Aman (safety) Berkhasiat (Efficacy) ASPEK Aspek Penajaminan mutu penerapan standardisasi pada sediaan obat herbal Jaminan khasiat berlandaskan hasil-

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2 Aman (safety) Berkhasiat (Efficacy) ASPEK

3 Aspek Penajaminan mutu penerapan standardisasi pada sediaan obat herbal Jaminan khasiat berlandaskan hasil- hasil penelitian ilmiah  sumber- sumber dapat dipertanggung jawabkan

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5 Safety  Medical opinion : it is impossible any medicine to have effects without side effects  If herbs are claimed to be free from side effects they are probably no effective either

6  Patients believe that herbs are safe  Many herbalists emphasize the same point  They refer to the most established remedies by millions of people since prehistory

7 Safe EUROPEAN HERBAL INFUSIONS ASSOCIATION Inventory list of Herbals considered as Food

8 Sumber Endogenous  Beberapa tanaman mengandung racun Sianida  Alkaloid : pirrolizidine  hepatotoxic  Memiliki kandnungan senyawa berkhasiat dengan Index terapi sempit; Digitalis, Datura stramonium (50 mg), Atropa belladona ( herba 50 mg, radix 30 mg)

9 Cyanide  Many common plants contain the natural form of cyanide, cyanic glucoside. Its presence may be the product of evolution, as it deters animals and insects from consuming the entire plant.

10 Pyrrolizidine Alkaloids  Pyrrolizidine alkaloids (PAs) are of special interest currently because several of them have been shown to cause toxic reactions in humans, primarily veno-occlusive liver disease, when ingested with foods or herbal medicines. Comfrey, a well-known medicinal herb characterized by U.S. FDA researchers as having been "one of the most popular herb teas in the world," contains PAs that are capable of causing liver damage

11 Exogenous Cemaran  Saat kultivasi ; kimia, biologi  Proses produksi Interaksi Herbal-herbal Herbal-modern Herbal-makanan

12 Microbiological contamination Eur Ph 2002  < 10 5 aerobic microorganisme /g or ml, including: - < 10 3 yeast and fungi /g or ml and - < 10 3 enterobacteria /g or ml  No detectable E. coli (in g or ml)  No detectable Salmonella sp. (in 10 g or ml)

13 Limits of some important pesticides(Eur Ph 2002) PestisideConcentratio n limit (mg/kg) Aldrin and dieldrin (sum of) Chloordane (sum of cis, trans and oxychlordane) DDT Endrin Fonofos Malatihon Parathion Permethrin Pyrethrins 0.05 1.0 0.05 1.0 0.5 1.0 3.0

14  Interactions  Pharmacokinetic  Pharmacodynamic

15 Farmakokinetik  Mempengaruhi absorpsi, distribusi, metabolisme atau ekskresi  Herbal laksatif mempengaruhi waktu transit akan menurunkan absorpsi obat  Hypericum perforatum menginduksi P- glikoprotein, menurunkan absorpsi substrat P-glikoprotein, spt : digoksin.  H. perforatum penginduksi CYP3A4, jika bersamaan dgn substrat, mis indinavir, menurunkan konst dan waktu paruh (t 1/2 )

16 Farmakodinamik  Interaksi farmakodinamik terjadi pada obat yang bekerja mirip/sama dengan obat herbal. Misalnya pemberian bersamaan antara obat herbal yang memiliki aktivitas antiplatelet dengan antikoagulan.  Penggunaan bersamaan efedrin dengan obat herbal yang kaya kofein.

17 Potential drug–herb interaction with antiplatelet/anticoagulant drugs A cross-sectional survey evaluating the use of herbal medicines in medical wards patients that may interfere with the effect of antiplatelet or anticoagulant therapy. Among the 250 patients participated, 42.4% were taking herbs with 76 patients using herbs for the past 12 months. Almost 31% patients were taking one or more of the specified herbal medicines [ginseng (Panax ginseng), garlic (Allium sativum), ginkgo (Gingko biloba) thought to interact with antiplatelet or anticoagulant therapy. The study showed that 21) of patients co-ingested specified herbs with antiplatelet or anticoagulant therapy, of which half of them were at risk of potential drug–herbinteractions. A large proportion of respondents involved in potential drug–herb interaction were elderly people. However, more than 90% of herbal users did not disclose the use of herbal medicine to their health professionals. It is thus prudent for all care givers to be aware of the possibility of drug–herb interaction and inquire about herbal use from patients.

18 Herb–drug interaction of silymarin or silibinin on the harmacokinetics of trazodone in rats Silymarin, one of the most popular herbal medicines, has been widely used for its hepatoprotective effects. This study investigates the effects of repeated dose of silymarin and its major ingredient, silibinin, on the pharmacokinetics of the antidepressant trazodone. Results indicate that pretreatment with an extremely high dose of 1.0 g/kg silymarin significantly decreases trazodone's AUC, (t 1/2,α ), elimination half-life (t 1/2,β ), and mean residence time (MRT). In conclusion, the present study finds no marked effects of silymarin and silibinin on the pharmacokinetics of trazodone under normal daily doses and the relative safety of taking the herb with trazodone

19 In vitro and in vivo assessment of herb drug interactions Herbal products contain several chemicals that are metabolized by phase 1 and phase 2 pathway. Due to their interaction with these enzymes and transporters there is a potential for alteration in the activity of drug metabolizing enzymes and transporters in presence of herbal components. Induction and inhibition of drug metabolizing enzymes and transporters by herbal component has been documented in several in vitro studies.. It appears that St. John's wort extract is probably one of the most important herbal product that increases the metabolism and decreases the efficacy of several drugs. Milk thistle on the other hand appears to have minimal effect on phase 1 pathways and limited data exists for phase 2 pathways and transporter activity in vivo. Further systematic studies are necessary to assess the significance of herb drug interactions.

20 Herb–drug interaction of Andrographis paniculata extract and andrographolide on the pharmacokinetics of theophylline in rats This study investigates effects of Andrographis paniculata extract on the pharmacokinetics of theophylline, a typical substrate of cytochrome P450 1A2 enzyme, in rats The results indicated that the clearance of theophylline was significantly increased and the AUC was reduced in both AG and APE pretreated groups at low-dose theophylline administration (1 mg/kg). The elimination half-life (t 1/2β ) and mean residence time (MRT) of theophylline were shortened by 14% and 17%, respectively, in the AG pretreated group when high-dose theophylline (5 mg/kg) was given. However, theophylline accumulated in rat of the group with APE pretreatment. This phenomenon suggests that some other herbal components contained in APE may interact with theophylline and retard its elimination when theophylline was administered at a high dose. Our results suggest that patients who want to use CYP1A2-metabolized drugs such as caffeine and theophylline should be advised of the potential herb–drug interaction, to reduce therapeutic failure or increased toxicity of conventional drug therap

21 Pharmacodynamicinteraction of the sedative effects of Ternstroemia pringlei (Rose) Standl. with six CNS depressant drugs in mice examine the sedative effects of the dried fruits of Ternstroemia pringlei and investigate a possible synergistic pharmacodynamicinteraction between the sedative effect of aqueous extract of this plant and six central nervous system (CNS) depressant drugs. The intraperitoneal administration of the hexane, dichloromethane, methanol and aqueous extracts of Ternstroemia pringlei showed a dose-dependent sedative effect. Ternstroemia pringlei aqueous extract combined with buspirone, diazepam, diphenhydramine, haloperidol or pentobarbital exerted a super-additive (synergistic) sedative interaction. Whereas the combination Ternstroemia pringlei extract plus ethanol resulted in a sub- additive (attenuate) sedative interaction. hese findings are in agreement with the traditional use of Ternstroemia pringlei in the treatment of insomnia, however it is a plant that interacts in a complex form with CNS depressant drugs. It may represent an advertence on the use of this plant concomitantly with other neuroactive drugs.

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23 PROOF OF THE EFFICACY The effect and effeteness of the drug must be established : 1. In review articles, handbook, and/or textbooks published by reputable institution; or 2. In controlled studies comparing the test substance with a placebo; or 3. In the experimental study findings which provide the same evidence in cases where findings of clinical tests alone do not suffice for issuance of an authorization recommendation; or 4. Through submission of scientifically and analyzed data; or 5. In conclusive experimental findings or additional useful observations or remarks in cases where the empirical findings alone do not suffice for issuance of an authorization recommendation

24 Fixed Herbal Drug Combinations 1. The use of components with identical or different points of attack leads to additive synergistic effects; and /or 2. The combination leads to a super additive effect of the fixed combination compared to that of the individual components; and/or 3. The combination leads to reduction or elimination of undesirable effects of individual components (eg., via dose reduction in components with equidirectional effects; and/or 4. The combination leads to a simplification of therapy or improvement in the therapy safety

25 Questionable Combinations 1. Significant pharmacokinetic and/or pharmacodynamic interactions that do not improve the risk-to-benefit ratio, or even worsen it 2. Significant differences in the half lives and/or duration of effect of the active ingredients. This must not necessarily apply if the applicant proves that the combination is clinically beneficial. Despite these differences; and/or 3. If a component added to prevent abuse causes unpleasant effects

26 EXTRACTs  Standardization of extracts: Quality of the herbal material Production methods Adjustment of Quality Analytical Quality control

27 Phtyomedicines  Liquid dosage form: Tinctures Syrups Medicinal oils Medicinal spirits Plant juices  Solid dosage forms: Granules, tablets, capsules

28 Phtytotherapy  Pharmacology ; therapeutic range, onset of action  Pharmacologic and clinical test  Indication: respiratory, CNS, grastrointestinal, cardiovascular, antiinflammatory, immune system, gynecologic remedies

29 Application of Phytomedicines  Diseases of the respiratory tract  Central nervous system disorders  Diseases of the stomach, bowel, liver, and bile  Urinary tract  Cardiovascular system  Dermatologic remedies and external anti-inflammatory agents  Nonspecific immune enhancers  Gynecologic remedies  Remedies for internal use in the treatment of rheumatic disorders and inflammatory conditions

30 PENGEMBANGAN OBAT TRADISIONAL Jamu Bentuk Sederhana Khasiat & Keamanan empirik Obat Herbal Terstandar Standardisasi Bahan Baku Aman & Berkhasiat (Uji praklinik) Fitofarmaka Uji praklinik Tek farmasi Uji Klinik

31 Natural Standard Grading Scale Tingkat BuktiKriteria A Bukti ilmiah yang kuat Bukti statistik signifikan manfaat dari >2 uji acak terkontrol dengan benar (RCTs), atau bukti dari satu dilakukan RCT benar dan salah satu benar dilakukan meta-analisis, atau bukti dari beberapa RCTs dengan mayoritas jelas melakukan percobaan dengan benar menunjukkan bukti statistik signifikan manfaat dan dengan bukti pendukung dalam ilmu pengetahuan dasar, penelitian hewan, atau teori.

32 Tingkat Bukti Kriteria B Bukti ilmiah baik Bukti statistik signifikan manfaat dari 1 atau 2 RCTs dengan benar, atau bukti manfaat dari ≥1 benar dilakukan meta-analisis atau bukti manfaat dari > 1 kohort / kasus- kontrol / uji tidak acak dan dengan bukti pendukung dalam ilmu pengetahuan dasar, penelitian hewan, atau teori. Kelas ini berlaku untuk situasi di mana dirancang RCT dengan baik melaporkan hasilnya negatif tetapi berlawanan dengan hasil efikasi positif dari percobaan lain yang kurang dirancang dengan baik atau beberapa dirancang dengan meta analisis baik, sambil menunggu bukti konfirmasi dari percobaan acak terkontrol tambahan yang dirancang dengan baik.

33 Tingkat BuktiKriteria C tidak jelas atau bukti ilmiah yang bertentangan Bukti manfaat dari ≥1 RCTs kecil tanpa ukuran yang memadai, signifikansi statistik, atau kualitas desain dengan kriteria objektif atau bukti bertentangan dari beberapa RCTs tanpa mayoritas jelas melakukan percobaan dengan benar menunjukkan bukti manfaat atau ketidakefektifan; atau bukti manfaat dari ≥1 kohort / kasus-kontrol / uji tidak acak dan tanpa bukti pendukung dalam ilmu pengetahuan dasar, penelitian hewan atau teori, atau bukti keberhasilan hanya dari ilmu pengetahuan dasar, penelitian hewan atau teori.

34 Tingkat BuktiKriteria D Bukti ilmiah negatif fair Bukti statistik negatif yang signifikan (yaitu, kurangnya bukti manfaat) dari kohort / kasus- kontrol / uji tidak acak, dan bukti dalam ilmu pengetahuan dasar, penelitian hewan, atau teori menyarankan kurangnya manfaat. Kelas ini juga berlaku untuk situasi dimana >1 RCT yang dirancang dengan baik melaporkan hasil negatif, walaupun adanya hasil efikasi positif dilaporkan dari percobaan lainnya yang kurang dirancang dengan baik atau meta-analisis. (catatan : jika ada ≥1 negatif RCTs yang dirancang dengan baik dan sangat menarik, ini akan menghasilkan sebuah kelas “F” meskipun hasil positif dari penelitian lainnya kurang dirancang dengan baik)

35 *Kriteria objektif berasal dari instrument yang divalidasi untuk mengevaluasi kualitas penelitian. Termasuk 5-titik skala yang dikembangkan oleh Jadad et al, di mana skor di bawah 4 dianggap menunjukkan kualitas metodelogi yang lebih rendah. Kelas F Bukti ilmiah negatif yang kuat Statistik bukti negatif yang signifikan (yaitu kurangnya bukti manfaat) dari satu atau lebih percobaan yang berkualitas tinggi dengan kriteria yang objektif Kurangnya bukti ilmiahTidak dapat mengevaluasi manfaat dikarenakan kurangnya data yang tersedia

36 Strategi Pencarian  Pencarian data dapat diperoleh dengan melalui media elektronik seperti AMED, CANCERLIT, CINAHL, CISCOM, perpustakaan cochrone, EMBASE, HerMed, abstrak internasional farmasi, Medline, NARALERT

37 Referensi Schultz et al. 2004. Rational Phytotherapy. Herbal-Drug Interaction and Adverse Effect (an evidence-based quick reference guide) Heinrich et al. 2004. Fundamentals of Pharmacognosy and Phytothetapy Materia Medica Natural Standar Herbal Pahramcoteraphy A Mun’im & E Hanani, 2011. Fitoterapi Dasar. PT Dian Rakyat On-line journals