ARTEMISININ, ARTESUNATE, MALARIA AND ANTIVIRAL STUDIES
Clin Nephrol. 2008 Nov;70(5):427-30.
Acute renal failure in a patient with severe malaria and dengue shock syndrome. Thaha M, Pranawa, Yogiantoro M, Tanimoto M, Tomino Y. Division of Nephrology-Hypertension, Department of Internal Medicine, Airlangga University School of Medicine, Surabaya, Indonesia. Malaria is an infectious disease caused by plasmodium, which lives and breeds in human blood cells, and is transmitted through the bites of Anopheles mosquitoes. Renal impairment, often caused by malaria, is acute renal failure (ARF) due to acute tubular necrosis (ATN). Dengue virus is transmitted from human to human through Aedes aegypti mosquito bites. Dengue hemorrhagic fever (DHF), the most severe stage of infection, is characterized by bleeding and shock tendencies (dengue shock syndrome, DSS). ARF is a less common complication in patients with DHF, with an incidence of less than 10%. Mixed infections of two infectious agents may cause overlapping symptoms and have been reported in Africa and India. We report here a patient with ARF due to mixed infection of severe malaria and DSS. The patient presented with fever and had a history of repeated malaria infection. Physical examination revealed stable vital signs and hepatosplenomegaly. Laboratory data showed hemoconcentration, thrombocytopenia and increased serum aminotransferase. Chest X-ray showed pleural effusion. A malarial antigen and thick smear examination showed the trophozoite stage of P. falciparum. On Day 3, blood pressure dropped to 80/60 mmHg, pulse was 120 beats/minute, weak, and body temperature 36.8 C, with icterus. Other tests revealed an increase of serum urea nitrogen and creatinine levels, and serologically anti-dengue IgG antibody (+) and anti-dengue IgM antibody (-). Based on these findings, we diagnosed the patient as having both malaria and DDS. We treated the patient with the parenteral anti-malarial agent, artemisinin. Supportive treatment and treatment of complications were also performed simultaneously for DSS. The patient experienced an oliguria episode but responded well to a diuretic. The patient was discharged after clinical and laboratory examinations showed positive progress. PMID: 19000545 [PubMed - indexed for MEDLINE] Clin Infect Dis. 2008 Sep 15;47(6):804-11.
The antiviral activities of artemisinin and artesunate. Efferth T, Romero MR, Wolf DG, Stamminger T, Marin JJ, Marschall M.
German Cancer Research Center, Pharmaceutical Biology, Im Neuenheimer Feld 280, Heidelberg, Germany.
[email protected] Traditional Chinese medicine commands a unique position among all traditional medicines because of its 5000 years of history. Our own interest in natural products from traditional Chinese medicine was triggered in the 1990s, by artemisinin-type sesquiterpene lactones from Artemisia annua L. As demonstrated in recent years, this class of compounds has activity against malaria, cancer cells, and schistosomiasis. Interestingly, the bioactivity of artemisinin and its semisynthetic derivative artesunate is even broader and includes the inhibition of certain viruses, such as human cytomegalovirus and other members of the Herpesviridae family (e.g., herpes simplex virus type 1 and Epstein-Barr virus), hepatitis B virus, hepatitis C virus, and bovine viral diarrhea virus. Analysis of the complete profile of the pharmacological activities and molecular modes of action of artemisinin and artesunate and their performance in clinical trials will further elucidate the full antimicrobial potential of these versatile pharmacological tools from nature. PMID: 18699744 [PubMed - indexed for MEDLINE] Clin Infect Dis. 2008 May 1;46(9):1455-7.
Artesunate as a potent antiviral agent in a patient with late drug-resistant cytomegalovirus infection after hematopoietic stem cell transplantation. Shapira MY, Resnick IB, Chou S, Neumann AU, Lurain NS, Stamminger T, Caplan O, Saleh N, Efferth T, Marschall M, Wolf DG. Hadassah Hebrew University Medical Center, Jerusalem, Israel. This is the first report of treatment of cytomegalovirus infection with artesunate, for a stem cell transplant recipient with a newly identified foscarnet-resistant and ganciclovir-resistant DNA polymerase L776M mutation. Artesunate treatment resulted in a 1.7-2.1-log reduction in viral load by treatment day 7, with a viral half-life of 0.9-1.9 days, indicating a highly effective block in viral replication. PMID: 18419454 [PubMed - indexed for MEDLINE] Antiviral Res. 2006 Feb;69(2):60-9. Epub 2005 Nov 21.
The anti-malaria drug artesunate inhibits replication of cytomegalovirus in vitro and in vivo. Kaptein SJ, Efferth T, Leis M, Rechter S, Auerochs S, Kalmer M, Bruggeman CA, Vink C, Stamminger T, Marschall M. Department of Medical Microbiology, University Hospital Maastricht, Maastricht, The Netherlands.
Treatment of human cytomegalovirus (HCMV) infections with any of the currently available antiviral agents is frequently associated with the occurrence of severe complications, seriously threatening the successful outcome of treatment. Therefore, the development of novel antiviral strategies is a challenging goal of current investigations. Previously, we reported that artesunate (ART) is an effective, non-cytotoxic inhibitor of HCMV in vitro. Here, we demonstrate that the efficacy of the antiviral effect of ART is augmented by co-treatment of HCMV-infected fibroblasts with ferrous iron, i.e. Ferrosanol, and/or the iron transfer-mediating molecule holotransferrin. This could alleviate the HCMV-induced modulation of cell surface expression of adhesion molecule Thy-1, suggesting that ART might be able to prevent pro-inflammatory effects of infection. The iron-enhanced, antiviral effect of ART could also be demonstrated in cultured cells infected with rat cytomegalovirus. Experiments using the RCMV/rat model showed that both the viral DNA load and virus titers in the salivary glands from infected rats were significantly reduced upon treatment with ART. Furthermore, an additive antiviral effect for ART together with each one of conventional anti-HCMV drugs, i.e. ganciclovir, cidofovir or foscarnet, was detected in HCMV-infected fibroblasts. These findings might open new perspectives regarding the use of ART in clinical trials. PMID: 16325931 [PubMed - indexed for MEDLINE] J Mol Med. 2002 Apr;80(4):233-42. Epub 2001 Dec 8.
Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses. Efferth T, Marschall M, Wang X, Huong SM, Hauber I, Olbrich A, Kronschnabl M, Stamminger T, Huang ES. Virtual Campus Rhineland-Palatinate, P.O. Box 4380, 55033 Mainz, Germany.
[email protected] Antiviral therapy of primary and recurrent infections with human cytomegalovirus is reserved for severe manifestations and faces several limitations. Presently candidates for novel drugs with lower adverse side effects and a minimized frequency of resistance formation are under investigation. Here we demonstrate that artesunate, an antimalaria drug with highly valuable pharmacological properties, possesses antiviral activity. A concentration-dependent inhibition of the replication of human cytomegaloviruses with wild-type phenotype was demonstrated in several cell lines. Inhibition was quantified using recombinant green fluorescent protein expressing virus variants. The IC50 values were in the same range for ganciclovir-sensitive and ganciclovir-resistant human cytomegalovirus, as calculated with 5.8+/-0.4 microM and 6.9+/-0.2 microM, respectively. This indicated a strong antiviral potential and a lack of cross-resistance. The optimal antiviral concentrations of artesunate were separable from those inducing cytotoxicity. In addition, the replication of viruses from three genera was seen to be artesunatesensitive to varying degrees. This suggests a mechanism linked to cellular activation pathways. Both the protein levels and the DNA binding activity of the two virus-induced cellular transcription factors Sp1 and NF-kappaB were found to be markedly reduced in the presence of artesunate. We also analyzed the cellular signaling kinase phosphoinositide 3-kinase, required for the activation of factors such as Sp1 and NF-kappaB in infected fibroblasts. The
phosphorylation of two downstream effectors of phosphoinositide 3-kinase, Akt and p70S6K, was markedly inhibited in the presence of artesunate. Thus, artesunate possesses attractive antiviral characteristics which are suggestively based on the interference with essential steps in the host cell kinase cascades. PMID: 11976732 [PubMed - indexed for MEDLINE] Prescrire Int. 2008 Aug;17(96):168-70.
Intravenous artesunate for severe malaria. [No authors listed] (1) Plasmodium falciparum malaria can be fatal in non-immune individuals. Artemisinin derivatives are effective in the treatment of simple malaria attacks, but what is their role in treating severe malaria? (2) It has been estimated that intravenous quinine halves the mortality rate due to malaria. However, it has frequent dose-dependent adverse effects (tinnitus, hearing disorders, dizziness), and carries a risk of rare life-threatening reactions. Intravenous quinine has been a standard treatment for many years; (3) A very large trial has been conducted among adults and children in Southeast Asia. The mortality rate was lower with intravenous artesunate: 15% versus 22% with intravenous quinine. Other, smaller trials have provided similar results. The two treatments have similar adverse effects; (4) In practice, in Southeast Asia, intravenous artesunate has the best risk-benefit balance of the treatments available for severe malaria. Elsewhere, in the absence of parasite resistance, quinine remains the standard treatment. Comparisons with artesunate are awaited. PMID: 19492495 [PubMed - indexed for MEDLINE] Trop Med Int Health. 2009 Mar;14(3):332-7. Epub 2009 Jan 28.
Cost-effectiveness of artesunate for the treatment of severe malaria. Lubell Y, Yeung S, Dondorp AM, Day NP, Nosten F, Tjitra E, Abul Faiz M, Yunus EB, Anstey NM, Mishra SK, Mohanty S, White NJ, Mills AJ. London School of Hygiene & Tropical Medicine, London, UK.
[email protected] OBJECTIVE: To explore the cost-effectiveness of artesunate against quinine based principally on the findings of a large multi-centre trial carried out in Southeast Asia. METHODS: Trial data were used to compare mortality of patients with severe malaria, treated with either artesunate or quinine. This was combined with retrospectively collected cost data to estimate the incremental cost per death averted with the use of artesunate instead of quinine. RESULTS: The incremental cost per death averted using artesunate was approximately 140 USD. Artesunate maintained this high level of cost-effectiveness also when allowing for the uncertainty surrounding the cost and effectiveness assessments. CONCLUSION: This analysis confirms the vast superiority of artesunate for treatment of severe malaria from an economic as well as a clinical perspective.
PMID: 19187518 [PubMed - indexed for MEDLINE] Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 2008 Oct 30;26(5):349-52.
[Artesunate in interrupting the transmission of Plasmodium falciparum] [Article in Chinese] Chen PQ, Xu Y, Chen D, He KR, Ou FZ, Fu CW, Fu LC, Li GQ. Tropical Medicine Institute, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
[email protected] OBJECTIVE: To observe the effect of artesunate (ATS) on the infectivity of Plasmodium falciparum gametocytes (PFG). METHODS: 31 volunteers with falciparum malaria and gametocytaemia were randomly divided into 3 groups: artesunate (ATS) group (15 cases), quinine (QN) group (10 cases) and placebo group (6 cases). Each case in ATS group received 6day course of oral artesunate (200 mg at 0, 6 and 24 hours then 100 mg daily for 4 days). Cases in QN group each received 21-dose course of quinine sulfate (500 mg/time) over seven days. Cases in placebo group took 2 tablets of vitamin B composites, three times per day for seven days. Peripheral PFG were counted daily in all cases until the clearance of PFG. Mosquitoes (Anopheles dirus) were fed with venous blood of patients on the 1st, 7th, 14th, 21st and 28th day, respectively. RESULTS: All cases in placebo group were PFG positive at the whole course by blood smear examinations. The PFG relative density in ATS group were (12.5+/-3.3)%, (1.2+/-0.4)%, (0.3+/-0.1)% on 7th, 14th, 21st day respectively, and the mean PFG clearance time was (22.0+/-1.4) d. The PFG relative density in QN group were (173.9+/-47.0)%, (112.5+/45.4)%, (32.5+/-17.8)% at 7th, 14th, 21st day respectively, and the mean clearance time of PFG was (32.5+/-2.1) d (t=4.731, P
