Interactive effects of methylphenidate and alcohol on discrimination, conditioned place preference and motor coordination in C57BL/6J mice

Introduction

Prior research indicates methylphenidate (MPH) and alcohol (ethanol, EtOH) interact to significantly affect responses humans and mice. The present studies tested the hypothesis that MPH and EtOH interact to potentiate ethanol-related behaviors in mice.

Methods

We used several behavioral tasks including: drug discrimination in MPH-trained and EtOH-trained mice, conditioned place preference (CPP), rota-rod and the parallel rod apparatus. We also used gas chromatographic methods to measure brain tissue levels of EtOH and the d- and l-isomers of MPH and the metabolite, ethylphenidate (EPH).

Results

In discrimination, EtOH (1 g/kg) produced a significant leftward shift in the MPH generalization curve (1–2 mg/kg) for MPH-trained mice, but no effects of MPH (0.625–1.25 mg/kg) on EtOH discrimination in EtOH-trained mice (0–2.5 g/kg) were observed. In CPP, the MPH (1.25 mg/kg) and EtOH (1.75 g/kg) combination significantly increased time on the drug paired side compared to vehicle (30.7 %), but this was similar to MPH (28.8 %) and EtOH (33.6 %). Footslip errors measured in a parallel rod apparatus indicated that the drug combination was very ataxic, with footslips increasing 29.5 % compared to EtOH. Finally, brain EtOH concentrations were not altered by 1.75 g/kg EtOH combined with 1.25 mg/kg MPH. However, EtOH significantly increased d-MPH and l-EPH without changing l-MPH brain concentrations.

Conclusions

The enhanced behavioral effects when EtOH is combined with MPH are likely due to the selective increase in brain d-MPH concentrations. These studies are consistent with observations in humans of increased interoceptive awareness of the drug combination and provide new clinical perspectives regarding enhanced ataxic effects of this drug combination.     

Enantioselective Pharmacokinetics of dl-threo-Methylphenidate in Humans

A definitive enantioselective pharmacokinetic evaluation of dl-threo-methylphenidate (MPH) was carried out in 11 healthy volunteers, all of whom received, in a randomized crossover design, three oral administrations of MPH: immediate release (IR), slow release (SR), and SR chewed before swallowing (CH). In addition, all subjects received MPH intravenously (IV) on a separate occasion. Both plasma and urine samples were collected for up to 16 hr after each drug administration. Significant enantioselective differences were found in pharmacokinetic parameters such as CL, MRT, Vd_ss, AUC₀ , and t_1/2. A profound distortion of the enantiomeric ratio for MPH (d 1) was evident in all plasma samples harvested after oral administration. After IV MPH, however, there was no significant distortion in the plasma d/1 ratio until 1.5 hr after dosing, whereafter there was a divergence of the plasma levels of the enantiomers. After oral administration of dl-MPH, the absolute bioavailability (F) of d-MPH was 0.23 and that of l-MPH was 0.05. There were no significant differences in renal clearance for d- or l-MPH after oral or IV administration, although the fraction of the dose excreted unchanged in the urine was significantly greater after IV MPH. These data suggest that enantioselective differences in the pharmacokinetics of oral MPH are the result of enantioselectivity in presystemic metabolism rather than in renal excretion, such that l-MPH is preferentially converted into l-ritalinic acid. Finally, it was found that chewing the slow release formulation led to a pharmacokinetic profile very similar to that of MPH-IR, suggesting that MPH-SR should not be prescribed for children who chew tablets.     

Pharmacokinetics of Coadministration of Guanfacine Extended Release and Methylphenidate Extended Release

Background

α₂-Adrenoceptor agonists are used adjunctively to psychostimulants in treating attention-deficit/hyperactivity disorder (ADHD) when psychostimulants alone do not sufficiently reduce symptoms. However, data on the pharmacokinetic profiles and safety of combination treatments in ADHD are needed.

Objective

The primary objective of this study was to evaluate the pharmacokinetic profiles of guanfacine extended release (GXR) and methylphenidate hydrochloride (MPH) extended release, alone and in combination.

Study Design

This was an open-label, randomized, three-period crossover, drug–drug interaction study.

Setting

The study was conducted at a single clinical research center.

Participants

Thirty-eight healthy adults were randomized in this study.

Interventions

Subjects were administered single oral doses of GXR (Intuniv^®; Shire Development LLC, Wayne, PA, USA) 4 mg, MPH (Concerta^®; McNeil Pediatrics, Titusville, NJ, USA) 36 mg, or GXR and MPH combined.

Main Outcome Measures

Guanfacine, dexmethylphenidate (d-MPH), and l-methylphenidate (l-MPH) levels were measured with blood samples collected predose and up to 72 h postdose. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms (ECGs).

Results

Thirty-five subjects completed the study. Analyses of the 90 % confidence intervals (CIs) for the geometric mean ratios of the maximum plasma concentration (C_max) and area under the concentration–time curve extrapolated to infinity (AUC_∞) values for guanfacine and d-MPH following administration of GXR or MPH alone or combined met strict bioequivalence criteria (90 % CIs within the interval of 0.80–1.25). Overall, combining GXR and MPH did not alter the pharmacokinetic parameters of either medication. Sixteen subjects (42.1 %) had at least one TEAE. The most commonly reported TEAEs included headache and dizziness following GXR, MPH, and GXR and MPH combined. Two subjects had clinically significant abnormalities in ECG results following coadministration: both events were mild and resolved the same day.

Conclusions

In this short-term, open-label study of healthy adults, coadministration of GXR and MPH did not result in significant pharmacokinetic drug–drug interactions. No unique TEAEs were observed with coadministration of GXR and MPH compared with either treatment alone.     

Ionically Fixed Polymeric Nanoparticles as a Novel Drug Carrier

Purpose

In this study, we have prepared a novel polymeric drug delivery system comprised of ionically fixed polymeric nanoparticles (IFPN) and investigated their potential as a drug carrier for the passive targeting of water-insoluble anticancer drugs.

Materials and Methods

For this purpose, the physicochemical characteristics of the IFPN were investigated by comparing them with conventional polymeric micelles. IFPN containing paclitaxel were prepared and evaluated for in vitro stability and in vivo pharmacokinetics.

Results

The IFPN were successfully fabricated using a monomethoxypolyethylene glycol-polylactide (mPEG-PLA) diblock copolymer and a sodium salt of d,l-poly(lactic acid) (d,l-PLACOONa) upon the addition of CaCl₂. The transmittance of the IFPN solution was much lower than that of a polymeric micelle solution at the same polymer concentration implicating an increase in the number of appreciable particles. The particle size of the IFPN was approximately 20～30 nm which is in the range of particle sizes that facilitate sterile filtration using a membrane filter. The IFPN also have a regular spherical shape with a narrow size distribution. The zeta potential of the IFPN was almost neutral, similar to that of the polymeric micelles. In contrast, mixed micelles with a combination of mPEG-PLA and d,l-PLACOONa prior to the addition of Ca²⁺ showed a negative charge (?17 mV), possibly due to the carboxyl anion of polylactic acid exposed on the surface of the micelles. The IFPN formulation was highly kinetically stable in aqueous medium compared to the polymeric micelle formulation. The molecular weight of d,l-PLACOONa in the IFPN and the mPEG-PLA/d,l-PLACOONa molar ratio had a great influence upon the kinetic stability of the IFPN. Pharmacokinetic studies showed that the area under the concentration vs time curve (AUC) of IFPN in blood was statistically higher (about two times) when compared with that of Cremophor EL-based formulation (Taxol^® equivalent) or polymeric micelle formulation.

Conclusions

The results suggests that the IFPN were retained in the circulation long enough to play a significant role as a drug carrier in the bloodstream, possibly resulting in improved therapeutic efficiency. Therefore, the IFPN are expected to be a promising novel polymeric nanoparticulate system for passive tumor targeting of water-insoluble anticancer drugs including paclitaxel.     

Triterpenoid saponins from the root of Anemone tomentosa

Three new triterpenoid saponins, tomentoside A (1), B (2) and C (3), along with four known saponins (4?C7) were isolated from the root of Anemone tomentosa. The structures of the new compounds were elucidated as 3-O-??-d-ribopyranosyl-(1??3)-??-l-rhamnopyranosyl-(1??2)-[??-d-glucopyranosyl-(1??4)]-??-l-arabinopyranosyl hederagenin 28-O-??-l-rhamnopyranosyl-(1??4)-??-d-glucopyranosyl-(1??6)-??-d-glucopyranoside (1), 3-O-??-d-ribopyranosyl-(1??3)-??-l-rhamnopyranosyl-(1??2)-[??-d-glucopyranosyl-(1??4)]-??-d-xylopyranosyl hederagenin 28-O-??-l-rhamnopyranosyl-(1??4)-??-d-glucopyranosyl-(1??6)-??-d-glucopyranoside (2) and 3-O-??-d-galactopyranosyl-(1??3)-??-l-rhamnopyranosyl-(1??2)-??-d-xylopyranosyl oleanolic acid 28-O-??-l-rhamnopyranosyl-(1??4)-??-d-glucopyranosyl-(1??6)-??-d-glucopyranoside (3) on the basis of chemical and spectral evidence. In the oligosaccharide chains of compound 3, the characteristic d-galactose residue is a rare structural feature and secondly encountered among triterpenoid saponins from Anemone.     

Adderall<Superscript>®</Superscript> produces increased striatal dopamine release and a prolonged time course compared to amphetamine isomers

Rationale

Adderall^® is currently used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD) and is composed of a novel mixture of approximately 24% l-amphetamine and 76% d-amphetamine salts. There are, however, no investigations of the pharmacological effects of this combination in vivo.

Objectives

The technique of high-speed chronoamperometry using Nafion^®-coated single carbon-fiber microelectrodes was used to study amphetamine-evoked dopamine (DA) release produced by Adderall^®, d-amphetamine, or d,l-amphetamine in the striatum of anesthetized male Fischer 344 (F344) rats. The amphetamine solutions were locally applied from micropipettes by pressure ejection.

Results

Local applications of Adderall^® resulted in significantly greater DA release signal amplitudes with prolonged time course of dopamine release and re-uptake as compared to d-amphetamine and d,l-amphetamine.

Conclusions

These data support the hypothesis that the combination of amphetamine enantiomers and salts in Adderall^® has effects on DA release, which result in increased and prolonged DA release, compared to d- and d,l-amphetamine.

     

A novel saponin from Manilkara hexandra seeds and anti-inflammatory activity

Chromatographic separation of acetone precipitate of the seeds of Manilkara hexandra has resulted in a novel saponin, 3-O-(β-d-apiofuranosyl-(1 → 3)-β-d-glucopyranosyl)-28-O-(α-l-rhamnopyranosyl(1 → 3)-β-d-xylopyranosyl(1 → 4)-α-l-rhamnopyranosyl(1 → 2)-α-l-arabinopyranosyl)-16-α-hydroxyprotobassic acid (Saponin 3), together with two known saponins isolated for the first time from the family Sapotaceae, viz, 3-O-β-d-glucopyranosyl(1 → 6)[(β-d-apiofuranosyl-(1 → 3)]-β-d-glucopyranosyl)-28-O-(α-l-rhamnopyranosyl(1 → 3)-β-d-xylopyranosyl(1 → 4)-α-l-rhamnopyranosyl(1 → 2)-α-l-arabinopyranosyl)-16α-hydroxyprotobassic acid (Saponin 1), 3-O-(β-d-glucopyranosyl)-28-O-(α-l-rhamnopyranosyl(1 → 3)-β-d-xylopyranosyl(1 → 4)-α-l-rhamnopyranosyl(1 → 2)-α-l-arabinopyranosyl)-protobassic acid, and 3-O-(β-d-glucopyranosyl)-28-O-(α-l-rhamnopyranosyl(1 → 3)-β-d-xylopyranosyl(1 → 4)-α-l-rhamnopyranosyl(1 → 2)-α-l-arabinopyranosyl)-protobassic acid (Saponin 2). Also, three known phenolic compounds were isolated for the first time from the species hexandra, viz, gallic acid, myrecetin, and quercetin. The chemical structures of the isolated saponin compounds were established by spectral techniques (UV, ¹H, ¹³C NMR, and MS). The acetone fraction containing the crude saponin mixture possessed a significant inhibitory effect on LPS-induced nitric oxide to the extent of 60 % compared to the LPS-stimulated cells and to the extent of 20 % compared to the control level showing significant anti-inflammatory activity. Acetone and MeOH seed extracts as well as the crude saponin fraction of M. hexandra showed no antioxidant activity as measured by DPPH assay (SC₅₀ = 217.65, 496.68, and 562.38 μg/ml, respectively) compared to that of ascorbic acid (SC₅₀ = 12.9). The MeOH seed extract showed no cytotoxic activity against three different human cancer cell lines, viz, colon carcinoma (HCT-116), hepatocellular carcinoma (Hep-G2), and breast adenocarcinoma (MCF-7), estimated by MTT assay (IC₅₀ = 95.20, 73.39, and 79.15 μg/ml, respectively).     

Population pharmacokinetic modeling and deconvolution of enantioselective absorption of eflornithine in the rat

Enantioselective pharmacokinetics and absorption of eflornithine in the rat was investigated using population pharmacokinetic modeling and a modified deconvolution method. Bidirectional permeability of l- and d-eflornithine was investigated in Caco-2 cells. The rat was administered racemic eflornithine hydrochloride as a single oral dose [40–3,000 mg/kg bodyweight (BW)] or intravenously (IV) (100–2,700 mg/kg BW infused over 60–400 min). Serial arterial blood samples were collected and l- and d-eflornithine were quantitated with a previously published chiral bioanalysis method. The D:L concentration ratio was determined in rat faeces. Intravenous l-and d-eflornithine plasma concentration–time data was analyzed using population pharmacokinetic modeling and described with a 3-compartment pharmacokinetic model with saturable binding to one of the peripheral compartments. Oral plasma concentration–time data was analyzed using a modified deconvolution method accounting for nonlinearities in the eflornithine pharmacokinetics. Clearance was similar for both enantiomers (3.36 and 3.09 mL/min). Oral bioavailability was estimated by deconvolution at 30 and 59 % for l- and d-eflornithine. The D:L concentration ratio in feces was 0.49 and the Caco-2 cell permeability was similar for both enantiomers (6–10 × 10^?8 cm/s) with no evident involvement of active transport or efflux. The results presented here suggest that the difference in the bioavailability between eflornithine enantiomers is caused by a stereoselective difference in extent rather than rate of absorption. The presented modified deconvolution method made it possible to account for the non-linear component in the suggested three-compartment pharmacokinetic model thus rapidly estimating eflornithine oral bioavailability.     

Effect of d-amphetamine on emotion-potentiated startle in healthy humans: implications for psychopathy and antisocial behaviour

Rationale

An emerging literature associates increased dopaminergic neurotransmission with altered brain response to aversive stimuli in humans. The direction of the effect of dopamine on aversive motivation, however, remains unclear, with some studies reporting increased and others decreased amygdala activation to aversive stimuli following the administration of dopamine agonists. Potentiation of the startle response by aversive foreground stimuli provides an objective and directional measure of emotional reactivity and is considered useful as an index of the emotional effects of different drugs.

Objective

We investigated the effects of two doses of d-amphetamine (5 and 10 mg), compared to placebo, for the first time to our knowledge, using the affect–startle paradigm.

Method

The study employed a between-subjects, double-blind design, with three conditions: 0 mg (placebo), and 5 and 10 mg d-amphetamine (initially n?=?20/group; final sample: n?=?18, placebo; n?=?18, 5 mg; n?=?16, 10 mg). After drug/placebo administration, startle responses (eyeblinks) to intermittent noise probes were measured during viewing of pleasant, neutral and unpleasant images. Participants’ general and specific impulsivity and fear-related personality traits were also assessed.

Results

The three groups were comparable on personality traits. Only the placebo group showed significant startle potentiation by unpleasant, relative to neutral, images; this effect was absent in both 5- and 10-mg d-amphetamine groups (i.e. the same effect of d-amphetamine observed at different doses in different people).

Conclusions

Our findings demonstrate a reduced aversive emotional response under d-amphetamine and may help to account for the known link between the use of psychostimulant drugs and antisocial behaviour.     

Are attention lapses related to d-amphetamine liking?

Rationale

A rich literature suggests that both impulsiveness and drug-induced euphoria are risk factors for drug abuse. However, few studies have examined whether sensitivity to the euphoric effects of stimulants is related to attention lapses, a behavioral measure of inattention sometimes associated with impulsivity.

Objective

The aim of the study was to examine ratings of d-amphetamine drug liking among individuals with high, moderate, and low attention lapses.

Methods

Ninety-nine healthy volunteers were divided into three equal-sized groups based on their performance on a measure of lapses of attention. The groups, who exhibited low, medium, and high attention lapses (i.e., long reaction times) on a simple reaction time task, were compared on their subjective responses (i.e., ratings of liking and wanting more drug) after acute doses of d-amphetamine (0, 5, 10, and 20 mg).

Results

Subjects who exhibited high lapses liked 20 mg d-amphetamine less than subjects who exhibited low lapses. These subjects also tended to report smaller increases in “wanting more drug” after d-amphetamine.

Conclusion

The findings suggest that participants who exhibit impaired attention may be less sensitive to stimulant-induced euphoria.     

Effect of age on methylphenidate-induced conditioned taste avoidance and related BDNF/TrkB signaling in the insular cortex of the rat

Rationale

Drug use and abuse is thought to be a function of the balance between its rewarding and aversive effects, such that the rewarding effects increase the likelihood of use while the drug’s dissociable aversive effects limit it. Adolescents exhibit a shift in this balance toward reward, which may ultimately lead to increased use. Importantly, recent work shows that adolescents are also protected from the aversive effects of many abusable drugs as measured by conditioned taste avoidance (CTA). However, such effects of methylphenidate (MPH, widely prescribed to adolescents with ADHD) have not been characterized.

Objectives

The effect of age on MPH-induced CTA was assessed. In addition, MPH-induced changes in brain-derived neurotrophic factor (BDNF) activity in the insular cortex (IC) and central nucleus of the amygdala (CeA), known to be important to CTA, were examined and related to CTAs in adolescents and adults.

Methods

CTAs induced by MPH (0, 10, 18, and 32 mg/kg) were assessed in adolescent (n = 34) and adult (n = 33) male Sprague Dawley rats. Following MPH CTA, IC and CeA tissue was probed for differences in BDNF and tropomyosin-related kinase receptor-B (TrkB) using Western blots.

Results

Blunted expression of MPH CTA was observed in the adolescents versus adults, which correlated with generally attenuated adolescent BDNF/TrkB activity in the IC, but the drug effects ran contrary to the expression of CTA.

Conclusions

Adolescents are protected from the aversive effects of MPH versus adults, but further work is needed to characterize the possible involvement of BDNF/TrkB.     

The effect of acute tryptophan depletion on mood and impulsivity in polydrug ecstasy users

Rationale

Several studies suggest users of 3,4-methylenedioxymethamphetamine (ecstasy) have low levels of serotonin. Low serotonin may make them susceptible to lowered mood.

Objective

This work aims to study the acute effects on mood and impulsivity of lowering serotonin levels with acute tryptophan depletion in polydrug ecstasy users and to determine whether effects were different in men and women.

Methods

In a double-blind cross-over study, participants who had used ecstasy at least 25 times (n?=?13) and nonuser controls (n?=?17) received a tryptophan-deficient amino acid mixture and a control amino acid mixture containing tryptophan, at least 1 week apart. Mood was measured using the profile of mood states, and impulsivity was measured with the Go/No-Go task.

Results

The main result shows that a lowering of mood after acute tryptophan depletion occurred only in female polydrug ecstasy users (n?=?7), relative to controls (n?=?9). Results from the Go/No-Go task suggested that impulsivity was not increased by acute tryptophan depletion in polydrug ecstasy users.

Limitation

The group sizes were small, when males and females were considered separately.

Conclusions

Women polydrug ecstasy users appear to be more susceptible than men to the effects of lowered serotonin levels. If use of ecstasy alone or in conjunction with other drugs causes progressive damage of serotonin neurons, women polydrug ecstasy users may become susceptible to clinical depression.     

Effects of coincident 5-HT1A receptor stimulation and NMDA receptor antagonism on l-DOPA-induced dyskinesia and rotational behaviors in the hemi-parkinsonian rat

Rationale

Serotonin 1A receptor (5-HT1AR) agonists reduce l-DOPA-induced dyskinesia and enhance motor function in experimental and clinical investigations of Parkinson’s disease (PD). While the mechanism(s) by which these effects occur are unclear, recent research suggests that modulation of glutamate neurotransmission contributes.

Objective

To further delineate the relationship between 5-HT_1A receptors and glutamate, the current study examined the effects of the 5-HT_1AR agonist, ±8-OH-DPAT and the N-methyl-d-aspartic acid receptor (NMDAR) antagonist, MK-801, on l-DOPA-induced motor behavior.

Materials and methods

Unilateral 6-hydroxydopamine lesioned male Sprague–Dawley rats were rendered dyskinetic with 1 week of daily l-DOPA (12 mg/kg, i.p.) + benserazide (15 mg/kg, i.p.). On test days, one group of rats received pretreatments of: ±8-OH-DPAT (0, 0.03, 0.1, 0.3 mg/kg, i.p.) or MK-801 (0, 0.03, 0.1, 0.3 mg/kg, i.p.). A second group was administered combined ±8-OH-DPAT (0, 0.03 or 0.1 mg/kg, i.p.) + MK-801 (0, 0.1 mg/kg, i.p.). Pretreatments were followed by l-DOPA administration, after which, abnormal involuntary movements (AIMs) and rotations were monitored. To investigate effects on motor performance, subthreshold doses of ±8-OH-DPAT (0.03 mg/kg, i.p.) + MK-801 (0.1 mg/kg, i.p.) were administered to l-DOPA-naïve hemiparkinsonian rats before the forepaw adjusting steps test.

Results

Individually, both ±8-OH-DPAT and MK-801 dose-dependently decreased l-DOPA-induced AIMs without affecting rotations. Combined subthreshold doses of ±8-OH-DPAT+MK-801 reduced l-DOPA-induced AIMs and potently enhanced contralateral rotations without altering l-DOPA-induced motor improvements.

Conclusions

The current results indicate a functional interaction between 5-HT_1AR and NMDAR that may improve pharmacological treatment of PD patients.     

An efficient, solvent-free microwave-assisted synthesis and antimicrobial screening of 1,6-dihydropyrimidine analogues

A series of compounds 4-(4-(4-aminophenyl)-6-(aryl)-1,6-dihydropyrimidin-2-ylthio)butanenitriles 5a–l were synthesised by the reaction of allyl cyanide 4 with 3a–l. Compounds 3a–l were prepared from reaction between various chalcones 1a–l and thiourea in presence of catalytic amount of potassium hydroxide. Compounds 3a–l, and 5a–l were prepared by classical as well as MWI methods. Structures of the compounds were characterized by IR, ¹H NMR, ¹³C NMR and mass spectral data. The newly synthesized compounds 5a–l were screened for their antimicrobial activity against different strains of bacteria and fungi using serial broth dilution method. Compounds 5e, 5g and 5k were found to be most active with MIC of 25?μg/mL against selected bacterial strains, while compound 5d, 5f, 5j and 5k were found to be most active with MIC 50?μg/mL against selected fungal strains.     

Rationale and conditions for the requirement of chiral bioanalytical methods in bioequivalence studies

Purpose

The aim of the present work was to assess the need for chiral bioanalytical methods in bioequivalence studies.

Methods

The samples from a bioequivalence study of two ibuprofen 2% oral suspensions that had shown bioequivalence for AUC and C_max, but not for t_max (medians of 2.0 and 0.75 h) with a non-chiral method were assayed with a chiral method to investigate whether there was an actual difference in the rate of absorption within the limits of C_max and AUC bioequivalence.

Results

The non-chiral method and the sum of concentrations of both enantiomers obtained with the chiral method gave a similar outcome (90% CI C_max non-chiral: 82.77–96.09, sum of enantiomers: 82.19–98.23; 90% CI AUC_t non-chiral: 107.23–115.49, sum of enantiomers: 105.73–121.35). However, the chiral method showed differences in AUC and C_max that resulted in non-bioequivalence for the individual enantiomers (90% CI C_max S-ibuprofen: 76.05–91.36, R-ibuprofen: 87.84–113.05; 90% CI AUC_t S-ibuprofen: 96.67–105.86, R-ibuprofen: 118.86–142.24). The differences in the pharmacokinetics of each enantiomer, and thus in the enantiomer concentration ratio, were dependent on the rate of absorption.

Conclusions

Due to the fact that in bioequivalence studies the rate of absorption of the new product is unknown, chiral bioanalytical methods should be employed for chiral drugs, such as ibuprofen, whose enantiomers exhibit different pharmacodynamic characteristics and whose enantiomer concentration ratio might be modified by the rate of absorption, irrespective of whether the eutomer is the minor enantiomer or the similarity of the pharmacokinetics of the enantiomers at a given rate of absorption.     

Antimicrobial screening of novel synthesized benzimidazole nucleus containing 4-oxo-thiazolidine derivatives

As a part of systematic investigation of synthesis, characterization and antimicrobial screening of some novel 3-(2-(6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-2-(aryl)thiazolidin-4-ones (3a–l), have been synthesized from Schiff bases of N-arylidene-2-(6-methyl-1H-benzo[d]imidazol-2-yl)anilines, (2a–l). The Schiff bases (2a–l) were prepared by condensation of different aldehydes with 2-(6-methyl-1H-benzo[d]imidazol-2-yl)aniline (1). The compound (1) was obtained from 2-amino benzoic acid and 4-methylbenzene-1,2-diamine. All the synthesized compounds were screened for in vitro antibacterial and antifungal activities on Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus pyogenes, Candida albicans, Aspergillus niger, and Aspergillus clavatus. The structures of the compounds synthesized were elucidated by IR, ¹H-NMR, ¹³C-NMR, and mass spectra.     

Synthesis,antimicrobial, and cytotoxic activities of novel benzimidazole derivatives bearing cyanopyridine and 4-thiazolidinone motifs

A series of 6-(1H-benzo[d]imidazol-2-yl)-2-(2-(3-nitrophenyl)-4-oxothiazolidin-yl)-4-(aryl)nicotinonitriles 5a–l were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, and mass spectrometry techniques. These novel compounds 5a–l were screened for their in vitro antimicrobial activity against different bacterial and fungal strains and in vitro cytotoxicity study (HeLa cell line) using MTT colorimetric assay. The results demonstrated that compounds 5c, 5e, and 5i–k exhibited excellent antibacterial activity, while compounds 5d, 5i, and 5k were found to be the most potent antifungal agents. From the standpoint of SAR studies, it was observed that the presence of electron donating groups remarkably enhanced the antimicrobial activity of newly synthesized compounds. Further, the results of preliminary MTT cytotoxicity studies on HeLa cells suggested that potent antimicrobial activity of 5c–e and 5i–k was accompanied by low cytotoxicity.     

Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease

Background and purpose:

Increased glutamatergic innervation of the substantia nigra pars reticulata (SNpr) and pars compacta (SNpc) may contribute to the motor deficits and neurodegeneration, respectively, in Parkinson''s disease (PD). This study aimed to establish whether activation of pre-synaptic group III metabotropic glutamate (mGlu) receptors reduced glutamate release in the SN, and provided symptomatic or neuroprotective relief in animal models of PD.

Experimental approach:

Broad-spectrum group III mGlu receptor agonists, O-phospho-l-serine (l-SOP) and l-2-amino-4-phosphonobutyrate (l-AP4), were assessed for their ability to inhibit KCl-evoked [³H]-d-aspartate release in rat nigral prisms or inhibit KCl-evoked endogenous glutamate release in the SNpr in vivo using microdialysis. Reversal of akinesia in reserpine-treated rats was assessed following intranigral injection of l-SOP and l-AP4. Finally, the neuroprotective effect of 7 days'' supra-nigral treatment with l-AP4 was examined in 6-hydroxydopamine (6-OHDA)-lesioned rats.

Key results:

l-SOP and l-AP4 inhibited [³H]-d-aspartate release by 33 and 44% respectively. These effects were blocked by the selective group III mGlu antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG). l-SOP also reduced glutamate release in the SNpr in vivo by 48%. Injection of l-SOP and l-AP4 into the SNpr reversed reserpine-induced akinesia. Following administration above the SNpc, l-AP4 provided neurochemical, histological and functional protection against 6-OHDA lesion of the nigrostriatal tract. Pretreatment with CPPG inhibited these effects.

Conclusions and implications:

These findings highlight group III mGlu receptors in the SN as potential targets for providing both symptomatic and neuroprotective relief in PD, and indicate that inhibition of glutamate release in the SN may underlie these effects.     

The d-amphetamine-treated Göttingen miniature pig: an animal model for assessing behavioral effects of antipsychotics

Rationale

Rodents are usually used to assess the ability of antipsychotic drugs to antagonize hyperlocomotion induced by dopamine agonists, such as the psychostimulant d-amphetamine. However, the substantial differences between rodents and humans may hinder extrapolation of experimental results to humans. For this reason, we speculated that Göttingen miniature pigs, which show strong physiological and genetic homology with humans, might be a better model for investigating the effects of antipsychotics. To investigate this, we determined whether d-amphetamine induced hyperlocomotion in miniature pigs and whether this effect was reversible by antipsychotics.

Materials and methods

d-Amphetamine was tested in the dose range of 0.2 to 2.0 mg kg^?1 for its ability to induce hyperactivity in the open field, and the effects of two antipsychotics, haloperidol and risperidone, on amphetamine-induced hyperactivity were examined.

Results

d-Amphetamine increased open-field activity at 0.2, 0.4, and 0.7 mg kg^?1 s.c. but not at higher doses. The stimulation of open-field activity induced by 0.4 mg kg^?1 s.c. d-Amphetamine was antagonized by haloperidol and risperidone (0.01 and 0.04 mg kg^?1 s.c.).

Conclusion

d-Amphetamine-induced hyperlocomotion in miniature pigs may be a useful model for studying the effect of putative antipsychotics.     

Involvement of nucleus accumbens AMPA receptor trafficking in augmentation of D- amphetamine reward in food-restricted rats

Rationale

Chronic food restriction (FR) increases behavioral responsiveness to drugs of abuse and associated environments. Pre- and postsynaptic neuroadaptations have been identified in the mesoaccumbens dopamine pathway of FR subjects but the mechanistic basis of increased drug reward magnitude remains unclear.

Objectives

Effects of FR on basal and d-amphetamine-induced trafficking of AMPA receptor subunits to the nucleus accumbens (NAc) postsynaptic density (PSD) were examined, and AMPA receptor involvement in augmentation of d-amphetamine reward was tested.

Materials and methods

FR and ad libitum fed (AL) rats were injected with d-amphetamine (2.5 mg/kg, i.p.) or vehicle. Brains were harvested and subcellular fractionation and Western analyses were used to assess AMPA receptor abundance in NAc homogenate and PSD fractions. A follow-up experiment used a curve-shift protocol of intracranial self-stimulation to assess the effect of 1-naphthylacetyl spermine (1-NASPM), a blocker of Ca²⁺-permeable AMPA receptors, on rewarding effects of d-amphetamine microinjected in NAc shell.

Results

FR increased GluA1 in the PSD, and d-amphetamine increased p-Ser845-GluA1, GluA1, GluA2, but not GluA3, with a greater effect in FR than AL rats. d-amphetamine lowered reward thresholds, with greater effects in FR than AL rats, and 1-NASPM selectively reversed the enhancing effect of FR.

Conclusions

Results suggest that FR leads to increased synaptic incorporation of GluA1 homomers to potentiate rewarding effects of appetitive stimuli and, as a maladaptive byproduct, d-amphetamine. The d-amphetamine-induced increase in synaptic p-Ser845-GluA1, GluA1, and GluA2 may contribute to the rewarding effect of d-amphetamine, but may also be a mechanism of synaptic strengthening and behavior modification.