A composition for use as Anti-addiction against mitragynine addiction symptoms

Abstract

The present invention provides a composition for use as anti-addiction in mitragynine addiction symptoms, characterized in that the composition comprises FPL 64176 as an active ingredient by reducing levels of calretinin and dopamine in a subject's brain.

Description

A COMPOSITION FOR USE AS ANTI-ADDICTION AGAINST MITRAGYNINE ADDICTION SYMPTOMS

[0001] The present invention relates to an addiction treatment, particularly related to a pharmaceutical composition for use as anti-addiction against mitragynine addiction symptoms.

[0002] Kratom is a plant that is traditionally used for treating fatigue, pain diarrhea, muscle discomfort, blood pressure, and to enhance stamina. However, its long-term or regular consumption leads to addiction. The addictive potential of kratom is due to the presence of a psychoactive alkaloid known as mitragynine exerting its action on the brain’s neurotransmitter systems. Mitragynine binds to opioid receptors, which exerts a stimulating effect on the users. Its long-term use potentially causes tolerance and dependence to occur. Signs of dependency on kratom consist of mood swings, anxiety, and physical withdrawal signs like trembling and muscle pain. Although kratom causes dependence, its positive impact on human health is indisputable. Mitragynine contains analgesic and medicinal properties such as for the treatment of pain, diarrhea, muscle discomfort, blood pressure, and to enhance stamina, provided it is used in the appropriate dosage. Hence, a total prohibition of kratom could result in a negative impact on the pharmaceutical sector. Instead, opting for a regulated or limited use of kratom would be a wiser decision.

[0003] One example of the FPL 64176 disclosure can be found in the article“Discovery and synthesis of methyl 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate (FPL 64176) and analogs: the first examples of a new class of calcium channel activators”, published in Journal of Medicinal Chemistry in 1993, volume 36, issue 19, pages 2739–2744, which discloses a class of calcium channel activator that does not act on the well-defined calcium channel modulator. However, the article does not disclose the use of the said drug to reverse drug addiction symptoms.

[0004] Another example is WO2010015037A1 which discloses a treatment or prevention of neurological conditions which include neurological diseases and disorders as well as neurodegenerative conditions associated with abnormal levels of dopamine by decreasing the number of dopaminergic cells. One example of a drug disclosed is FPL 64176 as a calcium channel activator. However, this disclosure does not address addiction resulting from mitragynine use or detail its specific mechanism of action.

[0005] As outlined above, various studies and disclosures have explored different aspects of these compounds. However, there remains a need for targeted research and solutions to address the specific demands for managing addiction and withdrawal symptoms associated with mitragynine.SUMMARY OF THE INVENTION

[0006] The following presents a simplified summary of the invention in order to provide a basic understanding of some aspects of the invention. This summary is not an extensive overview of the invention. Its sole purpose is to present some concepts of the invention in a simplified form as a prelude to the more detailed description that is presented later.

[0007] The objective of the present invention is to provide an anti-addiction against kratom or mitragynine addiction using a composition containing FPL 64176.

[0008] One aspect of the present invention provides a composition for use an anti-addiction against mitragynine addiction symptoms, characterized in that the composition comprises FPL 64176 as an active ingredient.

[0009] Another aspect of the present invention provides that the FPL 64176 is a 2,5-Dimethyl-4- [2-(phenyl methyl) benzoyl]-1H-pyrrole-3-carboxlic acid methyl ester.

[0010] Yet another aspect of the present invention provides that the FPL 64176 reverses mitragynine addiction by reducing levels of calretinin and dopamine in a subject’s brain.

[0011] Another aspect of the present invention provides that the concentration of the FPL 64176 in the composition is 0.9 nmol / L.

[0012] Yet another aspect of the present invention provides that the composition is formulated for administration in a pharmaceutically acceptable form to a subject in need thereof.

[0013] The present invention consists of features and a combination of parts hereinafter fully described and illustrated in the accompanying drawings, it is understood that various changes in the details may be made without departing from the scope of the invention or sacrificing any of the advantages of the present invention.BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

[0014] To further clarify various aspects of some embodiments of the present invention, a more particular description of the invention will be rendered by references to specific embodiments thereof, which are illustrated in the appended drawings. It is appreciated that these drawings depict only typical embodiments of the invention and are therefore not to be considered limiting of its scope. The invention will be described and explained with additional specificity and detail through the accompanying drawings in which:

[0015] illustrates a reversion of mitragynine addictive mechanism in the brain by treatment with FPL 64176 in accordance to an embodiment of the present invention;

[0016] illustrates a mitragynine addictive mechanism in the brain without FPL 64176 treatment in accordance to another embodiment of the present invention;

[0017] illustrates a formula structure for 2,5-Dimethyl-4-[2-(phenylmethyl) benzoyl]-1H-pyrrole-3-carboxlic acid methyl ester in accordance to an embodiment of the present invention;

[0018] is a graph showing a protein expression of calretinin varies across different treatments given in accordance to an embodiment of the present invention;

[0019] is a graph showing dopamine concentration varies across different treatments given after 4 days in accordance to an embodiment of the present invention;

[0020] is a graph showing protein expression of calretinin varies across different treatments given in accordance to an embodiment of the present invention;

[0021] is a graph showing protein expression of calretinin varies across different treatments given in accordance to an embodiment of the present invention; and

[0022] is a graph showing dopamine concentration varies across different treatments given after 8 days in accordance to an embodiment of the present invention.DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting but merely as a basis for claims. It should be understood that the drawings and detailed description thereto are not intended to limit the invention to the particular form disclosed, but on the contrary, the invention is to cover all modifications, equivalents and alternatives falling within the scope of the present invention as defined by the appended claims. As used throughout this application, the word "may" is used in a permissive sense (i.e., meaning having the potential to), rather than the mandatory sense (i.e., meaning must). Similarly, the words "include," "including," and "includes" mean including, but not limited to. Further, the words "a" or "an" mean "at least one” and the word "plurality" means one or more, unless otherwise mentioned. Where the abbreviations or technical terms are used, these indicate the commonly accepted meanings as known in the technical field.

[0024] The present invention is described hereinafter by various embodiments with reference to the accompanying drawing, wherein reference numerals used in the accompanying drawing correspond to the like elements throughout the description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiment set forth herein. Rather, the embodiment is provided so that this disclosure will be thorough and complete and will fully convey the scope of the invention to those skilled in the art. In the following detailed description, numeric values and ranges are provided for various aspects of the implementations described. These values and ranges are to be treated as examples only and are not intended to limit the scope of the claims. In addition, a number of materials are identified as suitable for various facets of the implementations. These materials are to be treated as exemplary, and are not intended to limit the scope of the invention.

[0025] The present invention discloses a composition for use as an anti-addiction against mitragynine addiction symptoms, characterized in that the composition comprises FPL 64176 as an active ingredient by reducing levels of calretinin and dopamine in the brain.

[0026] Reference is first made to, which shows a reversion of mitragynine addictive mechanism in the brain by treatment with FPL 64176. Rats were first injected with mitragynine for 4 days, followed by FPL 64176 injection for an additional 4 days. Post-treatment, brain dissection was performed to analyze the effects on calcium ion (Ca²⁺) channels.shows that the FPL 64176 treatment led to the unblocking of Ca²⁺ channels, resulting in decreased calretinin levels. This decrease in calretinin was associated with an increase in GABA neurotransmitter levels and a lack of activation in the dopamine system, ultimately leading to a reversal of kratom dependence. The composition is formulated for administration in a pharmaceutically acceptable form to a subject in need thereof.

[0027] In contrast,shows the addictive mechanism of mitragynine in the brain without FPL 64176 treatment. Rats were injected with mitragynine, followed by brain dissection.shows that mitragynine caused the blocking of Ca²⁺ channels, leading to an increase in calretinin levels. This increase in calretinin was associated with a decrease in GABA neurotransmitter levels and subsequent activation of the dopamine system, contributing to kratom dependence.

[0028] In accordance with an embodiment of the present invention, the FPL 64176 is a 2,5-Dimethyl-4- [2-(phenyl methyl) benzoyl]-1H-pyrrole-3-carboxlic acid methyl ester and it is a calcium channel modulator or activator. The concentration of the FPL 64176 used is 0.9 nmol / L.shows the formula structure for 2,5-Dimethyl-4-[2-(phenylmethyl) benzoyl]-1H-pyrrole-3-carboxlic acid methyl ester.

[0029] The present invention demonstrates that FPL 64176 can effectively decrease the negative effects of mitragynine addiction by targeting Ca²⁺ channels. Mitragynine, a main alkaloid in kratom, causes addiction by interfering with calcium Ca²⁺ function, resulting in higher calretinin levels and changed neurotransmitter activity. In particular, mitragynine leads to the inhibition of Ca²⁺ channels, leading to increased levels of calretinin. The increase in calretinin hinders GABAergic communication and promotes the stimulation of the dopamine system, leading to addiction and dependence.

[0030] FPL 64176 reverses these impacts by adjusting Ca²⁺ channel function which helps restore normal calcium ion movement. The treatment reduces the rise in calretinin amounts induced by mitragynine, consequently restoring normal GABA neurotransmitter function and preventing excessive dopamine system stimulation. By targeting these important elements, FPL 64176 reverses the addictive symptoms of kratom, successfully relieving withdrawal symptoms and reducing dependence behaviors.

[0031] Hereinafter, an example of the present invention will be provided for more detailed explanation by referring to Figures 4 to 8. The advantages of the present invention may be more readily understood and put into practical effect from this example. However, it is to be understood that the following example is not intended to limit the scope of the present invention in any way.ExamplesExample 1: Mitragynine-Induced Addiction

[0032] Example 1 describes an experiment conducted to investigate the underlying causes of addiction to mitragynine using Sprague-Dawley rats. Ten groups of rats were given different amounts of mitragynine (ranging from 0.25 mg / kg to 30 mg / kg) or ketum juice for four days in a row. The control group received a vehicle (non-active solution), and morphine served as a positive control for addiction. The rats’ behaviors were meticulously recorded, focusing on indicators of addiction such as headshakes, grooming, and writhing. At dosages starting from 5 mg of mitragynine and higher, observable changes in behavior were observed, indicating a noticeable development of physical dependence, such as an increase in headshakes and exploring. At the dosage of 30 mg, the rats showed a significant rise in grooming and writhing, providing additional evidence of addiction. The behavioral observations of the rats subjected to different treatments are shown in Table 1 below. The behavioral changes are scored through observation.

[0033] Table 1Example 2: Mechanism of Mitragynine Addiction

[0034] Pursuant to the behavioral observations, Example 2 describes an experiment conducted on the brain tissue harvested from the rats subjected to treatments in Example 1. Analysis of the brain tissue revealed significant increases in calretinin levels at 10 mg / kg and above, while dopamine levels increased at 5 mg / kg and above. This data shows how the addictive properties of mitragynine increase with dosage on how it affects neurotransmitter systems.shows a graph of a protein expression calretinin varies across different treatments given for Example 1.

[0035] Changes in dopamine levels caused by mitragynine are observed. High doses of mitragynine cause the blocking of Ca²⁺ channels in the hippocampus of the brain, as seen in rat studies. This blockade leads to a lack of Ca²⁺, causing an increase in calretinin, a protein that helps balance low levels of calcium. Increased levels of calretinin boost long-term potentiation (LTP) by decreasing the release of the GABA neurotransmitter. The dopamine modulation significantly affects the mesocorticolimbic circuit. More precisely, decreasing GABAergic activity removes inhibition from dopamine neurons, resulting in increased levels of dopamine. The activation of the dopamine system that occurs as a result is a major factor in addiction. However, at higher mitragynine doses (30 mg), there was a decrease in dopamine levels compared to lower doses because dopamine was broken down into dihydroxyphenylacetic (DOPAC) and homovanillic acid (HVA) through metabolism. This shows the intricate relationship between levels of neurotransmitters and behaviors related to addiction as shown in.Example 3: Reversal of Mitragynine Addiction

[0036] Example 3 is an experiment conducted to show reversal of the mitragynine addiction by separating rats into four groups: a control group, a mitragynine group, a combined mitragynine and FPL 64176 group 1 and group 2. Group 1 consisted of treating with mitragynine followed by FPL 64176 for 4 consecutive days, subsequently treat with Tween for another 4 days. Group 2 consisted of treating with mitragynine for 4 consecutive days and thereafter treating with FPL 64176 for the subsequent 4 days. As for FPL 64176-only group, the rats were treated with FPL 64176 for 4 days followed by Tween for another 4 days. Observations of behavior for 8 days indicated that rats exposed to mitragynine displayed notable signs of addiction. On the other hand, rats in the Mitragynine+FPL 64176 group (Group 1) and the FPL 64176-only group exhibited withdrawal behaviors that were comparable to those in the control group. In the 8 days observations experiments, both rats in the Group 1 and Group 2 Mitragynine+FPL 64176 and FPL 64176-only group exhibited withdrawal behaviors that were comparable to those in the control group. This indicates that FPL 64176 successfully reduces the addictive behaviors caused by mitragynine. These findings are further detailed in Tables 2 and 3 below, in which the behavioral observations are scored by observers.

[0037]

[0038] Table 3Example 4: Brain Analysis Post-Treatment

[0039] After the behavioral changes are observed, the brains of the rats are harvested and subjected to analysis. Example 4 shows the brain analysis after conducting behavioral assessments. In rats treated with mitragynine, calretinin levels were significantly higher compared to the control group. Nevertheless, administration of FPL 64176 resulted in a significant decrease in calretinin levels in these rats. This decrease is related to the demonstrated enhancements in behavior, indicating that FPL 64176 affects the calretinin levels, thus reversing the symptoms of addiction. Figures 6 and 7 present graphs illustrating the variation in calretinin protein expression across the different treatments used in Example 3.

[0040] Example 5: Dopamine Levels and Behavioral Correlations

[0041] Example 5 shows the dopamine levels and behavioral correlations. The dopamine levels in the brains of rats that received 30 mg mitragynine were similar to those in the control group because dopamine was converted into DOPAC and HVA, as shown in. Even with decreased dopamine levels, addictive behaviors like more headshakes, grooming, and writhing were still noticeable. Rats given either FPL 64176 with mitragynine or FPL 64176 alone had reduced dopamine levels compared to the control group but still showed behavior similar to the control group. This highlights the importance of FPL 64176's impact on dopamine levels, in addition to its effect on calretinin, in reversing addiction-related behaviors.

[0042] The examples show that FPL 64176 effectively combats the dependency induced by mitragynine through regulating calcium ion channel function, lowering calretinin and dopamine levels, and easing withdrawal symptoms and dependence actions. FPL 64176 is seen as a promising composition for treating kratom addiction and potentially other substance use disorders.

[0043] Various modifications to these embodiments are apparent to those skilled in the art from the description and the accompanying drawings. The principles associated with the various embodiments described herein may be applied to other embodiments. Therefore, the description is not intended to be limited to the embodiments shown along with the accompanying drawings but is to be providing broadest scope of consistent with the principles and the novel and inventive features disclosed or suggested herein. Accordingly, the invention is anticipated to hold on to all other such alternatives, modifications, and variations that fall within the scope of the present invention and appended claim.

[0044] It is to be understood that any prior art publication referred to herein does not constitute an admission that the publication forms part of the common general knowledge in the art.

[0045] In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

Claims

A composition for use as anti-addiction against mitragynine addiction symptoms, characterized in that the composition comprises FPL 64176 as an active ingredient.The composition as claimed in claim 1, wherein the FPL 64176 is a 2,5-Dimethyl-4- [2-(phenyl methyl) benzoyl]-1H-pyrrole-3-carboxlic acid methyl ester.The composition as claimed in claim 1, wherein the FPL 64176 reverses mitragynine addiction by reducing levels of calretinin and dopamine in a subject’s brain.The composition as claimed in claim 1, wherein the concentration of the FPL 64176 in the composition is 0.9 nmol / L.The composition as claimed in claim 1, wherein the composition is formulated for administration in a pharmaceutically acceptable form to a subject in need thereof.

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