Browsing Pathways

Acetylsalicylic acid, also known as ASA or aspirin, belongs to a class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs). In addition to its anti-inflammatory properties, aspirin also acts as an analgesic, antipyretic and antithrombotic agent. Like most other NSAIDs, aspirin exerts its therapeutic effects by inhibiting prostaglandin G/H synthase 1 and 2, better known as cyclooxygenase-1 and -2 or simply COX-1 and -2. COX-1 and -2 catalyze the conversion of arachidonic acid to prostaglandin G2 and prostaglandin G2 to prostaglandin H2. Prostaglandin H2 is the precursor to a number of other prostaglandins, such as prostaglandin E2, involved in pain, fever and inflammation. The antipyretic properties of aspirin arise from inhibition of prostaglandin E2 synthesis in the preoptic region of the hypothalamus. Interference with adhesion and migration of granulocytes, polymorphonuclear leukocytes and macrophages at sites of inflammation account for its anti-inflammatory effects. The analgesic effects of aspirin likely occur due to peripheral action at the site of injury and possibly within the CNS. Aspirin is unique from other NSAIDs in that it is an irreversible COX inhibitor. Aspirin irreversibly acetylates a serine side chain of COX rendering the enzyme inactive. Enzyme activity can only be regained by production of more cyclooxygenase. This unique property of aspirin and its higher selectivity for COX-1 over COX-2 makes it an effective antiplatelet agent. Platelets contain COX-1, a key enzyme in the production thromboxane A2 (TXA2), which is a potent inducer of platelet aggregation. Since platelets lack the ability to make more enzyme, TXA2 production is inhibited for the lifetime of the platelet (approximately 8 – 12 days). Aspirin is commonly used at low doses to prevent cardiovascular events such as strokes and heart attacks. At higher doses, aspirin may be used as an analgesic, anti-inflammatory and antipyretic. Aspirin may cause gastric irritation and bleeding by inhibiting the synthesis of prostaglandins that enhance and maintain the protective gastric mucous layer.

Ketoprofen (also known as (RS)-2-(3-benzoylphenyl)-propionic acid) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to treat rheumatoid arthritis, osteoarthritis, dysmenorrhea, and to alleviate moderate pain.. Ketoprofen can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Because of hypothalamus action, antipyretic effects may occur which will lead to vasodilation, increased peripheral blood flow and subsequent heat dissipation.

Oxaprozin (also named Daypro, Dayrun) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to relieve pain (analgesic) and reduce fever (antipyretic). Oxaprozin is also a type of ophthalmic anti-inflammatory medicines which may be used to help prevent eye constrict for pupil during surgery. Oxaprozin can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Since prostaglandin is the messenger molecules in the process of inflammation; hence, inhibition of prostaglandin synthesis can reduce the pain and inflammation.

Trisalicylate-Choline (also named Choline Magnesium Trisalicylate) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to treat pain and fever. Trisalicylate-Choline can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Decreased prostaglandin synthesis in many animal model's cell is caused by presence of trisalicylate-choline.

L-2-Hydroxyglutaric Aciduria (D-2-Hydroxyglutaric Aciduria ) is an autosomal recessive disease caused by a mutation in the L2HGDH gene which codes for L-2-Hydroxygluarate dehydrogenase. A deficiency in this enzyme results in accumulation of L-2-Hydroxyglutaric acid in plasma, spinal fluid, and urine; and L-lysine in plasma and spinal fluid. Symptoms, which present at birth, include ataxia, hypotonia, mental retardation, and seizures. Premature death often results. D-2-Hydroxyglutaric Aciduria is an autosomal recessive disease caused by a mutation in the D2HGDH gene which does for D-2-Hydroxygluarate dehydrogenase. A deficiency in this enzyme results in accumulation of D-2-Hydroxyglutaric acid in plasma, spinal fluid, and urine; oxoglutaric acid in urine; and gabba-aminobutyric acid in spinal fluid. Symptoms, which present at birth, include ataxia, hypotonia, mental retardation, and seizures. Premature death often results.

Hyperinsulinism-hyperammonemia syndrome (HHS; Glutamate dehydrogenase 1; GLUD1), an inherited condition, is caused by a defect in the GLUD1 gene which codes for mitochondrial glutamate dehydrogenase 1. It is a mitochondrial matrix enzyme, with a key role in the nitrogen and glutamate (Glu) metabolism and the energy homeostasis. An excessive activity of this enzyme results in high insulin and ammonia levels in blood; decrease level of glucose in blood. Symptoms and signs include shakiness, weakness, seizure, rapid pulse and confusion. Maintain normoglycemia is essencial to prevent neurologic damage. Some medications can be used to suppress insulin secretion.

Glycogen storage disease type 1A (GSD1A), or von Gierke disease, is caused by a defect in the G6PC gene which codes for Glucose-6-phosphatase. Glucose-6-phosphatase hydrolyzes glucose-6-phosphate to glucose and is responsible for the regulation of blood glucose level. A defect in this enzyme results in accumulation of glycogen in affected tissues, like liver and kidney; decreased glucose level; and accumulation of lactate. Glycogen storage disease type 1A causes clinically significant end-organ disease with significant morbidity. Usually it presents in childhood. Symptoms include seizures, irritability, pallor, hypotonia, tremors, loss of consciousness, apnea and hepatomegaly. There is no cure for glycogen storage disease type 1A. Diet therapy can help to prevent hypoglycemia and reduce the symptoms. Liver transplantation may be indicated in cases of hepatic malignancy.

Triosephosphate isomerase deficiency is a genetic disorder caused by a mutation in the TPI1 gene. The mutation of this gene causes the production of enzymes that are unstable or enzymes that have reduced activity. This means that cells have reduced energy supplies as glycolysis is compromised. This disorder causes anemia, movement problems and muscle weakness. As a result of the lack of red blood cells to carry oxygen through the body, patients may experience fatigue and shortness of breath. Movement problems appear in early infancy, typically before the age of 2 in patients with this disorder. Treatment includes blood transfusions.

Corticosterone methyloxidase type I (CMO-I) deficiency, also known as 18-hydroxylase deficiency or aldosterone deficiency among other names, is a genetic disorder that is autosomally linked and caused by a defective CYP11B2 gene. This gene encodes the cytochrome P450 11B2 mitochondrial protein, also called aldosterone synthase, which is used to catalyze the conversion of 18-hydroxycorticosterone to aldosterone. This leads to a decrease in the amount of aldosterone present in the cells, which is responsible for an increased amount of salt excreted in the urine, known as salt wasting. In CMO-I deficiency, aldosterone levels are so low that they are undetectable in plasma.

Congenital Lipoid Adrenal Hyperplasia (CLA),also called steroid 20-22 desmolase deficiency and lipoid CAH, is an autosomal recessive disorder and caused by a defective cholesterol side-chain cleavage enzyme. Cholesterol side-chain cleavage enzyme catalyzes the conversion of cholesterol into 20α-Hydroxycholesterol which is also a substrate of cholesterol side-chain cleavage enzyme. This disorder is characterized by a large accumulation of cholesterol in the mitochondrial. Symptoms of the disorder is not clear. Extra glucocorticoid and mineral replacement could be the potential treatments.