Pathways

Azathioprine is an immunosuppressor prodrug. It is used to treat rheumatoid arthritis, Crohn's disease, and ulcerative colitis. Also, azathioprine is used in the prevention of renal transplant rejection. This molecule is the prodrug of 6-mercaptopurine, also known as mercaptopurine, it is metabolized nonenzymatically by glutathione. Mercaptopurine is also a medication and an immunosuppressor. Azathioprine was synthesized in 1956 to produce a 6-mercaptopurine derivative with a better therapeutic index. The main activity of the drug is to induce cell apoptosis through the modulation of the ras-related C3 botulinum toxin substrate 1 (Rac1) in the B and T cells. Specifically, the 6-thioguanine triphosphate, one metabolite of azathioprine, modulates the activity of Rac1. Additionally, the molecule is thought to cause the inhibition of the synthesis of purine as well as to incorporate itself (6-thioguanine metabolite) in the DNA. Azathioprine is administered both as an oral tablet and as an intravenous injection.

Azathioprine is an immunosuppressive agent classified as a purine antagonist. It is used to treat rheumatoid arthritis as well as function to prevent kidney/renal transplant rejection through it's immunosuppressive effects. It's mechanism of action is tied to 6-mercaptopurine's mechanism of action as azathioprine is a prodrug to 6-mercaptopurine. Azathioprine is metabolized in the liver where it is converted to 6-mercaptopurine and transported to the site of action through the blood. 6-Mercaptopurine upon being taken up into cells through transporters is converted into it's metabolites that have specific actions. Many of 6-mercaptopurine's metabolites are expelled from the cell as there are drug resistant pumps which reduce the efficacy of the drug. 6-Mercaptopurine's metabolite 6-methylthiopurine 5'-monophosphate ribonucleotide inhibits the enzyme amidophosphoribosyltransferase which is apart of a key step in the purine de novo purine synthesis pathway. Amidophosphoribosyltransferase catalyzes the reaction between phosphoribosyl pyrophosphate and glutamine to produce 5-phosphoribosylamine and glutamic acid. This reaction is one of the first in the purine de novo synthesis pathway and it's inhibition halts downstream activity of the pathway to produce adenine, adenosine, guanine and guanosine. Adenine, adenosine, guanine and guanosine are key compounds for the replication of DNA and transcription of RNA so inhibition to it's production effects the cell's survival. Thiodeoxyguanosine 5'-diphosphate, another metabolite from 6-mercaptopurine, is incorporated into DNA creating fraudulent DNA that cannot be used also killing the cell. 6-Mercaptopurine's metabolite thioguanosine 5'-triphosphate inhibits ras-related c3 botulinum toxin substrate 1, a small GTPase protein that regulates many cellular events including apoptosis of activated T-cells. Through it's inhibition, activated T-cells aren't regulated anymore and undergo apoptosis lowering the immune system's defense, hence the immunosuppression. Azathioprine administration is either through an oral route or through intravenous injections.

Azathioprine is a purine antimetabolite prodrug that exerts cytotoxic effects via three mechanisms: via incorporation of thiodeoxyguanosine triphosphate into DNA and thioguanosine triphosphate into RNA, inhibition of de novo synthesis of purine nucleotides, and inhibition of Ras-related C3 botulinum toxin substrate 1, which induces apoptosis of activated T cells. Azathioprine is first converted _in vivo_ to mercaptopurine in the liver. Mercaptopurine then travels through the bloodstream and is transported into cells via nucleoside transporters. Mercaptopurine is converted to thioguanosince diphosphate through a series of metabolic reactions that produces the metabolic intermediates, thioinosine 5’-monophosphate, thioxanthine monophosphate, and thioguanosine monophosphate. Thioguanosine diphosphate is then converted via a thiodeoxyguanosine diphosphate intermediate to thiodeoxyguanosine triphosphate, which is incorporated into DNA. Thioguanosine diphosphate is also converted to thioguanosine triphosphate which is incorporated into RNA. The thioguanosine triphosphate metabolite also inhibits Ras-related C3 botulinum toxin substrate 1, a plasma membrane-associated small GTPase that regulates cellular processes, inducing apoptosis in activated T cells. Finally, de novo synthesis of purine nucleotides is inhibited by the methyl-thioinosine 5’-monophosphate metabolite, which inhibits amidophosphoribosyl-transferase, the enzyme that catalyzes one of the first steps in this pathway.

Azelastine is a histamine H1-receptor antagonist used intranasally to treat allergic and vasomotor rhinitis and in an ophthalmic solution to treat allergic conjunctivitis. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. H1-antihistamines act on H1 receptors in T-cells to inhibit the immune response, in blood vessels to constrict dilated blood vessels, and in smooth muscles of lungs and intestines to relax those muscles. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. H1-antihistamines act on H1 receptors in T-cells to inhibit the immune response, in blood vessels to constrict dilated blood vessels, and in smooth muscles of lungs and intestines to relax those muscles. Allergies causes blood vessel dilation which causes swelling (edema) and fluid leakage. Azelastine also inhibits the H1 histamine receptor on bronchiole smooth muscle myocytes. This normally activates the Gq signalling cascade which activates phospholipase C which catalyzes the production of Inositol 1,4,5-trisphosphate (IP3) and Diacylglycerol (DAG). Because of the inhibition, IP3 doesn't activate the release of calcium from the sarcoplasmic reticulum, and DAG doesn't activate the release of calcium into the cytosol of the endothelial cell. This causes a low concentration of calcium in the cytosol, and it, therefore, cannot bind to calmodulin.Calcium bound calmodulin is required for the activation of myosin light chain kinase. This prevents the phosphorylation of myosin light chain 3, causing an accumulation of myosin light chain 3. This causes muscle relaxation, opening up the bronchioles in the lungs, making breathing easier.

Azelastine is a second-generation H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.

Azelastine is a histamine H1-receptor antagonist used intranasally to treat allergic and vasomotor rhinitis and in an ophthalmic solution to treat allergic conjunctivitis. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. H1-antihistamines act on H1 receptors in T-cells to inhibit the immune response, in blood vessels to constrict dilated blood vessels, and in smooth muscles of lungs and intestines to relax those muscles. Allergies causes blood vessel dilation which causes swelling (edema) and fluid leakage. Azelastine inhibits the H1 histamine receptor on blood vessel endothelial cells. This normally activates the Gq signalling cascade which activates phospholipase C which catalyzes the production of Inositol 1,4,5-trisphosphate (IP3) and Diacylglycerol (DAG). Because of the inhibition, IP3 doesn't activate the release of calcium from the sarcoplasmic reticulum, and DAG doesn't activate the release of calcium into the cytosol of the endothelial cell. This causes a low concentration of calcium in the cytosol, and it, therefore, cannot bind to calmodulin. Calcium bound calmodulin is required for the activation of the calmodulin-binding domain of nitric oxide synthase. The inhibition of nitric oxide synthesis prevents the activation of myosin light chain phosphatase. This causes an accumulation of myosin light chain-phosphate which causes the muscle to contract and the blood vessel to constrict, decreasing the swelling and fluid leakage from the blood vessels caused by allergens.

Azelastine is a histamine H1-receptor antagonist used intranasally to treat allergic and vasomotor rhinitis and in an ophthalmic solution to treat allergic conjunctivitis. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. H1-antihistamines act on H1 receptors in T-cells to inhibit the immune response, in blood vessels to constrict dilated blood vessels, and in smooth muscles of lungs and intestines to relax those muscles. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.