Section VIII - Chemotherapy of Microbial Diseases doc

Section VII. Chemotherapy of Parasitic Infections Chapter 40. Drugs Used in the Chemotherapy of Protozoal Infections: Malaria Overview Malaria, caused by four species of Plasmodium, of which Plasmodium falciparum is the most dangerous, remains the world's most devastating human parasitic infection. This chapter deals with the properties and uses of important drugs used to treat and prevent this infection. Highly effective agents that act against asexual erythrocytic stages of malarial parasites responsible for clinical attacks include chloroquine, quinine, quinidine, mefloquine, atovaquone, and the artemisinin compounds. Less effective, slower-acting drugs in this category are proguanil, pyrimethamine, sulfonamides, sulfones, and the antimalarial antibiotics. Primaquine is the only drug used against latent tissue forms of Plasmodium vivax and Plasmodium ovale that cause relapsing infections. No single antimalarial agent has successfully controlled the spread of increasingly drug-resistant strains of P. falciparum. Instead, multidrug regimens are discussed as the optimal strategy to address this problem. Drugs Used in the Chemotherapy of Protozoal Infections: Malaria: Introduction Malaria remains the world's most devastating human parasitic infection, afflicting more than 500 million people and causing from 1.7 million to 2.5 million deaths each year (World Health Organization, 1997). Infection with Plasmodium falciparum causes much of this mortality, which preferentially affects children less than 5 years of age, pregnant women, and nonimmune individuals. Although mosquito-transmitted malaria virtually has been eliminated from North America, Europe, and Russia, its increasing prevalence in many parts of the tropics, especially sub- Saharan Africa, poses a major local health and economic burden and a serious risk to travelers from nonendemic areas. Practical, inexpensive, effective, and safe drugs, insecticides, and vaccines still are needed to combat malaria. In the 1950s, attempts to eradicate this scourge from most parts of the world failed, primarily because of the development of resistance to insecticides and antimalarial drugs. Since 1960, transmission of malaria has risen in most regions where the infection is endemic; chloroquine-resistant and multidrug-resistant strains of P. falciparum have spread, and the degree of drug resistance has increased. More recently, chloroquine-resistant strains of P. vivax also have been documented in Oceania. Nearly all antimalarial drugs were developed because of their action against asexual erythrocytic forms of malarial parasites that cause clinical illness. Efficacious, rapidly acting drugs in this category include chloroquine, quinine, quinidine, mefloquine, atovaquone, and the artemisinin compounds. Proguanil, pyrimethamine, sulfonamides, sulfones, and antimalarial antibiotics, such as the tetracyclines, are slower acting and less effective. Primaquine is the only drug used clinically to eradicate latent tissue forms that cause relapses of P. vivax and P. ovale infections. Due to the continuing spread of increasingly drug-resistant and multidrug-resistant strains of P. falciparum, no single agent successfully controls infections with these parasites. Instead, use of two or more antimalarial agents with complementary properties is recommended (seeWhite, 1997, 1999). The discovery of techniques for continuous maintenance of P. falciparum in vitro (Trager and Jensen, 1976) led to practical assays of susceptibility of these organisms to antimalarial drugs. This important advance, together with the imminent availability of the sequence of the entire 24.6- megabase P. falciparum genome (Su et al. , 1999 ), should reveal molecular targets for antimalarial drug action and resistance as well as for vaccine development. The biology of malarial infection must be appreciated in order to understand the actions and therapeutic uses of antimalarial drugs. Biology of Malarial Infection Nearly all human malaria is caused by four species of obligate intracellular protozoa of the genus Plasmodium. Although malaria can be transmitted by transfusion of infected blood and by sharing needles, human beings usually are infected by sporozoites injected by the bite of infected female mosquitoes (genus Anopheles). These parasite forms rapidly leave the circulation and localize in hepatocytes, where they transform, multiply, and develop into tissue schizonts (Figure 40–1). This primary asymptomatic tissue (preerythrocytic or exoerythrocytic) stage of infection lasts for 5 to 15 days, depending on the Plasmodium species. Tissue schizonts then rupture, each releasing thousands of merozoites that enter the circulation, invade erythrocytes, and initiate the erythrocytic stage of cyclic infection. Once the tissue schizonts burst in P. falciparum and Plasmodium malariae infections, no forms of the parasite remain in the liver. But in P. vivax and P. ovale infections, there persist tissue parasites that can produce relapses of erythrocytic infection months to years after the primary attack. The origin of such latent tissue forms is unclear. Once plasmodia enter the erythrocytic cycle, they cannot invade other tissues; thus, there is no tissue stage of infection for human malaria contracted by transfusion. In erythrocytes, most parasites undergo asexual development from young ring forms to trophozoites and finally to mature schizonts. Schizont- containing erythrocytes rupture, each releasing 6 to 24 merozoites, depending on the Plasmodium species. It is this process that produces febrile clinical attacks. The released merozoites invade more erythrocytes to continue the cycle, which proceeds until death of the host or modulation by drugs or acquired partial immunity. The periodicity of parasitemia and febrile clinical manifestations thus depend on the timing of schizogony of a generation of erythrocytic parasites. For P. falciparum, P. vivax, and P. ovale, it takes about 48 hours to complete this process. Synchronous rupture of infected erythrocytes and release of merozoites into the circulation lead to typical febrile attacks on days 1 and 3, hence the designation "tertian malaria." Actually the periodic febrile pattern is less regular in falciparum malaria due to a combination of asynchronous release of parasites and segregation of infected erythrocytes in the periphery. In P. malariae infection, schizogony requires about 72 hours, resulting in malarial attacks on days 1 and 4, or "quartan malaria." Figure 40–1. Life Cycle of Malaria. Some erythrocytic parasites differentiate into sexual forms known as gametocytes. After infected human blood is ingested by a female mosquito, exflagellation of the male gametocyte is followed by male gametogenesis and fertilization of the female gametocyte in the insect's gut. The resulting zygote, which develops as an oocyst in the gut wall, eventually gives rise to the infective sporozoite, which invades the salivary gland of the mosquito. The insect then can infect another human host by taking a blood meal. Each Plasmodium species causes a characteristic illness and shows distinguishing morphological features in blood smears: (1) P. falciparum causes malignant tertian malaria, the most dangerous form of human malaria. By invading erythrocytes of any age, this species can produce an overwhelming parasitemia, sequestration of infected erythrocytes in the peripheral microvasculature, hypoglycemia, hemolysis, and shock with multiorgan failure. Delay in treatment until after demonstration of parasitemia may lead to a fatal outcome even after the peripheral blood is free of parasites. If treated early, the infection usually responds with 48 hours to appropriate chemotherapy. If treatment is inadequate, recrudescence of infection may result from multiplication of parasites that persist in the blood. (2) P. vivax causes benign tertian malaria. Like the other benign malarias, it produces milder clinical attacks than does P. falciparum, because erythrocytes it infects are not sequestered in the peripheral microvasculature. P. vivax infection has a low mortality rate in untreated adults and is characterized by relapses caused by latent tissue forms. (3) P. ovale causes a rare malarial infection with a periodicity and relapses similar to those of P. vivax, but it is even milder and more readily cured. (4) P. malariae causes quartan malaria, an infection that is common in localized areas of the tropics. Clinical attacks may occur years after infection but are much rarer than after infection with P. vivax. Classification of Antimalarial Agents Antimalarials can be categorized by the stage of the parasite that they affect and the clinical indication for their use. Some drugs have more than one type of antimalarial activity. Drugs Used for Causal Prophylaxis These agents act on primary tissue forms of plasmodia within the liver, which are destined within less than a month to initiate the erythrocytic stage of infection. Invasion of erythrocytes and further transmission of infection are thereby prevented. Proguanil (formerly called chloroguanide) is the prototypic drug of this class, which has been extensively used for causal prophylaxis of falciparum malaria. Because of widespread drug resistance, however, it no longer provides reliable protection when used alone. Although primaquine also has such activity against P. falciparum, this potentially toxic drug is reserved for other clinical applications (seePrimaquine). Drugs Used to Prevent Relapse These compounds act on latent tissue forms of P. vivax and P. ovale remaining after the primary hepatic forms have been released into the circulation. Such latent tissue forms eventually mature, invade the circulation, and produce malarial attacks, i.e., relapsing malaria, months or years after the initial infection. Drugs active against latent tissue forms are used for terminal prophylaxis and for radical cure of relapsing malarial infections. For terminal prophylaxis, regimens with such a drug are initiated shortly before or after a person leaves an endemic area. To achieve radical cure, this type of drug is taken either during the long-term latent period of infection or during an acute attack. In the latter case, the agent is given together with an appropriate drug, usually chloroquine, to eradicate erythrocytic stages of P. vivax and P. ovale. Primaquine is the prototypical drug used to prevent relapse, the term reserved to specify recurring erythrocytic infection stemming from latent tissue plasmodia. Drugs (Blood Schizontocides) Used for Clinical and Suppressive Cure These agents act on asexual erythrocytic stages of malarial parasites to interrupt erythrocytic schizogony and thereby terminate clinical attacks (clinical cure). Such drugs also may produce suppressive cure, which refers to complete elimination of parasites from the body by continued therapy. Inadequate therapy with blood schizontocides may result in recrudescence of infection due to erythrocytic schizogony. With the notable exception of primaquine, virtually all antimalarial drugs used clinically were developed primarily for their activity against asexual parasite stages. These agents can be divided into two groups. The rapidly acting blood schizontocides include classical antimalarial alkaloids such as chloroquine, quinine, and their related derivatives quinidine and mefloquine. Atovaquone and the artemisinin antimalarial endoperoxides also are rapidly acting agents. Slower-acting, less effective blood schizontocides are exemplified by the antimalarial antifolate and antibiotic compounds. These drugs most commonly are used in conjunction with their more rapidly acting counterparts. Gametocytocides These agents act against sexual erythrocytic forms of plasmodia, thereby preventing transmission of malaria to mosquitoes. Chloroquine and quinine have gametocytocidal activity against P. vivax, P. ovale, and P. malariae, whereas primaquine displays especially potent activity against gametocytes of P. falciparum. However, antimalarials are not used clinically just for their gametocytocidal action. Sporontocides Such drugs ablate transmission of malaria by preventing or inhibiting formation of malarial oocysts and sporozoites in infected mosquitoes. Although chloroquine prevents normal plasmodial development within the mosquito, neither this nor other antimalarial agents are used clinically for this purpose. Regimens currently recommended for chemoprophylaxis in nonimmune individuals are given in Table 40–1, whereas regimens for treatment of malaria in nonimmune individuals are given in Table 40–2. Properties of individual agents are discussed in more detail in a separate section. Antimalarial Drugs Artemisinin and Derivatives History Artemisinin is a sesquiterpene lactone endoperoxide derived from the weed qing hao (Artemisia annua), also called sweet wormwood or annual wormwood. The Chinese have ascribed medicinal value to this plant for more than 2000 years (reviewed by Klayman, 1985). As early as 340 A.D., Ge Hong prescribed tea made from qing hao as a remedy for fevers, and in 1596 Li Shizhen recommended it to relieve the symptoms of malaria. By 1972, Chinese scientists had extracted and crystallized the major antimalarial ingredient, qinghaosu, now known as artemisinin. They synthesized three derivatives with greater antimalarial potency than artemisinin itself, namely dihydroartemisinin, a reduced product, artemether, an oil-soluble methyl ester, and artesunate, the water-soluble hemisuccinate salt of dihydroartemisinin. In 1979, the Chinese reported that artemisinin drugs were rapidly acting, effective, and safe for the treatment of patients with P. vivax or P. falciparum infections. More than two million people with malaria in China, Southeast Asia, and parts of Africa have since been treated with artemisinin or one of its semisynthetic derivatives without serious side effects or clinical evidence of drug resistance. These drugs are not yet available in the United States but are available in other countries. The antimalarial endoperoxides, especially when used in conjunction with a longer-acting blood schizontocide such as mefloquine, represent a major advance for the treatment of severe, multidrug-resistant falciparum malaria (Meshnick et al. , 1996; Newton and White, 1999). The chemical structures of artemisinin and some of its derivatives are shown below. Antiparasitic Activity The endoperoxide moiety is required for antimalarial activity of artemisinin compounds, whereas substitutions on the lactone carbonyl group markedly increase potency. These compounds act rapidly upon asexual erythrocytic stages of P. vivax and chloroquine-sensitive, chloroquine- resistant, and multidrug-resistant strains of P. falciparum. Their potency in vivo is 10- to 100-fold greater than that of other antimalarial drugs (White, 1997). They have gametocytocidal activity but do not affect either primary or latent tissue stage parasites. Thus, artemisinin compounds are not useful either for chemoprophylaxis or for preventing relapses of vivax malaria. The current model of artemisinin action involves two steps. First, intraparasitic heme iron of infected erythrocytes catalyzes cleavage of the endoperoxide bridge. This is followed by intramolecular rearrangement to produce carbon-centered radicals that covalently modify and damage specific malarial proteins (seeMeshnick et al. , 1996 ). Artemisinin and its derivatives also exhibit antiparasitic activity in vitro against several other protozoa including Leishmania major and Toxoplasma gondii and in vivo against schistosomes, but they are not used clinically to treat infections with these parasites. Absorption, Fate, and Excretion The disposition of the artemisinin compounds is incompletely understood due to difficulties with proper preservation of biological samples and reliable analytical assays. Indeed, few pharmacokinetic studies carried out in humans have been published (seeBarradell and Fitton, 1995; de Vries and Dien, 1996). Time to peak plasma levels for the artemisinin compounds varies from minutes to several hours, depending on the drug formulation and its route of administration. Likewise, the profile and extent of drug binding to plasma proteins is variable. Artemether and artesunate are both converted to dihydroartemisinin. Much of the hydrolysis of artesunate to dihydroartemisinin may occur presystemically. Artemisinin itself is metabolized to at least four inactive metabolites, although it is unclear whether dihydroartemisinin is formed as an intermediate (seede Vries and Dien, 1996). The antimalarial effect of artemisinin compounds results primarily from dihydroartemisinin, which rapidly disappears from plasma with a half-life of about 45 minutes. Little or none of the administered drugs or dihydroartemisinin is recovered in urine. Although artemisinin can induce CYP2C19 in humans (Svensson et al. , 1998 ), there is no evidence yet of clinically important drug interactions as a consequence. Therapeutic Uses Artemisinin compounds are the most rapidly acting, effective, and safe drugs for the treatment of severe malaria, including infections due to chloroquine- and multidrug-resistant strains of P. falciparum (seeWhite, 1999). They should not be used for prophylaxis of malaria or treatment of mild attacks (Meshnick et al. , 1996 ). Artemisinin drugs act more rapidly and produce less toxicity than the antimalarial alkaloids; moreover, they are just as effective against cerebral malaria. Although artemisinin and its derivatives can be used as single agents, infections often relapse unless therapy is continued for 5 to 7 days. A brief course of these agents given in tandem with a longer- acting quinoline or antibiotic antimalarial, e.g., mefloquine or doxycycline, usually prevents relapses and may delay the development of drug resistance (White, 1997, 1999). Although optimal dosage regimens have yet to be standardized, one strategy is to give a course of artesunate to reduce parasite burden rapidly, followed by one or two doses of mefloquine to eradicate the infection (White, 1999; Price et al. , 1999 ; seeTable 40–2). This approach has the advantage of reducing the frequency of side effects while retaining antimalarial efficacy. Individual endoperoxide antimalarials differ in formulation and clinical utility. Dihydroartemisinin can be given only orally. The oil-soluble artemether can be given only orally or intramuscularly. Artemisinin is effective when given orally or as a rectal suppository. Of the various artemisinin compounds, artesunate is perhaps the most versatile, because it is effective when given orally, intramuscularly, intravenously, or rectally. The intravenous formulation is particularly suitable for treating cerebral malaria, whereas suppositories are especially advantageous for treating patients with severe malaria in isolated areas. Toxicity and Contraindications Given for up to 7 days at therapeutic doses, the artemisinin endoperoxides appear to be surprisingly safe in human beings (seede Vries and Dien, 1996). Transient first-degree heart block, dose-related reversible decreases in reticulocyte and neutrophil counts, and temporary elevations of serum aspartate aminotransferase activity have been reported, but their clinical significance is not established. Brief episodes of drug-induced fever in human volunteers were noted in some studies but not in others. Because high doses of artemisinin drugs can produce neurotoxicity, prolongation of the QT interval, bone marrow depression, and fetal reabsorption in experimental animals, the possibility of long-term toxicity in human beings exists (seede Vries and Dien, 1996). But evidence thus far indicates that these effective drugs are remarkably safe for emergency treatment of severe, multidrug-resistant malaria, even in pregnant women (McGready et al. , 1998 ) and in children (Price et al. , 1999 ). Atovaquone History Based on the antiprotozoal activity of certain hydroxynaphthoquinones, atovaquone (MEPRON) was developed as a promising synthetic derivative with potent activity against Plasmodium species and opportunistic pathogens (Hudson et al. , 1991 ). Subsequent clinical studies revealed that atovaquone produced good responses but high rates of relapse in patients with uncomplicated falciparum malaria (Looareesuwan et al. , 1996 ). In contrast, use of proguanil with atovaquone evoked high cure rates with few relapses and minimal toxicity (Looareesuwan et al. , 1996 , 1999a). A fixed combination of atovaquone with proguanil (MALARONE) is now available in the United States (Looareesuwan et al. , 1999a ). Atovaquone also was developed for its activity against Pneumocystis carinii and T. gondii, pathogens that cause serious opportunistic infections in AIDS patients (Hughes et al. , 1990 ). After limited clinical trials, the United States Food and Drug Administration (FDA) approved this compound in 1992 for treatment of mild to moderate P. carinii pneumonia in patients intolerant to trimethoprim-sulfamethoxazole (seeChapter 44: Antimicrobial Agents: Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections). Atovaquone has some efficacy against human brain and eye infections with T. gondii and its use in combination with other antiparasitic agents is still being explored. Atovaquone has the chemical structure shown below: Antiparasitic Effects Atovaquone is a highly lipophilic analog of ubiquinone. In animal models and in vitro systems, it has potent activity against blood stages of plasmodia, tachyzoite and cyst forms of T. gondii, the fungus P. carinii, and Babesia species (Hughes et al. , 1990 ; Hudson et al. , 1991 ; Hughes and Oz, 1995). Atovaquone is highly potent against rodent malaria and P. falciparum, both in culture (IC 50 0.7 to 4.3 nM) and in Aotus monkeys (Hudson et al. , 1991 ). This compound selectively interferes with mitochondrial electron transport and related processes, such as ATP and pyrimidine biosynthesis in susceptible malaria parasites. Thus, atovaquone acts selectively at the cytochrome bc 1 complex of malaria mitochondria to inhibit electron transport and collapse the mitochondrial membrane potential (seeVaidya, 1998). Synergism between proguanil and atovaquone appears due to the capacity of proguanil as a biguanide to enhance the membrane-collapsing activity of atovaquone (Srivastava and Vaidya, 1999). Atovaquone likewise affects mitochondrial function in permeabilized T. gondii tachyzoites (Vercesi et al. , 1998 ). Absorption, Fate, and Excretion Because of its low water solubility, the bioavailability of atovaquone depends on formulation. A microfine suspension shows twofold greater oral bioavailability than do tablets. Drug absorption after a single oral dose is slow, erratic, and variable; increased by 2- to 3-fold by fatty food; and dose-limited above 750 mg. More than 99% of the drug is bound to plasma protein, so its concentration in cerebrospinal spinal fluid is less than 1% of that in plasma. Plasma level–time profiles often show a double peak, albeit with considerable variability; the first peak appears in 1 to 8 hours while the second occurs 1 to 4 days after a single dose. This pattern suggests an enterohepatic circulation, as does the long half-life, averaging 1.5 to 3 days. Atovaquone is not significantly metabolized by human beings. It is excreted in bile, and more than 94% of the drug is recovered unchanged in feces; only traces appear in the urine (Rolan et al. , 1997 ). Clearance of atovaquone may vary among different ethnic populations treated for falciparum malaria (Hussein et al. , 1997 ). Therapeutic Uses Atovaquone is used with a biguanide for treatment of malaria to obtain optimal clinical results and avoid emergence of drug-resistant plasmodial strains. A tablet containing a fixed dose of 250 mg of atovaquone and 100 mg of proguanil hydrochloride, taken orally, has been highly effective and safe in a 3-day regimen for treating mild to moderate attacks of chloroquine- and multidrug-resistant falciparum malaria (seeLooareesuwan et al. , 1999a and Table 40–2). The same regimen followed by primaquine produced excellent results in chloroquine-resistant vivax malaria (Looareesuwan et al. , 1999b ). To delay emergence of drug resistance, atovaquone plus proguanil is not recommended generally for prophylaxis of malaria, even though the combination is highly effective in adults and children. Such resistance develops readily when either drug is used alone. Opportunistic infections due to the fungus P. carinii or the protozoan T. gondii are especially serious threats to immunocompromised patients such as those with HIV infection and AIDS. Atovaquone remains an attractive alternative for prophylaxis and treatment of pulmonary P. carinii infection in patients who can take oral medication but cannot tolerate trimethoprim-sulfamethoxazole or parenteral pentamidine isethionate (seeChapters 44: Antimicrobial Agents: Sulfonamides, Trimethoprim- Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections and 49: Antimicrobial Agents: Antifungal Agents and the 9th edition of this textbook). T. gondii infections in these patients, especially cerebral lesions, have shown only limited dose-related positive responses to prolonged regimens of atovaquone (Torres et al. , 1997 ). Toxoplasma chorioretinitis in immunocompetent patients probably responds better to this drug (Pearson et al. , 1999 ). Atovaquone may have potential use in human infections due to Babesia species (Hughes and Oz, 1995). Toxicity and Contraindications Both in patients with acute falciparum malaria and in severely debilitated and immunocompromised patients such as those with AIDS, adverse effects directly attributable to atovaquone have been difficult to distinguish from manifestations of underlying disease. Atovaquone causes few side effects that require withdrawal of therapy. The most common reactions are rash, fever, vomiting, diarrhea, and headache. Vomiting and diarrhea may result in therapeutic failure due to decreased drug absorption. However, readministration of this drug within an hour of vomiting still may evoke a positive therapeutic response in patients with falciparum malaria (Looareesuwan et al. , 1999a ). Dose-related maculopapular rashes occur in about 20% of treated patients, but most are mild and do not progress even when therapy is continued. Caution would dictate, however, that atovaquone not be given to patients with histories of allergic skin reactions or possible allergy to the drug. Patients treated with atovaquone only occasionally exhibit abnormalities of serum transaminase and amylase levels. Atovaquone lacks proven efficacy against bacterial, viral, and most opportunistic infections that commonly afflict immunocompromised individuals; these infections must be treated separately. On balance, the drug appears to cause few acute adverse effects, but more clinical evaluation is needed, especially to detect possible rare, unusual, or long-term toxicity. An example of the last is the association of reversible vortex keratopathy with highly lipid-soluble antiparasitic drugs like atovaquone (Shah et al. , 1995 ). Precautions and Contraindications While atovaquone seems remarkably safe, the drug needs further evaluation in pediatric patients, older persons, pregnant women, and lactating mothers. Accordingly, the drug should be used with caution in these individuals. Routine tests for carcinogenicity, mutagenicity, and teratogenicity have been negative thus far, although therapeutic doses can cause maternal toxicity and interfere with normal fetal development in rabbits. Atovaquone may possibly compete with certain drugs for binding to plasma proteins, and therapy with rifampin, a potent inducer of cytochrome P450– mediated drug metabolism, can substantially reduce plasma levels of atovaquone, whereas plasma levels of rifampin are raised. Until it is known whether atovaquone induces or inhibits the hepatic metabolism or biliary uptake and elimination of other drugs, caution is advised in using the drug in patients with severe liver disease. Chloroquine and Congeners History Chloroquine (ARALEN) is one of a large series of 4-aminoquinolines investigated as part of the extensive cooperative program of antimalarial research in the United States during World War II. Beginning in 1943, thousands of these compounds were synthesized and tested for activity. Chloroquine eventually proved most promising and was released for field trial. When hostilities ceased, it was discovered that the compound had been synthesized and studied under the name of RESOCHIN by the Germans as early as 1934. Chemistry Chloroquine has the following chemical structure: Chloroquine closely resembles the obsolete 8-aminoquinoline antimalarials, pamaquine and pentaquine. It contains the same side chain as quinacrine but differs from this antimalarial in having a quinoline instead of an acridine nucleus and in lacking the methoxy moiety. The d, l, and dl forms of chloroquine have equal potency in duck malaria, but the d isomer is somewhat less toxic than the l isomer in mammals. A chlorine atom attached to position 7 of the quinoline ring confers the greatest antimalarial activity in both avian and human malarias. Research on the structure-activity relationships of chloroquine and related alkaloid compounds continues in an effort to find new, effective antimalarials with improved safety profiles that can be used successfully against chloroquine- and multidrug-resistant strains of P. falciparum (see below and, for example, Goldberg et al. , 1997 ; O'Neill et al. , 1998 ; Raynes, 1999). Amodiaquine is a congener of chloroquine that is no longer recommended for chemoprophylaxis of falciparum malaria because its use is associated with hepatic toxicity and agranulocytosis. Pyronaridine is a Mannich-base antimalarial that is structurally related to amodiaquine. This compound, developed by the Chinese in the 1970s, was shown to be well tolerated and effective against falciparum and vivax malarias. However, it cannot be recommended for routine use because [...]... elimination half-time of 6 hours (Fletcher et al., 1981) The apparent volume of distribution is several times that of total body water Primaquine is rapidly metabolized; only a small fraction of an administered dose is excreted as the parent drug Three identified oxidative metabolites of primaquine are 8-( 3-carboxyl-1methylpropylamino )-6 -methoxyquinoline, 5-hydroxy primaquine, and 5-hydroxy-6desmethylprimaquine... recommended Details of the history, pharmacology, and toxicology of halofantrine are presented in the 9th edition of this textbook Mefloquine History Mefloquine (LARIAM) is a product of the Malaria Research Program established in 1963 by the Walter Reed Institute for Medical Research to develop promising new compounds to combat emerging strains of drug-resistant P falciparum Of many 4-quinoline-methanols tested... mosquito fail to develop normally Mechanisms of Antimalarial Action and Resistance The active triazine metabolite of proguanil selectively inhibits the bifunctional dihydrofolate reductase-thymidylate synthetase of sensitive plasmodia, causing inhibition of DNA synthesis and depletion of folate cofactors This mechanism accounts for the slow antimalarial action of the antifolate biguanides compared to the... pyrimethamine and often in addition to quinine to treat chloroquine-resistant falciparum malaria, especially in parts of Africa The tetracyclines are slow-acting blood schizontocides that are used alone for short-term prophylaxis and along with quinine for the treatment of malaria due to multidrug-resistant strains of P falciparum Sulfonamides and Sulfones The sulfonamides and sulfones are slow-acting blood... contraindicated, travelers must resort to less-effective regimens In certain parts of Africa south of the Sahara, a combination of proguanil plus chloroquine is a common alternative for prophylaxis of chloroquine-resistant falciparum malaria In areas where chloroquine-resistant P falciparum is endemic, pyrimethamine-sulfadoxine is no longer recommended for prophylaxis because of potential drug toxicity Instead,... periods in areas where these infections are endemic (seeTable 40–1); prophylactic use of mefloquine for long-term residents of these regions should be avoided to prevent the selection of mefloquine-resistant parasites Mefloquine and halofantrine are currently the only agents capable of ensuring suppression and cure of infections with multidrugresistant P falciparum However, both medications can be given... existence of a chloroquine transporter (Sanchez et al., 1997) was supported by an elegant study indicating that chloroquine resistance in a P falciparum gene cross- mapped to a 36-kb segment of chromosome 7 (Su et al., 1997) This segment contains cg2, a gene that encodes a 330,000-dalton protein with complex polymorphisms, a set of which was associated with the chloroquine-resistant phenotype in 20 of 21... with a variety of different agents It should not be given with mefloquine because of increased risk of seizures Most importantly, this antimalarial opposes the action of anticonvulsants and increases the risk of ventricular arrhythmias from coadministration with amiodarone or halofantrine By increasing plasma levels of digoxin and cyclosporine, chloroquine also can increase the risk of toxicity from... plasma levels of quinine reach a maximum in 3 to 8 hours and, after distributing into an apparent volume of about 1.5 liters per kg in healthy individuals, decline with a half-life of about 11 hours after termination of therapy As reviewed by Krishna and White (1996), the pharmacokinetics of quinine change according to the severity of malarial infection Values for both the apparent volume of distribution... inhibition of two steps in an essential metabolic pathway (seeChapter 44: Antimicrobial Agents: Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections) The two steps involved are the utilization of p-aminobenzoic acid for the synthesis of dihydropteroic acid, which is catalyzed by dihydropteroate synthase and inhibited by sulfonamides, and the reduction of dihydrofolate . erythrocytic stages of P. vivax and chloroquine-sensitive, chloroquine- resistant, and multidrug-resistant strains of P. falciparum. Their potency in vivo is 1 0- to 100-fold greater than that of other. Section VII. Chemotherapy of Parasitic Infections Chapter 40. Drugs Used in the Chemotherapy of Protozoal Infections: Malaria Overview Malaria, caused by four species of Plasmodium, of which. chloroquine-resistant and multidrug-resistant strains of P. falciparum have spread, and the degree of drug resistance has increased. More recently, chloroquine-resistant strains of P. vivax