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1.
Nirmal Bhide David Lindenbach Margaret A. Surrena Adam A. Goldenberg Christopher Bishop S. Paul Berger Melanie A. Paquette 《Psychopharmacology》2013,227(3):533-544
Rationale
l-DOPA continues to be the primary treatment for patients with Parkinson’s disease; however, the benefits of long-term treatment are often accompanied by debilitating side effects known as dyskinesias. In recent years, several 5-HT1A receptor agonists have been found to reduce dyskinesia in clinical and experimental models of PD. The purported sigma-1 antagonist, BMY-14802 has been previously demonstrated to reduce l-DOPA induced dyskinesia in a 5-HT1A receptor dependent manner.Objective
In the present study, we extend these findings by examining the anti-dyskinetic potential of BMY-14802 against l-DOPA, the D1 receptor agonist SKF81297 and the D2 receptor agonist, quinpirole, in the hemi-parkinsonian rat model. In addition, the receptor specificity of BMY-14802’s effects was evaluated using WAY-100635, a 5-HT1A receptor antagonist.Results
Results confirmed the dose-dependent (20?>?10?>?5 mg/kg) anti-dyskinetic effects of BMY-14802 against l-DOPA with preservation of anti-parkinsonian efficacy at 10 mg/kg. BMY-14802 at 10 and 20 mg/kg also reduced dyskinesia induced by both D1 and D2 receptor agonists. Additionally, BMY-14802’s anti-dyskinetic effects against l-DOPA, but not SKF81297 or quinpirole, were reversed by WAY-100635 (0.5 mg/kg).Conclusion
Collectively, these findings demonstrate that BMY-14802 provides anti-dyskinetic relief against l-DOPA and direct DA agonist in a preclinical model of PD, acting via multiple receptor systems and supports the utility of such compounds for the improved treatment of PD. 相似文献2.
Keon Sung Shin Hyun Sook Choi Ting Ting Zhao Kwang Hoon Suh Ik Hyun Kwon Soon Ok Choi Myung Koo Lee 《Archives of pharmacal research》2013,36(6):759-767
The effects of berberine on long-term administration of l-DOPA in 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD) were investigated. Rat models of PD were prepared by 6-OHDA lesions in the ipsilateral sides, and then were treated with berberine (5 and 15 mg/kg) and/or l-DOPA (10 mg/kg) once daily for 21 days. Treatments with either concentration of berberine (5 and 15 mg/kg) in 6-OHDA-lesioned groups decreased the numbers of tyrosine hydroxylase (TH)-immunopositive neurons in the substantia nigra and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum as compared to 6-OHDA-lesioned groups. In addition, dopaminergic neuronal cell death of the ipsilateral sides in 6-OHDA-lesioned groups was attenuated by l-DOPA administration. However, both concentrations of berberine in 6-OHDA-lesioned groups treated with l-DOPA aggravated the numbers of TH-immunopositive neurons in the substantia nigra and the levels of dopamine, norepinephrine, DOPAC and HVA in the striatum as compared to rats not treated with berberine. These results suggest that berberine leads to the degeneration of dopaminergic neuronal cells in the substantia nigra in the rat model of PD with chronic l-DOPA administration. Long-term l-DOPA therapy that may involve possibly neurotoxic isoquinoline agents including berberine should involve monitoring for adverse symptoms. 相似文献
3.
Dupre KB Eskow KL Steiniger A Klioueva A Negron GE Lormand L Park JY Bishop C 《Psychopharmacology》2008,199(1):99-108
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-HT1A receptors and glutamate, the current study examined the effects of the 5-HT1AR 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-HT1AR and NMDAR that may improve pharmacological treatment of PD patients. 相似文献4.
Rationale
Glutamate receptor antagonists can improve the symptoms of Parkinson’s disease (PD) and reduce l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) in both animal models and humans, but usually produce intolerable side effects. Recent evidence suggests that upregulation of the major glutamate transporter, GLT-1, by the β-lactam antibiotic, ceftriaxone, can increase the removal of synaptic glutamate without producing noticeable side effects, and may provide an effective alternative to receptor antagonists for several neurodegenerative diseases.Objectives
We examined whether repeated i.p. injections of ceftriaxone would, like glutamate antagonists, reduce the deficits in contralateral forepaw stepping produced by unilateral injections of 6-OHDA into the medial forebrain bundle of rats and reduce LID (as measured by abnormal involuntary movements).Methods and results
In Experiment 1, daily injections of 100 mg/kg ceftriaxone improved contralateral forepaw stepping by 44 %, and these therapeutic effects were still apparent 29 days following the cessation of treatment. In Experiment 2, daily injections of 50 mg/kg ceftriaxone were as effective as daily injections of 10 mg/kg?l-DOPA in increasing contralateral forepaw stepping by 40 %. These therapeutic effects of ceftriaxone were decreased by an injection of 10 mg/kg of the selective GLT-1 antagonist, dihydrokainate (DHK), and were still evident 69 days after the cessation of ceftriaxone injections. Furthermore, ceftriaxone did not produce dyskinesia by itself and reduced the development, but not the expression, of LID.Conclusions
These data suggest that ceftriaxone, by producing a long-term increase in GLT-1 function and increasing the removal of synaptic glutamate, may offer several advantages over l-DOPA as therapy for PD. 相似文献5.
Evaluation of antioxidant activity of new constituents from the fruits of Lycium chinense 总被引:1,自引:0,他引:1
Ill-Min Chung Mohd Ali Praveen Nagella Nasir Ali Siddiqui Ateeque Ahmad 《Medicinal chemistry research》2014,23(8):3852-3860
Two new compounds as labd-7,11-dien-3β, 13α-diol-3α-l-arabinopyranosyl-(2a → 1b)-α-l-arabinopyranosyl-(2b → 1c)-α-l-arabinopyranosyl-(2c → 1d)-α-l-arabinopyranosyl-(2d → 1e)-α-l-arabinopyranosyl-(2e → 1f)-α-l-arabinopyranosyl-(2f → 1g)-α-l-arabinopyranoside (1), and 5 (6), 11 (12), 15 (15′), 5′ (6′), 11′ (12′)-decadehydro-β-carotenyl-4β,4′β-diol-4-α-l-arabinopyranosyl-(2a → 1b)-α-l-arabinopyranosyl-(2b → 1c)-α-l-arabinopyranosyl-(2c → 1d)-β-l-arabinopyranosido-4′-α-l-arabinopyranosyl-(2e → 1f)-α-l-arabinopyranosyl-(2f → 1g)-α-l-arabinopyranosyl-(2g → 1h)-α-l-arabinopyranosyl-(2h → 1i)-β-l-arabinopyranoside (2) along with known compound have been isolated from the methanol extract of fruits of Lycium chinense. Their chemical structures were established with the help of physical, chemical, and spectroscopic methods. The compounds 1 and 2 were investigated for scavenging of the diphenylpicrylhydrazyl (DPPH) radical scavenging activity, reducing power, and the phosphomolybdenum activity, and the results demonstrate that the compound (1) has potential as a natural antioxidant whereas the compound (2) exhibited moderate antioxidant activity. 相似文献
6.
Yi Wang Wei Kang Liang-jian Hong Wen-li Hai Xiao-yang Wang Hai-feng Tang Xiang-rong Tian 《Journal of natural medicines》2013,67(1):70-77
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. 相似文献
7.
Andreas Boldt Ulrich Gergs Julia Frenker Andreas Simm Rolf-Edgar Silber Udo Klöckner Joachim Neumann 《Naunyn-Schmiedeberg's archives of pharmacology》2009,380(4):293-301
We studied the effects of l-lysine in cardiac preparations of mice and men. Of note, l-lysine increased force of contraction in a concentration- and time-dependent manner in isolated electrically paced left atrium of mouse and in human right atrium. It further increased heart rate and left ventricular pressure in the isolated perfused mouse heart. In isolated adult mouse cardiomyocytes, the contractility as assessed by edge detection was increased as well as the Ca2+ transients after electrically pacing by field stimulation. However, using the patch clamp technique, no effect of l-lysine on action potential duration from a constant holding potential or on current through l-type calcium channels could be observed. However, l-lysine led to a depolarization of unclamped cells. Furthermore, effects of l-lysine were stereospecific, as they were not elicited by d-lysine. The inotropic effects of l-lysine were not abrogated by additionally applied l-ornithine or l-arginine (known inhibitors of lysine transport). However, l-lysine (5 mM) shifted the concentration–response curve for a positive inotropic effect of 5-hydroxytryptamine (5-HT; serotonin) in atrium of transgenic mice (with cardiac specific overexpression of 5-HT4 receptors) to higher concentrations. In summary, we describe a novel positive inotropic effect of an essential amino acid, l-lysine, in the mammalian heart. One might speculate that l-lysine treatment under certain conditions could sustain cardiac performance. Moreover, l-lysine is able to block, at least in part, cardiac 5-HT4 receptors. 相似文献
8.
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. 相似文献9.
Jacqueline Y. Eskander Eman G. Haggag Mohamed R. El-Gindi Mostafa M. Mohamedy 《Medicinal chemistry research》2014,23(2):717-724
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). 相似文献
10.
Maude St-Onge Ian Ajmo Diane Poirier Martin Laliberté 《Journal of medical toxicology》2013,9(3):266-269
Introduction
The object of the current communication is to discuss the theory and the evidence for the use of l-carnitine in calcium channel blocker and metformin poisonings.Case Report
A 68-year-old male known for hypertension and type II diabetes was admitted to the critical care unit of a community hospital following an overdose of amlodipine and metformin. The patient was intubated, ventilated, and hemodynamically supported with vasopressors. Despite calcium, glucagon, high-dose insulin (HDI), and lipid emulsion for calcium channel blocker and bicarbonate for metabolic acidosis, the patient remained hemodynamically unstable. The patient was considered too unstable to initiate continuous renal replacement therapy; and without access to extracorporeal life support, the administration of l-carnitine was administered as a last resort. One hour after l-carnitine, the norepinephrine requirements started to decrease, the patient began to improve and was subsequently extubated successfully without apparent sequelae in less than 4 days.Discussion
l-Carnitine combined with HDI may have helped with the calcium channel blocker (CCB) poisoning by decreasing insulin resistance, promoting intracellular glucose transport, facilitating the metabolism of free fatty acids, and increasing calcium channel sensitivity. It may have also stimulated oxidative utilization of glucose instead of converting pyruvate into lactate and contributed to decrease lactate production with metformin poisoning. 相似文献11.
Carl-Christer Johansson Peter Gennemark Per Artursson Angela Äbelö Michael Ashton Rasmus Jansson-Löfmark 《Journal of pharmacokinetics and pharmacodynamics》2013,40(1):117-128
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. 相似文献
12.
Overdose of γ-hydroxybutyrate (GHB) can result in severe respiratory depression. Monocarboxylate transporter (MCT) inhibitors, including l-lactate, increase GHB clearance and represent a potential treatment for GHB intoxication. GHB can also affect l-lactate clearance, and l-lactate has been reported to affect respiration. In this research, we characterize these toxicokinetic/toxicodynamic interactions between GHB and l-lactate using mechanistic modeling. Plasma, urine, and respiration data were taken from our previous study in which GHB and sodium l-lactate were administered alone and concomitantly in rats. A model incorporating active renal reabsorption for both agents fit GHB and l-lactate toxicokinetic data. The Km for renal reabsorption of GHB (650 μg/mL) was close to its Km for the proton-dependent MCT1 and that for l-lactate (13.5 μg/mL) close to its Km for the sodium-dependent SMCT1. Inhibition of reabsorption by both agents was necessary to model concomitant drug administration. The metabolic Km for l-lactate closely resembled that for MCT-mediated hepatic uptake in vitro, and GHB inhibited this process. l-lactate significantly inhibited respiration at a high dose, and an indirect response model was used to fit these data. GHB toxicodynamics was modeled as a direct effect delayed by nonlinear transport into the brain extracellular fluid, with a Km value of 1,865 μg/mL for brain uptake which is similar to the in vitro Km value determined in rat brain endothelial cells. This model was useful for characterizing multiple MCT-mediated interactions. Incorporation of many parameters that can be determined in vitro may allow for clinical translation of these interactions. 相似文献
13.
Xing-Xiang Peng Soledad Cabeza de Vaca Edward B. Ziff Kenneth D. Carr 《Psychopharmacology》2014,231(15):3055-3063
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. 相似文献14.
William C. Griffin III Robin W. McGovern Guinevere H. Bell Patrick K. Randall Lawrence D. Middaugh Kennerly S. Patrick 《Psychopharmacology》2013,225(3):613-625
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. 相似文献15.
Rationale
Continuous administration of d-amphetamine has shown promise as a treatment for psychostimulant addiction. In rodent studies, constant infusion of d-amphetamine (5 mg/kg/day) has been shown to reduce cocaine-reinforced responding in the dose range of 0.19–0.75 mg/kg/inf.Objectives
The present study tested whether these effects were a reflection of pharmacological interactions between d-amphetamine and cocaine or if they resulted from associative learning mechanismsMethods
After stable progressive ratio (PR) baselines were established, rats were implanted with subcutaneous osmotic minipumps filled with either d-amphetamine (5 mg/kg/day—groups 1 and 2) or saline (group 3). During the treatment period, groups 1 and 3 self-administered cocaine at a dose that was previously shown to produce the most robust effects in combination with d-amphetamine treatment (0.19 mg/kg/inf), while group 2 received passive cocaine infusions.Results
In replication of previous studies, d-amphetamine treatment resulted in a significant (35 %) decrease in breakpoints relative to saline controls. By contrast, no reductions in breakpoints were observed in animals that received passive cocaine infusions during the treatment period (group 2).Conclusions
Active self-administration of cocaine during the treatment period appears to be an important factor in reducing cocaine-reinforced breakpoints. These findings suggest learning mechanisms are involved in the therapeutic effects of continuous d-amphetamine, and pharmacological interaction mechanisms such as cross-tolerance cannot completely account for the observed decreases in cocaine seeking. 相似文献16.
Xian-Tao Zhang Lei Wang Shu-Wei Ma Qing-Wen Zhang Yue Liu Lei-Hong Zhang Wen-Cai Ye 《Journal of natural medicines》2013,67(2):375-380
Four new cycloartane glycosides, 3-O-β-d-xylopyranosyl-(1 → 6)-β-d-glucopyranosyl-(1 → 4)-β-d-fucopyranosyl (22S,24Z)-cycloart-24-en-3β,22,26-triol 26-O-(6-O-acetyl)-β-d-glucopyranoside (1), 3-O-α-l-arabinopyranosyl-(1 → 6)-β-d-glucopyranosyl-(1 → 4)-β-d-fucopyranosyl (22S,24Z)-cycloart-24-en-3β,22,26-triol 26-O-(6-O-acetyl)-β-d-glucopyranoside (2), 3-O-β-d-glucopyranosyl (24S)-cycloartane-3β,16β,24,25,30-pentaol 25-O-β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranoside (3) and 3-O-β-d-glucopyranosyl (24S)-cycloartane-3β,16β,24,25,30-pentaol 25-O-β-d-glucopyranosyl-(1 → 4)-β-d-glucopyranoside (4), were isolated from the aerial parts of Thalictrum fortunei. Their structures were established on the basis of extensive NMR and HR-ESI-MS analyses, along with acid hydrolysis. 相似文献
17.
Pattra Lapikanon Phichai Tovivich Won Sick Woo Jae Sue Choi 《Archives of pharmacal research》1983,6(1):29-33
From the roots ofRandia siamensis,d-mannitol, a mixture of β-sitosterol and campesterol, oleanolic acid acetate, oleanolic acid-3-α-l-arabinoside and mesembryanthemoidigenic acid as a sapogenin were isolated and characterized. 相似文献
18.
Chiobouaphong Phakeovilay Wannaporn Disadee Poolsak Sahakitpichan Somkit Sitthimonchai Prasat Kittakoop Somsak Ruchirawat Tripetch Kanchanapoom 《Journal of natural medicines》2013,67(1):228-233
A new phenylethanoid glycoside, isocassifolioside (8), and two new flavone glycosides, hispidulin 7-O-α-l-rhamnopyranosyl-(1′″ → 2″)-O-β-d-glucuronopyranoside (11) and pectolinaringenin 7-O-α-l-rhamnopyranosyl-(1′″ → 2″)-O-β-d-glucuronopyranoside (12) were isolated from the aerial portions of Ruellia tuberosa L., together with verbascoside (1), isoverbascoside (2), nuomioside (3), isonuomioside (4), forsythoside B (5), paucifloside (6), cassifolioside (7), hispidulin 7-O-β-d-glucuronopyranoside (9) and comanthoside B (10). The structure elucidations were based on analyses of chemical and spectroscopic data including 1D- and 2D-NMR. The isolated compounds 1–12 exhibited radical scavenging activity using ORAC assay. 相似文献
19.
Rosa Martha Perez Gutierrez 《Medicinal chemistry research》2013,22(4):1846-1855
Satureja macrostema (SM) is used with culinary and medicinal purposes. Methanol extract from SM was investigated for its phenolic content, antioxidant, hepatoprotective, and kidney protective activities. Liver and kidney damage were induced in rats with CCl4. Hepatoprotective efficacy was measured by the activity of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, cholesterol, high density lipoprotein and total protein, and lipid peroxidation. Kidney function was evaluated by measuring plasma urea and creatinine. Antioxidant activity was evaluated by measuring blood glutathione content, superoxide dismutase and catalase activities, and malondialdehyde equivalent; their activity was comparable to that of silymarin, a well-known hepatoprotective agent. Methanol extracts of S. macrostema showed potent antioxidant, kidney protective, and hepatoprotective activities; in-depth chromatographic investigation resulted in the identification of six new flavonoid glycosides: 5-hydroxy-3,6,4′-trimethoxyflavonol-7-C-α-l-rhamnopyranosyl-(1 → 3)-β-d-glucopyranoside (2), 4′-methoxy-5,7,3′,5′-tetra-hydroxyflavanone-3-O-β-d-rhamnopyranosyl-(1 → 2)-β-d-rhamnopyranoside (3), 5,4′-dimethoxy-7,3′,5′-trihydroxyflavanone-3-O-β-d-rhamnopyranoside (4), 5,3′,4′,5′-tetrahydroxyflavanone-7-O-β-d-rhamnopyranoside (5), 5,3′,4′,5′-tetramethoxyflavanone-7-O-β-d-rhamnopyranoside (6), and 5,4′-dimethoxy-3′-hydroxyflavone-7-β-d-rhamnopyranoside (8) along with three known compounds: 5-hydroxy-7,4′-dimethoxyflavone (1), prunin (7), and diosmin (9) that were isolated. Structural elucidation of the new compounds was established based on the spectral data. The present study revealed that S. macrostema leaves have a significant radical scavenging and hepatoprotective activity. 相似文献
20.
David Gervais Tim Corn Andrew Downer Stuart Smith Alan Jennings 《The AAPS journal》2014,16(4):784-790
In order to generate further characterisation data for the lyophilised product Erwinia chrysanthemi l-asparaginase, reconstituted drug product (DP; marketed as Erwinase or Erwinaze) was analysed for subvisible (2–10 μm) particulate content using both the light obscuration (LO) method and the newer flow-imaging microscopy (FIM) technique. No correlation of subvisible particulate counts exists between FIM and LO nor do the counts correlate with activity at both release and on stability. The subvisible particulate content of lyophilised Erwinia l-asparaginase appears to be consistent and stable over time and in line with other parenteral biopharmaceutical products. The majority (ca. 75%) of subvisible particulates in l-asparaginase DP were at the low end of the measurement range by FIM (2–4 μm). In this size range, FIM was unable to definitively classify the particulates as either protein or non-protein. More sensitive measurement techniques would be needed to classify the particulates in lyophilised l-asparaginase into type (protein and non-protein), so the LO technique has been chosen for on-going DP analyses. E. chrysanthemi l-asparaginase has a lower rate of hypersensitivity compared with native Escherichia coli preparations, but a subset of patients develop hypersensitivity to the Erwinia enzyme. A DP lot that had subvisible particulate counts on the upper end of the measurement range by both LO and FIM had the same incidence of allergic hypersensitivity in clinical experience as lots at all levels of observed subvisible particulate content, suggesting that the presence of l-asparaginase subvisible particulates is not important with respect to allergic response. 相似文献