EPILEPSIA, Issue 5 2006
Edgard Brice Ngoungou
Summary:,Purpose: Cerebral malaria (CM) is suspected to be a potential cause of epilepsy in tropical areas, but little information is available. The purpose of this study was to evaluate the role of CM in epilepsy among children in Mali. Methods: An exposed,nonexposed study was performed to identify children who had epilepsy after malaria in the 0- to 15-year age group. The exposure factor was CM defined according to World Health Organization (WHO) criteria, and the nonexposure factor was symptomatic malaria without the characteristics of CM (NCM). All the children underwent a screening questionnaire and were examined by a medical physician. After the screening phase, a specialist in neuropediatrics examined the children suspected to have epilepsy. EEG and computed tomography (CT) scans were performed in some of these patients. Results: In total, 101 subjects who had had CM and 222 who had had NCM were included. Fifty-four children (CM, 34; NCM, 20) were suspected to have epilepsy, and six were confirmed (CM, five; NCM, one). The incidence rate was 17.0 per 1000 person-years in the CM group and 1.8 per 1000 person-year in the NCM group; thus the relative risk (RR) was 9.4 [95% confidence interval (CI), 1.3,80.3; p = 0.02]. After adjustment on age and duration of follow-up, the RR was 14.3 (95% CI, 1.6,132.0; p = 0.01). Conclusions: The risk of sequelar epilepsy is significantly higher in the CM group compared with the NCM group. A reevaluation of this cohort should be carried out later to search for temporal epilepsy that appeared after age 10 years. [source]

Malaria sporozoite antigen-directed genome-wide response in transgenic Drosophila,

GENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 3 2009
Jizhou Yan
Abstract Malaria kills a million people annually. Understanding the relationship between a causative parasite, Plasmodium falciparum, and the mosquito vector might suggest novel prevention approaches. We created and transformed into Drosophila two genes encoding, thrombospondin-related adhesive protein (TRAP) and circumsporozoite protein (CSP), found on the cell surface of Plasmodium sporozoites. To understand a model insect's response, we induced these proteins separately and together, performing whole genome microarray analysis measuring gene expression changes. Gene ontology classification of responding genes reveals that TRAP and CSP strongly and differentially influence Drosophila genes involved with cell motility and gene regulation, respectively; however, the most striking effects are on the immune system. While immune-related genes are but modestly elevated compared with responses to sepsis, there is a marked repression of the Toll pathway. This suggests: (1) how Plasmodium infection of the mosquito might use TRAP and CSP to modulate the host insect's physiology to promote sporozoite survival and transmission to man and (2) that approaches to elevate expression of the mosquito's Toll pathway might lead to novel methods of malaria prevention. genesis 47:196,203, 2009. © 2009 Wiley-Liss, Inc. [source]

Innate immunity against malaria parasites in Anopheles gambiae

INSECT SCIENCE, Issue 1 2008
Yang Chen
Abstract Malaria continues to exert a huge toll in the world today, causing approximately 400 million cases and killing between 1-2 million people annually. Most of the malaria burden is borne by countries in Africa. For this reason, the major vector for malaria in this continent, Anopheles gambiae, is under intense study. With the completion of the draft sequence of this important vector, efforts are underway to develop novel control strategies. One promising area is to harness the power of the innate immunity of this mosquito species to block the transmission of the malaria parasites. Recent studies have demonstrated that Toll and Imd signaling pathways and other immunity-related genes (encoding proteins possibly function in recognition or as effector molecules) play significant roles in two different arms of innate immunity: level of infection intensity and melanization of Plasmodium oocysts. The challenges in the future are to understand how the functions of these different genes are coordinated in defense against malaria parasites, and if different arms of innate immunity are cross,regulated or coordinated. [source]

District health systems in a neoliberal world: a review of five key policy areas,

INTERNATIONAL JOURNAL OF HEALTH PLANNING AND MANAGEMENT, Issue S1 2003
Malcolm Segall
Abstract District health systems, comprising primary health care and first referral hospitals, are key to the delivery of basic health services in developing countries. They should be prioritized in resource allocation and in the building of management and service capacity. The relegation in the World Health Report 2000 of primary health care to a ,second generation' reform,to be superseded by third generation reforms with a market orientation,flows from an analysis that is historically flawed and ideologically biased. Primary health care has struggled against economic crisis and adjustment and a neoliberal ideology often averse to its principles. To ascribe failures of primary health care to a weakness in policy design, when the political economy has starved it of resources, is to blame the victim. Improvement in the working and living conditions of health workers is a precondition for the effective delivery of public health services. A multidimensional programme of health worker rehabilitation should be developed as the foundation for health service recovery. District health systems can and should be financed (at least mainly) from public funds. Although in certain situations user fees have improved the quality and increased the utilization of primary care services, direct charges deter health care use by the poor and can result in further impoverishment. Direct user fees should be replaced progressively by increased public finance and, where possible, by prepayment schemes based on principles of social health insurance with public subsidization. Priority setting should be driven mainly by the objective to achieve equity in health and wellbeing outcomes. Cost effectiveness should enter into the selection of treatments for people (productive efficiency), but not into the selection of people for treatment (allocative efficiency). Decentralization is likely to be advantageous in most health systems, although the exact form(s) should be selected with care and implementation should be phased in after adequate preparation. The public health service should usually play the lead provider role in district health systems, but non-government providers can be contracted if needed. There is little or no evidence to support proactive privatization, marketization or provider competition. Democratization of political and popular involvement in health enhances the benefits of decentralization and community participation. Integrated district health systems are the means by which specific health programmes can best be delivered in the context of overall health care needs. International assistance should address communicable disease control priorities in ways that strengthen local health systems and do not undermine them. The Global Fund to Fight AIDS, Tuberculosis and Malaria should not repeat the mistakes of the mass compaigns of past decades. In particular, it should not set programme targets that are driven by an international agenda and which are achievable only at the cost of an adverse impact on sustainable health systems. Above all the targets must not retard the development of the district health systems so badly needed by the rural poor. Copyright © 2003 John Wiley & Sons, Ltd. [source]

Knowledge and management of infants' pain by mothers in Ile Ife, Nigeria

INTERNATIONAL JOURNAL OF NURSING PRACTICE, Issue 4 2008
Adenike Olaogun
Mothers' knowledge and management of pain in infants were assessed in this study. A total of 130 mothers from two health centres in Ile Ife, Southwest, Nigeria were selected by systematic sampling method. Only 3.8% indicated that neonates experience pain. Malaria (46.2%) was the major cause of pain identified. Analgesic/antimalarials (56.9%) and breastfeeding (16.9%) are used in pain relief. To improve the quality of life of infants, mothers must be educated on the assessment, early detection and management of pain. [source]

Rapid production of a plasmid DNA encoding a malaria vaccine candidate via amino-functionalized poly(GMA- co -EDMA) monolith

AICHE JOURNAL, Issue 11 2008
Michael K. Danquah
Abstract Malaria is a global health problem; an effective vaccine is urgently needed. Due to the relative poverty and lack of infrastructure in malaria endemic areas, DNA-based vaccines that are stable at ambient temperatures and easy to formulate have great potential. While attention has been focused mainly on antigen selection, vector design and efficacy assessment, the development of a rapid and commercially viable process to manufacture DNA is generally overlooked. We report here a continuous purification technique employing an optimized stationary adsorbent to allow high-vaccine recovery, low-processing time, and, hence, high-productivity. A 40.0 mL monolithic stationary phase was synthesized and functionalized with amino groups from 2-Chloro-N,N-diethylethylamine hydrochloride for anion-exchange isolation of a plasmid DNA (pDNA) that encodes a malaria vaccine candidate, VR1020-PyMSP4/5. Physical characterization of the monolithic polymer showed a macroporous material with a modal pore diameter of 750 nm. The final vaccine product isolated after 3 min elution was homogeneous supercoiled plasmid with gDNA, RNA and protein levels in keeping with clinical regulatory standards. Toxicological studies of the pVR1020-PyMSP4/5 showed a minimum endotoxin level of 0.28 EU/mg pDNA. This cost-effective technique is cGMP compatible and highly scalable for the production of DNA-based vaccines in commercial quantities, when such vaccines prove to be effective against malaria. © 2008 American Institute of Chemical Engineers AIChE J, 2008 [source]

Antimalarial compounds isolated from plants used in traditional medicine

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2009
Joanne Bero
Abstract Objectives This review covers the compounds with antiplasmodial activity isolated from plants published from 2005 to the end of 2008, organized according to their phytochemical classes. Details are given for substances with IC50 values , 11 ,M. Key findings Malaria is a major parasitic disease in many tropical and subtropical regions and is responsible for more than 1 million deaths each year in Africa. The rapid spread of resistance encourages the search for new active compounds. Nature and particularly plants used in traditional medicine are a potential source of new antimalarial drugs as they contain molecules with a great variety of structures and pharmacological activities. Summary A large number of antimalarial compounds with a wide variety of structures have been isolated from plants and can play a role in the development of new antimalarial drugs. Ethnopharmacological approaches appear to be a promising way to find plant metabolites that could be used as templates for designing new derivatives with improved properties. [source]

Assessment of Adherence to Atovaquone-Proguanil Prophylaxis in Travelers

JOURNAL OF TRAVEL MEDICINE, Issue 4 2010
John C. DePetrillo MD
Background. Malaria continues to be a serious, world-wide infection. Atovaquone-proguanil is one of the prophylactic agents recommended for travelers to endemic regions. However, little information is available regarding adherence with this medication. A large proportion of malaria cases reported from travelers is due to non-adherence to prescribed regimens. This study was undertaken to analyze adherence with atovaquone-proguanil prophylaxis and specific factors contributing to non-adherence. Methods. Men and non-pregnant women ,18 years of age were eligible for inclusion. Enrolled travelers received a prescription for atovaquone-proguanil prophylaxis and were contacted by telephone within 3 weeks of return to the United States. A questionnaire was prepared by the authors to determine if subjects were adherent with the medication. Additional data included demographics, duration of malarious travel, previous use of prophylactic agents, underlying medical conditions, concurrent medications, and reasons for non-adherence. Results. Complete data were available for 104/124 (84%) participants: 49 (47%) men, 55 (53%) women. Average duration of malarious travel was 12 days, and 19 (18%) travelers reported previous travel to a malarious region. Ninety-two (89%) subjects were completely adherent with their prophylactic atovaquone-proguanil course. Adverse effects were seen in 6 (5%) travelers. Conclusions. Adherence with atovaquone-proguanil malaria prophylaxis is high among travelers from a non-endemic region. Adverse effects are minimal. Non-adherence was primarily attributable to travelers' perception of need. [source]

Imported Malaria in Children: A Comparative Study Between Recent Immigrants and Immigrant Travelers (VFRs)

JOURNAL OF TRAVEL MEDICINE, Issue 4 2010
Juan Arnáez MD
Background. In Europe, imported malarial cases occur in returning travelers and immigrants mostly from African countries. There have been an increasing number of cases in the past years in Spain. Methods. An analysis of all cases of malaria who attended at the Hospital of Mostoles in the Southwest of Madrid from 1995 to 2007 was performed. Clinical, epidemiological, laboratory, and parasitological findings were analyzed and compared between immigrants coming from endemic countries (recent immigrants) and children who traveled to endemic areas to visit friends and relatives (VFRs). Results. Sixty cases of imported malaria were detected. Most of the cases (59 of 60) were acquired in sub-Saharan Africa. The most common species was Plasmodium falciparum (43 of 60). Microscopic examination was positive in 95%, and the polymerase chain reaction (PCR) for Plasmodium achieved additional diagnosis in seven cases. Fourteen cases were VFRs; none of them used appropriate malaria chemoprophylaxis. Fever and thrombocytopenia were significantly more common among VFRs. They also had significantly higher parasite density. Twelve cases were asymptomatic at the time of diagnosis; all of them were recent immigrants. Conclusions. VFRs account for a significant number of childhood malarial cases. These patients had not taken malaria chemoprophylaxis and malarial cases were more severe. VFR children are a high-risk group, and pretravel advice should underline the risk for malaria. Recent immigrants can be asymptomatic and parasitemias are lower. Therefore, a high index of suspicion is necessary, and PCR for Plasmodium should be performed in case of negative thick smears. [source]

Atypical Plasmodium vivax Malaria in a Traveler: Bilateral Hydronephrosis, Severe Thrombocytopenia, and Hypotension

JOURNAL OF TRAVEL MEDICINE, Issue 2 2008
Pedro M. Rifakis MD
We report a case of Plasmodium vivax infection manifested as severe thrombocytopenia, bilateral hydronephrosis, and hypotension in a returning traveler from a malaria,endemic area in Venezuela. While most of the efforts to prevent malaria in travelers focus on the life-threatening consequences of Plasmodium falciparum malaria, nonimmune travelers who encounter infection with P vivax may also develop serious complications. This case highlights the importance of preventing malaria cases among nonimmune or semi-immune individuals traveling to P vivax,endemic areas. [source]

Atlas of Human Malaria (Atlante della Malaria Umana)

JOURNAL OF TRAVEL MEDICINE, Issue 2 2008
Giovanni Swierczynski
No abstract is available for this article. [source]

Acute Respiratory Distress Syndrome in Plasmodium vivax Malaria in Traveler Returning From Venezuela

JOURNAL OF TRAVEL MEDICINE, Issue 2 2006
Nuccia Saleri MD
No abstract is available for this article. [source]

The Use of a Rapid Diagnostic Test to Determine Malaria as a Cause of Death

JOURNAL OF TRAVEL MEDICINE, Issue 6 2003
François Chappuis
No abstract is available for this article. [source]

Suspected Allergy to Artemether,Lumefantrine Treatment of Malaria

JOURNAL OF TRAVEL MEDICINE, Issue 5 2003
Reinhard Krippner
No abstract is available for this article. [source]

The Efficacy of Chemoprophylaxis against Malaria with Chloroquine plus Proguanil, Mefloquine, and Atovaquone plus Proguanil in Travelers from Denmark

JOURNAL OF TRAVEL MEDICINE, Issue 3 2003
Kristian Kofoed
Background The risk of malaria infection in travelers is seldom known in detail and neither is the efficacy of different prophylactic regimens, due to a lack of controlled trials. Surveillance of malaria diagnosed after return can provide data on risk and efficacy. Methods An open case-control study was initiated. Imported cases were notified to our department and were studied in 320 permanent residents in Denmark, returning from abroad with malaria from 1997 to 1999. These were compared with a group of 600 travelers who were not infected with malaria and matched by age, sex, and destination. Information on the use of chemoprophylaxis and the length of stay in malarious areas were obtained by questionnaire. Results Two hundred cases of Plasmodium falciparum malaria were notified of which 103 had used chloroquine and proguanil, 16 mefloquine, and 3 atovaquone and proguanil as prophylaxis, whereas the rest had taken other drugs or no prophylaxis. This study showed that the risk increased with increasing exposure and that compliance was lower especially for mefloquine users in malaria cases compared with controls. The study provided the first comprehensive data on the use of atovaquone/proguanil to travelers. The estimated efficacy of chloroquine and proguanil, mefloquine, and atovaquone and proguanil in fully compliant users was 1:599, 1:2,232, and 1:1,943, respectively, P. falciparum cases per prescription. The country specific risk data showed that the risk of getting malaria varied from 1 per 140 travelers to Ghana to almost 1 per 40,000 to Thailand, providing data that allow the use of prophylaxis to be restricted to high-risk areas. Conclusion There was a considerable variation in risk between the countries with the highest risk in tropical Africa. Chloroquine and proguanil was less efficient compared with mefloquine. Atovaquone/proguanil (Malarone) was at least as efficient as mefloquine, but breakthroughs were observed. [source]

Epidemiological and Clinical Aspects of Malaria in Japan

JOURNAL OF TRAVEL MEDICINE, Issue 2 2003
Mikio Kimura
First page of article [source]

Preventing Malaria in International Travelers

JOURNAL OF TRAVEL MEDICINE, Issue 2001
FRCPC Guest editor, Jay S. Keystone MD
No abstract is available for this article. [source]

Reemergence of Malaria: Increasing Risks for Travelers

JOURNAL OF TRAVEL MEDICINE, Issue 2001
FRCPC, Jay S. Keystone MD
No abstract is available for this article. [source]

Imported Malaria in Pregnancy due to Plasmodium falciparum

JOURNAL OF TRAVEL MEDICINE, Issue 6 2001
Alfredo Focá
No abstract is available for this article. [source]

Malaria Antibodies and Mefloquine Levels among United Nations Troops in Angola

JOURNAL OF TRAVEL MEDICINE, Issue 3 2001
Eli Schwartz
Background: The United Nations deployed about 8,000 soldiers in a peacekeeping mission in Angola. Malaria is the most common disease there and consequently it was the major risk to the UN troops. Most of them are from malaria free areas. As a result of improper prophylactic measures there were many cases of malaria, including some deaths in 1995. In February,March 1996, an Israeli team was sent to Angola to evaluate the malaria situation among UN soldiers. This paper deals specifically with some aspects of chemoprophylaxis and diagnosis. The efforts were concentrated in one particular area where malaria incidence had been reported as the highest. Methods: Blood samples were collected from nonimmune soldiers who were using mefloquine as a prophylactic drug and were exposed to malaria. The mefloquine and the antimalarial antibody plasma levels were monitored. Results: While the local laboratory indicated that about 80% had a malaria episode, the serological results revealed that only 5 soldiers of the 56 (9%) examined had antimalarial antibodies, of which 3 were Angolans. Despite a controlled prophylactic regimen there was considerable variability in mefloquine plasma levels: 46% of the samples were below the required prophylactic level and 26% above it. All patients who were proven positive with malaria by both microscopic and serologic observation had a low level of mefloquine. Conclusions: In field conditions, a kit which identifies plasmodial antigens, is preferable, to a microscopic diagnostic method. Controlled mefloquine prophylaxis may not prevent malaria, especially when blood levels are low. The reason for the low mefloquine blood levels is not clear and needs further evaluation. [source]

Malaria Epidemiological Situation in Italy and Evaluation of Malaria Incidence in Italian Travelers

JOURNAL OF TRAVEL MEDICINE, Issue 1 2001
Roberto Romi
Background: Malaria was endemic throughout the country until it was eradicated nearly 50 years ago. Since then, mainly imported malaria cases have been reported to the National Health Service, with an increasing trend. The aim of this study was to present a detailed analysis of the current epidemiological situation of malaria in Italy, and to make a first attempt to calculate the incidence of malaria in Italian international travelers. Methods: An archive of confirmed malaria cases is available at the Istituto Superiore di Sanitá (ISS), the National Institute of Health of Italy, based on the mandatory report system. Data from each case report reported to the ISS from 1989 to 1997 have been analyzed. An evaluation of malaria incidence in Italian travelers has been also performed for the same period, based on the statistics provided by the Ministry of Transport. Results: From 1989 to 1997, a total of 5,898 microscopically confirmed malaria cases have been reported. Of these, 5,773 (97.9%) were imported cases, 106 cases (1.8%) were relapses of Plasmodium vivax or Plasmodium ovale infections, and 19 cases (0.3%) occurred in subjects who had never been out of Italy. During the period of study, 55 deaths due to Plasmodium falciparum malaria were reported, with a mean fatality rate of 1.2%. Malaria incidence in Italians who traveled to Africa was estimated to be 1.5/1000. These figures appeared to be 10,20 and 30,40 times greater than that recorded in travelers to Asia (0.11/1000) and Central-South America (0.04/1000) respectively. Conclusions: From 1989 to 1997, there has been a remarkable increase in the total number of imported malaria cases in Italy, which reached a peak of more than 800 cases/year in 1997. A constant increase in the number of cases affecting foreigners has been reported, while the cases among Italians have remained stable. From 1989 to 1997 the number of Italian intercontinental travelers has nearly doubled, but malaria incidence has remained quite stable. [source]

Malaria in Brazilian Military Personnel Deployed to Angola

JOURNAL OF TRAVEL MEDICINE, Issue 5 2000
COL L. Jose Sanchez
Background: Malaria represents one of the most important infectious disease threats to deployed military forces; most personnel from developed countries are nonimmune personnel and are at high risk of infection and clinical malaria. This is especially true for forces deployed to highly-endemic areas in Africa and Southeast Asia where drug-resistant malaria is common. Methods: We conducted an outbreak investigation of malaria cases in Angola where a total of 439 nonimmune Brazilian troops were deployed for a 6-month period in 1995,1996. A post-travel medical evaluation was also performed on 338 (77%) of the 439 soldiers upon return to Brazil. Questionnaire, medical record, thick/thin smear, and serum anti- Plasmodium falciparum antibody titer (by IFA) data were obtained. Peak serum mefloquine (M) and methylmefloquine (MM) metabolite levels were measured in a subsample of 66 soldiers (42 cases, 24 nonmalaria controls) who were taking weekly mefloquine prophylaxis (250 mg). Results: Seventy-eight cases of malaria occurred among the 439 personnel initially interviewed in Angola (attack rate = 18%). Four soldiers were hospitalized, and 3 subsequently died of cerebral malaria. Upon return to Brazil, 63 (19%) of 338 soldiers evaluated were documented to have had clinical symptoms and a diagnosis of malaria while in Angola. In addition, 37 (11%) asymptomatically infected individuals were detected upon return (< 1% parasitemia). Elevated, post-travel anti- P. falciparum IFA titers (, 1:64) were seen in 101 (35%) of 292 soldiers tested, and was associated with a prior history of malaria in-country (OR = 3.67, 95% CI 1.98,6.82, p < .001). Noncompliance with weekly mefloquine prophylaxis (250 mg) was associated with a malaria diagnosis in Angola (OR = 3.75, 95% CI 0.97,17.41, p = .03) but not with recent P. falciparum infection (by IFA titer). Mean peak levels (and ratios) of serum M and MM were also found to be lower in those who gave a history of malaria while in Angola. Conclusions: Malaria was a significant cause of morbidity among Brazilian Army military personnel deployed to Angola. Mefloquine prophylaxis appeared to protect soldiers from clinical, but not subclinical, P. falciparum infections. Mefloquine noncompliance and an erratic chemoprophylaxis prevention policy contributed to this large outbreak in nonimmune personnel. This report highlights the pressing need for development of newer, more efficacious and practical, prophylactic drug regimens that will reduce the malaria threat to military forces and travelers. [source]

Malaria at High Altitude

JOURNAL OF TRAVEL MEDICINE, Issue 3 2000
Rachel A. Bishop
No abstract is available for this article. [source]

Impact of irrigation on malaria in Africa: paddies paradox

MEDICAL AND VETERINARY ENTOMOLOGY, Issue 1 2001
J. N. Ijumba
Summary The high population growth rate of the African continent has led to an increased demand for food and is in danger of outstripping agricultural production. In order to meet this need, many governments have sought ways of improving food production by initiating large-scale irrigation projects, involving reclamation of arid and semi-arid areas for the cultivation of crops. Although crop irrigation promises one solution to alleviating hunger and encourages economic growth, irrigation has often been blamed for aggravating disease in local communities. Malaria is one of the major tropical diseases associated with irrigation schemes, and changes in the transmission pattern of this disease following irrigation development have been a perennial subject of debate. It has often been assumed that high numbers of malaria vector Anopheles mosquitoes (Diptera: Culicidae) resulting from irrigation schemes lead inevitably to increased malaria in local communities. However, recent studies in Africa have revealed a more complex picture. Increased numbers of vectors following irrigation can lead to increased malaria in areas of unstable transmission, where people have little or no immunity to malaria parasites, such as the African highlands and desert fringes. But for most of sub-Saharan Africa, where malaria is stable, the introduction of crop irrigation has little impact on malaria transmission. Indeed, there is growing evidence that for many sites there is less malaria in irrigated communities than surrounding areas. The explanation for this finding is still unresolved but, in some cases at least, can be attributed to displacement of the most endophilic and anthropophilic malaria vector Anopheles funestus Giles by An. arabiensis Patton with lower vectorial capacity, as the latter thrives more than the former in ricefields. Similarly, among members of the An. gambiae complex, some cytotypes of An. gambiae sensu stricto are more vectorial than others. For example, the Mopti form has high vectorial capacity and breeds perennially in irrigated sites, whereas the savanna form is often sympatric but more seasonal. Also we suggest that many communities near irrigation schemes benefit from the greater wealth created by these schemes. Consequently irrigation communities often have greater use of bednets, better access to improved healthcare and receive fewer infective bites compared with those outside such development schemes. Thus, in most cases, irrigation schemes in Africa do not appear to increase malaria risk, except in areas of unstable transmission. However, developers should take the opportunity to improve health-care facilities for local communities when planning irrigation schemes wherever they occur. [source]

Recent advances in antimalarial drug development

MEDICINAL RESEARCH REVIEWS, Issue 1 2007
Suryanaryana Vangapandu
Abstract Malaria caused by protozoa of the genus Plasmodium, because of its prevalence, virulence, and drug resistance, is the most serious and widespread parasitic disease encountered by mankind. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to commonly used drugs such as chloroquine, and the lack of affordable new drugs are the limiting factors in the fight against malaria. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. This review provides an in-depth look at the most significant progress made during the past 10 years in antimalarial drug development. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 1, 65,107, 2007 [source]

Plasmepsins as potential targets for new antimalarial therapy

MEDICINAL RESEARCH REVIEWS, Issue 5 2006
Karolina Ersmark
Abstract Malaria is one of the major diseases in the world. Due to the rapid spread of parasite resistance to available antimalarial drugs there is an urgent need for new antimalarials with novel mechanisms of action. Several promising targets for drug intervention have been revealed in recent years. This review addresses the parasitic aspartic proteases termed plasmepsins (Plms) that are involved in the hemoglobin catabolism that occurs during the erythrocytic stage of the malarial parasite life cycle. Four Plasmodium species are responsible for human malaria; P. vivax, P. ovale, P. malariae, and P. falciparum. This review focuses on inhibitors of the haemoglobin-degrading plasmepsins of the most lethal species, P. falciparum; Plm I, Plm II, Plm IV, and histo-aspartic protease (HAP). Previously, Plm II has attracted the most attention. With the identification and characterization of new plasmepsins and the results from recent plasmepsin knockout studies, it now seems clear that in order to achieve high-antiparasitic activities in P. falciparum -infected erythrocytes it is necessary to inhibit several of the haemoglobin-degrading plasmepsins. Herein we summarize the structure,activity relationships of the Plm I, II, IV, and HAP inhibitors. These inhibitors represent all classes which, to the best of our knowledge, have been disclosed in journal articles to date. The 3D structures of inhibitor/plasmepsin II complexes available in the protein data bank are briefly discussed and compared. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 5, 626,666, 2006 [source]

Regulation of Endothelial Cell Adhesion Molecule Expression in an Experimental Model of Cerebral Malaria

MICROCIRCULATION, Issue 6 2002
PHILLIPE R. BAUER
ABSTRACT Objective: Plasmodium falciparum malaria in humans and animal models of this disease have revealed changes in the infected host that are consistent with a systemic inflammatory response. Although it has been proposed that endothelial cell adhesion molecules (CAM) contribute to the adhesive interactions of Plasmodium -infected erythrocytes and immune cells with vascular endothelial cells, ECAM expression has not been systematically studied in Plasmodium -infected animals. Methods: In this study, the dual radiolabeled monoclonal antibody method was used to quantify the expression of different ECAMs (ICAM-1, VCAM-1, P-selectin, E-selectin) in different regional vascular beds of Plasmodium berghei ANKA-inffected mice (PbA), a well-recognized model of human cerebral malaria. The roles of T lymphocytes and certain cytokines (TNF-,, IL-12, IFN-,) in mediating the infection-induced expression of ICAM-1 and P-selectin were assessed by using relevant mutant mice. Results: Wild-type (WT) mice exhibited highly significant increases in the expression of ICAM-1, VCAM-1, and P-selectin (but not E-selectin) in all vascular beds on the 6th day of PbA infection. The PbA -induced upregulation of ICAM-1 was significantly blunted in mice that were either deficient in IFN-,, IL-12 (but not TNF1b) or T lymphocytes (Rag-1 deficiency); however, these responses were tissue specific. Conclusions: These findings indicate that vascular endothelial cells in most regional circulations assume an inflammatory phenotype and that cytokines and immune cells mediate this response in a tissue-specific manner. [source]

Comparative Investigation of the ATP-Binding Site of Human and Plasmodial Glycogen Synthase Kinase-3

MOLECULAR INFORMATICS, Issue 8 2009
Sebastian Kruggel
Abstract Malaria is still one of the most problematic infectious diseases besides AIDS and tuberculosis. Plasmodial glycogen synthase kinase-3 (PfGSK-3) has been proposed as a potential malaria target before but the plasmodial enzyme is not crystallized yet whereas there are several structures published of the human glycogen synthase kinase-3 (HsGSK-3). Here we describe the comparison of different PDB structures of the HsGSK-3 and corresponding homology models of PfGSK-3. The differences were investigated with molecular interaction fields and also by a docking study of the known inhibitors kenpaullone and flavopiridol. [source]

Double-stranded RNA-mediated gene silencing of cysteine proteases (falcipain-1 and -2) of Plasmodium falciparum

MOLECULAR MICROBIOLOGY, Issue 5 2002
Pawan Malhotra
Summary Malaria remains a public health problem of enormous magnitude, affecting over 500 million people every year. Lack of success in the past in the development of new drug/vaccines has mainly been attributed to poor understanding of the functions of different parasite proteins. Recently, RNA interference (RNAi) has emerged as a simple and incisive technique to study gene functions in a variety of organisms. In this study, we report the results of RNAi by double-stranded RNA of cysteine protease genes (falcipain -1 and -2) in the malaria parasite, Plasmodium falciparum. Using RNAi directed towards falcipain genes, we demonstrate that blocking the expression of these genes results in severe morphological abnormalities in parasites, inhibition of parasite growth in vitro and substantial accumulation of haemoglobin in the parasite. The inhibitory effects produced by falcipain double-stranded (ds)RNAs are reminiscent of the effects observed upon administering E-64, a cysteine protease inhibitor. The parasites treated with falcipain's dsRNAs also show marked reduction in the levels of corresponding endogenous falcipain mRNAs. We also demonstrate that dsRNAs of falcipains are broken into short interference RNAs , 25 nucleotides in size, a characteristic of RNAi, which in turn activates sequence-specific nuclease activity in the malaria parasites. These results thus provide more evidence for the existence of RNAi in P. falciparum and also suggest possibilities for using RNAi as an effective tool to determine the functions of the genes identified from the P. falciparum genome sequencing project. [source]