Duloxetine Hydrochloride (Cymbalta)

“To live is to suffer, to survive is to find some meaning in the suffering.” Nietzsche’s words ring true to many. Depression is romanticized at times due to its association with poets and artists, but in reality depression, especially major depressive disorder (MDD), can be debilitating. There are two types of depression: MDD and bipolar, also known as manic–depressive illness. Severe changes in mood is the primary clinical manifestation of both disorders. MDD presents as feelings of intense sadness and despair with little drive for either socialization or communication; physical changes such as insomnia, anorexia, and sexual dysfunction can also occur. Mania is manifested by excessive elation, irritability, insomnia, hyperactivity, and impaired judgment. It may afflict as much as 1% of the population. MDD is among the most common psychiatric disorders in humans, affecting up to 10% of men and 20% of women over the course of their lives. Among those affected, 28% experience a moderate degree of functional impairment, while 59% experience severe reductions in their normal functional ability. About 19 million Americans suffer from depression per year. In terms of disease burden, MDD ranks as the fourth most costly illness in the world, with estimated annual costs of depression in the US amounting to approximately $43.7 billion. While we all agree that depression exists, we do not all agree on the causes of depression. The exact causes of depression are not definitively known. However, in the 1950s, it was observed that in addition to its other pharmacological properties, reserpine (a Rauwolfia alkaloid) induced a depressive state in normal patients and also depleted levels of neurotransmitters such as norepinephrine (NE) and serotonin (5-HT). This observation and others led to the hypothesis that the biological basis of major mood disorders may include abnormal monoamine neurotransmission. Substances such as NE, serotonin, and dopamine (DA) mediate neurotransmission. These substances are released from presynaptic neurons, cross the synaptic gap, and interact with receptors on the postsynaptic cells. The synthesis, transmission, and processing of these neurotransmitters provide a number of points of intervention through which a pharmacological agent may affect transmission.

Characterization of 2β(R)-17-O-AcetylajmaIan: Acetylesterase — a Specific Enzyme Involved in the Biosynthesis of the Rauwolfia Alkaloid Ajmaline

A novel enzyme was isolated, partially purified (217-fold) and characterized from cell suspen­sion cultures of Rauwolfia serpentina Benth. The enzyme catalyzes one of the late biochemical reactions in the biosynthesis of ajmaline by hydrolysis of 17-O-acetylated alkaloids of the ajmalan group forming the appropriate deacetylated compounds. This esterase exhibits an unusually high substrate selectivity and exclusively accepts acetylated ajmaline derivatives with the naturally occurring 2β(R)-configuration. The properties of the enzyme were determined showing an optimum pH at 7.5, an isoelectric point of pH 4.9 and a relative molecular weight of 33 ± 2 kDa. Inhibition studies of enzyme activity point to the necessity of SH-groups. The esterase seems not to be inhibited by ajmaline. the end product of the pathway. The highest enzyme activities were observed in leaves and cell suspension tissues of the tribe Rauwolfieae which are known to synthe­size ajmaline and its congeners. The specific function of the esterase in the biosynthesis of the later alkaloids was established.