Pathways

Trastuzumab is a recombinant humanized IgG1 monoclonal antibody to the human epidermal growth factor receptor 2 (HER2) that is administered intravenously for the treatment of HER2 positive breast cancer (adjuvant therapy), metastatic HER2-positive breast cancer and HER2 positive gastric cancer. HER-2 is over expressed in these cancer cells and therefore trastuzumab targets these cancer cells over normal cells. The HER-2 receptor is a transmembrane tyrosine kinase receptor that consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain. HER-2 forms heterodimers with other EGFR proteins such as HER-1, HER-2 or HER-4 when they bind to ligands or may form homodimers with other HER-2 proteins. Following dimerization, transphosphorylation/ autophosphorylation of the tyrosine residues on the cytoplasmic domain of these receptors occurs. This activates a number of intracellular signaling pathways such as the raf/MAPK pathway, PI3K/akt pathway and PLC/PKC pathway. The activation of these pathways recruits nuclear factors that regulate genes involved in cell-cycle progression, proliferation, growth and survival. Trastuzumab binds to the extracellular domain of HER-2 and prevents dimerization. Inhibiting dimerization prevents the activation of the downstream intracellular signaling cascades initiated by the HER proteins. This therefore prevents the gene regulation necessary to promote cell-cycle progression, proliferation, growth and survival. Nuclear transcription affected by these pathways cannot occur, and therefore essential proteins are not produced. This causes cell cycle arrest and suppresses cell growth and proliferation and eventually the cancer cell undergoes apoptosis. Side effects such as headache, chills, cough, back pain, weakness and fatigue, upper respiratory symptoms including rhinitis and pharyngitis, angioedema, cardiotoxicity, anaphylaxis and GI disturbances including nausea, vomiting, abdominal pain, diarrhea.

Trastuzumab is an anti-EGFR drug used in the treatment of HER2-positive breast cancer. EGFR is linked multiple signalling pathways involved in tumour growth and angiogenesis such as the Ras/Raf pathway and the PI3K/Akt pathways. These pathways ultimately lead to the activation of transcription factors such as Jun, Fos, and Myc, as well as cyclin D1, which stimulates cell growth and mitosis. Uncontrolled cell growth and mitosis leads to cancer. Trastuzumab acts as an anticancer drug by binding to the extracellular domain of the EGFR and preventing its activation by epidermal growth factor. This in turn inhibits downstream signalling and prevents tumour growth.

Travoprost is a prostaglandin E1 analog that reduces the risk of NSAID-induced gastric ulcers. Travoprost stimulates prostaglandin receptors on parietal cells in the stomach to reduce gastric acid secretion. Travoprost activates prostaglandin EP3 receptors in parietal cells. Activation of this receptor triggers the Gi protein signaling cascade, inhibiting adenylate cyclase. Adenylate cyclase is responsible for converting ATP to cAMP, therefore, inhibition of adenylate cyclase reduces cytosolic cAMP concentration. cAMP is responsible for activating protein kinase A. With lower concentrations of cAMP, less protein kinase A is activated. Protein kinase A activates the proton pump in the luminal membrane of the parietal cell. The role of the proton pump is to secrete acid (H+) into the stomach lumen. With reduced protein kinase A activation, this decreases the activity of the proton pump, fewer H+ ions are pumped into the lumen, reducing the acidity and thus allowing stomach ulcers to heal and reducing the pain caused by the ulcers. Travoprost may also promote ulcer healing by increasing mucus and bicarbonate secretion and thickening the mucosal bilayer so the mucosa can generate new cells.

Metabolites of Travoprost are predicted with biotransformer.

Trazodone is an ethanolamine class H1 antihistamine used to treat insomnia and allergy symptoms such as hay fever and hives. It is also used with pyridoxine in the treatment of nausea and vomiting in pregnancy. 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. Wakefulness is regulated by histamine in the tuberomammillary nucleus, a part of the hypothalamus. Histidine is decarboxylated into histamine in the neuron. Histamine is transported into synaptic vesicles by a monoamine transporter then released into the synapse. Normally histamine would activate the H1 histamine receptor on the post-synaptic neuron in the tuberomammillary nucleus. Trazodone inhibits the H1 histamine receptor, preventing the depolarization of the post-synaptic neuron. This prevents the wakefulness signal from being sent to the major areas of the brain, causing sleepiness.

Trazodone is a drug that sometimes acts as a 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. 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. Trazodone 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.