Antiparasitic Drugs For Intestinal Parasite Infections From Worms

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Antiparasitic Drugs For Intestinal Parasite Infections From Worms

FIVE DRUGS COVER THE MOST COMMON PARASITIC WORM INFECTIONS

 

Introduction

 

The World Health Organization (WHO) has recommended community-wide

mass treatment of helminth (parasitic worm) infections. Virtually all

of the important parasitic worm infections in humans can be treated

with one of 5 anthelmintics currently in use: albendazole,

mebendazole, diethylcarbamazine, ivermectin and praziquantel. The aim

of anthelmintic therapy is to reduce the intensity of infection below

the level of clinical significance. However, measures must also be

taken to avoid the emergence of resistance against the available

therapies.

Over 25% of World Population Infected

 

The helminths that infect humans can be categorized into 3 groups:

 

* nematodes (round/thread/pinworms)

* trematodes (flukeworms)

* cestodes (tapeworms).

 

Together, these helminths infect more than a quarter of the world's

population, giving rise to much morbidity. With a few exceptions, the

occurrence of disease or disability because of the infection is

dependent on the intensity of infection: heavy infections are much

more likely to result in disease than light infections. Thus, although

the ideal aim of chemotherapy would be a complete cure, reduction of

the intensity of infection below the level of clinical significance

may be sufficient to reduce the occurrence of morbidity and to reduce

transmission.

Most Worms Do Not Multiply in Human Host

 

Helminths have complex life cycles, but in many of the species of

human parasites (with a few important exceptions), the adult worms do

not actually multiply in the human host. Thus, in most of these

helminth infections, each individual parasite may be considered to be

the result of a separately acquired infective stage.

 

However, a few of the helminths that infect humans can either complete

their entire life cycle in the same host (such as in strongyloidiasis)

or infect humans only during the larval phase (e.g. larva migrans,

hydatidosis, cysticercosis). They are much less common, but can cause

much more serious disease. Thus, the principal value of

chemotherapeutic agents in these infections is in the treatment of the

individual rather than in controlling transmission.

Five Agents Treat Most Infections

 

Many of the anthelmintics available for human use are effective

against several helminth species, and although there are over 20

different species of helminths that cause disease of global

significance in humans (see table 1), almost all of these infections

can be treated or controlled with one of 5 anthelmintics: the

benzimidazoles albendazole and mebendazole, diethylcarbamazine,

ivermectin, and praziquantel.

WHO Recommended Treatments

 

The WHO has made various recommendations regarding the treatment of

helminth infections. Essential agents for the treatment of intestinal

nematode infections listed by the WHO include pyrantel, levamisole*

and piperazine* , in addition to mebendazole and albendazole.

Moreover, they recommend metrifonate* and oxamniquine* , in addition

to praziquantel, for the treatment of schistosomes.

Useful Drug Combinations

 

Apart from monotherapy, various drug combinations have been suggested

to be useful in the treatment of parasitic worm infections in

particular situations.

Cimetidine Increases Drug Concentrations

 

The combined administration of cimetidine and mebendazole to patients

with hydatid cysts has been reported to result in greater serum

concentrations and therapeutic effects of mebendazole than when

mebendazole was used alone. In addition, a recent report on the use of

cimetidine in combination with albendazole for the treatment of cystic

echinococcosis also found that concentrations and therapeutic effects

of albendazole were significantly higher in patients receiving

combination therapy than in those receiving albendazole alone.

More Than One Infection

 

Simultaneous administration of praziquantel and a benzimidazole has

been suggested as a simple and cheap means of delivering treatment

against all 3 major geohelminths and the schistosomes.

 

Results from a multi-center, double-blind trial have shown that the

efficacy of concomitant albendazole and praziquantel therapy was

indistinguishable from the efficacy of each drug alone, and that the

frequency and severity of adverse effects were also unaffected.

Treatment During Pregnancy

 

The management of parasitic worm infections during pregnancy is not an

uncommon situation. However, there are some unsolved problems in

relation to the use of anthelmintics in pregnancy. One of the most

important is the issue of treating hookworm infections in pregnant

women, since they are at particularly high risk of developing

iron-deficiency anemia, especially in areas where nutritional anemia

is endemic.

Mebendazole

 

Although mebendazole has been reported to be teratogenic in rats, only

1 human malformation was recorded in a retrospective study of 112

pregnancies. In Sri Lanka, where anemia in pregnancy is a major

problem, and hookworm is endemic in many parts of the country, it has

been national policy since 1994 to treat all pregnant women with a

single course of mebendazole at the first antenatal visit after

completion of the first trimester.

Albendazole

 

Since albendazole is absorbed at a greater rate than mebendazole, it

is possible that it could be associated with more adverse effects.

 

However, teratogenicity was not reported among 10 cases of women who

were exposed accidentally to high doses of albendazole (for systemic

infection) during the first trimester and followed-up to term.

Diethylcarbamazine and Ivermectin

 

Diethylcarbamazine has been very widely used for the treatment of

human filariasis for several decades now, and ivermectin has been

widely used in community-based mass chemotherapy programs.

 

There are no reports of teratogenicity in humans in association with

the use of either drug. In the mouse, however, ivermectin has been

associated with cleft palate and occasional unexplained maternal

deaths, despite its safety in the rat and rabbit. As a result, it is

not recommended for use during pregnancy.

Praziquantel

 

Praziquantel has not been found to be teratogenic in animals, but

there are no satisfactory recorded studies during human pregnancy.

Drug Resistance to Be Avoided

 

As yet there is no confirmed report of anthelmintic drug resistance in

a soil-transmitted nematode infection in humans. However, resistance

to benzimidazoles, levamisole, and, to a lesser extent, avermectins,

are commonly reported in the veterinary literature. Thus, there is

understandable concern that this problem may threaten the use of

anthelmintic drugs for the control of soil-transmitted nematodes in

humans.

 

Chemotherapy should be used in such a way that the emergence of drug

resistance is delayed or circumvented, while health benefits continue

to accrue. Factors that can act against the development of drug

resistance include.

 

* treatment of only a proportion of the population in an infected

community (e.g. targeting school children), which will ensure that

some nematodes remain in the community and that the genes of these

survivors will dilute those of the nematodes experiencing selection

pressure

* giving treatment at intervals greater than those of the

nematode's generation time

* changing the drug of choice for a particular control program.

 

At the same time, development of a protocol for the detection of

suspected drug resistance, e.g. fecal egg count reduction tests, would

be prudent.

Hygiene Is Crucial

 

Helminthic infection is readily passed on through contact; therefore,

rigorous hygiene measures should be employed. Ideally, the infected

person and all family/community members should wash their hands

thoroughly prior to preparing, handling or eating food. Fingernails

should be kept short and scrubbed with a nailbrush. Children with

intestinal worms should wear underpants under pyjamas to prevent the

transmission of eggs to their fingers if they scratch during sleep.

Finally, infected patients should wash in the morning to remove any

eggs laid overnight.

Tables

Table 1. Comparative efficacy of the 5 most widely used anthelmintics

in the treatment of parasitic worm infections

 

 

 

 

 

 

Mebendazole

 

 

Albendazole

 

 

Diethylcarbamazine

 

 

Ivermectin

 

 

Praziquantel

 

Nematode (round/thread/pinworm) infections

 

Ascariasis

 

 

++

 

 

++

 

 

-

 

 

++

 

 

-

 

Trichuriasis

 

 

++

 

 

+

 

 

-

 

 

±

 

 

-

 

Hookworm infections

 

 

+

 

 

++

 

 

-

 

 

-

 

 

-

 

Strongyloidiasis

 

 

±

 

 

+

 

 

-

 

 

++

 

 

-

 

Enterobiasis

 

 

++

 

 

++

 

 

-

 

 

+

 

 

-

 

Trichinellosis

 

 

±

 

 

±

 

 

-

 

 

-

 

 

-

 

Intestinal capillariasis

 

 

+

 

 

+

 

 

-

 

 

-

 

 

-

 

Cutaneous larva migrans

 

 

-

 

 

+

 

 

-

 

 

-

 

 

-

 

Visceral larva migrans

 

 

+

 

 

+

 

 

+

 

 

-

 

 

-

 

Lymphatic filariasis

 

 

-

 

 

-

 

 

++

 

 

++

 

 

-

 

Onchocerciasis

 

 

-

 

 

-

 

 

(++)

 

 

++

 

 

-

 

Loiasis

 

 

-

 

 

-

 

 

(++)

 

 

++

 

 

-

 

Dracunculiasis

 

 

-

 

 

-

 

 

-

 

 

-

 

 

-

 

Cestode (tapeworm) and trematode (flukeworm) infections

 

Taeniasis

 

 

±

 

 

+

 

 

?

 

 

?

 

 

++

 

Hymenolepis nana infection

 

 

-

 

 

-

 

 

?

 

 

?

 

 

++

 

Cysticercosis

 

 

±

 

 

+

 

 

?

 

 

?

 

 

+

 

Echinococcosis

 

 

+

 

 

+

 

 

?

 

 

?

 

 

±

 

Schistosoma mansoni infection

 

 

±

 

 

-

 

 

?

 

 

?

 

 

++

 

S. haematobium infection

 

 

±

 

 

-

 

 

?

 

 

?

 

 

++

 

S. japonicum infection

 

 

-

 

 

-

 

 

?

 

 

?

 

 

++

 

Fascioliasis

 

 

-

 

 

-

 

 

?

 

 

?

 

 

±

 

Fasciolopsiasis

 

 

-

 

 

-

 

 

?

 

 

?

 

 

++

 

Clonorchiasis

 

 

-

 

 

±

 

 

?

 

 

?

 

 

+

 

Opisthorchiasis

 

 

-

 

 

±

 

 

?

 

 

?

 

 

+

 

Paragonimiasis

 

 

-

 

 

-

 

 

?

 

 

?

 

 

++

 

Symbols: ++ = highly effective; + = moderately effective; ± =

minimally effective; - = not effective/not used for this condition;

(++) = parasiticidal but associated with severe adverse reactions; ? =

information not available.

 

 

 

 

Table 2. Differential Features: Comparison of the 5 most widely used

anthelmintics in the treatment of parasitic worm infections

 

 

 

Drug

 

 

Mebendazole

 

 

Albendazole

 

 

Diethylcarbamazi ne

 

 

Ivermectin

 

 

Praziquantel

 

Class

 

 

Benzimidazole

 

 

Benzimidazole

 

 

Piperazine derivative

 

 

Macrocyclic lactone (avermectin)

 

 

Pyrazinoquinoline

 

Indications (see table 1 for more detailed spectrum)

 

 

Drug of choice for threadworm; also roundworm, whipworm, hookworm

infections

 

 

Adjunct to surgery in hydatid cysts caused by Echinococcus granulosus

or E. multilocularis, or primary treatment if surgery not available;

strongyloidia sis

 

 

Microfilariae and adult worms of Loa loa, Wuchereria bancrofti, Brugia

malayi

 

 

Drug of choice for onchocerciasis

 

 

Drug of choice for schistosomes. Highly effective in most tapeworma

and flukeworm infections

 

Age

 

 

Adults and children >2 yearsb

 

 

Adults and children >2 years

 

 

All ages

 

 

All ages

 

 

All ages

 

Usual oral dosage (UD)

 

 

100 mg twice daily for 3 days or 500 mg single dose

 

 

800 mg/day in divided doses for 28 days, followed by 14 drug-free days

per cyclec

 

 

Gradually increase over 3 days from 1 to 6 mg/kg/day in divided doses;

maintain for 21 days

 

 

150 µg/kg single dosed

 

 

40 mg/kg in divided doses 4-6 hours apart

 

Specific dosages

 

 

E. vermicularis: 100 mg single dose (repeat 2-4 times at 7- to 14-day

intervals if needed); C. philippinensis: 20- to 30-day course; E.

granulosus: </=50 mg/kg/day for 3-4 weeks

 

 

A. lumbricoides: 400mg single dose ; E. granulosis: UD, up to 3

treatment cycles; adjunct in surgical treatment of hydatid cysts: pre-

and/or post-surgery, UD, repeat once

 

 

 

 

 

 

 

 

S. japonicum: 60 mg/kg in 3 divided doses

 

Tolerability

 

 

GI disturbances, allergic reactions, raised liver enzyme levels,

alopecia, reversible bone marrow depression (more frequent with

high-dose therapy). High-dose therapy requires blood and liver monitoring

 

 

GI disturbances, headache, dizziness, changes in liver enzyme levels;

rarely reversible alopecia; rash, fever, blood disorders; allergic

shock if cyst leakage occurs; convulsions and meningism in cerebral

disease

 

 

Mild headache, general weakness, joint pains, anorexia, nausea and

vomiting; febrile reaction (in heavy infections), and small risk of

encephalopathy (in heavy L. loa infection); inpatient supervision

required; renal excretion in chronic renal disease

 

 

Dose-dependent fever, itching, dizziness, edema, mild Mazotti

reaction, minimal ocular inflammation in patients with eye

involvement, postural hypotension

 

 

Dose-dependent mild to moderate and transient dizziness, headache,

lassitude, limb pain, abdominal distress, bloody diarrhea

 

Contraindications

 

 

Pregnancye, breast-feeding

 

 

Pregnancyf, breast-feeding

 

 

Pregnancy

 

 

Pregnancyf

 

 

Pregnancy

 

bNot recommended for children <2 years.

cProlonged treatment may be required for the treatment of E.

multilocularis.

dRetreat at 6- to 12-month intervals until the adult worms die.

eWHO recommends that mebendazole not be administered during the first

trimester; however, the manufacturers have reported that the incidence

of malformations and spontaneous abortions is not greater than that

observed in the general population.

fNot recommended during the first trimester.

Abbreviations and symbol: GI = gastrointestinal; NA = not available;

= substantially reduced.

 

 

 

Source: World Health Organization