Primaquine plus clindamycin as a promising salvage therapy for Pneumocystis jirovecii pneumonia: A retrospective analysis in Japanese patients.

Treatment of intractable Pneumocystis jirovecii pneumonia (PCP) patients with primaquine (PQ) in combination with clindamycin (CLDM) was conducted by the Research Group on Chemotherapy of Tropical Diseases (RG-CTD), as a kind of compassionate use. Primaquine was not nationally licensed at the time but imported by RG-CTD for the use in a clinical research to investigate safety and efficacy in malaria treatment. Eighteen Japanese adult patients thus treated were analyzed. Prior to the treatment with PQ-CLDM, most of the patients had been treated with trimethoprim-sulfamethoxazole first, all of which being followed by pentamidine and/or atovaquone treatment. This combination regimen of PQ-CLDM was effective in 16 (89%) patients and developed adverse events (AEs) in five (28%) patients. AEs included skin lesions, methemoglobinemia, and hepatic dysfunction, though none of them were serious. As a second-line or salvage treatment for PCP, PQ-CLDM appears to be a better option than pentamidine or atovaquone. Currently in Japan, both PQ and CLDM are licensed drugs but neither of them is approved for treatment of PCP. Considering the potentially fatal nature of PCP, approval of PQ-CLDM for treating this illness should be urged.

Retrospective observational study of the use of artemether-lumefantrine in the treatment of malaria in Japan.

BACKGROUND: The Research Group on Chemotherapy of Tropical Diseases, Japan, introduced artemether-lumefantrine (AL) in late 2002, mainly for treating uncomplicated Plasmodium falciparum malaria. Because AL was on the market in Japan in March 2017, the effectiveness and safety of AL were analyzed to help medical personnel use AL optimally. METHODS: Case report forms submitted by the attending physicians were analyzed. When necessary, direct contact with the attending physicians was made to obtain detailed information. RESULTS: Effectiveness analysis was performed for 62 cases and safety analysis was performed for 66 cases. In P. falciparum malaria, the overall cure rate was 91.1% (51/56), of which the cure rates for Japanese and non-Japanese patients were 82.1% (23/28) and 100% (28/28), respectively. The successfully treated cases included severe P. falciparum malaria, with parasite densities exceeding 500,000/µL. Adverse events were reported in 14 patients, including delayed hemolytic anemia which occurred in the top four highest parasitemic cases. CONCLUSIONS: AL treatment failure in P. falciparum malaria may not be rare among non-immune individuals, including Japanese. The possibility of delayed hemolytic anemia, which occurs preferentially in high parasitemic cases, should be considered following AL treatment.

Severe delayed haemolytic anaemia associated with artemether-lumefantrine treatment of malaria in a Japanese traveller.

Delayed haemolytic anaemia has been reported in association with intravenous artesunate treatment in patients with severe Plasmodium falciparum malaria, and furthermore, oral artemisinin-based combination therapies including artemether-lumefantrine (AL) have also been incriminated. However, definite cases of delayed haemolytic anaemia associated with AL appear to be scarce, as reported cases were often treated concomitantly with other anti-malarials. In this study, we report a severe case of delayed haemolytic anaemia following AL alone in a Japanese traveller with severe parasitaemia caused by numerous P. falciparum parasites and a few P. vivax parasites. We also stress the need by further studies to differentiate between delayed haemolytic anaemia and blackwater fever, the latter being another malaria-related haemolytic condition, more clearly than they are now.

Imported malaria in pregnant women experienced in Japan.

INTRODUCTION: With ever-growing global exchanges, the number of travelers, including pregnant women, to the tropics is increasing, which poses a risk of contracting malaria. Although there are several reports on imported malaria in pregnancy from Western countries, those focusing on cases experienced in Japan are very limited. METHODS: We searched for cases of malaria in pregnancy in the treatment records submitted to the Research Group on Chemotherapy of Tropical Diseases, Japan, during the period 1993-2016. Literature searches were also conducted using an American and a Japanese search system. RESULTS: Ten cases of malaria in pregnant women were identified, including four cases with Plasmodium falciparum. Of eight evaluable cases, only one practiced malaria chemoprophylaxis. Among the nine evaluable cases, eight resulted in uneventful delivery and one P. falciparum case developed severe hepatic disturbance, disseminated intravascular coagulation, and intrauterine fetal death. After the initial attack, none of the Plasmodium vivax/Plasmodium ovale cases practiced chloroquine prophylaxis until delivery. One P. ovale case received a lower dose regimen of chloroquine as acute-stage therapy. CONCLUSION: This study demonstrated additional cases of imported malaria in pregnant women to the literature and highlighted various epidemiological, demographic, and clinical characteristics. Some of the clinical issues raised need to be investigated. Due to the paucity of the cases worldwide, sharing information among various countries is indispensable, and international guidelines which are now increasingly recommending the use of artemisinins in pregnant women should be referred.

Imported malaria in pregnant women: A retrospective pooled analysis.

BACKGROUND: Data on imported malaria in pregnant women are scarce. METHOD: A retrospective, descriptive study of pooled data on imported malaria in pregnancy was done using data from 1991 to 2014 from 8 different collaborators in Europe, the United States and Japan. National malaria reference centres as well as specialists on this topic were asked to search their archives for cases of imported malaria in pregnancy. A total of 631 cases were collated, providing information on Plasmodium species, region of acquisition, nationality, country of residence, reason for travel, age, gestational age, prophylactic measures and treatment used, as well as on complications and outcomes in mother and child. RESULTS: Datasets from some sources were incomplete. The predominant Plasmodium species was P. falciparum (78.5% of cases). Among the 542 cases where information on the use of chemoprophylaxis was known, 464 (85.6%) did not use chemoprophylaxis. The main reason for travelling was "visiting friends and relatives" VFR (57.8%) and overall, most cases of malaria were imported from West Africa (57.4%). Severe anaemia was the most frequent complication in the mother. Data on offspring outcome were limited, but spontaneous abortion was a frequently reported foetal outcome (n = 14). A total of 50 different variants of malaria treatment regimens were reported. CONCLUSIONS: Imported cases of malaria in pregnancy are mainly P. falciparum acquired in sub-Saharan Africa. Malaria prevention and treatment in pregnant travellers is a challenge for travel medicine due to few data on medication safety and maternal and foetal outcomes. International, collaborative efforts are needed to capture standardized data on imported malaria cases in pregnant women.

Optimal primaquine use for radical cure of Plasmodium vivax and Plasmodium ovale malaria in Japanese travelers--A retrospective analysis.

BACKGROUND: Recently, a dose of 30 mg (base) primaquine daily for 14 days is increasingly recommended for radical cure of Plasmodium vivax malaria. However, total primaquine doses, or those per body weight, are also recognized as important. In Japan, primaquine is not a licensed medicine, but has been used through the Research Group on Chemotherapy of Tropical Diseases for >3 decades. METHODS: Based on clinical records submitted to the Research Group, patients with P. vivax and Plasmodium ovale malaria treated with primaquine were analyzed to determine the efficacy and safety of the antimalarial drug. RESULTS: Seventy-five P. vivax cases, including 3 in children, and 19 P. ovale cases were enrolled. Five of the P. vivax cases demonstrated at least one relapse despite primaquine therapy. Total primaquine doses per body weight were obtained in 4 of the 5 relapsed patients, presenting 9 malaria episodes totally, and most of the primaquine failures were caused with a total dose ≤ 3.5 mg/kg. Liver function disturbance was reported in 2 cases. CONCLUSION: In order to optimize radical cure of P. vivax, the total primaquine dose per body weight should be considered, at least 3.5 mg/kg or even more if contracted in countries with significant drug resistance. Possibility of primaquine hepatotoxicity in chronic liver disease patients remains to be elucidated.

Prioritising immunisations for travel: international and Japanese perspectives.

Immunisation has traditionally played an important role in travel medicine practice and unlike routine immunisations, vaccines for travel are sought by and often paid for by the traveller. A convenient way of looking at vaccines for travel is by grouping them into those that are: Required, Routine, or Recommended, although this classification is not always consistent. Prioritising the use of vaccines classed as "Recommended" has proved the most controversial. There are a number of factors that influence both the traveller and health professional in this decision making process. The incidence rate and impact of a disease are thought by many to be the two most important factors to consider when prioritising vaccines. For travellers, the efficacy and adverse events associated with vaccines may also be important. This article reviews the role of immunisation in travel health with the aim of assisting travel health professionals prioritise their use of vaccines. It also highlights the need for travel medicine advisors worldwide to be aware of the differences between Japan and other nations with regard to national immunisation programmes, vaccine availability and vaccine uptake.

Efficacy and safety of paromomycin for treating amebiasis in Japan.

The clinical management of amebiasis is a growing concern, particularly among human immunodeficiency virus (HIV)-infected individuals who are predisposed to severe illness. Treatment with a luminal amebicide is strongly recommended following acute-stage treatment with a nitroimidazole. In 2004, the Japanese Research Group on Chemotherapy of Tropical Diseases introduced paromomycin, which was not nationally licensed, and offered it to a number of patients. From 2004 to 2011, 143 case records of amebiasis (123 with amebic colitis, 16 with amebic liver abscess, and 4 with both) in which patients were treated with paromomycin, mainly 1,500 mg/day for 9 or 10 days following metronidazole treatment, were submitted. Among 123 evaluable cases, 23 (18.7%) experienced possible adverse effects, the most common being diarrhea (17/123, 13.8%) and other gastrointestinal problems that were resolved after the completion or discontinuation of treatment. In addition, single cases of bloody stools associated with Clostridium difficile colitis, skin rash, and the elevation of liver enzymes were also reported, although the causal relationship was not clear. HIV infection did not appear to increase the incidence of adverse drug effects. Each of the 11 asymptomatic or mildly symptomatic amebic colitis cases became negative for stool cysts after paromomycin treatment. Paromomycin was shown to be safe and well tolerated, as well as effective in a special subset of amebic colitis cases.

[Pharmacotherapy of parasitic and tropical diseases in Japan].

Parasitic and tropical diseases are relatively rare in Japan. However, physicians have to realize that a patient may visit your hospital today, who is infected with a potentially fatal parasite. This review focuses on the treatment of the domestic and imported parasitic infections in Japan. Many of the drugs against parasitic diseases, especially imported protozoan diseases, have not been approved, nor have been covered by the National Health Insurance Policy. Therefore, patients who need pharmacotherapy with an unapproved drug have to be treated in one of the hospitals of the Research Group on Chemotherapy of Tropical Diseases, which imports effective drugs against major tropical diseases.

Efficacy and safety of atovaquone-proguanil in treating imported malaria in Japan: the second report from the research group.

Malaria remains an important health risk among travelers to tropical/subtropical regions. However, in Japan, only 2 antimalarials are licensed for clinical use - oral quinine and mefloquine. The Research Group on Chemotherapy of Tropical Diseases introduced atovaquone-proguanil in 1999, and reported on its excellent antimalarial efficacy and safety for treating non-immune patients with uncomplicated Plasmodium falciparum malaria (20 adult and 3 pediatric cases) in 2006. In the present study, additional cases of malaria were analyzed to confirm the efficacy and safety of this antimalarial drug. Fourteen adult and 2 pediatric cases of P. falciparum malaria and 13 adult cases and 1 pediatric case of P. vivax/ovale malaria were successfully treated with atovaquone-proguanil, including 3 P. falciparum cases in which the antecedent treatment failed. Two patients with P. vivax malaria were treated twice due to primaquine treatment failure as opposed to atovaquone-proguanil treatment failure. Except for 1 patient with P. falciparum malaria who developed a moderate liver function disturbance, no significant adverse effects were observed. Despite the intrinsic limitations of this study, which was not a formal clinical trial, the data showed that atovaquone-proguanil was an effective and well-tolerated therapeutic option; licensure of this drug in Japan could greatly contribute to individually appropriate treatment options.

Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system.

BACKGROUND: Concern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart. METHODS: The guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 µM), quinine (0.3 - 2.4 µM), halofantrine (0.1 - 2.0 µM) and mefloquine (0.1 - 2.0 µM). The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects. RESULTS: Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC50 values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine < quinine ≈ halofantrine. CONCLUSIONS: In this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity.

Knowledge, attitudes, and practices of Japanese travelers on infectious disease risks and immunization uptake.

BACKGROUND: There is concern that Japanese travelers are poorly protected against travel-associated infectious diseases including vaccine-preventable infections. This prompted us to study Japanese travelers for measures taken to reduce their risk of acquiring an infectious disease and their immunization uptake. METHODS: During April 2007 to May 2008, a questionnaire study was conducted using the European Travel Health Advisory Board (ETHAB) protocol and targeting Japanese group tour clients as well as individual travelers to developing countries. RESULTS: A total of 302 returned questionnaires were analyzed. While the majority (87.4%) sought general information on their destination, few (38.7%) sought the travel health information. Very few (2.0%) got the health information from travel medicine specialists. More than half were either unaware of the risks or thought there was no risk of hepatitis A, hepatitis B, and typhoid fever in their destination. Only half (50.7%) thought vaccines provided sufficient protection and very few (13.6%) believed that vaccines were safe. For most of the vaccine-preventable diseases, only fewer than 10% had received the vaccines. CONCLUSIONS: There is a need for specialized travel health services in Japan and health professionals should be encouraged to expand these services. Japanese travelers should be made aware of the importance of seeking pre-travel health advice and information on the health risks at their destination. Travel health professionals should provide a balanced view of the risks and benefits of immunization, and misperceptions about immunization should be addressed.

Elevated levels of vascular endothelial growth factor (VEGF) and soluble vascular endothelial growth factor receptor (VEGFR)-2 in human malaria.

In cerebral malaria, the binding of parasitized erythrocytes to the cerebral endothelium and the consequent angiogenic dysregulation play a key role in pathogenesis. Because vascular endothelial growth factor (VEGF) is widely regarded as a potent stimulator of angiogenesis, edema, inflammation, and vascular remodeling, the plasma levels of VEGF and the soluble form of the VEGF receptor (sVEGFR)-1 and -2 in uncomplicated malaria patients and healthy adults were measured by enzyme-linked immunosorbent assay (ELISA) to examine their roles in malaria. The results showed that VEGF and sVEGFR-2 levels were significantly elevated in malaria patients compared with healthy adults. Moreover, it was confirmed that malarial parasite antigens induced VEGF secretion from the human mast cell lines HMC-1 or KU812 cell. This is the first report to suggest that the interaction of VEGF and sVEGFR-2 is involved in the host immune response to malarial infection and that malarial parasites induce VEGF secretion from human mast cells.

Travelers' risk of malaria by destination country: a study from Japan.

BACKGROUND: Country-specific information on the incidence of malaria in travelers provides the most reliable data on which to base the pre-travel risk assessment. Some such studies have been conducted among Western travelers; however, to our knowledge, there have been no reports on Japanese travelers. METHODS: Malaria cases that were diagnosed between April 1999 and December 2005 and were reported to the national infectious disease surveillance body were used as the numerators after grouped into countries of disease acquisition. The denominators, the numbers of Japanese travelers visiting individual countries were derived from the recipient countries and obtained through a Japanese organization. RESULTS: In addition to the well-documented high risks in sub-Saharan countries, our study showed that travelers to Papua New Guinea were exposed to a significantly high risk of malaria. In Asia, Myanmar had the highest risk. Generally, malaria incidence rates among Japanese travelers were lower than those previously reported on Western travelers. However, the rates were rather comparable to the data obtained recently. CONCLUSIONS: These malaria incidence data in travelers should be taken into consideration for pre-travel risk assessment. They need to be constantly updated, and at the same time, limitations in data interpretation that are inherent in various study methodologies should also be clarified.

Preparedness for the spread of influenza: prohibition of traffic, school closure, and vaccination of children in the commuter towns of Tokyo.

In Greater Tokyo, many people commute by train between the suburbs and downtown Tokyo for 1 to 2 h per day. The spread of influenza in the suburbs of Tokyo should be studied, including the role of commuters and the effect of government policies on the spread of disease. We analyzed the simulated spread of influenza in commuter towns along a suburban railroad, using the individual-based Monte Carlo method, and validated this analysis using surveillance data of the infection in the Tokyo suburbs. This simulation reflects the mechanism of the real spread of influenza in commuter towns. Three measures against the spread of influenza were analyzed: prohibition of traffic, school closure, and vaccination of school children. Prohibition of traffic was not effective after the introduction of influenza into the commuter towns, but, if implemented early, it was somewhat effective in delaying the epidemic. School closure delayed the epidemic and reduced the peak of the disease, but it was not as effective in decreasing the number of infected people. Vaccination of school children decreased the numbers not only of infected children but also of infected adults in the regional communities.

Knowledge, attitudes, and practices of Japanese travelers towards malaria prevention during overseas travel.

BACKGROUND: There has been some concern that Japanese travelers are not adequately protected against malaria, especially when compared to Western travelers. Multi-national studies of knowledge, attitudes, and practices (KAP) regarding malaria risk have previously been conducted in travelers. METHODS: We conducted a KAP study in Japanese travelers using the same standardized questionnaire as the previous studies. Unlike those studies, questionnaires could not be distributed at departure lounges/gates at international airports, and therefore, travelers were sourced from several different study sites, targeting different populations. RESULTS: A total of 212 Japanese travelers who had visited malarious areas were enrolled, of which 63.2% had visited Asia and 28.3% visited sub-Saharan Africa. Significant shortcomings in KAP were noted with respect to lack of knowledge about symptoms of malaria, poor awareness of malaria risk at their destination, and non-adherence to adequate antimosquito measures. Chemoprophylaxis use was lower among Japanese travelers than travelers from other countries, even when confining to those traveling to sub-Saharan Africa. CONCLUSIONS: Japanese travel medicine providers and general practitioners who engage in pre-travel consultation should raise awareness of travelers about the seriousness of malaria, the need for improved compliance with chemoprophylaxis, and the importance of being properly prepared prior to departure.

Experience with intravenous metronidazole to treat moderate-to-severe amebiasis in Japan.

Twenty-eight cases of either intestinal amebiasis, amebic liver abscess, or both, most of which were of moderate-to-severe intensity, were treated with intravenous metronidazole, pioneered by the Research Group on Chemotherapy of Tropical Diseases, Japan. This study was not conducted as a formal clinical trial, and all patients either underwent colectomy for intestinal amebiasis, received oral metronidazole, or both. Despite these limitations, intravenous metronidazole was shown to be well tolerated and seemed to be very effective. This agent should be more widely recommended than previously thought for treating moderate-to-severe amebiasis, especially its intestinal form.

Malaria and mefloquine prophylaxis use among Japan Ground Self-Defense Force personnel deployed in East Timor.

BACKGROUND: Malaria poses a significant threat to military personnel stationed in endemic areas; therefore, it is important to examine the risks of military operations, particularly in areas where malaria-related data are scarce. The recent deployment of Japan Ground Self-Defense Force (JGSDF) for a peacekeeping operation in East Timor provided an opportunity to investigate these risks. The results of these studies may be translated into chemoprophylactic strategies for travelers. METHODS: A total of 1,876 members were deployed between April 2002 and September 2003. They consisted of three battalions; each remained for 6 months and was put on mefloquine prophylaxis. Malaria infection was investigated, including exposure to Plasmodium falciparum sporozoites, assessed by seroconversion for anticircumsporozoite (anti-CS) protein antibodies. Adherence to and adverse events (AEs) of mefloquine were studied via questionnaires. RESULTS: Four members were evacuated: one each with optic neuritis, lung cancer with brain metastasis, IgA nephropathy, and psychotic reactions that may have been precipitated by mefloquine. Six clinical episodes of Plasmodium vivax occurred, including one relapse, but there were no clinical cases of P falciparum, yielding a crude malaria attack rate of 0.32% for the 6-month period. Overall, 3.1% of the study population seroconverted for the anti-CS protein antibodies, with some regional differences noted. About 24% of questionnaire respondents, reported AEs; however, none of the AEs was severe. The AEs tended to emerge during the initial doses of chemoprophylaxis. CONCLUSIONS: The implementation of mefloquine prophylaxis among JGSDF personnel in East Timor, where P falciparum constitutes a moderate risk, appears to have been a success. Mefloquine prophylaxis was generally safe for Japanese unless predisposed to neuropsychiatric illness. However, given that mefloquine is the only chemoprophylactic agent available, a risk-benefit analysis tailored to the traveler is required for visits to countries such as East Timor.

[Evaluation of the resolving power of different angles in MPR images of 16DAS-MDCT].

In this study, we evaluated the resolving power of three-dimensional (3D) multiplanar reformation (MPR) images with various angles by using 16 data acquisition system multi detector row computed tomography (16DAS-MDCT) . We reconstructed the MPR images using data with a 0.75 mm slice thickness of the axial image in this examination. To evaluate resolving power, we used an original new phantom (RC phantom) that can be positioned at any slice angle in MPR images. We measured the modulation transfer function (MTF) by using the methods of measuring pre-sampling MTF, and used Fourier transform of image data of the square wave chart. The scan condition and image reconstruction condition that were adopted in this study correspond to the condition that we use for three-dimensional computed tomographic angiography (3D-CTA) examination of the head in our hospital. The MTF of MPR images showed minimum values at slice angles in parallel with the axial slice, and showed maximum values at the sagittal slice and coronal slice angles that are parallel to the Z-axis. With an oblique MPR image, MTF did not change with angle changes in the oblique sagittal slice plane, but in the oblique coronal slice plane, MTF increased as the tilt angle increased from the axial plane to the Z plane. As a result, we could evaluate the resolving power of a head 3D image by measuring the MTF of the axial image and sagittal image or the coronal image.