New indications of varenicline

Abstract

The present invention relates to the repurposing of the active substance varenicline for the treatment of medical conditions requiring analgesic-antipyretic (pain-relieving / fever-reducing), anti-inflammatory, and antiplaletet.

Description

[0001] New Indications of Varenicline

[0002] Field of the Invention

[0003] This invention relates to the use of the active substance varenicline, which is currently employed in smoking cessation therapy, in symptoms of inflammatory conditions such as pain, fever, redness and edema, as well as in coagulation disorders.

[0004] Non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used in analgesic, antipyretic, and anti-inflammatory treatments, play an effective role in the management of various inflammatory and pain-related conditions. NSAIDs act by inhibiting cyclooxygenase (COX) enzymes, thereby reducing prostaglandin (PG) synthesis, and in this way alleviate inflammation and pain. Within the same class, low dose (80 mg) acetylsalicylic acid (Aspirin) is also used as antiplatelet medicine to prevent coagulation. However, serious adverse effects have been reported in connection with the use of these drugs. During long-term use, adverse effects may arise on the gastric mucosa, renal functions, and the cardiovascular system.

[0005] It is known that NSAIDs can lead to gastric ulcers and gastrointestinal bleeding by suppressing the synthesis of PG (PGE2), which protects the gastric mucosa. These adverse effects are more pronounced in NSAIDs that inhibit COX-1. Inhibition of COX-1 reduces the formation of protective PGE2, rendering patients with a history of ulcers especially vulnerable. Although drugs that selectively inhibit the COX-2 enzyme have the potential to reduce these adverse effects, they cannot completely eliminate them.

[0006] Renal adverse effects also occur with the use of NSAIDs. Inhibition of COX-1 and COX-2 enzymes decreases the production of PGE2 and prostacyclin (PGI2) in the kidneys, negatively affecting renal functions. In a patient with normal kidney function, inhibition of PG synthesis usually does not pose a significant problem. However, in patients with renal impairment, the reduction in PG synthesis has more severe adverse effects, and when reduced by NSAIDs, it may lead to acute renal dysfunction (drug-induced acute kidney injury), fluid and electrolyte imbalances, renal papillary necrosis, and nephrotic syndrome. These adverse effects of NSAIDs are a major concern particularly for elderly patients and individuals at risk of kidney disease.

[0007] Cardiovascular adverse effects may also increase with the use of NSAIDs. These include thromboembolic events such as myocardial infarction and intravascular clotting, as well as atrial fibrillation (cardiac rhythm disturbances). The increased cardiovascular risks associated with NSAIDs, particularly during long-term use, represent a significant problem. Diclofenac is associated with adverse cardiovascular outcomes. It appears that diclofenac is the NSAID associated with the highest reported increase in such events. Therefore, the long-term use of NSAIDs should be carefully monitored in individuals at risk of cardiovascular disease.

[0008] As is well known, PGs produced via the COX enzyme in the arachidonic acid pathway mediate the cardinal signs of inflammation, including pain, increased body temperature (fever), redness, edema, inflammation, and loss of function. Today, corticosteroids and NSAIDs, which act on the COX pathway, are the most used agents in the treatment of inflammatory diseases to control pain and inflammation. However, these drugs are associated with gastrointestinal, hematological, cardiovascular, and hepatotoxic (liver-damaging) adverse effects, and there is currently no available alternative drug to NSAIDs that are widely used in clinical practice.

[0009] Selective inhibitors of COX-2 (Coxibs), which is expressed in immune system cells such as macrophages and functions within the inflammatory pathway, have been shown to increase the incidence of serious cardiovascular events. Beyond this, efforts have been made to develop new coxib derivatives aimed at reducing the cardiovascular risks associated with traditional NSAIDs. Starting with lumiracoxib, several dual-action compounds have been developed within the same molecule that possess both COX-2 inhibitory activity and thromboxane receptor antagonist (receptor-blocking) activity. However, none of these compounds have reached the stage of therapeutic use. Lumiracoxib, despite opening the path for the development of safer new coxibs as alternatives for pain management in patients at high cardiovascular risk, was not approved by the FDA (United States Food and Drug Administration) due to hepatotoxicity concerns.

[0010] The present invention, which is the subject of this application, proposes the repurposing of the active substance varenicline — already FDA-approved for use as an adjunct in smoking cessation therapy, for the treatment of inflammatory conditions owing to its analgesic (pain-relieving), antipyretic (fever-reducing), and anti-inflammatory properties. Varenicline selectively binds to a4p2 nicotinic acetylcholine receptors (nAChRs), increasing dopamine release and thereby reducing the desire to smoke. In addition, varenicline may alleviate inflammation by inhibiting the release of pro-inflammatory cytokines (TNF-a, IL-ip, IL-6). The use of varenicline for this new indication offers a safer and more effective alternative compared to existing treatment options. Considering the gastrointestinal, renal, and cardiovascular adverse effects caused by the long-term use of NSAIDs, the use of varenicline in the treatment of inflammatory conditions allows for the prevention of these side effects and enhances therapeutic efficacy. In addition to its anti-inflammatory effects, varenicline also exerts analgesic, antipyretic, and antiplatelet actions, thereby providing important advantages in clinical practice by reducing treatment costs and improving patient compliance.

[0011] In conclusion, the repurposing of varenicline as an analgesic, antipyretic, and antiinflammatory agent makes a significant contribution to public health. This novel use provides a safer and more effective option compared to current therapeutic alternatives, representing a major advancement in the management of pain and inflammation. By reducing treatment costs and improving adherence, it offers substantial benefits in the management of medical conditions. This invention presents the medical community with a new and effective therapeutic option, creating an opportunity for significant progress in the treatment of inflammatory diseases.

[0012] Varenicline (Champix®, Pfizer) is a molecule used in smoking cessation therapy that has a structure like the alkaloid cytisine (a plant-derived basic / alkaline compound) found in yellow broom (Cytisus species). Its effectiveness in smoking cessation is achieved through its partial agonist activity at central nervous system a4p2nAChRs (nicotinic acetylcholine receptors), which stimulates the receptor to produce physiological effects. Varenicline has also been demonstrated to be a potent full agonist of a7nAChRs.

[0013] In a transient middle cerebral artery ischemia model in mice, one week of varenicline treatment was shown to increase impaired forelimb use and reduce inflammation in the corpus striatum, as demonstrated by immunohistochemical analysis. In a murine model of emphysema induced by inhalation of porcine pancreatic elastase (PPE), varenicline administration reduced inflammation via a7nAChR activation and increased alveolar expansion, confirmed by immunohistochemical analysis. In this study, varenicline significantly reduced the numbers of macrophages, neutrophils, and T cells in the tissue through a7 nAChR activation.

[0014] Furthermore, a randomized controlled trial in smoking patients demonstrated that three months of varenicline therapy reduced oxidative stress, arteriosclerosis, and endothelial damage. These findings suggest that varenicline may suppress inflammatory responses. A limited number of recent studies have proposed that the anti-inflammatory effects of varenicline are mediated via a7nAChR activation.

[0015] Although the manufacturer (Pfizer) reported in 1999 that Champix® (varenicline 1 mg and 0.5 mg capsules) might be beneficial in inflammatory bowel diseases, no indication approval has been granted for this use, and the product has only been approved as an adjunct agent in smoking cessation therapy. The patent of Champix®, the varenicline-containing product manufactured by Pfizer, expired in May 2020. This allows any pharmaceutical company to obtain authorization for this new indication and market the product under a new brand name.

[0016] The use of varenicline for these new medical indications carries a lower potential for adverse effects compared to NSAIDs, since its anti-inflammatory activity does not rely on COX enzyme inhibition.

[0017] In the invention subject to this application, we have demonstrated for the first time that varenicline, used in smoking cessation therapy, has the potential to exert anti-inflammatory, analgesic, and antipyretic effects by suppressing elevated prostaglandin levels in inflammatory conditions. Our studies further showed that this effect of varenicline is associated with the reduction of inflammation, pain, platelet activation (blood clotting), and fever (increased body temperature).

[0018] The prior art does not disclose the technical features described in the present invention, nor the technical effects achieved by it. In current medical applications, there is no reported method of using varenicline that provides anti-inflammatory, analgesic, and antipyretic effects.

[0019] Summary of the Invention

[0020] The purpose of this invention is to utilize varenicline — currently used in smoking cessation therapy — for the treatment of inflammatory diseases by applying its anti-inflammatory, analgesic, antipyretic, antioxidant, and / or antiplatelet activities as a potential alternative to NSAIDs, which are associated with serious adverse effects.

[0021] Another objective of this invention is to provide a method of using varenicline that has the potential to exert anti-inflammatory effects by suppressing the cyclooxygenase (COX) pathway, which is upregulated during inflammation, thereby inhibiting PG synthesis and reducing COX-1, COX-2, PG, and ROS levels.

[0022] Description of the Figures:

[0023] Figure 1. Potential analgesic, antipyretic, antiplatelet, and anti-inflammatory effects of varenicline, demonstrated through the suppression of increased levels of inflammatory parameters such as cyclooxygenase enzymes (COX-1 and COX-2) and prostaglandins (PGE2, the stable analog of PGI2 [6-keto PGF2a], and TXA2) in an in vitro inflammation model induced by lipopolysaccharide (LPS) in macrophages.

[0024] Figure 2. Comparative illustration of the potential analgesic, antipyretic, antiplatelet, and anti-inflammatory effects of varenicline against currently used treatments — including non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and celecoxib, as well as the steroidal anti-inflammatory drug dexamethasone — via suppression of increased inflammatory parameters (COX-1, COX-2, PGE2, 6-keto PGF2a as the stable analog of PGI2, and TXA2) in an in vitro inflammation model induced by LPS in macrophages.

[0025] Figure 3. Potential contribution of a7 nicotinic acetylcholine receptors (a7nAChRs) to the analgesic, antipyretic, antiplatelet, and anti-inflammatory effects of varenicline, demonstrated by the suppression of increased inflammatory parameters (COX-1, COX-2, PGE2, 6-keto PGF2a, and TXA2) in an in vitro inflammation model induced by LPS in macrophages.

[0026] Figure 4. Potential antioxidant effect of varenicline, demonstrated through the suppression of increased reactive oxygen species (ROS) levels in an in vitro inflammation model induced by LPS in macrophages, and the possible contribution of a7nAChRs to this effect. Abbreviations: MEC = mecamylamine, a non-selective nAChR antagonist; MLA = methyllycaconitine, a selective a7nAChR antagonist.

[0027] Description of the Invention

[0028] The present invention relates to the repurposing of varenicline — used in smoking cessation therapy — for the treatment of inflammatory diseases by suppressing the cyclooxygenase (COX) pathway, thereby exerting analgesic, antipyretic, antiinflammatory and antioxidant properties, as well as antiplatelet potential.

[0029] It has been determined within the scope of the invention that varenicline, unexpectedly, exerts analgesic, antipyretic, antioxidant, and antiplatelet effects in inflammatory states by suppressing the COX pathway. The anti-inflammatory effect of varenicline is further supported — beyond prior findings — through the suppression of this pathway (see, for example, Figures 1-3).

[0030] Varenicline, an a7 nicotinic acetylcholine receptor (a7nAChR) agonist, was evaluated in murine RAW 264.7 macrophages employed as an in vitro inflammation model following lipopolysaccharide (LPS) stimulation, with the following objectives:

[0031] a) To investigate, in comparison with a steroidal anti-inflammatory agent (dexamethasone), a COX-2 selective inhibitor (celecoxib), and a non-selective COX inhibitor (ibuprofen), the inhibitory effects of varenicline on prostaglandins (PGE2, 6- keto-PGF2a as the stable analog of PGI2, and TXA2) and on their biosynthetic enzymes COX-1 and COX-2.

[0032] b) To investigate the inhibitory effects of varenicline on reactive oxygen species (ROS), and the contribution of a7nAChRs to this effect, using methyllycaconitine (a selective a7nAChR antagonist) and mecamylamine (a non-selective nAChR antagonist).

[0033] Considering the side effects of potent anti-inflammatory drugs, our results suggest that varenicline may be repurposed as a safer therapeutic agent for this purpose.

[0034] It has been observed that varenicline, through its ability to suppress prostaglandin (PG) synthesis, can be applied in the treatment of inflammatory diseases.

[0035] In our in vitro inflammation model using murine macrophage cell lines, the anti-inflammatory efficacy of varenicline appeared comparable to that of dexamethasone, a potent steroidal antiinflammatory agent used as a reference, based on its suppressive effect on pro-inflammatory cytokines, (previous application)

[0036] For the first time, our data showed that varenicline has the potential to exert antiinflammatory effects by suppressing COX-1, COX-2, PG, and ROS levels, which are elevated during inflammation.

Claims

CLAIMS1. A composition comprising varenicline, characterized by its use in the treatment of inflammatory diseases through suppression of the cyclooxygenase (COX) pathway.

2. The composition according to Claim 1, characterized by its use in the treatment of inflammatory diseases through suppression of COX-1, COX-2, prostaglandin, and / or reactive oxygen species (ROS) levels.

3. The composition according to Claim 1, characterized in that it is analgesic.

4. The composition according to Claim 1, characterized in that it is antipyretic.

5. The composition according to Claim 1, characterized in that it is antithrombotic.

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