MyMedR

Plasmodium knowlesi, a simian malaria parasite, is now recognised as the fifth cause of human malaria and can lead to fatal infections in humans. Knowlesi malaria cases are widely distributed in East and West Malaysia and account for more than 50% of admissions for malaria in certain hospitals in the state of Sarawak. This paper will begin with a description of the early studies on P. knowlesi, followed by a review of the epidemiology, diagnosis, clinical and laboratory features, and treatment of knowlesi malaria.

Matched MeSH terms: Antimalarials/therapeutic use

Pharmacokinetics of artemisinin-type compounds

Navaratnam V, Mansor SM, Sit NW, Grace J, Li Q, Olliaro P

Clin Pharmacokinet, 2000 Oct;39(4):255-70.

PMID: 11069212

Various compounds of the artemisinin family are currently used for the treatment of patients with malaria worldwide. They are characterised by a short half-life and feature the most rapidly acting antimalarial drugs to date. They are increasingly being used, often in combination with other drugs, although our knowledge of their main pharmacological features (including their absorption, distribution, metabolism and excretion) is still incomplete. Such data are particularly important in the case of combinations. Artemisinin derivatives are converted primarily, but to different extents, to the bioactive metabolite artenimol after either parenteral or gastrointestinal administration. The rate of conversion is lowest for artelinic acid (designed to protect the molecule against metabolism) and highest for the water-soluble artesunate. The absolute and relative bioavailability of these compounds has been established in animals, but not in humans, with the exception of artesunate. Oral bioavailability in animals ranges, approximately, between 19 and 35%. A first-pass effect is highly probably for all compounds when administered orally. Artemisinin compounds bind selectively to malaria-infected erythrocytes to yet unidentified targets. They also bind modestly to human plasma proteins, ranging from 43% for artenimol to 81.5% for artelinic acid. Their mode of action is still not completely understood, although different theories have been proposed. The lipid-soluble artemether and artemotil are released slowly when administered intramuscularly because of the 'depot' effect related to the oil formulation. Understanding the pharmacokinetic profile of these 2 drugs helps us to explain the characteristics of the toxicity and neurotoxicity. The water-soluble artesunate is rapidly converted to artenimol at rates that vary with the route of administration, but the processes need to be characterised further, including the relative contribution of pH and enzymes in tissues, blood and liver. This paper intends to summarise contemporary knowledge of the pharmacokinetics of this class of compounds and highlight areas that need further research.

Matched MeSH terms: Antimalarials/therapeutic use

Malaria--an overview

Gilles HM

J Infect, 1989 Jan;18(1):11-23.

PMID: 2644358

The epidemiology, clinical features, diagnosis, prognosis, management, chemotherapy and chemoprophylaxis of malaria are reviewed.

Matched MeSH terms: Antimalarials/therapeutic use

Fulltext Repurposing Antimalarials to Tackle the COVID-19 Pandemic

Krishna S, Augustin Y, Wang J, Xu C, Staines HM, Platteeuw H, et al.

Trends Parasitol, 2021 01;37(1):8-11.

PMID: 33153922 DOI: 10.1016/j.pt.2020.10.003

Artemisinin-based combination therapies (ACTs) have demonstrated in vitro inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Artemisinins have also shown anti-inflammatory effects, including inhibition of interleukin-6 (IL-6) that plays a key role in the development of severe coronavirus disease 2019 (COVID-19). There is now sufficient evidence for the effectiveness of ACTs, and in particular artesunate/pyronaridine, to support clinical studies for COVID-19 infections.

Matched MeSH terms: Antimalarials/therapeutic use*

Fulltext A study protocol for a randomised open-label clinical trial of artesunate-mefloquine versus chloroquine in patients with non-severe Plasmodium knowlesi malaria in Sabah, Malaysia (ACT KNOW trial)

Grigg MJ, William T, Dhanaraj P, Menon J, Barber BE, von Seidlein L, et al.

BMJ Open, 2014 Aug 19;4(8):e006005.

PMID: 25138814 DOI: 10.1136/bmjopen-2014-006005

INTRODUCTION: Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species.

METHODS AND ANALYSIS: ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (α 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis.

ETHICS AND DISSEMINATION: This study has been approved by relevant institutional ethics committees in Malaysia and Australia. Results will be disseminated to inform knowlesi malaria treatment policy in this region through peer-reviewed publications and academic presentations.

TRIAL REGISTRATION NUMBER: NCT01708876.

Matched MeSH terms: Antimalarials/therapeutic use*

Fulltext Plasmodium knowlesi infection: a diagnostic challenge

Fan L, Lee SY, Koay E, Harkensee C

BMJ Case Rep, 2013;2013:bcr2013009558.

PMID: 23608876 DOI: 10.1136/bcr-2013-009558

Plasmodium knowlesi malaria is an uncommon, but highly prevalent parasitic infection in parts of Malaysia. This is the case of a 14-year-old Singaporean boy presenting to our emergency department with an 11-day history of fever following a school trip to Malaysia. Hepatosplenomegaly was the only clinical finding; laboratory tests showed thrombocytopaenia, lymphopaenia, mild anaemia and liver transaminitis. Specific malaria antigen tests were negative, but the peripheral blood film showed plasmodia with atypical features, with a parasite load of 0.5%. PCR confirmed the diagnosis of P knowlesi. The patient was successfully treated with chloroquine. The clinical course of P knowlesi malaria is indistinguishable from that of Plasmodium falciparum. This case highlights the importance of taking detailed travel history, careful examination of malaria blood films and judicious use of molecular techniques. Antigen tests alone may have missed a malaria diagnosis altogether, while blood film examination may wrongly identify the species as Plasmodium malariae or P falciparum. Third-generation PCR assays can be used to reliably identify P knowlesi.

Matched MeSH terms: Antimalarials/therapeutic use

[Monkey malaria in a traveller from Malaysia]

van Hellemond JJ, van Genderen PJ

Ned Tijdschr Geneeskd, 2010;154:A1353.

PMID: 20456798

Matched MeSH terms: Antimalarials/therapeutic use

Efficacy and safety of chloroquine for treatment in patients with uncomplicated Plasmodium vivax infections in endemic countries

Naing C, Aung K, Win DK, Wah MJ

Trans R Soc Trop Med Hyg, 2010 Nov;104(11):695-705.

PMID: 20850161 DOI: 10.1016/j.trstmh.2010.08.009

Chloroquine (CQ) is a relatively inexpensive drug for treatment of malaria. If efficacy of CQ is still assumed, then it should be indicated in malaria treatment policies as the drug of choice for uncomplicated Plasmodium vivax malaria in endemic countries with resource constraints. The objective of this review is to summarize the existing evidence on the relative efficacy and safety of CQ in treating patients with uncomplicated P. vivax malaria in endemic countries. We searched online data bases (PUBMED, MEDLINE, EMBASE, The Cochrane Library) and the reference lists of the retrieved articles. Fifteen randomized controlled trials (n=6215) assessing the relative efficacy and safety of CQ for treatment of uncomplicated P. vivax malaria were included. CQ monotherapy was compared to CQ plus primaquine (PQ), artemisinin/artemether, artemisinin based combination therapy, quinine, CQ plus tafenoquine, chlorguanil plus dapsone, azithromycin, or placebo. Treatment efficacy was not significantly different between the CQ monotherapy group and that of the CQ with PQ 14 day group at 28 day follow-up (55/711, 7.7% vs 35/712, 4.9%; P=0.16). Evidence from the trials identified for this review draw a fairly clear conclusion about the relative efficacy and safety of CQ for treating uncomplicated P. vivax malaria infection. However, further research in this field with well powered, randomized, non-inferiority design, using the standardized protocol is needed.

Matched MeSH terms: Antimalarials/therapeutic use*

Ethnobotanical study on some Malaysian anti-malarial plants: a community based survey

Al-Adhroey AH, Nor ZM, Al-Mekhlafi HM, Mahmud R

J Ethnopharmacol, 2010 Oct 28;132(1):362-4.

PMID: 20723596 DOI: 10.1016/j.jep.2010.08.006

Various plants species are used in the traditional medicine for the treatment of malaria. This is the first community based ethnobotanical study in Peninsular Malaysia.

Matched MeSH terms: Antimalarials/therapeutic use

Fulltext [A fifth plasmodium that can cause malaria]

Myrvang B

Tidsskr. Nor. Laegeforen., 2010 Feb 11;130(3):282-3.

PMID: 20160773 DOI: 10.4045/tidsskr.09.0554

Since 2004, malaria with a "fifth" plasmodium, Plasmodium knowlesi (common in macaque monkeys), has been diagnosed in a number of people in Southeast Asia. This article gives a short overview of the epidemiology, clinical picture, diagnostics and treatment of P. knowlesi infection.

Matched MeSH terms: Antimalarials/therapeutic use

Fulltext A retrospective prevalence study of malaria in an aborigine hospital in Gombak, Selangor, Malaysia

Jamaiah I, Rohela M, Nissapatorn V, Mohamad Azlan H, Nor Adli AR, Shahrul Rizan I, et al.

Southeast Asian J. Trop. Med. Public Health, 2006;37 Suppl 3:1-4.

PMID: 17547040

This was a five-year retrospective study (1999-2004) on the prevalence of malaria at the Aborigine Hospital, Gombak, Malaysia. A total of 94 malaria cases was analysed. The highest case reports were for the year 2000, with 32 cases (34%), and the lowest was in 2004, with only 1 (1%). The majority of cases reported were among the Semai tribe (44%), followed by the Temiar tribe (34%) and the unspecified tribe (s) (20%). Females (53%) were more commonly affected than males (47%). The majority of cases were within the age group 1-5 years (51%). Plasmodium falciparum was the most common species reported in this study, at 57%, followed by Plasmodium vivax (38%) and 5% mixed infection of P. falciparum and P. vivax. Most patients (27%) stayed for more than one month in hospital. Most patients came from Kuala Lipis, Pahang, (78%). The most common complication was anemia (38%) followed by splenomegaly (18%); only 2% had cerebral malaria. All patients were treated with the standard anti-malarial drugs. No deaths were reported in this study.

Matched MeSH terms: Antimalarials/therapeutic use

Fulltext The challenges of introducing routine G6PD testing into radical cure: a workshop report

Ley B, Luter N, Espino FE, Devine A, Kalnoky M, Lubell Y, et al.

Malar J, 2015 Sep 29;14:377.

PMID: 26416229 DOI: 10.1186/s12936-015-0896-8

The only currently available drug that effectively removes malaria hypnozoites from the human host is primaquine. The use of 8-aminoquinolines is hampered by haemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Recently a number of qualitative and a quantitative rapid diagnostic test (RDT) format have been developed that provide an alternative to the current standard G6PD activity assays. The WHO has recently recommended routine testing of G6PD status prior to primaquine radical cure whenever possible. A workshop was held in the Philippines in early 2015 to discuss key challenges and knowledge gaps that hinder the introduction of routine G6PD testing. Two point-of-care (PoC) test formats for the measurement of G6PD activity are currently available: qualitative tests comparable to malaria RDT as well as biosensors that provide a quantitative reading. Qualitative G6PD PoC tests provide a binomial test result, are easy to use and some products are comparable in price to the widely used fluorescent spot test. Qualitative test results can accurately classify hemizygous males, heterozygous females, but may misclassify females with intermediate G6PD activity. Biosensors provide a more complex quantitative readout and are better suited to identify heterozygous females. While associated with higher costs per sample tested biosensors have the potential for broader use in other scenarios where knowledge of G6PD activity is relevant as well. The introduction of routine G6PD testing is associated with additional costs on top of routine treatment that will vary by setting and will need to be assessed prior to test introduction. Reliable G6PD PoC tests have the potential to play an essential role in future malaria elimination programmes, however require an improved understanding on how to best integrate routine G6PD testing into different health settings.

Matched MeSH terms: Antimalarials/therapeutic use

Fulltext Evaluation of the sensitivity in vitro of Plasmodium falciparum and in vivo of Plasmodium chabaudi Malaria to various drugs and their combinations

Rahman NNNA

Med J Malaysia, 1997 Dec;52(4):390-8.

PMID: 10968116

K1 strain of Plasmdoium falciparum is resistant in vitro to chloroquine, pyrimethamine and sulfadoxine. Response of this strain to combinations of antimalarial drugs in the in vitro hypoxanthine incorporation test was coupled with that of a line of strain NF54 relatively sensitive to chloroquine and fully sensitive to other antimalarials. Pyrimethamine and sulfadoxine showed potentiative synergism against NF54 and less marked against K1. Erythromycin and chloroquine showed potentiation, but less marked against NF54. Quinine and clindamycin had an additive effect against NF54 but potentiated against K1. Combinations of chloroquine with quinine or amodiaquine or of amodiaquine with clindamycin or erythromycin showed mild antagonistic or additive effects. In vivo studies in mice, using the 4-day suppressive test, the AS(3CQ) clone of Plasmodium chabaudi was resistant to pyrimethamine and chloroquine but sensitive to sulfadoxine. Similar combinations as above were carried out and their responses were compared between the resistant and sensitive strains. For both strains, the combinations of chloroquine-erythromycin, pyrimethamine-sulfadoxine, quinine-clindamycin showed potentiation; antagonistic effects were observed in chloroquine-amodiaquine combinations whereas when amodiaquine combined with erythromycin the effect was additive. Amodiaquine-clindamycin and chloroquine-quinine combinations have an antagonistic effect against the sensitive strain but additive against the resistant strain.

Matched MeSH terms: Antimalarials/therapeutic use

Fansidar resistant falciparum malaria acquired in South East Asia

Black F, Bygbjerg I, Effersøe P, Gomme G, Jepsen S, Jensen GA

Trans R Soc Trop Med Hyg, 1981;75(5):715-6.

PMID: 7036431

A case of Plasmodium falciparum malaria resistant to Fansidar (sulphadoxine plus pyrimethamine) at a level corresponding to R III and resistant to chloroquine is reported. The infection was most certainly acquired in Malaysia, but diagnosed and treated in a non-malarious area. Normal resorption and elimination rates of the Fansidar components excludes cure failure due to abnormal drug fate in the host. P. falciparum parasites from the patient have been maintained in vitro cultures. The patient was permanently cured with mefloquine.

Matched MeSH terms: Antimalarials/therapeutic use

Fulltext Case Report: Case Series of Human Plasmodium knowlesi Infection on the Southern Border of Thailand

Ngernna S, Rachaphaew N, Thammapalo S, Prikchoo P, Kaewnah O, Manopwisedjaroen K, et al.

Am J Trop Med Hyg, 2019 12;101(6):1397-1401.

PMID: 31595871 DOI: 10.4269/ajtmh.19-0063

Although human infections of Plasmodium knowlesi have been found throughout Southeast Asia, most cases originated from Malaysian Borneo. In Thailand, P. knowlesi malaria was considered extremely rare. However, during October 2017-September 2018, there was a surge in the number of reported P. knowlesi cases. Here, a series of six cases of P. knowlesi malaria found during this period in Songkhla and Narathiwat provinces of southern Thailand are presented. All cases were confirmed by polymerase chain reaction. The unprecedented case number in the affected area is a warning sign of an increasing P. knowlesi burden in the south of Thailand.

Matched MeSH terms: Antimalarials/therapeutic use

Fulltext Case Report: Two Cases of Recurring Ovale Malaria in Sarawak, Malaysia, after Successful Treatment of Imported Plasmodium falciparum Infection

Liew JWK, Ooi CH, Snounou G, Lau YL

Am J Trop Med Hyg, 2019 12;101(6):1402-1404.

PMID: 31595863 DOI: 10.4269/ajtmh.19-0305

Here are two cases of recurring ovale malaria in Sarawak, Malaysia, that are likely relapses that occurred 1-2 months after successful treatment of the initial imported falciparum malaria with artemisinin-based combined therapy. The patients have no history or recollection of previous malaria episodes. These cases add to the limited evidence on the relapsing nature of Plasmodium ovale, after a febrile episode. In regions where P. ovale is not known to be autochthonous, active follow-up of treated imported malaria patients is highly recommended following their return, particularly to areas nearing or having achieved elimination.

Matched MeSH terms: Antimalarials/therapeutic use

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