Mesa-redonda: A nutrição e a fitoterapia

As particularidades da prescrição de fitoterápicos

Prof. Leandro Medeiros Farmacêutico e doutorando em Inovação Terapêutica | UFPE

Grupo de Pesquisas em Práticas Integrativas e Complementares | FG/Laureate International Universities Coordenação da pós-graduação em Fitoterapia: prescrição e aplicabilidade clínica | iPGS

Grupo de Trabalho em Fitoterapia | CRN6

Salvador, 2014

Legislação vigente

3"

PLANTAS"MEDICINAIS"(Lei"5991/1973)"

DROGAS"VEGETAIS"

DERIVADO(VEGETAL((EXTRATOS)(

FITOTERÁPICO(

MANIPULADO" INDUSTRIALIZADO(

MEDICAMENTO(FITOTERÁPICO(

(REGISTRO"COMUM"OU"SIMPLIFICADO)"(RDC"26/2014)"

PRODUTO(TRADICIONAL(FITOTERÁPICO((REGISTRO"

SIMPLIFICADO"OU"NOTIFICADO)"(RDC"26/2014"e"IN"02/2014)"

(FARMÁCIAS(DE(MANIPULACÃO((RDC"67/2007"/"

87/2008)"

FARMÁCIAS(VIVAS((RDC"18/2013)"

Uso"medicinal"

Chás"alimenLcios"(RDC(27/2010;(RDC(219/2006;(RDC(267/2005;(RDC(277/2005(

Uso"não"medicinal"

Chás"medicinais"(RDC"26/2014)"

Uso"medicinal"

CHÁS MEDICINAIS

–  Substitui o termo “droga vegetal notificado”

–  Drogas vegetais com fins medicinais a serem preparadas por infusão, decocção ou maceração pelo consumidor

–  Entram na categoria de produto tradicional fitoterápico

–  Não podem conter excipientes em suas formulações (apenas drogas vegetais)

CARACTERÍSTICA DOS FITOTERÁPICOS

low-density lipoprotein (LDL) in vitro in a concentration-dependent manner.(10) Silybin appears to be the constituent ofsilymarin responsible for the LDL antioxidant effect. In contrast,silichristin and silydianin appeared to act as pro-oxidants, butwithout significantly reducing the total LDL antioxidant capacityof silymarin.Free radicals are recognised as having an important role in

several pathological processes, including inflammation, necrosis,fibrosis, atherosclerosis, carcinogenesis and ageing and in thehepatotoxic mechanisms of various substances. The antioxidantactivity of silymarin is thought to contibute to its hepatoprotectiveproperties.(11, G55)

Hepatoprotective properties In vitro studies using isolatedhepatocytes have documented the protective activity of silymarinand several of its components against cell damage induced byvarious cytotoxic substances.(1)

In vivo studies in rats and mice have demonstrated thehepatoprotective activity of silymarin and silybin in acute livertoxicity induced by various toxic agents with different mechan-isms of action, including carbon tetrachloride, galactosamine,thioacetamide, ethanol, paracetamol (acetaminophen), thallium,phalloidin and a-amanitin (the main toxic constituents of themushroom A. phalloides).(1) Experimental studies in chronic livertoxicity induced by repeated administration of carbon tetrachlor-ide, heavy metals, thioacetamide and several drugs, includingazathioprine and indometacin, have also demonstrated thatadministration of silymarin and silybin protects againstdamage.(1) Other studies have reported protective effects ofsilymarin against liver injury induced by ischaemia(12) and gammairradiation.(13)

Studies in rabbits fed a high-fat diet for 12 weeks have shownthat histopathological alterations were least advanced in animalswhich also received a silymarin–phospholipid complex.(14) In rats,silymarin inhibited the development of diet-induced hypercholes-terolaemia.(15) The hypocholesterolaemic effects of silymarin maybe due to the effects of silymarin on lipoprotein metabolism.(16)

The effects of silymarin on biliary bile salt secretion have beenseen in studies in rats.(17) Intraperitoneal silymarin (25, 50, 100and 150mg/kg/day) for five days induced a dose-dependentincrease in bile flow and bile salt secretion. Stimulation of bilesalt secretion was mainly accounted for by an increase in thebiliary secretion of the hepatoprotective bile salts b-muricholateand ursodeoxycholate.

Nephroprotective properties Silibinin injected into rats prior toadministration of cisplatin afforded protection of glomerular andproximal tubular function.(18, 19) Silibinin does not affect thecytotoxic activity of cisplatin.(19) Intraperitoneal silibinin (5mg/kg) administered to rats 30 minutes before ciclosporin decreasedciclosporin-induced lipid peroxidation but produced no protectiveeffect on the glomerular filtration rate.(20)

Anticancer activity Silybin at concentrations of 0.1–20 mmol/Linhibited the growth of drug-resistant ovarian cancer cells anddoxorubicin-resistant breast cancer cells in vitro.(21) Furthermore,silybin in the range of 0.1–1.0 mmol/L potentiated the effect ofcisplatin and doxorubicin in experimental tumour cell lines. Whenapplied to the skin of SENCAR mice, silymarin gave protectionagainst the effects of the tumour promoters 12-O-tetradecanoyl-phorbol (TPA) and okaidic acid (OA).(22) Topical application ofsilymarin prior to that of TPA and OA completely inhibitedinduction of tumour necrosis factor a (TNFa) mRNA expressionin the epidermis. Substantial protection from photocarcinogenesisin mice treated with phorbol ester or 7,12-dimethylbenz(a)anthracene has been demonstrated.(23) The antitumour effect isprimarily at stage 1 tumour promotion and silymarin acts byinhibiting cyclooxygenase 2 (COX-2) and interleukin 1a (IL-1a).(24) Such effects may involve inhibition of promoter-inducedoedema, hyperplasia, the proliferation index and oxidant state.(25)

Treatment of serum-starved human prostate carcinoma DU145cells with silymarin resulted in significant inhibition of transform-ing growth factor a (TGFa)-mediated activation of the epidermalgrowth factor receptor erbB1.(26) There was also a decrease intyrosine phosphorylation of an immediate downstream target, theadapter protein SHC, together with a decrease in binding toerbB1. In the silymarin-treated cell lines there was a significantinduction of the cyclin-dependent kinase inhibitors (CDKIs) Cip1/p21 and Kip/p27 concomitant with a significant decrease in CDK4expression, but no changes in the levels of CDK2 and CDK6 andtheir associated cyclins E and D1, respectively. Additionalexperiments showed that there was a significant inhibition ofconstitutive tyrosine phosphorylation of both erbB1 and SHC, but

Figure 2 Milk thistle (Silybum marianum).

Figure 3 Milk thistle – dried drug substance (leaf).

Milk Thistle 431

M

Dosage

Dosages for oral administration (adults) for traditional usesrecommended in standard herbal reference texts are given below.

Fruit Crude drug 12–15 g daily in divided doses (equivalent tosilymarin 200–400mg daily).(G3)

Herb Approximately 1.5 g of finely chopped material as a tea, twoor three cups daily.The doses of silymarin used in clinical trials have ranged from

280–800mg/day (equivalent to milk thistle extract 400–1140mg/day standardised to contain 70% silibinin).(3) For hepaticdisorders, doses of up to 140mg (equivalent to 60mg silibinin)two or three times daily have been suggested.(G43)

In Germany, the recommended regimen for treatment ofAmanita phalloides poisoning with a standardised silymarinpreparation (Legalon) is a total dose of silibinin (as the disodiumdihemisuccinate) (20mg/kg body weight) over 24 hours, dividedinto four intravenous infusions each given over a 2-hourperiod.(G43, G55)

Pharmacological Actions

Several pharmacological activities have been documented for milkthistle fruit, including hepatoprotective, antioxidant, anti-inflam-matory, antifibrotic and antitumour properties, as well asinhibition of lipid peroxidation, stimulation of protein biosynth-

esis and acceleration of liver regeneration. Silymarin (an isomermixture comprising mainly silibinin, silichristin and silidianin) isthe pharmacologically active component of milk thistle fruit;silibinin is the main component of silymarin. There is an extensiveliterature on the pharmacological effects of silymarin andsilibinin, particularly with regard to their hepatoprotectiveactivity which provides supporting evidence for the clinical uses.The pharmacology and clinical efficacy of milk thistle have beenreviewed.(1–3,G50, G55) The following represents a summary ofselected publications on this subject.There is a lack of research investigating the pharmacological

effects of preparations of milk thistle leaf.(G2,G32,G35)

In vitro and animal studies

Antioxidant activity Silymarin and silibinin (silybin) areantioxidants that react with free radicals (e.g. reactive oxygenspecies) transforming them into more stable and less reactivecompounds.(1, 4–6) Silymarin and silybin have been reported toinihibit lipid peroxidation induced by iron-linked systems in ratliver microsomes(7, 8) and protect against phenylhydrazine-inducedlipid peroxidation in rat erythrocytes.(1) Furthermore, in rats,intraperitoneal silymarin has been shown to increase totalglutathione in the liver, intestine and stomach and to improvethe reduced glutathione to oxidised glutathione ratio.(9) Silymarinhas been shown to inhibit copper-induced oxidation of human

Figure 1 Selected constituents of milk thistle.

430 Milk Thistle

M

Dosage

Dosages for oral administration (adults) for traditional usesrecommended in standard herbal reference texts are given below.

Fruit Crude drug 12–15 g daily in divided doses (equivalent tosilymarin 200–400mg daily).(G3)

Herb Approximately 1.5 g of finely chopped material as a tea, twoor three cups daily.The doses of silymarin used in clinical trials have ranged from

280–800mg/day (equivalent to milk thistle extract 400–1140mg/day standardised to contain 70% silibinin).(3) For hepaticdisorders, doses of up to 140mg (equivalent to 60mg silibinin)two or three times daily have been suggested.(G43)

In Germany, the recommended regimen for treatment ofAmanita phalloides poisoning with a standardised silymarinpreparation (Legalon) is a total dose of silibinin (as the disodiumdihemisuccinate) (20mg/kg body weight) over 24 hours, dividedinto four intravenous infusions each given over a 2-hourperiod.(G43, G55)

Pharmacological Actions

Several pharmacological activities have been documented for milkthistle fruit, including hepatoprotective, antioxidant, anti-inflam-matory, antifibrotic and antitumour properties, as well asinhibition of lipid peroxidation, stimulation of protein biosynth-

esis and acceleration of liver regeneration. Silymarin (an isomermixture comprising mainly silibinin, silichristin and silidianin) isthe pharmacologically active component of milk thistle fruit;silibinin is the main component of silymarin. There is an extensiveliterature on the pharmacological effects of silymarin andsilibinin, particularly with regard to their hepatoprotectiveactivity which provides supporting evidence for the clinical uses.The pharmacology and clinical efficacy of milk thistle have beenreviewed.(1–3,G50, G55) The following represents a summary ofselected publications on this subject.There is a lack of research investigating the pharmacological

effects of preparations of milk thistle leaf.(G2,G32,G35)

In vitro and animal studies

Antioxidant activity Silymarin and silibinin (silybin) areantioxidants that react with free radicals (e.g. reactive oxygenspecies) transforming them into more stable and less reactivecompounds.(1, 4–6) Silymarin and silybin have been reported toinihibit lipid peroxidation induced by iron-linked systems in ratliver microsomes(7, 8) and protect against phenylhydrazine-inducedlipid peroxidation in rat erythrocytes.(1) Furthermore, in rats,intraperitoneal silymarin has been shown to increase totalglutathione in the liver, intestine and stomach and to improvethe reduced glutathione to oxidised glutathione ratio.(9) Silymarinhas been shown to inhibit copper-induced oxidation of human

Figure 1 Selected constituents of milk thistle.

430 Milk Thistle

M

Dosage

Dosages for oral administration (adults) for traditional usesrecommended in standard herbal reference texts are given below.

Fruit Crude drug 12–15 g daily in divided doses (equivalent tosilymarin 200–400mg daily).(G3)

Herb Approximately 1.5 g of finely chopped material as a tea, twoor three cups daily.The doses of silymarin used in clinical trials have ranged from

280–800mg/day (equivalent to milk thistle extract 400–1140mg/day standardised to contain 70% silibinin).(3) For hepaticdisorders, doses of up to 140mg (equivalent to 60mg silibinin)two or three times daily have been suggested.(G43)

In Germany, the recommended regimen for treatment ofAmanita phalloides poisoning with a standardised silymarinpreparation (Legalon) is a total dose of silibinin (as the disodiumdihemisuccinate) (20mg/kg body weight) over 24 hours, dividedinto four intravenous infusions each given over a 2-hourperiod.(G43, G55)

Pharmacological Actions

Several pharmacological activities have been documented for milkthistle fruit, including hepatoprotective, antioxidant, anti-inflam-matory, antifibrotic and antitumour properties, as well asinhibition of lipid peroxidation, stimulation of protein biosynth-

esis and acceleration of liver regeneration. Silymarin (an isomermixture comprising mainly silibinin, silichristin and silidianin) isthe pharmacologically active component of milk thistle fruit;silibinin is the main component of silymarin. There is an extensiveliterature on the pharmacological effects of silymarin andsilibinin, particularly with regard to their hepatoprotectiveactivity which provides supporting evidence for the clinical uses.The pharmacology and clinical efficacy of milk thistle have beenreviewed.(1–3,G50, G55) The following represents a summary ofselected publications on this subject.There is a lack of research investigating the pharmacological

effects of preparations of milk thistle leaf.(G2,G32,G35)

In vitro and animal studies

Antioxidant activity Silymarin and silibinin (silybin) areantioxidants that react with free radicals (e.g. reactive oxygenspecies) transforming them into more stable and less reactivecompounds.(1, 4–6) Silymarin and silybin have been reported toinihibit lipid peroxidation induced by iron-linked systems in ratliver microsomes(7, 8) and protect against phenylhydrazine-inducedlipid peroxidation in rat erythrocytes.(1) Furthermore, in rats,intraperitoneal silymarin has been shown to increase totalglutathione in the liver, intestine and stomach and to improvethe reduced glutathione to oxidised glutathione ratio.(9) Silymarinhas been shown to inhibit copper-induced oxidation of human

Figure 1 Selected constituents of milk thistle.

430 Milk Thistle

M

Dosage

Dosages for oral administration (adults) for traditional usesrecommended in standard herbal reference texts are given below.

Fruit Crude drug 12–15 g daily in divided doses (equivalent tosilymarin 200–400mg daily).(G3)

Herb Approximately 1.5 g of finely chopped material as a tea, twoor three cups daily.The doses of silymarin used in clinical trials have ranged from

280–800mg/day (equivalent to milk thistle extract 400–1140mg/day standardised to contain 70% silibinin).(3) For hepaticdisorders, doses of up to 140mg (equivalent to 60mg silibinin)two or three times daily have been suggested.(G43)

In Germany, the recommended regimen for treatment ofAmanita phalloides poisoning with a standardised silymarinpreparation (Legalon) is a total dose of silibinin (as the disodiumdihemisuccinate) (20mg/kg body weight) over 24 hours, dividedinto four intravenous infusions each given over a 2-hourperiod.(G43, G55)

Pharmacological Actions

Several pharmacological activities have been documented for milkthistle fruit, including hepatoprotective, antioxidant, anti-inflam-matory, antifibrotic and antitumour properties, as well asinhibition of lipid peroxidation, stimulation of protein biosynth-

esis and acceleration of liver regeneration. Silymarin (an isomermixture comprising mainly silibinin, silichristin and silidianin) isthe pharmacologically active component of milk thistle fruit;silibinin is the main component of silymarin. There is an extensiveliterature on the pharmacological effects of silymarin andsilibinin, particularly with regard to their hepatoprotectiveactivity which provides supporting evidence for the clinical uses.The pharmacology and clinical efficacy of milk thistle have beenreviewed.(1–3,G50, G55) The following represents a summary ofselected publications on this subject.There is a lack of research investigating the pharmacological

effects of preparations of milk thistle leaf.(G2,G32,G35)

In vitro and animal studies

Antioxidant activity Silymarin and silibinin (silybin) areantioxidants that react with free radicals (e.g. reactive oxygenspecies) transforming them into more stable and less reactivecompounds.(1, 4–6) Silymarin and silybin have been reported toinihibit lipid peroxidation induced by iron-linked systems in ratliver microsomes(7, 8) and protect against phenylhydrazine-inducedlipid peroxidation in rat erythrocytes.(1) Furthermore, in rats,intraperitoneal silymarin has been shown to increase totalglutathione in the liver, intestine and stomach and to improvethe reduced glutathione to oxidised glutathione ratio.(9) Silymarinhas been shown to inhibit copper-induced oxidation of human

Figure 1 Selected constituents of milk thistle.

430 Milk Thistle

MDosage

Dosages for oral administration (adults) for traditional usesrecommended in standard herbal reference texts are given below.

Fruit Crude drug 12–15 g daily in divided doses (equivalent tosilymarin 200–400mg daily).(G3)

Herb Approximately 1.5 g of finely chopped material as a tea, twoor three cups daily.The doses of silymarin used in clinical trials have ranged from

280–800mg/day (equivalent to milk thistle extract 400–1140mg/day standardised to contain 70% silibinin).(3) For hepaticdisorders, doses of up to 140mg (equivalent to 60mg silibinin)two or three times daily have been suggested.(G43)

In Germany, the recommended regimen for treatment ofAmanita phalloides poisoning with a standardised silymarinpreparation (Legalon) is a total dose of silibinin (as the disodiumdihemisuccinate) (20mg/kg body weight) over 24 hours, dividedinto four intravenous infusions each given over a 2-hourperiod.(G43, G55)

Pharmacological Actions

Several pharmacological activities have been documented for milkthistle fruit, including hepatoprotective, antioxidant, anti-inflam-matory, antifibrotic and antitumour properties, as well asinhibition of lipid peroxidation, stimulation of protein biosynth-

esis and acceleration of liver regeneration. Silymarin (an isomermixture comprising mainly silibinin, silichristin and silidianin) isthe pharmacologically active component of milk thistle fruit;silibinin is the main component of silymarin. There is an extensiveliterature on the pharmacological effects of silymarin andsilibinin, particularly with regard to their hepatoprotectiveactivity which provides supporting evidence for the clinical uses.The pharmacology and clinical efficacy of milk thistle have beenreviewed.(1–3,G50, G55) The following represents a summary ofselected publications on this subject.There is a lack of research investigating the pharmacological

effects of preparations of milk thistle leaf.(G2,G32,G35)

In vitro and animal studies

Antioxidant activity Silymarin and silibinin (silybin) areantioxidants that react with free radicals (e.g. reactive oxygenspecies) transforming them into more stable and less reactivecompounds.(1, 4–6) Silymarin and silybin have been reported toinihibit lipid peroxidation induced by iron-linked systems in ratliver microsomes(7, 8) and protect against phenylhydrazine-inducedlipid peroxidation in rat erythrocytes.(1) Furthermore, in rats,intraperitoneal silymarin has been shown to increase totalglutathione in the liver, intestine and stomach and to improvethe reduced glutathione to oxidised glutathione ratio.(9) Silymarinhas been shown to inhibit copper-induced oxidation of human

Figure 1 Selected constituents of milk thistle.

430 Milk Thistle

M

Silybum marianum

PRESCRIÇÃO DE FITOTERÁPICOS POR NUTRICIONISTAS

CFN | RE 525/2013

Isentos de prescrição médica

Exclusivamente por via oral

Não associado a substâncias bioativas, mesmo que de origem vegetal, ou ainda a nutrientes

Relacionados com o campo de atuação do nutricionista

Baseados em evidências científicas ou na tradicionalidade de uso

Aspectos da prescrição

Informações gerais

• Dados do nutricionista (nome, endereço, contatos, número de registro no CRN)

• Dados do paciente (nome)

O que deve constar em uma prescrição de fitoterápicos?

CFN, 2013

O que deve constar em uma prescrição de fitoterápicos?Prescrição de chás medicinais

Nome botânico da(s) espécie(s) vegetal(is) (sendo opcional, adicionar o nome popular)

Droga vegetal

Parte da planta utilizada

Forma de preparo

Quantidade da droga vegetal / dose

Tempo de contato da droga vegetal com a água

Técnica de preparo: infusão, decocção ou maceração

Modo de uso

Quantidade a ser tomada

Horário, frequência e duração do tratamentoAnvisa, 2014

CFN, 2013

O que deve constar em uma prescrição de fitoterápicos?Prescrição de chás medicinais

Utilizar referências oficiais para o preparo de chás

Formulário de Fitoterápicos da Farmacopeia Brasileira (2011)

RDC 10/2010 (ANVISA)

Referências bibliográficas listadas na RDC 26/2014 (ANVISA)

Anvisa, 2014CFN, 2013

Dra. Joyce Gomes de MoraesCRN6: 3484

Para: Aline Kelly da Silva

Rx:Allium sativum (alho) …. droga vegetal do bulbo

Modo de preparo:

• Cobrir o conteúdo de 1 colher de café rasa em 30 mL de água• Deixar em temperatura ambiente por 1 hora• Agitar ocasionalmente e coar

Tomar 1 cálice (30 mL), 2x/dia, antes das refeições, por 3 meses.

Dra. Joyce Gomes de MoraesCRN6: 3484

Para: Aline Kelly da Silva

Rx:Cinnamomum verum (canela) …. droga vegetal da casca

Modo de preparo:

• Colocar o conteúdo de 4 colheres de café rasa em 150 mL de água fria• Ferver por cerca de 3 a 5 minutos• Deixar em contato por 15 minutos• Coar, em seguida

Tomar 1 xícara (150 mL), 3x/dia, antes das refeições, por 3 meses.

Dra. Joyce Gomes de MoraesCRN6: 3484

Para: Aline Kelly da Silva

Rx:Cynara scolymus (alcachofra) …. droga vegetal da folha

Modo de preparo:

• Colocar 150 mL (1 xícara) de água fervente sobre 1 colher de sobremesa da droga vegetal, em um recipiente apropriado

• Abafar por cerca de 15 minutos• Coar, em seguida

Tomar 1 xícara (150 mL), 3x/dia, antes das refeições, sempre que os sintomas surgirem.

O que deve constar em uma prescrição de fitoterápicos?Prescrição de medicamentos fitoterápicos, produtos tradicionais fitoterápicos e fitoterápicos manipulados

Nome botânico da(s) espécie(s) vegetal(is) (sendo opcional, adicionar o nome popular)

Derivado da droga vegetal (extrato seco, tintura, extrato líquido) ou droga vegetal (pó)

Padronização do marcador (para derivados da droga vegetal)

Posologia

Via de administração e forma farmacêutica

Dosagem (dose, frequência e duração do tratamento)

Modo de uso

Quantidade a ser tomada

Horário, frequência e duração do tratamentoAnvisa, 2014

CFN, 2013

Dra. Joyce Gomes de MoraesCRN6: 3484

Para: Aline Kelly da Silva

Rx:

Tomar uma dose, logo após as refeições, 2x ao dia, por 60 dias.

Obs.: Não repetir receita.

Allium sativum (extrato seco, 5% de alicina) 50 mg

Camellia sinensis (extrato seco, 50% de polifenois totais)

250 mg

Aviar em cápsulas 120 doses

Dra. Joyce Gomes de MoraesCRN6: 3484

Para: Aline Kelly da Silva

Rx:

Diluir o conteúdo de um sachê em 1 copo d’água e tomar 30 minutos antes das refeições,2x ao dia, por 30 dias.

Obs.: Não repetir receita.

Plantago ovata (pó) 3,0 g

Amorphophallus kinjac (pó) 1,0 g

Aviar em sachê 60 doses

Pontos críticos

A RE 525/2013 não contempla a prescrição de fitoterápicos industrializados pelo nome comercial

Prescrição de fármacos alopáticos (sintéticos ou semissintéticos), fitofármacos (medicamentos) e substâncias bioativos isolados/nutracêuticos (alimentos) por nutricionistas

Associações de extratos vegetais: sinergismo farmacológico

Padronização do marcador

Formas farmacêuticas e adesão ao tratamento

Relacionamento nutricionista-farmacêutico

E-mail: leandro.a.medeiros@gmail.com

Facebook: @leandro.a.medeiros

Twitter: @PharmD_Leandro

Instagram: @leandro_a_medeiros

Obrigado!