The present study was designed to investigate the antimalarial activity of synthetic hepcidin and its effect on cytokine secretion in mice infected with Plasmodium berghei. The mice were infected with P. berghei intravenously and treated with hepcidin according to 4-day suppression test and Rane's test. The serum levels of interleukins (IL-1β, IL-2, IL-6, IL-10, IL-12p70, and IL-17A), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) in the experimental mice were determined using a cytometric bead array (CBA) kit. The survival rate of the infected mice was also registered. Additionally, the serum iron, alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin (BIL) were detected to evaluate liver functions. Hepcidin exerted direct anti-malarial function in vivo and increased survival rate in a dose-dependent manner. In addition, the secretion of T helper cell type 1 (Th1), Th2, and Th17 cytokines, TNF-α, and IFN-γ were inhibited by hepcidin. In conclusion, our results demonstrated that synthetic hepcidin exerts in vivo antimalarial activity and possesses anti-inflammatory function, which provides a basis for future design of new derivatives with ideal anti-malarial activity.
Animals ; Antimalarials ; chemical synthesis ; pharmacology ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Hepcidins ; chemical synthesis ; pharmacology ; Humans ; Interleukin-10 ; immunology ; Interleukin-17 ; immunology ; Malaria ; drug therapy ; immunology ; mortality ; parasitology ; Male ; Mice ; Plasmodium berghei ; drug effects ; genetics ; metabolism

The parasite Plasmodium falciparum causes severe malaria and is the most dangerous to humans. However, it exhibits resistance to their drugs. Farnesyltransferase has been identified in pathogenic protozoa of the genera Plasmodium and the target of farnesyltransferase includes Ras family. Therefore, the inhibition of farnesyltransferase has been suggested as a new strategy for the treatment of malaria. However, the exact functional mechanism of this agent is still unknown. In addition, the effect of farnesyltransferase inhibitor (FTIs) on mitochondrial level of malaria parasites is not fully understood. In this study, therefore, the effect of a FTI R115777 on the function of mitochondria of P. falciparum was investigated experimentally. As a result, FTI R115777 was found to suppress the infection rate of malaria parasites under in vitro condition. It also reduces the copy number of mtDNA-encoded cytochrome c oxidase III. In addition, the mitochondrial membrane potential (DeltaPsim) and the green fluorescence intensity of MitoTracker were decreased by FTI R115777. Chloroquine and atovaquone were measured by the mtDNA copy number as mitochondrial non-specific or specific inhibitor, respectively. Chloroquine did not affect the copy number of mtDNA-encoded cytochrome c oxidase III, while atovaquone induced to change the mtDNA copy number. These results suggest that FTI R115777 has strong influence on the mitochondrial function of P. falciparum. It may have therapeutic potential for malaria by targeting the mitochondria of parasites.
Antimalarials/*pharmacology ; Enzyme Inhibitors/*pharmacology ; Farnesyltranstransferase/*antagonists & inhibitors/genetics/*metabolism ; Humans ; Malaria, Falciparum/drug therapy/*parasitology ; Mitochondria/*drug effects/metabolism ; Plasmodium falciparum/drug effects/*enzymology/genetics ; Protozoan Proteins/*antagonists & inhibitors/genetics/metabolism ; Quinolones/*pharmacology

Pyronaridine and artesunate have been shown to be effective in falciparum malaria treatment. However, pyronaridine is rarely used in Hainan Island clinically, and artesunate is not widely used as a therapeutic agent. Instead, conventional antimalarial drugs, chloroquine and piperaquine, are used, explaining the emergence of chloroquine-resistant Plasmodium falciparum. In this article, we investigated the sensitivity of P. falciparum to antimalarial drugs used in Hainan Island for rational drug therapy. We performed in vivo (28 days) and in vitro tests to determine the sensitivity of P. falciparum to antimalarial drugs. Total 46 patients with falciparum malaria were treated with dihydroartemisinin/piperaquine phosphate (DUO-COTECXIN) and followed up for 28 day. The cure rate was 97.8%. The mean fever clearance time (22.5+/-10.6 hr) and the mean parasite clearance time (27.3+/-12.2 hr) showed no statistical significance with different genders, ages, temperatures, or parasite density (P>0.05). The resistance rates of chloroquine, piperaquine, pyronarididine, and artesunate detected in vitro were 71.9%, 40.6%, 12.5%, and 0%, respectively (P<0.0001). The resistance intensities decreased as follows: chloroquine>piperaquine>pyronarididine>artesunate. The inhibitory dose 50 (IC50) was 3.77x10(-6) mol/L, 2.09x10(-6) mol/L, 0.09x10(-6) mol/L, and 0.05x10(-6) mol/L, and the mean concentrations for complete inhibition (CIMC) of schizont formation were 5.60x10(-6) mol/L, 9.26x10(-6) mol/L, 0.55x10(-6) mol/L, and 0.07x10(-6) mol/L, respectively. Dihydroartemisinin showed a strong therapeutic effect against falciparum malaria with a low toxicity.
Adolescent ; Adult ; Aged ; Antimalarials/*pharmacology/*therapeutic use ; Child ; Child, Preschool ; China ; Female ; Humans ; Inhibitory Concentration 50 ; Malaria, Falciparum/*drug therapy/parasitology ; Male ; Middle Aged ; Parasitic Sensitivity Tests ; Plasmodium falciparum/*drug effects ; Treatment Outcome ; Young Adult

Pyronaridine and artesunate have been shown to be effective in falciparum malaria treatment. However, pyronaridine is rarely used in Hainan Island clinically, and artesunate is not widely used as a therapeutic agent. Instead, conventional antimalarial drugs, chloroquine and piperaquine, are used, explaining the emergence of chloroquine-resistant Plasmodium falciparum. In this article, we investigated the sensitivity of P. falciparum to antimalarial drugs used in Hainan Island for rational drug therapy. We performed in vivo (28 days) and in vitro tests to determine the sensitivity of P. falciparum to antimalarial drugs. Total 46 patients with falciparum malaria were treated with dihydroartemisinin/piperaquine phosphate (DUO-COTECXIN) and followed up for 28 day. The cure rate was 97.8%. The mean fever clearance time (22.5+/-10.6 hr) and the mean parasite clearance time (27.3+/-12.2 hr) showed no statistical significance with different genders, ages, temperatures, or parasite density (P>0.05). The resistance rates of chloroquine, piperaquine, pyronarididine, and artesunate detected in vitro were 71.9%, 40.6%, 12.5%, and 0%, respectively (P<0.0001). The resistance intensities decreased as follows: chloroquine>piperaquine>pyronarididine>artesunate. The inhibitory dose 50 (IC50) was 3.77x10(-6) mol/L, 2.09x10(-6) mol/L, 0.09x10(-6) mol/L, and 0.05x10(-6) mol/L, and the mean concentrations for complete inhibition (CIMC) of schizont formation were 5.60x10(-6) mol/L, 9.26x10(-6) mol/L, 0.55x10(-6) mol/L, and 0.07x10(-6) mol/L, respectively. Dihydroartemisinin showed a strong therapeutic effect against falciparum malaria with a low toxicity.
Adolescent ; Adult ; Aged ; Antimalarials/*pharmacology/*therapeutic use ; Child ; Child, Preschool ; China ; Female ; Humans ; Inhibitory Concentration 50 ; Malaria, Falciparum/*drug therapy/parasitology ; Male ; Middle Aged ; Parasitic Sensitivity Tests ; Plasmodium falciparum/*drug effects ; Treatment Outcome ; Young Adult

No abstract available.
Adult ; Anti-Bacterial Agents/therapeutic use ; Antimalarials/therapeutic use ; Clindamycin/therapeutic use ; Female ; Humans ; Malaria, Vivax/*diagnosis/drug therapy/parasitology ; Neutrophils/*parasitology ; Plasmodium vivax/growth & development/*isolation & purification ; Pregnancy ; Quinine/therapeutic use ; Trophozoites/cytology

While imported falciparum malaria has been increasingly reported in recent years in Korea, clinicians have difficulties in making a clinical diagnosis as well as in having accessibility to effective anti-malarial agents. Here we describe an unusual case of imported falciparum malaria with severe hemolytic anemia lasting over 2 weeks, clinically mimicking a coinfection with babesiosis. A 48-year old Korean man was diagnosed with severe falciparum malaria in France after traveling to the Republic of Benin, West Africa. He received a 1-day course of intravenous artesunate and a 7-day course of Malarone (atovaquone/proguanil) with supportive hemodialysis. Coming back to Korea 5 days after discharge, he was readmitted due to recurrent fever, and further treated with Malarone for 3 days. Both the peripheral blood smears and PCR test were positive for Plasmodium falciparum. However, he had prolonged severe hemolytic anemia (Hb 5.6 g/dl). Therefore, 10 days after the hospitalization, Babesia was considered to be potentially coinfected. A 7-day course of Malarone and azithromycin was empirically started. He became afebrile within 3 days of this babesiosis treatment, and hemolytic anemia profiles began to improve at the completion of the treatment. He has remained stable since his discharge. Unexpectedly, the PCR assays failed to detect DNA of Babesia spp. from blood. In addition, during the retrospective review of the case, the artesunate-induced delayed hemolytic anemia was considered as an alternative cause of the unexplained hemolytic anemia.
Anemia, Hemolytic/chemically induced/*etiology/*pathology ; Anti-Bacterial Agents/therapeutic use ; Antimalarials/therapeutic use ; Artemisinins/adverse effects/therapeutic use ; Atovaquone/therapeutic use ; Azithromycin/therapeutic use ; Babesiosis/complications/*diagnosis/drug therapy/*pathology ; Benin ; Blood/parasitology ; Coinfection/diagnosis/pathology ; Drug Combinations ; France ; Humans ; Korea ; Malaria, Falciparum/complications/*diagnosis/drug therapy/*pathology ; Male ; Middle Aged ; Plasmodium falciparum/*isolation & purification ; Proguanil/therapeutic use ; Travel ; Treatment Outcome

Genetic characteristics of Plasmodium falciparum may play a role in the treatment outcome of malaria infection. We have studied the association between diversity at the merozoite surface protein-1 (msp-1), msp-2, and glutamate-rich protein (glurp) loci and the treatment outcome of uncomplicated falciparum malaria patients along the Thai-Myanmar border who were treated with artemisinin derivatives combination therapy. P. falciparum isolates were collected prior to treatment from 3 groups of patients; 50 cases of treatment failures, 50 recrudescences, and 56 successful treatments. Genotyping of the 3 polymorphic markers was analyzed by nested PCR. The distribution of msp-1 alleles was significantly different among the 3 groups of patients but not the msp-2 and glurp alleles. The allelic frequencies of K1 and MAD20 alleles of msp1 gene were higher while RO33 allele was significantly lower in the successful treatment group. Treatment failure samples had a higher median number of alleles as compared to the successful treatment group. Specific genotypes of msp-1, msp-2, and glurp were significantly associated with the treatment outcomes. Three allelic size variants were significantly higher among the isolates from the treatment failure groups, i.e., K1270-290, 3D7610-630, G650-690, while 2 variants, K1150-170, and 3D7670-690 were significantly lower. In conclusion, the present study reports the differences in multiplicity of infection and distribution of specific alleles of msp-1, msp-2, and glurp genes in P. falciparum isolates obtained from treatment failure and successful treatment patients following artemisinin derivatives combination therapy.
Adult ; Antigens, Protozoan/genetics ; Antimalarials/*therapeutic use ; Artemisinins/*therapeutic use ; Female ; Gene Frequency ; *Genetic Variation ; Genotype ; Humans ; Malaria, Falciparum/*drug therapy/*parasitology ; Male ; Merozoite Surface Protein 1/genetics ; Myanmar ; Plasmodium falciparum/*classification/*genetics/isolation & purification ; Polymerase Chain Reaction ; Protozoan Proteins/genetics ; Thailand ; Treatment Failure

OBJECTIVETo evaluate the effect of preventive medicine for residents living around mosquito breeding water during rest period of malaria by delimiting a certain range.

METHODThe study adopted the stratified cluster random sampling method to select subjects from 6 counties in the high epidemic area along and north of the Huai River since March 2007. Then the villages of 6 counties were stratified into five levels according to the case reported in year 2006, and one village was randomly selected from each level, thereby 30 villages were selected in total.300-500 subjects were interviewed in each village, and in total 12 860 subjects were recruited in the study. The five selected villages in each county were allocated to three intervention groups according to the block randomization method. The first intervention group included 9 villages, 4362 people; the second intervention group was consisted of 12 villages, 4471 people; the non-intervention group had 9 villages, 4027 people. The basic information of the subjects were collected by questionnaire to analyze the relation between malaria cases and the distribution of the mosquito breeding water, then accordingly delimited the range for preventive medicine. Group 1 received the delimiting preventive medicine treatment, group 2 received routine medicine treatment, while non-treatment group received no treatment. The morbidity, standardized morbidity, net change of morbidity (the D-value of the standardized morbidity before and after the intervention), age-specified incidence, and the protective rate (PR), effectiveness index (IE) and the capture rate of the delimited method group were then calculated.

RESULTSGroup 1 had 1219 (27.9%) people taking medicine and Group 2 had 219 (4.9%) people. In 2006, before the prevention conducting, the high incidence aging group in the first, second and nonintervention group was separately people aging 50 - 59, 60 - 69 and ≥ 70 years old; whose incidence was 36.22‰ (18/497), 40.11‰ (15/374) and 34.88‰ (9/258) respectively. After the intervention, the high incidence aging groups in the first and second intervention group changed to the population over 70 years old, with incidence at 9.17‰ (3/327) and 22.01‰ (7/318) respectively; while the high incidence aging groups in the nonintervention group changed to people aging between 30-39 years old, with the rate at 24.88‰ (10/402). In 2006, the morbidity of malaria in the first, second intervention group and nonintervention group was separately 18.78‰ (83/4420), 20.27‰ (93/4587) and 14.61‰ (53/3627); while the standardized incidence was separately 18.85‰, 20.72‰ and 14.89‰. In 2007, after the prevention conducting, the morbidity in the three groups was 2.75‰ (12/4362), 11.63‰ (52/4471) and 12.17‰ (49/4027), respectively; while the standardized incidences was 2.81‰, 12.75‰ and 12.35‰, respectively. The net value of changes of morbidity in the three groups was separately 16.04%, 7.97% and 2.54%. The difference in net values of changes of morbidity between intervention group 1 and 2 had statistical significance (χ(2) = 7.74, P < 0.05). Comparing with the nonintervention group, the PR and IE in intervention group 1 was separately 84.2% and 6.31; while the capture rate was 69.2% (9/13).

CONCLUSIONThe delimiting preventive medicine treatment during rest period of malaria was very effective for eliminating the potential infection source of malaria and reducing the morbidity of malaria.

Adolescent ; Adult ; Aged ; Animals ; Child ; Child, Preschool ; China ; epidemiology ; Culicidae ; physiology ; Humans ; Incidence ; Infant ; Infant, Newborn ; Malaria ; drug therapy ; epidemiology ; prevention & control ; Middle Aged ; Water ; parasitology ; Young Adult

The anti-malarial potential of different parts of Allophylus africanus P. Beauv and Tragia benthamii Baker were determined in vivo for suppressive, curative and cytotoxic activities in mice receiving 0.2 mL of a standard inoculum size of 1 × 10(7) infected erythrocytes of Plasmodium berghei (NK-65) intraperitoneally. The A. africanus extracts suppressed parasitaemia following administration to infected mice by 92.82%-97.81% on day 7 post-infection against 96.81% for chloroquine. The infected extract-treated animals had significantly moderate (P < 0.05) packed cell volume (PCV) compared with the infected, untreated animals. Phytochemical screening revealed a predominance of tannins, saponins, flavonoids and carbohydrates in all parts of A. africanus, and alkaloids instead of flavonoids in the extract of T. benthamii. The results suggest that the extract possesses considerable antimalarial activity. These results support further studies on A. africanus.
Animals ; Antimalarials ; administration & dosage ; chemistry ; Drug Evaluation, Preclinical ; Euphorbiaceae ; chemistry ; Female ; Humans ; Malaria ; drug therapy ; parasitology ; Male ; Mice ; Plant Extracts ; administration & dosage ; chemistry ; Plasmodium berghei ; drug effects ; Sapindaceae ; chemistry

Malaria, the most common vector-borne parasite infection worldwide, results from infection by Plasmodium species. Approximately 80% of malaria cases are caused by P. vivax, which is broadly distributed from tropical to temperate regions; P. falciparum is the second most common infectious species. P. malariae and P. ovale are responsible for a relatively small proportion of malaria cases. Here, we report the case of a 23-yr-old Korean woman who acquired a P. malariae infection while visiting the Republic of Ghana in West Africa for business. She was diagnosed with P. malariae malaria on the basis of peripheral blood smear (PBS) and species-specific conventional and real-time PCR assays for 18S rRNA. She was treated with hydroxychloroquine, and the resulting PBS examination on day 2 suggested that negative conversion occurred. At her 1-month follow-up, however, both the PBS examination and molecular test for malaria demonstrated recurrent parasitemia. We started rescue therapy with mefloquine, and the patient recovered successfully. This is an important finding suggesting possible late recrudescence of a chloroquine-resistant P. malariae strain identified not only by its morphological features, but also by molecular tests.
Antimalarials/therapeutic use ; Drug Resistance ; Female ; Humans ; Hydroxychloroquine/therapeutic use ; Malaria/*diagnosis/drug therapy/parasitology ; Mefloquine/therapeutic use ; Plasmodium malariae/genetics/*isolation & purification ; RNA, Ribosomal, 18S/genetics ; Real-Time Polymerase Chain Reaction ; Recurrence ; Young Adult