Pathways

Brexanolone can be found under the brand name Zulresso, and it is the first drug to have ever been approved by the US FDA specifically for the treatment of postpartum depression (PPD) in adult females. Since PPD, like various other types of depression, is characterized by feelings of sadness, worthlessness or guilt, cognitive impairment, and/or possibly suicidal ideation, it is considered a life-threatening condition. Studies have consequently found that PPD can genuinely have profound negative effects on the maternal-infant bond and later infant development. The development and availability of brexanolone for the treatment of PPD in adult females subsequently provides a new and promising therapy where few existed before. In particular, the use of brexanolone in treating PPD is surrounded with promise because it acts in part as a synthetic supplement for possible deficiencies in endogenous brexanolone (allopregnanolone) in postpartum women susceptible to PPD whereas many commonly used anti-depressive medications elicit actions that may modulate the presence and activity of substances like serotonin, norepinephrine, and/or monoamine oxidase but do not mediate activities directly associated with PPD like natural fluctuations in the levels of endogenous neuroactive steroids like allopregnanolone. Brexanolone is a neuroactive steroid that occurs naturally (referred to as natural allopregnanolone) in the body when the female sex hormone progesterone is metabolized. This steroid compound is also believed to exhibit activity as a barbiturate-like, positive allosteric modulator of both synaptic and extrasynaptic GABA(a) receptors. In doing so, brexanolone can enhance the activity of GABA at such receptors by having GABA(a) receptor calcium channels open more often and for longer periods of time. Furthermore, it is believed that brexanolone elicits such action on GABA(a) receptors at a binding site that is distinct from those associated with benzodiazepines. Concurrently, GABA is considered the principal inhibitory neurotransmitter in the human body. When GABA binds to GABA(a) receptors found in neuron synapses, chloride ions are conducted across neuron cell membranes via an ion channel in the receptors. With enough chloride ions conducted, the local, associated neuron membrane potentials are hyperpolarized - making it more difficult or less likely for action potentials to fire, ultimately resulting in less excitation of the neurons, like those involved in neuronal pathways that may be in part responsible for eliciting certain traits of PPD like stress, anxiety, etc. Postpartum depression (PPD) is a mood disorder that can affect women after childbirth. Women with PPD experience feelings of extreme sadness, anxiety, and exhaustion that can make it difficult or even dangerous for them to perform various daily activities or care for themselves or for others, including newborn. Although the exact pathophysiology of PPD remains unknown, it is believed that altered profiles and rapid, unpredictable fluctuations in the blood concentrations of neuroactive steroids like endogenous brexanolone (among others), GABA, and GABA receptors occur in women who are at risk of PPD after childbirth. In particular, within the context of PPD, it is proposed that endogenous brexanolone levels can quickly drop or fluctuate variedly after childbirth and that GABA(a) receptor levels and expression are decreased and down-regulated throughout pregnancy. Such fluctuations and decreases may consequently leave women susceptible to the possibility of PPD. As a medication, synthetic brexanolone can subsequently facilitate a return of positive allosteric modulator GABA(a) modulation while GABA(a) receptor levels and expression gradually return to normal in the time following postpartum. As such, studies suggest the potential for the development of brexanolone as a new mechanism for treatment of PPD that is directly related to the underlying pathophysiology as opposed to many other antidepressant medications whose pharmacological actions are usually entirely unrelated. In the liver, progesterone is metabolized to 5-alpha-dihydroprogesterone (5-alpha-DHP) via 5-alpha-reductase, which is then further metabolized by 3-alpha-hydroxysteroid-dehydrogenase (3-alpha-HSD) to allopregnanolone. Some side effects of using brexanolone may include dizziness, drowsiness, fainting, and a spinning sensation.

Bretylium is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Bretylium passes through the liver and is then excreted from the body mainly through the kidney.

Brassinosteroids are plant hormones used in many processes including growth, immunity and the development of plants. This pathway depicts brassinosteroid synthesis in a cell from the species Arabidopsis thaliana, or mouse-ear cress. This species in particular has provided recent insight on brassinosteroid’s role in plant growth through molecular genetics. The pathway begins with campesterol, a compound created through steroid biosynthesis. As brassinosteroid synthesis moves along, compounds react inter-connectedly with many different proteins, to finally create 26-hydroxybrassinolide. Some of the proteins commonly used in this pathway include cytochrome P450 90B1, cytochrome P450 90D2, cytochrome P450 85A2 and 3-epi-6-deoxocathasterone 23-monooxygenase CYP90D1. These proteins are found in various locations throughout the plant cell, such as the membrane, the endoplasmic reticulum, and the mitochondrial matrix. The proteins that a dark green indicate reactions taking place in the plasma membrane.

Bovine thrombin is a coagulation factor also known under the brand name Thrombin-jmi, used to prevent bleeding during surgery. It is bovine thrombin that behaves like endogenous thrombin, converting fibrinogen to fibrin necessary for clot formation. The speed at which the clotting takes place is dependent on the concentration of bovine thrombin and fibrinogen present. It is metabolized in the same way as endogenous thrombin, it is inactivated by endogenous plasma inhibitors. It is administered as a topical and then cleared via thrombin inhibitor complexes and or through internalization and degradation by the endothelium.

Bosutinib is a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML), a cancer characterized by increased and unregulated growth of white blood cells in the bone marrow and the accumulation of these cells in the blood. The cause of CML pathophysiology is the BCR-ABL fusion protein - the result of a genetic abnormality known as the Philadelphia chromosome in which Abelson Murine Leukemia viral oncogene homolog 1 (ABL1) translocates within the Breakpoint Cluster Region (BCR) gene on chromosome 22. BCR-ABL is a cytoplasm-targeted constitutively active tyrosine kinase that activates several oncogenic pathways which promote increased cell proliferation and survival including the MAPK/ERK Pathway, the JAK-STAT Pathway, and the PI3K/Akt pathway. Bosutinib is considered a second generation BCR-ABL inhibitor (Imatinib being the progenitor) that inhibits BCR-ABL activity by binding a highly conserved ATP binding site to effectively lock the tyrosine kinase in an inactive conformation. As a result, phosphate is unable to be transferred from ATP to activate oncogenic signalling cascades. For greater detail, refer to the pathway titled BCR-ABL Action in CML Pathogenesis. Bosutinib is able to bind ABL with greater affinity than Imatinib, perhaps due to its ability to bind both inactive and intermediate conformations of the protein. It is therefore administered to patients with Imatinib resistance. Bosutinib may have a safer toxicity profile than both Imatinib and Dasatinib because it does not significantly inhibit the receptors KIT and PDGFR. Notably, Bosutinib is ineffective against the T315I mutation in BCR-ABL, and further research is necessary.