Upload
others
View
11
Download
0
Embed Size (px)
Citation preview
Surash Ramanathan PhD
Centre For Drug Research (CDR)
Universiti Sains Malaysia
Kajian Ketum Sejak 2007 • Pencarian mengenai ‘ketum’ dalam PubMed. (1950 – 2017)
menghasilkan 172 kertas jurnal, dikategorikan di bawah disiplin
berikut:
• Kimia dan biologi - 59
• Farmakologi - 43
• Neurosains - 19
• Epidemiologi - 12
• Laporan kes – 19 (Ketum poisoning )
• Kertas ulasan - 20
• Pusat Penyelidikan Dadah dan Ubat-ubatan (USM)telah
menerbitkan sebanyak 50 kertas jurnal daripada jumlah
tersebut (172)
We lead
• Presentation outline
• Brief info on history of ketum
• Traditional usage/ Ketum Pharmacology
• Brief Phytochemistry
• Ketum toxicity
• Current updates on ketum studies
• Addressing the Gap
We lead
Introduction
Mitragyna speciosa (Korth.) locally known as Ketum or Biak (Malaysia) and Kratom or Krathom (Thailand).
• A psychotropic plant under Mitragyna genus, Rubiaceae (Coffee) family.
Native to Malaysia and Thailand, and widely cultivated in Southeast Asia (Indonesia).
• Possesses both stimulant- and opioid-like activities
Kratom leaves are long used as a general analgesic, substitute to opioids or a treatment for opioids withdrawal symptoms.
• Peter Willem Korthals (1807-
1892)
• Ahli botani Belanda
• Ditemui pada 1839
• Mitragyna speciosa (Korth)
PENEMUAN
Botani Asal Spesis
Afrika Barat Mitragyna inermis or M. Africana
Mitragyna ciliate
Mitragyna stipulosa
Afrika Timur Mitragyna rubrostipulate
India dan Asia Tenggara Mitragyna hirtusa
Mitragyna tubulosa
Mitragyna diversifolia (M. javanica)
Mitragyna speciosa
Mitragyna parvifolia
Mitragyna rotundifolia
M. diversifolia M. parvifolia
M. speciosa M. diversifolia dan M. parvifolia digunakan sebagai bahan
pengganti
Kurang berkesan seperti M. speciosa
Mitraginina hanya dijumpai dalam M. speciosa
Analisis molekul M. speciosa secara rDNA ITS (Internal
Transcribed Spacer)
Holmes, E.M. Some medical products
from the Straits settlements.
Pharmaceutical Journal
Vol. 54: 1095-1096 (1845)
(Beberapa produk perubatan dari Negeri-
negeri Selat)
Dictionary of the Economic Product: Isaac Henry
Burkill (Pengarah Botanic Gardens, Singapura)
(Nota mengenai rawatan candu)
Wray, L . Notes on the opium
Remedy. The Pharmaceutical
Journal Vol 2: 453 (1907)
We lead
Kegunaan Tradisional
• Rawatan tradisonal (Pelbagai penyakit: demam, cirit-birit, batuk, sakit ,ubat cacing, kronik,tonik,tenaga batin,
• Penagih dadah mangambil untuk mengawal genjala tarikan
• (Burkill, 1935; Jansen and Prast, 1988; Hassan et al., 2013)
Malaysia
• mengawal kesakitan (68% Pain management
• Kegelisahan dan kemurungun (66%)
U.S
Penggunaan telah lama (Dekad) di kalangan masyarakat
Air Ketum (Decoction)
Pill ekstrak, serbuk ketum, dibeli melalui vendor internet. Ketulenan ???
We lead
Ketum leaves
Consumption
• Freshly chewed
• Brewed and consumed as an herbal tea
• In the West, dried leaves are used with tea / coffee, or ingested as herbal decoction (Singh et al., 2014).
Traditional use
• Mild stimulant
• Pain relieving
• Antipyretic
• Antihypertensive
• Antidiarrheal
• Diabetic
Lacking scientific support
Produk tempatan
Red Malay Kratom $11.99
Green Malaysian
$14.99 - $179.99
Green Malay Kratom
$12.99
Red Vein Malay
Kratom Capsules
$24.99 - $89.99
We lead
Farmakologi Ketum
Air Ketum : daun ketum di rebus
Bahan aktif ketum : Mitragynine(alkaloid)
Terdapat >40 alkaloid .
Mitragynine di katakan bahan yang bertanggungjawab untuk kebanyakan kesan farmakologi ketum
Kesan farmakologi. Antidepresi , anxiolitik, analgesik (pain relief) , teraputik yang lain
Kesan farmalokogi alkaloid yang lain masih tidak boleh di pertikaikan , kajian terperinci sedang di jalankan.
Liabiliti ketagihan (Abuse liability of ketum ) masih tidak terbukti . Kajian preclinical pada peringkat awal
Kajian klinikal (Control clinical trial still lacking )
Kebanyakkan kajian lapangan yang di lakukan berasaskan “survey” & Self reporting studies on ketum users
We lead
Phytochemistry
More than 40 alkaloids were isolated from 1907 – 2014 (Brown et al., 2017).
Mitragynine is the most abundant pharmacologically active alkaloid -12% (Malaysia) to 66% (Thai) of the total alkaloid extract (Ponglux et al., 1994; Takayama et al., 1998)
7-hydroxymitragynine – a minor but more active alkaloid (< 2%) (Ponglux et al., 1994).
Other major alkaloids – paynantheine, speciogynine and speciociliatine (6 – 8% of alkaloid extract) (Takayama et al., 1998).
We lead
We lead
Adakah Ketum opiat?
• Ketum bukan opiate (natural product)
• Tidak mempunya struktur seperti morphine tetapi ia boleh mengikat pada reseptor opiate (morphine)
• Oleh itu, ia memberi kesan se-akan opiate tetapi kurang kesan sampingan
• Berpotensi dijadikan ‘opiate substitute therapy’.
Mitragynine (ketum) Morphine (opiate)
morfina
Mitragynine
Penindihan Mitragynine dan morfina
1: tapak anionik , 2 : tapak fenolik
Discovery Studio
Pandangan 1
Pandangan 2
We lead
Is Kratom an opiate?
Alkaloid class Non opiate Opiate
Targets • Opioid receptors (Mu, kappa) • Also bind to serotonin,
dopamine, adrenergic, adenosine receptors (Boyer et al.,2008; Kruegel et al., 2016)
• Mu opioid receptor (selective)
Mechanism of actions
• Partial MOR agonist • Activate MOR in a different
pathway –bias β-arrestin pathway
• Less side effects
• Full MOR agonist • Opiate induced side effects
such as respiratory depression, tolerance, dependence etc.
We lead
0
50
100
65.66 61.92 54.22
89.52 90.21
7
58.77 64.41
Affin
ity
CNS Receptor binding data of Mitragynine
(Boyer et al., 2008;
Kruguel et al., 2016)
respiratory depression Addiction
Lain-lain titik akhir opioid
• Penekanan pernafasan: Mitragynine (18.4 mg/kg),
codeine (2.5 mg/kg) dan morphine (30 mg/kg) diberikan
secara i.p. dalam model kucing
• Kadar pernafasan menjadi perlahan disebabkan oleh
codeine and morphine
• Tiada perubahan dalam kumpulan Mitragynine
• Tiada depresi dalam pernafasan di laporkan di
kalangan pengguna ketum di Malaysia .(Darsan et al
We lead
Ketum toxicity (Animal)
Preclinical Literature survey
In house laboratory studies
Mitragynine /ketum only toxic at higher dosages .
Mice - LD50 Mitragynine (477mg/kg)
Alkaloid extract - LD50(591mg/kg)
(Rats) :Subcronic (1,10,100 mg/kg) for 28 days (oral):
: No death recorded .
: Safety Dose dos 1-10 mg/kg
: Toxic Dose 100 mg/kg , Histopathological ( Liver
& Kidney)
Macko et al (1972): Reanmongkol et al (2007) Janchawee et al
(2007);Sabetghadam et al (2013) Harizal et al (2010) Kamal et al
(2012)
Potensi Penyalahgunaan
• Pengguna ketum secara berpanjangan (16-30 tahun) menyebabkan anoreksia, hilang berat badan, insomnia, pigmentasi kulit terutamanya di pipi, mulut kering, kencing kerap dan sembelit. (Suwanlert, 1995)
• Berbanding dengan gejala-gejala penarikan opiat, gejala-gejala penarikan ketum tidak berpanjangan & parah seperti opiat
• Pengguna ketum boleh menahan gejala penarikan ketum tanpa rawatan
• Gejala tarikan ketum biasanya berlarutan hingga 2-3 hari; hanya masalah ketidakselesaan seperti masalah susah tidur & kebimbangan berlarutan hingga 2-3 minggu.
(Singh et al., 2014)
KEBERGANTUNGAN: Pengambilan dadah secara
berterusan untuk mencegah atau mengurangkan gangguan
fizikal atau psikologi akibat sindrom tarikan
KETAGIHAN: Penggunaan dadah secara terpaksa dan tidak
terkawal walaupun kesan buruknya diketahui. Ciri-ciri
ketagihan termasuk keasyikan untuk memperolehi dadah,
penggunaan secara terpaksa, kecenderungan untuk
menagih semula, hilang kawalan dan penafian
Data sedia ada menunjukkan ketum menyebabkan
kebergantungan dan bukannya ketagihan
We lead
Clinical Trials on Ketum- Thailand
• A study by S.Trakulsirichai in Thailand- 2015
• The study was approved by Institutional Review Board of the Faculty of Medicine, Ramathibodi Hospital, Mahidol University.
• This was the first human study on the pharmacokinetic parameters from 10 chronic Ketum users.
• Ketum tea was prepared dosed to the subjects
• Pharmacokinetic parameters • T ½ : Long half life • linear pharmacokinetics. • Kratom would be a good candidate for
opioid substitute in patients who are addicted to these substances.
• As for the clinical and safety aspects, no serious adverse effect was found during the study.
• The median duration of abuse was 1.75 years.
We lead
Clinical Trials on Ketum- Malaysia
First controlled clinical trials
Number of participants: 26 Tested with: kratom and placebo decoctions Dosing: 1.6mg/kg
Randomized, double blind, placebo-controlled study.
PLASMA SAMPLES- blood samples for concentration of Mitragynine
Additional outcomes: • blinding procedures • CPT task unpleasantness • visual analogue scales • vital signs • objective and subjective
assessments of withdrawal symptoms
COLD PRESSOR TASK- Pain onset and tolerance
We lead
Clinical Trials on Ketum- Malaysia
In terms of safety,
No discomfort, unusual symptoms,
No signs of withdrawal symptoms were reported or observed.
Therapeutic Effect
Pain relief (Analgesic) was observed
Generalized conclusion : Need to repeat in bigger population , Healthy volunteers, different dosage
We lead
Ketum ubat atau mudarat
Benefit vs Risk (assessment )
We lead
Current assessment
• As of to date Ketum abuse properties is not proven .
• Two clinical trials with chronic Ketum users have been conducted with the approval of Human ethics committee (no adverse reactions were reported )
• Animal toxicity studies indicate that ketum is not toxic at lower doses
• No death was reported in south Asia region after prolong consumption of ketum by users
• Field studies on ketum users indicated daily intake of air ketum was in the range of 1.6 to 5.5 mg/kg (Malaysian study)
• Ketum poising reported in the west : probably due to adulterated or contamination product purchased via internet vendor . The subjects have medical history of chronic disease etc
Toksikologi (Manusia)
• Kes kematian yg dikaitkan dgn pengambilan ketum
disebabkan ianya diambil bersama dengan:
• dadah opiod (oksikodon, o- desmetiltramadol)
• benzodiazepina
• alkohol
• ubat-ubatan (amitriptilina, propilheksidrina, prometazina)
(Nelson et al., 2010, Mc Whirter & Morris, 2010; Kroonstad et al., 2011;
Sheleg & Collins, 2011)
We lead
Addressing the GAP
NIDA/FDA requirement for future preclinical &
clinical studies
• However the current publish data on ketum & Mitragynine preclinical (animal) toxicity were done empirically .
• Lacking GLP procedure
• Source of ketum ? Purity ? Stability ?
• Need the line of custody
• (Authentic source of ketum for future preclinical & clinical studies ) to establish the safety & efficacy of ketum
We lead
Future Studies to establish
Fasa perkembangan (Drug development)
Pre-Klinikal Klinikal
• Fasa Praklinikal (Animal : two mammalian species)
• Kajian toksik • Kajian ADME
(Penyerapan,sebaran, metabolisma, penyingkiran
• Dose permulaan yang sesuai &
selamat untuk kajian klinikal • Mengenal pasti kesan kesan
toksik yang perlu di awasi semasa kajian klinikal
• Fasa klinikal
• Health Human volunteers & Patients (Fasa Klinikal )
• Fasa 1 ( Healthy Human: Safety & Tolerance)
• Fasa 2 in Patients (Efficacy)
• Fasa 3 in larger Population(efficacy)
FDA : Investigational of New Drug/ IND
“Kita jangan haramkan pengambilan dan
eksploitasi kajian untuk ketum kerana kalau
diharamkan, kita akan kerugian kerana tumbuhan
bernilai tinggi ini tidak terdapat di banyak negara”
“Ketum adalah satu daripada biodiversiti,
tumbuhan di negara kita yang tinggi nilainya serta
mudah ditanam”
Datuk Seri Wan Junaidi Tuanku Jaafar
MENTERI Sumber Asli dan Alam Sekitar
Berita Harian 1 Ogos 2017
We lead
Thank you
We lead
We lead