Transdermal Phytotherapeutic Agent
General knowledge of medical and historical experience with cannabidiol as well as marketability and scientific plausibility of the ICBD project are assumed; furthermore, FEAT generally refrains from overall contextual connections in public discussion, for reasons of protection of expertise knowledge! In addition, this discussion may not and cannot be used for research purposes. Only research fragments - structurally - are presented on the basis of which individual steps in scientific research procedure can be reconstructed plausibly. Accordingly, this project outline is also subject to copyright protection. IP infringements are sanctioned in accordance with. § 106 Copyright Act (UrhG) Section 78 para. 3 no. 4 German Criminal Code (StGB). ©FEAT
Our skin represents the final "line of defense" of our immune systems. Billions of pathogens are pelting it every day like water on rock... this would be the ideal state! But among the otherwise often deadly viruses, pathological parasites and fungi, infectious bacteria and, increasingly, cancer-causing environmental toxins, more and more are finding ways to trick and penetrate this fortress called our skin. Part of the responsibility for this lies in the toxic diversity of synthetic cosmetics, with which we are led, conditioned by vanity, to burden our skin with more defenses than it could ever be upgraded with! It is true that it still protects us quite well due to its enormous "learning intelligence," in that its innate - and acquired - immune system is constantly "developing.” Nevertheless, the pathological collective course, across all walks of life, testifies dramatically to the extent to which the immunizing defense struggle of our border organ increasingly succumbs to the pathogens descending upon us. We can see this most clearly in the increased cases of skin cancer.
The fact that our skin nevertheless has many available defense strategies has long lulled us into a false sense of security, since diseases of immunocompromised skin take considerably longer to result in a viable outbreak than intestinally induced ones, for example. The protective cover that actually surrounds our organism perfectly with 1) its countless, almost impermeable corneocytes nested within and between each other, 2) its microbiological sensory system in the form of our skin flora, with its many "good" fungi and bacteria, as well as 3) its chemical acid protective mantle, with an ideal pH value of 5.5 ... all of which nevertheless do not provide the desired longterm protection, unless 4) their sorely neglected and underestimated barrier factor can provide sufficient immune protection. This is also especially relevant insofar as pathogens that perforate, undermine or otherwise agitate the three barriers mentioned above, through mechanical, chemical or simply toxic actions (which is already almost standard practice in the
modern cosmetics industry) quickly gain the upper hand, as our dermal immune defense system is by no means attuned to such enemy presence.
The CBD-based transdermal phytotherapeutic agent presented here supports the skin’s own immune system, as mentioned above, in such a way that the uniquely acting cannabinoid receptors allow and help transmission of immunizing information for important key functions, whereby not least, the typical defense cells in the form of TH, I-memory, T-killer cells, etc., also receive lasting support. In tantum, this means: Our CBD-based ©Immulotion restabilizes our dermal immune defense system without being detrimental to our vanity. On the contrary: ©Immulotion immunizes and regenerates our skin equally well! How exactly? FEAT expertise protected until market launch!
(Immunizing CBD Lotion)
The following should be noted: The cannabis plant contains ≈ 120 cannabinoids; these can be recognized by their typical tricyclic structure, each with a phenol ring, including a pentyl group in the meta position as well as a central pyran ring and a monounsaturated cyclohexyl ring. Tetrahydrocannabinol, the psychoactive cannabinoid par excellence, is now considered to have been studied relatively thoroughly, having been the topic of much medical research. In our ICBD project, the first step is to ensure that the aforementioned tetrahydrocannabinol (THC) is clearly isolated from the other ≈119 cannabinoids, in order to process the latter in a medically responsible and legally justifiable way in the next step, so that ICBD can finally be classified as a kosher-certifiable food.
Therefore, in the subsequent step, it is just as important, after deduction of the cannabinoid CBD, to be able to also establish or definitively prove that the remaining ≈118 cannabinoids are not psychoactive. For example, the flavonoid cannflavin A and CBD have also been investigated for their medicinal efficacy - they are completely non-psychoactive! And since then, only those typical C21 compounds have been generally attributed to the cannabinoids in Cannabis Sativa L.. Their phytopharmacological aspect is now also attributed to those with binding cannabinoid receptors. These so-called phytocannabinoids are themselves divided into the following cannabinoid subgroups:
Cannabinoids of the delta-9-tetrahydrocannabinol type
Cannabinoids of the cannabidiol type
Cannabinoids of the cannabichromene type
Cannabinoids of the cannabichromene type
Other cannabinoids of the cannabinol and cannabinodiol type
Other cannabinoids of different types (cannbicyclol type, cannabielsoin type, cannabitriol type
All these cannabinoids can only be distinguished from each other by their structure. In 1987, Prof. Howlett (Saint Louis University in Missouri) demonstrated for the first time, before the Cannabis Congress in Melbourne, Canada, that cannabinoid effects can be receptor-mediated. In plain language, this means that C effects can arise through the binding of cannabinoids to specific binding sites on cells of the human body. These binding sites are already referred to as cannabinoid receptors. This is crucially relevant in that the human organism has very specific cannabinoid binding sites on the surface of many cell types, which in turn allows our bodies to produce endocannabinoids. This leads us to the next point, specifically that under this kind of endogenous cannabinoid system, the aforementioned cannabinoid receptors (CB) act as fatty acid derivatives and thus bind - and activate - those endocannabinoids!
Some of these cannabinoid receptors belong to the "G-protein coupled” receptors. These can then be detected in the central nervous system as well as in many peripheral tissues and organs. But cannabinoid receptor-1 (CB1) is found mainly in our nervous system. What does this mean? A large number of these receptors are expressed from the ends of the central and peripheral nerves, preventing the release of other neurotransmitters. Our nervous system is thus protected from over-activation. And while CB1 receptors are expressed primarily in regions of our brain, where they influence our movement, memory and processing of pain, cannabinoid receptor-2 (CB2) is primarily located in our immune cells (leukocytes, spleen, tonsils, etc.).
The function of CB2 is, therefore, modulation via release of cytokines, which are responsible for inflammation and general regulation of our immune system. So, to get to the point: As long as the CB2 receptors are activated, such substances are also considered non-psychoactive! Animal experiments have shown, in addition, that the endocannabinoid system has an anti-infection effect in the event of tissue damage, and is also able to develop analgesic, anti-inflammatory and neuroprotective effects. Cannabinoids are, therefore, able to have an equally protective effect on our acquired and innate immunity. Furthermore, they are able to modulate both the central and the peripheral inflammatory processes within our nervous system.
In 1992, Prof. Dr. Raphael Mechoulam (from the Hebrew University in Jerusalem) identified the first endocannabinoid. In reference to the Sanskrit word "Ananda," meaning bliss, he named it "Anandamide," adding “Amide” to note its chemical structure. In the brain, endocannabinoids act as derivatives of unsaturated fatty acids, namely as neuromodulators. Since then, the following endocannabinoids have been identified:
Anandamide (N-arachidonoyl ethanolamide)
0 - arachidonoyl dopamine
2 - arachidonoyl glyceryl ether
2 - arachidonoyl glycerol (2-AG)
Of these, anandamid + 2-AG have been most thoroughly researched, to the extent that both can be formed in/by the human body, as required from membrane-bound precursors by phospholipase C + D (= enzymes that cleave phospholipids into the fatty acids R1COOH and R2COOH respectively, as well as into other lipophilic substances, with C cleaving before the phosphorus atom and D after the phosphorus atom of the phosphate group). This will
finally allow them to stimulate cannabinoid receptors. In addition, anandamide + arachidonoyl dopamine (NADA) can also bind to the vanilloid receptor (Transient Receptor Potential Vanilloid)* (*ion channel in sensory nerve cells of the central + peripheral nervous system - similar in vertebrates - pain receptor for perception of acute and/or potentially tissue-damaging, usually painful stimuli. Its effect on development of pain makes it an ideal research object for developing new analgesics, apart from its contribution to sharpening our sense of taste).
Immunization Aid Through Endocannabinoids
It is well known that many cell types are capable of producing endocannabinoids, but our immune cells do it best. In this way, the purinergic receptors, stimulated by adenosine triphosphate, on the microglial cells (the only cell type in the parenchyma of our CNS) stimulate endocannabinoid production controlled by calcium, with full force as soon as an inflammatory process is present. This leads to increased concentrations of 2-arachidonoyl glycerol (2-AG) und arachidonyl ethanolamide (anandamide, AEA) in the brain and spinal cord.
In healthy tissue, on the other hand, the main task of the endogenous cannabinoid system is mainly that of maintaining basic physiological processes, which is partly due to a constitutive basic content of endocannabinoids and partly due to their only very minor fluctuations in concentration. In the case of pathological changes, however, there are drastic tissue-specific changes in the endocannabinoid concentration. In a healthy CNS, endocannabinoids are involved in regulating synaptic plasticity and thereby, in controlling cognitive functions and emotions. They modulate our neuronal circuits in specific regions of our central nervous system (CNS).
In 1993 LP discovered for the first time that, in the basal ganglia (core areas of the end brain, telencephalon, below the cerebral cortex, Cortex cerebri = subcortical basal nuclei, important for functional aspects of motor, cognitive and limbic regulation, such as spontaneity, affect, willpower, initiative, drive, step-by-step planning, anticipatory thinking, expectations, motor selection, further multitasking, etc.) and in the cerebellum a particularly high CB1-receptor density prevails. There, CB1 acts in the area of our sensory and autonomic nervous system, not only regulating our pain perception, but also allowing cardiovascular + gastrointestinal processes to be controlled by the CB1 located there.
Furthermore, endocannabinoids in hypothalamic zones are involved in controlling different regulatory circuits, e.g., for improving control of our food intake. However, in contrast to the endocannabinoids that primarily target the CB1 receptor in the CNS, activation of CB2 receptors is generally very closely linked to modulation of our cellular and humoral immune response. Thus, CB2 has a considerable effect on inflammatory processes. Meanwhile, endocannabinoids also play a key role when our CNS becomes ill, with a resulting loss of neurons.
Under such harsh conditions, both CB receptors (1 + 2) are involved. Endocannabinoids exert a direct influence on individual neurons via CB1 receptors, whereas CB2 receptors are found mostly on microglial cells (a type of cell belonging to the immune system, playing a central role in pathological changes in the brain). Endocannabinoids can also thus indirectly influence survival of neurons and therefore the extent of neuronal damage via the CB2 receptor. By inhibiting the excitatory neurotransmission induced by the neurotransmitter glutamate and thus, counteracting excessive activation of glutamate receptors, the endocannabinoids also ultimately slow down the increase in neuronal damage.
Finally, it must be noted that, unlike many other chemical signalling substances, endocannabinoids are only produced if and when there is a need for them, and are then released by the respective cell. In addition, they are metabolized into other biologically active substances, since otherwise the degradation of 2-AG produces "arachidonic acid” and the metabolization of AEA via cyclooxygenase produces "prostaglandin E2"* both of which are proinflammatory mediators! *(1. modulates platelet aggregation, 2. activates sensory nerve endings, 3. inhibits the release of neurotransmitters in the autonomic nervous system as well as lipolysis, 4. promotes vasodilatation, etc. see reference in Art. 4, para. 5).
The well-known route from medicinal plant to medicine is always via the "drug” and its pharmaceutical development, so in modern phytotherapy this is mostly via the extract concerned, with particular consideration given to material and structural composition. The herbal extract, however, is always to be weighed only in its original, natural and unaltered form, easily digestible for us. The extract is then divided into its ingredient groups, evaluated according to their main/active substances, active and pharmaceutically relevant co-effective ingredients, framework and co-formulants. This diversity of substances in the extract leads to the typical phytopharmacological problem of never being completely identifiable. For this reason, the raw material extract production should focus on reproducibility, which needs to be as standardized as possible, as this already includes many measures leading to reproducible extract market quality and the active substances derived from it.
For example, the active ingredient content in the extract can be standardized, provided that an appropriately standardized extract is available. Such standardization, however, results from adjusting a drug in powder form or an extract to match a fixed standard value, specifying minimum and maximum content, related to a substance or a group of substances, which may be considered as determining the impact.
Information about the ingredients, origin and effect of commercially available CBD preparations is mostly incomplete or even watered down. It is by no means sufficient to know whether such a preparation is available without the psychoactive THC mentioned earlier. As already mentioned, the generally advertised THC in the raw CBD extract is only 1 of ≈ 120 known cannabinoids, whereas not even 10% of all cannabinoids in/from this plant have been examined for their complex mechanisms of action in the human body. And those cannabinoids that have already been subject to more thorough investigation have mostly only been studied in animal experiments.
This short look at the complex, and in many cases complementary interdependent CBD substances in and for the human body is intended to provide an initial, albeit rather superficial insight into the effective complexity of this ICBD product, yet at the same time to point out the responsible approach and care required in marketing it. For example, the CBD plant extract origin and purity must be ensured, above all, along with controlled transport conditions, and of course toxic residues must be checked.
The reason why this test is indispensable can be seen, for example, from the likewise aforementioned fact that the CBD plant extract must be tested for toxicity (Art. 3, last paragraph), specifically "endocannabinoids, contrary to other chemical signaling substances, are only produced when there is a need for them [under normal conditions!] in order to then be released accordingly by the respective cell, since otherwise "arachidonic acid” is produced during breakdown of 2-AG and "prostaglandin E” is produced during metabolization of AEA via cyclooxygenase - both proinflammatory mediators! This indispensable balance of many factors influencing our health alone makes it clear that CBD may only be administered generally if it is ensured that complicating conditions - or mere predispositions that could lead to such when CBD is administered - do not have a proinflammatory effect on CBD intake, which is well tolerated under normal conditions.
A brief explanation: Each case of inflammation is almost always accompanied by changes at the molecular level, whereby the trigger stimuli lead to altered gene expression via signal cascades, under which the proinflammatory mediators are expressed. The E2 prostaglandins represented here, for example, are only short-lived, locally effective mediators; they are hormone-like eicosanoids, acting both as autocrine and paracrine, working directly at the site of their synthesis.
In other words: E2 prostaglandins are primarily synthesized in the endoplasmic reticulum and are secreted from the cell. They are, therefore, jointly responsible for many pathological processes. In particular, these include inflammatory reactions, increased sensitivity to pain, bone development, integrity of gastric mucosa, platelet aggregation, renal blood flow, etc. Their synthesis takes place by hydrolysis of membrane phospholipids by phospholipase A. The resulting arachidonic acid is oxidized by COX (cyclooxygenases = enzymes that initiate prostaglandin synthesis from arachidonic acid), producing the unstable intermediate product prostaglandin G2. This PGG2 is then converted to prostaglandin H2 by the peroxidase activity of COX. PGH2 is then the decisive starting molecule for many prostaglandins and *thromboxanes (*prostaglandin-related eicosanoids, which occur primarily in platelets and are thus named after them).
ICBD should, therefore, only be dosed/applied such that the prostaglandin receptors on the cell membrane remain bound to specific "signal transduction pathways", since PGE2 is probably one of the most important prostaglandins of all. For example, it has an effect on inflammatory processes and rheumatic diseases insofar as their inhibitors (in prostaglandin synthesis) have pain-relieving and, above all, anti-inflammatory effects. PGE2 is also involved in the development of fever.
Furthermore, bacterial populations often stimulate the epithelium of the organum vasculosum laminae terminalis (a circumventricular organ, part of the hypothalamus), which eventually results in expression of COX-2, leading to an increase in PGE2 synthesis.
In the stomach, however, PGE2 has a mucosa-protective effect and inhibits production of gastric acid (not necessarily beneficial). PGE2 (together with PGI2 = eicosanoid as mentioned above) is the main prostaglandin, which influences vascular permeability (tissue swelling), is involved in development of redness, is responsible for pain induced by other inflammatory substances (histamine, bradykinin), as PGE2 sensitizes nociceptive nerve endings.
Potential Placing on the Market
The purpose of this brief summary on ICBD has been to emphasize the anti-inflammatory effect of CBD extract, along with establishing here that ICBD contains very little THC, if any at all. For this purpose, the effect of the ICBD extract on prostaglandin E2 synthesis, as well as on cyclooxygenase-2 protein synthesis and on the release of various cytokines (interleukin-1β, interleukin-6…) was discussed, regardless of indication of tumor necrosis factor-α!
It remains to be noted that CBD is never completely THC-free, especially with use of common industrial manufacturing processes. Against this background, it is a medical responsibility to approve the form of marketing as well as the applicability of such a substance, if and only if certain residual risk factors are considered to be eliminated generally. With this in mind, the following form of application is recommended currently:
We'll keep it short: Our skin is by far the largest human organ. It protects our bodies in many ways, but primarily against the billions of pathogens attacking us every day. However, our skin is slightly underestimated in terms of immune defense, although it nevertheless has the greatest importance. On the contrary, vanity means that people expect to be subject to major weakening of their immune systems due to toxic cosmetics. As a broad-based assistance to defense, administration of CBD in the form of Immulotion would be advisable. This has a regenerative and epithelial tissue-strengthening effect, as well as being protective and antioxidant. Dermal application as opposed to gastrointestinal absorption of CBD is thus indirect, yet sustainable - and risk-free! The secret know-how of the transdermal phytotherapeutic agent on which this is based, by means of applied biomolecular synthesis processes, is the real key for the aforementioned interplay of biophysical and multi-transient neuro-receptors with microbiochemical auto-application mechanisms and complementary functional modes of action when CBD is applied to the skin.
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