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Natural products for drug discovery
Abstracts / Toxicology Letters 259S (2016) S4–S62
it is presumed that human being daily ingest is about 1 g. Several flavonoid compounds display antioxidant, antimicrobial and antiinflammatory properties among other possible beneficial effects, therefore they have been proposed for the alternative prevention of neurodegenerative diseases including cancer. Furthermore, flavonoids exert specific effects on receptors and enzymes of mammalian organisms inhibiting prostaglandin biosynthesis which explain its anti-inflammatory properties. On the other hand, the cytochrome P450 (CYP) enzyme family plays an important role in the metabolism of endogenous chemicals including fatty acids and prostaglandins as well as xenobiotics like aromatic hydrocarbons, alcohol, several pharmaceutical drugs and other environmental carcinogens. The metabolites resulting from CYP activity on promutagens/carcinogens leads to reactive molecules capable to bind proteins and DNA promoting the initiation of the carcinogenic process. That’s why the inhibition of CYP has been proposed as an alternative mechanism to prevent cancer and other degenerative diseases. The objective of this work is to compare the CYP inhibition potencies of the most representative flavonoids in the plant kingdom and to test its mutagenic potential. To accomplish the first part we used in silico and in vitro methodologies in the presence of human CYP1A recombinant enzymes. The mutagenicity of the chosen molecules will be tested in microbial systems in the presence and absence of human CYP. Results show that the presence of hydroxyl groups attached to flavonoid A, B or C rings reduced its CYP1A inhibitory effect. Results of the CYP inhibitory properties of other natural molecules like bergamottin, dehydrobergamottin and naringenin will be presented. http://dx.doi.org/10.1016/j.toxlet.2016.07.072 S07-3 Regulation of natural products R. Linval DePass, DURECT Corporation, Cupertino, CA, USA Natural products have historically been an important source for new medicines. About half of all drugs used today are derived from natural sources including half of all drugs approved since 1994. In general, new drugs derived from natural products must meet the same standards of efficacy and safety as compounds that were synthesized in the laboratory, but there are considerable differences in the way these principles are applied in various countries. In the USA, the FDA is responsible for assuring the efficacy and safety of all new drugs including those derived from natural products. In 2002 the FDA established a group dedicated to reviewing the data from submissions based on natural products. Then, the FDA published the first guidance document called the Botanical Drug Product Guidance in 2004. In August, 2015, the FDA published their most recent draft guidance document, the Botanical Drug Development Guidance for Industry. FDA has received and reviewed more than 600 investigational new drug (IND) applications and pre-IND requests. In addition, two new drug applications (NDA) have been approved for natural products. Since natural product-based drugs are complex mixtures and most products have been used as medicinal plants or dietary supplements, FDA will often take a flexible regulatory approach to toxicology studies and early phase clinical trials for such drugs. However, regulatory requirements for Phase 3 trials and NDA approval are the same as for synthetic drugs. In the European Union (EU), the European Medicines Agency (EMA), as well as national competent authorities, regulates new drugs including those derived from natural products. A simplified registration procedure for traditional herbal medicinal products was introduced in 2004, and a Committee on Herbal Medicinal Products
S15
was established in the same year. There are three main regulatory pathways for bringing an herbal medicinal product to the market in the EU. The “traditional use registration” requires no clinical trials as long as sufficient safety data and plausible efficacy are demonstrated. The “well-established use marketing authorization” depends on a review of the scientific literature to establish an acceptable level of safety and recognized efficacy. Finally, a company may submit a “stand alone or mixed application” that includes the company’s own data, sometimes combined with data from the literature. In Japan, traditional herbal medicinal products, sometimes called Kampo medicines, are very popular and are available both as over the counter (OTC) and prescription products. In Japan, the per capita consumption of herbal medicines may be the highest in the world. Kampo drugs are regulated in essentially the same way as synthetic drugs by the Ministry of Health, Labour and Welfare. In conclusion, natural products have traditionally provided a large proportion of approved drugs, and the regulation of these products will continue to be a challenge for global regulatory authorities as the need to establish the efficacy and safety of such products will only increase with the increase and aging of the global population. http://dx.doi.org/10.1016/j.toxlet.2016.07.073 S07-4 Natural products for drug discovery Faz E. Marrero Group of Biopharmaceutical Development, Health Direction, Centro Nacional de Sanidad Agropecuaria, CENSA, Apdo. #10, San José de las Lajas, La Habana, Cuba The contemporary procedures involved in natural product research have greatly contributed to restore the interest in natural compounds as drug candidates in last decades. The evolution of genomic has allowed the identification of relevant therapeutic targets in many diseases including complex polygenic diseases. In addition, less than 10% of the world’s biodiversity have been tested for biological activity. Moreover, natural products (NPs) that are found to be biologically active in pharmacological assays are generally small molecules with drug-like properties, it means capable of being absorbed and metabolised by the body. It is particularly important when searching for lead molecules against newly discovered targets for which there are no known small molecule leads. Pharmacological studies to obtain new molecules that concerns different relevant diseases as cancer, type 2 diabetes, antimicrobials, among other, obtained from natural sources constitute a hopeful research field where the great biodiversity observed mainly in tropical countries is still waiting to be explored. The in vitro evaluation of natural extracts oriented to obtain new active molecules constitutes a valuable tool for the screening of the biological activity in an appropriate therapeutic target battery. The bio-guided fractioning will help to find new promising molecules. The specificity of the mechanism associated to particular pharmacological targets brings also the opportunity to investigate the pathogenesis of definite disease at cellular and molecular level and also offers the opportunity to establish the mechanism of action involved in the traditional use of medical plants. The present work brings an example of the predictive strategy to screening natural candidates obtained from six Cuban medicinal plants for type 2 diabetes based on PTP-1B and DPP-IV inhibitory activity and in vitro glucose uptake. The promising candidate will transit for regulatory protocols to demonstrate its safety, efficacy and quality. http://dx.doi.org/10.1016/j.toxlet.2016.07.074
it is presumed that human being daily ingest is about 1 g. Several flavonoid compounds display antioxidant, antimicrobial and antiinflammatory properties among other possible beneficial effects, therefore they have been proposed for the alternative prevention of neurodegenerative diseases including cancer. Furthermore, flavonoids exert specific effects on receptors and enzymes of mammalian organisms inhibiting prostaglandin biosynthesis which explain its anti-inflammatory properties. On the other hand, the cytochrome P450 (CYP) enzyme family plays an important role in the metabolism of endogenous chemicals including fatty acids and prostaglandins as well as xenobiotics like aromatic hydrocarbons, alcohol, several pharmaceutical drugs and other environmental carcinogens. The metabolites resulting from CYP activity on promutagens/carcinogens leads to reactive molecules capable to bind proteins and DNA promoting the initiation of the carcinogenic process. That’s why the inhibition of CYP has been proposed as an alternative mechanism to prevent cancer and other degenerative diseases. The objective of this work is to compare the CYP inhibition potencies of the most representative flavonoids in the plant kingdom and to test its mutagenic potential. To accomplish the first part we used in silico and in vitro methodologies in the presence of human CYP1A recombinant enzymes. The mutagenicity of the chosen molecules will be tested in microbial systems in the presence and absence of human CYP. Results show that the presence of hydroxyl groups attached to flavonoid A, B or C rings reduced its CYP1A inhibitory effect. Results of the CYP inhibitory properties of other natural molecules like bergamottin, dehydrobergamottin and naringenin will be presented. http://dx.doi.org/10.1016/j.toxlet.2016.07.072 S07-3 Regulation of natural products R. Linval DePass, DURECT Corporation, Cupertino, CA, USA Natural products have historically been an important source for new medicines. About half of all drugs used today are derived from natural sources including half of all drugs approved since 1994. In general, new drugs derived from natural products must meet the same standards of efficacy and safety as compounds that were synthesized in the laboratory, but there are considerable differences in the way these principles are applied in various countries. In the USA, the FDA is responsible for assuring the efficacy and safety of all new drugs including those derived from natural products. In 2002 the FDA established a group dedicated to reviewing the data from submissions based on natural products. Then, the FDA published the first guidance document called the Botanical Drug Product Guidance in 2004. In August, 2015, the FDA published their most recent draft guidance document, the Botanical Drug Development Guidance for Industry. FDA has received and reviewed more than 600 investigational new drug (IND) applications and pre-IND requests. In addition, two new drug applications (NDA) have been approved for natural products. Since natural product-based drugs are complex mixtures and most products have been used as medicinal plants or dietary supplements, FDA will often take a flexible regulatory approach to toxicology studies and early phase clinical trials for such drugs. However, regulatory requirements for Phase 3 trials and NDA approval are the same as for synthetic drugs. In the European Union (EU), the European Medicines Agency (EMA), as well as national competent authorities, regulates new drugs including those derived from natural products. A simplified registration procedure for traditional herbal medicinal products was introduced in 2004, and a Committee on Herbal Medicinal Products
S15
was established in the same year. There are three main regulatory pathways for bringing an herbal medicinal product to the market in the EU. The “traditional use registration” requires no clinical trials as long as sufficient safety data and plausible efficacy are demonstrated. The “well-established use marketing authorization” depends on a review of the scientific literature to establish an acceptable level of safety and recognized efficacy. Finally, a company may submit a “stand alone or mixed application” that includes the company’s own data, sometimes combined with data from the literature. In Japan, traditional herbal medicinal products, sometimes called Kampo medicines, are very popular and are available both as over the counter (OTC) and prescription products. In Japan, the per capita consumption of herbal medicines may be the highest in the world. Kampo drugs are regulated in essentially the same way as synthetic drugs by the Ministry of Health, Labour and Welfare. In conclusion, natural products have traditionally provided a large proportion of approved drugs, and the regulation of these products will continue to be a challenge for global regulatory authorities as the need to establish the efficacy and safety of such products will only increase with the increase and aging of the global population. http://dx.doi.org/10.1016/j.toxlet.2016.07.073 S07-4 Natural products for drug discovery Faz E. Marrero Group of Biopharmaceutical Development, Health Direction, Centro Nacional de Sanidad Agropecuaria, CENSA, Apdo. #10, San José de las Lajas, La Habana, Cuba The contemporary procedures involved in natural product research have greatly contributed to restore the interest in natural compounds as drug candidates in last decades. The evolution of genomic has allowed the identification of relevant therapeutic targets in many diseases including complex polygenic diseases. In addition, less than 10% of the world’s biodiversity have been tested for biological activity. Moreover, natural products (NPs) that are found to be biologically active in pharmacological assays are generally small molecules with drug-like properties, it means capable of being absorbed and metabolised by the body. It is particularly important when searching for lead molecules against newly discovered targets for which there are no known small molecule leads. Pharmacological studies to obtain new molecules that concerns different relevant diseases as cancer, type 2 diabetes, antimicrobials, among other, obtained from natural sources constitute a hopeful research field where the great biodiversity observed mainly in tropical countries is still waiting to be explored. The in vitro evaluation of natural extracts oriented to obtain new active molecules constitutes a valuable tool for the screening of the biological activity in an appropriate therapeutic target battery. The bio-guided fractioning will help to find new promising molecules. The specificity of the mechanism associated to particular pharmacological targets brings also the opportunity to investigate the pathogenesis of definite disease at cellular and molecular level and also offers the opportunity to establish the mechanism of action involved in the traditional use of medical plants. The present work brings an example of the predictive strategy to screening natural candidates obtained from six Cuban medicinal plants for type 2 diabetes based on PTP-1B and DPP-IV inhibitory activity and in vitro glucose uptake. The promising candidate will transit for regulatory protocols to demonstrate its safety, efficacy and quality. http://dx.doi.org/10.1016/j.toxlet.2016.07.074