Pathways

Meclizine (Meclozine) is a first-generation piperazine 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.

Meclizine is an 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. Allergies causes blood vessel dilation which causes swelling (edema) and fluid leakage. Meclizine 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.

Meclizine is 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. 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.

Meclofenamic acid is a nonsteroidal anti-inflammatory (NSAID) with antipyretic and antigranulation activities. It also inhibits prostaglandin biosynthesis. It is used for the treatment of mild to moderate pain. It targets the prostaglandin G/H synthase-1 (COX-1) and prostaglandin G/H synthase-2 (COX-2) in the cyclooxygenase pathway. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 convert arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. Meclofenamic acid inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Moreover, in vitro, meclofenamic acid was found to be an inhibitor of human leukocyte 5-lipoxygenase activity; that may be responsible for the anti-inflammatory action of this drug. Meclofenamic acid is administered as an oral capsule.

Metabolites of Medifoxamine are predicted with biotransformer.

Medium-chain acyl-CoA dehydrogenase deficiency, which is also known as MCADD, is a rare inherited inborn error of metabolism (IEM) medium-chain fatty acid metabolism. The estimated birth prevalence of MCADD is between 1 in 4 900 to 1 in 27 000 in Caucasian populations and is highest in Northern European individuals. Worldwide birth prevalence is 1 in 14 600. MCADD is an autosomal recessive disorder associated with a mutation in the enzyme medium-chain acyl-CoA dehydrogenase (MCAD). MCAD is an enzyme that catalyzes the initial step in each cycle of medium-chain fatty acid beta-oxidation in the mitochondria of cells. MCAD’s action results in the introduction of a trans-double-bond between C2 and C3 of the acyl-CoA thioester substrate. Defects in MCAD leads to the accumulation of medium-chain fatty acids in the blood, lowering the blood's pH and causing acidosis. Likewise, individuals with MCADD have difficulty metabolizing fats. As a result, MCADD is characterized by intolerance to prolonged fasting, recurrent episodes of hypoglycemic coma with medium-chain aciduria, impaired ketogenesis, and low plasma and tissue carnitine levels. Intolerance to fasting and hypoglycemia result from the inability to gain energy and make sugar from fat stores, which is how most excess energy from food is stored. It is rare for the signs and symptoms of MCADD to first appear during adulthood. Typically, they manifest during infancy or early childhood and can include lethargy, hypoglycemia, and vomiting. MCAD-deficient individuals are at risk for breathing difficulties, liver problems, seizures, brain damage, coma, and sudden death. Fasting or illnesses (e.g. viral infections) can trigger related problems. Infants and young children with MCADD need to eat frequently to prevent hypoglycemia or a metabolic crisis. MCADD is occasionally mistaken for Reye syndrome, a severe disorder that may manifest in children during apparent recovery from viral infections such as flu or chickenpox. The majority of Reye syndrome cases are associated with aspirin use during these viral infections.