Pathways

Mevalonic aciduria, also called MVA, is an extremely rare inherited inborn error of metabolism (IEM) and an autosomal recessive disorder caused by a defective mevalonate kinase gene. It is manifested by high levels of mevalonic acid in the urine and other body fluids. Approximately 30 patients with mevalonic aciduria (MVA) have been reported worldwide. MVA is classified as a disorder of branched-chain organic acid metabolism because the substrate for the reaction with mevalonate kinase, HMG-CoA, is a product of leucine catabolism. Mevalonate kinase is an enzyme that plays a critical role in the synthesis of cholesterol, ubiquinone for the electron transport chain, and dolichol for the synthesis of the oligosaccharides for glycoproteins. MVA is also considered a disorder of cholesterol metabolism and isoprenoid biosynthesis. Affected individuals have short stature, psychomotor retardation, progressive cerebellar ataxia, febrile crises, hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rashes. Individuals also exhibit dysmorphic features and progressive visual impairment. Life expectancy with individuals with MVA is relatively short and death may occur from infancy to late childhood. MVA is one of two types of mevalonate kinase deficiency. MVA is the most severe type while the less severe type is called hyperimmunoglobulinemia D syndrome (HIDS).

Mevalonic aciduria, also called MVA, is an extremely rare inherited inborn error of metabolism (IEM) and an autosomal recessive disorder caused by a defective mevalonate kinase gene. It is manifested by high levels of mevalonic acid in the urine and other body fluids. Approximately 30 patients with mevalonic aciduria (MVA) have been reported worldwide. MVA is classified as a disorder of branched-chain organic acid metabolism because the substrate for the reaction with mevalonate kinase, HMG-CoA, is a product of leucine catabolism. Mevalonate kinase is an enzyme that plays a critical role in the synthesis of cholesterol, ubiquinone for the electron transport chain, and dolichol for the synthesis of the oligosaccharides for glycoproteins. MVA is also considered a disorder of cholesterol metabolism and isoprenoid biosynthesis. Affected individuals have short stature, psychomotor retardation, progressive cerebellar ataxia, febrile crises, hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rashes. Individuals also exhibit dysmorphic features and progressive visual impairment. Life expectancy with individuals with MVA is relatively short and death may occur from infancy to late childhood. MVA is one of two types of mevalonate kinase deficiency. MVA is the most severe type while the less severe type is called hyperimmunoglobulinemia D syndrome (HIDS).

Mevalonic aciduria, also called MVA, is an extremely rare inherited inborn error of metabolism (IEM) and an autosomal recessive disorder caused by a defective mevalonate kinase gene. It is manifested by high levels of mevalonic acid in the urine and other body fluids. Approximately 30 patients with mevalonic aciduria (MVA) have been reported worldwide. MVA is classified as a disorder of branched-chain organic acid metabolism because the substrate for the reaction with mevalonate kinase, HMG-CoA, is a product of leucine catabolism. Mevalonate kinase is an enzyme that plays a critical role in the synthesis of cholesterol, ubiquinone for the electron transport chain, and dolichol for the synthesis of the oligosaccharides for glycoproteins. MVA is also considered a disorder of cholesterol metabolism and isoprenoid biosynthesis. Affected individuals have short stature, psychomotor retardation, progressive cerebellar ataxia, febrile crises, hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rashes. Individuals also exhibit dysmorphic features and progressive visual impairment. Life expectancy with individuals with MVA is relatively short and death may occur from infancy to late childhood. MVA is one of two types of mevalonate kinase deficiency. MVA is the most severe type while the less severe type is called hyperimmunoglobulinemia D syndrome (HIDS).

This pathway illustrates the mexiletine targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Mexiletine is a Class 1B antiarrhythmic drug with electrophysiological effects similar to lidocaine and tocainide. Mexiletine preferentially binds to voltage-gated sodium channels in their inactive state inhibiting the sodium current (I-Na) responsible for the rapid depolarization phase of the cardiac myocyte action potential. Inhibition of I-Na increases the cells’ threshold of excitability. The membrane-stabilizing effects of mexiletine causes a slight decrease in the action potential duraction. Mexiletine was developed as an alternative to lidocaine, which is subject to rapid hepatic metabolism and has a short half-life of only 15 – 30 minutes. Mexiletine is subject to less first pass metabolism compared to lidocaine and can be administered as chronic oral therapy. Mexiletine may be used to treat ventricular arrhythmias.

Mexiletine is a class 1B antiarrhythmic agent used in the treatment of documented ventricular arrhythmias that warrant treatment. Mexiletine (INN) (sold under the brand names Mexitil and Namuscla) is a medication used to treat abnormal heart rhythms, chronic pain, and some causes of muscle stiffness. Common side effects include abdominal pain, chest discomfort, drowsiness, headache, and nausea. It works as a non-selective voltage-gated sodium channel blocker and belongs to the Class IB group of anti-arrhythmic medications. Mexiletine, like lidocaine, inhibits the inward sodium current required for the initiation and conduction of impulses, thus reducing the rate of rise of the action potential, Phase 0. It achieves this reduced sodium current by inhibiting sodium channels. Mexiletine decreases the effective refractory period (ERP) in Purkinje fibers in the heart. The decrease in ERP is of lesser magnitude than the decrease in action potential duration (APD), which results in an increase in the ERP/APD ratio.

Mexiletine is an oral drug used as a Type 1B antiarrhythmic drug. It is used to treat conditions including sustained ventricular tachycardia, ventricular pre-excitation and cardiac dysrhythmias. Mexiletine acts in neurons where it inhibits voltage gated sodium channels in the pre synaptic neurons. In neurons, voltage gated sodium channels allow sodium to come into the neuron triggering the depolarization phase. the potassium channels are responsible for the repolarization phase to bring the neuron back to resting potential. The action potentials created travel down the axon of the neuron and at the nerve terminal, calcium channels open, allowing calcium to enter the cell. Calcium entry causes synaptic vesicles containing neurotransmitters like glutamate to fuse with the membrane and expel the neurotransmitter into the synapse. Glutamate binds to AMPA and NMDA receptor on the post synaptic neurons where they cause excitation of the neuron. By blocking the voltage gated sodium channels, mexiletine prevents the depolarization phase, inhibiting action potential generation and the release of excitatory neurotransmitter like glutamate. Pre and post synaptic neuronal firing are therefore reduced. Mexiletine works as a “use-dependent” block. This means that it preferentially binds to channels that are being opened. In neurons that are repetitively firing, their sodium channels are being opened more often, and as a result, mexiletine is able to produce a greater block in these neurons. It also possesses some anticholinergic and local anesthetic properties. Side effects of mexiletine include nausea, vomiting, headaches, feeling dizzy, or feeling hot and flushed.

Mezlocillin is a broad-spectrum penicillin beta-lactam antibiotic used in the treatment of bacterial infections caused by susceptible, usually gram-positive, organisms. Mezlocillin binds to and inactivates penicillin-binding proteins (PBP) located on the inner membrane of the bacterial cell wall. Inactivation of PBPs interferes with the cross-linkage of peptidoglycan chains necessary for bacterial cell wall strength and rigidity. This interrupts the final stage of bacterial cell wall synthesis and results in the weakening of the bacterial cell wall and eventually causing cell lysis.

mglur5--> erk