Development and validation of rapid and sensitive LC methods with PDA and fluorescence detection for determination of piribedil in rat plasma and brain tissues and their pharmacokinetic application.

Simple, selective and sensitive high-performance liquid chromatographic (HPLC) bioanalytical methods using fluorescence (FL) and photodiode array (PDA) detectors were developed and validated for determination of piribedil (PBD), an anti-Parkinson's drug, in rat plasma and brain samples, with telmisartan as internal standard (IS). Protein precipitation technique was used to extract PBD from both biological matrices. Chromatographic separation was achieved on a Phenomenex Kinetex C18 end-capped column (250 × 4.6 mm, 5 µm), with 38:62 v/v acetonitrile and ammonium acetate buffer (pH 5.0) as mobile phase at 1.0 mL/min flow rate. Linear response in the concentration ranges 5-300 and 150-3000 ng/mL in plasma, and 15-900 and 450-9000 ng/g in brain tissue were achieved in FL and PDA detectors, respectively. The chromatograms were extracted at 239 nm in case of PDA detection and at excitation wavelength of 239 nm and emission wavelength of 385 nm in case of FL detection. FL detection was found to be more sensitive compared with PDA detection. The developed methods were successfully employed in determining the plasma time course, brain distribution and the pharmacokinetic parameters of PBD following intravenous bolus administration of the drug in male Wistar rats.

[The use of piribedil for the prevention of falls in elderly patients with metabolic syndrome].

Effects of pirebedil used to prevent falls in elderly patients with metabolic syndrome are discussed. A prospective controlled study showed that therapy with pirebedil significantly decreases the frequency of falls, reduces severity of pro-inflammatory and pro-oxidative activities, improves cognitive abilities. Prevention of falls by virtue of improved cognitive abilities is a new clinical effect of pirebedil and gives reason to recommend it for the treatment of geriatric patients with metabolic syndrome.

Design and evaluation of thermo-responsive nasal in situ gelling system dispersed with piribedil loaded lecithin-chitosan hybrid nanoparticles for improved brain availability.

Piribedil (PBD) is a compound that has shown efficacy in clinical trials to treat motor and non-motor symptoms of Parkinson's disease. However, drug delivery issues like low oral bioavailability, high dosing frequency (3-5 tablets/day), gastrointestinal side-effects reduced the clinical use of PBD. In this work, we have developed lecithin-chitosan hybrid nanoparticles (PBD-LCNs) to improve the direct nose to brain uptake of PBD. PBD-LCNs were optimized using hybrid design approach based on DoE. The mean particle size and drug loading of PBD-LCNs were 147 nm, and 12%, respectively. The PBD-LCNs showed good stability and were found to be nearly spherical in shape. Further, the optimized LCNs were loaded in methylcellulose thermo-responsive in situ gel (PBD-LCN-ISG) to overcome rapid mucociliary clearance upon intranasal administration. Plasma and brain pharmacokinetic studies in rats showed that PBD-LCN-ISG increased the relative bioavailability of PBD in brain (AUCbrain) by about 6.4-folds and reduced the (Cmax)plasma by 3.7-folds when compared to plain intranasal suspension of PBD (PBD-Susp). Further, PBD-Susp showed limited direct nose to brain uptake with DTP values less than 0, while the optimized PBD-LCNs showed DTP value of 56% indicating efficient direct nose to brain uptake. Overall, the development of nanoformulations significantly improved the direct nose to brain uptake of PBD.

[Current approaches to management of patients with mild cognitive impairment]. / Sovremennye podkhody k vedeniiu patsientov s umerennymi kognitivnymi narusheniiami.

Mild cognitive impairment (MCI) is an intermediate stage between normal aging and dementia. The prevalence of MCI among elderly people is 12-17% but the risk of progression of cognitive impairment and development of dementia during 5 years is up to 70%. Cerebral vascular diseases and initial stages of neurodegenerative processes are the cause of MCI. Clinical characteristics of MCI depend on the main etiological factor. To decrease the severity of symptoms and prevent the progression of cognitive impairment in MCI patients, pharmacotherapy and non-medication methods, including diet optimization, stimulation of mental and physical activity, are used. Dopaminergic and noradrenergic therapy is most prevalent among pharmacological methods.

Current status of dopamine agonists in Parkinson's disease management.

The occurrence of late side effects of long term levodopa therapy (fluctuations in motor performance, abnormal movements, and symptoms unresponsive to dihydroxyphenylalanine) led to the search for novel anti-Parkinsonian drugs. Dopamine agonists are one of the newer families of anti-Parkinsonian agents, and they include ergot derivatives and apomorphine, which can be used in the different stages of Parkinson's disease. Ergot derivatives (bromocriptine, lisuride, pergolide) are believed to act independently of the dying cells of the substantia nigra, acting instead directly on postsynaptic dopamine receptors in the striatum. They are usually used in combination with levodopa when late side effects occur, especially 'wearing-off' or decreased efficacy of levodopa. They can also be prescribed earlier in combination with levodopa in de novo Parkinsonian patients, and in this setting are thought to delay the occurrence of late adverse motor effects. In some patients, monotherapy with relatively high doses of ergot derivatives can be used as initial treatment. However, their efficacy often decreases after 1 to 3 years, thus justifying a late combination with levodopa. Apomorphine is a non-ergot derivative dopamine agonist, which is used subcutaneously for the treatment of severe 'off' refractory periods, in combination with other dopaminergic drugs without changing the patient's routine drug regimen.

Kinetics of piribedil and effects on dopamine metabolism: hepatic biotransformation is not a determinant of its dopaminergic action in rats.

The importance of hepatic metabolism in relation to the central (dopaminergic) effects of piribedil (PD) is still not really known. Plasma and brain kinetics and the effects on striatal dopamine (DA) metabolism of the parent drug and its known metabolites were therefore evaluated in rats, a species widely used in neurochemical studies of this drug. PD injected intraperitoneally (IP, 15-60 mg/kg) and centrally (ICV, 100-200 micrograms/rat) lowered striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylacetic acid (HVA) content and the intensity and time-course of the neurochemical effects were route- and dose-relatedly dependent on brain PD kinetics. The catechol (M1), p-hydroxylated (M2) and N-oxide (M3) metabolites of the drug were detectable only in trace amounts in rat brain and only at the highest IP dose tested; when administered ICV at doses equimolar to PD they caused no decrease in striatal DA metabolites, although striatal concentrations were higher than after IP PD, being comparable to or higher than those of the ICV parent drug. These data suggest that metabolites do not contribute to the dopaminergic effects of PD in rats.

Retinal dopaminergic receptor affinity and ocular pharmacokinetic profile of piribedil.

Binding studies on retinal dopamine receptors have revealed the existence of both D1 and D2 receptors. Human retina micro-autoradiographs confirm the distribution of dopaminergic receptors in the plexiform layers. Piribedil, a dopaminergic agonist, is able to bind to D2 receptors, while its metabolite (S584) preferentially displaces D1-specific radioligands. These results demonstrate that piribedil has a dopamine-like pharmacological profile including direct interaction with receptors. When instilled into the rabbit eye, piribedil penetrates rapidly and accumulates in the pigmented epithelia--the iris ciliary body and chorioretina--before being rapidly cleared. Macro-autoradiographs confirm this distribution and show the levels to be compatible with the affinity of piribedil for retinal dopaminergic receptors.

Adsorptive stripping voltammetric behaviour of azomethine group in pyrimidine-containing drugs.

The stripping voltammetric behaviour of buspirone hydrochloride (BUS) and piribedil (PIR), as models of pyrimidine-containing compounds, was studied using a hanging mercury drop electrode (HMDE). A sensitive adsorptive stripping voltammetric method for determination of such drugs is described. The voltammetric peaks were obtained at -1.23 and -1.22 V for BUS and PIR. respectively, which correspond to the reduction of the azomethine group of pyrimidine ring in Britton-Robinson buffer (pH 7). Factors such as pH of supporting electrolyte, accumulation potential and time and instrumental parameters were optimized. Calibration plots and regression data validation, accuracy, precision, limits of detection, limits of quantification, and other aspects of analytical merit are presented. The applicability of the method was evaluated through determination of BUS and PIR in tablet dosage forms. A preliminary study of the analysis of plasma samples, spiked with the investigated drug, after a simple extraction procedure is described.

Formulation and in vitro-in vivo evaluation of piribedil solid lipid micro- and nanoparticles.

Modification of the dissolution rate and, thus, the enhancement of the bioavailability of a dopaminergic drug, piribedil, which has a low aqueous solubility and short elimination half-life have been the aim in this study. Preparations of micron and submicron particles using solid lipid carriers have been performed for this purpose. For the avoidance of solvent residues resulting from the preparation technique, cold and hot homogenization methods have been used to prepare solid lipid particles. After obtaining an appropriate particle size, piribedil loading and preparation yield by the use of those two methods, various formulations have been prepared with different lipid, drug and surfactant materials. The factors mentioned were found to affect properties of the particles, and the release rate was found to be the fastest in acidic medium. Suspensions of pure piribedil and a formulation, selected according to the results obtained from in vitro dissolution and particle size experiments, were compared using tremor tests in mice. The same suspensions were applied perorally to rabbits and bioavailability of the solid lipid particle was found to be higher than the pure piribedil. After an in vitro-in vivo evaluation of piribedil solid lipid particles developed for Parkinson's disease therapy, it has been determined that release rate could be controlled and piribedil bioavailability could be improved.

Differential regional and kinetics effects of piribedil and bromocriptine on dopamine metabolites: a brain microdialysis study in freely moving rats.

Brain microdialysis coupled to HPLC was applied to freely moving rats to investigate the regional kinetics of piribedil and bromocriptine on the extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in striatum, nucleus accumbens, and frontal cortex. Both D2 agonists (20 mg/kg i.p.) decreased DOPAC and HVA in the three brain regions. The responsiveness of frontal cortex to both compounds was greater than those previously reported with other dopaminergic drugs. Regional and temporal differences were observed under piribedil: DOPAC and HVA levels decreased more in the nucleus accumbens than in striatum or frontal cortex but increased over basal values from the 5th hour in the frontal cortex suggesting a late stimulatory effect of piribedil on dopamine synthesis in this area. Such regional effects differentiate piribedil from most other D2 agonists and could explain some behavioural and therapeutic actions possibly related to involvement of nucleus accumbens or/and frontal cortex.