Transdermal selegiline: the new generation of monoamine oxidase inhibitors.
ABSTRACT The clinical use of monoamine oxidase inhibitors (MAOIs) has declined due to concerns about food and drug interactions and waning physician experience. Evidence indicates that MAOIs are effective in depressive disorders, in particular depression with atypical features. Efforts to address safety issues have led to the development of more selective and reversible MAOIs, such as moclobemide. Selegiline, a selective monoamine oxidase B inhibitor, has been approved for the adjunctive treatment of Parkinson's disease at low doses. At higher doses, oral selegiline is also effective in major depressive disorder (MDD) but loses its selectivity and has the potential for tyramine interactions. To overcome these problems, a transdermal formulation of selegiline, the selegiline transdermal system (STS), was developed with novel pharmacokinetic and pharmacodynamic properties. Compared with oral administration, transdermal selegiline leads to sustained plasma concentrations of the parent compound, increasing the amount of drug delivered to the brain and decreasing metabolite production. In addition, STS allows targeted inhibition of central nervous system monoamine A (MAO-A) and monoamine B isoenzymes with minimal effects on MAO-A in the gastrointestinal and hepatic systems, thereby reducing the risk of interactions with tyramine-rich foods (the "cheese-reaction"). Clinical trials have found 6 mg/24 hours of STS to be effective in MDD without the need for dietary restrictions. The efficacy and safety profile of STS supports its use in MDD. It is possible that STS may demonstrate benefit in MDD with atypical features or MDD resistant to other antidepressants. However, more research is needed. Clinicians should familiarize themselves with the properties and indications for the new generation of MAOIs.
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ABSTRACT: The objective was to investigate the anodal iontophoresis of the MAO-B inhibitors rasagiline (RAS) and selegiline (SEL) across porcine and human skin in vitro. Passive delivery of RAS and SEL from aqueous solution was minimal; however, increasing current density from 0.1 to 0.3 and 0.5mA/cm(2) produced a linear increase in steady-state iontophoretic flux (J(ss,RAS)=49.1i(d)+27.9 (r(2)=0.96) and J(ss,SEL)=27.8i(d)+25.8 (r(2)=0.98)). In the absence of background electrolyte, a four-fold change in donor concentration (10, 20 and 40mM) did not produce a statistically significant increase in cumulative permeation of either drug after iontophoresis at 0.5mA/cm(2) for 7h. Co-iontophoresis of acetaminophen confirmed that electromigration was the dominant transport mechanism for both drugs (∼90%). Total iontophoretic delivery of RAS and SEL across porcine and human skin in vitro was statistically equivalent (RAS: 1512.7±163.7 and 1523.6±195.9μg/cm(2), respectively, and SEL: 1268.7±231.2 and 1298.3±253.3μg/cm(2), respectively). Transport efficiencies for RAS and SEL were good (ranged from 6.81 to 8.50 and 2.86 to 3.61%, respectively). Furthermore, the delivery efficiency, i.e., the fraction of the drug in the formulation that was delivered was very high (>56% at 0.5mA/cm(2)). Cumulative permeation of RAS and SEL from carbopol gels, potential drug reservoirs for iontophoretic systems, was 891.5±148.3 and 626.6±162.4μg/cm(2), respectively; this was less than from solution and was tentatively attributed to either different partitioning or slower drug diffusion in the gel matrix. The results demonstrated that therapeutic amounts of rasagiline and selegiline could be easily delivered by transdermal iontophoresis with simple gel patches of modest surface area.International Journal of Pharmaceutics 08/2012; 438(1-2):202-8. DOI:10.1016/j.ijpharm.2012.08.037 · 3.79 Impact Factor
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ABSTRACT: Treatment of depression remains unsatisfactory, especially in view of the fact that most depressed patients do not achieve remission. The older efficacious antidepressants have largely been abandoned in favor of newer, better-tolerated antidepressants. However, older antidepressants are still considered to be quite useful by some. This article reviews the efficacy issues related to the older versus newer antidepressants and the usefulness of older antidepressants (namely tricyclic antidepressants) in some special indications such as pain and enuresis management. Finally, the article makes some suggestions for improving the management of depression through a possible increase in use of older antidepressants. Needs Assessment: Older antidepressants (tricyclic antidepressants and monoamine oxidase inhibitors) have been used less and less frequently by both psychiatrists and primary care physicians. Nevertheless, these are highly efficacious medications with possible use in various additional indications (eg, pain management in primary care, enuresis management in pediatrics). Review of the literature reveals that these medica-tions are underappreciated. Yet, there is a desire to bring these efficacious substances back, perhaps in a better-tolerated version. Therefore, physicians should be aware of their continuous usefulness and should familiarize themselves with their use. Learning Objectives: • Identify the pros and cons of using older antidepressants. • Identify various indications and patient subpopulations where older antidepressants may be useful. • Understand the need to improve the quality of treatment for depression. • Consider innovative approaches to treating depression. Target Audience: Primary care physicians and psychiatrists. CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s) TM . Physicians should only claim credit commensurate with the extent of their participation in the activity. Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the plan-ning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclo-sure to the audience of their discussions of unlabeled or unapproved drugs or devices.