- Email: [email protected]
Praziquantel – quality, dosages and markers of resistance
356
Research Update
References 1 Bull, P.C. et al. (1998) Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nat. Med. 4, 358–360 2 Pain, A. et al. (2001) Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria. Proc. Natl. Acad. Sci. U. S. A. 98, 1805–1810 3 Fried, M. et al. (1998) Maternal antibodies block malaria. Nature 395, 851–852 4 Reeder, J.C. et al. (1999) The adhesion of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A is mediated by P. falciparum erythrocyte membrane protein 1. Proc. Natl. Acad. Sci. U. S. A. 96, 5198–5202 5 Freitas-Junior, L.H. et al. (2000) Frequent ectopic recombination of virulence factor genes in
TRENDS in Parasitology Vol.17 No.8 August 2001
6
7
8
9
telomeric chromosome clusters of P. falciparum. Nature 407, 1018–1022 Smith, J.D. et al. (2000) Classification of adhesive domains in the Plasmodium falciparum erythrocyte membrane protein 1 family. Mol. Biochem. Parasitol. 110, 293–310 Gamain B. et al. (2001) Modifications in the CD36 binding domain of the Plasmodium falciparum variant antigen are responsible for the inability of chondroitin sulfate A adherent parasites to bind CD36. Blood 97, 3268–3274 Pouvelle, B. et al. (2000) Cytoadhesion of Plasmodium falciparum ring-stage-infected erythrocytes. Nat. Med. 6, 1264–1268 Bull, P.C. et al. (2000) Plasmodium falciparuminfected erythrocytes: agglutination by diverse Kenyan plasma is associated with severe disease and young host age. J. Infect. Dis. 182, 252–259
Patrick E. Duffy* Malaria Antigen Discovery Program, Seattle Biomedical Research Institute, WA 98109, USA. *e-mail: [email protected] Alister G. Craig Liverpool School of Tropical Medicine, UK L3 5QA.
Dror I. Baruch Laboratories of Parasitic Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Praziquantel – quality, dosages and markers of resistance Chris C. Appleton and Amadou Mbaye The fourth and last meeting of Concerted Action on Praziquantel (PZQ), sponsored by the European Commission1–3, was held in Rome, Italy from 31 March to 1 April, 2001. Highlights of the meeting were new findings on the quality of generic drugs, an initiative to promote the Africa-wide distribution of PZQ and new results in the search for markers of PZQ-resistant schistosomes.
The key topic was undoubtedly the analysis of additional praziquantel (PZQ) samples from various manufacturers, collected in the field in Asia and Africa.
Table 1. Summary of results of the second round of tests on praziquantel from different sourcesa Manufacturer
Sample collected in
% PZQ content Impurities declared BP USP (accept ± 10%)
Disintegration Dissolution
Shin Poong, Korea
China
100
P
P
P
Anhui Huanian, China
China
100
P
P
P
P
Cosmos, Kenya
Kenya
98
P
P
P
P
Waterland, The Netherlands
Cameroon
99
P
P
P
P
P
GMC, Khartoum
Sudan
93
P
P
Fc
Fd
International Ltd, Canada
Sudan
0b
–
–
–
–
GPO, Bangkok
Thailand
102
P
P
P
P
Quality and price of PZQ
Shelys, Tanzania
Tanzania
95
Fe
P
P
P
D. Cioli (Institute of Cell Biology, Rome, Italy) noted that, as before3, the generic preparations tested were generally of high quality. One product had less than optimal disintegration and dissolution properties and another contained impurities (Table 1), but these shortcomings were noted in samples from only three of the 19 manufacturers and it is unclear whether they affect the efficacy of the tablets. The faults were minor compared with those of a sample from Sudan (Fig. 1) that contained no PZQ at all! Following this disturbing discovery, immediate steps were taken to inform all relevant authorities about the counterfeit product. The satisfactory quality of most generics tested is important to the success of schistosome control programmes, because most of the samples were collected in the field and therefore represent the drug as it is given to people.
Lab. Wolfs, Belgium
Cameroon
98
P
P
P
P
Bayer, Germany
Zimbabwe
100
P
P
P
P
Medochemie, Cyprus
Nigeria
99
P
P
P
P
Biomedecine, Belgium
Nigeria
97
P
P
P
P
http://parasites.trends.com
aSee
Ref. 3 for first round results. bIdentical results were obtained for two independent samples from International Ltd, Canada. cDisintegration time is >30 <50 min, instead of the allowable maximum of 30 min. d53% of PZQ dissolved in 60 min, instead of the allowable minimum of 75%. eTotal impurities have an area of 451781 (arbitrary units), instead of the allowable maximum of 370 067 units. fAbbreviations: BP, British Pharmacopeia; F, fail according to standards of BP 1998 and USP 23; GMC, General Medicines Company; GPO, Government Pharmaceutical Organization; P, pass according to standards of BP 1998 and USP 23; PZQ, praziquantel; USP, US Pharmacopeia.
The panel considered that a price of 10 US cents per tablet was acceptable at ‘country level’, although most user countries pay considerably more. Demands for lower prices should be considered carefully, to avoid compromising drug quality, but it was noted that tablets could be obtained for 8 cents and 7 cents, respectively, in Egypt and Korea.
The Gates initiative
A Schistosomiasis Control Initiative is to be funded by the Bill and Melinda Gates Foundation, through the Harvard School of Public Health, and details were presented by A. Fenwick (SVDP, Cairo, Egypt). Countries in sub-Saharan Africa can apply to the Foundation for funds to help to make PZQ available to infected people. The project will consider
1471-4922/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4922(01)02028-1
Research Update
Fig. 1. A generic brand of the antischistosomal drug praziquantel (PZQ) collected in Sudan was found to contain no PZQ.
applications from countries where PZQ can be administered through existing delivery systems – school-based or via health care units, or both. The project will work closely with the World Health Organization and partners such as the World Bank, World Food Programme, European Union and USAID. Is 40 mg kg–1 a sub-curative dose?
The opinion of the panel was that resistance to PZQ exists, but that the phenomenon is of limited magnitude and not yet a public health problem4. PZQ remains effective in reducing prevalence and intensity. The need for increased dosages was debated but the conclusion was that, while 40 mg kg–1 continues to give good control of morbidity, there is no reason for change. However, research into combination chemotherapy to stave off resistance in nonresponders was recommended, and the use of PZQ with oxamniquine or metrifonate was suggested for the control of Schistosoma
TRENDS in Parasitology Vol.17 No.8 August 2001
mansoni and S. haematobium, respectively. Metrifonate is no longer distributed by Bayer, but can be produced by generic manufacturers and is available in Kenya. The effectiveness of artemisinin derivatives against the juvenile worm stage, on which PZQ has no effect, was noted. A combination of PZQ with these compounds might be useful in ‘hotspots’ of intense transmission in nonmalarious areas – although there will be few such places in Africa – and would be helpful in areas such as Morocco where transmission control is needed to eliminate remaining cases. New antischistosomal drugs?
Since Bilharz discovered the pathology of the disease in 1851, the only real success in improving the lives of people with schistosomiasis has been the introduction of single-dose oral drugs in the 1970s. No new drugs have been developed since the discovery of PZQ, and PZQ is not the perfect antischistosomal drug because it does not affect young stages of the parasite. New compounds need to be developed or existing ones improved, and we cannot wait for such progress until resistance becomes an obstacle. We should learn the lessons from our experience with so many antibiotics and antimalarial agents, and be pro-active in our research. Small, but measurable, differences are being discovered between schistosome isolates with decreased susceptibility to
357
PZQ and ‘wild-type’ sensitive schistosomes. Such differences include not only survival after drug exposure in vivo (M. Ismail, Zagazig University, Egypt; M. Doenhoff, University of Bangor, UK) and in vitro (L. Pica-Mattoccia, Institute of Cell Biology, Rome, Italy), but also surface changes, muscle tension, calcium influx (S. Botros, Theodor Bilharz Institute, Cairo, Egypt) and lysosome staining (J. Kusel, University of Glasgow, UK). Initial attempts to define the dominance/recessivity of resistance were reported (Pica-Mattoccia, Rome, Italy). References 1 Renganathan, E. and Cioli, D. (1988) An international initiative on praziquantel use. Parasitol. Today 14, 390–391 2 Kusel, J. and Hagan, P. (1999) Praziquantel – its use, cost and possible development of resistance. Parasitol. Today 15, 352–354 3 Doenhoff, M.J., Kimani, G. and Cioli, D. (2000) Praziquantel and the control of schistosomiasis. Parasitol. Today 16, 364–366 4 Cioli, D. (2000) Praziquantel: is there real resistance and are there alternatives? Curr. Opin. Infect. Dis. 13, 659–663
Chris Appleton* School of Life & Environmental Sciences, University of Natal, Durban, 4041 South Africa. *e-mail: [email protected] Amadou Mbaye Programme de Lutte Controle la Bilharziose, BP 519, St Louis, Senegal.
Websites of interest Animated illustrations of moments in the life of the malaria parasite Workers at The Walter & Eliza Hall Institute of Medical Research, Melbourne, Australia have made some movies showing phases in the parasite’s life cycle from entry through the mosquito proboscis onwards: see http://www. wehi.edu.au/wehi-tv/movies/malaria.html Malaria Vaccine Development: Status Report http://www.niaid.nih.gov/dmid/malaria/malariavac.htm Updated in January 2001 and written by Stephanie James and Louis Miller. The sound of mosquitoes! http://www.arbovirus.health.nsw.gov.au/areas/arbovirus/mosquit/mosquitoes.htm#sounds Sponsorship of the mosquito list ([email protected]) The list is now sponsored by the American Mosquito Control Association, a scientific/educational, not-for-profit public service association (see http://www.mosquito.org/about.html) but will continue to be owned, operated – and moderated – by John VanDyk (Iowa State University, USA). Its membership roster is no longer public, preventing spammers from harvesting e-mail addresses.
http://parasites.trends.com
Research Update
References 1 Bull, P.C. et al. (1998) Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nat. Med. 4, 358–360 2 Pain, A. et al. (2001) Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria. Proc. Natl. Acad. Sci. U. S. A. 98, 1805–1810 3 Fried, M. et al. (1998) Maternal antibodies block malaria. Nature 395, 851–852 4 Reeder, J.C. et al. (1999) The adhesion of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A is mediated by P. falciparum erythrocyte membrane protein 1. Proc. Natl. Acad. Sci. U. S. A. 96, 5198–5202 5 Freitas-Junior, L.H. et al. (2000) Frequent ectopic recombination of virulence factor genes in
TRENDS in Parasitology Vol.17 No.8 August 2001
6
7
8
9
telomeric chromosome clusters of P. falciparum. Nature 407, 1018–1022 Smith, J.D. et al. (2000) Classification of adhesive domains in the Plasmodium falciparum erythrocyte membrane protein 1 family. Mol. Biochem. Parasitol. 110, 293–310 Gamain B. et al. (2001) Modifications in the CD36 binding domain of the Plasmodium falciparum variant antigen are responsible for the inability of chondroitin sulfate A adherent parasites to bind CD36. Blood 97, 3268–3274 Pouvelle, B. et al. (2000) Cytoadhesion of Plasmodium falciparum ring-stage-infected erythrocytes. Nat. Med. 6, 1264–1268 Bull, P.C. et al. (2000) Plasmodium falciparuminfected erythrocytes: agglutination by diverse Kenyan plasma is associated with severe disease and young host age. J. Infect. Dis. 182, 252–259
Patrick E. Duffy* Malaria Antigen Discovery Program, Seattle Biomedical Research Institute, WA 98109, USA. *e-mail: [email protected] Alister G. Craig Liverpool School of Tropical Medicine, UK L3 5QA.
Dror I. Baruch Laboratories of Parasitic Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Praziquantel – quality, dosages and markers of resistance Chris C. Appleton and Amadou Mbaye The fourth and last meeting of Concerted Action on Praziquantel (PZQ), sponsored by the European Commission1–3, was held in Rome, Italy from 31 March to 1 April, 2001. Highlights of the meeting were new findings on the quality of generic drugs, an initiative to promote the Africa-wide distribution of PZQ and new results in the search for markers of PZQ-resistant schistosomes.
The key topic was undoubtedly the analysis of additional praziquantel (PZQ) samples from various manufacturers, collected in the field in Asia and Africa.
Table 1. Summary of results of the second round of tests on praziquantel from different sourcesa Manufacturer
Sample collected in
% PZQ content Impurities declared BP USP (accept ± 10%)
Disintegration Dissolution
Shin Poong, Korea
China
100
P
P
P
Anhui Huanian, China
China
100
P
P
P
P
Cosmos, Kenya
Kenya
98
P
P
P
P
Waterland, The Netherlands
Cameroon
99
P
P
P
P
P
GMC, Khartoum
Sudan
93
P
P
Fc
Fd
International Ltd, Canada
Sudan
0b
–
–
–
–
GPO, Bangkok
Thailand
102
P
P
P
P
Quality and price of PZQ
Shelys, Tanzania
Tanzania
95
Fe
P
P
P
D. Cioli (Institute of Cell Biology, Rome, Italy) noted that, as before3, the generic preparations tested were generally of high quality. One product had less than optimal disintegration and dissolution properties and another contained impurities (Table 1), but these shortcomings were noted in samples from only three of the 19 manufacturers and it is unclear whether they affect the efficacy of the tablets. The faults were minor compared with those of a sample from Sudan (Fig. 1) that contained no PZQ at all! Following this disturbing discovery, immediate steps were taken to inform all relevant authorities about the counterfeit product. The satisfactory quality of most generics tested is important to the success of schistosome control programmes, because most of the samples were collected in the field and therefore represent the drug as it is given to people.
Lab. Wolfs, Belgium
Cameroon
98
P
P
P
P
Bayer, Germany
Zimbabwe
100
P
P
P
P
Medochemie, Cyprus
Nigeria
99
P
P
P
P
Biomedecine, Belgium
Nigeria
97
P
P
P
P
http://parasites.trends.com
aSee
Ref. 3 for first round results. bIdentical results were obtained for two independent samples from International Ltd, Canada. cDisintegration time is >30 <50 min, instead of the allowable maximum of 30 min. d53% of PZQ dissolved in 60 min, instead of the allowable minimum of 75%. eTotal impurities have an area of 451781 (arbitrary units), instead of the allowable maximum of 370 067 units. fAbbreviations: BP, British Pharmacopeia; F, fail according to standards of BP 1998 and USP 23; GMC, General Medicines Company; GPO, Government Pharmaceutical Organization; P, pass according to standards of BP 1998 and USP 23; PZQ, praziquantel; USP, US Pharmacopeia.
The panel considered that a price of 10 US cents per tablet was acceptable at ‘country level’, although most user countries pay considerably more. Demands for lower prices should be considered carefully, to avoid compromising drug quality, but it was noted that tablets could be obtained for 8 cents and 7 cents, respectively, in Egypt and Korea.
The Gates initiative
A Schistosomiasis Control Initiative is to be funded by the Bill and Melinda Gates Foundation, through the Harvard School of Public Health, and details were presented by A. Fenwick (SVDP, Cairo, Egypt). Countries in sub-Saharan Africa can apply to the Foundation for funds to help to make PZQ available to infected people. The project will consider
1471-4922/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4922(01)02028-1
Research Update
Fig. 1. A generic brand of the antischistosomal drug praziquantel (PZQ) collected in Sudan was found to contain no PZQ.
applications from countries where PZQ can be administered through existing delivery systems – school-based or via health care units, or both. The project will work closely with the World Health Organization and partners such as the World Bank, World Food Programme, European Union and USAID. Is 40 mg kg–1 a sub-curative dose?
The opinion of the panel was that resistance to PZQ exists, but that the phenomenon is of limited magnitude and not yet a public health problem4. PZQ remains effective in reducing prevalence and intensity. The need for increased dosages was debated but the conclusion was that, while 40 mg kg–1 continues to give good control of morbidity, there is no reason for change. However, research into combination chemotherapy to stave off resistance in nonresponders was recommended, and the use of PZQ with oxamniquine or metrifonate was suggested for the control of Schistosoma
TRENDS in Parasitology Vol.17 No.8 August 2001
mansoni and S. haematobium, respectively. Metrifonate is no longer distributed by Bayer, but can be produced by generic manufacturers and is available in Kenya. The effectiveness of artemisinin derivatives against the juvenile worm stage, on which PZQ has no effect, was noted. A combination of PZQ with these compounds might be useful in ‘hotspots’ of intense transmission in nonmalarious areas – although there will be few such places in Africa – and would be helpful in areas such as Morocco where transmission control is needed to eliminate remaining cases. New antischistosomal drugs?
Since Bilharz discovered the pathology of the disease in 1851, the only real success in improving the lives of people with schistosomiasis has been the introduction of single-dose oral drugs in the 1970s. No new drugs have been developed since the discovery of PZQ, and PZQ is not the perfect antischistosomal drug because it does not affect young stages of the parasite. New compounds need to be developed or existing ones improved, and we cannot wait for such progress until resistance becomes an obstacle. We should learn the lessons from our experience with so many antibiotics and antimalarial agents, and be pro-active in our research. Small, but measurable, differences are being discovered between schistosome isolates with decreased susceptibility to
357
PZQ and ‘wild-type’ sensitive schistosomes. Such differences include not only survival after drug exposure in vivo (M. Ismail, Zagazig University, Egypt; M. Doenhoff, University of Bangor, UK) and in vitro (L. Pica-Mattoccia, Institute of Cell Biology, Rome, Italy), but also surface changes, muscle tension, calcium influx (S. Botros, Theodor Bilharz Institute, Cairo, Egypt) and lysosome staining (J. Kusel, University of Glasgow, UK). Initial attempts to define the dominance/recessivity of resistance were reported (Pica-Mattoccia, Rome, Italy). References 1 Renganathan, E. and Cioli, D. (1988) An international initiative on praziquantel use. Parasitol. Today 14, 390–391 2 Kusel, J. and Hagan, P. (1999) Praziquantel – its use, cost and possible development of resistance. Parasitol. Today 15, 352–354 3 Doenhoff, M.J., Kimani, G. and Cioli, D. (2000) Praziquantel and the control of schistosomiasis. Parasitol. Today 16, 364–366 4 Cioli, D. (2000) Praziquantel: is there real resistance and are there alternatives? Curr. Opin. Infect. Dis. 13, 659–663
Chris Appleton* School of Life & Environmental Sciences, University of Natal, Durban, 4041 South Africa. *e-mail: [email protected] Amadou Mbaye Programme de Lutte Controle la Bilharziose, BP 519, St Louis, Senegal.
Websites of interest Animated illustrations of moments in the life of the malaria parasite Workers at The Walter & Eliza Hall Institute of Medical Research, Melbourne, Australia have made some movies showing phases in the parasite’s life cycle from entry through the mosquito proboscis onwards: see http://www. wehi.edu.au/wehi-tv/movies/malaria.html Malaria Vaccine Development: Status Report http://www.niaid.nih.gov/dmid/malaria/malariavac.htm Updated in January 2001 and written by Stephanie James and Louis Miller. The sound of mosquitoes! http://www.arbovirus.health.nsw.gov.au/areas/arbovirus/mosquit/mosquitoes.htm#sounds Sponsorship of the mosquito list ([email protected]) The list is now sponsored by the American Mosquito Control Association, a scientific/educational, not-for-profit public service association (see http://www.mosquito.org/about.html) but will continue to be owned, operated – and moderated – by John VanDyk (Iowa State University, USA). Its membership roster is no longer public, preventing spammers from harvesting e-mail addresses.
http://parasites.trends.com