Browsing Pathways

Valdecoxib is an oral non-steroidal anti-inflammatory drug given to treat osteoarthritis and dysmenorrhoea. It targets the 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 converts 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. Valdecoxib enters the cell via the solute carrier family 22-member 8 transporter and inhibits the action of COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2. The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Side effects of valdecoxib may include diarrhea, nausea, upset stomach, headache, indigestion, stomach cramps, upper respiratory tract infection (nose, throat, or sinuses), back pain, dizziness, gas, muscle pain, rash, and stuffy nose.

(2E)-Glutaconylcarnitine is an acylcarnitine. The general role of acylcarnitines is to transport acyl-groups, organic acids and fatty acids, from the cytoplasm into the mitochondria so that they can be broken down to produce energy. First,(2E)-glutaconic acid is transported into the cell via the long-chain fatty acid transport protein 1 (FATP1), where it undergoes a reaction to form(2E)-glutaconyl-CoA, facilitated by the Long-chain fatty-acid CoA ligase 1 protein, which adds a CoA to the compound. (2E)-glutaconyl-CoA then enters a reaction with L-carnitine, which is transported into the cell by the organic cation/carnitine transporter 2, to form (2E)-glutaconylcarnitine, catalyzed by carnitine O-palmitoyltransferase. This enzyme resides in the mitochondrial outer membrane, and as the reaction takes place, the (2E)-glutaconylcarnitine is moved into the mitochondrial intermembrane space. Following the reaction, (2E)-glutaconylcarnitine is transported into the mitochondrial matrix by a mitochondrial carnitine/acylcarnitine carrier protein found in the mitochondrial inner membrane. Once in the matrix, (2E)-glutaconylcarnitine and CoA are catalyzed by the carnitine O-palmitoyltransferase 2 enzyme found in the mitochondrial inner membrane to once again form (2E)-glutaconyl-CoA and L-carnitine. (2E)-Glutaconyl-CoA then enters into mitochondrial beta-oxidation to form aceytl-CoA. Acetyl-CoA can go on to enter the TCA cycle, or it can react with L-carnitine to form L-acetylcarnitine and CoA in a reaction catalyzed by Carnitine O-acetyltransferase. This reaction can occur in both directions, and L-acetylcarnitine and CoA can react to form acetyl-CoA and L-carnitine in certain circumstances. Finally, acetyl-CoA in the cytosol can be catalyzed by acetyl-CoA carboxylase 1 to form malonyl-CoA, which inhibits the action of carnitine O-palmitoyltransferase 1, preventing (2E)-glutaconyl-CoA from forming (2E)-glutaconylcarnitine and preventing it from being transported into the mitochondria. Malonyl-CoA can also react to form acetyl-CoA, in a reaction that removes a carbon dioxide molecule catalyzed by malonyl-CoA decarboxylase.

Diazepam is a benzodiazepine with anticonvulsant, anxiolytic, muscle relaxant, sedative and amnesic effects. Due to its effects it's used to treat severe anxiety disorders, short term insomnia, acute repetitive seizures, alcohol withdrawal. and possibly epilepsy. Diazepam binds to various regions of the brain and spinal cord where GABA A receptors are. It binds to an allosteric site between the alpha and gamma subunits of the receptor increasing the inhibitory effects of GABA. Diazepam is administered orally, through intramuscular injection or rectally in a gel form. If administered orally, absorption is rapidly and completely absorbed from the GI epithelium but decreases in the presence of food. Due to its high affinity for plasma proteins, diazepam also has a high volume of distribution and can cross the blood brain barrier. Overdosing of diazepam usually has the symptoms of more intense therapeutic effects with extreme overdosage leading to coma, cardio-respiratory depression and apnoea. Overdose of benzodiazepines like diazepam should be closely monitored especially if the patient has taken other respiratory depressing drugs like alcohol as it could be fatal.

Cisplatin is a chemotherapeutic alkylating agent that causes intrastand crosslinks that is more difficult to repair than regular DNA. Cisplatin diffuses into the cell either through the membrane or through metal transporter like CTR1. In the cytosol, the low concentration of chloride relative to the extracellular space causes hydrolysis of cisplatin into its aquo complex which goes into the nucleus and binds to DNA bases. It preferentially binds to guanine but can also bind to adenine bases. It's used for treated testicular cancer, ovarian cancer and other solid tumors and it targets all parts of the cell cycle (cell-cycle non specific). Most patients will eventually develop resistance to cisplatin though as cancer cells will decrease uptake or pump it out of the cell through exocytotic vesicles. Patients will has have increased production of cellular thiols like GSH which inactivates the aquated cisplatin by forming a complex with it. Cisplatin is administered intravenously usually to the site of the tumor. Cisplatin can cause nephrotoxicity due to ROS generation as well as nausea and vomiting.

Ifosfamide is an alkylating agent administered intravenously that is used in chemotherapy against various cancers. It works by crosslink DNA guanine residues. Ifosfamide is converted into 4-hydroxyifosfamide through various hepatic CYP450. 4-Hydroxyifosfmamide can be converted to its tautomer aldophosphamide or to an inactive form 4-ketoifosfamide. Aldophosphamide is taken into cancer/tumor cells where it is converted to its cytotoxic form isophosphamide mustard which crosslinks the DNA after being converted to it's carbocation form. In the process of isophosphamide mustard production, acrolein is produced which is a potent lung irritant and causes hemorrhagic cystitis. Side effects of ifosfamide is myelosuppression, immunosuppression and hemorrhagic cystitis (caused by acrolein).

Irinotecan is a semi-synthetic analogue of camptothecin which is a topoisomerase IB inhibitor. It is used to treat colorectal cancer. It's mechanism of action against topoisomerase I is that it forms a tertiary complex between the DNA and the topoisomerase I enzyme causing double strand breaks. It first has to be metabolized by liver carboxylesterase 1 into SN-38, which is the active metabolite that inhibits topoisomerase. SN-38 can be inactivated by UGT1A1 into SN-38 glucuronide which upregulated in some individuals leading to irinotecan resistance. Individuals might also have a reduced function variant of UGT1A1 which can lead to increased metabolism of irinotecan and leads to irinotecan toxicity. Toxicity of irinotecan leads to gastrointestinal complications as well as nausea, vomiting and headaches. Irinotecan is administered usually intravenously as a solution.

Spectinomycin is an aminocyclitol antibiotic used to treat susceptible strains of gram-negative bacteria, Neisseria gonorrhoeae. It is used (as its dihydrochloride pentahydrate) to treat gonorrhea. It is produced by the bacterium Streptomyces spectabilis. Spectinomycin is an inhibitor of protein synthesis in the bacterial cell by binding to the 30S ribosomal subunit. As a result, this agent interferes with the initiation of protein synthesis and with proper protein elongation. This eventually leads to bacterial cell death.