BACKGROUND: In mammals, the master circadian pacemaker is localized in an area of the ventral hypothalamus known as the suprachiasmatic nucleus (SCN). Previous studies have shown that pacemaker neurons in the SCN are highly coupled to one another, and this coupling is crucial for intrinsic self-sustainability of the SCN central clock, which is distinguished from peripheral oscillators. One plausible mechanism underlying the intercellular communication may involve direct electrical connections mediated by gap junctions. METHODS: We examined the effect of mefloquine, a neuronal gap junction blocker, on circadian Period 2 (Per2) gene oscillation in SCN slice cultures prepared from Per2::luciferase (PER2::LUC) knock-in mice using a real-time bioluminescence measurement system. RESULTS: Administration of mefloquine causes instability in the pulse period and a slight reduction of amplitude in cyclic PER2::LUC expression. Blockade of gap junctions uncouples PER2::LUC-expressing cells, in terms of phase transition, which weakens synchrony among individual cellular rhythms. CONCLUSION: These findings suggest that neuronal gap junctions play an important role in synchronizing the central pacemaker neurons and contribute to the distinct self-sustainability of the SCN master clock.
Animals ; Circadian Rhythm ; Electrical Synapses ; Gap Junctions* ; Hypothalamus ; Luminescent Measurements ; Mammals ; Mefloquine* ; Mice* ; Neurons ; Phase Transition ; Suprachiasmatic Nucleus*

Primary cilia have critical roles in coordinating multiple cellular signaling pathways. Dysregulation of primary cilia is implicated in various ciliopathies. To identify specific regulators of autophagy, we screened chemical libraries and identified mefloquine, an anti-malaria medicine, as a potent regulator of primary cilia in human retinal pigmented epithelial (RPE) cells. Not only ciliated cells but also primary cilium length was increased in mefloquine-treated RPE cells. Treatment with mefloquine strongly induced the elongation of primary cilia by blocking disassembly of primary cilium. In addition, we found that autophagy was increased in mefloquine-treated cells by enhancing autophagic flux. Both chemical and genetic inhibition of autophagy suppressed ciliogenesis in mefloquine-treated RPE cells. Taken together, these results suggest that autophagy induced by mefloquine positively regulates the elongation of primary cilia in RPE cells.
Autophagy* ; Cilia* ; Humans ; Mefloquine ; Retinaldehyde ; Small Molecule Libraries

Mefloquine is a common anti-malarial agent used for the treatment and prophylaxis of malaria. Here we report a case of a 39-year-old, otherwise healthy woman from South Korea, who had developed visual and auditory hallucination with sleep disturbance after oral administration of mefloquine before traveling to an endemic region. To our knowledge, this would be the first reported case of mefloquine-induced psychosis in South Korea to date. This report underlines the importance of awareness and detection of neuropsychiatric side effects of mefloquine.
Administration, Oral ; Female ; Hallucinations ; Humans ; Malaria ; Mefloquine ; Psychotic Disorders ; Republic of Korea

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

Adult ; Aged ; Antimalarials ; therapeutic use ; Female ; Humans ; Immune Reconstitution Inflammatory Syndrome ; drug therapy ; JC Virus ; immunology ; Leukoencephalopathy, Progressive Multifocal ; drug therapy ; Male ; Mefloquine ; therapeutic use ; Middle Aged ; Treatment Outcome

In Korea, Plasmodium vivax (P. vivax) is the most common agent of malaria infection. However, as travel to regions where malaria is endemic increases, so do the numbers of Plasmodium falciparum and mixed infections. P. falciparum predominates, while P. vivax is rare in west-central Africa. We report on a case of mixed malaria infection with severe hemolytic anemia caused by P. falciparum and P. vivax in a 38-year-old man after traveling to Angola. A diagnosis of P. falciparum malaria was made by microscopic examination. However, both P. vivax and P. falciparum were detected by the polymerase chain reaction (PCR). As a radical cure P. vivax, the patient was treated with mefloquine, artemether, and primaquine. Both P. falciparum and P. vivax had disappeared from peripheral blood by admission day 4, however, low grade fever and headache persisted, and his hemoglobin and hematocrit levels were depleted. A peripheral blood smear was negative for both P. vivax and P. falciparum; however, a direct anti-globulin test and anti-nuclear antibody test were positive, suggesting immune hemolytic anemia. After conservative treatment, which included a transfusion with packed red blood cells (RBC), his symptoms and signs showed improvement and laboratory findings were normalized.
Adult ; Africa ; Anemia, Hemolytic ; Angola ; Artemisinins ; Coinfection ; Erythrocytes ; Fever ; Headache ; Hematocrit ; Hemoglobins ; Humans ; Korea ; Malaria ; Mefloquine ; Plasmodium falciparum ; Plasmodium vivax ; Polymerase Chain Reaction ; Primaquine

Malarial infection is one of the most important tropical diseases, but also increasing in the temperate regions. Severe malaria with organ dysfunction is commonly associated with Plasmodium falciparum, but rarely with Plasmodium vivax. Malarial hepatitis is also unusual in P. falciparum and very rare in P. vivax. Only 3 cases of malarial hepatitis caused by P. vivax have been reported in the world. Because the presence of hepatitis in malaria indicates a more severe illness with higher incidence of other complications and poor prognosis, malarial patients should be meticulously monitored for hepatic dysfunction with or without jaundice. We report here a case of malarial hepatitis caused by P. vivax that was presented by fever, general ache, nausea, fatigue, and significant elevation of aminotransferase and bilirubin.
Abdomen/ultrasonography ; Antimalarials/therapeutic use ; Erythrocytes/immunology/parasitology ; Fatigue/etiology ; Hepatitis/*diagnosis/etiology/ultrasonography ; Humans ; Malaria, Vivax/complications/*diagnosis/drug therapy ; Male ; Mefloquine/therapeutic use ; Nausea/etiology ; Plasmodium vivax/isolation & purification ; Primaquine/therapeutic use ; Young Adult

The aim of the present study was to investigate antimalarial drug pressure resulting from the clinical use of different antimalarials in Thailand. The phenotypic diversity of the susceptibility profiles of antimalarials, i.e., chloroquine (CQ), quinine (QN), mefloquine (MQ), and artesunate (ARS) in Plasmodium falciparum isolates collected during the period from 1988 to 2003 were studied. P. falciparum isolates from infected patients were collected from the Thai-Cambodian border area at different time periods (1988-1989, 1991-1992, and 2003), during which 3 different patterns of drug use had been implemented: MQ + sulphadoxine (S) + pyrimethamine (P), MQ alone and MQ + ARS, respectively. The in vitro drug susceptibilities were investigated using a method based on the incorporation of [3H] hypoxanthine. A total of 50 isolates were tested for susceptibilities to CQ, QN, MQ, and ARS. Of these isolates, 19, 16, and 15 were adapted during the periods 1988-1989, 1991-1993, and 2003, respectively. P. falciparum isolates collected during the 3 periods were resistant to CQ. Sensitivities to MQ declined from 1988 to 2003. In contrast, the parasite was sensitive to QN, and similar sensitivity profile patterns were observed during the 3 time periods. There was a significantly positive but weak correlation between the IC50 values of CQ and QN, as well as between the IC50 values of QN and MQ. Drug pressure has impact on sensitivity of P. falciparum to MQ. A combination therapy of MQ and ARS is being applied to reduce the parasite resistance, and also increasing the efficacy of the drug.
Animals ; Antimalarials/*pharmacology/therapeutic use ; Artemisinins/pharmacology/therapeutic use ; Chloroquine/pharmacology/therapeutic use ; *Drug Resistance ; Humans ; Malaria/drug therapy/*parasitology ; Mefloquine/pharmacology/therapeutic use ; Parasitic Sensitivity Tests/methods ; Plasmodium falciparum/*drug effects/isolation & purification ; Quinine/pharmacology/therapeutic use ; Thailand

Artemisinin-based combination therapy (ACT) is currently promoted as a strategy for treating both uncomplicated and severe falciparum malaria, targeting asexual blood-stage Plasmodium falciparum parasites. However, the effect of ACT on sexual-stage parasites remains controversial. To determine the clearance of sexual-stage P. falciparum parasites from 342 uncomplicated, and 217 severe, adult malaria cases, we reviewed and followed peripheral blood sexualstage parasites for 4 wk after starting ACT. All patients presented with both asexual and sexual stage parasites on admission, and were treated with artesunate-mefloquine as the standard regimen. The results showed that all patients were asymptomatic and negative for asexual forms before discharge from hospital. The percentages of uncomplicated malaria patients positive for gametocytes on days 3, 7, 14, 21, and 28 were 41.5, 13.1, 3.8, 2.0, and 2.0%, while the percentages of gametocyte positive severe malaria patients on days 3, 7, 14, 21, and 28 were 33.6, 8.2, 2.7, 0.9, and 0.9%, respectively. Although all patients were negative for asexual parasites by day 7 after completion of the artesunate-mefloquine course, gametocytemia persisted in some patients. Thus, a gametocytocidal drug, e.g., primaquine, may be useful in combination with an artesunate-mefloquine regimen to clear gametocytes, so blocking transmission more effectively than artesunate alone, in malaria transmission areas.
Adolescent ; Adult ; Animals ; Antimalarials/*pharmacology/therapeutic use ; Artemisinins/*pharmacology/therapeutic use ; Drug Evaluation ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Germ Cells/*drug effects/growth & development ; Humans ; Malaria, Falciparum/*drug therapy/parasitology ; Male ; Mefloquine/*pharmacology/therapeutic use ; Plasmodium falciparum/*drug effects/growth & development ; Severity of Illness Index ; Thailand ; Treatment Outcome

BACKGROUND: Mefloquine is widely used for a chemoprophylactic agent against malaria, however, there is a tendency to avoid mefloquine as preventive medicine due to its side effects. Therefore, we carried out this study to provide travelers with safety information regarding consumption of mefloquine through a prospective research for adverse reactions. MATERIALS AND METHODS: The study had been estimated for the relationship between administration of mefloquine and symptoms of which person had been prescribed of mefloquine at the International Clinic of National Medical Center from May 1, 2006 to October 30, 2006 by phone interviews every three days prior to departure and 4 times every week following a return from the travel. RESULTS: Adverse reactions had been reported in 73 (18.6%) persons among 393 travelers who had taken mefloquine with the figure of 38 (52.1%) males, 35 (47.9%) females and 98 (24.9%) occurrences of adverse reactions. The most common adverse reaction was febrile sensation. Most (96%) of adverse reactions had been detected in 3 weeks after being taken mefloquine and there was no difference between sex and age. Most of travelers who had complained the symptoms got better spontaneously or through the symptomatic treatment. Some travelers had taken other medicines and had gotten several vaccinations concurrently. Only 3 cases that took medicine for hypothyroidism were related to adverse reactions of mefloquine (P<0.05). CONCLUSION: There were adverse reactions which were reported in 18.6% of travelers after taking mefloquine and malraria hasn't occurred. So mefloquine is considered as a primary preventive agent against malaria.
Female ; Humans ; Hypothyroidism ; Malaria ; Male ; Mefloquine* ; Preventive Medicine ; Prospective Studies ; Sensation ; Vaccination