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Strategies in the chemotherapy of schistosomiasis
IIDN1
Int :cti(. tls Disc", -s .Ncv ,,sl tt
Editor P a u l D. H o e p r i c h , MD
Volume 6, Number 1, January 1987
Division of Infectious and Immunologic Diseases University of California, Davis Medical Center
Associate Editors R u t h M. L a w r e n c e , MD
L a r r y K. Pickering, MD
Charles W. S t r a t t o n , MD
Division of Infectious Diseases Texas Tech University Health Sciences Center
Program in Infectious Diseases and Clinical Microbiology The University of Texas Medical School at Houston
Department of Pathology Vanderbilt University Medical Center
HIIt~lll ,
Strategies in the Chemotherapy of Schistosomiasis A l f r e d W. S e n f t
Spontaneous Bacterial Peritonitis Hoi Ho and Stuart M. Polly
CASE R E P O R T Ronald A. Sherman COMMENTS ON CURRENT PUBLICATIONS
Elsevier 0278-2316/87/$0.00 + 2.20
Strategies in the Chemotherapy of Schistosomiasis A l f r e d W . S e n f t , MD Division of Biology and Medicine, Brown University, Providence, Rhode Island The adult schistosomes that infect humans and other mammals are large (0.5 to 15 mm long), cylindrical trematodes that dwell in venules as male or female worms--unlike the hermaphroditic state of most other parasitic flukes. After the larval cercariae emerge from snails, they penetrate the skin of the final host, migrating first to the lungs, where organogenesis begins. They then proceed to the liver sinusoids where further growth, maturation, and mating ensue. Adult worms move into various afferent vessels of the portal venous system, or into the venular network of the urinary bladder. Adult schistosomes are not attacked effectively by humoral antibodies, and they are not easily killed by the cellular components of body defenses. In fact, they seem not to be recognized as foreign by the immunosurveillance system, apparently because they are able to coat themselves with host-derived antigens. In the absence of effective treat-
ment, adult schistosomes may live for decades. While they do not multiply in the body, the unending production of eggs, as well as hemoglobin-derived pigment ejected as a byproduct of digestion of erythrocytes, leads to severe immunofibrotic reaction in the gut, bladder, and liver. Eventually, a severely infected patient may succumb to a combination of intestinal peri-oval lesions, liver failure from heptofibrosis, varicosities secondary to portal hypertension, or intercurrent infections. Secondary carcinomas may develop at the site of intense tissue reaction, eg, in the bladder in the case of infection with Schistosoma hematobium. Surgical removal of worms has been achieved by first administering drugs that immobilize the schistosomes, followed by filtering the portal blood. In the few instances in which such an heroic intervention was carried out, hundreds of worms were trapped on the filter. But such a procedure demands special medi-
ISSN 0278-2316
I D I N D N 6 ( I ) I - 8 , 1987
2 I n l c c t i o u s D i s e a s e s N e w s l e t t e r 6( 1 )
.lanuar\ 1987
cal facilities, and is not possible for the millions of patients with schistosomiasis who live in developing countries. Considerable progress has been made in designing immunologic approaches to prevent infection, or to control the body burden of worms. In mouse models, partial protection against challenge resulted from passive immunization, as well as from active immunization with components of the worm tegument. However, achieving solid immunity in humans by administering selected antigens is a development that will not be available for some time. Chemotherapy thus remains the mainstay for the treatment of patients infected with schistosomes. Many antischistosomal agents have been tried in therapy, and particular drugs are best discussed in relation to the physiological targets against which they are aimed.
Carbohydrate Metabolism Heavy metals were first used in the treatment of bilharziasis in 1917 with the IV application of potassium antimonyl tartrate. It was exceedingly toxic and over subsequent decades less toxic agents became available, eg, stib0phen (Fuadin), antimony dimercaptosuccinate (Astiban), both trivalent antimonials. These latter two drugs supply antimony in a metastable configuration that de-chelates to allow for the formation of mercapto-antimony bonds within the worms. The major target appears to be phosphofructokinase (PFK), a regulatory enzyme also utilized by humans. Although h u m a n P F K binds antimony with only about 1% of the avidity of the schistosomal enzyme, some toxicity in humans may arise from interaction with human PFK. Thus, although intereference with schisto-
somal glycolytic fermentative metabolism is an effective target, the problem of host reactions to this class of compounds has resulted in the current phasing out of heavy metal chemotherapy. Besides having an active catabolism of glucose, schistosomes also accumulate and store glycogen. Niridazole (NRZ) inhibits the anabolism of glycogen and facilitates glycogenolysis. Schistosomes exposed to N R Z rapidly deplete glycogen stores found in integumentary tubercles and in muscular tissue. In humans, metabolites of N R Z cause transient disturbances of function of the central nervous system, depress immune competence, may inhibit spermiogenesis, and produce extremely malodorous urine. Used primarily against S c h i s t o s o m a mansoni and S. h e m a t o b i u m , N R Z has the advantages of peroral administration, and cost of only about $1.00/case. It is well tolerated in children if they have normal liver function, yielding cure rates of about 70% after an 8-day course. In adults, the cure rate is about 85%, but almost half of adults stop treatment because of adverse reactions. Oxamniquine (Vancil, OXM) is more costly than NRZ, but is also perorally administrable. Its mode of action is not known. In a recent, large-scale antischistosomal campaign in Brazil, reinfection in children five years after treatment with OXM was a major problem. Thus, eradication of a worm burden was not followed by long-term immunity.
Neurotropic Drugs Metrifonate (MTR) is an organophosphate compound that blocks schistosomal acetylcholinesterase while having little effect on the human enzyme. The effect on schistosomes is to produce flaccidity that
may or may not be lethal. Schistos o m a m a n s o n i are swept in the portal blood to the liver; while the liver is inhospitable to adult worms, some survive to migrate back to afferent portal vessels. In contrast, when S. h e m a t o b i u m are paralyzed by dichlorovos (the active form of MTR), they are swept into the lungs where they are trapped and die. As a result, clinically, MTR is much more effective against S. hematob i u m than against either S. m a n s o n i or S c h i s t o s o m a j a p o n i c u m .
Newer Drugs Praziquantel (PZQ) is the first perorally administrable drug that is fully effective against all species of schistosomes. In addition, it is effective against most other flukes and most cestodes parasitic in humans. When schistosomes are exposed to micromolar concentrations of PZQ, within seconds they contract vigorously, contorting into tight spiral coils. Their tegument undergoes dramatic destruction as many regions of the outer lamellae are shredded and stripped away; bullae and microblebs form in the tegument, particularly on and around the worm tubercles (Figure 1). Denuded regions ooze lipids, and antigens are exposed that attract cellular elements of host defenses. With breeching of the tegument, it may be that schistosomes become vulnerable to destruction by phagocytic cells. The destabilization of the tegument appears to result from the entry of external calcium into the worms. Recently, several calcium channel blockers, such as verapamil and nifedipine, were found to cause similar lesions. While the latter drugs would be expected to limit ingress of calcium, the effect of PZQ is to facilitate influx; that is the destructive effect of drugs that (continued on page 7)
Infectious Diseases Newsletter (ISSN 0278-2316) is issued monthly in one indexed volume per year by Elsevier Science Publishing Co., Inc., 52 Vanderbih Avenue, New York, NY 10017, Printed in USA at 25 Sand Creek Road. Albany, NY 12205. Subscription price per year: institutions, $112.00; individuals, $56.00. For air mail to Europe. add $21.00; for air mail elsewhere, add $24.00. Second-class postage pending at New York. NY. and at additional mailing offices Postmaster: Send address changes to Infectious Diseases Newsletter, Elsevier Science Publishing C o . lnc , 52 Vanderbilt Avenue. New York, NY 10017.
© 1987 Elsevier Science Publishing Co., Inc. 0278-2316 87 $0.00- 2.20
Int :cti(. tls Disc", -s .Ncv ,,sl tt
Editor P a u l D. H o e p r i c h , MD
Volume 6, Number 1, January 1987
Division of Infectious and Immunologic Diseases University of California, Davis Medical Center
Associate Editors R u t h M. L a w r e n c e , MD
L a r r y K. Pickering, MD
Charles W. S t r a t t o n , MD
Division of Infectious Diseases Texas Tech University Health Sciences Center
Program in Infectious Diseases and Clinical Microbiology The University of Texas Medical School at Houston
Department of Pathology Vanderbilt University Medical Center
HIIt~lll ,
Strategies in the Chemotherapy of Schistosomiasis A l f r e d W. S e n f t
Spontaneous Bacterial Peritonitis Hoi Ho and Stuart M. Polly
CASE R E P O R T Ronald A. Sherman COMMENTS ON CURRENT PUBLICATIONS
Elsevier 0278-2316/87/$0.00 + 2.20
Strategies in the Chemotherapy of Schistosomiasis A l f r e d W . S e n f t , MD Division of Biology and Medicine, Brown University, Providence, Rhode Island The adult schistosomes that infect humans and other mammals are large (0.5 to 15 mm long), cylindrical trematodes that dwell in venules as male or female worms--unlike the hermaphroditic state of most other parasitic flukes. After the larval cercariae emerge from snails, they penetrate the skin of the final host, migrating first to the lungs, where organogenesis begins. They then proceed to the liver sinusoids where further growth, maturation, and mating ensue. Adult worms move into various afferent vessels of the portal venous system, or into the venular network of the urinary bladder. Adult schistosomes are not attacked effectively by humoral antibodies, and they are not easily killed by the cellular components of body defenses. In fact, they seem not to be recognized as foreign by the immunosurveillance system, apparently because they are able to coat themselves with host-derived antigens. In the absence of effective treat-
ment, adult schistosomes may live for decades. While they do not multiply in the body, the unending production of eggs, as well as hemoglobin-derived pigment ejected as a byproduct of digestion of erythrocytes, leads to severe immunofibrotic reaction in the gut, bladder, and liver. Eventually, a severely infected patient may succumb to a combination of intestinal peri-oval lesions, liver failure from heptofibrosis, varicosities secondary to portal hypertension, or intercurrent infections. Secondary carcinomas may develop at the site of intense tissue reaction, eg, in the bladder in the case of infection with Schistosoma hematobium. Surgical removal of worms has been achieved by first administering drugs that immobilize the schistosomes, followed by filtering the portal blood. In the few instances in which such an heroic intervention was carried out, hundreds of worms were trapped on the filter. But such a procedure demands special medi-
ISSN 0278-2316
I D I N D N 6 ( I ) I - 8 , 1987
2 I n l c c t i o u s D i s e a s e s N e w s l e t t e r 6( 1 )
.lanuar\ 1987
cal facilities, and is not possible for the millions of patients with schistosomiasis who live in developing countries. Considerable progress has been made in designing immunologic approaches to prevent infection, or to control the body burden of worms. In mouse models, partial protection against challenge resulted from passive immunization, as well as from active immunization with components of the worm tegument. However, achieving solid immunity in humans by administering selected antigens is a development that will not be available for some time. Chemotherapy thus remains the mainstay for the treatment of patients infected with schistosomes. Many antischistosomal agents have been tried in therapy, and particular drugs are best discussed in relation to the physiological targets against which they are aimed.
Carbohydrate Metabolism Heavy metals were first used in the treatment of bilharziasis in 1917 with the IV application of potassium antimonyl tartrate. It was exceedingly toxic and over subsequent decades less toxic agents became available, eg, stib0phen (Fuadin), antimony dimercaptosuccinate (Astiban), both trivalent antimonials. These latter two drugs supply antimony in a metastable configuration that de-chelates to allow for the formation of mercapto-antimony bonds within the worms. The major target appears to be phosphofructokinase (PFK), a regulatory enzyme also utilized by humans. Although h u m a n P F K binds antimony with only about 1% of the avidity of the schistosomal enzyme, some toxicity in humans may arise from interaction with human PFK. Thus, although intereference with schisto-
somal glycolytic fermentative metabolism is an effective target, the problem of host reactions to this class of compounds has resulted in the current phasing out of heavy metal chemotherapy. Besides having an active catabolism of glucose, schistosomes also accumulate and store glycogen. Niridazole (NRZ) inhibits the anabolism of glycogen and facilitates glycogenolysis. Schistosomes exposed to N R Z rapidly deplete glycogen stores found in integumentary tubercles and in muscular tissue. In humans, metabolites of N R Z cause transient disturbances of function of the central nervous system, depress immune competence, may inhibit spermiogenesis, and produce extremely malodorous urine. Used primarily against S c h i s t o s o m a mansoni and S. h e m a t o b i u m , N R Z has the advantages of peroral administration, and cost of only about $1.00/case. It is well tolerated in children if they have normal liver function, yielding cure rates of about 70% after an 8-day course. In adults, the cure rate is about 85%, but almost half of adults stop treatment because of adverse reactions. Oxamniquine (Vancil, OXM) is more costly than NRZ, but is also perorally administrable. Its mode of action is not known. In a recent, large-scale antischistosomal campaign in Brazil, reinfection in children five years after treatment with OXM was a major problem. Thus, eradication of a worm burden was not followed by long-term immunity.
Neurotropic Drugs Metrifonate (MTR) is an organophosphate compound that blocks schistosomal acetylcholinesterase while having little effect on the human enzyme. The effect on schistosomes is to produce flaccidity that
may or may not be lethal. Schistos o m a m a n s o n i are swept in the portal blood to the liver; while the liver is inhospitable to adult worms, some survive to migrate back to afferent portal vessels. In contrast, when S. h e m a t o b i u m are paralyzed by dichlorovos (the active form of MTR), they are swept into the lungs where they are trapped and die. As a result, clinically, MTR is much more effective against S. hematob i u m than against either S. m a n s o n i or S c h i s t o s o m a j a p o n i c u m .
Newer Drugs Praziquantel (PZQ) is the first perorally administrable drug that is fully effective against all species of schistosomes. In addition, it is effective against most other flukes and most cestodes parasitic in humans. When schistosomes are exposed to micromolar concentrations of PZQ, within seconds they contract vigorously, contorting into tight spiral coils. Their tegument undergoes dramatic destruction as many regions of the outer lamellae are shredded and stripped away; bullae and microblebs form in the tegument, particularly on and around the worm tubercles (Figure 1). Denuded regions ooze lipids, and antigens are exposed that attract cellular elements of host defenses. With breeching of the tegument, it may be that schistosomes become vulnerable to destruction by phagocytic cells. The destabilization of the tegument appears to result from the entry of external calcium into the worms. Recently, several calcium channel blockers, such as verapamil and nifedipine, were found to cause similar lesions. While the latter drugs would be expected to limit ingress of calcium, the effect of PZQ is to facilitate influx; that is the destructive effect of drugs that (continued on page 7)
Infectious Diseases Newsletter (ISSN 0278-2316) is issued monthly in one indexed volume per year by Elsevier Science Publishing Co., Inc., 52 Vanderbih Avenue, New York, NY 10017, Printed in USA at 25 Sand Creek Road. Albany, NY 12205. Subscription price per year: institutions, $112.00; individuals, $56.00. For air mail to Europe. add $21.00; for air mail elsewhere, add $24.00. Second-class postage pending at New York. NY. and at additional mailing offices Postmaster: Send address changes to Infectious Diseases Newsletter, Elsevier Science Publishing C o . lnc , 52 Vanderbilt Avenue. New York, NY 10017.
© 1987 Elsevier Science Publishing Co., Inc. 0278-2316 87 $0.00- 2.20