Endogenous adenosine release from hippocampal slices excitatory amino acid agonists stimulate release,antagonists reduce the electrically-evoked release

Summary The effect of excitatory amino acids and their antagonists on adenosine and inosine release has been investigated on unstimulated and electrically stimulated hippocampal slices.On unstimulated slices N-methyl-D-aspartate (NMDA), quisqualate and glutamate concentration-dependently evoked the release of adenosine and inosine. The effect of NMDA and quisqualate was antagonized by the NMDA receptor antagonist D(–)-2-amino-7-phosphonoheptanoic acid (D-AP7; 100 mol/1) and the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX; 10 mol/1) respectively. Glutamate (2 and 10 mmol/1)-evoked adenosine and inosine release was not antagonized by the NMDA and non-NMDA receptor antagonists indicating that the effect of glutamate is due to a metabolic rather than a receptor-mediated effect.Electrical field stimulation at 10 Hz also evoked a release of endogenous adenosine and inosine. Tetrodotoxin (0.5 gmol/1) abolished and absence of Ca²⁺ markedly reduced the electrically evoked release of adenosine and inosine. Adenosine and inosine release evoked by electrical stimulation at 20 Hz was significantly reduced in the presence of the NMDA receptor antagonist D-AP7, while at 10 Hz no consistent decrease was seen. In the presence of D-AP7 plus DNQX the 10 Hz-evoked adenosine and inosine release was reduced to about half. These data suggest that the electrically evoked release of adenosine and inosine is partly mediated by the release of excitatory amino acids which act at both non-NMDA and NMDA receptors. Send offprint requests to F. Pedata at the above address     

(-)-Deprenyl inhibits tyramine-induced noradrenaline release, but not tyramine-induced dopamine release or potassium-induced noradrenaline release, from rat brain synaptosomes.

The effect of (-)-deprenyl (selegiline), a therapeutic agent for Parkinson's disease, on the tyramine-induced release of catecholamine from rat brain synaptosomes was studied using a superfusion system. Tyramine (10(-7) to 10(-5)M) enhanced the release of [3H]noradrenaline (NA) and [3H]dopamine (DA) from forebrain and striatal synaptosomes in a dose-dependent manner. (-)-Deprenyl (5x10(-5)M) had no effect on spontaneous catecholamine release, suggesting that it has no tyramine-like catecholamine releasing effect. Pretreatment with (-)- or (+)-deprenyl (5x10(-5)M) significantly prevented the tyramine (10(-6)M)-induced NA release, but not DA release. The inhibitory action of (-)-deprenyl was not observed on potassium (15mM)-induced NA release. (-)-Desmethyldeprenyl (5x10(-5)M), a metabolite of (-)-deprenyl, and a monoamine oxidase-A (MAO-A) inhibitor, clorgyline (5x10(-5)M), failed to block the tyramine-induced NA and DA release. Although (+)-deprenyl, a potent DA uptake inhibitor, did not inhibit tyramine-induced DA release, a catecholamine uptake inhibitor nomifensine (5x10(-5)M) did. In summary, (-)-deprenyl at a dose inhibiting tyramine-induced NA release did not have any effect on tyramine-induced DA release or potassium-induced NA release.     

Storage,release, uptake,and inactivation of purines

Adenine nucleotides are released into the interstitial space during platelet thrombus formation and neurotransmission. ATP has also been reported to be released from the heart and endothelial cells in some studies. Ecto ATPase, ADPase, and 5′-nucleotidase activities capable of hydrolyzing ATP sequentially to adenosine are present in many cell types and may serve to terminate the actions of the nucleotides. The opposing effects of adenosine and ATP on the same cell types have suggested a modulatory role for adenosine of the actions of extracellular ATP and that the rates of hydrolysis of nucleotides might be regulated. Consistent with this it has been found that the balance between feedforward inhibition of 5′-nucleotidase by ADP and/or ATP and preferential delivery of AMP from ADPase to 5′-nucleotidase determines the rate of adenosine production and that this differs in different cell types. Alternatively, adenosine may be produced intracellularly as a result of an imbalance between energy demand and supply. There are at least two different cytosolic forms of 5′-nucleotidase. Degradation of ATP during increased metabolic activity results in an increase in intracellular AMP concentration. Either cytosolic enzyme has a high KM (2–5 mM) and would thus respond to this increase with a proportional rise in the rate of adenosine production. The nucleoside transporter is essential to allow the diffusion of adenosine to extracellular receptor sites. In general, adenosine must be taken up via the nucleoside transporter before it is inactivated either by phosphorylation by adenosine kinase in the micromolar range or by deamination by adenosine deaminase at higher concentrations. © 1993 Wiley-Liss, Inc.     

Riluzole, a glutamate release inhibitor, and motor behavior

Riluzole (2-amino-6-trigluoromethoxy benzothiazole) has neuroprotective, anticonvulsant, anxiolytic and anesthetic qualities. These effects are mediated by blockade of glutamate transmission, stabilizing of sodium channels and blockade of γ-aminobutyric acid (GABA) reuptake. The action profile of riluzole is dominated by its effects on glutamate transmission which are predominately mediated by N-methyl-D-aspartate (NMDA) receptor-linked processes in vitro. In vivo studies show that blockade and stimulation of the different NMDA receptor complex binding sites or AMPA receptors modulate motor behavior in a characteristic manner. It was therefore interesting to examine if blockade of glutamatergic transmission by riluzole induced similar behavioral effects as direct NMDA/AMPA receptor antagonists and if these effects are mediated by a specific receptor. The effects of riluzole alone and in combination with several other neuroactive compounds on the central nervous system was assessed by behavioral paradigms to evaluate sniffing behavior, locomotion, ataxia and rigidity. Accompanying compounds included the NMDA receptor agonist NMDA, the partial glycine site agonist D-cycloserine (DCS), and the α-amino-3-hydroxy-5-phenyl-4-isoxazolepropionic acid (AMPA) receptor antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzo-diazepine HCl]. Riluzole influenced neither stereotyped sniffing behavior nor locomotion but impaired motor coordination and attenuated rigidity induced by blockade of dopamine D1 and D2 receptor antagonists when given alone. At higher doses spontaneous behavioral activity decreased and motor coordination was more impaired. Augmentation of the riluzole effects were observed when NMDA, but not GYKI 52466, was coadministered. The glycine site agonist DCS increased the anticataleptic properties of riluzole. The results indicate that when given alone, riluzole has a behavioral profile resembling that of competitive NMDA receptor antagonists. However, coadministration of riluzole with NMDA/AMPA receptor ligands suggests that this assumption is incorrect, and that riluzole affects glutamatergic transmission by a more indirect mechanism. Nevertheless, the profile of riluzole together with its pre- and postsynaptic blockade of glutamatergic transmission implies beneficial properties in diseases where an overactive glutamate system induces chronic neurotoxicity and/or acute behavioral effects. Received: 15 December 1997 / Accepted: 12 May 1998     

Preparation,characterisation, and drug release from thermoresponsive microspheres

An emulsion polymerisation method for the preparation of thermoresponsive hydrogel microspheres based on N-isopropylacrylamide is described in this paper. It was found that microsphere size distribution could be altered by varying the rate of stirring during the polymerisation process and also by modifying the concentration of lecithin. Microspheres were imaged in the fully hydrated state using environmental scanning electron microscopy (ESEM). Thermoresponsive release of a model drug from the microspheres was found to be a function of microsphere size, with improved control as microsphere size increased.     

Drug release modeled by dissolution,diffusion, and immobilization

This article presents a novel drug release model that combines drug dissolution, diffusion, and immobilization caused by adsorption of the drug to the tablet constituents. Drug dissolution is described by the well-known Noyes-Whitney equation and drug adsorption by a Langmuir-Freundlich adsorption isotherm, and these two processes are included as source and sink terms in the diffusion equation. The model is applicable to tablets that disintegrate into a number of approximately spherical fragments. In order to simplify the analysis it is assumed that liquid absorption, matrix swelling, and tablet disintegration are much faster than drug dissolution and subsequent drug release. The resulting model is shown to yield release characteristics in good agreement with those observed experimentally.     

Schizophrenia: Basic,release, reactive and defect processes

Recent development in the classification of schizophrenic psychopathology and research on the mechanism of action of neuroleptic drugs are reviewed in the light of a proposal by Chapman and McGhie in 1963 that schizophrenic morbidity might be significantly reduced by an appropriate cognitive management. It is concluded that current findings in cognitive psychology and neuropsychology support the Chapman and McGhie proposal, but that a clinical application of their proposal requires a recognition of the multidimensionality of positive and negative schizophrenic syndromes. These syndromes, it is suggested, are constituted by underlying basic, release, reactive and defect processes. Basic and release processes, it is postulated, stem from frontal lobe dysfunction. Reactive processes are composed of cognitive distortions of basic and release experiences and should be open to a cognitive management. Defect processes are constituted by coexisting minimal brain dysfunction. This proposal is at odds with the dopamine hypothesis of schizophrenia but is consistent with a dopamine hypothesis of neuroleptic action. The implications of the proposal for both the neuroleptic and non-neuroleptic pharmacotherapy of schizophrenia are outlined. In particular the development of intermittent pharmacotherapy is noted and the likely significance of emerging cognitive managements for clinical problems for the future assessment of clinical trails of pharmacological agents in schizophrenia.     

Design,in vitro release characterization and pharmacokinetics of novel controlled release pellets containing levodropropizine

Abstract

This study was performed to investigate the in vitro release characteristics of levodropropizine (LDP) from novel dual-coated sustained release (SR) pellets, and evaluate the pharmacokinetics of a novel controlled release (CR) preparation composed of the dual-coated SR pellets and immediate release (IR) LDP pellets. The dual-coated SR pellets composed of a drug-loaded nonpareil core, a sub-coating layer (HPMC 6cps) and an SR-coating layer (Aquacoat® ECD, Eudragit® RS 30D or Kollicoat® SR 30D) were prepared by a bottom-spray fluidized bed-coating method. The drug release from the dual-coated SR pellets coated with Aquacoat® ECD followed a zero-order profile in water, and the drug release was not affected by the coating level of the sub-coating layer and stable under the accelerated storage condition (40?°C, 75% RH) for 6 months. The CR preparation showed significantly decreased values of maximum drug concentration (C_max) and elimination rate (K) than the reference product (LEVOTUS® SYR) but the similar bioavailability (F?=?95.43%). The novel CR preparation presents promising delivery of LDP with an immediate and sustained release manner, with similar clinical effect as the commercial IR product.     

卡托普利延迟起释型缓释片的研制

目的 制备适用于临睡前服用，间隔4～6h后于次日凌晨开始释放药物并持续释放较长一段时间的卡托普利延缓片。方法用干压包衣技术制备卡托普利延缓片，中心组合设计优化处方，人工神经网络预测释药时滞，在SAS上进行多元线性回归，并对优化结果进行验证，从而确定衣层处方。然后以卡托普利缓释片为对照制剂，以相似因子f2为筛选指标，确定片芯组成，从而确定最终处方。结果所优化的卡托普利延缓片体外释药时滞为5h，开始释放后与对照制剂有良好的相似性(L=64．06)，体外释放符合一级动力学规律。结论以干压包衣技术制得包芯片，由衣层控制延迟释放的释药时滞，由衣层和片芯共同控制药物缓慢释放。     

Similar bioavailability of dexmethylphenidate extended (bimodal) release, dexmethyl-phenidate immediate release and racemic methylphenidate extended (bimodal) release formulations in man

OBJECTIVE: The d-isomer of methylphenidate (d-MPH) is the pharmacologically active part of the racemic mixture of methylphenidate (d,l-MPH), which has been used for decades in the treatment of attention-deficit/hyperactivity disorder (ADHD). A modified release formulation with bimodal release for the pure d-enantiomer (Focalin XR) has been developed to enable a fast onset of action and a sustained activity for once-daily administration. It was intended to achieve a bimodal concentration-time profile as observed after administration of two immediate release Focalin tablets. The pharmacokinetics of this d-MPH bimodal release formulation were compared with a d-MPH immediate release formulation and a similar bimodal release formulation of d,l-MPH in healthy adult volunteers. MATERIALS AND METHODS: 25 volunteers received a single 20 mg dose of d-MPH bimodal release formulation, two 10 mg doses of a d-MPH immediate release formulation given 4 h apart and a single 40 mg dose of d,l-MPH bimodal release formulation (1 : 1 ratio for d : l enantiomers). The washout between treatments in this 3-way crossover study was 7 days. RESULTS: All three formulations were well-tolerated at the doses tested. The d-MPH bimodal release formulation generated two distinct d-MPH plasma concentration peaks and both peak concentrations and the time to peak were similar to those of the d-MPH immediate release formulation given 4 h apart and the d,l-MPH bimodal release formulation. The three formulations had Cmax and AUC0-infinity values of 15.5 +/- 4.3 ng/ml and 119 +/- 41 ng x h/ml for bimodal release d-MPH, 17.9 +/- 5.3 ng/ml and 115 +/- 40 ng A h/ml for immediate release d-MPH, and 16.4 +/- 4.4 ng/ml and 122 +/- 36 ng x h/ml for d,l-MPH bimodal release, respectively. CONCLUSIONS: In summary, the 20 mg extended (bimodal) release formulation of d-MPH (Focalin XR) demonstrated a bimodal concentration-time profile and was bioequivalent to two 10 mg doses of immediate release d-MPH (Focalin) and was bioequivalent to 40 mg extended (bimodal) release d,l-MPH (Ritalin LA).     

Feasibility, stability and release performance of a time-dependent insulin delivery system intended for oral colon release

The aim of the present work was to evaluate the viability of a time-dependent delivery platform (Chronotopic^TM) in preparing an insulin-based system intended for oral colon delivery. The main objectives were to assess the influence of the manufacturing process and storage conditions on the protein stability. Insulin-loaded cores were manufactured by direct compression and were subsequently coated with hydroxypropyl methylcellulose (HPMC) in a top-spray fluid bed up to increasing weight gains, namely 20%, 60% and 100%. In order to evaluate the impact the operating conditions may have on the protein integrity, insulin and its main degradation products (A21-desamido insulin - A21, Other Insulin-Related Compounds - OIRCs, and High-Molecular Weight Proteins - HMWPs) were assayed on samples collected after each process step by chromatographic methods. Furthermore, long-term (4 °C) and accelerated (25 °C-60% RH) stability studies were carried out on tablet cores and coated systems by assessing insulin, A21, OIRC and HMWP percentages throughout a one-year storage period. In addition, the in vitro release behaviour was investigated during the same study period. The overall results indicated that the manufacturing process is not detrimental for insulin integrity and that 4 °C storage temperature alters neither the protein content nor the release performances of the device.It was therefore concluded that insulin-containing systems intended for oral colon delivery can be obtained by the Chronotopic^TM technology.     

Ropinirole 24-hour prolonged release and ropinirole immediate release in early Parkinson's disease: a randomized,double-blind,non-inferiority crossover study

ABSTRACT

Objective: This study compares once-daily ropinirole 24-h prolonged release and three-times-daily ropinirole immediate release in patients with early Parkinson's disease.

Methods: This multicentre, double-blind, non-inferiority crossover study involved 161 patients randomized to one of four formulation sequences: (1) immediate release–immediate release–prolonged release; (2) immediate release–prolonged release–prolonged release; (3) prolonged release–prolonged release–immediate release; (4) prolonged release–immediate release–immediate release. During a 12-week dose-titration period, ropinirole immediate release was titrated according to the approved labelling; titration of ropinirole 24-h prolonged release started at a higher dose and was more rapid. Patients then entered three consecutive, flexible-dose, 8-week maintenance periods. At the end of the first maintenance period, half of the patients in each formulation group switched to the same or closest dose of the alternative formulation; remaining patients switched at the end of the second maintenance period.

Results: At the end of titration, before the first dose switch, there were substantial reductions in mean Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. During maintenance periods, both groups showed similar efficacy on the UPDRS motor score. Overall mean (standard error) change from period baseline was ?0.1 (0.28) for ropinirole 24-h prolonged release, and 0.6 (0.30) for ropinirole immediate release (adjusted mean treatment difference ?0.7; 95% confidence interval [CI]: ?1.51, 0.10; p?= 0.0842). The upper limit of the 95%?CI was less than the predefined threshold of 3?points for non-inferiority. Ropinirole 24-h prolonged release was well-tolerated when titrated more rapidly than ropinirole immediate release; overnight switching between formulations was also well-tolerated. Study limitations included complexity of the non-inferiority study design and the forced dose-titration schedule.

Conclusion: Ropinirole 24-h prolonged release was effective and well-tolerated in patients with early Parkinson's disease.     

Adriamycin-loaded niosomes: drug entrapment, stability and release

The effect of encapsulation of adriamycin into niosomes, and its resultant chemical purity, was studied by means of HPLC and high-speed scanning spectrophotometry (the simultaneous use of which allowed investigation of potential non-fluorescent drug degradation products), and the process shown not to adversely affect the drug. Efficiency of entrapment of aqueous solutions of the drug was apparently dependent on neither vesicle composition nor method of production, and evidence of a degree of surfactant-adriamycin association was provided by the high entrapment values. Light-induced drug degradation was reduced by niosome encapsulation, and efflux of entrapped adriamycin was decreased by inclusion of cholesterol into the vesicles, in a manner similar to that reported for liposome preparations. Thus only chemically pure adriamycin was entrapped in, and released from, niosomes.