Evaluation of anticonvulsants for possible use in neuropathic pain

Neuropathic pain is a kind of pain related with functional abnormality of neurons. Despite large progress in pharmacotherapy, neuropathic pain is still considered an unmet need. Nowadays, there are few drugs registered for this condition, such as pregabalin, gabapentin, duloxetine, carbamazepine, and lidocaine. Among them, pregabalin, gabapentin and carbamazepine are well known antiepileptic drugs. Among the group of new antiepileptic drugs, which are addressed to 1% of human world population suffering from seizures, it turned out that 30% of the seizures resistant to pharmacotherapy has not enough market to justify the costs of drug development. Therefore, it is already a phenomenon that researchers turn their projects toward a larger market, related with possible similar mechanism. Anticonvulsant mechanism of action is in the first place among primary indications for drugs revealing potential analgesic activity. Therefore, many drug candidates for epilepsy, still in preclinical stage, are being evaluated for activity in neuropathic pain. This review is focusing on antiepileptic drugs, which are evaluated for their analgesic activity in major tests related with neuropathic pain. Relation between structure, mechanism of action and result in tests such as the Chung model (spinal nerve ligation SNL), the Bennett model (chronic constriction injury of sciatic nerve CCI) and other tests are considered. The first examples are carbamazepine, gabapentin, and lacosamide as drugs well established in epilepsy market as well as drug candidates such as valnoctamide, and other valproic acid derivatives, novel biphenyl pyrazole derivatives, etc. Moreover, clinical efficacy related with listed animal models has been discussed

Red blood cell deformability and aggregation in chronic venous disease patients with varicose veins

Introduction: Red blood cells’ (RBC) rheological properties are disturbed in chronic venous disease (CVD). The aim of the study was to compare deformability and aggregation of erythrocytes taken from the varicose vein and the antecubital vein of patients with chronic venous disease.Materials and Methods: Blood samples were taken from twelve CVD patients presenting clinical, aetiological, anatomical and pathological elements (CEAP) stages II and III. Blood was sampled from varicose veins and antecubital veins of patients (as control). Deformability and aggregation of RBC were analysed with a Laser-assisted Optical Rotational Cell Analyser (LORCA).Results: A significant increase in deformability was found in varicose vein RBC for shear stress values 4.24, 8.23 and 15.96 Pa as compared to RBC from the antecubital vein. The aggregation index was significantly lower and aggregation halftime was significantly increased for RBC taken from antecubital veins than for RBC from varicose veins.Discussion: In conclusion, RBC taken from varicose and antecubital veins of CVD patients are not entirely rheologically comparable and show different deformability and aggregation. Varicose vein RBC are more deformable and show a higher tendency for aggregation than antecubital vein RBC. Perhaps the deformability of varicose vein RBC has been increased as a compensation mechanism in subjects with CVD, due to increased resistance in their microcirculation

Antioxidant activity of xanthone derivatives

Certain xanthone derivatives, such as these present in mangosteen fruits, show strong antioxidant activity. On the other hand, evidences accumulated that oxidative stress is involved in epileptogenesis. Therefore, the aim of the present study was to estimate total antioxidant capacity (expressed as a ferric reducing antioxidant power - FRAP) and evaluate ability to scavenge free radicals (DPPH methods) by xanthone derivatives showing antiepileptic activity. Selected 2-(aminomethyl)-9H-xanthen-9-one derivatives shared structural features, such as chlorine substituent in xanthone ring and different chiral (or not) alkanol groups at the nitrogen atom. The results of antioxidant activities among racemates revealed the highest activity for compound (R/S)-3 (31.7% in diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and (0.184 ± 0.003 mM Fe2+/L) in FRAP assay. Among tested pair of enantiomers we observed that (R)-1 and (R)-2 showed higher reduction capacity ((R)ñ1: 0.096 ± 0.007 mM Fe2+/L; (R)-2: 0.048 ± 0.005 mM Fe2+/L, respectively) and strongerDPPH scavenging activity ((R)-1: 31 ± 3.0%; (R)-2: 29 ± 2.5%, respectively) comparing to their (S)-enantiomers and racemates

Synthesis and evaluation of anticonvulsant activity of N-(2,5-dimethylphenoxy)- and N-[(2,3,5-trimethylphenoxy)alkyl]aminoalkanols

A series of new N-(2,5-dimethylphenoxy)- and N-(2,3,5-trimethylphenoxy)alkylaminoalkanols [I-XVII] was synthesized and evaluated for anticonvulsant activity. Pharmacological tests included maximal electroshock (MES) and subcutaneous pentetrazole seizure threshold (scMet) assays as well as neurotoxicity (TOX) evaluation in mice after intraperitoneal (i.p.) administration and/or in rats after oral (p.o.) administration. The most active compound was R-2N-[(2,3,5-trimethylphenoxy)ethyl]aminobutan-1-ol, which exhibited 100% activity in MES at the dose of 30 mg/kg body weight (mice, i.p.) and 75% activity in MES at 30 mg/kg b.w. (rats, p.o.) without neurotoxicity at the active doses

In vitro effect of pentoxifylline and lisofylline on deformability and aggregation of red blood cells from healthy subjects and patients with chronic venous disease

Purpose. The aim of the study was to assess the in vitro potency of pentoxifylline (PTX) and one of its most active metabolites lisofylline (LSF) to improve rheological properties of red blood cells (RBC) from healthy individuals and patients with chronic venous disease (CVD). Additionally, the study aimed to compare the effects of PTX and LSF on RBC deformability and aggregation. Methods. Blood samples were collected from healthy volunteers (antecubital vein) and from CVD patients (varicose and antecubital vein). Deformability and aggregation of RBC were assessed using Laser-assisted Optical Rotational Cell Analyser (LORCA). Results. PTX and LSF increased RBC elongation significantly. Additionally, RBC incubation with PTX resulted in a marked decrease in RBC aggregation. PTX reduced the tendency towards the formation of RBC aggregates and of their stability. The beneficial effect of PTX on RBC aggregation was most apparent for those cells whose aggregation tendency and aggregate stability was the greatest. Conclusions. In vitro addition of PTX or LSF effectively increased deformability of RBC from healthy donors and patients with CVD. Thus, LSF may contribute to the in vivo hemorheological effects of pentoxifylline. On the other hand, there was no significant effect of LSF on aggregation of RBC in vitro. Hence, LSF has no contribution to this particular effect of PTX. Additionally, the present study demonstrated the use of RBC with impaired deformability and aggregation for the evaluation of in vitro rheological activity of xenobiotics