WO2021249608A2 - A novel medicament for immune modulation and treating chronic or hyper inflammation - Google Patents
A novel medicament for immune modulation and treating chronic or hyper inflammation Download PDFInfo
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- WO2021249608A2 WO2021249608A2 PCT/EG2021/000016 EG2021000016W WO2021249608A2 WO 2021249608 A2 WO2021249608 A2 WO 2021249608A2 EG 2021000016 W EG2021000016 W EG 2021000016W WO 2021249608 A2 WO2021249608 A2 WO 2021249608A2
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- anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Definitions
- a novel medicament for immune modulation and treating chronic or hyper inflammation is provided.
- Present medicament comprises of (-)-anabasine as an active ingredient at 0.1: 0.15 mg/kg of body weight and a pharmacologically acceptable excipient , diluent or carrier .
- 2- (-)-Anabasine is pyridine and piperidine alkaloid .
- Alkaloids are a class of natural products known to have wide pharmacological activity and have great potential for the development of new drugs for several pathologies .
- CAP cholinergic anti-inflammatory pathway
- the brain cholinergic neurons Activated by peripheral or central stimuli, the brain cholinergic neurons deliver the information to efferent vagus nerves which innervate peripheral organs and release acetylcholine that can inhibit the production of pro-inflammatory cytokines by interacting with a7nAchR on inflammatory cells ⁇ 2 ⁇ .
- CAP could be implemented by activation of the macrophage a7 receptor by acetylcholine, nicotine, or other agonists, selectively inhibits production of pro-inflammatory cytokines while leaving anti-inflammatory cytokines undisturbed .
- Clinical studies have also reported negative correlation between concentrations of a7nAChR agonists and pro-inflammatory mediators' levels ⁇ 3 ⁇ .
- a7nAchR activation showed benefits for septic conditions by improving bacterial clearance of macrophages (4) . It also appeared to maintain integrity of pulmonary endothelium ⁇ 5 ⁇ . Furthermore ,cx7nAChR was also identified expressed in mitochondria, and it could regulate cytokines production and cellular apoptosis after being activated by intracellular acetylcholine (Ach) (6).
- cx7nAChR cascades might evoke multiple antiinflammatory mechanisms of T cells to maintain immune homeostasis as a7nAChR activation augmented the suppressive effects of CD4+CD25+ Tregs by up-regulating expressions of cytotoxic T- lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3), and decreasing IL-2 levels ⁇ 7 ⁇ .
- CTLA cytotoxic T- lymphocyte-associated antigen
- Foxp3 forkhead/winged helix transcription factor p3
- Activating cx7nAchR effectively diminished the production of pro- inflammatory cytokines and restored disturbed function of immune cells ⁇ 8 ⁇ .
- a7 nAChRs activation by specific agonists or positive allosteric modulators is emerging to have a key role in preventing or controlling inflammatory cytokines storm , that common complication not only of covid-19 and flu but of other respiratory diseases caused by coronaviruses such as SARS and MERS. but also associated with some non-infectious diseases such as chronic systemic inflammation and systemic inflammation . That strategy could be the key in preventing the coronavirus-19’s deadly effects , Besides, antecedent protective characteristics , pursuing to save lives until immune system can destroy it .
- systemic inflammation via an increase in proinflammatory cytokines, plays an important role in the pathogenesis of type 2 diabetes and metabolic syndrome, mostly by promoting insulin resistance; however, pancreatic beta cell function may also be affected via cytokine-induced apoptosis . And under a strong cytokine “pressure” by long-time of systemic inflammation and/or high concentration exposure to cytokines , islet can develop dysfunctional responses, which result in both impaired insulin secretion and insulitis development. In this perspective, cytokines pathways could represent potential therapeutic targets to control efficiently glucose metabolism and to prevent autoimmune damage.
- this administering causes nicotinic acetylcholine receptors heterologous desensitization which may has the pivotal role in normalizing and treating them permanently via the mechanism of nicotinic acetylcholine receptors function modulation bv phosphorylation beside the induced conformational changing in them particularly in alpha7 ligand binding domain .
- Receptors function modulation also may last longlv after removal of (L) anabasine due to the permanent loss of functional channels within prolonged desensitizationf S imasko et al.,1986;Boyd,1987; Lukas, 1991; Buisson and Bertrand, 2002).
- This administering also negatively adapts signaling pathways .
- ALL these mutations may lead to a specific cholinergic modulation of allergic effector cells.mast cells, basophils, and eosinophils.
- this desensitization also shapes cholinergic signaling which regulates and drives skeletal muscles contraction including airways smooth muscle. which plays an integral part in the pathophysiology of asthma.
- nicotinic acetylcholine receptors in the peripheral nervous system transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system , Heterologous desensitization also may thereafter leads these receptors to internalization .
- Role of receptor-mediated endocytosis is will recognized up take downregulation of transmembrane signal transduction but can also promote sustained signal transduction . It is actively implicated in transducing signals from the cell periphery to the nucleus .
- nAChRs are expressed in many regions of central and peripheral nervous system and x7 nAChR is present in various non- neuronal tissues as lung cells , epithelial cells , fibroblasts , endothelial cells , blood cells , gila and all types of immune cells antecedent mechanisms which downregulate incoming signals in last involved cells in the pathophysiology of asthma and (AD) permanently , likely have an integral key role in terminating asthma types , chest allergy and atopic dermatitis permanently .
Abstract
Present invention is a designation of a novel medicament for immune modulation and treating chronic or hyper inflammation. Its active ingredient is anabasine or its salt. It was designed for example to treat some of auto immune diseases permanently such as asthma and atopic dermatitis by one medication course, to stop the progression and development of diabetes type 2 in diabetics and restoring their blood sugar to normal with respect to administration in the disease early stages, to prevent the incidence and development of autoimmune Diabetes Type 1 resulted from T cell-mediated damage of pancreatic β-cells and loss of insulin production. Further, it plays a pivotal and protective role in treating hazardous infections caused by diverse pathogens to promote and accelerate recovery, including COVID -19 with its variants.
Description
Title Of The Invention
A novel medicament for immune modulation and treating chronic or hyper inflammation .
Technical Field
Therapeutic drugs discovery .
Background Art
In continuation to the filed patent application in the Egyptian office in June,
9 , 2020. serial number 768 / 2020 .
Disclosure Of The Invention
1- Present medicament comprises of (-)-anabasine as an active ingredient at 0.1: 0.15 mg/kg of body weight and a pharmacologically acceptable excipient , diluent or carrier .
2- (-)-Anabasine is pyridine and piperidine alkaloid . Alkaloids are a class of natural products known to have wide pharmacological activity and have great potential for the development of new drugs for several pathologies .
3- (-)-Anabasine has a full agonist action on a7 nicotinic acetylcholine receptors {Perspective in molecular toxinology - page 302 {which are pharmacological targets for inflammation , they are also widely expressed by cells of the immune system and by cells with a secondary role in pathogen defense.
4- The principal therapeutic effects of current medicament are supposed to be obtained from targeting alpha7 nicotinic acetylcholine receptor (a7nAChR {-mediated anti-inflammatory effects through modulation of pro-inflammatory cytokines. This “cholinergic anti-inflammatory pathway” (CAP) modulates the immune system through cholinergic mechanisms that act on alpha7 receptors expressed on macrophages and immune cells. (CAP), which is composed of efferent vagus nerve, acetylcholine and al subunit of the nicotinic acetylcholine receptor (a7nAchR), has been reported to attenuate excessive inflammation in critical settings{l}. Activated by peripheral or central stimuli, the brain cholinergic neurons deliver the information to efferent vagus nerves which innervate peripheral organs and release acetylcholine that can
inhibit the production of pro-inflammatory cytokines by interacting with a7nAchR on inflammatory cells {2} . (CAP) could be implemented by activation of the macrophage a7 receptor by acetylcholine, nicotine, or other agonists, selectively inhibits production of pro-inflammatory cytokines while leaving anti-inflammatory cytokines undisturbed . Clinical studies have also reported negative correlation between concentrations of a7nAChR agonists and pro-inflammatory mediators' levels {3} .
Additionally, a7nAchR activation showed benefits for septic conditions by improving bacterial clearance of macrophages (4) . It also appeared to maintain integrity of pulmonary endothelium {5} . Furthermore ,cx7nAChR was also identified expressed in mitochondria, and it could regulate cytokines production and cellular apoptosis after being activated by intracellular acetylcholine (Ach) (6).
On the other hand , cx7nAChR cascades might evoke multiple antiinflammatory mechanisms of T cells to maintain immune homeostasis as a7nAChR activation augmented the suppressive effects of CD4+CD25+ Tregs by up-regulating expressions of cytotoxic T- lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3), and decreasing IL-2 levels {7} . Activating cx7nAchR effectively diminished the production of pro- inflammatory cytokines and restored disturbed function of immune cells {8} .
Consequently , a7 nAChRs activation by specific agonists or positive allosteric modulators is emerging to have a key role in preventing or controlling inflammatory cytokines storm , that common complication not only of covid-19 and flu but of other respiratory diseases caused by coronaviruses such as SARS and MERS. but also associated with some non-infectious diseases such as chronic systemic inflammation and systemic inflammation . That strategy could be the key in preventing the coronavirus-19’s deadly effects , Besides, antecedent protective characteristics , pursuing to save lives until immune system can destroy it .
On the other hand , systemic inflammation, via an increase in proinflammatory cytokines, plays an important role in the pathogenesis of type 2 diabetes and metabolic syndrome, mostly by promoting insulin resistance; however, pancreatic beta cell function may also be affected via cytokine-induced apoptosis . And under a strong cytokine
“pressure” by long-time of systemic inflammation and/or high concentration exposure to cytokines , islet can develop dysfunctional responses, which result in both impaired insulin secretion and insulitis development. In this perspective, cytokines pathways could represent potential therapeutic targets to control efficiently glucose metabolism and to prevent autoimmune damage.
In a study using NOD mice, it was demonstrated that the neurons innervating pancreatic b-cells were lost before any damage in the islets could be detected {9} . - Current medicament at mentioned doses is described to be administered, for example by oral route twice per day for a period from 30 : 45 days for asthmatics and patients of chest allergy according to severity and condition development and from 21: 40 days for patients of atopic dermatitis according to severity and condition development . Herein medication is one course only . - As fundamental causes of asthma types , chest allergy and atopic dermatitis are not completely understood to date , administering current medicament as described terminates them permanently . mentioned unique effect is probably elucidated as anabasine has a full agonist action on a7 nicotinic acetylcholine receptors which found in the central and peripheral nervous system, muscle, and many other tissues of human body. At the neuromuscular junction . So repeated(-)- anabasine administering as described above to patients of same conditions at this minor concentration, for one course . so far from reported toxic dose and also teratogenic dose which was reported at 2.6 mg/kg animals body weight , this administering causes nicotinic acetylcholine receptors heterologous desensitization which may has the pivotal role in normalizing and treating them permanently via the mechanism of nicotinic acetylcholine receptors function modulation bv phosphorylation beside the induced conformational changing in them particularly in alpha7 ligand binding domain . Receptors function modulation also may last longlv after removal of (L) anabasine due to the permanent loss of functional channels within prolonged desensitizationf S imasko et al.,1986;Boyd,1987; Lukas, 1991; Buisson and Bertrand, 2002).This administering also negatively adapts signaling pathways . ALL these mutations may lead to a specific cholinergic modulation of allergic effector cells.mast cells, basophils, and eosinophils. Furthermore this desensitization also shapes cholinergic
signaling which regulates and drives skeletal muscles contraction including airways smooth muscle. which plays an integral part in the pathophysiology of asthma. It is responsible for acute bronchoconstriction, which is potentiated by constrictor hyper responsiveness, impaired relaxation and length adaptation .Thus this shaping may modulate or normalize its contractile properties . On the other hand , nicotinic acetylcholine receptors in the peripheral nervous system transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system , Heterologous desensitization also may thereafter leads these receptors to internalization . Role of receptor-mediated endocytosis is will recognized up take downregulation of transmembrane signal transduction but can also promote sustained signal transduction . It is actively implicated in transducing signals from the cell periphery to the nucleus . Herein noteworthy point , After receptors-mediated endocytosis process resulting it has been proposed that there are mechanisms((permanentlvi) downregulating incoming all antecedent signals are strong enough to shut down signaling completely without additional signal- transducing mechanisms .Considering that nAChRs are expressed in many regions of central and peripheral nervous system and x7 nAChR is present in various non- neuronal tissues as lung cells , epithelial cells , fibroblasts , endothelial cells , blood cells , gila and all types of immune cells antecedent mechanisms which downregulate incoming signals in last involved cells in the pathophysiology of asthma and (AD) permanently , likely have an integral key role in terminating asthma types , chest allergy and atopic dermatitis permanently . These mechanisms sequently are attributed to nAChRs internalization induced by heterologous desensitization resulted from prolonged nAChRs exposure to low concentration of a 7nAChR agonist (-)-anabasine .
References
1 -Pavlov VA, Tracey KJ. Controlling inflammation: the cholinergic antiinflammatory pathway. BiochemSoc Trans. 2006;34:1037-40
Su X, Lee JW, Matthay ZA, Mednick G, Uchida T, Fang X. et at. Activation of the alpha7 nAChR reduces acid-induced acute lung injury in mice and rats. Am J Respir Cell Mol Biol. 2007;37:186-92
2-Rosas-Ballina M, Tracey KJ. Cholinergic control of inflammation. J Intern Med. 2009;265:663-79 r> - :i - I \/ Q 7h ann M Yann H Rotchkina Gl. Watkins LR. et
al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature . 2000;405:458-62
Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007; 117:289-96
3- Kox M, Porripe JC, Gordinou De Gouberville MC, Van Der Hoeven JG, Hoedemaekers CW, Pickkers P. Effects of the alpha7 nicotinic acetylcholine receptor agonist GTS-21 on the innate
immune response in humans. Shock. 2011;36:5-11
4-Su X, Matthay MA, Malik AB. Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury. J Immunol. 2010;184:401-10
Sitapara RA, Antoine DJ, Sharma L, Patel VS, Ashby CR Jr, Gorasiya S. et al: The alpha7 nicotinic acetylcholine receptor agonist GTS-21 improves bacterial clearance in mice by restoring hyperoxia-compromised macrophage function. Mol Med. 2014;20:238-47
5-Costantini TW, Krzyzaniak M, Cheadle GA, Putnam JG, Hageny AM, Lopez N. et al. Targeting alpha-7 nicotinic acetylcholine receptor in the enteric nervous system: a cholinergic agonist prevents gut barrier failure after severe burn injury. Am J Pathol. 2012;181 :478-86
Roman J, Koval M. Control of lung epithelial growth by a nicotinic acetylcholine receptor: the other side of the coin. Am J Pathol. 2009; 175:1799-801
6-Gergalova G, Lykhmus O, Kalashnyk O, Koval L, Chernyshov V, Kryukova E. et al. Mitochondria express alpha7 nicotinic acetylcholine receptors to regulate Ca2+ accumulation and cytochrome c release: study on isolated mitochondria. PLoS One. 2012;7:e31361
Lu B, Kwan K, Levine YA, Olofsson PS, Yang H, Li J. et al. alpha7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release. Mol Med. 2014;20:350-8
7- Wang DW, Zhou RB, Yao YM, Zhu XM, Yin YM, Zhao GJ. et al. Stimulation of alpha7 nicotinic acetylcholine receptor by nicotine increases suppressive capacity of naturally occurring CD4+CD25+ regulatory T cells in mice in vitro. J PharmacolExp Ther. 2010;335: 553-61
8-Huston JM, Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R, Rosas- Ballina M. et al. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit Care Med. 2007;35:2762-8
Pavlov VA, Ochani M, Yang LH, Gallowitsch-Puerta M, Ochani K, Lin X. et al. Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit Care Med. 2007;35:1139-44
9- Saravia F, Homo-Delarche F. Is innervation an early target in autoimmune diabetes? Trends Immunol. (2003) 24:574-9. doi: 10.1016/j.it.2003.09.010
Claims
Claims
1- Use of anabasine in the preparation of a human medicament for immune modulation and treating chronic or hyper inflammation .
2- Use of anabasine in the preparation of a human medicament for the innate immune modulation and treating chronic or hyper inflammation .
3- The use according to either claim 1 or 2 is for the treatment of auto immune diseases and as an immune modulator medicament for these diseases .
4- The use according to either claim 1 or 2 is for the treatment of all infections types as microbial infections , protozoan infections , prion disease and other infections including those caused by ectoparasites , as an immune modulator and pivotal / protective treatment .
5- The use according to either claim 1 or 2 is for inhibiting or controlling hypercytokinemia induced by infectious or non-infectious etiologies as an immune modulator .
6- The use according to either claim 1 or 2 is for the therapeutic treatment of diabetes type 2 , stopping the progression and development of diabetes type 2 in diabetics and restoring their blood sugar to normal with respect to the administration in disease first / early stages as an immune modulator .
7- The use according to either claim lor 2 is a treatment for preventing the incidence and development of autoimmune Diabetes Type 1 , particularly which resulted from T cell- mediated damage of pancreatic b-cells and loss of insulin production as an immune modulator .
8- The use according to either claim 1 or 2 is for the therapeutic treatment of asthma types, chest allergy and atopic dermatitis permanently .
9- The use according to either claim 1 or 2 is for the therapeutic treatment of chronic systemic inflammation , systemic inflammation or systemic inflammation response syndrome particularly which due to internal (genetic mutations/variations) factors and as an immune modulator medicament .
10- The use according to claim 1 or 2 or 3 or 4 or 5 or 9 wherein subject in need to such treatment is an animal .
11- The pharmaceutical composition of the said medicament according to any preceding claim is comprising of anabasine as an active ingredient or its salt and a pharmacologically acceptable excipient , diluent or carrier.
12- The pharmaceutical composition of the said medicament according to claims from 1 to 10 is comprising of anabasine as an active ingredient at concentration of anabasine from 0.01 mg /kg : 3.5 mg / kg of body weight or its salt and a pharmacologically acceptable excipient , diluent or carrier.
13- The use according to any preceding claim wherein said medicament with said pharmaceutical composition is for systemic , local or topical administration .
14- The use according to any preceding claim wherein said medicament with said pharmaceutical composition further comprises or may be co-administered with an existing therapeutic agent for achieving , treating or managing any said purposes , diseases or conditions in claims 1 to 9 .
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2021286756A AU2021286756A1 (en) | 2020-06-09 | 2021-06-07 | A novel medicament for immune modulation and treating chronic or hyper inflammation |
| GB2300774.3A GB2612481A (en) | 2020-06-09 | 2021-06-07 | A novel medicament for immune modulation and treating chronic or hyper inflammation |
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| EG2020060768 | 2020-06-09 | ||
| EG2020060768 | 2020-06-09 |
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| WO2021249608A2 true WO2021249608A2 (en) | 2021-12-16 |
| WO2021249608A3 WO2021249608A3 (en) | 2022-02-03 |
| WO2021249608A4 WO2021249608A4 (en) | 2022-04-07 |
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| PCT/EG2021/000016 WO2021249608A2 (en) | 2020-06-09 | 2021-06-07 | A novel medicament for immune modulation and treating chronic or hyper inflammation |
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| AU (1) | AU2021286756A1 (en) |
| GB (1) | GB2612481A (en) |
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Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2142610C (en) * | 1992-08-31 | 2003-09-16 | William R. Kem | Anabaseine derivatives useful in the treatment of degenerative diseases of the nervous system |
| US5977144A (en) * | 1992-08-31 | 1999-11-02 | University Of Florida | Methods of use and compositions for benzylidene- and cinnamylidene-anabaseines |
| US20050288333A1 (en) * | 2004-06-08 | 2005-12-29 | Kem William R | Controlling angiogenesis with anabaseine analogs |
| US7662965B2 (en) * | 2006-01-26 | 2010-02-16 | Cornerstone Therapeutics, Inc. | Anabaseine derivatives, pharmaceutical compositions and method of use thereof |
| CN104169269A (en) * | 2011-08-29 | 2014-11-26 | Rcp发展股份有限公司 | Products for anti-inflammation support |
| US10667515B2 (en) * | 2016-11-20 | 2020-06-02 | Iowa State University Research Foundation, Inc. | (S)-5-ethynyl-anabasine, derivatives thereof, and related compositions and methods of making and using |
| MX2020010908A (en) * | 2018-04-16 | 2021-03-25 | Poviva Corp | Compositions infused with nicotine compounds and methods of use thereof. |
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2021
- 2021-06-07 WO PCT/EG2021/000016 patent/WO2021249608A2/en active Application Filing
- 2021-06-07 GB GB2300774.3A patent/GB2612481A/en active Pending
- 2021-06-07 AU AU2021286756A patent/AU2021286756A1/en active Pending
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| Publication number | Publication date |
|---|---|
| WO2021249608A4 (en) | 2022-04-07 |
| AU2021286756A1 (en) | 2023-03-23 |
| WO2021249608A3 (en) | 2022-02-03 |
| GB2612481A (en) | 2023-05-03 |
| GB202300774D0 (en) | 2023-03-08 |
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