Emetine and Dehydroemetine
The alkaloids emetine and dehydroemetine are obtained by separation from extracts of ipecac. They occur as levorota-tory, light-sensitive white powders that are insoluble in water. The alkaloids readily form water-soluble salts. Solutions of the hydrochloride salts intended for intramuscular injection should be adjusted to pH 3.5 and stored in light-resistant containers.
Emetine and dehydroemetine exert a direct amebicidal action on various forms of E. histolytica. They are protoplasmic poisons that inhibit protein synthesis in protozoal and mammalian cells by preventing protein elongation. Because their effect in intestinal amebiasis is solely symptomatic and the cure rate is only 10% to 15%, they should be used only in combination with other agents. The high concentrations of the alkaloids achieved in the liver and other tissues after intramuscular injection provide the basis for their high effectiveness against hepatic abscesses and
other extraintestinal forms of the disease. Toxic effects limit the usefulness of emetine. It causes a high frequency of gastrointestinal distress (especially nausea and diarrhea), cardiovascular effects (hypotension and arrhythmias), and neuromuscular effects (pain and weakness). A lower incidence of cardiotoxicity has been associated with the use of dehydroemetine (Mebadin), which is available from the CDC and is also amebicidal.
Emetine and dehydroemetine have also been used to treat balantidial dysentery and fluke infestations, such as fascio-liasis and paragonimiasis.
4,4'-(Pentamethylenedioxy)dibenzamidine diisethionate (NebuPent, Pentam 300) is a water-soluble crystalline salt that is stable to light and air. The principal use of pentamidine is for the treatment of pneumonia caused by the opportunistic pathogenic protozoan P. carinii, a frequent secondary invader associated with AIDS. The drug may be administered by slow intravenous infusion or by deep intramuscular injection for PCP. An aerosol form of pentami-dine is used by inhalation for the prevention of PCP in high-risk patients infected with HIV who have a previous history of PCP infection or a low peripheral CD4+ lymphocyte count.
Both the inhalant (aerosol) and parenteral dosage forms of pentamidine isethionate are sterile lyophilized powders that must be made up as sterile aqueous solutions prior to use. Sterile water for injection must be used to reconstitute the aerosol, to avoid precipitation of the pentamidine salt. Adverse reactions to the drug are common. These include cough and bronchospasm (inhalation) and hypertension and hypoglycemia (injection).
Pentamidine has been used for the prophylaxis and treatment of African trypanosomiasis. It also has some value for treating visceral leishmaniasis. Pentamidine rapidly disappears from the plasma after intravenous injection and is distributed to the tissues, where it is stored for a long period. This property probably contributes to the usefulness of the drug as a prophylactic agent.
3-[4-(4-Chlorophenyl)-cyclohexyl]-2-hydroxy-1,4-naph-thoquinone (Mepron) is a highly lipophilic, water-insoluble analog of ubiquinone 6, an essential component of the mitochondrial electron transport chain in microorganisms. The structural similarity between atovaquone and ubiquinone suggests that the former may act as an antimetabolite for the latter and thereby interfere with the function of electron transport enzymes.
Atovaquone was originally developed as an antimalarial drug, but Plasmodium falciparum was found to develop a rapid tolerance to its action. More recently, the effectiveness of atovaquone against P. carinii was discovered. It is a currently recommended alternative to trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment and prophylaxis of PCP in patients intolerant to this combination. Atovaquone was also shown to be effective in eradicating T. gondii in preclinical animal studies.
The oral absorption of atovaquone is slow and incomplete, in part because of the low water solubility of the drug. Aqueous suspensions provide significantly better absorption than do tablets. Food, especially if it has a high fat content, increases atovaquone absorption. Significant enterohepatic recycling of atovaquone occurs, and most (nearly 95%) of the drug is excreted unchanged in the feces. In vivo, atovaquone is largely confined to the plasma, where it is extensively protein bound (>99.9%). The half-life of the drug ranges from 62 to 80 hours. The primary side effect is gastrointestinal intolerance.
Eflornithine is used for the treatment of West African sleeping sickness, caused by Trypanosoma brucei gambiense. It is specifically indicated for the meningoencephalitic stage of the disease. Eflornithine is a myelosuppressive drug that causes high incidences of anemia, leukopenia, and thrombocytopenia. Complete blood cell counts must be monitored during the course of therapy.
The irreversible inactivation of ornithine decarboxylase by eflornithine is accompanied by decarboxylation and release of fluoride ion from the inhibitor,90 suggesting enzyme-catalyzed activation of the inhibitor. Only the ( —) isomer, stereochemically related to l-ornithine, is active.
Eflornithine is supplied as the hydrochloride salt. It may be administered either intravenously or orally. Approximately 80% of the unchanged drug is excreted in the urine. Penetration of eflornithine into the CSF is facilitated by inflammation of the meninges.
Nifurtimox is 4-[(5-nitrofurfurylidene) amino]-3-methylth-iomorpholine-1,1-dioxide, or Bayer 2502 (Lampit). The observation that various derivatives of 5-nitrofuraldehyde possessed, in addition to their antibacterial and antifungal properties, significant and potentially useful antiprotozoal activity eventually led to discovery of particular nitrofurans with antitrypanosomal activity.
The most important of such compounds is nifurtimox because of its demonstrated effectiveness against T. cruzi, the parasite responsible for South American trypanosomiasis. In fact, use of this drug represents the only clinically proven treatment for both acute and chronic forms of the disease. Nifurtimox is available in the United States from the CDC.
Nifurtimox is administered orally. Oral bioavailability is high, but considerable first-pass metabolism occurs. The half-life of nifurtimox is 2 to 4 hours. The drug is poorly tolerated, with a high incidence of nausea, vomiting, abdominal pain, and anorexia reported. Symptoms of central and peripheral nervous system toxicity also frequently occur with nifurtimox.
N-Benzyl-2-nitroimidazole-1-acetamide (Radanil, Rochagan) is a nitroimidazole derivative that is used for the treatment of Chagas disease. It is not available in the United States but is used extensively in South America. The effectiveness of benznidazole is similar to that of nifurtimox. Therapy for American trypanosomiasis with oral benznidazole requires several weeks and is frequently accompanied by adverse effects such as peripheral neuropathy, bone marrow depression, and allergic-type reactions.
2-p-(4,6-Diamino-s-triazin-2-yl-amino)phenyl-4-hydroxy-methyl-1,3,2-dithiarsoline (Mel B, Arsobal) is prepared by reduction of a corresponding pentavalent arsanilate to the trivalent arsenoxide followed by reaction of the latter with 2,3-dimercapto-1-propanol (British anti-Lewisite [BAL]). It has become the drug of choice for the treatment of the later stages of both forms of African trypanosomiasis. Melarsoprol has the advantage of excellent penetration into the CNS and, therefore, is effective against meningoen-cephalitic forms of T. gambiense and T. rhodesiense. Trivalent arsenicals tend to be more toxic to the host (as well as the parasites) than the corresponding pentavalent compounds. The bonding of arsenic with sulfur atoms tends to reduce host toxicity, increase chemical stability (to oxidation), and improve distribution of the compound to the arsenoxide. Melarsoprol shares the toxic properties of other arsenicals, however, so its use must be monitored for signs of arsenic toxicity.
Sodium antimony gluconate (Pentostam) is a pentavalent antimonial compound intended primarily for the treatment of various forms of leishmaniasis. It is available from the CDC as the disodium salt, which is chemically stable and freely soluble in water. The 10% aqueous solution used for either intramuscular or intravenous injection has a pH of approximately 5.5. Like all antimonial drugs, this drug has a low therapeutic index, and patients undergoing therapy with it should be monitored carefully for signs of heavy metal poisoning. Other organic antimonial compounds are used primarily for the treatment of schistosomiasis and other flukes.
The antileishmanial action of sodium stibogluconate requires its reduction to the trivalent form, which is believed to inhibit phosphofructokinase in the parasite.
2,3-Dimercapto-1-propanol, BAL, or dithioglycerol is a foul-smelling, colorless liquid. It is soluble in water (1:20) and alcohol. It was developed by the British during World War II as an antidote for "Lewisite," hence the name British anti-Lewisite or BAL. Dimercaprol is effective topically and systematically as an antidote for poisoning caused by arsenic, antimony, mercury, gold, and lead. It can, therefore, also be used to treat arsenic and antimony toxicity associated with overdose or accidental ingestion of organoarseni-cals or organoantimonials.
These are relatively nontoxic, metabolically conjugated (as glucuronides), and rapidly excreted.
BAL may be applied topically as an ointment or injected intramuscularly as a 5% or 10% solution in peanut oil.
Suramin sodium is a high-molecular-weight bisurea derivative containing six sulfonic acid groups as their sodium salts. It was developed in Germany shortly after World War I as a byproduct of research efforts directed toward the development of potential antiparasitic agents from dyestuffs.
The drug has been used for more than half a century for the treatment of early cases of trypanosomiasis. Not until several decades later, however, was suramin discovered to be a long-term prophylactic agent whose effectiveness after a single intravenous injection is maintained for up to 3 months. The drug is tightly bound to plasma proteins, causing its excretion in the urine to be almost negligible.
Tissue penetration of the drug does not occur, apparently because of its high molecular weight and highly ionic character. Thus, an injected dose remains in the plasma for a very long period. Newer, more effective drugs are now available for short-term treatment and prophylaxis of African sleeping sickness. Suramin is also used for prophylaxis of onchocerciasis. It is available from the CDC.
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