins of the coronavirus and carry the potential threat of an antibody-dependent enhancement of infection after infected with any strain of coronavirus. At the same time, none of the new vaccines has been tested on animals, data from preclinical studies are completely absent, no attempts were made to somehow circumvent the antibody-dependent effect, which leads to autoimmune pathologies in case of contact with an antigen. Since the S-protein subunits have sequences homologous to the human syncytin proteins, which play a key role in the formation of the placenta, the formation of antibodies that are capable of binding not only S-proteins, but also syncytins, can lead to sterilization [8].

I would also like to draw your attention to DNA vaccines. Adenoviruses are transporters which carry a foreign, artificially synthesized S-protein gene in these DNA-vaccines. Such “vaccines” are not different from methods of genomic editing using the same transporters, as was shown in an animal model when trying to eliminate nystagmus in homozygous GPR143 knocked out mice [9, 10].
Thus, DNA vaccines are direct threat of uncontrolled editing of the human genome. The manufacturers of the presented vaccines had to test all these and many other potential threats in animal models and cell lines during the preclinical phase of the studies. However, this stage of testing was eliminated. In the case of any vaccines the manufacturers are not talking about either genetic features or any personalization. It raises doubts about the quality and suitability of the proposed drugs.






Список литературы

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