G6 Pd Presentation
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Tafenoquine is a novel antimalarial drug being developed as a preventative treatment for malaria. It is in the same class as primaquine but is less toxic and longer acting, requiring only weekly dosing compared to primaquine's daily dosing. For patients with G6PD deficiency, an enzyme deficiency affecting 400 million people worldwide, tafenoquine's safety is still being evaluated as antimalarials in this class can cause hemolysis or breaking apart of red blood cells. The latest research indicates the parent compounds rather than metabolites may be responsible for toxicity, and further studies will explore tafenoquine's hemolytic effects in G6PD deficient patients.
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- 1. 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.
- 2. Tafenoquine Malaria G6PD Def.
- 3. Malaria Malaria Half of the global population at risk* * http://www.cdc.gov/malaria/about/facts.html
- 6. Malaria Malaria Half 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
- 7. 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.
- 8. Malaria Malaria Treatment chloroquine atovaquone-proguanil (Malarone®) artemether-lumefantrine (Coartem®) mefloquine (Lariam®) quinine quinidine doxycycline (used in combination with quinine) clindamycin (used in combination with quinine) primaquine * http://www.cdc.gov/malaria/about/facts.html
- 10. 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.
- 11. 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.
- 12. G6PD Deficiency Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Treatment Avoidance Fava beans – Mediterranean Diet Infection – causes oxidative stress Oxidant Drugs – “AAA” Antibiotics (sulfa drugs) Antipyretics Antimalarials??? “AAA”
- 13. G6PD Deficiency Inherited – X-linked, Recessive
- 14. G6PD Deficiency
- 15. G6PD Deficiency Oxidative stress causes the RBC’s to break apart Inherited – X-linked, Recessive Biochemistry
- 17. Glutathione
- 18. NADP+
- 19. to
- 20. NADPH
- 21. Free radicalsReduces Which fights
- 22. G6PD Deficiency Why is the biochemistry important? Understand how the drugs cause the oxidative stress. Remember “AAA”? Antibiotics (sulfa drugs) Antipyretics Antimalarials??? Antimalarials
- 23. G6PD Deficiency Malaria Treatment chloroquine atovaquone-proguanil (Malarone®) artemether-lumefantrine (Coartem®) mefloquine (Lariam®) quinine quinidine doxycycline (used in combination with quinine) clindamycin (used in combination with quinine) primaquine “quin” Drugs
- 24. Tafenoquine Malaria G6PD Def.
- 25. 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.
- 26. Tafenoquine Problem with Primaquine 5-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.
- 27. Tafenoquine vs. Primaquine Tafenoquine Less toxic Longer Acting Weekly dosing More Potent At least 10 times more potent than primaquine Primaquine More toxic Sorter Acting Daily dosing Less potent
- 28. 5-(m-trifluoromethylphenyl) Tafenoquine vs. Primaquine
- 29. 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* *Shiraki, H. (2011). Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives. Journal of Medicinal Chemistry, 54, 131-142.
- 30. Tafenoquine ? Malaria G6PD Def.
Editor's Notes
- What I am going to talk about today is two separate disease states that are often comorbid and one emerging treatment that provides treatment in an area that was previously difficult to treat. The first disease state is malaria. Which, according to the Center for Disease Control, potentially affects half of the worlds population. In 2008 alone, 190-311 million clinical episodes and 708k – 1.003 million deaths.
- What I am going to talk about today is two separate disease states that are often comorbid and one emerging treatment that provides treatment in an area that was previously difficult to treat. The first disease state is malaria. Which, according to the Center for Disease Control, potentially affects half of the worlds population. In 2008 alone, 190-311 million clinical episodes and 708k – 1.003 million deaths.
- What I am going to talk about today is two separate disease states that are often comorbid and one emerging treatment that provides treatment in an area that was previously difficult to treat. The first disease state is malaria. Which, according to the Center for Disease Control, potentially affects half of the worlds population. In 2008 alone, 190-311 million clinical episodes and 708k – 1.003 million deaths.
- What I am going to talk about today is two separate disease states that are often comorbid and one emerging treatment that provides treatment in an area that was previously difficult to treat. The first disease state is malaria. Which, according to the Center for Disease Control, potentially affects half of the worlds population. In 2008 alone, 190-311 million clinical episodes and 708k – 1.003 million deaths.
- Malaria is a parasite infection that is transmitted via mosquito bite which infects the blood stream. The parasite causes patients to get violently ill with flu-like symptoms. This condition, if left untreated can result in death.
- Typically if someone gets a malaria infection, there is a well established treatment protocol which includes the drugs in this list.
- The second disease state is called Glucose-6-Phosphate Dehydrogenase. G6PD Deficiency is a disease state where a vital enzyme is deficient in the body of those affected. It is actually the most common enzyme deficiency world wide affecting approximately 400 million people. The most commonly affected population groups are of African, Asian, Mediterranean, or Middle-Eastern descent.
- The second disease state is called Glucose-6-Phosphate Dehydrogenase. G6PD Deficiency is a disease state where a vital enzyme is deficient in the body of those affected. It is actually the most common enzyme deficiency world wide affecting approximately 400 million people. The most commonly affected population groups are of African, Asian, Mediterranean, or Middle-Eastern descent.
- As an enzyme deficiency state, there is no direct treatment for G6PD. The treatment of choice is avoidance. We treat these patients by having them avoid compounds that are likely to cause a reaction.
- This means that the typically only directly effects males.
- So, an effected father will transmit the disease to all of his daughters and none of his sons. Whereas, a carrier mother will transmit the disease to half of her children. Half of her daughter will be carriers and half of her sons will be directly affected with the condition.
- G6PD, under normal conditions, is responsible for the maintenance of Nicotinamide adenine dinucleotide phosphate (NADP+) and its conversation to NADPH. NADPH is responsible for regenerating glutathione and the removal of free radicals which cause damage to blood cells.Free radicals are molecules that are missing an electron. Generally, free radicals attack the nearest stable molecule, "stealing" its electron. When the "attacked" molecule loses its electron, it becomes a free radical itself, beginning a chain reaction. Once the process is started, it can cascade, finally resulting in the disruption of a living cell.Glutathione eliminates the free radical by donating the needed electron and converting the free radical into a more stable byproduct such as water (H2O).
- These are some of the drugs that are typically used for malaria treatment. However, they are either contraindicated in G6PD patients, high risk, possibly dose restricted, not indicated for prophylactic treatment. The biggest problem is the rapid spread of drug resistant malarial strains.
- Because GSH works to remove the oxidant stress which leads to cell damage, the lack of G6PD activity enhances the sensitivity of the red cells to the oxidant assault.7 It is generally believed that the metabolites of 8-AQ are the toxic species to erythrocytes, not parent compounds, at clinically relevant concentration. (Bolchoz, L. J. C.; Budinsky, R. A.; McMillan, D. C.; Jollow, D. J. Primaquine-induced Hemolytic Anemia: Formation and Hemotoxicity of the Arylhydroxylamine Metabolite 6-Methoxy-8-hydroxylaminoquinoline. J. Pharmacol. Exp. Ther. 2001, 297, 509–515. )In general, putative 5-hydroxy-8-aminoquinolines are thought to be responsible for the hemotoxic compounds.9-13 These metabolites are capable of forming semiquinoneimine radical and iminoquinolinone under physiological conditions, leading to the subsequent generation of hydrogen peroxide and oxidative stress in erythrocytes14 (Scheme 1). To avoid the quinoneimine metabolite formation and thus the hemolytic side effects, a series of derivatives of 2 were reported over the years.3b,15-17 However, the new derivatives of 2 either lost antimalarial activity or retained both activity and hemolytic toxicity.