Chad M. VanDenBerg

Tyramine Pressor Sensitivity During Treatment With the Selegiline Transdermal System 6 mg/24 h in Healthy Subjects

The oral tyramine pressor test was administered to healthy males during treatment with a selegiline transdermal system (STS; 6 mg/24 h). The tyramine sensitivity factor (TSF) was calculated from the ratio of baseline and on‐treatment tyramine pressor doses. The tyramine sensitivity factor value following 9 days of treatment with the selegiline transdermal system was 1.85 ± 0.10. Extended treatment, 33 days, produced a small, clinically nonmeaningful increase in this value. The tyramine sensitivity factor for the selegiline transdermal system was similar to that following treatment with 10 mg/d of oral selegiline capsules but more than 20 times less than observed during tranylcypromine treatment. A larger increase in the tyramine sensitivity factor was observed following extended selegiline transdermal system treatment at a higher dose (12 mg/24 h), which was significantly decreased following coadministration of tyramine capsules with a meal. These results suggest a wide tyramine safety margin for the selegiline transdermal system and provide evidence that the 6‐mg/24‐h selegiline transdermal system can be administered safely without dietary tyramine restrictions.

Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6 mg/24 h) : A comparison with oral selegiline capsules

The selegiline transdermal system is a monoamine oxidase inhibitor that was recently approved by the US Food and Drug Administration for the treatment of major depressive disorder. The current study was conducted during the selegiline transdermal system development program to characterize the single‐dose pharmacokinetics and absolute bioavailability of selegiline administered by the 6‐mg/24‐h selegiline transdermal system in healthy volunteers. Selegiline transdermal system results were compared with those obtained after a single 10‐mg oral dose of selegiline HCl. The selegiline pharmacokinetics differed greatly between the 2 routes of administration. Transdermal selegiline administration reduced metabolism and produced a high, sustained plasma selegiline concentration over the dosing period, with an absolute bioavailability of 73%. By contrast, oral dosing produced a sharp plasma selegiline peak that occurred within 1 hour and declined rapidly, with an absolute bioavailability of 4%. The data provide the basis for therapeutic advantages of the selegiline transdermal system in administering antidepressant doses of selegiline.

Tyramine Pharmacokinetics and Reduced Bioavailability with Food

Tyramine challenge studies have demonstrated that it requires approximately twice the amount of tyramine administered with a meal compared to administration after a fast to elicit the same effect, suggesting a reduction in bioavailability of tyramine when administered with food. The pharmacokinetics of tyramine when administered in a fasted versus a fed state were studied. A single 200‐mg dose of tyramine was administered orally to healthy subjects both after an overnight fast and during a meal. Systemic exposure to tyramine was reduced by 53% (p < 0.05), and the maximum concentration of tyramine was reduced by 72% (p < 0.05) when the dose was administered during a meal. Tyramine maximum serum concentration was observed between 20 minutes and 1 hour when the dose was administered after an overnight fast and appeared to be delayed and/or prolonged by administration during a meal. Tyramine oral clearance was 135 ± 55.4 L/min, maximum observed serum concentration was 37.7 ± 26.01 ng/mL, and tyramine elimination half‐life was 0.533 (range: 0.330–0.668) hours after administration to fasted subjects. Tyramine bioavailability was significantly reduced when administered with a meal compared to after a fast. The results suggest that larger amounts of dietary tyramine will be required to induce a pressor response equivalent to that following encapsulated tyramine administered in the fasted state.

Cholinesterase inhibitors for the treatment of Alzheimer's disease in the elderly.

The treatment of Alzheimer’s disease is of increasing importance as the population ages and the number of people with the disease increases. The aetiology of Alzheimer’s disease is complex and therefore treatment strategies rely on generalised pathological findings. Cholinesterase inhibitors enhance a generalised deficit of central nervous system acetylcholine and are the first class of agents specifically approved for the treatment of Alzheimer’s disease.The clinical efficacy of the different cholinesterase inhibitors is similar; however, differences in pharmacodynamic and pharmacokinetic parameters can influence tolerability and safety in the elderly population. Concomitant disease states, significant drug interactions and the altered kinetics and dynamics seen in elderly patients can also affect treatment outcome.Although cholinesterase inhibitors are not ‘curative’ for Alzheimer’s disease, clinical evidence indicates that these drugs can significantly delay the progress of cognitive impairment. Consequently, they represent a useful treatment for the symptoms of Alzheimer’s disease in the elderly.

Selegiline Transdermal System: An Examination of the Potential for CYP450‐Dependent Pharmacokinetic Interactions With 3 Psychotropic Medications

Selegiline transdermal system (STS) is a recently approved monoamine oxidase inhibitor antidepressant. This article reports results from 3 studies examining the potential for cytochrome P450–dependent pharmacokinetic interactions between STS and 3 psychotropic medications that might be coadministered. Three open‐label, randomized, Latin square, 3‐sequence crossover design studies were conducted with healthy volunteers to determine the pharmacokinetic parameters of STS 6 mg/24 h and test drug (alprazolam, olanzapine, or risperidone) when administered alone and concomitantly. All pharmacokinetic parameters of interest were unaltered following selegiline or test drug monotherapy when compared to concomitant therapy. This was confirmed by least squares mean ratios and their 90% confidence intervals of loge‐transformed Cmax and AUCτ values, using either standard bioequivalence criteria of 80% to 125% or study‐defined 70% to 143% boundary criteria. These results demonstrate that STS 6 mg/24 h may provide an antidepressant option that is unlikely to result in CYP450‐mediated pharmacokinetic drug‐drug interactions.

Duloxetine in the treatment of chronic pain due to fibromyalgia and diabetic neuropathy.

Duloxetine is a serotonin-norepinephrine reuptake inhibitor approved by the US Food and Drug Administration for the treatment of fibromyalgia and painful diabetic neuropathy at doses of 60 mg daily. Duloxetine has been shown to significantly improve the symptoms of chronic pain associated with these disorders, as measured by the Fibromyalgia Impact Questionnaire, Brief Pain Inventory scores, the Clinical Global Impressions Scale, and other various outcome measures in several placebo-controlled, randomized, double-blind, multicenter studies. Symptom improvement generally began within the first few weeks, and continued for the duration of the study. In addition, the efficacy of duloxetine was found to be due to direct effects on pain symptoms rather than secondary to improvements in depression or anxiety. Adverse events including nausea, constipation, dry mouth, and insomnia, were mild and transient and occurred at relatively low rates. In conclusion, duloxetine, a selective inhibitor for the serotonin and norepinephrine transporters, is efficacious in the treatment of chronic pain associated with fibromyalgia or diabetic neuropathy, and has a predictable tolerability profile, with adverse events generally being mild to moderate.

Evaluation of the Potential for Pharmacodynamic and Pharmacokinetic Drug Interactions Between Selegiline Transdermal System and Two Sympathomimetic Agents (Pseudoephedrine and Phenylpropanolamine) in Healthy Volunteers

Selegiline transdermal system is a recently approved monoamine oxidase inhibitor antidepressant. Medications that inhibit monoamine oxidase type A can augment the pressor effects of sympathomimetic amines, increasing the potential for hypertensive crisis. This study examined the potential for drug‐drug interactions during treatment with selegiline transdermal system and pseudoephedrine or phenylpropanolamine. Two studies were conducted with 25 healthy volunteers to assess changes in blood pressure and heart rate during administration of pseudoephedrine or phenylpropanolamine alone or together with selegiline transdermal system. No significant differences in mean maximum changes in vital signs occurred with pseudoephedrine. No significant differences were found in mean maximum changes in systolic heart rate with phenylpropanolamine; however, 4 of 12 subjects each experienced 1 isolated protocol‐defined minimal pressor response without concurrent adverse effects (1 with phenylpropanolamine alone; 3 with phenylpropanolamine + selegiline transdermal system). Pharmacokinetic parameters obtained following selegiline transdermal system and pseudoephedrine or phenylpropanolamine were unremarkable. The results suggest that selegiline transdermal system 6 mg/24 h does not significantly alter the pharmacodynamics or pharmacokinetics of either pseudoephedrine or phenylpropanolamine when administered to healthy volunteers; however, it is prudent to avoid coadministration of selegiline transdermal system and sympathomimetics.

Duloxetine in the treatment of generalized anxiety disorder.

Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) which is FDA approved for the treatment of generalized anxiety disorder (GAD) in doses of 30 mg to 120 mg daily. Duloxetine has been shown to significantly improve symptoms of GAD as measured through the Hamilton Anxiety Rating Scale (HAMA), the Clinical Global Impressions Scale (CGI-I), and other various outcome measures in several placebo-controlled, randomized, double blind, multi-center studies. Symptom improvement began within the first few weeks, and continued for the duration of the studies. In addition, duloxetine has also been shown to improve outcomes in elderly patients with GAD, and in GAD patients with clinically significant pain symptoms. Duloxetine was noninferior compared with venlafaxine XR. Duloxetine was found to have a good tolerability profile which was predictable and similar to another SNRI, venlafaxine. Adverse events (AEs) such as nausea, constipation, dry mouth, and insomnia were mild and transient, and occurred at relatively low rates. It was found to have a low frequency of drug interactions. In conclusion, duloxetine, a selective inhibitor for the serotonin and norepinephrine transporters, is efficacious in the treatment of GAD, and has a predictable tolerability profile, with AEs generally being mild to moderate.

Disposition of D‐Serine in Healthy Adults

G neurotransmission dysfunction may contribute to the underlying pathogenesis of schizophrenia. The N-methyl-D-asparate (NMDA) receptor is a subtype of the ionotropic glutamate receptors. The most compelling link between NMDA neurotransmission and schizophrenia concerns the mechanism of action of the psychotomimetic drug phencyclidine and the dissociative anesthetic ketamine, both being NMDA antagonists. These NMDA antagonists cause not only psychotic symptoms but also negative symptoms and cognitive deficits. Glutamate and glycine (or D-serine) serve as coagonists at the NMDA receptor, and D-serine has stronger affinity to the glycine site of NMDA receptors than glycine. D-serine also modulates neuronal migration and long-term potentiation. Importantly, D-serine levels and the percentage of D-serine of the total serine in serum and cerebral spinal fluid (CSF) are significantly lower in schizophrenic patients than in controls. The importance of D-serine in schizophrenia and its clinical manifestations, including cognitive dysfunction, has become the focus of schizophrenia research. Accordingly, potentiation of NMDA receptor-mediated neurotransmission has been proposed as a treatment alternative of schizophrenia. Several studies demonstrated the clinical benefits of treating schizophrenia with NMDA-glycine full agonists, including D-serine, glycine and D-alanine, or the partial agonist D-cycloserine. Based on in vitro work, D-serine appears to be the most potent compound. Small pilot studies in patients with schizophrenia reported that D-cycloserine reduced negative symptoms, whereas D-serine and glycine improved both negative and cognitive symptoms. Furthermore, D-serine improved the positive symptoms in patients with chronic schizophrenia on stable doses of antipsychotics. In these previous clinical trials, D-serine at 30 mg/kg/day was added on to typical antipsychotic drugs or atypicals that included risperidone, olanzapine, and clozapine in chronically stable patients. D-serine 2000 mg/day was added to risperidone in acutely exacerbated individuals, and these patients also demonstrated improvement in positive symptoms. These studies used either a twice-daily (bid) or 3 times a day (tid) dosing strategy. However, the pharmacokinetics of D-serine have not yet been studied, and the pharmacokinetic profile of D-serine was examined in Han Chinese healthy individuals.

Disposition of olanzapine in Chinese schizophrenic patients.

The disposition of olanzapine was evaluated in 21 male chronic schizophrenic patients. A single 10 mg dose of olanzapine was administered and blood sampling performed over the following 120 hours. The mean (+/- SD) oral clearance and elimination half-life of olanzapine were 51.5+/-61.6 l/h and 30.9+/-4.3 hours, respectively. A wide interpatient variability was found. Compared to the population norms, no significant differences were observed between different populations and Chinese patients in olanzapine disposition.