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Advanced therapy medicinal products, considered special medications, requires Anvisa approval for use and commercialization in Brazil. They include the advanced cellular therapy products, tissue engineering products and gene therapy products, which due to their complexity involve innovation and risks, optimized regulatory channels for their development and life cycle monitoring. The scientific elements and the compliance with applicable regulatory aspects are fundamental pillars for the advancement of clinical trials, the positive evidence of the benefit-risk profile and the definition of the critical quality attributes, from the perspective of making safe, effective and high-quality products available to the population. The approval models of these products in Brazil adapt to the specificities and characteristics of the technology and the patient target population, with accelerated regulatory analyses, use in emergency situations by risk controls and specific monitoring mechanisms, principally those related to rare diseases without other therapeutic alternatives. The opportune access to the advance therapy product with safety, efficacy and quality involves innovative normative elements that include the long-term follow-up of the safety and efficacy and of the adaptive pharmacovigilance requisites, as well as the traceability mechanisms for the start-off materials, products and patients.

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OBJECTIVE: Chresta martii is broadly used by folk medicine due to its anti-inflammatory effects, but there is a lack of preclinical data on its pharmacological mechanisms. This study investigated the efficacy of Chresta martii ethanolic extract (CEE) in the zymosan-induced temporomandibular joint arthritis (TMJ) and evaluated the possible role of TNF-α, nitric oxide (NO), and heme oxygenase-1 (HO-1). METHODS: Male Wistar rats (160-220 g) were pre-treated with CEE (100, 200 or 400 mg/kg; v.o) 1 h before zymosan injection (2 mg; i.art). Mechanical hypernociception (g) was assessed 4 h later. The trigeminal ganglion was collected for TNF-α quantification (ELISA), total cell count and myeloperoxidase activity (MPO) were assayed in the synovial lavage 6 h after arthritis induction. Additionally, animals were pre-treated with L-NAME (30 mg/kg; i.p.) or ZnPP-IX (3 mg/kg, s.c.) to assess the involvement of NO and HO-1, respectively. RESULTS: CEE 400 mg/kg (v.o) increased (p < 0.05) hypernociception threshold, reduced the cell counts and MPO activity in the synovial lavage, as well as decreased TNF-α levels in the trigeminal ganglion. ZnPP-IX abolished the analgesic effect of CEE, but not L-NAME. CONCLUSION: The anti-inflammatory and antinociceptive effects of CEE depended on the HO-1 pathway integrity and TNF-α suppression.

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ETHNOPHARMACOLOGICAL RELEVANCE: Mucuna pruriens (Mp) belongs to Leguminosae family, it is native of tropical regions and used to treat several maladies such as urinary, neurological, and menstruation disorders, constipation, edema, fever, tuberculosis, ulcers, diabetes, arthritis, dysentery, and cardiovascular diseases. Mp seeds are rich in bioactive compounds, for instance, lectins, a heterogeneous group of proteins and glycoproteins with a potential role as therapeutic tools for several conditions, including gastric disorders. This study investigated the acute toxicity, gastroprotective, and antioxidant activities of a lectin from Mucuna pruriens seeds (MpLec) on ethanol-induced gastropathy model in mice. MATERIAL AND METHODS: Mice received MpLec (5 or 10 mg/kg; i.v.) and were observed for acute toxicity signs; in another experimental series, mice were pre-treated with MpLec (0.001; 0.01 or 0.1 mg/kg, i.v.), ranitidine (80 mg/kg, p.o.), or saline (0.3 mL/30g, i.v.) before ethanol 99.9% (0.2 mL/animal, p.o.), and euthanized 30 min after ethanol challenge. Macroscopic and microscopic gastric aspects, biochemical parameters (tissue hemoglobin levels, iron-induced lipid peroxidation, GSH content, SOD activity, and gastric mucosal PGE2) were measured. Additionally, pharmacological tools (yohimbine, indomethacin, naloxone, L-NAME) were opportunely used to clarify MpLec gastroprotective mechanisms of action. RESULTS: No toxicity signs nor death were observed at acute toxicity tests. MpLec reduced ethanol-induced gastric damage, edema, and hemorrhagic patches formation, as well as decreased lipid peroxidation, SOD activity, and increased GSH content. Yohimbine and indomethacin prevented MpLec effects, suggesting the involvement of alpha-2 adrenoceptors and prostaglandins in the MpLec-mediated effects. CONCLUSION: MpLec does not present toxicity signs and shows gastroprotective and antioxidant activities via alpha-2 adrenoceptors and prostaglandins in the ethanol-induced gastropathy model.

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ETHNOPHARMACOLOGICAL RELEVANCE: Species of Chresta genus- are recognized by the population of northeastern Brazil as traditional herbs used to treat gastric diseases and other disorders. AIM OF THE STUDY: This work aimed to find out the action mechanism of Chresta martii hydro alcoholic extract gastro protective effect in the model of ethanol-induced gastropathy. MATERIAL AND METHODS: Gastropathy was assessed by percentual damaged area determination in photographs of mice opened stomachs. Fasted mice treated with ethanol 99.9% (0.2 ml/animal, p.o.) were pre-treated with Chresta martii hydro alcoholic extract (HAE) (50, 100 or 200 mg/kg, p.o.), ranitidine (80 mg/kg, p.o.) or saline (5 ml/kg; p.o.) in different experimental sets, in which pharmacological tools (naloxone, indomethacin, N(ω)-Nitro-L-arginine methyl ester hydrochloride (L-NAME) or yohimbine) were added in order to clarify a possible action mechanism. Animals were sacrificed 30 min after ethanol challenge to stomach analysis. Determination of non-protein sulfhydryl groups and tissue hemoglobin, besides histological assessment (H&E) were taken to fully characterize the HAE gastro protective effect. RESULTS: HAE (100 and 200 mg/kg) was able to protect mucosa against ethanol gastropathy in presence of three (naloxone, indomethacin and L-NAME) of four antagonist/inhibitor tools. The HAE effect was reversed only by yohimbine, showing the alpha-2 adrenoceptors participation on gastro protective effect of this extract. HAE histological characteristics, NP-SH and Hb were compatible with the protective effects. CONCLUSIONS: HAE possesses gastroprotective effects in an ethanol-induced gastropathy model in mice, corroborating the traditional use of this family of plants to treat gastric disorders. This activity is mediated by alpha-2 adrenoceptors activation, but not by nitric oxide release, opioid receptor activation or prostaglandin synthesis. HAE also has antioxidant activity that is thought to either play a role in this biological activity or to be a byproduct of alpha-2 adrenergic complex activation.

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AIMS: To establish a new model of zymosan-induced temporomandibular joint (TMJ) arthritis in the rat and to investigate the role of nitric oxide. METHODS: Inflammation was induced by an intra-articular injection of zymosan into the left TMJ. Mechanical hypernociception, cell influx, vascular permeability, myeloperoxidase activity, nitrite levels, and histological changes were measured in TMJ lavages or tissues at selected time points. These parameters were also evaluated after treatment with the nitric oxide synthase (NOS) inhibitors L-NAME or 1400 W. RESULTS: Zymosan-induced TMJ arthritis caused a time-dependent leucocyte migration, plasma extravasation, mechanical hypernociception, and neutrophil accumulation between 4 and 24 h. TMJ immunohistochemical analyses showed increased inducible NOS expression. Treatment with L-NAME or 1400 W inhibited these parameters. CONCLUSION: Zymosan-induced TMJ arthritis is a reproducible model that may be used to assess both the mechanisms underlying TMJ inflammation and the potential tools for therapies. Nitric oxide may participate in the inflammatory temporomandibular dysfunction mechanisms.

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BACKGROUND: Lichens produce a variety of substances that possesses pharmacological actions. However, rare products are submitted to rigorous scientific tests or have the risk potential or side effects evaluated. The lack of medical and sanitary control, absence of accurate botanical identification or purity certification, founded in diverse natural products, may represent great danger to population health. This work aimed to evaluate toxic effects and anti-inflammatory action in vivo of Teloschistes flavicans (Sw.) Norm. (TFN) unrefined extracts, as well as determinate its main constituents. METHODS: The carrageenan induced paw edema and cotton pellet implant induced granuloma methods were utilized, besides a classic acute toxicity test. TFN acetone extract inhibited carrageenan paw edema on 60, 120, and 180 min (inhibition percentiles of 45.03%, 60.59% and 41.72%). RESULTS: TFN ethereal (inhibition percentiles of 23.95% and 29.01%) and chloroform (inhibition percentiles of 28.8% and 22.04%) extracts inhibited edema on 120 and 180 min. None of the extract inhibited the granuloma development. None of the extract caused death or other acute toxicity signs. Vicanicine (60.26% in ethereal extract and 51.17% in acetone extract), parietine (9.60% in ethereal extract and 15.38% on second), falacinol (0.78% in ether and 14.95% in acetone) and very low concentration of falacinal (0.15% in ethereal extract and 3.32% in acetone extract) were detected in the medicine. CONCLUSIONS: The tested extracts have antiedematogenic activity, but are not effective on subchronic inflammation. The extracts do not present toxic effects in administered doses.

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The search for new anti-inflammatory drugs has been constant in several research centers. The use of the Bioisostery concept allows the elaboration of new bioactive compounds with different properties through the introduction of substitute groups in one or more positions of a main molecule with known biological activity. Preliminary works accomplished at our laboratory with 2,4-thiazolidinedione isosters demonstrated inhibitory activity on edema formation for N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28) and N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) rhodanine (GS26). We verified the antiedematogenic and ulcerogenic activity of these two compounds in Wistar rats. The carrageenan induced paw edema suffered significant (p<0.05) inhibition (28.36% on average) for GS28 (100 mg/kg; v.o.) during the entire time of the experiment. GS26 (50 and 100 mg/kg; v.o.) significantly inhibited (p<0.05) the paw edema dextran induced (22.1 and 27.8%, for the respective doses) after 180 min. The compounds GS26 and GS28 did not show ulcerogenic activity on gastric mucous. The results suggest antiedematogenic action for both compounds without the appearance of gastric lesions.

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