prof niraldo palestra de abertura do curso de fitoterapia clínica parte 3 sp
DESCRIPTION
Palestra inicial do Curso de Fitoterapia Clínica MEDLEX turma SP 01TRANSCRIPT
Prof. Dr. Niraldo Paulino
1. Aspectos históricos, legais e éticos. Desafios e Oportunidades
na Fitoterapia Médica
Um exemplo super-interessante de
estudo científico de Fitoterápico
Uma abordagem completa do estudo
farmacocinético de um produto farmacêutico
derivado de planta medicinal em humanos.
Parte 3
APRESENTAÇÃO DO PRODUTO
HELIORAL
DESENVOLVIMENTO TECNOLÓGICO:
VALIDAÇÃO BOTÂNICA
FERNBLOCK
FERNBLOCK (EPL): descrição botânica
• Polypodium leucotomos
• Familia Polypodiaceae
• Gênero Phebodium – Crescem naturalmente como plantas epífitas em
diversas palmeiras
– América Central • “Calaguala”
• Medicina popular – Antiinflamatorio (psoriasis, dermatitis atópica)
Reprodução
Por meio de esporos
– Que são lançados ao vento e quando encontram condições favoráveis, germinan dando lugar a novas plantas.
Planta adulta de Phlebodium
Germinação controlada
Rosetas e esporócitos sob germinação controlada
.
Plantas desenvolvidas
FERNBLOCK (EPL): cultivo
o Plantação localizada em no Lago YOJOA HONDURAS em Olancho.
o Padronização das condições de cultivo
o Sem uso de defensivos agrícolas.
HELIORAL
DESENVOLVIMENTO TECNOLÓGICO:
VALIDAÇÃO QUÍMICA
FERNBLOCK
FERNBLOCK (EPL): composição
• Extrato aquoso constituido por: – POLIFENÓIS: 3-10 % (p/p)
• Ácido Ferúlico
• Ácido Cafeico
• Ácido Cinámico
– MONOSACÁRIDEOS: 1-12 % (p/p) • Fructose, manose e glicose
– FLAVONÓIDES
– EPL é una fonte natural de substâncias antioxidantes, principalmente
rico em derivados fenólicos
FERNBLOCK (EPL): Laudo de análise
GARANTIA DE QUALIDADE
Reprodutibilidade na produção do fitomedicamento!!
In summary, the presence of both free and conjugated phenolics, such as caffeic and chlorogenic acids,
and the presence of different chlorogenic isomers point toward the relevance of the shikimik pathway in
ferns, and the importance of phenolic compounds as secondary metabolites related to plant
photoprotection (28). In addition to photoisomerization of cinnamic and related phenolic acids, the in
vivo photocyclodimerization has been described and related to cell wall stabilization (29). The presence
of cyclodimers of the phenolic acids herein described, either in Fernblock or as a consequence of UV
irradiation of the extract, is currently under study in our laboratories.
3,4-Dihydroxybenzoic acid Chlorogenic acid
4-Hydroxybenzoic acid Caffeic acid Vanillic acid
4-hydroxycinnamic acid
Neochlorogenic acid
Ferulic acid
COMPARATIVE ANALYSIS BETWEEN IFC Polypodium leucotomos extract
(batch P-07) and VIAFARMA (HUZHOU) Polypodium leucotomos extract
(batch 20070418) (Internal code IFCE 1195):
ATENÇÃO!! “Nem tudo que se parece é igual...”
IFC (PLE)
Advantages
VIAFARMA (PLE)
Disadvantages
1.In vivo photoprotector
2.Natural water based extraction
process
3.Phenol content and in vitro
photoprotective activity the same if not
better
4. Demonstrated anti-oxidant activity
5. Over 12 clinical trials In leading
institution like Harvard and Sloane
Kettering demonstrating;
Anti-oxidant activity
Anti-aging activity
Photo-Inmuno Protection
Photo protection
6. Over 15 years farmacovigilance and
safety data.
7.Registered and commercialed in over
42 countries
8. Registered with USFDA as ODI and
Self Affirmed GRAS
10. On-going pre-clinical and clinical
research.
11. Certified GLP/GMP extraction
processes assuring consistent quality
and stability.
12. Certified QA/QC processes
assuring consistent quality and
stability.
1. No photoprotective activity in vivo
2.Chemical extraction process
Industrial Farmacéutica Cantabria, S.A. Pirita, 6 28850 Torrejón de Ardoz MADRID (España) Tel.: (34) 91 676 90 82 Fax: (34) 91 677 20 41 [email protected]
HELIORAL
DESENVOLVIMENTO TECNOLÓGICO:
VALIDAÇÃO BIOLÓGICA
FERNBLOCK
In summary, these results underline the antioxidant and photoimmunoprotective properties of the PL extract
orally given in an in vivo model. PL-treated animals are less affected by UVR irradiation, chiefly noted in
decreased GSSG levels and a more favourable GSH⁄ GSSG ratio, and inhibition of UVR-mediated LC
depletion. These and other results strongly suggest the need to extend the concept of photoprotection,
currently restricted mainly to erythema development, which is the most extended criteria to evaluate the
efficacy of photoprotective measures. Oral administration of such antioxidant, photoprotective substances
would provide an excellent, hassle-free complement to the recommended use of topical sunscreens.
Overall, the effects of P. leucotomos predominated with or without exposure to UVA or UVB radiation in both keratinocytes and fibroblasts, respectively. PL improved membrane integrity, inhibited lipid peroxidation, stimulated elastin expression and inhibited MMP-1 expression in both fibroblasts and keratinocytes. The only exception to the predominant effects of P. leucotomos was in the inhibition of MMP-1 expression only in combination with UV radiation, particularly UVB, in fibroblasts
REGULAÇÃO BIOQUIMICA NA CÉLULA
O sistema bioquímico
complexo que produz
espontaneamente
formas radicalares de
oxigênio reativo (ROS)
a cada movimento de
respiração celular.
Esses radicias livres
são consumidos pelos
nossos sistemas de
defesa antioxidante:
SOD, CAT, GSHpx, etc...
REGULAÇÃO DA RESPOSTA ANTIOXIDANTE
Além disso, fatores ambientais: inflamação, radiação, agentes químicos, lesão de reperfusão, podem induzir radicais livres
adicionais nas células levando a danos celulares.
Geração de radicais livres
Oxidação de proteínas
Radical
superóxido
Radical
peroxil Radical
Alcoxil
Radical
Hidroxil
Outros
Controle da
transcrição gênica
NFKapaB e AP1
Controle da
diferenciação
celular
Mudança estrutural das proteínas
de regeneração celular
P. leucotomos e seus derivados
fenólicos e flavonóides apresentam
forte atividade ANTIOXIDANTE
e SEQUESTRANTE DE
RADICAIS LIVRES
Polypodium leucotomos
P. leucotomos e seus derivados
fenólicos e flavonóides apresentam
forte atividade INIBITÓRIA
SOBRE OS FATORES DE
TRANSCRIÇÃO NUCLEAR
Polypodium leucotomos
Efeito do P. leucotomos na reação oxidativa
induzida por radiação solar
In summary, P. leucotomos demonstrated dual protective eVects on the ECM for anti-skin aging via the inhibition of the ECM proteolytic enzymes and the stimulation of TIMPs, structural ECM collagens (types I, III, V), and TGF- in Wbroblasts. P. leucotomos’s anti-cancer eVects encompass the inhibition of MMPs and TGF- and stimulation of TIMPs in melanoma cells. In addition, P. leucotomos anti-aging and anti-cancer mechanism lies in its direct inhibition of MMPs. The eVects of P. leucotomos on Wbroblasts and melanoma cells may be partly via its cell-speciWc regulation of TGF- expression and partly via its antioxidant property. Polypodium leucotomos is used for the treatment of psoriasis (Difur®) and for photoprotection (Fernblock®) [18, 20]. Its topical or oral administration is tolerated without toxicity; for protection against UV radiation or PUVA (Psoralen § UVA) mediated phototoxicity, depletion of langerhans cells, erythema and skin damage [18, 20, 21, 23, 35]. P. leucotomos is readily absorbed and metabolized cellularly [18]. We therefore infer an in vivo potential of P. leucotomos for antiskin aging and anti-cancer, respectively, via speciWc beneWcial regulation of ECM remodeling.
Epiderme Epiderme ERITEMA
Estímulo inflamatório
O2-
Vaso
Macrófagos PMN
ROS
Apoptose ou Necrose
PGs AA
COX
EDEMA
NO Citocinas
PGE2
Linfócitos
Carrageina
Inflamação
Efeito do P. leucotomos na reação inflamatória tópica
induzida por radiação solar
Estímulos TLR
Myd-88 IRAK
TRAF6
NIK
p50 p65
p50 p65
IKK IKK
IB
TNF-
iNOS
COX-2
IL-12
NO
PG
IL1
Redução da inflamação e da angiogênese associada ao P. leucotomos
Quimioterápicos, LPS
Ativação de
receptores tipo TLR
Desencadeia uma
cascata de fosforilação
Ativação da
quinase do
IkappaB
Fosforilação do
inibidor do NFkB
Liberação do Fator
de Transcrição
Nuclear NFkB
Translocação
nuclear para a
ativação da
expressão gênica Expressão de
inúmeros genes
pró-inflamatórios Expressão de
genes das citocinas
IL1, 12 e TNF-
Expressão de
genes da
cicloxigenase 2
Aumento da
produção de PGE2,
PGF2 ...
Inflamação:
aumento da
permeabilidade
vascular,
vasodilatação,
migração celular,
etc…
Condições ideiais
para o crescimento
do tumor e
metástase
Specifically, PL has the capacity to neutralize free radicals, membrane-lipid peroxidation, and various ROS
(19, 20). It is possible that PL’s ability to prevent UVB radiation-induced immunosuppression and skin
ancer in mice is accomplished through its antioxidant properties as other antioxidants have been shown to
inhibit UVB-induced immune suppression in mouse models (21–24). ROS are thought to be involved in the
in the decrease in Langerhans cell numbers and the inhibition of CHS observed after exposure of murine
skin to UVB radiation (21) and ROS-induced lipid peroxidation of membrane lipids may impair antigen
presenting function in the remaining Langerhans cell. In addition, ROS increase TNF-a production (25), a
mediator important in CHS suppression in UVB-irradiated mouse skin (26). In this regard, PL has been
shown to inhibit TNF-a release stimulated by exposure of human keratinocytes to solar simulator radiation (27). Furthermore, PL inhibitsthe photoisomerization of trans-urocanic acid to cis-urocanic acid, another mediator implicated in UVB-induced immune suppression (28).
Photodermatology, Photoimmunology & Photomedicine 24, 134–141 2007
In conclusion, this study shows that anapsos is able to modulate the immune
response after surgery, by expressing an inhibitory effect on Th2 pathway
activation with no effect on Th1 pathway activation. This might be very important
in trauma and clinical surgery with regard to modulator treatment of the
postoperative immune response, since anapsos might prevent the shifting
Th1/Th2 balance and, in addition, preserve inflammationfollowing tissue repair
processes, and avoid “hyperinflammation” consecutive to immunosuppression
induced by surgery.
Carcinogenic stimulus
Rac2 Cdc42
GTP
Rac2 Cdc42
GDP
P
+
MKK3MKK6
p38
TLR
Myd-88 IRAK
TRAF6
NIK IKK
IKK
IB
p50 p65
p50 p65 TNF-
IL-1
iNOS
COX-2
IL-12
NO
PG
Mecanismos imunomodulador que justifica a melhoria da
resposta imune após o uso de P. leucotomos
Carcinogenic stimulus
Estímulos carcinogenicos
externos
Ativação de proteinas da
classe Ras (GTPase)
Prenilação pós-
translacional
Ativação de proteinas
quinases ativadas por
mitógenos
Ativação da p38-MAPK
Ativação do fator de
modulação imunologica
Aumento da
resposta
imune celular
P. leucotomos
P. leucotomos
P. leucotomos
In addition, PL downregulates TNF-a and iNOS expression induced by SSR. UV radiation induces TNF-a
expression (42). Interestingly, UV irradiation also induces expression of TNF-a receptors (43), which
suggests that TNF-a mediates the inflammatory reaction in skin induced by UV irradiation. On the other
hand, iNOS is also induced by UV irradiation in HaCaT cells (44). Increased iNOS expression causes
elevated levels of NO, which is one of the causal factors of erythema formation. The inhibitory effect of PL
on NO production and iNOS expression strongly suggests that NO increase is caused by de novo
synthesized iNOS. Finally, TNF-a and iNOS up-regulation are linked to increased apoptosis [reviewed in
Refs. (45,46)], thus inhibition of UV-mediated TNF-a and iNOS expression by PL is a likely cause for the
observed decrease in apoptosis. In summary, these findings greatly extend previous observations on the
photoprotective effect of PL, and represent a rigorous approach to explain its molecular basis, providing a
rationale for increased cell survival, decreased inflammation and changes in pigmentation observed both in
vivo and in vitro.
Conclusions
Originally described as a natural alternative for the treatment of inflammatory skin disorders such as psoriasis, P. leucotomos is a
more powerful tool than previously thought. It combines extremely low toxicity with proven beneficial effects, even with oral
administration. These include antioxidant properties, the capability to inhibit t-UCA photoisomerization (which makes it a very
valuable additive in sunscreen formulations), and the ability to block UV-induced apoptosis and DNA photodamage
andimmunosuppression. It seems clear that P. leucotomos is not an alternative to traditional sunscreen use, but it provides a very
effective complement for sensitive skin phototypes and adds extra protec- S. Gonzalez, J.L. Alonso-Lebrero, R. Del Rio and P.
Jaen 7 Table II: Beneficial effects of P. leucotomos. On... Molecular effects Short-term effects Long-term effects References
Generation of free Inhibits ROS Relieves photoaging, (32, 62, 75) radicals generation prevents tumor formation Generation of
other Inhibits t-UCA (Predicted) (64) deleterious photoisomerization, Relieves immunometabolites photodecomposition
suppression and tumor formation Inflammation Inhibits cell death and Reduces erythema, Relieves photoaging, (35, 45, 50, 51,
53) apoptosis sunburn* prevents tumor formation DNA damage Decreases the Reduces SOS (Predicted) Inhibits (53) formation of
response tumorigenesis pyrimidine dimers Immunosuppression Prevents depletion (Predicted) Reduces (Predicted) Inhibits (51,
53, 73, 74) of eLC recurrent infections chronic inflammation and cancer *Oral administration of P. leucotomos (1,080 mg)
increases skin tolerance to sunlight by a factor of 2.81 (48). ROS = reactive oxygen species; UCA = urocanic acid; SOS = the
SOS response: the depression of multiple genes encoding DNA repair proteins, leading to more rapid DNA repair and enhanced
bacterial survival; eLC = epidermal Langerhans cells. tion in cases in which exposure to UV radiation cannot be avoided, such as
those in UVB phototherapy and psoralens-UVA treatments.
HELIORAL
DESENVOLVIMENTO TECNOLÓGICO:
INOVAÇÃO EM FITOTERAPIA
FERNBLOCK
Recentes trabalhos científicos (2012) sobre P. leucotomos