MedGen

Tafenoquine is an antimalarial agent that was approved by the FDA in 2018 for preventing malaria (brand name Arakoda, 100 mg tablets), and for the radical cure of malaria (brand name Krintafel, 150 mg tablets) caused by Plasmodium vivax (P. vivax). Malaria is caused by the Plasmodium parasite, which infects mosquitos and is spread to humans when an infected mosquito bites a person. In 2018 the World Health Organization (WHO) estimated 228 million cases of malaria occurred worldwide. There are several clinical patterns of malaria that are caused by different species of the parasite. In P. vivax malaria, the parasite can lie dormant in the liver as hypnozoites, until it emerges weeks or months later, to cause a relapse of malaria. In combination with an antimalarial active against the blood stage parasites, tafenoquine provides a radical cure of P. vivax by targeting its dormant liver stage, thus preventing malaria relapse. Tafenoquine is the second drug of its kind (with hypnozoiticidal activity) to be approved by the FDA. The first was primaquine, approved in 1952. Because of its longer half-life, tafenoquine can be dosed less frequently than primaquine, which may improve compliance. For example, when used for the radical cure of P. vivax malaria, tafenoquine is taken as a single 300 mg dose (in uncomplicated cases, in persons aged 16 years and older). In contrast, primaquine radical cure is recommended to be given daily over 14 days, or higher doses over 7 days. Tafenoquine, like primaquine, should not be used in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In the case of tafenoquine, an individual with <70% of normal G6PD activity is considered deficient and should not take the drug. Worldwide, approximately 400 million people have a deficiency of the G6PD enzyme, but most are asymptomatic and do not know they are at risk. A lack of G6PD in red blood cells makes the cells susceptible to damage by oxidative stress. Usually, only low levels of oxidative stress occur naturally, and so the condition is undetected. However, certain drugs, which include tafenoquine and primaquine, are oxidizing agents. In people with G6PD deficiency, these drugs cause irreparable oxidative damage to the red blood cells, which are then rapidly destroyed (hemolysis). This can lead to a potentially life-threatening deficiency of mature red blood cells (hemolytic anemia). The FDA-approved drug label for tafenoquine states that testing for G6PD must be performed before starting tafenoquine therapy, and that all individuals should be monitored for signs of hemolysis. In addition, because of the risk of tafenoquine causing fetal harm in a woman pregnant with a fetus with G6PD deficiency, pregnancy testing is highly recommended in women of reproductive age. Consequently, tafenoquine therapy is contraindicated in adults when the G6PD status is either unknown, intermediate or deficient, namely, enzyme activity lower than 70%, in pregnancy, and in breastfeeding mothers when the infant’s G6PD status is either unknown or deficient. To date, no safety studies have been reported in children. [from Medical Genetics Summaries]

Hydroxychloroquine, which is closely related to chloroquine, can be used for the prevention and treatment of some forms of malaria and rheumatic conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Malaria is an infection caused by the Plasmodium parasite, transmitted via mosquito bites. Hydroxychloroquine sulfate is indicated for the prevention and treatment of uncomplicated malaria due to sensitive strains of Plasmodium falciparum (P. falciparum), Plasmodium vivax (P. vivax), Plasmodium malariae (P. malariae), Plasmodium ovale (P. ovale), and Plasmodium knowlesi (P. knowlesi) by both the US Centers for Disease Control (CDC) and World Health Organization (WHO). Resistance to chloroquine and hydroxychloroquine has been reported in Plasmodium species, thus hydroxychloroquine therapy is not recommended if the infection arose in a region with known resistance. Most P. falciparum infections are resistant to the 4-aminoquinolines (chloroquine and hydroxychloroquine), and as such these drugs are no longer used widely for these infections. Hydroxychloroquine must be co-administered with an 8-aminoquinoline compound for the radical cure of P. vivax or P. ovale infection to eliminate the hypnozoite forms of these parasites. Additionally, hydroxychloroquine is indicated for the treatment of many rheumatoid conditions in adults, including chronic discoid lupus erythematosus, systemic lupus erythematosus, as well as acute and chronic rheumatoid arthritis. Hydroxychloroquine has also been used in an off-label capacity for the management of Sjögren syndrome. Hydroxychloroquine accumulates in cellular acidic compartments such as the parasitic food vacuole and mammalian lysosomes, leading to alkalinization of these structures. Among antimalarial medications, hydroxychloroquine is less likely than other medicines to cause hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals; however, the U.S. FDA-approved drug label states there is still a risk of acute hemolytic anemia (AHA). In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) performed a systematic review of the available clinical literature and found low-to-no risk of AHA for individuals with G6PD deficiency who take hydroxychloroquine. It should be noted that G6PD deficiency has a range of severity; CPIC advises caution for all medications when used by an individual with a severe G6PD deficiency with chronic non-spherocytic hemolytic anemia (CNSHA). Regardless of G6PD phenotype, chronic use of hydroxychloroquine can cause irreversible retinal damage and regular visual exams are recommended by the FDA. [from Medical Genetics Summaries]

Primaquine is a potent antimalarial medication indicated for the radical cure of malaria caused by Plasmodium vivax (P. vivax) and Plasmodium ovale (P. ovale) species. Malaria is a blood borne infection caused by infection of Plasmodium parasites that is spread by mosquitos. The P. vivax and P. ovale species present a particular challenge to treat because the parasitic life cycle includes a dormant, liver-specific stage that is not susceptible to other antimalarial medications. Thus, primaquine is often used with other therapies such as chloroquine or artemisinin-based medicines that target the reproductive, active forms of the parasite. Primaquine is also used to prevent transmission of malaria caused by Plasmodium falciparum (P. falciparum) species. A single, low dose (SLD) of primaquine has gametocidal activity, which does not cure the individual but does provide malaria transmission control. Primaquine is a pro-drug that must be activated by the cytochrome P450 (CYP) enzyme system. Metabolism by the cytochrome P450 member 2D6 (CYP2D6) and cytochrome P450 nicotinamide adenine dinucleotide phosphate (NADPH):oxidoreductase (CPR) generates 2 hydroxylated active metabolites that generate hydrogen peroxide (H2O2). This causes significant oxidative stress to the malarial parasite and the host human cells. Individuals who are glucose-6-phosphate dehydrogenase (G6PD) deficient are particularly susceptible to oxidative stress and may experience acute hemolytic anemia (AHA). Before starting a course of primaquine, individuals should be tested for G6PD deficiency to ensure safe administration. According to the FDA-approved drug label, individuals with severe G6PD deficiency should not take primaquine. The World Health Organization (WHO) recommends that individuals with G6PD deficiency should be treated with a modified course of primaquine therapy. The recommended course for individuals with G6PD deficiency is a single dose once per week for 8 weeks, while the standard course is daily administration for 14 days. The Clinical Pharmacogenetics Implementation Consortium (CPIC) reports that the risk of adverse effects of primaquine therapy for G6PD-deficient individuals is dose-dependent, with the SLD regimen presenting the least risk. Primaquine is contraindicated during pregnancy and is not recommended for breastfeeding individuals when the G6PD status of the baby is unknown. Primaquine is not approved for individuals under 6 months of age. Individuals with acute illness that are prone to granulocytopenia or individuals taking another hemolytic medication are also contraindicated from taking primaquine. [from Medical Genetics Summaries]

An accumulation of free radical groups in the body inadequately neutralized by antioxidants, which creates a potentially unstable and damaging cellular environment linked to tissue damage. [from HPO]

Lymphangiosarcoma occurring in patients with chronic lymphedema often following radical mastectomy but also reported in relation to congenital and other secondary forms of chronic lymphedema. [from SNOMEDCT_US]

One of the most common malignant tumors afflicting men. The majority of carcinomas arise in the peripheral zone and a minority occur in the central or the transitional zone of the prostate gland. Grossly, prostatic carcinomas appear as ill-defined yellow areas of discoloration in the prostate gland lobes. Adenocarcinomas represent the overwhelming majority of prostatic carcinomas. Prostatic-specific antigen (PSA) serum test is widely used as a screening test for the early detection of prostatic carcinoma. Treatment options include radical prostatectomy, radiation therapy, androgen ablation and cryotherapy. Watchful waiting or surveillance alone is an option for older patients with low-grade or low-stage disease. [from NCI]

An adenocarcinoma arising from the prostate gland. It is one of the most common malignant tumors afflicting men. The majority of adenocarcinomas arise in the peripheral zone and a minority occurs in the central or the transitional zone of the prostate gland. Grading of prostatic adenocarcinoma predicts disease progression and correlates with survival. Several grading systems have been proposed, of which the Gleason system is the most commonly used. Gleason sums of 2 to 4 represent well-differentiated disease, 5 to 7 moderately differentiated disease and 8 to 10 poorly differentiated disease. Prostatic-specific antigen (PSA) serum test is widely used as a screening test for the early detection of prostatic adenocarcinoma. Treatment options include radical prostatectomy, radiation therapy, androgen ablation and cryotherapy. Watchful waiting or surveillance alone is an option for older patients with low-grade or low-stage disease. [from NCI]

A malignant germ cell neoplasm arising from the testis. It is composed of primitive epithelial cells arranged in solid, papillary, and glandular configurations. Most patients present with a testicular mass, which may be associated with pain. More than half of the patients have metastatic disease at diagnosis. The form of treatment following radical orchiectomy is stage dependent. [from NCI]

A carcinoma arising from the renal parenchyma. There is a strong correlation between cigarette smoking and the development of renal cell carcinoma. The clinical presentation includes : hematuria, flank pain and a palpable lumbar mass. A high percentage of renal cell carcinomas are diagnosed when an ultrasound is performed for other purposes. Radical nephrectomy is the standard intervention procedure. Renal cell carcinoma is generally considered to be resistant to radiation treatment and chemotherapy. [from MONDO]