Pathways

Akt (v-Akt Murine Thymoma Viral Oncogene) is a serine kinase that is involved in mediating various biological responses, such as inhibition of apoptosis and stimulation of cell proliferation. Activation of Akt can begin with several events, mainly the binding of a ligand to a receptor in the cell membrane. Most common ligands activating Akt include growth factors, cytokines, mitogens and hormones. The actions of Akt in the cell are numerous and diverse, but all result in anti-apoptosis, or pro-cell proliferation effects. These physiological roles of Akt include involvement in metabolism, protein synthesis, apoptosis pathways, transcription factor regulation and the cell cycle. The downstream targets of Akt include BAD (BCL2 Antagonist of Cell Death), Caspase-9, FKHRL (Forkhead Transcriptional Factor), IKK (I-KappaB Kinase), and mTOR (Mammalian Target of Rapamycin). Akt inhibits apoptosis by phosphorylating the BAD component of the BAD/BclXL (Bcl2 Related Protein Long Isoform) complex. Phosphorylated BAD binds to 14-3-3, causing dissociation of the BAD/BclXL complex and allowing cell survival. Akt activates IKK, which ultimately leads to NF-KappaB activation and cell survival. Other direct targets of Akt are members of the FKHRL. In the presence of survival factors, Akt1 phosphorylates FKHRL1, leading to the association of FKHRL1 with 14-3-3 proteins and its retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation and target gene activation. Within the nucleus, FKHRL1 most likely triggers apoptosis by inducing the expression of genes that are critical for cell death, such as the Fas ligand (TNF superfamily, member 6) gene. Another notable substrate of Akt is the protease Caspase-9. Phosphorylation of Caspase-9 decreases apoptosis by directly inhibiting the protease activity. Akt may also be involved in activation of the nutrient-dependent Thr/Ser kinase, mTOR.

Metabolites of Ajmaline are predicted with biotransformer.

Ajmaline is an antiarrhythmic used to manage a variety of forms of tachycardias. It can be found under the brand names Gilurytmal, Ritmos, and Aritmina. An alkaloid found in the root of Rauwolfia serpentina, among other plant sources. It is a class Ia antiarrhythmic agent that apparently acts by changing the shape and threshold of cardiac action potentials. Ajmaline produces potent sodium channel blocking effects and a very short half-life which makes it a very useful drug for acute intravenous treatments. The drug has been very popular in some countries for the treatment of atrial fibrillation in patients with the Wolff–Parkinson–White syndrome and in well tolerated monomorphic ventricular tachycardias. It has also been used for many years as a drug to challenge the conduction system of the heart in cases of bundle branch block and syncope. In these cases, abnormal prolongation of the HV interval has been taken as a proof for infrahisian conduction defects tributary for permanent pacemaker implantation. The class I antiarrhythmic agents interfere with the sodium channel. A class IA agent lengthens the action potential (right shift) which brings about improvement in abnormal heart rhythms. This drug in particular has a high affinity for the Nav 1.5 sodium channel. Some side effects of using ajmaline may include warm flushes, tingling skin, vertigo, and eye twitches.