Pharmacology_Katzung

Pharmacology_Katzung. Bithionol is an alternative to triclabendazole for the treatment of fascioliasis (sheep liver fluke) and an alternative to praziquantel for the treatment of paragonimiasis. After ingestion, bithionol reaches peak blood levels in 4–8 hours. Excretion appears to be mainly via the kidney. For treatment of paragonimiasis and fascioliasis, the dosage of bithionol is 30–50 mg/kg in two or three divided doses, given orally after meals on alternate days for 10–15 doses. For pulmonary paragonimiasis, cure rates are over 90%. For cerebral paragonimiasis, repeat courses may be necessary. Adverse Reactions, Contraindications, & Cautions


Pharmacology_Katzung

Pharmacology_Katzung. Adverse Reactions, Contraindications, & Cautions Adverse effects, which occur in up to 40% of patients, are generally mild and transient, but occasionally their severity requires interruption of therapy. These problems include diarrhea, abdominal cramps, anorexia, nausea, vomiting, dizziness, and headache. Skin rashes may occur after a week or more of therapy, suggesting a reaction to antigens released from dying worms. Bithionol should be used with caution in children younger than 8 years because there has been limited experience in this age group. Diethylcarbamazine is a drug of choice in the treatment of filariasis, loiasis, and tropical eosinophilia. It has been replaced by ivermectin for the treatment of onchocerciasis.


Pharmacology_Katzung

Pharmacology_Katzung. Diethylcarbamazine is a drug of choice in the treatment of filariasis, loiasis, and tropical eosinophilia. It has been replaced by ivermectin for the treatment of onchocerciasis. Diethylcarbamazine, a synthetic piperazine derivative, is rapidly absorbed from the gastrointestinal tract; after a dose of 0.5 mg/kg, peak plasma levels are reached within 1–2 hours. The plasma half-life is 2–3 hours in the presence of acidic urine but about 10 hours if the urine is alkaline, a Henderson-Hasselbalch trapping effect (see Chapter 1). The drug rapidly equilibrates with all tissues except fat. It is excreted, principally in the urine, as unchanged drug and the N-oxide metabolite. Dosage should be reduced in patients with renal impairment. Diethylcarbamazine immobilizes microfilariae and alters their surface structure, displacing them from tissues and making them more susceptible to destruction by host defense mechanisms. The mode of action against adult worms is unknown.


Pharmacology_Katzung

Pharmacology_Katzung. The drug should be taken after meals. 1.


Pharmacology_Katzung

Pharmacology_Katzung. Wuchereria bancrofti, Brugia malayi, Brugia timori, and Loa loa—Diethylcarbamazine is the drug of choice for treatment of infections with these parasites because of its efficacy and lack of serious toxicity. Microfilariae of all species are rapidly killed; adult parasites are killed more slowly, often requiring several courses of treatment. The drug is highly effective against adult L loa. The extent to which W bancrofti and B malayi adults are killed is not known, but after appropriate therapy microfilariae do not reappear in the majority of patients. Lymphatic filariasis is treated with 2 mg/kg three times a day for 12 days, and loiasis is treated with the same regimen for 2–3 weeks. Antihistamines may be given for the first few days of therapy to limit allergic reactions, and corticosteroids should be started and doses of diethylcarbamazine lowered or interrupted if severe reactions occur. Cures may require several courses of treatment. For patients with high L loa worm burdens


Pharmacology_Katzung

Pharmacology_Katzung. should be started and doses of diethylcarbamazine lowered or interrupted if severe reactions occur. Cures may require several courses of treatment. For patients with high L loa worm burdens (more than 2500 circulating parasites/mL), strategies to decrease risks of severe toxicity include (a) apheresis, if available, to remove microfilariae before treatment with diethylcarbamazine, or (b) therapy with albendazole, which is slower acting and better tolerated, followed by therapy with diethylcarbamazine or ivermectin. Diethylcarbamazine may also be used for chemoprophylaxis against filarial infections (300 mg weekly or 300 mg on 3 successive days each month for loiasis; 50 mg monthly for bancroftian and Malayan filariasis).


Pharmacology_Katzung

Pharmacology_Katzung. 2. Other uses—For tropical eosinophilia, diethylcarbamazine is given orally at a dosage of 2 mg/kg three times daily for 2–3 weeks. Diethylcarbamazine is effective in Mansonella streptocerca infections, since it kills both adults and microfilariae. Limited information suggests that the drug is not effective, however, against adult Mansonella ozzardi or Mansonella perstans and that it has limited activity against microfilariae of these parasites. An important application of diethylcarbamazine has been mass treatment to reduce the prevalence of W bancrofti infection, generally in combination with ivermectin or albendazole. This strategy has led to excellent progress in disease control in a number of countries. Adverse Reactions, Contraindications, & Cautions


Pharmacology_Katzung

Pharmacology_Katzung. Reactions to diethylcarbamazine, which are generally mild and transient, include headache, malaise, anorexia, weakness, nausea, vomiting, and dizziness. Adverse effects also occur as a result of the release of proteins from dying microfilariae or adult worms. Reactions can be particularly severe with onchocerciasis, but diethylcarbamazine is no longer commonly used for this infection because ivermectin is equally efficacious and less toxic. Reactions to dying microfilariae are usually mild in W bancrofti, more intense in B malayi, and occasionally severe in L loa infections. Reactions include fever, malaise, papular rash, headache, gastrointestinal symptoms, cough, chest pain, and muscle or joint pain. Leukocytosis is common and eosinophilia may increase with treatment. Proteinuria also may occur. Symptoms are most likely to occur in patients with heavy loads of microfilariae. Retinal hemorrhages and, rarely, encephalopathy have been described. Local reactions may occur in the


Pharmacology_Katzung

Pharmacology_Katzung. also may occur. Symptoms are most likely to occur in patients with heavy loads of microfilariae. Retinal hemorrhages and, rarely, encephalopathy have been described. Local reactions may occur in the vicinity of dying adult or immature worms. These include lymphangitis with localized swellings in W bancrofti and B malayi, small wheals in the skin in L loa, and flat papules in M streptocerca infections. Patients with attacks of lymphangitis due to W bancrofti or B malayi should be treated during a quiescent period between attacks. Caution is advised when using diethylcarbamazine in patients with hypertension or renal disease.


Pharmacology_Katzung

Pharmacology_Katzung. This tetracycline antibiotic is described in more detail in Chapter 44. Doxycycline has recently been shown to have significant macrofilaricidal activity against W bancrofti, suggesting better activity than any other available drug against adult worms. Activity is also seen against onchocerciasis. Doxycycline acts indirectly, by killing Wolbachia, an intracellular bacterial symbiont of filarial parasites. It may prove to be an important drug for filariasis and onchocerciasis, both for treatment of active disease and in mass chemotherapy campaigns. Ivermectin is the drug of choice in strongyloidiasis and onchocerciasis. It is also an alternative drug for a number of other helminthic infections (Table 53–1).


Pharmacology_Katzung

Pharmacology_Katzung. Ivermectin is the drug of choice in strongyloidiasis and onchocerciasis. It is also an alternative drug for a number of other helminthic infections (Table 53–1). Ivermectin, a semisynthetic macrocyclic lactone derived from the soil actinomycete Streptomyces avermitilis, is a mixture of avermectin B1a and B1b. Ivermectin is available only for oral administration in humans. The drug is rapidly absorbed, reaching maximum plasma concentrations 4 hours after a 12-mg dose. Ivermectin has a wide tissue distribution and a volume of distribution of about 50 L. Its half-life is about 16 hours. Excretion of the drug and its metabolites is almost exclusively in the feces.


Pharmacology_Katzung

Pharmacology_Katzung. Ivermectin appears to paralyze nematodes and arthropods by intensifying γ-aminobutyric acid (GABA)-mediated transmission of signals in peripheral nerves. In onchocerciasis, ivermectin is microfilaricidal. It does not effectively kill adult worms but blocks the release of microfilariae for some months after therapy. After a single standard dose, microfilariae in the skin diminish rapidly within 2–3 days, remain low for months, and then gradually increase; microfilariae in the anterior chamber of the eye decrease slowly over months, eventually clear, and then gradually return. With repeated doses of ivermectin, the drug appears to have a low-level macrofilaricidal action and to permanently reduce microfilarial production. 1. Onchocerciasis—Treatment is with a single oral dose of ivermectin, 150 mcg/kg, with water on an empty stomach.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Onchocerciasis—Treatment is with a single oral dose of ivermectin, 150 mcg/kg, with water on an empty stomach. Doses are repeated; regimens vary from monthly to less frequent (every 6–12 months) dosing schedules. After acute therapy, treatment is repeated at 12-month intervals until the adult worms die, which may take 10 years or longer. With the first treatment only, patients with microfilariae in the cornea or anterior chamber may be treated with corticosteroids to avoid inflammatory eye reactions. Ivermectin also now plays a key role in onchocerciasis control. Annual mass treatments have led to major reductions in disease transmission. However, evidence of diminished responsiveness after mass administration of ivermectin has raised concern regarding selection of drug-resistant parasites. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Strongyloidiasis—Treatment consists of 200 mcg/kg once daily for 2 days. In immunosuppressed patients with disseminated infection, repeated treatment is often needed, and cure may not be possible. In this case, suppressive therapy—ie, once monthly—may be helpful. 3. Other parasites—Ivermectin reduces microfilariae in B malayi and M ozzardi infections but not in M perstans infections. It has been used with diethylcarbamazine and albendazole for the control of W bancrofti, but it does not kill adult worms. In loiasis, although the drug reduces microfilaria concentrations, it can occasionally induce severe reactions and appears to be more dangerous in this regard than diethylcarbamazine. Ivermectin is also effective in controlling scabies, lice, and cutaneous larva migrans and in eliminating a large proportion of ascarid worms. Adverse Reactions, Contraindications, & Cautions


Pharmacology_Katzung

Pharmacology_Katzung. In strongyloidiasis treatment, infrequent adverse effects of ivermectin include fatigue, dizziness, nausea, vomiting, abdominal pain, and rashes. In onchocerciasis treatment, adverse effects are principally from the killing of microfilariae and can include fever, headache, dizziness, somnolence, weakness, rash, increased pruritus, diarrhea, joint and muscle pains, hypotension, tachycardia, lymphadenitis, lymphangitis, and peripheral edema. This reaction starts on the first day and peaks on the second day after treatment. It occurs in 5–30% of persons and is generally mild, but it may be more frequent and more severe in individuals who are not long-term residents of onchocerciasis-endemic areas. A more intense reaction occurs in 1–3% of persons and a severe reaction in 0.1%, including high fever, hypotension, and bronchospasm. Corticosteroids are indicated in these cases, at times for several days. Toxicity diminishes with repeated dosing. Swellings and abscesses occasionally occur at


Pharmacology_Katzung

Pharmacology_Katzung. fever, hypotension, and bronchospasm. Corticosteroids are indicated in these cases, at times for several days. Toxicity diminishes with repeated dosing. Swellings and abscesses occasionally occur at 1–3 weeks, presumably at sites of adult worms. Some patients develop corneal opacities and other eye lesions several days after treatment. These are rarely severe and generally resolve without corticosteroid treatment. It is best to avoid concomitant use of ivermectin with other drugs that enhance GABA activity, eg, barbiturates, benzodiazepines, and valproic acid. Ivermectin should not be used during pregnancy. Safety in children younger than 5 years has not been established.


Pharmacology_Katzung

Pharmacology_Katzung. Mebendazole is a synthetic benzimidazole that has a wide spectrum of antihelminthic activity and a low incidence of adverse effects. Less than 10% of orally administered mebendazole is absorbed. The absorbed drug is protein-bound (>90%), is rapidly converted to inactive metabolites (primarily during its first pass in the liver), and has a half-life of 2–6 hours. It is excreted mostly in the urine, principally as decarboxylated derivatives, as well as in the bile. Absorption is increased if the drug is ingested with a fatty meal. Mebendazole probably acts by inhibiting microtubule synthesis; the parent drug appears to be the active form. Efficacy of the drug varies with gastrointestinal transit time, with intensity of infection, and perhaps with the strain of parasite. The drug kills hookworm, Ascaris, and Trichuris eggs.


Pharmacology_Katzung

Pharmacology_Katzung. Mebendazole is indicated for use in ascariasis, trichuriasis, hookworm and pinworm infections, and certain other helminthic infections. It can be taken before or after meals; the tablets should be chewed before swallowing. For pinworm infection, the dose is 100 mg once, repeated at 2 weeks. For ascariasis, trichuriasis, hookworm, and Trichostrongylus infections, a dosage of 100 mg twice daily for 3 days is used for adults and for children older than 2 years. Cure rates are good for pinworm infections and ascariasis but have been disappointing in recent studies of trichuriasis, although efficacy for trichuriasis is better than that of albendazole. Cure rates are also low for hookworm infections, but a marked reduction in the worm burden occurs in those not cured. For intestinal capillariasis, mebendazole is used at a dosage of 200 mg twice daily for 21 or more days. In trichinosis, limited reports suggest efficacy against adult worms in the intestinal tract and tissue larvae. Treatment


Pharmacology_Katzung

Pharmacology_Katzung. mebendazole is used at a dosage of 200 mg twice daily for 21 or more days. In trichinosis, limited reports suggest efficacy against adult worms in the intestinal tract and tissue larvae. Treatment is three times daily, with fatty foods, at 200–400 mg per dose for 3 days and then 400–500 mg per dose for 10 days; corticosteroids should be co-administered for severe infections.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse Reactions, Contraindications, & Cautions Short-term mebendazole therapy for intestinal nematodes is nearly free of adverse effects. Mild nausea, vomiting, diarrhea, and abdominal pain have been reported infrequently. Rare side effects, usually with high-dose therapy, are hypersensitivity reactions (rash, urticaria), agranulocytosis, alopecia, and elevation of liver enzymes. Mebendazole is teratogenic in animals and therefore contraindicated in pregnancy. It should be used with caution in children younger than 2 years because of limited experience and rare reports of convulsions in this age group. Plasma levels may be decreased by concomitant use of carbamazepine, phenytoin, or ritonavir, and increased by cimetidine. Mebendazole should be used with caution in patients with cirrhosis.


Pharmacology_Katzung

Pharmacology_Katzung. Metrifonate is a safe, low-cost alternative drug for the treatment of Schistosoma haematobium infections. It is not active against Schistosoma mansoni or Schistosoma japonicum. It is not available in the USA. Metrifonate, an organophosphate, is rapidly absorbed after oral administration. After the standard oral dose, peak blood levels are reached in 1–2 hours; the half-life is about 1.5 hours. Clearance appears to be through nonenzymatic transformation to dichlorvos, its active metabolite. Metrifonate and dichlorvos are well distributed to the tissues and are completely eliminated in 24–48 hours. The mode of action is thought to be cholinesterase inhibition, temporarily paralyzing adult worms, resulting in their transit from bladder vasculature to small arterioles in the lungs, where they are killed. The drug is not effective against S haematobium eggs; live eggs continue to pass in the urine for several months after all adult worms have been killed.


Pharmacology_Katzung

Pharmacology_Katzung. In the treatment of S haematobium, an oral dose of 7.5–10 mg/kg is given three times at 14-day intervals. Cure rates on this schedule are 44–93%, with marked reductions in egg counts in those not cured. Metrifonate was also effective as a prophylactic agent when given monthly to children in a highly endemic area, and it has been used in mass treatment programs. In mixed infections with S haematobium and S mansoni, metrifonate has been successfully combined with oxamniquine. Adverse Reactions, Contraindications, & Cautions Some studies note mild and transient cholinergic symptoms, including nausea and vomiting, diarrhea, abdominal pain, bronchospasm, headache, sweating, fatigue, weakness, dizziness, and vertigo. Metrifonate should not be used after recent exposure to insecticides or drugs that might potentiate cholinesterase inhibition. It is contraindicated in pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. Niclosamide is a second-line drug for the treatment of most tapeworm infections, but it is not available in the USA. Niclosamide is a salicylamide derivative. It appears to be minimally absorbed from the gastrointestinal tract—neither the drug nor its metabolites have been recovered from the blood or urine. Adult worms (but not ova) are rapidly killed, presumably due to inhibition of oxidative phosphorylation or stimulation of ATPase activity. The adult dose of niclosamide is 2 g once, given in the morning on an empty stomach. The tablets must be chewed thoroughly and then swallowed with water. 1.


Pharmacology_Katzung

Pharmacology_Katzung. The adult dose of niclosamide is 2 g once, given in the morning on an empty stomach. The tablets must be chewed thoroughly and then swallowed with water. 1. Taenia saginata (beef tapeworm), Taenia solium (pork tapeworm), and Diphyllobothrium latum (fish tapeworm)—A single 2-g dose of niclosamide results in cure rates of over 85% for D latum and about 95% for T saginata. It is probably equally effective against T solium. Cysticercosis can theoretically occur after treatment of T solium infections, because viable ova are released into the gut lumen after digestion of segments, but no such cases have been reported. 2. Other tapeworms—Most patients treated with niclosamide for Hymenolepis diminuta and Dipylidium caninum infections are cured with a 7-day course of treatment; a few require a second course. Praziquantel is superior for Hymenolepis nana (dwarf tapeworm) infection. Niclosamide is not effective against cysticercosis or hydatid disease. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Intestinal fluke infections—Niclosamide can be used as an alternative drug in the treatment of Fasciolopsis buski, Heterophyes heterophyes, and Metagonimus yokogawai infections. The standard dose is given every other day for three doses. Adverse Reactions, Contraindications, & Cautions Infrequent, mild, and transitory adverse events include nausea, vomiting, diarrhea, and abdominal discomfort. Alcohol should not be consumed during or for 1 day after treatment. Safety has not been established in pregnancy or for children younger than 2 years. Oxamniquine is an alternative to praziquantel for the treatment of S mansoni infections. It has also been used extensively for mass treatment. It is not effective against S haematobium or S japonicum. It is not available in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. Oxamniquine, a semisynthetic tetrahydroquinoline, is readily absorbed orally; it should be taken with food. Its plasma half-life is about 2.5 hours. The drug is extensively metabolized to inactive metabolites and excreted in the urine—up to 75% in the first 24 hours. Intersubject variations in serum concentration have been noted, which may explain some treatment failures. Oxamniquine is active against both mature and immature stages of S mansoni but does not appear to be cercaricidal. The mechanism of action is unknown. Contraction and paralysis of the worms results in detachment from terminal venules in the mesentery and transit to the liver, where many die; surviving females return to the mesenteric vessels but cease to lay eggs. Strains of S mansoni in different parts of the world vary in susceptibility. Oxamniquine has been effective in instances of praziquantel resistance.


Pharmacology_Katzung

Pharmacology_Katzung. Oxamniquine is safe and effective in all stages of S mansoni disease, including advanced hepatosplenomegaly. The drug is generally less effective in children, who require higher doses than adults. It is better tolerated with food. Optimal dosage schedules vary for different regions of the world. In the western hemisphere and western Africa, the adult oxamniquine dosage is 12–15 mg/kg given once. In northern and southern Africa, standard schedules are 15 mg/kg twice daily for 2 days. In eastern Africa and the Arabian peninsula, standard dosage is 15–20 mg/kg twice in 1 day. Cure rates are 70–95%, with marked reduction in egg excretion in those not cured. In mixed schistosome infections, oxamniquine has been successfully used in combination with metrifonate. Adverse Reactions, Contraindications, & Cautions


Pharmacology_Katzung

Pharmacology_Katzung. Adverse Reactions, Contraindications, & Cautions Mild symptoms occur in more than one-third of patients receiving oxamniquine. Central nervous system symptoms (dizziness, headache, drowsiness) are most common; nausea and vomiting, diarrhea, colic, pruritus, and urticaria also occur. Infrequent adverse effects are low-grade fever, an orange to red discoloration of the urine, proteinuria, microscopic hematuria, and transient leukopenia. Seizures have been reported rarely. Since the drug makes many patients dizzy or drowsy, it should be used with caution in patients whose work or activity requires mental alertness (eg, no driving for 24 hours). It should be used with caution in those with a history of epilepsy. Oxamniquine is contraindicated in pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. Piperazine is an alternative for the treatment of ascariasis, with cure rates over 90% when taken for 2 days, but it is not recommended for other helminth infections. Piperazine is available as the hexahydrate and as a variety of salts. It is readily absorbed, and maximum plasma levels are reached in 2–4 hours. Most of the drug is excreted unchanged in the urine in 2–6 hours, and excretion is complete within 24 hours. Piperazine causes paralysis of ascaris by blocking acetylcholine at the myoneural junction; live worms are expelled by peristalsis. For ascariasis, the dosage of piperazine (as the hexahydrate) is 75 mg/kg (maximum dose, 3.5 g) orally once daily for 2 days. For heavy infections, treatment should be continued for 3–4 days or repeated after 1 week.


Pharmacology_Katzung

Pharmacology_Katzung. Occasional mild adverse effects include nausea, vomiting, diarrhea, abdominal pain, dizziness, and headache. Neurotoxicity and allergic reactions are rare. Piperazine should not be given to pregnant women, patients with impaired renal or hepatic function, or those with a history of epilepsy or chronic neurologic disease. Praziquantel is effective in the treatment of schistosome infections of all species and most other trematode and cestode infections, including cysticercosis. The drug’s safety and effectiveness as a single oral dose have also made it useful in mass treatment of several infections.


Pharmacology_Katzung

Pharmacology_Katzung. Praziquantel is a synthetic isoquinoline-pyrazine derivative. It is rapidly absorbed, with a bioavailability of about 80% after oral administration. Peak serum concentrations are reached 1–3 hours after a therapeutic dose. Cerebrospinal fluid concentrations of praziquantel reach 14–20% of the drug’s plasma concentration. About 80% of the drug is bound to plasma proteins. Most of the drug is rapidly metabolized to inactive monoand polyhydroxylated products after a first pass in the liver. The half-life is 0.8–1.5 hours. Excretion is mainly via the kidneys (60–80%) and bile (15–35%). Plasma concentrations of praziquantel increase when the drug is taken with a high-carbohydrate meal or with cimetidine; bioavailability is markedly reduced by phenytoin, carbamazepine, or corticosteroids.


Pharmacology_Katzung

Pharmacology_Katzung. Praziquantel appears to increase the permeability of trematode and cestode cell membranes to calcium, resulting in paralysis, dislodgement, and death. In schistosome infections of experimental animals, praziquantel is effective against adult worms and immature stages, and it has a prophylactic effect against cercarial infection. Praziquantel tablets are taken with liquid after a meal; they should be swallowed without chewing because their bitter taste can induce retching and vomiting. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Schistosomiasis—Praziquantel is the drug of choice for all forms of schistosomiasis. The dosage is 20 mg/kg per dose for two (S mansoni and S haematobium) or three (S japonicum and S mekongi) doses at intervals of 4–6 hours. High cure rates (75–95%) are achieved when patients are evaluated at 3–6 months; there is marked reduction in egg counts in those not cured. The drug is effective in adults and children and is generally well tolerated by patients in the hepatosplenic stage of advanced disease. There is no standard regimen for acute schistosomiasis (Katayama syndrome), but standard doses as described above, often with corticosteroids to limit inflammation from the acute immune response and dying worms, are recommended. Increasing evidence indicates rare S mansoni drug resistance, which may be countered with extended courses of therapy (eg, 3–6 days at standard dosing) or treatment with oxamniquine. Effectiveness of praziquantel for chemoprophylaxis has not been established.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Clonorchiasis, opisthorchiasis, and paragonimiasis— Standard dosing is 25 mg/kg three times daily for 2 days for each of these fluke infections. 3. Taeniasis and diphyllobothriasis—A single dose of praziquantel, 5–10 mg/kg, results in nearly 100% cure rates for T saginata, T solium, and D latum infections. Because praziquantel does not kill eggs, it is theoretically possible that larvae of T solium released from eggs in the large bowel could penetrate the intestinal wall and give rise to cysticercosis, but this hazard is probably minimal. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Neurocysticercosis—Albendazole is now the preferred drug, but when it is not appropriate or available, praziquantel has similar efficacy. Indications for praziquantel are similar to those for albendazole. The praziquantel dosage is 100 mg/kg/d in three divided doses for 1 day, then 50 mg/kg/d to complete a 2to 4-week course. Clinical responses to therapy vary from dramatic improvements of seizures and other neurologic findings to no response and even progression of the disease. Praziquantel—but not albendazole—has diminished bioavailability when taken concurrently with a corticosteroid. Recommendations on use of both antihelminthics and corticosteroids in neurocysticercosis vary. 5. Hymenolepis nana—Praziquantel is the drug of choice for H nana infections and the first drug to be highly effective. A single dose of 25 mg/kg is taken initially and repeated in 1 week. 6.


Pharmacology_Katzung

Pharmacology_Katzung. 5. Hymenolepis nana—Praziquantel is the drug of choice for H nana infections and the first drug to be highly effective. A single dose of 25 mg/kg is taken initially and repeated in 1 week. 6. Hydatid disease—In hydatid disease, praziquantel kills protoscoleces but does not affect the germinal membrane. Praziquantel may be used as an adjunct with albendazole preand post-surgery. In addition to its direct action, praziquantel enhances the plasma concentration of albendazole. 7. Other parasites—Limited trials showed effectiveness of praziquantel at a dosage of 25 mg/kg three times daily for 1–2 days against fasciolopsiasis, metagonimiasis, and other forms of heterophyiasis. Praziquantel was not effective for fascioliasis, however, even at dosages as high as 25 mg/kg three times daily for 3–7 days. Adverse Reactions, Contraindications, & Cautions


Pharmacology_Katzung

Pharmacology_Katzung. Adverse Reactions, Contraindications, & Cautions Mild and transient adverse effects are common. They begin within hours after ingestion of praziquantel and may persist for about 1 day. Most common are headache, dizziness, drowsiness, and lassitude; others include nausea, vomiting, abdominal pain, loose stools, pruritus, urticaria, arthralgia, myalgia, and low-grade fever. Mild and transient elevations of liver enzymes have been reported. Several days after starting praziquantel, low-grade fever, pruritus, and skin rashes (macular and urticarial), sometimes associated with worsened eosinophilia, may occur, probably due to the release of proteins from dying worms rather than direct drug toxicity. The intensity and frequency of adverse effects increase with dosage such that they occur in up to 50% of patients who receive 25 mg/kg three times daily.


Pharmacology_Katzung

Pharmacology_Katzung. In neurocysticercosis, neurologic abnormalities may be exacerbated by inflammatory reactions around dying parasites. Common findings in patients who do not receive corticosteroids, usually presenting during or shortly after therapy, are headache, meningismus, nausea, vomiting, mental changes, and seizures (often accompanied by increased cerebrospinal fluid pleocytosis). More serious reactions, including arachnoiditis, hyperthermia, and intracranial hypertension, may also occur. Corticosteroids are commonly used with praziquantel in the treatment of neurocysticercosis to decrease the inflammatory response, but this is controversial and complicated by knowledge that corticosteroids decrease the plasma level of praziquantel up to 50%. Praziquantel is contraindicated in ocular cysticercosis, because parasite destruction in the eye may cause irreparable damage. Some workers also caution against use of the drug in spinal neurocysticercosis.


Pharmacology_Katzung

Pharmacology_Katzung. Praziquantel is safe and well tolerated in children. Recent data suggest that the drug can be given safely during pregnancy. Because praziquantel induces dizziness and drowsiness, patients should not drive during therapy and should be warned regarding activities requiring particular physical coordination or alertness. Pyrantel pamoate is a broad-spectrum antihelminthic highly effective for the treatment of pinworm, ascaris, and Trichostrongylus orientalis infections. It is moderately effective against both species of hookworm. It is not effective in trichuriasis or strongyloidiasis. Oxantel pamoate, an analog of pyrantel not available in the USA, has shown better efficacy against trichuriasis than any other single agent and promising activity in combination with albendazole or ivermectin for this indication. Pyrantel/oxantel pamoate combinations are widely used in veterinary medicine and have been studied for some human indications.


Pharmacology_Katzung

Pharmacology_Katzung. Pyrantel pamoate is a tetrahydropyrimidine derivative. It is poorly absorbed from the gastrointestinal tract and active mainly against luminal organisms. Peak plasma levels are reached in 1–3 hours. Over half of the administered dose is recovered unchanged in the feces. Pyrantel is effective against mature and immature forms of susceptible helminths within the intestinal tract but not against migratory stages in the tissues or against ova. The drug is a neuromuscular blocking agent that causes release of acetylcholine and inhibition of cholinesterase; this results in paralysis of worms, followed by expulsion. The standard dose is 11 mg (base)/kg (maximum, 1 g), given orally once with or without food. For pinworm, the dose is repeated in 2 weeks, and cure rates are greater than 95%. The drug is available in the USA without prescription for this indication.


Pharmacology_Katzung

Pharmacology_Katzung. For ascariasis, a single dose yields cure rates of 85–100%. Treatment should be repeated if eggs are found 2 weeks after treatment. For hookworm infections, a single dose is effective against light infections; but for heavy infections, especially with Necator americanus, a 3-day course is necessary to achieve 90% cure rates. A course of treatment can be repeated in 2 weeks. Adverse Reactions, Contraindications, & Cautions Pyrantel’s adverse effects are infrequent, mild, and transient. They may include nausea, vomiting, diarrhea, abdominal cramps, dizziness, drowsiness, headache, insomnia, rash, fever, and weakness. Pyrantel should be used with caution in patients with liver dysfunction, as transient aminotransferase elevations have been noted. Experience with the drug in pregnant women and children younger than 2 years is limited. Thiabendazole is an alternative to ivermectin or albendazole for the treatment of strongyloidiasis and cutaneous larva migrans.


Pharmacology_Katzung

Pharmacology_Katzung. Thiabendazole is an alternative to ivermectin or albendazole for the treatment of strongyloidiasis and cutaneous larva migrans. Thiabendazole is a benzimidazole compound. Although it is a chelating agent that forms stable complexes with a number of metals, including iron, it does not bind calcium. Thiabendazole is rapidly absorbed after ingestion. With a standard dose, drug concentrations in plasma peak within 1–2 hours; the half-life is 1.2 hours. The drug is almost completely metabolized in the liver to the 5-hydroxy form; 90% is excreted in the urine in 48 hours, largely as the glucuronide or sulfonate conjugate. Thiabendazole can also be absorbed from the skin. The mechanism of action of thiabendazole is probably the same as that of other benzimidazoles (inhibition of microtubule synthesis). The drug has ovicidal effects against some parasites.


Pharmacology_Katzung

Pharmacology_Katzung. The standard dosage, 25 mg/kg (maximum 1.5 g) twice daily, should be given after meals. Tablets should be chewed. For Strongyloides infection, treatment is for 2 days. Cure rates are reportedly 93%. A course can be repeated in 1 week if indicated. In patients with hyperinfection syndrome, the standard dose is continued twice daily for 5–7 days. For cutaneous larva migrans, thiabendazole cream can be applied topically, or the oral drug can be given for 2 days (although albendazole is less toxic and therefore preferred). Adverse Reactions, Contraindications, & Cautions


Pharmacology_Katzung

Pharmacology_Katzung. Adverse Reactions, Contraindications, & Cautions Thiabendazole is much more toxic than other benzimidazoles and more toxic than ivermectin, so other agents are now preferred for most indications. Common adverse effects include dizziness, anorexia, nausea, and vomiting. Less common problems are epigastric pain, abdominal cramps, diarrhea, pruritus, headache, drowsiness, and neuropsychiatric symptoms. Irreversible liver failure and fatal Stevens-Johnson syndrome have been reported. Experience with thiabendazole is limited in children weighing less than 15 kg. The drug should not be used in pregnancy or in the presence of hepatic or renal disease. Ivermectin Mectizan, Stromectol Mebendazole Generic, Vermox Metrifonate Trichlorfon, Bilarcil Oxamniquine Vansil, Mansil Piperazine Generic, Vermizine Pyrantel pamoate Ascarel, Pamix, Pin Rid, Pin-X Ashrafi K et al: Fascioliasis: A worldwide parasitic disease of importance in travel medicine. Travel Med Infect Dis 2014;12:636.


Pharmacology_Katzung

Pharmacology_Katzung. Pyrantel pamoate Ascarel, Pamix, Pin Rid, Pin-X Ashrafi K et al: Fascioliasis: A worldwide parasitic disease of importance in travel medicine. Travel Med Infect Dis 2014;12:636. Bagheri H et al: Adverse drug reactions to anthelmintics. Ann Pharmacother 2004;38:383. Brunetti E, White AC Jr: Cestode infestations: Hydatid disease and cysticercosis. Infect Dis Clin North Am 2012;26:421. Colley DG et al: Human schistosomiasis. Lancet 2014;383:2253. Danso-Appiah A et al: Drugs for treating Schistosoma mansoni infection. Cochrane Database Syst Rev 2013;2:CD000528. Debrah AY et al: Doxycycline leads to sterility and enhanced killing of female Onchocerca volvulus worms in an area with persistent microfilaridermia after repeated ivermectin treatment: A randomized, placebo-controlled, double-blind trial. Clin Infect Dis 2015;61:517. Del Brutto OH: Clinical management of neurocysticercosis. Expert Rev Neurother 2014;14:389.


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Pharmacology_Katzung. Del Brutto OH: Clinical management of neurocysticercosis. Expert Rev Neurother 2014;14:389. Fox LM: Ivermectin: Uses and impact 20 years on. Curr Opin Infect Dis 2006; 19:588. Fst T et al: Manifestation, diagnosis, and management of foodborne trematodiasis. BMJ 2012;344:e4093. Garcia HH et al: Efficacy of combined antiparasitic therapy with praziquantel and albendazole for neurocysticercosis: A double-blind, randomised controlled trial. Lancet Infect Dis 2014;14:687. Henriquez-Camacho C et al: Ivermectin versus albendazole or thiabendazole for Strongyloides stercoralis infection. Cochrane Database Syst Rev 2016:CD007745. Kappagoda S, Singh U, Blackburn BG: Antiparasitic therapy. Mayo Clin Proc 2011;86:561. Keiser J, Utzinger J: Efficacy of current drugs against soil-transmitted helminth infections: Systematic review and meta-analysis. JAMA 2008;299:1937.


Pharmacology_Katzung

Pharmacology_Katzung. Keiser J, Utzinger J: Efficacy of current drugs against soil-transmitted helminth infections: Systematic review and meta-analysis. JAMA 2008;299:1937. Kincaid L et al: Management of imported cutaneous larva migrans: A case series and mini-review. Travel Med Infect Dis 2015;13:382. Knopp S et al: Albendazole and mebendazole administered alone or in combination with ivermectin against Trichuris trichiura: A randomized controlled trial. Clin Infect Dis 2010;51:1420. Knopp S et al: Nematode infections: Filariases. Infect Dis Clin North Am 2012;26:359. Knopp S et al: Nematode infections: Soil-transmitted helminths and trichinella. Infect Dis Clin North Am 2012;26:341. Levecke B et al: Assessment of anthelmintic efficacy of mebendazole in school children in six countries where soil-transmitted helminths are endemic. PLoS Negl Trop Dis 2014;8:e3204.


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Pharmacology_Katzung. Levecke B et al: Assessment of anthelmintic efficacy of mebendazole in school children in six countries where soil-transmitted helminths are endemic. PLoS Negl Trop Dis 2014;8:e3204. Matthaiou DK et al: Albendazole versus praziquantel in the treatment of neurocysticercosis: A meta-analysis of comparative trials. PLoS Negl Trop Dis 2008;2:e194. McManus DP et al: Diagnosis, treatment, and management of echinococcosis. BMJ 2012;344:e3866. Medical Letter: Drugs for parasitic infections. Med Lett Drugs Ther 2013; Supplement. Mejia R, Nutman TB: Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis. Curr Opin Infect Dis 2012;25:458. Metzger WG, Mordmler B: Loa loa-does it deserve to be neglected? Lancet Infect Dis 2014;14:353.


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Pharmacology_Katzung. Metzger WG, Mordmler B: Loa loa-does it deserve to be neglected? Lancet Infect Dis 2014;14:353. Moser W et al: Efficacy and safety of oxantel pamoate in school-aged children infected with Trichuris trichiura on Pemba Island, Tanzania: A parallel, randomised, controlled, dose-ranging study. Lancet Infect Dis 2016;16:53. Nash TE, Garcia HH: Diagnosis and treatment of neurocysticercosis. Nat Rev Neurol 2011;7:584. Olveda RM et al: Efficacy and safety of praziquantel for the treatment of human schistosomiasis during pregnancy: A phase 2, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis 2016;16:199. Pawluk SA et al: A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole. Clin Pharmacokinet 2015;54:371. Qian MB, et al: Clonorchiasis. Lancet 2016;387:800. Reddy M et al: Oral drug therapy for multiple neglected tropical diseases: A systematic review. JAMA 2007;298:1911.


Pharmacology_Katzung

Pharmacology_Katzung. Qian MB, et al: Clonorchiasis. Lancet 2016;387:800. Reddy M et al: Oral drug therapy for multiple neglected tropical diseases: A systematic review. JAMA 2007;298:1911. Soukhathammavong PA et al: Low efficacy of single-dose albendazole and mebendazole against hookworm and effect on concomitant helminth infection in Lao PDR. PLoS Negl Trop Dis 2012;6:e1417. Speich B et al: Efficacy and safety of albendazole plus ivermectin, albendazole plus mebendazole, albendazole plus oxantel pamoate, and mebendazole alone against Trichuris trichiura and concomitant soil-transmitted helminth infections: A four-arm, randomised controlled trial. Lancet Infect Dis 2015;15:277. Speich B et al: Oxantel pamoate-albendazole for Trichuris trichiura infection. N Engl J Med 2014;370:610. Steinmann P et al: Efficacy of single-dose and triple-dose albendazole and mebendazole against soil-transmitted helminths and Taenia spp.: A randomized controlled trial. PLoS One 2011;6:e25003.


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Pharmacology_Katzung. Steinmann P et al: Efficacy of single-dose and triple-dose albendazole and mebendazole against soil-transmitted helminths and Taenia spp.: A randomized controlled trial. PLoS One 2011;6:e25003. Supali T et al: Doxycycline treatment of Brugia malayi-infected persons reduces microfilaremia and adverse reactions after diethylcarbamazine and albendazole treatment. Clin Infect Dis 2008;46:1385. Tamarozzi F et al: Acceptance of standardized ultrasound classification, use of albendazole, and long-term follow-up in clinical management of cystic echinococcosis: A systematic review. Curr Opin Infect Dis 2014;27:425. Taylor MJ et al: Lymphatic filariasis and onchocerciasis. Lancet 2010;376:1175. Zwang J, Olliaro PL: Clinical efficacy and tolerability of praziquantel for intestinal and urinary schistosomiasis-a meta-analysis of comparative and non-comparative clinical trials. PLoS Negl Trop Dis 2014;8:e3286.


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Pharmacology_Katzung. The presentation is highly suggestive of cystic hydatid disease (infection with Echinococcus granulosus), which is transmitted by eggs from the feces of dogs in contact with livestock. Other causes of liver fluid collections include ame-bic and pyogenic abscesses, but these are usually not cystic in appearance. For echinococcosis, a typical cystic lesion and positive serology support the diagnosis, and treatment generally entails albendazole in conjunction with cautious surgery or percutaneous aspiration. One approach entails treatment with albendazole followed by aspiration to con-firm the diagnosis and, if it is confirmed, to remove most of the infecting worms.


Pharmacology_Katzung

Pharmacology_Katzung. Edward Chu, MD are the possible benefits of adjuvant chemotherapy? The patient receives a combination of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) as adjuvant therapy. One week after receiving the first cycle of therapy, he experiences significant toxicity in the form of myelosup-pression, diarrhea, and altered mental status. What is the most likely explanation for this increased toxicity? Is there any role for genetic testing to determine the etiology of the increased toxicity? A 55-year-old man presents with increasing fatigue, 15-pound weight loss, and a microcytic anemia. Colonoscopy identifies a mass in the ascending colon, and biopsy specimens reveal well-differentiated colorectal cancer (CRC). He undergoes surgical resection and is found to have high-risk stage III CRC with five positive lymph nodes. After surgery, he feels entirely well with no symptoms. Of note, he has no other illnesses. What is this patient’s overall prognosis? Based on his prognosis, what


Pharmacology_Katzung

Pharmacology_Katzung. In 2016, approximately 1.68 million new cancer cases were diagnosed in the USA, and nearly 600,000 individuals are expected to die from this disease. Cancer is the second most common cause of death in the United States, accounting for 1 in 4 deaths. It is a disease characterized by a defect in the normal control mechanisms that govern cell survival, proliferation, and differentiation. Cells that have undergone neoplastic transformation usually express cell surface antigens that may be of normal fetal type, and they may display other signs of apparent immaturity. They may exhibit qualitative or quantitative chromosomal abnormalities, including various translocations and the appearance of amplified gene sequences. It is now well established that a small subpopulation of cells, referred to as tumor stem cells, reside within a tumor mass. They retain the ability to undergo repeated cycles of proliferation as well as to migrate to distant sites in the body to colonize various organs in the


Pharmacology_Katzung

Pharmacology_Katzung. tumor stem cells, reside within a tumor mass. They retain the ability to undergo repeated cycles of proliferation as well as to migrate to distant sites in the body to colonize various organs in the process called metastasis. Such tumor stem cells thus can express clonogenic (colony-forming) capability, and they are characterized by chromosome abnormalities reflecting their genetic instability, which leads to progressive selection of subclones that can survive more readily in the multicellular environment of the host. This genetic instability also allows them to become resistant to chemotherapy and radiotherapy. The invasive and metastatic processes as well as a series of metabolic abnormalities associated with the cancer result in tumor-related symptoms and eventual death of the patient unless the neoplasm can be eradicated with treatment.


Pharmacology_Katzung

Pharmacology_Katzung. The incidence, geographic distribution, and behavior of specific types of cancer are related to multiple factors, including sex, age, race, genetic predisposition, and exposure to environmental carcinogens. Of these factors, environmental exposure is probably most important. Exposure to ionizing radiation has been well documented as a significant risk factor for a number of cancers, including acute leukemias, thyroid cancer, breast cancer, lung cancer, soft tissue sarcoma, and basal cell and squamous cell skin cancers. Chemical carcinogens (particularly those in tobacco smoke) as well as azo dyes, aflatoxins, asbestos, benzene, and radon all have been well documented as leading to a wide range of human cancers. ABVD Doxorubicin (Adriamycin, hydroxydaunorubicin), bleomycin, vinblastine, dacarbazine CHOP Cyclophosphamide, doxorubicin (Adriamycin, hydroxydaunorubicin), vincristine (Oncovin), prednisone CMF Cyclophosphamide, methotrexate, fluorouracil


Pharmacology_Katzung

Pharmacology_Katzung. CHOP Cyclophosphamide, doxorubicin (Adriamycin, hydroxydaunorubicin), vincristine (Oncovin), prednisone CMF Cyclophosphamide, methotrexate, fluorouracil COP Cyclophosphamide, vincristine (Oncovin), prednisone FAC 5-Fluorouracil, doxorubicin (Adriamycin, hydroxydaunorubicin), cyclophosphamide FEC 5-Fluorouracil, epirubicin, cyclophosphamide FOLFIRI 5-Fluorouracil, leucovorin, irinotecan FOLFOX 5-Fluorouracil, leucovorin, oxaliplatin MP Melphalan, prednisone MOPP Mechlorethamine, vincristine (Oncovin), procarbazine, prednisone PCV Procarbazine, lomustine, vincristine PEB Cisplatin (platinum), etoposide, bleomycin VAD Vincristine, doxorubicin (Adriamycin, hydroxydaunorubicin), dexamethasone XELOX Capecitabine, oxaliplatin


Pharmacology_Katzung

Pharmacology_Katzung. Several viruses have been implicated in the etiology of various human cancers. For example, hepatitis B (HBV) and hepatitis C (HCV) are associated with the development of hepatocellular cancer; HIV is associated with Hodgkin’s and non-Hodgkin’s lymphomas; human papillomavirus (HPV) is associated with cervical cancer, anal and penile cancers, and oropharyngeal head and neck cancer; Epstein-Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is associated with nasopharyngeal cancer, Burkitt’s lymphoma, and Hodgkin’s lymphoma; and Merkel cell polyomavirus (MCV) causes Merkel cell cancer, a rare but aggressive form of skin cancer. Expression of virus-induced neoplasia may also depend on additional host and environmental factors that modulate the transformation process. Cellular genes are known that are homologous to the transforming genes of the retroviruses, a family of RNA viruses, and induce oncogenic transformation. These mammalian cellular genes, known as oncogenes, have


Pharmacology_Katzung

Pharmacology_Katzung. are known that are homologous to the transforming genes of the retroviruses, a family of RNA viruses, and induce oncogenic transformation. These mammalian cellular genes, known as oncogenes, have been shown to code for specific growth factors and their corresponding receptors. These genes may be amplified (increased number of gene copies) or mutated, both of which can lead to constitutive over-expression in malignant cells. The bcl-2 family of genes represents a series of pro-survival genes that promotes survival by directly inhibiting apoptosis, a key pathway of programmed cell death.


Pharmacology_Katzung

Pharmacology_Katzung. Another class of genes, known as tumor suppressor genes, may be deleted or mutated, which gives rise to the neoplastic phenotype. The p53 gene is the best-established tumor suppressor gene identified to date, and the normal wild-type gene appears to play an important role in suppressing malignant transformation. Of note, p53 is mutated in up to 50% of all human solid tumors, including liver, breast, colon, lung, cervix, bladder, prostate, and skin.


Pharmacology_Katzung

Pharmacology_Katzung. With present methods of treatment, when the tumor remains localized at the time of diagnosis, about one-third of patients are cured with local treatment strategies, such as surgery or radiotherapy. Earlier diagnosis might lead to increased cure rates with such local treatment. In the remaining cases, however, early micrometastasis is a characteristic feature, indicating that a systemic approach with chemotherapy is required for effective cancer management. In patients with locally advanced disease, chemotherapy is often combined with radiotherapy to allow for subsequent surgical resection to take place, and such a combined modality approach has led to improved clinical outcomes. At present, about 50% of patients who are initially diagnosed with cancer can be cured. In contrast, chemotherapy alone is able to cure less than 10% of all cancer patients when the tumor is diagnosed at an advanced stage.


Pharmacology_Katzung

Pharmacology_Katzung. Chemotherapy is presently used in three main clinical settings: (1) primary induction treatment for advanced disease or for cancers for which there are no other effective treatment approaches, (2) neoadjuvant treatment for patients who present with localized disease, for whom local forms of therapy such as surgery or radiation, or both, are inadequate by themselves, (3) adjuvant treatment to local methods of treatment, including surgery, radiation therapy, or both.


Pharmacology_Katzung

Pharmacology_Katzung. Primary chemotherapy refers to chemotherapy administered as the primary treatment in patients who present with advanced cancer for which no alternative treatment exists. This has been the main approach in treating patients with advanced metastatic disease, and in most cases, the goals of therapy are to relieve tumor-related symptoms, improve overall quality of life, and prolong time to tumor progression. Studies in a wide range of solid tumors have shown that chemotherapy in patients with advanced disease confers survival benefit when compared with supportive care, providing sound rationale for the early initiation of drug treatment. However, cancer chemotherapy can be curative in only a small subset of patients who present with advanced disease. In adults, these curable cancers include Hodgkin’s and non-Hodgkin’s lymphoma, acute myelogenous leukemia, germ cell cancer, and choriocarcinoma, while the curable childhood cancers include acute lymphoblastic leukemia, Burkitt’s lymphoma,


Pharmacology_Katzung

Pharmacology_Katzung. Hodgkin’s and non-Hodgkin’s lymphoma, acute myelogenous leukemia, germ cell cancer, and choriocarcinoma, while the curable childhood cancers include acute lymphoblastic leukemia, Burkitt’s lymphoma, Wilms’ tumor, and embryonal rhabdomyosarcoma.


Pharmacology_Katzung

Pharmacology_Katzung. Neoadjuvant chemotherapy refers to the use of chemotherapy in patients who present with localized cancer for which alternative local therapies, such as surgery, exist but which have been shown to be less than completely effective. At present, neoadjuvant therapy is most often administered in the treatment of anal cancer, bladder cancer, breast cancer, gastroesophageal cancer, laryngeal cancer, locally advanced non-small cell lung cancer (NSCLC), osteogenic sarcoma, and locally advanced rectal cancer. For diseases such as anal cancer, gastroesophageal cancer, laryngeal cancer, NSCLC, and rectal cancer, optimal clinical benefit is derived when chemotherapy is administered with radiation therapy either concurrently or sequentially. The goal of the neoadjuvant approach is to reduce the size of the primary tumor so that surgical resection can be made easier and more effective. In addition, with rectal cancer and laryngeal cancer, the administration of combined modality ther apy prior to


Pharmacology_Katzung

Pharmacology_Katzung. of the primary tumor so that surgical resection can be made easier and more effective. In addition, with rectal cancer and laryngeal cancer, the administration of combined modality ther apy prior to surgery can result in sparing of vital normal organs, such as the rectum or larynx. In general, additional chemotherapy is given for a defined period of time, usually 3–4 months, after surgery has been performed.


Pharmacology_Katzung

Pharmacology_Katzung. One of the most important roles for cancer chemotherapy is as an adjuvant to local treatment modalities such as surgery, and this has been termed adjuvant chemotherapy. In this setting, chemotherapy is administered after surgery has been performed, and the goal of chemotherapy is to reduce the incidence of both local and systemic recurrence and to improve the overall survival of patients.


Pharmacology_Katzung

Pharmacology_Katzung. In general, chemotherapy regimens with clinical activity against advanced disease may have curative potential following surgical resection of the primary tumor, provided the appropriate dose and schedule are administered. Adjuvant chemotherapy is effective in prolonging both disease-free survival (DFS) and overall survival (OS) in patients with breast cancer, colon cancer, gastric cancer, NSCLC, Wilms’ tumor, anaplastic astrocytoma, and osteogenic sarcoma. Patients with primary malignant melanoma at high risk of local or systemic recurrence derive clinical benefit from adjuvant treatment with the biologic agent interferon α (IFN-α), although this treatment must be given for 1 year’s duration for maximal clinical efficacy. Finally, the antihormonal agents tamoxifen, anastrozole, and letrozole are effective in the adjuvant therapy of postmenopausal women with early-stage breast cancer whose breast tumors express the estrogen receptor (see Chapter 40 for additional details). However,


Pharmacology_Katzung

Pharmacology_Katzung. are effective in the adjuvant therapy of postmenopausal women with early-stage breast cancer whose breast tumors express the estrogen receptor (see Chapter 40 for additional details). However, because these agents are cytostatic rather than cytocidal, they must be administered on a long-term basis, with the standard recommendation being 5 years’ duration.


Pharmacology_Katzung

Pharmacology_Katzung. The key principles of cell cycle kinetics were initially developed using the murine L1210 leukemia as the experimental model system (Figure 54–1). However, drug treatment of human cancers requires a clear understanding of the differences between the characteristics of this rodent leukemia and of human cancers, as well as an understanding of the differences in growth rates of normal target tissues between mice and humans. For example, L1210 is a rapidly growing leukemia with a high percentage of cells synthesizing DNA, as measured by the uptake of tritiated thymidine (the labeling index). Because L1210 leukemia has a growth fraction of 100% (ie, all its cells are actively progressing through the cell cycle), its life cycle is consistent and predictable.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 54–1 Log-kill hypothesis: relationship of tumor cell number to time of diagnosis, symptoms, treatment, and survival. Three alternative approaches to drug treatment are shown for comparison with the course of tumor growth when no treatment is given (dashed line). In the protocol diagrammed at top, treatment (indicated by the arrows) is given infrequently, and the result is manifested as prolongation of survival but with recurrence of symptoms between courses of treatment and eventual death of the patient. The combination chemotherapy treatment diagrammed in the middle section is begun earlier and is more intensive. Tumor cell kill exceeds regrowth, drug resistance does not develop, and “cure” results. In this example, treatment has been continued long after all clinical evidence of cancer has disappeared (1–3 years). This approach has been established as effective in the treatment of childhood acute leukemia, testicular cancers, and Hodgkin’s lymphoma. In the treatment


Pharmacology_Katzung

Pharmacology_Katzung. of cancer has disappeared (1–3 years). This approach has been established as effective in the treatment of childhood acute leukemia, testicular cancers, and Hodgkin’s lymphoma. In the treatment diagrammed near the bottom of the graph, early surgery has been employed to remove the primary tumor and intensive adjuvant chemotherapy has been administered long enough (up to 1 year) to eradicate the remaining tumor cells that comprise the occult micrometastases.


Pharmacology_Katzung

Pharmacology_Katzung. Based on the murine L1210 model, the cytotoxic effects of anticancer drugs follow log cell-kill kinetics. As such, a given agent would be predicted to kill a constant fraction of cells as opposed to a constant number. Thus, if a particular dose of an individual drug leads to a 3-log kill of cancer cells and reduces the tumor burden from 1010 to 107 cells, the same dose used at a tumor burden of 105 cells reduces the tumor mass to 102 cells. Cell kill is, therefore, proportional, regardless of tumor burden. The cardinal rule of chemotherapy—the invariable inverse relation between cell number and curability— was established with the murine L1210 leukemia model, and this relationship is clearly applicable to hematologic malignancies, such as acute leukemias and lymphomas.


Pharmacology_Katzung

Pharmacology_Katzung. Although growth of murine leukemias simulates exponential cell kinetics, mathematical modeling data suggest that most human solid tumors do not grow in such an exponential manner. Rather, the experimental data in human solid cancers support a Gompertzian model of tumor growth and regression. The critical distinction between Gompertzian and exponential growth is that the growth fraction of the tumor is not constant with Gompertzian kinetics but instead decreases exponentially with time (exponential growth is matched by exponential retardation of growth, due to blood supply limitations and other factors). The growth fraction peaks when the tumor is approximately one-third its maximum size. According to the Gompertzian model, when a patient with advanced cancer is treated, the tumor mass is larger, its growth fraction is low, and the fraction of cells killed is, therefore, small. An important feature of Gompertzian growth is that response to chemotherapy in drug-sensitive tumors depends,


Pharmacology_Katzung

Pharmacology_Katzung. its growth fraction is low, and the fraction of cells killed is, therefore, small. An important feature of Gompertzian growth is that response to chemotherapy in drug-sensitive tumors depends, in large measure, on where the tumor is in its particular growth curve.


Pharmacology_Katzung

Pharmacology_Katzung. Information on cell and population kinetics of cancer cells explains, in part, the limited effectiveness of most available anticancer drugs. A schematic summary of cell cycle kinetics is presented in Figure 54–2. This information is relevant to the mode of action, indications, and scheduling of cell cycle– specific (CCS) and cell cycle–nonspecific (CCNS) drugs. Agents falling into these two major classes are summarized in Table 54–1. The Role of Drug Combinations With rare exceptions (eg, choriocarcinoma and Burkitt’s lymphoma), single drugs are unable to cure cancers when they are in an advanced stage. In the 1960s and early 1970s, drug Synthesis of cellular components needed for DNA synthesis Replication of DNA genome


Pharmacology_Katzung

Pharmacology_Katzung. Synthesis of cellular components needed for DNA synthesis Replication of DNA genome FIGURE 54–2 Cell cycle and cancer. A conceptual depiction of the cell cycle phases that all cells—normal and neoplastic—must traverse before and during cell division. The percentages given represent the approximate percentage of time spent in each phase by a typical malignant cell; the duration of G1, however, can vary markedly. Many of the effective anti-cancer drugs exert their action on cells traversing the cell cycle and are called cell cycle-specific (CCS) drugs (see Table 54–1). A second group of agents called cell cycle-nonspecific (CCNS) drugs can sterilize tumor cells whether they are cycling or resting in the G0 compartment. CCNS drugs can kill both G0 and cycling cells (although cycling cells are more sensitive). TABLE 54–1 Cell cycle effects of major classes of anti-cancer drugs.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 54–1 Cell cycle effects of major classes of anti-cancer drugs. combination regimens were developed based on the known biochemical actions of available anti-cancer drugs rather than on their clinical efficacy. Such regimens were, however, largely ineffective. The era of effective combination chemotherapy began when a number of active drugs from different classes became available for use in combination in the treatment of the acute leukemias and lymphomas. Following this initial success with hematologic malignancies, combination chemotherapy was extended to the treatment of solid tumors.


Pharmacology_Katzung

Pharmacology_Katzung. The use of combination chemotherapy is important for several reasons. First, it provides maximal cell kill within the range of toxicity tolerated by the host for each drug as long as dosing is not compromised. Second, it provides a broader range of interaction between drugs and tumor cells with different genetic abnormalities in a heterogeneous tumor population. Finally, it may prevent and/or slow the subsequent development of cellular drug resistance. Of note, these same concepts apply to the therapy of chronic infections, such as HIV and tuberculosis. Certain principles have guided the selection of drugs in the most effective drug combinations, and they provide a paradigm for the development of new drug therapeutic programs. 1.


Pharmacology_Katzung

Pharmacology_Katzung. Certain principles have guided the selection of drugs in the most effective drug combinations, and they provide a paradigm for the development of new drug therapeutic programs. 1. Efficacy: Only drugs known to have some level of clinical efficacy when used alone against a given tumor should be selected for use in combination. If available, drugs that produce complete remission in some fraction of patients are preferred to those that produce only partial responses. 2. Toxicity: When several drugs of a given class are available and are equally effective, a drug should be selected on the basis of toxicity that does not overlap with the toxicity of other drugs in the combination. Although such selection leads to a wider range of adverse effects, it minimizes the risk of a lethal effect caused by multiple insults to the same organ system by different drugs and allows dose intensity to be maximized. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Optimum scheduling: Drugs should be used in their optimal dose and schedule, and drug combinations should be given at consistent intervals. Because long intervals between cycles negatively affect dose intensity, the treatment-free interval between cycles should be the shortest time necessary for recovery of the most sensitive normal target tissue, which is usually the bone marrow. 4. Mechanism of interaction: There should be a clear understanding of the biochemical, molecular, and pharmacokinetic mechanisms of interaction between the individual drugs in a given combination, to allow for maximal antitumor effect. Omission of a drug from a combination may allow overgrowth by a tumor clone sensitive to that drug alone and resistant to other drugs in the combination. 5.


Pharmacology_Katzung

Pharmacology_Katzung. 5. Avoidance of arbitrary dose changes: An arbitrary reduction in the dose of an effective drug in order to add other less effective drugs may reduce the dose of the most effective agent below the threshold of effectiveness and destroy the ability of the combination to cure disease in a given patient.


Pharmacology_Katzung

Pharmacology_Katzung. Dose intensity is one of the main factors limiting the ability of chemotherapy or radiation therapy to achieve cure. As described in Chapter 2, the dose-response curve in biologic systems is usually sigmoidal in shape, with a threshold, a linear phase, and a plateau phase. For chemotherapy, therapeutic selectivity is dependent on the difference between the dose-response curves of normal and tumor tissues. In experimental animal models, the dose-response curve is usually steep in the linear phase, and a reduction in dose when the tumor is in the linear phase of the dose-response curve almost always results in a loss in the capacity to cure the tumor effectively before a reduction in the antitumor activity is observed. Although complete remissions may continue to be observed with dose reductions down to as low as 20% of the optimal dose, residual tumor cells may not be entirely eliminated, thereby allowing for eventual relapse. Because toxicities are usually associated with anticancer


Pharmacology_Katzung

Pharmacology_Katzung. down to as low as 20% of the optimal dose, residual tumor cells may not be entirely eliminated, thereby allowing for eventual relapse. Because toxicities are usually associated with anticancer drugs, it is often appealing for clinicians to avoid acute toxicity by simply reducing the dose and/or by increasing the time interval between each cycle of treatment. However, such empiric modifications in dose represent a major cause of treatment failure, especially in patients with drug-sensitive tumors.


Pharmacology_Katzung

Pharmacology_Katzung. A positive relationship between dose intensity and clinical efficacy has been documented in several solid tumors, including advanced ovarian, breast, lung, and colon cancers, as well as in hematologic malignancies, such as the lymphomas. At present, there are three main approaches to dose-intense delivery of chemotherapy. The first approach, dose escalation, involves increasing the doses of the respective anti-cancer agents. The second strategy is administration of anti-cancer agents in a dose-intense manner by reducing the interval between treatment cycles, while the third approach involves sequential scheduling of either single agents or combination regimens. Each of these strategies is presently being applied to the treatment of a wide range of solid cancers, including breast, colorectal, and NSCLC, and in general, such dose-intense regimens have significantly improved clinical outcomes.


Pharmacology_Katzung

Pharmacology_Katzung. A fundamental problem in cancer chemotherapy is the development of cellular drug resistance. Primary or inherent resistance refers to drug resistance in the absence of prior exposure to available standard agents. The presence of inherent drug resistance was first proposed by Goldie and Coleman in the early 1980s and was thought to result from the genomic instability associated with the development of most cancers. For example, mutations in the p53 tumor suppressor gene occur in up to 50% of all human tumors. Preclinical and clinical studies have shown that loss of p53 function leads to resistance to radiation therapy as well as resistance to a wide range of anti-cancer agents. Defects in the mismatch repair enzyme family, which are tightly linked to the development of familial and sporadic colorectal cancer, are associated with resistance to several unrelated anti-cancer agents, including fluoropyrimidines, thiopurines, and cisplatin/carboplatin. In contrast to primary resistance,


Pharmacology_Katzung

Pharmacology_Katzung. colorectal cancer, are associated with resistance to several unrelated anti-cancer agents, including fluoropyrimidines, thiopurines, and cisplatin/carboplatin. In contrast to primary resistance, acquired resistance develops in response to exposure to a given anti-cancer agent. Experimentally, drug resistance can be highly specific to a single drug and is usually based on a specific change in the genetic machinery of a given tumor cell with amplification or increased expression of one or more genes. In other instances, a multidrug-resistant phenotype occurs, associated with increased expression of the MDR1 gene, which encodes a cell surface transporter glycoprotein (P-glycoprotein, see Chapter 5). This form of drug resistance leads to enhanced drug efflux and reduced intracellular accumulation of a broad range of structurally unrelated anti-cancer agents, including the anthracyclines, vinca alkaloids, taxanes, camptothecins, epipodophyllotoxins, and even small molecule inhibitors, such


Pharmacology_Katzung

Pharmacology_Katzung. of a broad range of structurally unrelated anti-cancer agents, including the anthracyclines, vinca alkaloids, taxanes, camptothecins, epipodophyllotoxins, and even small molecule inhibitors, such as imatinib.


Pharmacology_Katzung

Pharmacology_Katzung. The major clinically useful alkylating agents (Figure 54–3) have a structure containing a bis(chloroethyl)amine, ethyleneimine, or nitrosourea moiety, and they are classified in several different groups. Among the bis(chloroethyl)amines, cyclophosphamide, mechlorethamine, melphalan, and chlorambucil are the most useful. Ifosfamide is closely related to cyclophosphamide but has a somewhat different spectrum of activity and toxicity. Thiotepa and busulfan are used to treat breast and ovarian cancer, and chronic myeloid leukemia, respectively. The major nitrosoureas are carmustine (BCNU) and lomustine (CCNU). Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action As a class, the alkylating agents exert their cytotoxic effects via transfer of their alkyl groups to various cellular constituents. Alkylation of DNA within the nucleus probably represents the major interaction leading to cell death. However, these drugs react chemically with sulfhydryl, amino, hydroxyl, carboxyl, and phosphate groups of other cellular nucleophiles as well. The general mechanism of action of these drugs involves intramolecular cyclization to form an ethyleneimonium ion that may directly or through formation of a carbonium ion transfer an alkyl group to a cellular constituent. In addition to alkylation, a secondary mechanism that occurs with nitrosoureas involves carbamoylation of lysine residues of proteins through formation of isocyanates.


Pharmacology_Katzung

Pharmacology_Katzung. The major site of alkylation within DNA is the N7 position of guanine; however, other bases are also alkylated albeit to lesser degrees, including N1 and N3 of adenine, N3 of cytosine, and O6 of guanine, as well as phosphate atoms and proteins associated with DNA. These interactions can occur on a single strand or on both strands of DNA through cross-linking, as most major alkylating agents are bifunctional, with two reactive groups. Alkylation of guanine can result in miscoding through abnormal base pairing with thymine or in depurination by excision of guanine residues. FIGURE 54–3 Structures of major classes of alkylating agents.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 54–3 Structures of major classes of alkylating agents. The latter effect leads to DNA strand breakage through scission of the sugar-phosphate backbone of DNA. Cross-linking of DNA appears to be of major importance to the cytotoxic action of alkylating agents, and replicating cells are most susceptible to these drugs. Thus, although alkylating agents are not cell cycle-specific, cancer cells are most susceptible to this class of drugs in late G1 and S phases of the cell cycle. The mechanism of acquired resistance to alkylating agents may involve increased capability to repair DNA lesions through increased expression and activity of DNA repair enzymes, decreased cellular transport of the alkylating drug, and increased expression or activity of glutathione and glutathione-associated proteins, which are needed to conjugate the alkylating agent, or increased glutathione S-transferase activity, which catalyzes the conjugation.


Pharmacology_Katzung

Pharmacology_Katzung. The adverse effects associated with alkylating agents are generally dose-related and occur primarily in rapidly growing tissues such as bone marrow (myelosuppression), gastrointestinal tract (diarrhea), and reproductive system. Nausea and vomiting also can be a serious issue with a number of these agents. In addition, they are potent vesicants and can damage tissues at the site of administration as well as produce systemic toxicity. As a class, alkylating agents are carcinogenic in nature, and there is an increased risk of secondary malignancies, especially acute myelogenous leukemia.


Pharmacology_Katzung

Pharmacology_Katzung. Cyclophosphamide is one of the most widely used alkylating agents. One significant advantage of this compound relates to its high oral bioavailability. As a result, it can be administered via the oral and intravenous routes with equal clinical efficacy. It is inactive in its parent form and must be activated to cytotoxic metabolites by liver microsomal enzymes (Figure 54–4). The cytochrome P450 mixed-function oxidase system converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are delivered to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mustard and acrolein—occurs. The liver appears to be protected through the enzymatic formation of the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide. The major toxicities of the individual alkylating agents are outlined in Table 54–2 and discussed below.


Pharmacology_Katzung

Pharmacology_Katzung. The major toxicities of the individual alkylating agents are outlined in Table 54–2 and discussed below. These drugs appear to be non-cross-resistant with other alkylating agents; all require biotransformation, which occurs by nonenzymatic decomposition, to metabolites with both alkylating and carbamoylating activities. The nitrosoureas are highly lipid-soluble and are able to readily cross the blood-brain barrier, making them effective in the treatment of brain tumors. Although the majority of alkylations by the nitrosoureas are on the N7 position of guanine in DNA, the critical alkylation responsible for cytotoxicity appears to be on the O6 position of guanine, which leads to FIGURE 54–4 Cyclophosphamide metabolism. TABLE 54–2 Alkylating agents and platinum analogs: Clinical activity and toxicities. CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 54–4 Cyclophosphamide metabolism. TABLE 54–2 Alkylating agents and platinum analogs: Clinical activity and toxicities. CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia. G-C crosslinks in DNA. After oral administration of lomustine, peak plasma levels of metabolites appear within 1–4 hours; central nervous system concentrations reach 30–40% of the activity present in the plasma. Urinary excretion appears to be the major route of elimination from the body. One naturally occurring sugar-containing nitrosourea, streptozocin, is interesting because it has minimal bone marrow toxicity. This agent has activity in the treatment of insulin-secreting islet cell carcinoma of the pancreas. Several other compounds have mechanisms of action that involve DNA alkylation as their cytotoxic mechanism of action. These agents include procarbazine, dacarbazine, and bendamustine. Their clinical activities and toxicities are listed in Table 54–2.


Pharmacology_Katzung

Pharmacology_Katzung. Procarbazine is an orally active methylhydrazine derivative, and in the clinical setting, it is used in combination regimens for Hodgkin’s and non-Hodgkin’s lymphoma as well as for brain tumors. The precise mechanism of action of procarbazine is uncertain; however, it inhibits DNA, RNA, and protein biosynthesis; prolongs interphase; and produces chromosome breaks. Oxidative metabolism of this drug by microsomal enzymes generates azoprocarbazine and H2O2, which may be responsible for DNA strand scission. A variety of other drug metabolites are formed that may be cytotoxic. One metabolite is a weak monoamine oxidase (MAO) inhibitor, and adverse events can occur when procarbazine is given with other MAO inhibitors as well as with sympathomimetic agents, tricyclic antidepressants, antihistamines, central nervous system depressants, antidiabetic agents, alcohol, and tyramine-containing foods.


Pharmacology_Katzung

Pharmacology_Katzung. There is an increased risk of secondary cancers in the form of acute leukemia, and its carcinogenic potential is thought to be higher than that of other alkylating agents. Dacarbazine is a synthetic compound that functions as an alkylating agent following metabolic activation in the liver by oxidative N-demethylation to the monomethyl derivative. This metabolite spontaneously decomposes to diazomethane, which generates a methyl carbonium ion that is believed to be the key cytotoxic species. Dacarbazine is administered parenterally and is used in the treatment of malignant melanoma, Hodgkin’s lymphoma, soft tissue sarcomas, and neuroblastoma. The main dose-limiting toxicity is myelosuppression, but nausea and vomiting can be severe in some cases. This agent is a potent vesicant, and care must be taken to avoid extravasation during drug administration.


Pharmacology_Katzung

Pharmacology_Katzung. Bendamustine is a bifunctional alkylating agent consisting of a purine benzimidazole ring and a nitrogen mustard moiety. As with other alkylating agents, it forms cross-links with DNA resulting in singleand double-stranded breaks, leading to inhibition of DNA synthesis and function. This molecule also inhibits mitotic checkpoints and induces mitotic catastrophe, which leads to cell death. Of note, the cross-resistance between bendamustine and other alkylating agents is only partial, thereby providing a rationale for its clinical activity despite the development of resistance to other alkylating agents. This agent is approved for use in chronic lymphocytic leukemia, with activity also observed in Hodgkin’s and non-Hodgkin’s lymphoma, multiple myeloma, and breast cancer. The main dose-limiting toxicities include myelosuppression and mild nausea and vomiting. Hypersensitivity infusion reactions, skin rash, and other skin reactions occur rarely.


Pharmacology_Katzung

Pharmacology_Katzung. Three platinum analogs are currently used in clinical practice: cisplatin, carboplatin, and oxaliplatin. Cisplatin (cis-diamminedichloroplatinum [II]) is an inorganic metal complex that was initially discovered through a serendipitous observation that neutral platinum complexes inhibited division and filamentous growth of Escherichia coli. Several platinum analogs were subsequently synthesized. Although the precise mechanism of action of the platinum analogs is unclear, they exert their cytotoxic effects in the same manner as alkylating agents. As such, they kill tumor cells in all stages of the cell cycle and bind DNA through the formation of intrastrand and interstrand cross-links, thereby leading to inhibition of DNA synthesis and function. The primary binding site is the N7 position of guanine, but covalent interaction with the N3 position of adenine and O6 position of cytosine also can occur. In addition to targeting DNA, the platinum analogs have been shown to bind to both


Pharmacology_Katzung

Pharmacology_Katzung. of guanine, but covalent interaction with the N3 position of adenine and O6 position of cytosine also can occur. In addition to targeting DNA, the platinum analogs have been shown to bind to both cytoplasmic and nuclear proteins, which may also contribute to their cytotoxic and antitumor effects. The platinum complexes appear to synergize with certain other anticancer drugs, including alkylating agents, fluoropyrimidines, and taxanes. The major toxicities of the individual platinum analogs are outlined in Table 54–2.


Pharmacology_Katzung

Pharmacology_Katzung. Cisplatin has major antitumor activity in a broad range of solid tumors, including non-small cell and small cell lung cancer, esophageal and gastric cancer, cholangiocarcinoma, head and neck cancer, and genitourinary cancers, particularly testicular, ovarian, and bladder cancer. When used in combination regimens, cisplatin-based therapy has led to the cure of nonseminomatous testicular cancer. Cisplatin and the other platinum analogs are cleared by the kidneys and excreted in the urine. As a result, dose modification is required in patients with renal dysfunction.


Pharmacology_Katzung

Pharmacology_Katzung. Carboplatin is a second-generation platinum analog whose mechanisms of cytotoxic action, mechanisms of resistance, and clinical pharmacology are identical to those described for cisplatin. As with cisplatin, carboplatin has broad-spectrum activity against a wide range of solid tumors. However, in contrast to cisplatin, it exhibits significantly less renal and gastrointestinal toxicity. Its main dose-limiting toxicity is myelosuppression. It has, therefore, been widely used in transplant regimens to treat refractory hematologic malignancies. Moreover, since vigorous intravenous hydration is not required for carboplatin therapy, carboplatin is viewed as an easier agent to administer to patients, and as such, it has replaced cisplatin in various combination chemotherapy regimens.


Pharmacology_Katzung

Pharmacology_Katzung. Oxaliplatin is a third-generation diaminocyclohexane platinum analog. Its mechanism of action and clinical pharmacology are identical to those of cisplatin and carboplatin. However, tumors that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects are not cross-resistant to oxaliplatin, and this finding may explain the clinical activity of this platinum compound in colorectal cancer. Oxaliplatin was initially approved for use as second-line therapy in combination with the fluoropyrimidine 5-fluorouracil (5-FU) and leucovorin, termed the FOLFOX regimen, for metastatic colorectal cancer. There are various iterations of the FOLFOX regimen, which have now become the most widely used combinations in the first-line treatment of advanced colorectal cancer. This regimen also plays a major role in the adjuvant therapy of stage III colon cancer and high-risk stage II colon cancer. Clinical activity has also been observed in other gastrointestinal cancers, such as


Pharmacology_Katzung

Pharmacology_Katzung. also plays a major role in the adjuvant therapy of stage III colon cancer and high-risk stage II colon cancer. Clinical activity has also been observed in other gastrointestinal cancers, such as pancreatic, gastroesophageal, and hepatocellular cancer. Neurotoxicity is the main dose-limiting toxicity, and it is manifested by a peripheral sensory neuropathy. There are two forms of neurotoxicity, an acute form that is often triggered and worsened by exposure to cold, and a chronic form that is dose-dependent. Although the chronic form of oxaliplatin toxicity is dependent on the cumulative dose of drug administered, it tends to be more readily reversible than that observed with cisplatin-induced neurotoxicity.


Pharmacology_Katzung

Pharmacology_Katzung. The antimetabolites represent an important class of agents that have been rationally designed and synthesized based on knowledge of critical cellular processes involved in DNA biosynthesis. The individual antimetabolites and their respective clinical spectrum and toxicities are presented in Table 54–3 and are discussed below.


Pharmacology_Katzung

Pharmacology_Katzung. Methotrexate (MTX) is a folic acid analog that binds with high affinity to the active catalytic site of dihydrofolate reductase (DHFR). This results in inhibition of synthesis of tetrahydrofolate (THF), the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. Inhibition of these metabolic processes interferes with the formation of DNA, RNA, and key cellular proteins (see Figure 33–3). Intracellular formation of polyglutamate metabolites, with the addition of up to 5–7 glutamate residues, is critically important for the therapeutic action of MTX, and this process is catalyzed by the enzyme folylpolyglutamate synthase (FPGS). MTX polyglutamates are selectively retained within cancer cells, and they display increased inhibitory effects on enzymes involved in de novo purine nucleotide and thymidylate biosynthesis, making them important determinants of MTX’s cytotoxic action.


Pharmacology_Katzung

Pharmacology_Katzung. Several resistance mechanisms to MTX have been identified, and they include (1) decreased drug transport via the reduced folate carrier or folate receptor protein, (2) decreased formation of cytotoxic MTX polyglutamates, (3) increased levels of the target enzyme DHFR through gene amplification and other genetic mechanisms, and (4) altered DHFR protein with reduced affinity for MTX. Recent studies have suggested that decreased accumulation of drug through activation of the multidrug resistance transporter P170 glycoprotein also may result in drug resistance.


Pharmacology_Katzung

Pharmacology_Katzung. MTX is administered by the intravenous, intrathecal, or oral route. However, oral bioavailability is saturable and erratic at doses greater than 25 mg/m2. Renal excretion is the main route of elimination and is mediated by glomerular filtration and tubular secretion. As a result, dose modification is required in the setting of renal dysfunction. Care must also be taken when MTX is used in the presence of drugs such as aspirin, nonsteroidal anti-inflammatory agents, penicillin, and cephalosporins, as these agents inhibit the renal excretion of MTX. The biologic effects of MTX can be reversed by administration of the reduced folate leucovorin (5-formyltetrahydrofolate) or by L-leucovorin, which is the active enantiomer. Leucovorin rescue is used in conjunction with high-dose MTX therapy to rescue normal cells from undue toxicity, and it has also been used in cases of accidental drug overdose. The main adverse effects are listed in Table 54–3.


Pharmacology_Katzung

Pharmacology_Katzung. Pemetrexed is a pyrrolopyrimidine antifolate analog with activity in the S phase of the cell cycle. As in the case of MTX, it is TABLE 54–3 Antimetabolites: Clinical activity and toxicities. Drug Mechanism of Action Clinical Applications Toxicity Capecitabine Inhibits TS; incorporation of FUTP into RNA Breast cancer, colorectal can-Diarrhea, hand-foot syndrome, resulting in alteration in RNA processing; cer, gastroesophageal cancer, myelosuppression, nausea and incorporation of FdUTP into DNA resulting hepatocellular cancer, pancreatic vomiting in inhibition of DNA synthesis and function cancer 5-Fluorouracil Inhibits TS; incorporation of FUTP into RNA Colorectal cancer, anal cancer, breast Nausea, mucositis, diarrhea, bone resulting in alteration in RNA processing; cancer, gastroesophageal cancer, marrow depression, neurotoxicity incorporation of FdUTP into DNA resulting head and neck cancer, hepatocellular in inhibition of DNA synthesis and function cancer


Pharmacology_Katzung

Pharmacology_Katzung. Methotrexate Inhibits DHFR; inhibits TS; inhibits de novo Breast cancer, head and neck cancer, Mucositis, diarrhea, myelosup purine nucleotide synthesis osteogenic sarcoma, primary central pression with neutropenia and nervous system lymphoma, non-thrombocytopenia Hodgkin’s lymphoma, bladder cancer, choriocarcinoma Pemetrexed Inhibits TS, DHFR, and purine nucleotide Mesothelioma, non-small cell lung Myelosuppression, skin rash, synthesis cancer mucositis, diarrhea, fatigue, hand-foot syndrome Cytarabine Inhibits DNA chain elongation, DNA synthesis and repair; inhibits ribonucleotide reductase with reduced formation of dNTPs; incorporation of cytarabine triphosphate into DNA Gemcitabine Inhibits DNA synthesis and repair; inhibits ribonucleotide reductase with reduced formation of dNTPs; incorporation of gemcitabine triphosphate into DNA resulting in inhibition of DNA synthesis and function


Pharmacology_Katzung

Pharmacology_Katzung. Fludarabine Inhibits DNA synthesis and repair; inhibits ribonucleotide reductase; incorporation of fludarabine triphosphate into DNA; induction of apoptosis AML, ALL, CML in blast crisis Pancreatic cancer, bladder cancer, breast cancer, non-small cell lung cancer, ovarian cancer, non-Hodgkin’s lymphoma, soft tissue sarcoma Non-Hodgkin’s lymphoma, CLL Nausea and vomiting, myelosuppression with neutropenia and thrombocytopenia, cerebellar ataxia Nausea, vomiting, diarrhea, myelosuppression Myelosuppression, immunosuppression, nausea and vomiting, fever, myalgias, arthralgias


Pharmacology_Katzung

Pharmacology_Katzung. Nausea, vomiting, diarrhea, myelosuppression Myelosuppression, immunosuppression, nausea and vomiting, fever, myalgias, arthralgias Cladribine Inhibits DNA synthesis and repair; inhibits Hairy cell leukemia, CLL, Myelosuppression, nauribonucleotide reductase; incorporation of non-Hodgkin’s lymphoma sea and vomiting, and cladribine triphosphate into DNA; induction immunosuppression of apoptosis 6-Mercaptopurine Inhibits de novo purine nucleotide synthe-AML Myelosuppression, immunosup(6-MP) sis; incorporation of triphosphate into RNA; pression, and hepatotoxicity incorporation of triphosphate into DNA 6-Thioguanine Same as 6-MP ALL, AML Same as 6-MP ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; DHFR, dihydrofolate reductase; dNTP, deoxyribonucleotide triphosphate; FdUTP, 5-fluorodeoxyuridine-5′-triphosphate; FUTP, 5-fluorouridine-5′-triphosphate; TS, thymidylate synthase.


Pharmacology_Katzung

Pharmacology_Katzung. transported into the cell via the reduced folate carrier and requires activation by FPGS to yield higher polyglutamate forms. While this agent targets DHFR and enzymes involved in de novo purine nucleotide biosynthesis, its main mechanism of action is inhibition of thymidylate synthase (TS). Pemetrexed is currently approved for use in combination with cisplatin in the treatment of mesothelioma, as a single agent in the second-line therapy of NSCLC, in combination with cisplatin for the first-line treatment of NSCLC, and most recently, as maintenance therapy in patients with NSCLC whose disease has not progressed after four cycles of platinum-based chemotherapy. As with MTX, pemetrexed is mainly excreted in urine, and dose modification is required in patients with renal dysfunction. The main adverse effects include myelosuppression, skin rash, mucositis, diarrhea, fatigue, and hand-foot syndrome. Of note, vitamin supplementation with folic acid and vitamin B12 has been shown to


Pharmacology_Katzung

Pharmacology_Katzung. The main adverse effects include myelosuppression, skin rash, mucositis, diarrhea, fatigue, and hand-foot syndrome. Of note, vitamin supplementation with folic acid and vitamin B12 has been shown to significantly reduce the toxicities associated with pemetrexed, while not interfering with clinical efficacy. The hand-foot syndrome is manifested by painful erythema and swelling of the hands and feet, and treatment with the steroid dexamethasone is effective in reducing the incidence and severity of this skin toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Pralatrexate is a 10-deaza-aminopterin antifolate analog, and as in the case of MTX, it is transported into the cell via the reduced folate carrier (RFC) and requires activation by FPGS to yield higher polyglutamate forms. This molecule was originally designed to be a more potent substrate for the RFC-1 carrier protein and to serve as an improved substrate for FPGS. This agent inhibits DHFR, inhibits enzymes involved in de novo purine nucleotide biosynthesis, and also inhibits TS. Pralatrexate is presently approved for use in the treatment of relapsed or refractory peripheral T-cell lymphoma. Consistent with other antifolate analogs, pralatrexate is mainly excreted in the urine, and dose modification is required in renal dysfunction. The main adverse effects include myelosuppression, skin rash, mucositis, diarrhea, and fatigue. As with pemetrexed, vitamin supplementation with folic acid and vitamin B12 appears to reduce the toxicities associated with pralatrexate, without interfering


Pharmacology_Katzung

Pharmacology_Katzung. rash, mucositis, diarrhea, and fatigue. As with pemetrexed, vitamin supplementation with folic acid and vitamin B12 appears to reduce the toxicities associated with pralatrexate, without interfering with clinical efficacy.


Pharmacology_Katzung

Pharmacology_Katzung. 5-Fluorouracil (5-FU) is inactive in its parent form and requires activation via a complex series of enzymatic reactions to ribosyl and deoxyribosyl nucleotide metabolites. One of these metabolites, 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP), forms a covalently bound ternary complex with the enzyme TS and the reduced folate 5,10-methylenetetrahydrofolate, a reaction critical for the de novo synthesis of thymidylate. Formation of this ternary complex results in inhibition of DNA synthesis through “thymineless death.” 5-FU is converted to 5-fluorouridine-5′triphosphate (FUTP), which is then incorporated into RNA, where it interferes with RNA processing and mRNA translation. 5-FU is also converted to 5-fluorodeoxyuridine-5′-triphosphate (FdUTP), which is subsequently incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function. Thus, the cytotoxicity of 5-FU is thought to be mediated by the combined effects of both DNAand RNA-mediated events.


Pharmacology_Katzung

Pharmacology_Katzung. 5-FU is administered intravenously, and the clinical activity of this drug is highly schedule-dependent. Because of its extremely short half-life, approximately 10–15 minutes, infusion administration schedules have been generally favored over bolus schedules. Up to 80–85% of an administered dose of 5-FU is catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD). There is an autosomal recessive pharmacogenetic syndrome involving partial or complete deficiency of the DPD enzyme that is seen in up to 5% of cancer patients. In this particular setting, severe, excessive toxicity is observed with the classic triad of myelosuppression, GI toxicity in the form of diarrhea and/or mucositis, and neurotoxicity.


Pharmacology_Katzung

Pharmacology_Katzung. 5-FU remains the most widely used agent in the treatment of colorectal cancer, both as adjuvant therapy and for advanced disease. It also has activity against a wide range of solid tumors, including cancers of the breast, stomach, pancreas, esophagus, liver, head and neck, and anus. Major toxicities include myelosuppression, gastrointestinal toxicity in the form of mucositis and diarrhea, skin toxicity manifested by the hand-foot syndrome, and neurotoxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Capecitabine is a fluoropyrimidine carbamate prodrug with 70–80% oral bioavailability. As with 5-FU, capecitabine is inactive in its parent form and undergoes extensive metabolism in the liver by the enzyme carboxylesterase to an intermediate, 5′-deoxy-5-fluorocytidine. This metabolite is then converted to 5′-deoxy-5-fluorouridine by the enzyme cytidine deaminase. These two initial steps occur mainly in the liver. The 5′-deoxy5-fluorouridine metabolite is finally hydrolyzed by thymidine phosphorylase to 5-FU directly in the tumor. The expression of thymidine phosphorylase has been shown to be significantly higher in a broad range of solid tumors than in corresponding normal tissue, particularly in breast cancer and colorectal cancer (CRC).