Pyrrolizidine alkaloids (PAs) are a widespread class of hepatotoxic heterocyclic organic compounds found in approximately 3% of world flora. Some PAs have been shown to have genotoxic and carcinogenic effects. The present study focuses on the toxicity effects of four dry extracts obtained from medicinal plants (Senecio vernalis, Symphytum officinale, Petasites hybridus and Tussilago farfara), on two aquatic organisms, Artemia salina and Daphnia magna, and the correlation with their PAs content. A new GC-MS method, using a retention time (TR)-5MS type capillary column was developed. PAs Kovats retention indices, for this type of column were computed for the first time. The lethal dose 50% (LC50) values for the two invertebrate models were correlated (Pearson's coefficient, >0.9) and the toxicity was PA concentration-dependent, for three of the four extracts. All tested extracts were found to be toxic in both aquatic organism models. The results can be used to develop a GC-MS validated method for the assay of PAs in medicinal plants with a further potential application in the risk assessment study of PAs toxicity in humans.

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor), risperidone (atypical antipsychotic) and febuxostat (gout medication, xanthine oxidase inhibitor) in the cuprizone mouse model of acute demyelination, hypothesizing an antagonistic effect on TRPA1 calcium channels. Cuprizone and drugs were administered to C57BL6/J mice for five weeks and locomotor activity, motor performance and cold sensitivity were assessed. Mice brains were harvested for histological staining and assessment of oxidative stress markers. Febuxostat and metabolites of venlafaxine (desvenlafaxine) and risperidone (paliperidone) were tested for TRPA1 antagonistic activity. Following treatment, venlafaxine and risperidone significantly improved motor performance and sensitivity to a cold stimulus. All administered drugs ameliorated the cuprizone-induced deficit of superoxide dismutase activity. Desvenlafaxine and paliperidone showed no activity on TRPA1, while febuxostat exhibited agonistic activity at high concentrations. Our findings indicated that all three drugs offered some protection against the effects of cuprizone-induced demyelination. The agonistic activity of febuxostat can be of potential use for discovering novel TRPA1 ligands.

Vincristine is prescribed in many neoplastic diseases such as acute lymphoblastic leukaemia, Hodgkin's disease, non-Hodgkin's lymphomas, breast cancer, small cell lung cancer, cervical cancer, multiple myeloma. The neurotoxicity of vincristine is severe, being a dose limiting factor that depends on the cumulative dose and the frequency of administration. Data from clinical and preclinical studies show therapeutic potential for atypical opioid analgesics in neuropathic pain. In this research we investigated the analgesic potential for tramadol and dextromethorphan in animal model of vincristine-induced peripheral neuropathy. The peripheral neuropathy was induced in male Wistar rats by the daily intraperitoneal (i.p.) administration of vincristine sulphate 0.1 mg/kg/day, 5 days followed by 2 days break and then another 5 days of vincristine. Analgesics were given daily seven days after the vincristine treatment in the following doses: tramadol 5 mg/kg bw, dextromethorphan 20 mg/kg bw. We tracked the evolution of allodynia and mechanical hyperalgesia under analgesic treatment. Following the processing of experimental data, the first dose of tramadol significantly increased maximum response time, both in the assessment of allodynia and hyperalgesia. A single dose of dextromethorphan produced a significant inhibition of allodynia induced by vincristine (increases the time to response for paw retraction with 32.65 %, p < 0.001, vs vincristine group). Tramadol lead to the maximum anti-allodynic effect, immediately after the discontinuation of vincristine (141.73%, p < 0.001). Tramadol showed therapeutic potential in combating neuropathic pain induced by the administration of Vinca alkaloids. RezumatVincristina este prescrisă în numeroase bolile neoplazice precum: leucemie limfoblastică acută, boală Hodgkin, limfoame non-Hodgkin, cancer mamar, cancer pulmonar cu celule mici, cancer de col uterin, mielom multiplu. Neurotoxicitatea vincristinei este severă fiind un factor care limitează doza și este influențată de doza cumulativă și de frecvența dintre administrări. Date din studiile clinice și preclinice arată potențialul terapeutic al analgezicelor opioide atipice în durerea neuropată. În aceast studiu am investigat potențialul analgezic pentru tramadol și dextrometorfan în modelul experimental de neuropatie periferică indusă de vincristină. Neuropatia periferică a fost indusă la șobolani masculi Wistar prin administrare zilnică intraperitoneală (i.p.) a sulfatului de vincristină 0,1 mg/kg/zi, 5 zile, o pauză de 2 zile și apoi încă 5 zile de vincristină. Analgezicele au fost administrate zilnic la șapte zile după tratamentul cu vincristină în următoarele doze: tramadol 5 mg/kg corp, dextrometorfan 20 mg/kg corp. Am urmărit evoluția alodiniei și hiperalgeziei mecanice în urma tratamentului cu analgezice. În urma prelucrării datelor experimentale, prima doză de tramadol a crescut semnificativ timpul de răspuns, atât în evaluarea alodiniei cât și a hiperalgeziei. Doar după administrarea unei doze unice, dextrometorfanul a p...

A series of new compounds with quinazolin-4-one structure, synthesized by the , was studied. Five of them were selected, conventionally named S1, S2, S3, S4, S5, and investigated in terms of their potential influence on the central nervous system (CNS). For this purpose, the antidepressant effect was determined using the forced swimming test; the anxiolytic/ anxiogenic effect was determined using the suspended plus-shaped maze (Ugo Basile); the effect on the motor activity was determined using the Ugo Basile activity cage; and the potential analgesic effect was investigated using the hot plate test (Ugo Basile). Compounds S3 and S5 lowered the motor activity and showed an anxiolytic effect, while S1 and S2 proved to have antidepressant and analgesic effects.A good correlation between antidepressant and analgesic effects was observed, consistent with the fact that analgesic drugs, by increasing norepinephrine and serotonin levels in the pain inhibiting descendent pathways, can be used as co-analgesics in therapy.  quinazolin-4-one derivatives, antidepressant, anxiolytic, analgesic, pharmacological research Highlights  S1 and S2 reduced the immobilization time in the forced swimming test by 25.98%, respectively 28.45%  S3 and S5 have been shown to have relatively similar pharmacological profiles with respect to influence on HMA and VMA Keywords

Beta-3 adrenergic receptors have important physiological implications, being expressed in many places in the body, including brown adipose tissue. Of the effects studied in preclinical research on lipid metabolism attributable to stimulation of these receptors, we can mention the increased thermogenesis and metabolic rate in the brown adipose tissue, reduction of body weight in obese diabetic rats, lowering of intra-abdominal and subepithelial fat in nonobese and nondiabetic rats, decrease of triglyceride, and increase of HDL cholesterol levels. Carbohydrate metabolism is also changed by beta-3 adrenergic agonists, the most prevalent effects being blood glucose lowering in diabetic rats, increasing insulin secretion of the pancreas, or increasing glucose tolerance. Metabolic effects of 13 newly synthesized compounds of beta-phenylethylamine structure and reference BRL 37344 were investigated in order to identify a potential affinity for beta-3 adrenergic receptors. The antidiabetic and hypolipemiant effects were investigated on a rat model of alloxan-induced diabetes. The results demonstrated that new betaphenylethylamine derivatives produced marked biological activity over lipid profile. All compounds have markedly decreased the values of total cholesterol, LDL cholesterol, and triglycerides and also have increased the values of antiatherogenic HDL cholesterol. The effects were significantly more intense than the reference substance BRL 37344.