g6 pd presentation

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


Malaria

MalariaHalf of the global population at risk*

2008○ Up to 311 million cases*

○ Up to 1,003,000 deaths*


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


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*


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


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

?

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