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TAFENOQUINE: A NOVEL PREVENTATIVE TREATMENT FOR MALARIA IN G-6-P-D DEFICIENT PATIENTS
Prepared for LEO Pharma
January 14, 2011
By M. Christian Armstrong, M.D. M.H.S.A.
Malaria G6PD Def.
Tafenoquine
Malaria
MalariaHalf of the global population at risk*
* http://www.cdc.gov/malaria/about/facts.html
Malaria
* http://www.cdc.gov/malaria/about/facts.html
Malaria
* http://www.cdc.gov/malaria/about/facts.html
Malaria
MalariaHalf of the global population at risk*
2008○ Up to 311 million cases*
○ Up to 1,003,000 deaths*
* http://www.cdc.gov/malaria/about/facts.html
Malaria
What is Malaria?A parasite infection*
○ Infects the blood stream
Flu-like symptoms*
○ High fever○ Chills/Shaking
Death*
○ 1 child <5 years old every 30 seconds**
* http://www.cdc.gov/malaria/about/facts.html** Butcher, G. A.; Sinden, R. E.; Curtis, C. Malaria: New ideas, old problems, new technologies. Parasitol. Today 2000, 16, 43–44.
Malaria Malaria Treatment
chloroquine atovaquone-proguanil (Malarone®)artemether-lumefantrine
(Coartem®)mefloquine (Lariam®) quininequinidinedoxycycline (used in combination
with quinine)clindamycin (used in combination
with quinine)primaquine
* http://www.cdc.gov/malaria/about/facts.html
Malaria G6PD Def.
G6PD Deficiency
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
MC enzyme deficiency worldwide Approximately 400 million people affected*
MC populations: African, Asian, Mediterranean, or Middle-
Eastern descent*
In the USA up to 10% black males are affected*
* Frank, J.E. (2005). Diagnosis and management of g6pd deficiency. American Family Physician, 72(7), 1277-1282.
G6PD Deficiency
What is G6PD?It is a disease state that causes acute
hemolysis (RBC’s break apart) when the patient has an infection, ingestion of fava beans, or exposure to an oxidative drug.*
* Frank, J.E. (2005). Diagnosis and management of g6pd deficiency. American Family Physician, 72(7), 1277-1282.
G6PD Deficiency
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency TreatmentAvoidance
○ Fava beans – Mediterranean Diet○ Infection – causes oxidative stress○ Oxidant Drugs – “AAA”
Antibiotics (sulfa drugs)AntipyreticsAntimalarials??? “AAA”
G6PD Deficiency
Inherited – X-linked, Recessive
G6PD Deficiency
G6PD Deficiency
Oxidative stress causes the RBC’s to break apart
Inherited – X-linked, Recessive Biochemistry
G6PD Deficiency
Biochemistry – summary
• G6PD
Reduces
• NADP+
• to• NADPH
Which is responsible for • Glutathione
Which fights
• Free radicals
Which damage blood cells
G6PD Deficiency
Why is the biochemistry important?Understand how the drugs cause the
oxidative stress. Remember “AAA”?
Antibiotics (sulfa drugs)AntipyreticsAntimalarials???
Antimalarials
G6PD Deficiency
Malaria Treatmentchloroquineatovaquone-proguanil (Malarone®)artemether-lumefantrine (Coartem®)mefloquine (Lariam®) quininequinidinedoxycycline (used in combination with quinine)clindamycin (used in combination with quinine)primaquine
“quin” Drugs
Malaria G6PD Def.
Tafenoquine
Tafenoquine
What is tafenoquine?An 8-aminoquinoline (8-AQ) antimalairal* Same family as pamaquine and primaquine*
Derivative of primaquine*
*Shiraki, H. (2011). Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives. Journal of Medicinal Chemistry, 54, 131-142.
Tafenoquine Problem with
Primaquine5-hydroxy-8-
aminoquinolines○ Semiquinoneimine
radical formation*
○ Iminoquinolione formation*
Derivatives formed○ Lost anitmalarial
activity*
○ Retained hemolytic toxicity*
*Shiraki, H. (2011). Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives. Journal of Medicinal Chemistry, 54, 131-142.
Tafenoquine vs. Primaquine Tafenoquine
Less toxicLonger Acting
○ Weekly dosingMore Potent
○ At least 10 times more potent than primaquine
PrimaquineMore toxicSorter Acting
○ Daily dosingLess potent
5-(m-trifluoromethylphenyl)
Tafenoquine vs. Primaquine
Tafenoquine
*Shiraki, H. (2011). Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives. Journal of Medicinal Chemistry, 54, 131-142.
Latest Research:Parent compounds of primaquine and
tafenoquine may be the active species*Metabolites are responsible for toxicity*Next round of research will study hemolytic
side effect in G6PD deficient condition*
Malaria G6PD Def.
Tafenoquine
?
