The Influence of Selected Antipsychotic Drugs on Biochemical Aspects of Alzheimer's Disease.

The aim of this study was to assess the potency of selected antipsychotic drugs (haloperidol (HAL), bromperidol (BRMP), benperidol (BNP), penfluridol (PNF), pimozide (PIM), quetiapine (QUET) and promazine (PROM)) on the main pathological hallmarks of Alzheimer's disease (AD). Binary mixtures of donepezil and antipsychotics produce an anti-BuChE effect, which was greater than either compound alone. The combination of rivastigmine and antipsychotic drugs (apart from PNF) enhanced AChE inhibition. The tested antipsychotics (excluding HAL and PNF) significantly reduce the early stage of Aß aggregation. BRMP, PIM, QUET and PROM were found to substantially inhibit Aß aggregation after a longer incubation time. A test of human erythrocytes hemolysis showed that short-term incubation of red blood cells (RBCs) with QUET resulted in decreased hemolysis. The antioxidative properties of antipsychotics were also proved in human umbilical vein endothelial cells (HUVEC); all tested drugs were found to significantly increase cell viability. In the case of astrocytes, BNP, PNF, PIM and PROM showed antioxidant potential.

Comparison of 2 blind approaches to the paravertebral brachial plexus regional block in canine cadavers.

The paravertebral brachial plexus block (PVB) provides thoracic limb analgesia. The objective was to describe a blind craniocaudal (CC) approach to the PVB and compare its accuracy, time, and difficulty of performance with a blind dorsoventral (DV) approach. The operator was initially trained by experienced clinicians to perform both approaches on 5 cadavers. Next, a CC or DV approach to the PVB was performed on both thoracic limbs of 20 cadavers (20 for each approach). Methylene blue dye was equally divided into 4 aliquots to stain the ventral branches of the sixth to eighth cervical and first thoracic spinal nerves. Successfully stained (stain ≥ 1 cm) spinal nerves were counted. The time to perform each approach was recorded and ease of performance was scored using a numerical scale (1 "easy" to 4 "difficult"). The phrenic nerve was checked for stain. A Wilcoxon signed-rank test was used to compare approaches. The data are presented as median (interquartile range; minimum to maximum range). The number of stained nerves with the CC approach 3 (1; 2 to 4), was higher than the DV approach 2 (2; 0 to 4) (P = 0.002). The time (in seconds) to perform the CC approach 125 (79; 70 to 194), was not different from the DV approach 142 (54; 101 to 232) (P = 0.084). The CC approach 2 (2; 1 to 4) was easier to perform than the DV approach 3 (1; 2 to 4) (P = 0.024). No phrenic nerve staining was observed with either approach. The CC approach is an alternative to the DV approach for performing the PVB in dogs.

Le bloc du plexus brachial paravertébral (PVB) fournit une analgésie du membre thoracique. L'objectif était de décrire une approche craniocaudale (CC) aveugle du PVB et de comparer sa précision, son temps et sa difficulté de performance avec une approche dorso-ventrale (DV) aveugle. L'opérateur a été initialement formé par des cliniciens expérimentés pour effectuer les deux approches sur cinq cadavres. Ensuite, une approche CC ou DV du PVB a été réalisée sur les deux membres thoraciques de 20 cadavres (20 pour chaque approche). Le colorant bleu de méthylène a été divisé de manière égale en quatre aliquotes pour colorer les branches ventrales des sixième à huitième nerfs cervicaux et rachidiens thoraciques. Les nerfs spinaux colorés avec succès (coloration ≥ 1 cm) ont été comptés. Le temps d'exécution de chaque approche a été enregistré et la facilité d'exécution a été notée à l'aide d'une échelle numérique (1 « facile ¼ à 4 « difficile ¼). Le nerf phrénique a été vérifié pour la coloration. Un test des rangs signés de Wilcoxon a été utilisé pour comparer les approches. Les données sont présentées sous forme de médiane (intervalle interquartile; intervalle minimum à maximum). Le nombre de nerfs colorés avec l'approche CC 3 (1; 2 à 4) était plus élevé que l'approche DV 2 (2; 0 à 4) (P = 0,002). Le temps (en secondes) pour effectuer l'approche CC 125 (79; 70 à 194) n'était pas différent de l'approche DV 142 (54; 101 à 232) (P = 0,084). L'approche CC 2 (2; 1 à 4) était plus facile à réaliser que l'approche DV 3 (1; 2 à 4) (P = 0,024). Aucune coloration du nerf phrénique n'a été observée avec l'une ou l'autre approche. L'approche CC est une alternative à l'approche DV pour réaliser le PVB chez le chien.(Traduit par Docteur Serge Messier).

Erythrocytes as model cells for biocompatibility assessment, cytotoxicity screening of xenobiotics and drug delivery.

Erythrocytes (RBCs) represent the main cell component in circulation and recently have become a topic of intensive scientific interest. The relevance of erythrocytes as a model for cytotoxicity screening of xenobiotics is under the spotlight of this review. Erythrocytes constitute a fundamental cellular model to study potential interactions with blood components of manifold novel polymer or biomaterials. Morphological changes, subsequent disruption of RBC membrane integrity, and hemolysis could be used to determine the cytotoxicity of various compounds. Erythrocytes undergo a programmed death (eryptosis) which could serve as a good model for evaluating certain mechanisms which correspond to apoptosis taking place in nucleated cells. Importantly, erythrocytes can be successfully used as a valuable cellular model in examination of oxidative stress generated by certain diseases or multiple xenobiotics since red cells are subjected to permanent oxidative stress. Additionally, the antioxidant capacity of erythrocytes, and the activity of anti-oxidative enzymes could reflect reactive oxygen species (ROS) generating properties of various substances and allow to determine their effects on tissues. The last part of this review presents the latest findings on the possible application of RBCs as drug delivery systems (DDS). In conclusion, all these findings make erythrocytes highly valuable cells for in vitro biocompatibility assessment, cytotoxicity screening of a wide variety of substances as well as drug delivery.

Quetiapine and novel PDE10A inhibitors potentiate the anti-BuChE activity of donepezil.

The symptoms of Alzheimer's disease (AD) do not include only memory loss and cognitive decline but also neuropsychiatric manifestation. These AD-related symptoms are usually treated with the aid of antipsychotics; however, their effects on cognition and safety remain unexplored. The present study determines the effects of quetiapine, an atypical antipsychotic, and two imidazo[1,2-a]pyrimidine-based inhibitors of PDE10A on the activity of human cholinesterases. Quetiapine moderately inhibited BuChE (IC50 = 6.08 ± 1.64 µmol/L) but improved the anti-BuChE properties of donepezil by decreasing its IC50 value. Both PDE10A inhibitors were found to possess moderate anti-AChE properties. The combined mixtures of donepezil and imidazo[1,2-a]pyrimidine analogues produce a synergistic anti-BuChE effect which was greater than either compound alone, improving the IC50 value by approximately six times. These favourable interactions between quetiapine, PDE10A inhibitors and clinically approved donepezil, resulting in improved anti-BuChE activity, can lead to a wider variety of potent AD treatment options.

Is metformin a geroprotector? A peek into the current clinical and experimental data.

Nowadays we observe a growing scientific interest and need to develop novel research approach that target ageing. Metformin, apart from its proven efectiveness as a glucose-lowering agent, was found to exert multidirectional effects because of its cardioprotective, anti-inflammatory and anti-cancer activity. Recently, metformin has become a subject of interest of many researchers as a promising drug with anti-ageing properties; however, its impact on clinical ageing features is still hypothetical. Nevertheless, results of cellular experiments and animal studies confirm that metformin has advantageous effects on ageing. Additionally, a number of clinical trials prove positive effects of metformin on the prevalence of age-related diseases (ARD), including cardiovascular disease or carcinoma. We have observed a significant advancement in human research since a few randomised clinical trials evaluating the impact of metformin on ageing were launched. Here, we present an investigation on anti-ageing properties of metformin, and provide the explanation of mechanisms and pathways implicated in this function. We also analyse available clinical evidence on healthspan extension, all-cause mortality and ARD. Finally, we discuss currently conducted randiomized clinical trials which aim to explore metformin potential as an anti-ageing drug in humans.

An investigation into the pleiotropic activity of metformin. A glimpse of haemostasis.

The most characteristic features of type 2 diabetes mellitus (T2DM) are hyperglycaemia and insulin resistance, however, patients with T2DM are at higher risk of cardiovascular disease (CVD) and atherosclerosis. Diabetes, frequently related to metabolic and vascular impairments, is also associated with thrombosis, increased blood coagulation and an imbalance between coagulation and fibrinolysis. Metformin is the most often used oral glucose-lowering agent; its beneficial properties include lowering insulin resistance, weight reduction and cardioprotection. Available data suggest that the advantageous properties of metformin stem from its favourable effects on endothelium, and anti-oxidative and anti-inflammatory properties. This paper reviews the favourable impact of metformin on endothelial function, with particular emphasis on the release of endogenous molecules modulating the state of the vascular endothelium and coagulation. It also summarizes the present knowledge on the influence of metformin on platelet activity and plasma haemostasis, including clot formation, stabilization and fibrinolysis. Its findings confirm that metformin should constitute first line therapy of T2DM subjects; however, more comprehensive methodical studies are required to discover the full potential of this drug.

Generation 2 (G2) - Generation 4 (G4) PAMAM dendrimers disrupt key plasma coagulation parameters.

The aim of the research was to evaluate the effects of G2 - G4 PAMAM dendrimers on basic plasma haemostasis parameters (Partially Activated Thrombin Time (APTT), Prothrombin Time (PT), Thrombin Time (TT)) as well as the activity of factor X, antithrombin III (AT), protein C and plasmin. Furthermore, tissue factor (TF) synthesis in endothelial cells and viability of smooth muscle cells in the presence of PAMAM dendrimers was investigated. APTT, PT and TT were performed according to the available commercial methods. The activity of factor X was conducted based on deficient plasma factor X. Protein C, AT and plasmin activity were measured spectrophotometrically using chromogenic substrates. Intracellular TF production in human umbilical vein endothelial cells (HUVECs) was measured using immunohistochemical method. Viability of Human Aortal Smooth Muscle cells (hAoSMCs) was established using WST-1 assay. PAMAM dendrimers decreased activity of factor X, and concomitantly prolonged PT and APTT. We also demonstrated shortened TT and increased fibrinogen concentrations in plasma treated with G4 PAMAM dendrimers, suggesting formation of fibrinogen aggregates. G2 - G4 PAMAM dendrimers decreased the activity of both naturally occurring anticoagulants AT and protein C. G2 and G3 PAMAM dendrimers did not affect the proteolytic reaction with plasmin. PAMAM dendrimers were found not to trigger TF production in undisturbed endothelial cells. PAMAM dendrimers, depending on the concentration and generation decreased viability of AoSMCs. The results presented within the current study suggest complex but mostly undesirable effect of G2 - G4 PAMAM dendrimers on plasma haemostasis and underscore the need for further in-depth research.

The Associations between Central Nervous System Diseases and Haemostatic Disorders.

The aim of this review was to examine the relationship between the occurrence of central nervous system (CNS) diseases, the medicines used in their treatment and the blood coagulation process. The paper mainly focuses on the effects of antidepressant and antipsychotic drugs. Special attention has been paid to the influence of drugs on platelets, the vascular endothelium, plasma coagulation and fibrinolysis, regarding coagulation.

Influence of preoperative septic peritonitis and anastomotic technique on the dehiscence of enterectomy sites in dogs: A retrospective review of 210 anastomoses.

OBJECTIVE: To determine the influence of preoperative septic peritonitis (PSP) and stapled versus hand-sewn anastomoses on the dehiscence of intestinal resection and anastomosis (IRA). We hypothesized that the incidence of IRA dehiscence would be greater (1) when performed with PSP and (2) for hand-sewn anastomoses. STUDY DESIGN: Retrospective. ANIMAL POPULATIONS: Client-owned dogs at Michigan State University Veterinary Teaching Hospital. METHODS: Records of dogs surviving 72 hours after IRAs between 2003 and 2013 were reviewed for age, gender, neuter status, weight, presence of PSP, preoperative albumin, IRA indication and location, anastomotic technique, suture type, postoperative dehiscence and timing, duration of hospitalization, last follow-up, and other complications. Univariate logistic regression and chi-square analysis were used to screen prognostic factors; factors with P < .3 were included in a multivariate analysis. RESULTS: Two hundred and ten IRAs in 198 dogs fulfilled the inclusion criteria. Dehiscence was diagnosed in 11.4% cases, 6.6% without PSP, and 21.1% with PSP (P = .01). Indication for IRA did not influence the risk of dehiscence. No association was detected between anastomotic technique and IRA dehiscence in dogs without PSP (stapled 4.2%, hand-sewn 8.1%); however, stapled anastomoses were less likely to dehisce in dogs with PSP (stapled 9.7%, hand-sewn 28.9%). Risk factors for dehiscence included PSP (P = .005) and hand-sewn technique (P = .02). CONCLUSION: Our results confirmed that PSP is a risk factor for dehiscence of IRA and suggest that patients with PSP may be a unique surgical population, in which stapling may be preferred over hand-sewn anastomoses after enterectomies.