PubMed · 10674772
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J L Miller. 2000-02-01. Study provides additional support for hypericum extract.. https://doi.org/10.1093/ajhp%2F57.3.208
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The plasma membrane transporters that clear extracellular serotonin (5-HT) and norepinephrine (NE), serotonin transporters (SERTs) and NE transporters (NETs), have received considerable attention over the past four decades because of their roles in amine neurotransmitter inactivation. In addition, they interact with many centrally active drugs, including multiple classes of antidepressants such as the serotonin-selective reuptake inhibitors, typified by fluoxetine (Prozac), and the more recently developed norepinephrine-selective transporter antagonists, such as reboxetine. The therapeutic utility of these agents supports biogenic amine theories of affective disorders and raises the question as to whether SERT and NET exhibit a functional genetic variation that could influence risk for behavioral disorders. Although evidence exists that a promoter polymorphism in SERT may influence behavioral states, this contention is not without complexity and its mechanism of action remains poorly understood. The identification of coding variants of NETs and SERTs would offer important opportunities to connect genotype to phenotype. However, given the limited frequency of transporter coding variations evident to date in general population surveys or in psychiatric genetic studies, the identification of informative functional variants of transporters will likely require refined phenotypes. In this regard, NET and SERT play critical roles in cardiovascular and gastrointestinal physiology, respectively. This perspective reviews recent human and mouse studies that suggest how peripheral autonomic phenotypes, linked to genetic disruption of NET and SERT function, can aid in the phenotypic segregation needed for advanced theories of biogenic amine dysfunction and pharmacogenetics.
Intramolecular endo-cyclization reactions of N-acyliminium ions have seen wide application for the synthesis of heterocyclic compounds. The corresponding exocyclic variant, which would provide 1-aminotetralin derivatives, for example, has little precedent. We have discovered that acyclic N-acylcarbamates can be readily reduced to the corresponding N-acylhemiaminal derivatives in high yield using DIBAL as the reducing agent. These intermediates are remarkably stable and, if desired, can be purified and stored. The acyclic N-acylhemiaminals undergo both intra- and intermolecular nucleophilic addition reactions mediated by strong Lewis acids, such as TiCl(4). Diastereoselectivity, induced either by a substituent on the newly formed ring, or by utilizing a chiral ester on the carbamic acid, was disappointingly low. This methodology was successfully applied to the synthesis of the racemic form of the marketed antidepressant sertraline.
Depression is common among patients recovering from a myocardial infarction (MI). Approximately 1 in 6 patients with MI experience major depression and at least twice as many as that have significant symptoms of depression soon after the event. Post-MI depression is an independent risk factor for increased mortality. Although the mechanism responsible for this association has not yet been defined, depression is clearly associated with poor compliance with risk-reducing recommendations, with abnormalities in autonomic tone that may make patients more susceptible to ventricular arrhythmias, and with increased platelet activation. Coronary revascularization procedures also appear to be used less often in those with post-MI depression than in comparable patients without mood disorder. Ongoing research will address whether treating depression improves prognosis. Until this question is answered, efforts should focus on enhancing adherence to treatment regimens in this group of patients, who are clearly at risk for noncompliance. Cardiac rehabilitation programs and increasing levels of social support may help improve symptoms and should be recommended to all patients. Treatment of depression itself should be individualized until safety and efficacy are determined for antidepressant therapy in patients who recently have had an MI.