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Pamidronate next on list as potential cure for leishmaniasis
Newsdesk Pamidronate next on list as potential cure for leishmaniasis As the search for a satisfactory leishmaniasis therapy continues, US researchers report that pamidronate, a bisphosphonate drug typically used in the treatment of osteoporosis, is effective against experimental cutaneous leishmaniasis (J Infect Dis 2002; 186: 138–40). Noris Rodriguez and colleagues (University of Illinois at UrbanaChampaign) injected Leishmania mexicana amazonensis parasites subcutaneously into the footpads of mice, in which lesions of measurable size developed after 2–3 months. Intraperitoneal injections were given daily and lesion size was recorded once a week. There were four trials of activity of pamidronate at different doses: 10mg/kg 1-day or 3-day treatment showed only small lesion reduction with ulceration, and at 5mg/kg for 5 days lesions were smaller and did not ulcerate, but reactivated 7 weeks after start of experiment.
10mg/kg of pamidronate for 5 days, however, produced significant lesion reduction 2 weeks after start of treatment. Lesions were fully resolved by week 13. Several bisphosphonates have recently shown significant activity against Leishmania donovani in vitro, and several are potent inhibitors of bone resorption and in clinical use for the treatment of osteoporosis and Paget’s disease, among other diseases. Action on bone is based on binding of bisphosphonate moiety to the bone mineral and inhibition of the osteoclast’s enzyme FPPS (farnesyl pyro-phosphate synthase). Expressed FPPS is also potently inhibited by bisphosphonates in the trypanosomatid parasite Trypanosoma cruzi, in which FPPS is postulated to be the major target of bisphosphonates. Peter Selby (Manchester Royal Infirmary, Manchester, UK) commented that, although bisphosph-
onates were initially thought to act specifically on bone, they also have an important action on cell death. “The chemical properties are the only feature that make bisphosphonates specific to bone, so it is likely that they could be targeted into other cells. The real question is how researchers might target those other cells.” The total lesion regression of the Rodriguez study suggests that the compound has leishmanicidal activty and does not produce apparent toxic effects. However, since the effective dose of pamidronate is higher than that administered so far in people without toxic side-effects, it is possible that currently approved clinical regimens of the drug are not high enough to cure human cutaneous leishmaniasis. The researchers believe, however, that pamidronate could be a useful lead compound in the synthesis of news drugs against this disease. Rachael Paterson
Scientists join smallpox vaccine controversy that NYCBH strains had been very widely used in countries where smallpox was endemic and “had brought about major reductions in the worldwide incidence of smallpox” before the WHO had begun to distribute the Lister strain, which, he claimed, had been chosen for its ease of manufacture and “not because of any perceived performance advantage in the face of the disease”. The NSHPC report also stated that the most likely source of starting material for a bioterrorist group would be the former Soviet Union. The report concludes that any vaccine against a smallpox attack should use derivatives of the vaccine strains that were successful during the eradication campaign—ie, NYCBH, not Lister strains, which were “mainly viewed as maintenance vaccines”.
THE LANCET Infectious Diseases Vol 2 September 2002
PHLS
Scientists on both sides of the Atlantic have attacked a US report claiming that the New York City Board of Health (NYCBH) smallpox vaccine (vaccinia virus) should be the strain of choice for stockpiling against a possible bioterrorist attack. The UK government has been criticised for choosing the Lister strain of vaccine—not on scientific grounds but because the vaccine contract was awarded Vaccinia virus to Powderject, a company headed by Paul Drayson, a generous donor to the ruling Labour Party. Criticism intensified when Stephen Prior (Potomac Institute, Arlington, VA, USA), author of the US National Security Health Policy Center (NSHPC) report, told The Times (July 30) that he “could find no reason why the [UK] government did not choose the same vaccine as the US”. Prior said
http://infection.thelancet.com
But Donald Henderson, adviser to the US government and formerly chief of WHO’s smallpox-eradication campaign, says: “The Prior report is nonsense. The Lister strain was tested as severely and regularly as NYCBH and appeared to be equivalent in all respects”. Government authorities, he adds, “are most comfortable in dealing with the strains with which they have had the most experience”—hence the choice of the Lister strain in the UK and NYCBH in the USA. “The report looked rather biased, as though it had been written on behalf of a pharmaceutical company”, adds John Oxford (Royal London Hospital, UK). “Differences in the efficacy of vaccines used at different times in the eradication campaign are not explicable by the strain of vaccine used. Many factors were involved.” Of the potential bioterrorism threat from Soviet-derived smallpox material, Oxford says, “I don’t buy that . . . We simply don’t know where a new threat might come from”. Dorothy Bonn
515
For personal use. Only reproduce with permission from The Lancet Publishing Group.
10mg/kg of pamidronate for 5 days, however, produced significant lesion reduction 2 weeks after start of treatment. Lesions were fully resolved by week 13. Several bisphosphonates have recently shown significant activity against Leishmania donovani in vitro, and several are potent inhibitors of bone resorption and in clinical use for the treatment of osteoporosis and Paget’s disease, among other diseases. Action on bone is based on binding of bisphosphonate moiety to the bone mineral and inhibition of the osteoclast’s enzyme FPPS (farnesyl pyro-phosphate synthase). Expressed FPPS is also potently inhibited by bisphosphonates in the trypanosomatid parasite Trypanosoma cruzi, in which FPPS is postulated to be the major target of bisphosphonates. Peter Selby (Manchester Royal Infirmary, Manchester, UK) commented that, although bisphosph-
onates were initially thought to act specifically on bone, they also have an important action on cell death. “The chemical properties are the only feature that make bisphosphonates specific to bone, so it is likely that they could be targeted into other cells. The real question is how researchers might target those other cells.” The total lesion regression of the Rodriguez study suggests that the compound has leishmanicidal activty and does not produce apparent toxic effects. However, since the effective dose of pamidronate is higher than that administered so far in people without toxic side-effects, it is possible that currently approved clinical regimens of the drug are not high enough to cure human cutaneous leishmaniasis. The researchers believe, however, that pamidronate could be a useful lead compound in the synthesis of news drugs against this disease. Rachael Paterson
Scientists join smallpox vaccine controversy that NYCBH strains had been very widely used in countries where smallpox was endemic and “had brought about major reductions in the worldwide incidence of smallpox” before the WHO had begun to distribute the Lister strain, which, he claimed, had been chosen for its ease of manufacture and “not because of any perceived performance advantage in the face of the disease”. The NSHPC report also stated that the most likely source of starting material for a bioterrorist group would be the former Soviet Union. The report concludes that any vaccine against a smallpox attack should use derivatives of the vaccine strains that were successful during the eradication campaign—ie, NYCBH, not Lister strains, which were “mainly viewed as maintenance vaccines”.
THE LANCET Infectious Diseases Vol 2 September 2002
PHLS
Scientists on both sides of the Atlantic have attacked a US report claiming that the New York City Board of Health (NYCBH) smallpox vaccine (vaccinia virus) should be the strain of choice for stockpiling against a possible bioterrorist attack. The UK government has been criticised for choosing the Lister strain of vaccine—not on scientific grounds but because the vaccine contract was awarded Vaccinia virus to Powderject, a company headed by Paul Drayson, a generous donor to the ruling Labour Party. Criticism intensified when Stephen Prior (Potomac Institute, Arlington, VA, USA), author of the US National Security Health Policy Center (NSHPC) report, told The Times (July 30) that he “could find no reason why the [UK] government did not choose the same vaccine as the US”. Prior said
http://infection.thelancet.com
But Donald Henderson, adviser to the US government and formerly chief of WHO’s smallpox-eradication campaign, says: “The Prior report is nonsense. The Lister strain was tested as severely and regularly as NYCBH and appeared to be equivalent in all respects”. Government authorities, he adds, “are most comfortable in dealing with the strains with which they have had the most experience”—hence the choice of the Lister strain in the UK and NYCBH in the USA. “The report looked rather biased, as though it had been written on behalf of a pharmaceutical company”, adds John Oxford (Royal London Hospital, UK). “Differences in the efficacy of vaccines used at different times in the eradication campaign are not explicable by the strain of vaccine used. Many factors were involved.” Of the potential bioterrorism threat from Soviet-derived smallpox material, Oxford says, “I don’t buy that . . . We simply don’t know where a new threat might come from”. Dorothy Bonn
515
For personal use. Only reproduce with permission from The Lancet Publishing Group.