- Email: [email protected]
Intralesional artemisinin for the treatment of cutaneous leishmaniasis
Correspondence / Medical Hypotheses 72 (2009) 223–234
disease [7]. The protective effect of serum bilirubin against coronary artery disease was also investigated in patients with Gilbert’s disease, a genetic disorder of impaired bilirubin conjugation causing mild to moderate elevations of unconjugated bilirubin. Vitek et al. [8] reported that the prevalence of ischemic heart disease in patients with Gilbert’s disease was 2%, compared to 12.1% in a general control population, suggesting that chronic hyperbilirubinemia may prevent the development of ischemic heart disease by increasing the serum antioxidant capacity. In conclusion, several studies show that bilirubin exhibits potent antioxidant properties. Experimental studies reported cytoprotective effects of bilirubin, protecting against oxidative stress. Thus it can be hypothesized that bilirubin administration can help prevent CIN in high risk patients. This hypothesis should be tested in animal studies. The results, if positive, will have an important impact on the prognosis of patients having contrast exposures.
233
[2] Katholi RE, Woods WT, Taylor GJ, et al. Oxygen free radicals and contrast nephropathy. Am J Kidney Dis 1998;32:64–71. [3] Lameire NH. Contrast-induced nephropathy-prevention and risk reduction. Nephrol Dial Transpl 2006;21(Suppl. 1):i11–23. [4] Sedlak TW, Snyder SH. Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle. Pediatrics 2004;113:1776–82. [5] Leung N, Croatt AJ, Haggard JJ, Grande JP, Nath KA. Acute cholestatic liver disease protects against glycerol-induced acute renal failure in the rat. Kidney Int 2001;60:1047–57. [6] Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Williams RR. Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease. Arterioscler Thromb Vasc Biol 1996;16:250–5. [7] Levinson SS. Relationship between bilirubin, apolipoprotein B, and coronary artery disease. Ann Clin Lab Sci 1997;27:185–92. [8] Vitek L, Jirsa M, Brodanova M, et al. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis 2002;160:449–56.
Burcin Halacli Tevfik Ecder * Department of Internal Medicine, Division of Nephrology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey * Tel.: +90 212 4142317/32890; fax: +90 212 4142022 E-mail address: [email protected] (T. Ecder)
References [1] Finn WF. The clinical and renal consequences of contrast-induced nephropathy. Nephrol Dial Transpl 2006;21(Suppl. 1):i2–i10.
doi:10.1016/j.mehy.2008.09.014
Intralesional artemisinin for the treatment of cutaneous leishmaniasis Qinghaosu (artemisinin) is an effective antimalarial compound derived from a traditional Chinese herbal remedy, qinghao or Artemisia annue L. (sweet or annual wormwood, family Asteraceae). It is endemic to the northern parts of Chahar and Suiyuan provinces in China where it is known as ‘quinghao’ (green herb) and it has been used to treat chills and fever for more than 2000 years [1]. In 1977, the active constituent of qinghaosu was found to be sesquiterpene lactone peroxide [2]. The endoperoxide moiety, essential for the antimalarial activity, is unusual in natural products. The toxicity of qinghaosu and several derivatives is quite low, with chemotherapeutic indices of malaria of over 2000 [1].
The effectiveness of artemisinin against some other parasites such as Schistosoma japonincum [7], Schistosoma mansoni [8], Clonorchis sinensis [9] and Neospora caninum [10] has been previously accomplished. In our center we experimentally observed that intralesional injection of artemisinin in addition to sodium stibogluconate reduced the duration of wound healing from one year to approximately 3 months in the 93.2% of the individuals. It also reduced the severity and duration of symptoms in 87.3% of patients. Regardless of the precise mechanism of action, this unique endoperoxide sesquiterpene lactone and its derivatives hold great promise for the future effective therapy of malaria, and presumably of cutaneous leishmaniasis lesions.
Hypothesis
References
Artemisinin is considered a potent antimalarial drug, even against chloroquine- and quinine-resistant Plasmodium falciparum and other malaria causing parasites. Its activity is based on an unusual mechanism of action, still the object of much debate, which most likely involves the formation of free-radical intermediates, originating from the direct interaction of the endoperoxide group with the heme iron and leading to the alkylation of malarial-specific proteins [3]. Structure–activity studies have shown that the labile peroxide bond is essential for antimalarial activity [4]. Artemisinin and its derivatives have been reported to exert several toxic effects including damage to parasite membranes and inhibition of inosine monophosphate dehydrogenase and succinic acid dehydrogenase, causing mitochondrial swelling, decreasing parasite cytochrome oxidase activity, and triggering rapid decreases in parasite protein synthesis [5]. At a molecular level, the Endoperoxide Bridge in artemisinin is cleaved by free heme or iron, leading to the generation of an unstable oxygen-centered radical [6]. This radical species subsequently causes selective alkylation of malarial proteins leading to destruction of the membranes of Plasmodium.
[1] Garnier T, Mantyla A, Jarvinen T, Lawrence MJ, Brown MB, Croft SL. Topical buparvaquone formulations for the treatment of cutaneous leishmaniasis. J Pharm Pharmacol 2007;59:41–9. [2] Klayman DL. Quinghaosu (artemisinin): an antimalarial drug from China. Science 1985;228:1049–55. [3] Coordinating Group for Research in the Structure of Qing Hqu Sau. A new type of sesquiterpene lactone-qing hao sau. K’o Hsueh T’ung Pao 1977;22:142 [in Chinese; English abstract in Chem Abstr1997;87:98788]. [4] Bilia AR, Melillo de Malgalhaes P, Bergonzi MC, Vincieri FF. Simultaneous analysis of artemisinin and flavonoids of several extracts of Artemisia annua L. obtained from a commercial sample and a selected cultivar. Phytomedicine 2006;13:487–93. [5] Gu HM, Lu BF, Qu ZX. Activities of 25 derivatives of artemisinin against chloroquine-resistant Plasmodium berghei. Act Pharmacol Sin 1980;1:48–50. [6] Sen R, Bandyopadhyay S, Dutta A, Mandal G, Ganguly S, Saha P, et al. Artemisinin triggers induction of cell-cycle arrest and apoptosis in Leishmania donovani promastigotes. J Med Microbiol 2007;56:1213–8. [7] Xiao SH, Booth M, Tanner M. The prophylactic effect of artemether against Schistosoma japonicum infections. Parasitol Today 2000;16:122–6. [8] Xiao SH, Brian AC. In vitro and In vivo studies of the Effect of artemether in Schistosoma mansoni. Antimicrob Agents Chemother 1989;33:1557–62. [9] Chen R, Qu W, Zeng M, Li J. Effect of qinghaosu and its derivatives on Clonorchis sinensis in rats. Yaoxue Tongbao 1983;18:410–1 [in Chinese; English abstract in Chem Abstr 1984;100:17251]. [10] Kim JT, Park JY, Seo HS, et al. In vitro antiprotozoal effects of artemisinin on Neospora caninum. Vet Parasitol 2002;103:53–63.
234
Correspondence / Medical Hypotheses 72 (2009) 223–234
Fariborz Ghaffarpasand Seyed Reza Seraj Hamid Reza Heiran Student Research Committee, Fasa University of Medical Sciences,
P.O. Box 7461686688, Fasa, Iran Tel.: +98 9173095214; fax: +98 7312227091 E-mail address: [email protected] (F. Ghaffarpasand)
doi:10.1016/j.mehy.2008.09.015
Was the Justinian Plague caused by the 1918 flu virus? The influenza pandemic of 1918 caused more deaths than any single infectious disease event in human history. The Black Death (1347–1351) had the highest kill rate on a world human population basis of any disease in historical times. Scott and Duncan [1] noted a number of important features of the Black Death not consistent with Y. pestis as the causative pathogen: an apparently person-to-person transmission of the disease, and a rate faster and to places that rats and fleas did not go, and a kill rate far higher than in modern disease caused by the bacterium. Scott and Duncan suggested a hemorrhagic virus such as Ebola as the cause of the Black Death. However, such viruses have never been known to cause a worldwide pandemic. As an alternative we suggested [2] that the 1918 pandemic influenza strain be considered. The symptom/sign in Black Death sufferers of bullae in the axila and groin is not typically seen in flu victims, but perhaps it could have been occurred in the past to a populace naïve to influenza. Here we want to put forth pandemic influenza as a possible cause of ‘‘Justinian’s” Plague that ravaged the Mediterranean, near East, Western and South-Central Europe from 540 to 543 CE. As we noted [2], if lymphocyte DNA could be extracted from dental pulp one could look for evidence of anti-(pandemic) influenza in individuals who died after, but not before the Black Death or Justinian Plague. Here we add another possible way to test pandemic infludoi:10.1016/j.mehy.2008.09.014
enza as a cause of these plagues: In genome scans signals could be sought in time and populations — for example with those native to the Americas as ‘‘out” groups — for genes that mediate survival to influenza. References [1] Scott S, Duncan CJ. Biology of plagues: evidence from historical opulations. New York: Cambridge University Press; 2001. [2] Altschuler EL, Kariuki YM. Did the 1918 flu virus cause the Black Death? Medical Hypotheses 2008. doi:10.1016/j.mehy.2008.07.011.
Eric Lewin Altschuler Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey, University Hospital, 150 Bergen Street, B-403, Newark, NJ 07103, USA Tel.: +973 972 5439; fax: +973 972 5725 E-mail address: [email protected] Yvonne M. Kariuki Department of Health Sciences, New Jersey City University, Jersey City, NJ 07305, USA
disease [7]. The protective effect of serum bilirubin against coronary artery disease was also investigated in patients with Gilbert’s disease, a genetic disorder of impaired bilirubin conjugation causing mild to moderate elevations of unconjugated bilirubin. Vitek et al. [8] reported that the prevalence of ischemic heart disease in patients with Gilbert’s disease was 2%, compared to 12.1% in a general control population, suggesting that chronic hyperbilirubinemia may prevent the development of ischemic heart disease by increasing the serum antioxidant capacity. In conclusion, several studies show that bilirubin exhibits potent antioxidant properties. Experimental studies reported cytoprotective effects of bilirubin, protecting against oxidative stress. Thus it can be hypothesized that bilirubin administration can help prevent CIN in high risk patients. This hypothesis should be tested in animal studies. The results, if positive, will have an important impact on the prognosis of patients having contrast exposures.
233
[2] Katholi RE, Woods WT, Taylor GJ, et al. Oxygen free radicals and contrast nephropathy. Am J Kidney Dis 1998;32:64–71. [3] Lameire NH. Contrast-induced nephropathy-prevention and risk reduction. Nephrol Dial Transpl 2006;21(Suppl. 1):i11–23. [4] Sedlak TW, Snyder SH. Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle. Pediatrics 2004;113:1776–82. [5] Leung N, Croatt AJ, Haggard JJ, Grande JP, Nath KA. Acute cholestatic liver disease protects against glycerol-induced acute renal failure in the rat. Kidney Int 2001;60:1047–57. [6] Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Williams RR. Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease. Arterioscler Thromb Vasc Biol 1996;16:250–5. [7] Levinson SS. Relationship between bilirubin, apolipoprotein B, and coronary artery disease. Ann Clin Lab Sci 1997;27:185–92. [8] Vitek L, Jirsa M, Brodanova M, et al. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis 2002;160:449–56.
Burcin Halacli Tevfik Ecder * Department of Internal Medicine, Division of Nephrology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey * Tel.: +90 212 4142317/32890; fax: +90 212 4142022 E-mail address: [email protected] (T. Ecder)
References [1] Finn WF. The clinical and renal consequences of contrast-induced nephropathy. Nephrol Dial Transpl 2006;21(Suppl. 1):i2–i10.
doi:10.1016/j.mehy.2008.09.014
Intralesional artemisinin for the treatment of cutaneous leishmaniasis Qinghaosu (artemisinin) is an effective antimalarial compound derived from a traditional Chinese herbal remedy, qinghao or Artemisia annue L. (sweet or annual wormwood, family Asteraceae). It is endemic to the northern parts of Chahar and Suiyuan provinces in China where it is known as ‘quinghao’ (green herb) and it has been used to treat chills and fever for more than 2000 years [1]. In 1977, the active constituent of qinghaosu was found to be sesquiterpene lactone peroxide [2]. The endoperoxide moiety, essential for the antimalarial activity, is unusual in natural products. The toxicity of qinghaosu and several derivatives is quite low, with chemotherapeutic indices of malaria of over 2000 [1].
The effectiveness of artemisinin against some other parasites such as Schistosoma japonincum [7], Schistosoma mansoni [8], Clonorchis sinensis [9] and Neospora caninum [10] has been previously accomplished. In our center we experimentally observed that intralesional injection of artemisinin in addition to sodium stibogluconate reduced the duration of wound healing from one year to approximately 3 months in the 93.2% of the individuals. It also reduced the severity and duration of symptoms in 87.3% of patients. Regardless of the precise mechanism of action, this unique endoperoxide sesquiterpene lactone and its derivatives hold great promise for the future effective therapy of malaria, and presumably of cutaneous leishmaniasis lesions.
Hypothesis
References
Artemisinin is considered a potent antimalarial drug, even against chloroquine- and quinine-resistant Plasmodium falciparum and other malaria causing parasites. Its activity is based on an unusual mechanism of action, still the object of much debate, which most likely involves the formation of free-radical intermediates, originating from the direct interaction of the endoperoxide group with the heme iron and leading to the alkylation of malarial-specific proteins [3]. Structure–activity studies have shown that the labile peroxide bond is essential for antimalarial activity [4]. Artemisinin and its derivatives have been reported to exert several toxic effects including damage to parasite membranes and inhibition of inosine monophosphate dehydrogenase and succinic acid dehydrogenase, causing mitochondrial swelling, decreasing parasite cytochrome oxidase activity, and triggering rapid decreases in parasite protein synthesis [5]. At a molecular level, the Endoperoxide Bridge in artemisinin is cleaved by free heme or iron, leading to the generation of an unstable oxygen-centered radical [6]. This radical species subsequently causes selective alkylation of malarial proteins leading to destruction of the membranes of Plasmodium.
[1] Garnier T, Mantyla A, Jarvinen T, Lawrence MJ, Brown MB, Croft SL. Topical buparvaquone formulations for the treatment of cutaneous leishmaniasis. J Pharm Pharmacol 2007;59:41–9. [2] Klayman DL. Quinghaosu (artemisinin): an antimalarial drug from China. Science 1985;228:1049–55. [3] Coordinating Group for Research in the Structure of Qing Hqu Sau. A new type of sesquiterpene lactone-qing hao sau. K’o Hsueh T’ung Pao 1977;22:142 [in Chinese; English abstract in Chem Abstr1997;87:98788]. [4] Bilia AR, Melillo de Malgalhaes P, Bergonzi MC, Vincieri FF. Simultaneous analysis of artemisinin and flavonoids of several extracts of Artemisia annua L. obtained from a commercial sample and a selected cultivar. Phytomedicine 2006;13:487–93. [5] Gu HM, Lu BF, Qu ZX. Activities of 25 derivatives of artemisinin against chloroquine-resistant Plasmodium berghei. Act Pharmacol Sin 1980;1:48–50. [6] Sen R, Bandyopadhyay S, Dutta A, Mandal G, Ganguly S, Saha P, et al. Artemisinin triggers induction of cell-cycle arrest and apoptosis in Leishmania donovani promastigotes. J Med Microbiol 2007;56:1213–8. [7] Xiao SH, Booth M, Tanner M. The prophylactic effect of artemether against Schistosoma japonicum infections. Parasitol Today 2000;16:122–6. [8] Xiao SH, Brian AC. In vitro and In vivo studies of the Effect of artemether in Schistosoma mansoni. Antimicrob Agents Chemother 1989;33:1557–62. [9] Chen R, Qu W, Zeng M, Li J. Effect of qinghaosu and its derivatives on Clonorchis sinensis in rats. Yaoxue Tongbao 1983;18:410–1 [in Chinese; English abstract in Chem Abstr 1984;100:17251]. [10] Kim JT, Park JY, Seo HS, et al. In vitro antiprotozoal effects of artemisinin on Neospora caninum. Vet Parasitol 2002;103:53–63.
234
Correspondence / Medical Hypotheses 72 (2009) 223–234
Fariborz Ghaffarpasand Seyed Reza Seraj Hamid Reza Heiran Student Research Committee, Fasa University of Medical Sciences,
P.O. Box 7461686688, Fasa, Iran Tel.: +98 9173095214; fax: +98 7312227091 E-mail address: [email protected] (F. Ghaffarpasand)
doi:10.1016/j.mehy.2008.09.015
Was the Justinian Plague caused by the 1918 flu virus? The influenza pandemic of 1918 caused more deaths than any single infectious disease event in human history. The Black Death (1347–1351) had the highest kill rate on a world human population basis of any disease in historical times. Scott and Duncan [1] noted a number of important features of the Black Death not consistent with Y. pestis as the causative pathogen: an apparently person-to-person transmission of the disease, and a rate faster and to places that rats and fleas did not go, and a kill rate far higher than in modern disease caused by the bacterium. Scott and Duncan suggested a hemorrhagic virus such as Ebola as the cause of the Black Death. However, such viruses have never been known to cause a worldwide pandemic. As an alternative we suggested [2] that the 1918 pandemic influenza strain be considered. The symptom/sign in Black Death sufferers of bullae in the axila and groin is not typically seen in flu victims, but perhaps it could have been occurred in the past to a populace naïve to influenza. Here we want to put forth pandemic influenza as a possible cause of ‘‘Justinian’s” Plague that ravaged the Mediterranean, near East, Western and South-Central Europe from 540 to 543 CE. As we noted [2], if lymphocyte DNA could be extracted from dental pulp one could look for evidence of anti-(pandemic) influenza in individuals who died after, but not before the Black Death or Justinian Plague. Here we add another possible way to test pandemic infludoi:10.1016/j.mehy.2008.09.014
enza as a cause of these plagues: In genome scans signals could be sought in time and populations — for example with those native to the Americas as ‘‘out” groups — for genes that mediate survival to influenza. References [1] Scott S, Duncan CJ. Biology of plagues: evidence from historical opulations. New York: Cambridge University Press; 2001. [2] Altschuler EL, Kariuki YM. Did the 1918 flu virus cause the Black Death? Medical Hypotheses 2008. doi:10.1016/j.mehy.2008.07.011.
Eric Lewin Altschuler Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey, University Hospital, 150 Bergen Street, B-403, Newark, NJ 07103, USA Tel.: +973 972 5439; fax: +973 972 5725 E-mail address: [email protected] Yvonne M. Kariuki Department of Health Sciences, New Jersey City University, Jersey City, NJ 07305, USA