Protective effects of selegiline against amyloid beta-induced anxiety-like behavior and memory impairment.

BACKGROUND: Alzheimer's disease (AD) is a complex and common neurodegenerative disorder. The present study aimed to investigate the potential effects of selegiline (SEL) on various aspects of memory performance, anxiety, and oxidative stress in an AD rat model induced by intracerebroventricular injection of amyloid beta1-42 (Aß1-42). METHODS: Oral administration of SEL at a dose of 0.5 mg/kg/day was performed for 30 consecutive days. Following the 30 days, several tests, including the open-field, elevated plus-maze, novel object recognition, Morris water maze, and passive avoidance learning were conducted to assess locomotor activity, anxiety-like behavior, recognition memory, spatial memory, and passive avoidance memory, respectively. RESULTS: The results indicate that the induction of AD in rats led to recognition memory, spatial memory, and passive avoidance memory impairments, as well as increased anxiety. Additionally, the AD rats exhibited a decrease in total antioxidant capacity and an increase in total oxidant status levels, suggesting an imbalance in oxidative-antioxidant status. However, the administration of SEL improved memory performance, reduced anxiety, and modulated oxidative-antioxidant status in AD rats. CONCLUSIONS: These findings provide evidence that SEL may alleviate anxiety-like behavior and cognitive deficits induced by Aß through modulation of oxidative-antioxidant status.

Chronic Oral Selegiline Treatment Mitigates Age-Related Hearing Loss in BALB/c Mice.

Age-related hearing loss (ARHL), a sensorineural hearing loss of multifactorial origin, increases its prevalence in aging societies. Besides hearing aids and cochlear implants, there is no FDA approved efficient pharmacotherapy to either cure or prevent ARHL. We hypothesized that selegiline, an antiparkinsonian drug, could be a promising candidate for the treatment due to its complex neuroprotective, antioxidant, antiapoptotic, and dopaminergic neurotransmission enhancing effects. We monitored by repeated Auditory Brainstem Response (ABR) measurements the effect of chronic per os selegiline administration on the hearing function in BALB/c and DBA/2J mice, which strains exhibit moderate and rapid progressive high frequency hearing loss, respectively. The treatments were started at 1 month of age and lasted until almost a year and 5 months of age, respectively. In BALB/c mice, 4 mg/kg selegiline significantly mitigated the progression of ARHL at higher frequencies. Used in a wide dose range (0.15-45 mg/kg), selegiline had no effect in DBA/2J mice. Our results suggest that selegiline can partially preserve the hearing in certain forms of ARHL by alleviating its development. It might also be otoprotective in other mammals or humans.

Evaluation of monoamine oxidase A and B type enzyme occupancy using non-radiolabelled tracers in rat brain.

Monoamine oxidase (MAO) enzymes, type A and B metabolise the amine neurotransmitters of the body. Selective inhibition of either enzyme is an approach for treating neurodegenerative and stress-induced disorders, and inhibition of an enzyme is proportional to the binding of the MAO inhibitor. Conventionally, the binding of test compounds to enzymes is assessed by radiolabelled ligands in ex vivo and in vivo occupancy assays. Regulatory restrictions and turnaround time are the limitations of the methods that use radiolabelled ligands. But the use of non-radiolabelled tracers and sensitive mass spectrometry (LC-MS/MS) based assays accelerated the determination of target occupancy in pre-clinical species. A report on use of non-radiolabelled ligand in in vivo MAO occupancy assay is not available. The objectives of the present study were to optimise non-radiolabelled harmine and deprenyl as selective tracers in MAO-A and MAO-B occupancy assays and evaluate MAO occupancy of test compounds in rat brain. Tracer optimisation resulted in a detectable, stable, and low ratio (<3.0) of tracer concentrations between any two brain tissues. In occupancy assay, tracer was intravenously administered (10 µg/kg, harmine or 60 µg/kg, L-deprenyl) after the treatment with test compound (clorgyline or tranylcypromine or pargyline or phenelzine or thioperamide). Specific brain tissues were isolated at a defined interval and tracer concentrations were quantified using LC-MS/MS method. Pre-treatment with MAO inhibitors resulted in a decrease (maximum, 80-85%) in harmine or an increase (maximum, 85-300%) in L-deprenyl concentrations. But we considered the change in tracer concentration, relative to the vehicle and positive control groups to calculate MAO occupancy. The observed selectivity and ratio of occupancies (ED50) of test compound towards MAO-A and MAO-B are comparable with the results from in vitro radiolabelled ligand-based inhibition assay. The results demonstrated the application of these non-radiolabelled tracers as suitable pre-clinical tools to determine MAO occupancy.

Synthetic enhancer compounds, besides acting on biogenic amine system, influence the glutamate transmission and stress response.

Pharmaceutically available enhancer selegiline/(-)-deprenyl (DEP) in the clinically used dose shows antidepressant effect, but nothing is known about this effect in enhancer dose, and its effect on co-morbid anxiety. Moreover, data about the antidepressant/antianxiety effects of the serotonin-influencing enhancer, (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP) are also missing. The aim of the present paper is to establish the role of enhancer regulation in anxiety and follow the changes in the phosphorylation of glutamate subunits in prefrontal cortex as well as stress-related organ and hormonal changes as possible background mechanism. The effect of 3-week-treatment of rats with specific (0.001 mg/kg for DEP, 0.0001 mg/kg for BPAP) and non-specific (0.1 mg/kg for DEP, 0.05 mg/kg for BPAP) enhancer doses were evaluated on anxiety-like behavior in the elevated plus maze (EPM) and open-field (OF) tests. Phosphorylated glutamatergic GluR1 and GluN2B subunits were analyzed by Western blot. Changes in the stress-regulatory system were evaluated by measuring the organ weights and blood corticosterone concentrations. Non-specific enhancer doses had a tendency for anxiolysis on EPM, while only 0.1 mg/kg DEP elevated motility in OF. Specific enhancer doses significantly increased the expression of both glutamatergic receptor subunits; non-specific doses elevated only pGluR1. Treatments had no effects on stress-like organ weights; however, the specific enhancer doses significantly reduced the dark phase resting corticosterone levels. The study proved the enhancer-sensitivity of the glutamatergic transmitter system and suggested enhancer-induced stabilization of stress-hormone levels without major impact on non-stimulated anxiety-like behavior.

Rapid and sustained improvement in treatment-refractory depression through use of acute intravenous ketamine and concurrent transdermal selegiline: A case series.

BACKGROUND: Treatment resistant depression is a significant source of morbidity and mortality. For patients having failed or unable to undergo the electroconvulsive therapy procedure few effective alternative treatments exist. METHODS: A case series is presented where six patients with treatment resistant depression failing both electroconvulsive therapy and oral antidepressants are concomitantly treated with short course intravenous ketamine and longer term selegiline transdermal system. RESULTS: All six patients experienced clinical improvement with intravenous ketamine, with resolution of suicidality, increased food intake, and commitment to treatment adherence. Five patients showed sustained improvement with the selegiline transdermal system. One patient discontinued selegiline after developing peripheral edema and palpitations. LIMITATIONS: This case series included only patients experiencing moderate to severe treatment resistant depression. Availability of long-term follow-up data not available in some cases. CONCLUSION: Intravenous ketamine with simultaneous administration of the selegiline transdermal system is one strategy for treating treatment resistant depression in patients having failed or unable to undergo the electroconvulsive therapy procedure.

Long-Term Selegiline Monotherapy for the Treatment of Early Parkinson Disease.

OBJECTIVES: The aim of this open-label study was to investigate the long-term safety and efficacy of selegiline as monotherapy in Japanese patients with early Parkinson disease (PD). METHODS: We conducted a 56-week prospective study in patients with early PD (N = 134) who had previously completed the randomized, double-blind, placebo-controlled phase III trial of selegiline monotherapy for 12 weeks. In the present study, dosing was titrated from 2.5 to 10 mg/d in increments of 2.5 mg/d for 2 weeks. From the seventh week, the dosage was maintained at 10 mg/d until week 56. The primary outcome was any change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score (part I + II + III) from baseline. Secondary outcomes, including changes in the UPDRS subscores and safety profile, were also evaluated. RESULTS: Ninety-one (67.9%) patients completed the 56-week study. Treatment with selegiline significantly reduced total UPDRS score from week 4 (mean ± SD, -2.62 ± 3.83; P < 0.0001) to week 56 (-3.39 ± 9.27; P < 0.01). The peak effect was seen at week 20 (-5.79 ± 5.57; P < 0.0001). In addition, we found similar improvements in the UPDRS parts II and III scores. The incidence rate of adverse drug reactions was 44.3% (58 patients) and did not increase during the period of 10 mg selegiline administration. CONCLUSIONS: Long-term monotherapy with selegiline (10 mg/d) was effective and well tolerated in patients with early PD in this 56-week study.

Design of selegiline-loaded bio-nanosuspension for the management of depression using novel bio-retardant from Manilkara zapota.

Objective: Depression is one of the most frequent psychiatric and potentially life-threatening disorders. This research work can offer a potential for delivery of selegiline moiety via ocular route in bio-nanosuspension mode for the effective management of depression after preclinical performance screening. Methods: The selegiline-loaded bio-nanosuspension was prepared using novel bio-retardant isolated from fruit pulp of Manilkara zapota (Sapodilla) by sonication solvent evaporation method with different ratios (0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, and 1%) and with standard polymer HPMC (0.1%, 0.2%, 0.3%, 0.4%, and 0.5%). The prepared formulations were evaluated for pH stability studies, %entrapment efficiency, in vitro drug release, particle size, polydispersity index (PDI), zeta potential, and stability studies. Results: The prepared bio-nanosuspension was subjected to the best formulation based on comparison of above-mentioned evaluation parameters, so Fb2 (0.1%) formulation was found to be the best formulation showing an R2 value of 0.9814, T50% of 29.7 h, and T80% of 65.25 h. According to the release kinetics, the best fit model was found to be the Korsmeyer-Peppas with the Fickian diffusion (Higuchi matrix) as the mechanism of drug release. Manilkara zapota (Sapodilla) provided excellent stability for the formulation and resulting particle size for the best formulation was found to be 252 nm. The bio-nanosuspension had PDI of 0.35 with zeta potential of -8.91 mV. Conclusion: The prepared bio-nanosuspension was found to be safe and compatible with the ophthalmic delivery for treatment of depression.

Adjuvant potential of selegiline in treating acute toxicity of aluminium phosphide in rats.

Aluminium phosphide (AlP) is a highly toxic substance with a high mortality rate and no effective antidote. Once exposed to the moisture and acidic conditions of the stomach, AlP releases toxic phosphine (PH3 ) gas, which results in severe toxicity in poisoned subjects. Selegiline is a monoamine oxidase inhibitor with antioxidant and anti-apoptotic properties, which is mostly prescribed for the treatment of mood disorders and Parkinson's disease. Since AlP has detrimental effects on cardiac physiology and mitochondrial function, we tested the protective effects of acute selegiline treatment on cardiac mitochondrial function, redox status and electrocardiographic parameters in rats after AlP poisoning. To do this, AlP was given to rats by gavage to induce toxicity. Selegiline was injected intraperitoneally in the treatment groups 1 hour after AlP poisoning. Selegiline treatment after AlP intoxication was not associated with a significant difference in the mortality rate of animals. However, selegiline reduced oxidative stress (decreased the reactive oxygen species and malondialdehyde) and increased glutathione in the cardiac tissue of rats exposed to AlP. Further, the mitochondrial membrane potential (ΔΨm) collapse reversed after treatment with selegiline. Selegiline also improved the electrocardiographic (ECG) parameters and enhanced heart rate. The histopathological evaluation revealed that selegiline eliminated the inflammation and injuries induced by AlP in the stomach and duodenum, as well as cardiac tissue. In conclusion, selegiline treatment can ameliorate the AlP-induced cardiac and gastrointestinal injuries in rats via boosting redox status and mitochondrial function with no significant effect on survival. We suggest that using selegiline, apart from other clinical treatments, may improve the quality of treatment process for AlP toxicity.

Pharmacokinetics of selegiline, R-methamphetamine, R-amphetamine, and desmethylselegiline in oral fluid after a single oral administration of selegiline.

BACKGROUND: Chiral analysis is a crucial way to differentiate selegiline (SG) intake from drug abuse. Oral fluid (OF) has been successfully used as an alternative matrix for blood testing in several pharmacokinetic studies. OBJECTIVE: The aim of this study is to describe the pharmacokinetics of SG and its main metabolites in OF after a single oral administration of SG which is meaningful for results interpretation in forensic analysis. METHODS: Ten milligrams of SG were orally administered to 8 volunteers, and OF samples were collected for up to 96 hours by having participants spit into polypropylene tubes without stimulation. These samples were submitted to liquid-liquid extraction before analysis by liquid chromatography-tandem mass spectrometry operating in positive ion multiple-reaction monitoring mode. RESULTS AND CONCLUSIONS: After oral administration, each analyte could be detected in OF specimens from all volunteers with an initial detection time of 0.50 hours. The Cmax values of SG, R-MA, R-AM and DM-SG were 50.93-992.67 ng/mL, 29.78-653.64 ng/mL, 8.22-150.15 ng/mL, and 4.34-16.25 ng/mL, respectively, at 0.5 hours, 1-11 hours, 1.5-11 hours, and 0.5-6 hours post dose. The times when the compounds were last determined in OF were 5-24 hours for SG, 52-96 hours for R-MA, 31-96 hours for R-AM, and 13-31 hours for DM-SG after oral administration. There is a period of time in OF in which only MA and AM are present without SG and DM-SG after a single dose of SG. The pharmacokinetic data could provide supplementary interpretation for OF tests in forensic science and drug treatment programs.

Biopharmaceutical Potential of Selegiline Loaded Chitosan Nanoparticles in the Management of Parkinson's Disease.

BACKGROUND: Selegiline hydrochloride, a hydrophilic anti-Parkinson' moiety, undergoes extensive first-pass metabolism and has low bioavailability. A process to obtain of selegiline (SH) loaded chitosan nanoparticles was attempted to circumvent the above problem, through intranasal delivery. METHODS: SH loaded polymeric nanoparticles were prepared by ionic gelation of chitosan with tripolyphosphate, and stabilized by tween 80/ poloxamer 188. The resulting nanoparticles (NPs) were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, entrapment efficiency, particle size, zeta potential and surface morphology by scanning electron microscopy. Further, they were schematically evaluated for mucoadhesive strength, in-vitro drug release, release kinetics, pharmacokinetics, catalepsy, akinesia, in-vivo lipid peroxidation, nitrite levels, glutathione, catalase enzyme levels in brain and physicochemical stability parameters. RESULTS: Selegiline nanoparticles (SP18) produced were in size of 63.1 nm, polydispersity index of 0.201, zeta potential of +35.2 mV, mucoadhesion of 65.4% and entrapment efficiency of 74.77%. Selegiline showed biphasic release from nanoparticles, over a period of 36 h, with Fickian diffusion controlled release profile. Maximum concentration of SH in plasma was recognized as 52.71 ng/ml at 2 h for SP18, 20.09 ng/ml at 1 h for marketed formulation, and 21.69 ng/ ml for drug solution. SH loaded NPs showed a reversive effect in catalepsy and akinesia behaviour. This effect was especially pronounced in rats receiving SH loaded CS-NPs. Significant decrease in lipid peroxidation and nitrite concentration; increase in reduced glutathione and catalase enzyme levels were obtained due to antioxidant characteristics of SH, which turned to be useful to treat Parkinson's disease. CONCLUSION: Selegiline loaded chitosan nanoparticles form an effective non-invasive drug delivery system of direct nose to brain targeting in Parkinson's disease.

Development and Characterization of Nasal Delivery of Selegiline Hydrochloride Loaded Nanolipid Carriers for the Management of Parkinson's Disease.

INTRODUCTION: Parkinson's Disease (PD) is one of the most common age-related neurodegenerative disorders which is marked with the loss of dopaminergic neurons. The present study performed on the nose to brain delivery of selegiline hydrochloride loaded nano lipid carrier, suggests that the nasal route is a good mean of targeting the drug directly into the brain. METHODS AND MATERIALS: Nanostructured lipid carriers were prepared by using hot homogenization. Selegiline hydrochloride loaded NLCs and rotenone treatment were given at a dose of 10 mg/kg administered from 14th day to 28th day. Behavioral parameters were determined at 7th, 14th, 21st and 28th day. On the 28th day, animals were sacrificed for biochemical estimation. RESULTS: The optimized drug loaded NLC formulation has shown 93±5.25% entrapment efficiency and 51.96% loading capacity. Optimized NLCs formulation has shown 70% release within 10 hours and after that, the release of the drug is sustained up to 22 hours (97%). Pharmacological action of the drug was found to restore the behavioral parameters in rotenone-induced rats. CONCLUSION: Nano Lipid Carrier (NLCs) therapeutics has emerged as a prominent method for the treatment of Parkinson's Disease (PD) as it offers targeted delivery and enhances the therapeutic efficacy of neurotherapeutics. It is concluded from the studies that, Selegiline HCl loaded nano lipid carrier which was administered through nasal route has the potential to be used in the management therapy of Parkinson's disease.

L­Deprenyl exerts cytotoxicity towards acute myeloid leukemia through inhibition of mitochondrial respiration.

The identification of large numbers of genetic mutations in immature myeloid cells has made it difficult to identify specific targets for acute myeloid leukemia (AML) therapy. Although current pharmacological targets for controlling cancer are focused on identifying genetic mutations, it is hard to develop the specific drugs to achieve complete remission due to complex and variable genetic mutations. To overcome the failure of the genetic mutation theory, the present study targeted mitochondrial metabolism as a strategy for inducing anti­leukemic activity, based on evidence that AML cells have an abnormally high amount of mitochondria and that somatic mutations can alter metabolic flux in cancer. It was found that L­deprenyl, which is clinically available for the treatment of Parkinson's disease, exerts anti­mitochondria activity in KG­1α cells, as assessed by detection of oxygen consumption rate (OCR) and extracellular acidification (ECAR) using XF analyzer, respectively. Using a luciferase assay for detecting adenosine triphosphate (ATP) content, it was found that suppression of mitochondrial activity led to ATP depletion and was associated with potent cytotoxic activity. L­deprenyl is known to target monoamine oxidase­B (MAO­B) on the outer membrane of mitochondria, therefore, the activity of MAO­A and ­B was measured based on the fluorometric detection of H2O2 produced by the enzyme reaction. Notably, MAO­A and -B activity was low in AML cells and the present findings suggested that the anticancer effect of L­deprenyl was independent of MAO­B. Change of mitochondrial respiration­ and glycolysis­related gene expression levels were measured by reverse transcription­quantitative polymerase chain reaction. Consistent with the aforementioned results, treatment with L­deprenyl reduced the mRNA level of mitochondrial respiration­ and glycolysis­related genes. Collectively, the present results identify L­deprenyl as a novel candidate for the treatment of AML through inhibition of mitochondrial respiration.

[The effect of deprenyl and isatin administration to mice on the proteomic profile of liver isatin-binding proteins]. / Vliianiia vvedeniia deprenila i izatina mysham na profil' izatin-sviazyvaiushchikh belkov pecheni.

Isatin (indol-2,3-dione) is an endogenous indole found in the brain, peripheral tissues and biological body fluids of humans and animals. Its wide spectrum of biological activity is realized via interaction with numerous isatin-binding proteins; these include proteins playing an important role in the development of neurodegenerative pathology. In the context of the neuroprotective effect, the effect of isatin is comparable to the effects of deprenyl, a pharmacological agent used for treatment of Parkinson's disease. In this study, the effects of the course of deprenyl (1 mg/kg) and isatin (20 mg/kg) administration for 21 days on the profile of the isatin-binding proteins of the liver of mice have been investigated. Proteomic profiling of liver isatin-binding proteins of control mice by means of 5-aminocaproylisatin as an affinity ligand resulted in identification of 105 proteins. Treatment of animals with a low dose of isatin slightly decreased (up to 91), while injections of deprenyl slightly increased (up to 120) the total number of isatin-binding proteins. 75 proteins were common for all three groups; they represented from 62.5% (in deprenyl treated mice) and 71% (in control mice), to 82% (isatin treated mice) of the total number of identified liver isatin-binding proteins. Proteomic analysis of the isatin-binding proteins of mice treated with isatin (20 mg/kg) or deprenyl (1 mg/kg) for 21 days revealed a representative group of proteins (n=30) that were sensitive to the administration of these substances. Taking into account the previously obtained results, it is reasonable to suggest that the change in the profile of isatin-binding proteins may be attributed to accumulation of isatin and deprenyl in the liver and interaction with target proteins prevents their subsequent binding to the affinity sorbent. In this context, the identified isatin-binding liver proteins of control animals that do not bind to the affinity sorbent (immobilized isatin analogue) after treatment of animals with either deprenyl or isatin appear to be specific targets directly interacting with isatin in vivo.

Box-Behnken experimental design for preparation and optimization of the intranasal gels of selegiline hydrochloride.

Selegiline hydrochloride (SL) is chosen as an adjunct for the control of clinical signs of Parkinsonian patients. The aim of the present work is to develop and optimize thermosensitive gels using Pluronic (F-127) for enhancing transport of SL into the brain through the nasal route. SL gels were prepared using a cold method and the Box-Behnken experimental design methodology. Drug (SL), gelling agent (F-127), and emulsifier (Propylene glycol, PG) were selected as independent variables, while the gelation temperature, gel strength, pH, gel content, and gel erosion were considered as dependent variables. For further understanding of the interaction between the various variables, contour plots and surface plots were also applied. Selected formulations, like S10 (contain 25 mg SL, 20 g F-127, and 1 g PG) and S14 (contain 50 mg SL, 18 g F-127 and 1 g PG), had a clear appearance in the sol form, with gelling temperature of the nasal gel ranging between 33 and 34, respectively. The gel strength of the formulations varied from 4.67 and 0.68 mm and the drug content was 100%. The pH of the formulations ranged between 6.71 and 7.11. Detachment force was acceptable (63.69-244.16 N/cm2) to provide prolonged adhesion. In vitro, drug release studies showed that the prepared formulations could release SL for up to 8 h. Permeation flux for the S10 gel was 0.0002 mg/min/cm2. Results demonstrated that the potential use of SL gels can enhance the therapeutic effect of SL through the intranasal administration.

Selegiline Nanoformulation in Attenuation of Oxidative Stress and Upregulation of Dopamine in the Brain for the Treatment of Parkinson's Disease.

Objective of this study was to determine whether the prepared nanoemulsion would be able to deliver selegiline to the brain by intranasal route, improving its bioavailability. Antioxidant activity, pharmacokinetic parameters, and dopamine concentration were determined. Oxidative stress models, which had Parkinson's disease-like symptoms, were used to evaluate the antioxidant activity of nanoemulsion loaded with selegiline in vivo. The antioxidant activity was evaluated by 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay and reducing power assay, which showed high scavenging efficiency for selegiline nanoemulsion compared to pure selegiline. Biochemical estimation results showed that the levels of antioxidant enzymes, including glutathione and superoxide dismutase, were increased, whereas the levels of thiobarbituric acid-reactive substances were decreased in intranasally administered selegiline nanoemulsion-treated group when compared with haloperidol-induced Parkinson's disease group (control). Moreover, selegiline nanoemulsion was found to be successful in decreasing the dopamine loss, indicating that nanoemulsion is a potential approach for intranasal delivery of selegiline to decrease the damage due to free radicals, thus avoiding consequent biochemical alterations that arise during Parkinson's disease. Brain:blood ratio of 2.207 > 0.093 of selegiline-loaded nanoemulsion (intranasally administered) > selegiline solution (administered intravenously), respectively, at 0.5 hours showed direct nose-to-brain delivery of drug bypassing blood-brain barrier. Selegiline-loaded nanoemulsion administered intranasally showed significantly high dopamine concentration (16.61 ± 3.06 ng/mL) compared to haloperidol-treated rats (8.59 ± 1.00 ng/mL) (p < 0.05). In this way, intranasal delivery of selegiline nanoemulsion might play an important role in the better management of Parkinson's disease.

Menière's disease: combined pharmacotherapy with betahistine and the MAO-B inhibitor selegiline-an observational study.

OBJECTIVES: Since oral betahistine has a very high first-pass effect (ca. 99%), metabolized by monoamine oxidases (MAO), the benefits of a high-dosage betahistine monotherapy were compared with those of a lower dosage of betahistine in combination with the MAO-B inhibitor (MAO-B) selegiline on the frequency of acute attacks of vertigo in patients with Menière's disease (MD). METHODS: Thirteen adults aged 40-75 years (mean 58.9 years; six females) had initially been treated with a high dosage of betahistine dihydrochloride for at least 1 year. Under this therapy, all of them had ≤ 1 attack for ≥ 3 months prior to the combination pharmacotherapy. Subsequently, they received 5 mg/day selegiline and the dosage of betahistine was reduced to about one tenth and then individually adjusted to the dosage needed to achieve the same treatment response (≤ 1 per 3 months, observational period of at least 6 months). RESULTS: The initial dosage for the long-term "titration" of the attacks of vertigo was 9-80 24-mg tablets/day (mean 37.3), i.e. 216-1920 mg/day (mean 895.4 mg/day). After the combination with selegiline, the dosage needed to achieve the same benefit for ≥ 3 months was 3-36 24-mg tablets (mean 8.5), i.e., 72-864 mg/day [mean 204.9 mg/day, p < 0.001 (paired t test)]. One patient transiently stopped the treatment with selegiline, another one reduced the dosage to 2.5 mg/day and the attacks re-occurred after 2-4 weeks. Six out of 13 patients reported transient fullness of the head during the combined treatment; in 2 of them this went away when they switched to 2.5 mg bid. In the longer term (> 9 months), one patient had to increase the selegiline dosage to 5 mg bd, one patient stopped the treatment with selegiline. CONCLUSIONS: The achievement of the same clinical effect with a significantly lower (about 1/5) dosage of betahistine can be explained by the inhibition of the MAO-B by selegiline leading to higher serum concentrations of betahistine. This approach is in line with recent developments to bypass the first-pass effect of betahistine by transbuccal or intranasal application. Despite the substantial methodological limitations of such an observational study, this combined pharmacotherapy could be an alternative to a high-dosage monotherapy with betahistine of MD.

Effect of Concomitant Medications on the Safety and Efficacy of Extended-Release Carbidopa-Levodopa (IPX066) in Patients With Advanced Parkinson Disease: A Post Hoc Analysis.

OBJECTIVES: Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/RYTARY/NUMIENT) produces improvements in "off" time, "on" time without troublesome dyskinesia, and Unified Parkinson Disease Rating Scale scores compared with immediate-release (IR) CD-LD or IR CD-LD plus entacapone (CLE). Post hoc analyses of 2 ER CD-LD phase 3 trials evaluated whether the efficacy and safety of ER CD-LD relative to the respective active comparators were altered by concomitant medications (dopaminergic agonists, monoamine oxidase B [MAO-B] inhibitors, or amantadine). METHODS: ADVANCE-PD (n = 393) assessed safety and efficacy of ER CD-LD versus IR CD-LD. ASCEND-PD (n = 91) evaluated ER CD-LD versus CLE. In both studies, IR- and CLE-experienced patients underwent a 6-week, open-label dose-conversion period to ER CD-LD prior to randomization. For analysis, the randomized population was divided into 3 subgroups: dopaminergic agonists, rasagiline or selegiline, and amantadine. For each subgroup, changes from baseline in PD diary measures ("off" time and "on" time with and without troublesome dyskinesia), Unified Parkinson Disease Rating Scale Parts II + III scores, and adverse events were analyzed, comparing ER CD-LD with the active comparator. RESULTS AND CONCLUSIONS: Concomitant dopaminergic agonist or MAO-B inhibitor use did not diminish the efficacy (improvement in "off" time and "on" time without troublesome dyskinesia) of ER CD-LD compared with IR CD-LD or CLE, whereas the improvement with concomitant amantadine failed to reach significance. Safety and tolerability were similar among the subgroups, and ER CD-LD did not increase troublesome dyskinesia. For patients on oral LD regimens and taking a dopaminergic agonist, and/or a MAO-B inhibitor, changing from an IR to an ER CD-LD formulation provides approximately an additional hour of "good" on time.

Partial reversal of the effort-related motivational effects of tetrabenazine with the MAO-B inhibitor deprenyl (selegiline): Implications for treating motivational dysfunctions.

People with depression and Parkinsonism frequently show effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue. Tasks that assess effort-related choice are being used as animal models of these motivational symptoms. The present studies characterized the ability of monoamine oxidase (MAO) inhibitors with varying selectivity profiles to reverse the low effort bias induced by the monoamine storage inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans, and because of its selective inhibition of VMAT-2, it preferentially depletes DA at low doses. Effort-based decision making is studied with tasks offering choices between high effort options leading to highly valued reinforcers vs. low effort/low reward options. Tetrabenazine shifted choice behavior, reducing selection of fixed ratio 5 lever pressing, but increasing intake of the concurrently available but less preferred lab chow. These effects of 0.75mg/kg tetrabenazine were attenuated by co-administration of the MAO-B inhibitor deprenyl (selegiline). The ability of deprenyl to reverse the effects of tetrabenazine was marked by an inverted-U shaped dose response curve, with the middle dose (2.5mg/kg) being effective. In contrast, neither the MAO-A selective antagonist moclobemide nor the nonselective drug pargyline reversed the effects of tetrabenazine, and moclobemide decreased lever pressing when administered alone. Deprenyl was originally developed as an antiparkinsonian drug, but it also has been shown to have antidepressant effects in humans and induce antidepressant-like effects in classical rodent models of depression. These studies have implications for the potential use of MAO-B inhibitors as treatments for the motivational symptoms of depression and Parkinsonism.

Appraisal of Transdermal Water-in-Oil Nanoemulgel of Selegiline HCl for the Effective Management of Parkinson's Disease: Pharmacodynamic, Pharmacokinetic, and Biochemical Investigations.

In the present study, the potential of transdermal nanoemulsion gel of selegiline hydrochloride for the treatment of Parkinson's disease was investigated. Water-in-oil nanoemulsions were developed by comparing low- and high-energy methods and were subjected to thermodynamic stability tests, in vitro permeation, and characterization studies. In vitro studies indicated that components of nanoemulsion acted as permeation enhancers with highest flux of 3.531 ± 1.94 µg/cm2/h from nanoemulsion SB6 containing 0.5 mg selegiline hydrochloride, 3% distilled water, 21% S mix (Span 85, Tween 80, PEG 400), and 76% isopropyl myristate by weight. SB6 with the least droplet size of 183.4 ± 0.35 nm, polydispersity index of 0.42 ± 0.06 with pH of 5.9 ± 0.32 and viscosity of 22.42 ± 0.14 cps was converted to nanoemulsion gel NEGS4 (viscosity = 22,200 ± 400 cps) by addition of Viscup160® for ease of application and evaluated for permeation, safety, and pharmacokinetic profile in Wistar rats. It provided enhancement ratio 3.69 times greater than conventional gel. NEGS4 showed 6.56 and 5.53 times increase in bioavailability in comparison to tablet and conventional gel, respectively, along with sustained effect. Therefore, the developed water-in-oil nanoemulsion gel promises to be an effective vehicle for transdermal delivery of selegiline hydrochloride.