ARGEMONE MEXICANA From Plant to Phytomedicine From extract to Isolation of "active compounds"?
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ARGEMONE MEXICANA From Plant to Phytomedicine From extract to Isolation of “active compounds”?
Antimalarial compounds Quinine from the bark of Cinchona sp Rubiaceae, MT South America From 1600 to 1820 isolation of quinine Artemisinin from lhe eaves, Artemisia annua L. Asteraceae, MT China Plant used 2000 year before, 1972 isolation of Artemisinin
WHO, 2010 WHO Global Malaria Programme, Good procurement practices for artemisinin-based antimalarial medicines
Argemone mexicana STEP ONE: Survey "households" (2002) Retrospective epidemiological survey of 952 children with malaria (0-16 years) Finkolo (Sikasso). Argemone mexicana (Papaveraceae) and five other plants associated with good disease progression.
Argemone mexicana L. Papaveraceae
Pantropical grass (Mexico, India, Africa: Benin, Mali, Sudan)
characterized by thorny leaves ("blessed thistle Caribbean or
prickly poppy"), yellow flowers, yellow latex abundant.
Argemone mexicana • STEP TWO: Ethnobotanical Surveys (2003) Use of family A. mexicana (17.80%) by 79 Health healers including 9 women 118 recipes based antimalarial of 66 plants • Literature review, eight plants the least studied
Argemone mexicana • STEP THREE: preclinical studies (2003) Anti-plasmodial activity in vitro: Argemone mexicana, Securinega virosa, Spondias mombin and Opilia celtidifolia with IC50 between 1.00 and 4.01 micrograms / ml. Chloroquine (IC50 of 0.05 micrograms / ml). (Sangare, 2003, Diallo et al., 2005; Graz et al., 2005).
Argemone mexicana • STEP THREE: preclinical studies Toxicity Study Decoction oral 300mg/kg/jour/30 days No toxic effects on hematological and biochemical parameters (Sanogo et al., 2008). Safety of decoction
Argemone mexicana STEP FOUR: Ethno-Medical Evidence (2005) Observational clinical study dose / response Missidougou. Clinical and laboratory monitoring for 28 days in 84 patients treated for malaria with the TMP decoction of A. mexicana at different doses. Dose-dependent action. Adequate clinical response in 72.5% of patients with the best dose. 89% of adequate clinical responses in patients over 5 years.
Argemone mexicana STEP FIVE (2006): Randomized clinical study: for the treatment of uncomplicated malaria. Decoction of Argemone mexicana (200 patients) to ACTs (artesunate-amodiaquine) (100 patients) Before treatment, positive thick in 87% of patients diagnosed as malaria by the TMP. Clinical and laboratory monitoring for three months.
Argemone mexicana STEP FIVE (2006): Randomized clinical study: Results in both groups: On clinical signs of uncomplicated malaria, no statistically significant differences. Movement towards severe malaria
Argemone mexicana STEP SIX: phytomedicines (2009 to 2012) STEPS IN PROGRESS: Production and clinical trial of herbal tea (2010-2011) Promoting the use of SUMAFOURA TIEMOGO BENGALY (Mission Team Argemone November 2010) Production of the Tea (DMT 2011) Study on healthy volunteers and clinical trial (DMT INRSP - Mali Association Geneva - Aidemet Ong - MRTC) in progress.
Argemone mexicana
Isolation of “active compounds”
• For agricultural selection of best plants
• For standardisation
• For quality control
• What is an “active compound”?LC-MS analysis of Argemone decoction
15.93
370.15 15.93
100 370.15
100
95 Base Peak 95
90 Allocryptopine
90 85
80
75
85 70
80
65 Berberine
60 17.67
55
336.16
75 50
45
70 40
35
65 30
11.15
25 Protopine 17.17
297.04 15.28 354.21
60 20
12.47 18.68
15
14.01 354.13
Relative Abundance
10
55 17.67 317.17 317.17 348.13
5
336.16 0
50 11 12 13 14 15 16 17 18 19
45
40
35
30
25
11.15
20
297.04
3.01 33.97
15 29.63
250.47 15.28 26.42 282.05
10 354.13 415.03 341.28
3.94 18.68
9.64
276.05 348.13
5 314.13
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time (min)
7Argemone alkaloids - activity
P. falciparum* T. cruzi T. b. brucei Cytotoxicity**
IC50 (µg/mL)
protopine (A1) 0.32 >32.00 10.75 >32.00
allocryptopine (A2) 1.46 >32.00 10.49 >32.00
berberine (A3) 0.32 0.32 1.66 3.20
A4 8.58 7.85 >32.00 24.78
sanguinarine 7.02 7.42 >32.00 16.26
0.4
0.3
0.2
IAnalysis
Inhibition of β-hematin 0.1
formation 0
-0.1
-0.2 A2
-0.3 A1 A3
-0.4
*IC50 < 2.0 µg/mL: highly active
** On human fibroblasts (MRC-5). IC50 < 10 µg/mL: highly toxic6
Calculated concentrations of berberine, allocryptopine and
protopine in the decoction of A. mexicana leaves obtained by
QNMR
Previous study
160.0 AM-3
150
140.0
120.0 90
100.0
mg/L
80.0 92
60.0
20 90
40.0
20.0
0.0
23
Berberine
Allocryptopine
Protopine
6Argemone: FUTURE PROSPECTS
Diploma student Post-doc Senior research fellow
Metabolization studies Absorption studies Studies of analytical
In vitro In vitro conditions Clinical studies:
Human and rat microsome •Absorption studies using •LC/MS and NMR detection pharmacokinetics
studies Caco-2 cells conditions
•Microsomal incubation with •P-glycoprotein •Decoction quality control
individual alkaloids •Enzymatic inhibition during
(berberine, protopine, microsomal incubation
allocryptopine) and
combination of them
In vivo studies - SCID mice Identification of active compounds +
activity in the P. metabolites
falciparum animal model
Pure chemical Argemone
entities Of guaranteed quality
Public Health
Clinical studies
Studies
12Pharmacokinetic study Phase 1b clinical trial using Argemone mexicana in healthy adults infected or not infected with Plasmodium falciparum in Mali: pharmacokinetics and observational study. Experimental procedure: open clinical trial phase 1b
Pharmacokinetic study General Objective The main objective is to study the pharmacokinetics, pharmacodynamics and tolerability of the decoction of the aerial parts of Argemone mexicana (AM), administered in healthy volunteers tested according to the traditional in a comparative clinical study conducted in 2006 by DMT
Pharmacokinetic study Specific objectives • determine the terminal half-life of active compounds in the blood product • determine the kinetics of active compounds produced in the blood and urine • determine the AUC (Area Under the Curve), clearance and distribution volume of the active compounds in the blood product • to benchmark (between the volunteers, between plasma concentration and the concentration in erythrocytes) with the use of AM
Pharmacokinetic study Specific objectives • Identify adverse events associated with the use of AM • determine the parasite clearance time and parasite density (when it occurs) associated with the use of argemone • determine the parasitological failure rates associated with the taking of argemone • determine the rate of reinfection or recrudescence of parasites associated with the use of AM .
Pharmacokinetic study • Methodology • Healthy adult volunteers with / without asymptomatic malaria • Samples of blood at different time intervals after ingestion of A. mexicana decoction • Analysis of blood
Argemone mexicana STEPS in progress: Evaluation and Production of SYRUP SUMAFURA (2010 -2012) Production of a pilot batch of phytomedicine (2010) DMT project funded INRSP 2011 in progress: Evaluation of the effectiveness and safety of syrup. Industrial production test of syrup
Argemone mexicana SYRUP SUMAFURA 3rd prize at the National Exhibition of Inventions and technological innovations worth 500,000 CFA DISTRIBUTION OF THE SUM OF: 25% to TMP Mr TIEMOGO Bengaly 75% premium as motivational support staff of the DMT
SUMAFOURA TIEMOGO BENGALY
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