The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

This review presents a historical overview of drug discovery and the non-clinical stages of the drug development process, from initial target identification and validation, through in silico assays and high throughput screening (HTS), identification of leader molecules and their optimization, the selection of a candidate substance for clinical development, and the use of animal models during the early studies of proof-of-concept (or principle). This report also discusses the relevance of validated and predictive animal models selection, as well as the correct use of animal tests concerning the experimental design, execution and interpretation, which affect the reproducibility, quality and reliability of non-clinical studies necessary to translate to and support clinical studies. Collectively, improving these aspects will certainly contribute to the robustness of both scientific publications and the translation of new substances to clinical development.

RESUMO:Objetivou-se com este trabalho avaliar a produção de massa e o teor de flavonoides de plantas de marcela cultivadas com fósforo e cama de frango e colhidas em duas épocas. Estudou-se a combinação de doses de P2O5 (0, 100, 200 e 300 kg ha-1) na forma de superfosfato triplo, com e sem cama de frango (10 t ha-1), arranjados como fatorial 4x2, no delineamento blocos casualizados, com quatro repetições. Foram feitas duas colheitas das plantas, consideradas como parcelas subdivididas no tempo. A propagação foi indireta, com semeio em bandejas e transplante ao campo. As plantas foram colhidas aos 195 e 223 dias após o transplantio - DAT. A altura máxima das plantas foi de 1,14 m com uso da cama de frango e de 0,97 m sem cama, aos 195 dias após o transplantio. A produção máxima de massa fresca de parte aérea das plantas foi de 30,31 t ha-1 na colheita aos 223 DAT, enquanto a de massa seca foi de 11,38 t ha-1, ambas com o uso de 300 kg ha-1 de P2O5.A massa fresca de inflorescências foi maior (4,08 t ha-1) com adição de cama de frango ao solo e menor (3,49 t ha-1) sem cama de frango; em resposta às doses de fósforo, cresceram linearmente, sendo a máxima de 4,65 t ha-1 com uso de 300 kg ha-1 de P2O5, independente da época de colheita. A massa seca de inflorescências foi máxima de 2,38 t ha-1 com o uso de 300 kg ha-1 P2O5 na colheita aos 223 DAT. A maior produção de massa seca e o maior teor de flavonoides das inflorescências foram obtidos com o cultivo das plantas de marcela em solo com cama de frango (10 t ha-1) e com P2O5 (300 kg ha-1) na colheita aos 223 dias após o transplantio.

ABSTRACT:The aim of this experiment was to evaluate the biomass yield and flavonoid contents of Achyrocline satureioides grown under different levels of phosphate fertilizer in association with broiler litter, during two successive harvests. Four levels of P2O5 (0, 100, 200 and 300 kg ha-1), as triple superphosphate, and two levels of broiler litter (0 and 10 t ha-1) were arranged as a 4x2 factorial design in randomized blocks with four replications. Two harvests of plants, considered as split-plot, were made. Seeds were sown in polystyrene trays then transplanted to the experimental field and harvested at 195 and 223 days after transplanting (DAT). The maximum heights of the plants were 1.14 m under the addition of broiler litter and 0.97 m without it, at 195 days after transplanting. The highest yields of total fresh weight (30.31 ton ha-1) and dry weight (11.38 ton ha-1) were obtained at 223 DAT, both with the concentration of 300 kg ha-1 P2O5. The fresh weight of the inflorescences was greater under the addition of broiler litter (4.08 ton ha-1) than without it (3.49 ton ha-1). The plants grew linearly in response to the use of phosphate, and the maximum yield was 4.65 ton ha-1 under the concentration of 300 kg ha-1P2O5, regardless of the harvest season. The dry weight of the inflorescences reached maximum yield (2.38 ton ha-1) at 223 DAT, in response to the use of 300 kg ha-1P2O5. The highest yield of dry weight and the highest contents of flavonoids from the inflorescences were obtained when A. satureioides was grown under the concentration of P2O5 (300 kg ha-1) with the addition of broiler litter (10 ton ha-1) and harvested at 223 DAT.

Foi realizado um levantamento das plantas medicinais mais solicitadas a raizeiros do centro da cidade de Campo Grande, Mato Grosso do Sul, ou por eles indicadas. Esse levantamento foi efetuado em duas épocas distintas: 1992 e 2002. A compilação dos dados revelou que 27 espécies foram citadas em 1992 e 32 em 2002. As seis espécies mais freqüentemente consumidas (Maytenus cf. macrodonta, "cancorosa"; Baccharis trimera, "carqueja"; Achyrocline alata, "jateí-kaá"; Stryphnodendron adstringens, "barbatimão"; Cochlospermum regium, "algodãozinho", e Echinodorus macrophyllus, "chapéu-de-couro") foram adquiridas para identificação e avaliação preliminar da sua qualidade. Nas duas épocas, a qualidade das plantas medicinais apresentava itens que reprovavam seu consumo. Em ambos os levantamentos, observou-se uma constância das espécies mais utilizadas e uma coerência satisfatória com os dados disponíveis sobre os hábitos da automedicação da população do município. Os motivos e sintomas mais freqüentes para a aquisição de plantas medicinais foram os relacionados ao uso analgésico, sistemas genitourinário, respiratório e osteomuscular, dispepsia/má digestão e tecido conjuntivo.

A survey of the medicinal plants requested from and/or indicated by herb sellers operating in the central area of Campo Grande, Mato Grosso do Sul, Brazil, was performed at two different times - 1992 and 2002. The first survey revealed 27 species being used; the second one, 32 species. The species most often consumed (Maytenus cf. macrodonta, ‘cancorosa’; Baccharis trimera, ‘carqueja’; Achyrocline alata, ‘jateí-kaá’; Stryphnodendron adstringens, ‘barbatimão’; Cochlospermum regium, ‘algodãozinho’, and Echinodorus macrophyllus, ‘chapéu-de-couro’) were acquired for identification and evaluation of their quality. On both occasions, the quality of the samples was negatively affected by features that made them inappropriate for human consumption. The results of both surveys agreed as to the species most used. Also, a satisfactory degree of coherence was found regarding the data available on the self-medication behavior of the population of Campo Grande. These medicinal plants were more often sought for analgesic use and for symptoms related to the genitourinary, respiratory and skeletomuscular systems, connective tissue and dyspepsia/maldigestion.