Transdermal selegiline: targeted effects on monoamine oxidases in the brain

Wecker, Lynn; James, Stephanie; Copeland, Natalie; Pacheco, Mary A.

doi:10.1016/s0006-3223(02)01892-9

Cited by 45 publications

(30 citation statements)

References 15 publications

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“…The high intrinsic clearance of l-deprenyl in humans, indeed, makes it difficult to achieve clinically effective plasma concentrations following oral doses. For these reasons, transdermal l-deprenyl formulations have been developed recently, which, give rise to persistent (minimal peak-trough fluctuations), high plasma levels of the parent compound, with high amounts of the drug being delivered to the brain and a low metabolite production (33)(34).…”

Section: Discussionmentioning

confidence: 99%

CYP-Dependent Metabolism of PF9601N, A New Monoamine Oxidase-B Inhibitor, by C57BL / 6 Mouse and Human Liver Microsomes

et al. 2007

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-Purpose. The selective monoamine oxidase-B (MAO-B) inhibitor, ldeprenyl, is still used for treating Parkinson's patients, however, a disadvantage of its use lies in the formation of l-amphetamine and lmethamphetamine. Subsequently, this has promoted the design of a novel, more potent, MAO-B inhibitor PF9601N, which also has neuroprotective and antioxidant properties. The aim of this work was to investigate the effect of treatment with PF9601N on its own phase I hepatic metabolism.Kinetic parameters of PF9601N CYP-dependent N-dealkylation reaction was also studied and compared with those of l-deprenyl. Methods. C57BL/6 mice were treated with PF9601N for 4 days. After CYP content and related monooxygenase activities were assayed in liver microsomes of control and treated animals. Results. CYP activities, cytochrome b 5 content, NADPH-cytochrome P450 reductase and various monooxygenase activities were unaffected by in vivo PF9601N treatment. With microsomes from both control and treated mice, the PF9601N-dealkylation product, FA72, was the only detected metabolite with its formation rate following an hyperbolic, Michaelis-Menten curve. Among various inhibitors, only ketoconazole inhibited the FA72 formation rate, indicating a major involvement for CYP3A. Apparent Km and Vmax values generated by human liver microsomes were similar to those found with mouse microsomes. Ketoconazole inhibition indicates that CYP3A is one of the major enzymes involved in PF9601N metabolism also by human liver microsomes. In mouse liver microsomes, the intrinsic clearance of PF9601N was significantly lower than that of ldeprenyl suggestive of an improved bioavailability for the former. Conclusion. The observed favourable metabolic profile may suggest suitability of PF9601N for clinical use.

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Section: Discussionmentioning

confidence: 99%

CYP-Dependent Metabolism of PF9601N, A New Monoamine Oxidase-B Inhibitor, by C57BL / 6 Mouse and Human Liver Microsomes

et al. 2007

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“…83 Given that the dietary restrictions required with use of a nonselective MAOI are largely related to inhibition of mucosal MAO isozymes, a transdermal delivery system for selegiline was developed to allow selective targeting of brain MAOs. 84 This treatment has shown antidepressant efficacy in three placebo-controlled trials 85,86 (data on file, Somerset Pharmaceuticals, Tampa, FL), though two other placebo-controlled trials have shown no benefit 86 (data on file, Somerset Pharmaceuticals) ( Table 2).…”

Section: Pharmacological Interventionsmentioning

confidence: 99%

Advances in the treatment of depression

Holtzheimer

Nemeroff

2006

NeuroRX

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Summary: Depression is a highly prevalent and disabling condition associated with significant morbidity and mortality. Currently available treatments for depression include tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, various atypical antidepressants, and electroconvulsive therapy. Although these treatments are effective, a significant number of patients do not respond or achieve sustained remission despite aggressive management. Advances in the neurobiology of depression have suggested a number of novel targets for antidepressant treatment. Based on an improved understanding of the neurobiology of depression, several novel pharmacologic and nonpharmacologic interventions are being developed. Pharmacologic developments include CRF antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, NMDA glutamate receptor antagonists, transdermal selegiline, so-called "triple" reuptake inhibitors, and augmentation of typical antidepressant medications with atypical antipsychotics. Nonpharmacologic advances have largely involved focal brain stimulation techniques including vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, and deep brain stimulation. For the most part, the data on these treatments are preliminary, and more study is needed to clarify their potential clinical benefit. However, it is clear that further study of the neurobiology of depression will continue to provide a rationale for developing innovative targets for antidepressant therapies.

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“…Finally, symptoms of gastrointestinal and somatic distress, sleep disturbance, and movement disorders and mania have been temporally linked to abrupt discontinuation of TCAs (Garner et al, 1993). was reported to also inhibit MAO-A in several brain regions tested (Wecker et al, 2003).…”

Section: Side-effect Profilementioning

confidence: 99%

“…For instance, in a recent animal study, the inhibition of MAOs in gastrointestinal tissue with transdermal selegiline appeared to be less than that in brain, and doses that produced maximal MAO-A inhibition in brain inhibited MAO-A in gastrointestinal tissue by only 30-40% (Wecker et al, 2003). Treating major depression with transdermal selegiline appears effective Bodkin and Amsterdam, 2002) and also safe, even in the absence of a tyramine-restricted diet .…”

Section: Side-effect Profilementioning

confidence: 99%

Monoaminergic‐based Pharmacotherapy for Depression

Papakostas¹,

Fava²

2005

Biology of Depression

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Although recent advances in neuropharmacology, neuroendocrinology, molecular biology, and pharmacogenetics have been instrumental in bringing about potential treatments for depression which are fundamentally unrelated to their predecessors, including substance P antagonists, glutaminergic agents, and corticotropinreleasing factor (CRF) antagonists, nevertheless it was agents that influenced the function of monoamine receptors and transporters that were discovered initially by serendipity and then developed as treatments for depression. The development of such compounds also served as a framework for the understanding of depression as a medical illness affecting brain functioning. As a result of these efforts, our field has gained further understanding of the role of monoamines in depression. In previous chapters, the relevance of monoamines in the underlying pathophysiology of depression was reviewed. In the following chapter we will focus on describing the contemporary role of monoaminergic agents in the treatment of depression. 6.

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Transdermal selegiline: targeted effects on monoamine oxidases in the brain

Cited by 45 publications

References 15 publications

CYP-Dependent Metabolism of PF9601N, A New Monoamine Oxidase-B Inhibitor, by C57BL / 6 Mouse and Human Liver Microsomes

CYP-Dependent Metabolism of PF9601N, A New Monoamine Oxidase-B Inhibitor, by C57BL / 6 Mouse and Human Liver Microsomes

Advances in the treatment of depression

Monoaminergic‐based Pharmacotherapy for Depression

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