Microencapsulated Dopamine (DA)-Induced Restitution of Function in 6-OHDA-Denervated Rat Striatum in vivo: Comparison Between Two Microsphere Excipients

Biodegradable controlled-release microsphere systems made with the biocompatible biodegradable polyester excipient poly [DL lactide-co-glycolide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microspheres encapsulated within two different polymer excipients into denervated- striatal tissue assures a prolonged release of the transmitter in vivo. Moreover, in this regard, the results show that there were clear cut temporal differences in the effect of the two DA microsphere formulations compared in this study, probably reflecting variations in the actual composition (i.e., lactide to glycolide ratio) of the two copolymer excipients examined. This technology has considerable potential for basic research with possible clinical application

Pyrolytic carbon microelectrodes for impedance based cell sensing

Référence bibliographique : Rol, 107199Appartient à l’ensemble documentaire : Pho20RolImage de press

Successful switching from risperidone to cariprazine in a schizophrenic patient with pronounced functional deficit. Case report

A 22-year-old male was admitted to an in-patient psychiatric unit for treatment, after a period of 2 years of increasing psychotic symptoms corresponding to a very severe case of schizophrenia across the entire scale of symptom disorder domains along with some drug abuse comorbidity. Previous treatments with olanzapine (OLA) and risperidone (RIS) had been at best partly successful toward his positive symptoms with no, or even worsening effects on the negative symptomatology. Given the gravity of the latter symptoms and functional impairment of our patient, he might thus have been a candidate for clozapine (CLZ) treatment. It was however decided to switch his antipsychotic treatment to cariprazine (CAR), an agent with a novel pharmacological and clinical profile, because of its favorable pharmacodynamic, pharmacokinetic, and tolerability/safety properties. In a follow-up on the patient 6 months after discharge he is not fully recovered, but the recovery attained reflects a marked functional improvement compared to before the RIS-to-CAR switch. The remarkable response to CAR observed may, speculatively, be in line with the suggestion that CAR could offer an alternative, safer, and more tolerable monotherapy approach (vs. CLZ) for patients with severe negative symptoms and functional deficiency resistant to standard antipsychotic treatment. He appears to occasionally still be taking drugs, but no worsening of positive symptoms has been noted. Whether or not he could reach full recovery if he would abstain entirely from drugs of abuse remains an open question

Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach.

The receptors mediating the hemodynamic responses to cannabinoids are not clearly defined due to the multifarious pharmacology of many commonly used cannabinoid ligands. While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands. The present studies attempted to unravel the pharmacology underlying the in vivo hemodynamic responses to ACEA (CB1 agonist), O-1602 (GPR55 agonist), AM251 (CB1 antagonist), and cannabidiol (CBD; GPR55 antagonist). Agonist and antagonist profiles of each ligand were determined by ligand-induced GTPcS binding in membrane preparations expressing rat and mouse CB1 and GPR55 receptors. Blood pressure responses to ACEA and O-1602 were recorded in anesthetized and conscious mice (wild type, CB1 / and GPR55 / ) and rats in the absence and presence of AM251 and CBD. ACEA demonstrated GTPcS activation at both receptors, while O-1602 only activated GPR55. AM251 exhibited antagonist activity at CB1 and agonist activity at GPR55, while CBD demonstrated selective antagonist activity at GPR55. The depressor response to ACEA was blocked by AM251 and attenuated by CBD, while O-1602 did not induce a depressor response. AM251 caused a depressor response that was absent in GPR55 / mice but enhanced by CBD, while CBD caused a small vasodepressor response that persisted in GPR55 / mice. Our findings show that assessment of the pharmacological profile of receptor activation by cannabinoid ligands in in vitro studies alongside in vivo functional studies is essential to understand the role of cannabinoids in hemodynamic control

Preclinical Pharmacology of [2-(3-Fluoro-5-Methanesulfonyl-phenoxy)Ethyl](Propyl)amine (IRL790), a Novel Dopamine Transmission Modulator for the Treatment of Motor and Psychiatric Complications in Parkinson Disease.

IRL790 ([2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine, mesdopetam) is a novel compound in development for the clinical management of motor and psychiatric disabilities in Parkinson disease. The discovery of IRL790 was made applying a systems pharmacology approach based on in vivo response profiling. The chemical design idea was to develop a new type of DA D3/D2 receptor type antagonist built on agonist rather than antagonist structural motifs. We hypothesized that such a dopamine antagonist with physicochemical properties similar to agonists would exert antidyskinetic and antipsychotic effects in states of dysregulated dopaminergic signaling while having little negative impact on physiologic dopamine transmission and, hence, minimal liability for side effects related to dopamine-dependent functions. At the level of in vivo pharmacology, IRL790 displays balancing effects on aberrant motor phenotypes, reducing l-DOPA-induced dyskinesias in the rodent 6-hydroxydopamine lesion model and reducing psychostimulant-induced locomotor hyperactivity elicited by pretreatment with either d-amphetamine or dizocilpine, without negatively impacting normal motor performance. Thus, IRL790 has the ability to normalize the behavioral phenotype in hyperdopaminergic as well as hypoglutamatergic states. Neurochemical and immediate early gene (IEG) response profiles suggest modulation of DA neurotransmission, with some features, such as increased DA metabolites and extracellular DA, shared by atypical antipsychotics and others, such as increased frontal cortex IEGs, unique to IRL790. IRL790 also increases extracellular levels of acetylcholine in the prefrontal cortex and ventral hippocampus. At the receptor level, IRL790 appears to act as a preferential DA D3 receptor antagonist. Computational docking studies support preferential affinity at D3 receptors with an agonist-like binding mode. SIGNIFICANCE STATEMENT: This paper reports preclinical pharmacology along with molecular modeling results on IRL790, a novel compound in clinical development for the treatment of motor and psychiatric complications in advanced Parkinson disease. IRL790 is active in models of perturbed dopaminergic and glutamatergic signaling, including rodent 6-hydroxydopamine l-DOPA-induced dyskinesias and psychostimulant-induced hyperactivity, in a dose range that does not impair normal behavior. This effect profile is attributed to interactions at dopamine D2/D3 receptors, with a 6- to 8-fold preference for the D3 subtype

Electronic structure and magnetic properties of the linear chain cuprates Sr_2CuO_3 and Ca_2CuO_3

Sr_2CuO_3 and Ca_2CuO_3 are considered to be model systems of strongly anisotropic, spin-1/2 Heisenberg antiferromagnets. We report on the basis of a band-structure analysis within the local density approximation and on the basis of available experimental data a careful analysis of model parameters for extended Hubbard and Heisenberg models. Both insulating compounds show half-filled nearly one-dimensional antibonding bands within the LDA. That indicates the importance of strong on-site correlation effects. The bonding bands of Ca_2CuO_3 are shifted downwards by 0.7 eV compared with Sr_2CuO_3, pointing to different Madelung fields and different on-site energies within the standard pd-model. Both compounds differ also significantly in the magnitude of the inter-chain dispersion along the crystallographical a-direction: \approx 100 meV and 250 meV, respectively. Using the band-structure and experimental data we parameterize a one-band extended Hubbard model for both materials which can be further mapped onto an anisotropic Heisenberg model. From the inter-chain dispersion we estimate a corresponding inter-chain exchange constant J_{\perp} \approx 0.8 and 3.6 meV for Sr_2CuO_3 and Ca_2CuO_3, respectively. Comparing several approaches to anisotropic Heisenberg problems, namely the random phase spin wave approximation and modern versions of coupled quantum spin chains approaches, we observe the advantage of the latter in the reproduction of reasonable values for the N\'eel temperature T_N and the magnetization m_0 at zero temperature. Our estimate of $J_{\perp}$ gives the right order of magnitude and the correct tendency going from Sr_2CuO_3 to Ca_2CuO_3. In a comparative study we also include CuGeO_3.Comment: 23 pages, 5 figures, 1 tabl

Does In Vitro Potency Predict Clinically Efficacious Concentrations?

The in vitro affinity of a compound for its target is an important feature in drug discovery, but what remains is how predictive in vitro properties are of in vivo therapeutic drug exposure. We assessed the relationship between in vitro potency and clinically efficacious concentrations for marketed small molecule drugs (n = 164) and how they may differ depending on therapeutic indication, mode of action, receptor type, target localization, and function. Approximately 70% of compounds had a therapeutic unbound plasma exposure lower than in vitro potency; the median ratio of exposure in relation to in vitro potency was 0.32, and 80% had ratios within the range of 0.007 to 8.7. We identified differences in the in vivo-to-in vitro potency ratio between indications, mode of action, target type, and matrix localization, and whether or not the drugs had active metabolites. The in vitro-assay variability contributions appeared to be the smallest; within the same drug target and mode of action the within-variability was slightly broader; but both were substantially less compared with the overall distribution of ratios. These data suggest that in vitro potency conditions, estimated in vivo potency, required level of receptor occupancy, and target turnover are key components for further understanding the link between clinical drug exposure and in vitro potency