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  3. Section VIII - Chemotherapy of Microbial Diseases

Section VIII - Chemotherapy of Microbial Diseases

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. Sectio

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  1. 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
  2. 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.
  3. 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
  4. 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
  5. 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.
  6. 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
  7. 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
  8. (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 (IC50 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 bc1 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
  9. 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
  10. 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
  11. of a lack of standardized dosage regimens and because its possible long-term toxicity has yet to be adequately evaluated (Naisbitt et al., 1998). Hydroxychloroquine (PLAQUENIL), in which one of the N-ethyl substituents of chloroquine is -hydroxylated, is essentially equivalent to chloroquine against falciparum malaria. This analog is preferred over chloroquine for treatment of mild rheumatoid arthritis and lupus erythematosus because, given in the high doses required, it may cause less ocular toxicity than chloroquine would (Easterbrook, 1999). Pharmacological Effects Antimalarial Actions Chloroquine is highly effective against erythrocytic forms of P. vivax, P. ovale, P. malariae, and chloroquine-sensitive strains of P. falciparum. It exerts activity against gametocytes of the first three plasmodial species but not against those of P. falciparum. The drug has no activity against latent tissue forms of P. vivax or P. ovale and thus cannot cure infections with these species. Other Effects Chloroquine or its analogs are used for therapy of conditions other than malaria. Their use to treat hepatic amebiasis is described in Chapter 41: Drugs Used in the Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections. Chloroquine and hydroxychloroquine have been used as secondary drugs to treat a variety of chronic diseases, because both alkaloids concentrate in lysosomes and have antiinflammatory properties. Thus, high doses of these compounds, often together with other agents, have clinical efficacy in rheumatoid arthritis, systemic lupus erythematosus, discoid lupus, sarcoidosis, and photosensitivity diseases such as porphyria cutanea tarda and severe polymorphous light eruption (Danning and Boumpas, 1998; Fritsch et al., 1998; Baltzan et al., 1999). Mechanisms of Antimalarial Action of and Resistance to Chloroquine and Other Antimalarial Quinolines Asexual malaria parasites flourish in host erythrocytes by digesting hemoglobin in their acidic food vacuoles, a process that generates free radicals and heme (ferriprotoporphyrin IX) as highly reactive by-products. After nucleation aided by histidine-rich proteins and perhaps by lipids, heme polymerizes into an insoluble unreactive malarial pigment termed hemozoin. Quinoline blood schizontocides that behave as weak bases concentrate in food vacuoles of susceptible plasmodia, where they increase pH, inhibit the peroxidative activity of heme, and disrupt its nonenzymatic polymerization to hemozoin. Failure to inactivate heme then kills the parasites via oxidative damage to membranes, digestive proteases, and possibly other critical biomolecules (reviewed by Foley and Tilley, 1998). Of possible mechanisms for the action of the malarial quinolines, inhibition of heme polymerization appears crucial. Recent kinetic studies indicate that radiolabeled chloroquine, quinidine, and mefloquine bind first to heme and then prevent further heme polymerization by incorporating as heme-quinoline complexes into growing heme polymer chains. This unifying model also may apply to amodiaquine, quinacrine, and quinine but not to primaquine (Sullivan et al., 1996; Mungthin et al., 1998). Whether resulting accumulation of heme, heme-quinoline complexes, or both suffices to kill the parasites or other actions of the antimalarial quinolines are required is unknown (Ginsburg et al., 1998; Bray et al., 1998; Loria et al., 1999). Intrinsic resistance of erythrocytic asexual forms of P. falciparum to antimalarial quinolines, especially chloroquine, has been slow to develop but is now common worldwide, particularly in
  12. areas of extensive antimalarial drug use (Figure 40–2). Chloroquine resistance is emphasized here even though resistance mechanisms probably differ between antimalarial quinoline classes (see below). More than 20 years ago, Fitch and coworkers noted that chloroquine-sensitive falciparum parasites concentrated the drug to higher levels than did chloroquine-resistant organisms ( Fitch et al., 1979). Reasons for the relatively reduced levels of chloroquine in food vacuoles of chloroquine- resistant parasites have yet to be completely clarified. These could include differences in plasmodial uptake and transport of chloroquine to food vacuoles as well as differences in vacuolar influx, efflux, and trapping of drug (Goldberg et al., 1997; Bray et al., 1998; Foley and Tilley, 1998). Figure 40–2. Distribution of Malaria and Chloroquine-Resistant Plasmodium Falciparum, 1993. Source: Centers for Disease Control and Prevention. Chloroquine export initially attracted attention because verapamil, an inhibitor of P-glycoprotein– mediated drug efflux by multidrug-resistant (MDR) tumor cells, enhanced chloroquine efflux and partially restored susceptibility of resistant P. falciparum to this drug (seeFoley and Tilley, 1998). Indeed, two homologues of mdr genes, pfmdr1 and pfmdr2, were later identified in P. falciparum (Wilson et al., 1989; Foote et al., 1989). But neither gene was linked to chloroquine resistance in genetic studies (Wellems et al., 1990). One, pfmdr1, encodes a P-glycoprotein–like protein, Pgh1, which, when overexpressed, may even confer relative sensitivity to chloroquine but resistance to antimalarial aminoalcohols such as mefloquine, halofantrine, and quinine (Cowman et al., 1994). Moreover, field studies failed to link chloroquine resistance to alterations in pfmdr1 (von Seidlein et al., 1997; Póvoa et al., 1998; Zalis et al., 1998), and inhibitors of P-glycoprotein–mediated transport when given with chloroquine have not proven clinically effective in treating chloroquine- resistant falciparum malaria. Thus, based on evidence accumulated from both laboratory strains and clinical isolates, resistance to chloroquine, mefloquine/halofantrine, and quinine probably involves at least three nonidentical mechanisms (seeZalis et al., 1998; Reed et al., 2000). More recently, the proposed 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-
  13. 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 progeny examined; the finding of one chloroquine-sensitive strain with the same set of polymorphisms indicated that this set was necessary but not sufficient to confer chloroquine resistance. The same genetic study supported clinical evidence that South American and Asian/African P. falciparum have separate origins of chloroquine resistance. The CG2 protein (the product of cg2) was located both at the parasite periphery and in association with hemozoin in the food vacuoles, consistent with a role in chloroquine transport (Su et al., 1997). Further studies confirmed an incomplete but positive association of cg2 polymorphisms with chloroquine resistance in clinical isolates from travelers returning from endemic regions (Durand et al., 1999). Indeed, chemical probes to identify CG2 already may have been identified (Goldberg et al., 1997). In summary, resistance to the antimalarial quinolines probably involves multiple mechanisms under complex multigenic control. Absorption, Fate, and Excretion Chloroquine is well absorbed from the gastrointestinal tract and rapidly from intramuscular and subcutaneous sites. The drug distributes relatively slowly into a very large apparent volume (over 100 liters/kg; seeKrishna and White, 1996). This is due to extensive sequestration of chloroquine in tissues, particularly liver, spleen, kidney, lung, melanin-containing tissues, and, to a lesser extent, brain and spinal cord. Chloroquine binds moderately (60%) to plasma proteins and undergoes appreciable biotransformation via the hepatic cytochrome P450 system to two active metabolites, desethylchloroquine and bisdesethylchloroquine (seeDucharme and Farinotti, 1996). These metabolites may reach concentrations in plasma 40% and 10% of that of chloroquine, respectively. The S(+) enantiomer of chloroquine exhibits both greater binding to plasma proteins and a greater metabolic clearance than the R(–) enantiomer (seeKrishna and White, 1996). The renal clearance of chloroquine is about half of its total systemic clearance. Unchanged chloroquine and its major metabolite account for more than 50% and 25% of the urinary drug products, respectively, and the renal excretion of both compounds is increased by acidification of the urine. Both in adults and children, chloroquine exhibits complex pharmacokinetics such that plasma levels of the drug shortly after dosing are determined primarily by the rate of distribution rather than elimination (seeKrishna and White, 1996). Because of extensive tissue binding, a loading dose is required to achieve effective concentrations in plasma. After parenteral administration, rapid entry together with slow exit of chloroquine from a small central compartment can result in transiently high and potentially lethal concentrations of the drug in plasma. Hence, chloroquine is given either slowly by constant intravenous infusion or in small divided doses by the subcutaneous or intramuscular routes (Foley and Tilley, 1998). Chloroquine is safer when given orally because the rates of absorption and distribution are more closely matched; peak plasma levels are achieved in about 3 to 5 hours after dosing by this route. The half-life of chloroquine increases from a few days to weeks as plasma levels decline, reflecting the transition from slow distribution to even slower elimination from extensive tissue stores. The terminal half-life ranges from 30 to 60 days, and traces of the drug can be found in the urine for years after a therapeutic regimen. Therapeutic Uses Chloroquine is the most versatile antimalarial drug available, but its usefulness has declined in those parts of the world where strains of P. falciparum have emerged that are relatively or absolutely resistant to its action. The compound is superior to quinine in that it is more potent and less toxic, and it need be given only once weekly as a suppressive agent. Chloroquine has neither
  14. prophylactic nor radical curative value in human P. vivax or P. ovale malarias. However, except in Oceania and other areas where relatively resistant strains of P. vivax are reported (Newton and White, 1999), chloroquine is very effective in terminating or suppressing acute attacks of malaria caused by these plasmodial species. Relapses of vivax malaria may occur after chloroquine is discontinued, but intervals between their appearance are prolonged. Primaquine can either be given with chloroquine to eradicate this infection or reserved for use until after a patient leaves an endemic area. Chloroquine is highly effective for the prophylaxis and cure of malarias due to P. malariae and sensitive strains of P. falciparum that still exist in limited geographic areas (Figure 40–2). The drug rapidly controls the clinical symptoms and parasitemia of acute malarial attacks. Most patients become completely afebrile within 24 to 48 hours after receiving therapeutic doses, and thick smears of peripheral blood generally are negative by 48 to 72 hours. If patients fail to respond during the second day of chloroquine therapy, resistant strains of P. falciparum should be suspected and therapy instituted with quinine or another rapidly acting blood schizontocide. Although chloroquine can be given safely by parenteral routes to comatose or vomiting patients until the drug can be taken orally, quinidine gluconate usually is given. In comatose children, chloroquine is well absorbed and effective when given through a nasogastric tube. Tables 40–1 and 40–2 provide information about recommended prophylactic and therapeutic dosage regimens involving the use of chloroquine. These regimens are subject to modification according to clinical judgment and geographic patterns of chloroquine resistance. For example, persons living in areas of high endemicity often develop partial resistance to malaria and may require little or no chemotherapy. Toxicity and Side Effects Taken in proper doses, chloroquine is an extraordinarily safe drug. Acute chloroquine toxicity is most frequently encountered when therapeutic or high doses are administered too rapidly by parenteral routes (see above). Toxic manifestations relate primarily to the cardiovascular and central nervous systems. Cardiovascular effects include hypotension, vasodilation, suppressed myocardial function, cardiac arrhythmias, and eventual cardiac arrest. Confusion, convulsions, and coma indicate central nervous system dysfunction. Chloroquine doses of more than 5 g given parenterally usually are fatal. Prompt treatment with mechanical ventilation, epinephrine, and diazepam may be lifesaving. Doses of chloroquine used for oral therapy of the acute malarial attack may cause gastrointestinal upset, headache, visual disturbances, and urticaria. Pruritus also occurs, most commonly among dark-skinned persons. Prolonged medication with suppressive doses occasionally causes side effects such as headache, blurring of vision, diplopia, confusion, convulsions, lichenoid skin eruptions, bleaching of hair, widening of the QRS interval, and T-wave abnormalities. These complications usually disappear soon after the drug is withheld. Rare instances of hemolysis and blood dyscrasias have been reported. Chloroquine may cause discoloration of nail beds and mucous membranes. Chloroquine can interfere with the immunogenicity of certain vaccines (Brachman et al., 1992; Horowitz and Carbonaro, 1992; Pappaioanou et al., 1986). High daily doses (>250 mg) of chloroquine or hydroxychloroquine used for treatment of diseases other than malaria can result in irreversible retinopathy and ototoxicity. Retinopathy presumably is related to drug accumulation in melanin-rich tissues and can be avoided if the daily dose is 250 mg or less (seeRennie, 1993). Prolonged therapy with high doses of either 4-aminoquinoline also can cause toxic myopathy, cardiopathy, and peripheral neuropathy; these reactions improve if the drug is promptly withdrawn (Estes et al., 1987). Rarely, neuropsychiatric disturbances, including suicide, may be related to overdose.
  15. Precautions and Contraindications This topic has been briefly reviewed by Griffin (1999). Chloroquine is not recommended for treating individuals with epilepsy or myasthenia gravis. The drug should be used cautiously if at all in the presence of hepatic disease or severe gastrointestinal, neurological, or blood disorders. If such disorders occur during the course of therapy, the drug should be discontinued. Chloroquine can cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency (see"Primaquine," below). Concomitant use of gold or phenylbutazone with chloroquine should be avoided because of the tendency of all three agents to produce dermatitis. Chloroquine should not be prescribed for patients with psoriasis or other exfoliative skin conditions because it causes severe reactions. Chloroquine interacts 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 these agents. For patients receiving long-term, high-dose therapy, ophthalmological and neurological evaluation is recommended every 3 to 6 months. Diaminopyrimidines History Based on their ability to antagonize folic and folinic acids in supporting the growth of Lactobacillus casei, a number of diaminopyrimidines were tested for inhibitory activity against other pathogenic organisms. Several 2,4-diaminopyrimidines, including pyrimethamine (DARAPRIM) and the antibacterial agent trimethoprim, exhibited significant antimalarial activity in animal models. Pyrimethamine was later found to be especially effective against plasmodia infecting human beings (seeSymposium, 1952). The antifolate combination (FANSIDAR) of pyrimethamine and sulfadoxine, a long-acting sulfonamide, has been used extensively for prophylaxis and suppression of human malarias, especially those caused by chloroquine-resistant strains of P. falciparum. Resistance to this formulation rapidly developed in Indochina and is now widespread except in parts of Africa, where the drug combination is used primarily by indigenous populations to suppress attacks of chloroquine-resistant falciparum malaria. It is no longer recommended for long-term prophylaxis because of the risk of toxicity (see below). Pyrimethamine has the following chemical structure: Antiprotozoal Effects Antimalarial Actions Pyrimethamine is a slow-acting blood schizontocide with antimalarial effects in vivo similar to those of proguanil (see below). However, pyrimethamine has greater antimalarial potency because it acts directly on malarial parasites, and its half-life is much longer than that of cycloguanil, the active metabolite of proguanil. Unlike proguanil, pyrimethamine does not show marked efficacy
  16. against hepatic forms of P. falciparum. At therapeutic doses, pyrimethamine fails to eradicate latent tissue forms of P. vivax or gametocytes of any plasmodial species. The antimalarial effects of both pyrimethamine and proguanil have been reviewed by Davey (1963) and by Hill (1963). Action against Other Protozoa High doses of pyrimethamine given concurrently with sulfadiazine is the preferred therapy for toxoplasmosis, an infection with Toxoplasma gondii that can be particularly severe in infants and immunosuppressed individuals (seeChapter 41: Drugs Used in the Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections). Mechanisms of Antimalarial Action and Resistance In an elegant series of investigations, the 2,4-diaminopyrimidines were shown to act by inhibiting dihydrofolate reductase of plasmodia at concentrations far lower than those required to produce comparable inhibition of the mammalian enzymes (Ferone et al., 1969). Plasmodial dihydrofolate reductase, unlike its mammalian counterparts, possesses both dihydrofolate reductase and thymidylate synthetase activities. Synergism between pyrimethamine and the sulfonamides or sulfones is explained by 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 to tetrahydrofolate, which is catalyzed by dihydrofolate reductase and inhibited by pyrimethamine. Inhibition by antifolates is manifested late in the life cycle of malarial parasites by failure of nuclear division at the time of schizont formation in erythrocytes and liver. This mechanism is consistent with the slow onset of action of the antifolate as compared with the quinoline antimalarials. However, resistance to pyrimethamine does develop in regions of prolonged or extensive drug use. Dihydrofolate reductase–thymidylate synthetase genes have been cloned and sequenced in strains of P. falciparum that are either sensitive or resistant to pyrimethamine. Several different mutations have been identified that produce single amino acid changes linked to pyrimethamine resistance; these changes are thought to decrease the binding affinity of pyrimethamine for its active site on the dihydrofolate reductase moiety of the parasite enzyme. The primary change associated with pyrimethamine resistance is a substitution of asparagine for serine at position 108 (S108N). Secondary mutations associated with increasing levels of resistance result from amino acid substitutions at Arg50, Ile51, Arg59, and Leu164; of these, the Leu164 change most markedly enhances pyrimethamine resistance when associated with the primary S108N mutation. These and other amino acid changes in various combinations also may contribute to pyrimethamine resistance. However, the pattern of amino acid substitutions differs from that observed for resistance to cycloguanil, even though cross resistance can occur between these structurally related compounds that target plasmodial dihydrofolate reductase (see"Proguanil"; Cowman, 1998; Cortese and Plowe, 1998). Absorption, Fate, and Distribution After oral administration pyrimethamine is slowly but completely absorbed; it reaches peak plasma levels in about 4 to 6 hours. The compound binds to plasma proteins and accumulates mainly in kidneys, lungs, liver, and spleen. It is eliminated slowly with a half-life in plasma of about 80 to 95 hours. Concentrations that are suppressive for responsive plasmodial strains remain in the blood for about 2 weeks, but these are lower in patients with malaria (Winstanley et al., 1992). Several
  17. metabolites of pyrimethamine appear in the urine, but their identities and antimalarial properties have not been fully characterized. Pyrimethamine also is excreted in the milk of nursing mothers. Therapeutic Uses Pyrimethamine is not a first-line antimalarial. The drug is virtually always given with either a sulfonamide or sulfone to enhance its antifolate activity, but it still acts slowly relative to the quinoline blood schizontocides, and its prolonged elimination encourages the selection of resistant parasites. The use of pyrimethamine should be restricted to the suppressive treatment of chloroquine-resistant falciparum malaria in areas, e.g., parts of Africa, where resistance to antifolates has not yet fully developed. Travelers to these areas are instructed to carry a treatment dose of pyrimethamine–sulfadoxine to take in case of a presumed malarial illness. Medical attention should be sought as soon as possible thereafter. Pyrimethamine together with a short- acting sulfonamide such as sulfadiazine also may be used as an adjunct to quinine to treat an acute malarial attack. Dosage regimens for both of these indications are given in Tables 40–1 and 40–2. Pyrimethamine–sulfadoxine is no longer recommended for prophylaxis because of toxicity due to the accompanying sulfonamide (see below). The combination has been used with mefloquine for prophylaxis and treatment of multidrug-resistant falciparum malaria, but the regimens employed risked greater toxicity and offered little advantage over the use of mefloquine alone (seePalmer et al., 1993). High doses of pyrimethamine plus sulfadiazine is the treatment of choice for infections with Toxoplasma gondii in immunocompromised adults; if such patients are left untreated, these infections rapidly progress to a fatal outcome (seeKasper, 1998; Chapter 41: Drugs Used in the Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections). Initial therapy consists of an oral loading dose of 200 mg followed by 50 to 75 mg of pyrimethamine daily for 4 to 6 weeks along with 4 to 6 g of sulfadiazine daily in four divided doses. Leucovorin (folinic acid), 10 to 15 mg daily, should be taken for the same period to prevent bone marrow toxicity (see below). For subsequent long-term suppressive therapy, lower doses of pyrimethamine (25 to 50 mg daily) and sulfadiazine (2 to 4 g daily) may suffice. To deal with toxicity, pyrimethamine often has been used with agents such as clindamycin, spiramycin, or other macrolides (seeKasper, 1998). Infants with congenital, placentally transmitted toxoplasmosis usually respond positively to oral pyrimethamine (0.5 to 1.0 mg/kg daily) and oral sulfadiazine (100 mg/kg daily) given over a one-year period. Toxicity, Precautions, and Contraindications Antimalarial doses of pyrimethamine alone cause little toxicity except occasional skin rashes and depression of hematopoiesis. Excessive doses produce a megaloblastic anemia, resembling that of folate deficiency, that responds readily to drug withdrawal or treatment with folinic acid. At very high doses pyrimethamine is teratogenic in animals, but there is no evidence for such toxicity in human beings. Sulfonamides or sulfones, rather than pyrimethamine, usually account for the toxicity associated with coadministration of these antifolate drugs (seeChapter 44: Antimicrobial Agents: Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections). The combination of pyrimethamine (25 mg) and sulfadoxine (500 mg) (FANSIDAR) is no longer recommended for antimalarial prophylaxis, because in about 1:5000 to 1:8000 individuals, it causes severe and even fatal cutaneous reactions, such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. This combination also has been
  18. associated with serum-sickness- type reactions, urticaria, exfoliative dermatitis, and hepatitis. Pyrimethamine–sulfadoxine is contraindicated for individuals with previous reactions to sulfonamides, for lactating mothers, and for infants less than 2 months old. Administration of pyrimethamine with dapsone (MALOPRIM, a drug combination unavailable in the United States) occasionally has been associated with agranulocytosis. Higher doses of pyrimethamine (75 mg daily), used along with sulfadiazine (4 to 6 g daily) to treat toxoplasmosis, produce skin rashes, bone marrow suppression, and renal toxicity in about 40% of immunocompromised patients. However, much of this toxicity is probably due to sulfadiazine (seeKasper, 1998, and Chapter 44: Antimicrobial Agents: Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections). Halofantrine Halofantrine (HALFAN) is a phenanthrene methanol antimalarial drug with blood schizontocidal properties similar to those of the quinoline antimalarials. This compound was originally developed and has been used as an alternative to quinine and mefloquine to treat acute malarial attacks caused by chloroquine-resistant and multidrug-resistant strains of P. falciparum. Because halofantrine displays erratic bioavailability, potentially lethal cardiotoxicity, and extensive cross resistance with mefloquine, its use generally is not 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 based on their structural similarity to quinine, mefloquine displayed high antimalarial activity in animal models and emerged from clinical trials as safe and highly effective against drug-resistant strains of P. falciparum (Schmidt et al., 1978). Mefloquine was first used to treat chloroquine-resistant falciparum malaria in Thailand, where it was formulated with pyrimethamine–sulfadoxine (FANSIMEF) to delay development of drug-resistant parasites. This strategy failed, largely because slow elimination of mefloquine fostered the selection of resistant parasites at subtherapeutic drug concentrations (seeWhite, 1999). Mefloquine now is recommended for oral use exclusively for the prophylaxis and chemotherapy of chloroquine-resistant or multidrug-resistant falciparum malaria. This quinoline is most effective for treating uncomplicated drug-resistant falciparum malaria when given 48 hours after the parasite burden has been substantially reduced by prior administration of an artemisinin antimalarial (see"Artemisinin and Derivatives," above) (White, 1997, 1999). The antimalarial activity, pharmacokinetic properties, therapeutic efficacy, and side effects of this drug have been extensively reviewed (Palmer et al., 1993; Schlagenhauf, 1999). The chemical structure of mefloquine is shown below:
  19. Antimalarial Actions Mefloquine exists as a racemic mixture of four optical isomers with about the same antimalarial potency. It is a highly effective blood schizontocide, especially against mature trophozoite and schizont forms of malarial parasites. Mefloquine has no activity against early hepatic stages and mature gametocytes of P. falciparum or latent tissue forms of P. vivax. The drug may have some sporontocidal activity but is not used clinically for this purpose. Mechanisms of Antimalarial Action and Resistance The exact mechanism of action of mefloquine is unknown (see"Mechanisms of Antimalarial Action of and Resistance to Chloroquine and Other Antimalarial Quinolines," above). As a blood schizontocide, mefloquine behaves like quinine in many respects but does not intercalate with DNA. The two compounds produce similar morphological changes in early erythrocytic ring stages of P. falciparum and P. vivax (Schmidt et al., 1978). Like quinine, mefloquine competes for accumulation of chloroquine and inhibits chloroquine-induced clumping of pigment in erythrocytic plasmodia (Fitch et al., 1979). Mefloquine causes swelling of the parasitic food vacuoles in P. falciparum. Like chloroquine, low extracellular concentrations of mefloquine raise the intravacuolar pH of plasmodia in excess of that predicted from passive distribution of a weak base. This suggests that mefloquine is concentrated in plasmodia by an unknown mechanism. Mefloquine may act by both inhibiting heme polymerization and forming toxic complexes with free heme that damage membranes and interact with other plasmodial components (seePalmer et al., 1993; Sullivan et al., 1998). The orientation of the hydroxyl and amine groups with respect to each other in mefloquine may be essential for its hydrogen bonding and antimalarial activity (Karle and Karle, 1991). Certain isolates of P. falciparum exhibit resistance to mefloquine, especially those obtained from people exposed to the drug. Individuals harboring resistant parasites generally require larger than the usual doses of mefloquine to control their infections. Depending on their geographic origin and history of exposure to antimalarial drugs, many isolates of P. falciparum also display multidrug- resistant phenotypes. This raises the question of common or overlapping mechanisms responsible for intrinsic or acquired resistance to mefloquine and its structurally related antimalarials (seePalmer et al., 1993). Genes in the multidrug-resistant (MDR) family can play a role in the resistance of P. falciparum to mefloquine. Products of this gene family lower intracellular concentrations of drugs in mammalian cells by increasing their efflux in an ATP-dependent manner; this effect is inhibited by some Ca2+ channel blockers but not by others. In P. falciparum, a gene of this family, pfmdr1, is usually but not always amplified, that is, the gene copy number is increased
  20. in parasites unresponsive in vitro to mefloquine and halofantrine (seeWilson et al., 1993; Lim et al., 1996). In contrast, there is no clear-cut association between chloroquine resistance and amplification of pfmdr1 (Mungthin et al., 1999). Patterns of resistance to mefloquine and quinine usually but not always overlap, suggesting that genetic differences aside from pfmdr1 can play a differential role in resistance to these structurally related compounds (Zalis et al., 1998). The stereoselectivity of mefloquine resistance (and action) has yet to be characterized. Absorption, Fate, and Excretion Mefloquine is taken orally because parenteral preparations cause severe local reactions. The drug is well absorbed, a process enhanced by the presence of food. Probably due to extensive enterogastric and enterohepatic circulation, plasma levels of mefloquine rise in a biphasic manner to their peak in about 17 hours. The drug is widely distributed, highly bound ( 98%) to plasma proteins, and slowly eliminated with a terminal half-life of about 20 days. The biotransformation of mefloquine has not been well characterized in human beings, although several metabolites are formed. Plasma levels of the inactive mefloquine 4-carboxylic acid exceed those of mefloquine itself and decline at about the same rate. In human beings, excretion is mainly by the fecal route; only about 10% of mefloquine appears unchanged in the urine. This is consistent with evidence that mefloquine undergoes biliary excretion and extensive enterohepatic circulation in animals. The (+) and (–) enantiomers of mefloquine exhibit quite different pharmacokinetic characteristics that relate to their biodisposition (Hellgren et al., 1997). However, changes in the pharmacokinetics of racemic mefloquine that can occur as a result of age, ethnicity, pregnancy, and malarial illness do not substantially affect dosing regimens (seePalmer et al., 1993; Schlagenhauf, 1999). Therapeutic Uses Mefloquine should be reserved for the prevention and treatment of malaria caused by chloroquine- resistant and multidrug-resistant P. falciparum. The drug is especially useful as a prophylactic agent for nonimmune travelers who stay for only brief 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 multidrug- resistant P. falciparum. However, both medications can be given only orally, which is a major disadvantage for acutely ill patients, who are best treated with parenteral preparations of quinidine or quinine. Because of possible cross resistance, misuse of either mefloquine or halofantrine is likely to encourage the selection of falciparum parasites resistant to both drugs and possibly to quinine as well (seeWilson et al., 1993). Clinical resistance to mefloquine can be overcome by increasing the dose, but only at the cost of increased drug toxicity. Vomiting frequently occurs when high single or divided doses of mefloquine are used to treat a malarial attack. Patients should be observed and the full dose repeated if vomiting occurs within the first hour. Typical dosage schedules for monotherapy of falciparum malaria with mefloquine are given in Table 40–2. These may be modified; for example, lower doses than shown are effective for suppression of malarial attacks in partially immune individuals. More information about this topic is provided in the review by Palmer and colleagues (1993). To treat uncomplicated attacks of malaria due to chloroquine- and multidrug-resistant strains of P. falciparum, recent evidence indicates that mefloquine is most effective when used in tandem with an artemisinin compound such as artesunate (see"Artemisinin and Derivatives," above) (White, 1997, 1999). The artemisinin derivative is given first to reduce the parasite burden followed by mefloquine therapy to enhance parasite clearance and prevent recrudescence of infection. Studies
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