抗疟药咯萘啶与磺胺多辛及乙胺嘧啶配伍治疗恶性疟治疗结果…

本文对咯萘啶与磺胺多辛和乙胺嘧啶配伍，多年来在海南和云南的抗药性地区恶性疟的结果进行综合分析，认为这种配伍不宜用于抗经性恶性疟地区的防治。因为：（１）未能明显地延缓恶性疟原虫对该种伍用产生扩展抗药性，纵向监测于用药８年后，出现ＲⅢ病列，药后２４ｈ的减虫率明显下降；（２）恶性疟治疗后２８ｄ，６０％左右的病例仍携带配子体，经大劣按蚊和微小按蚊血餐后，在涎腺中可查见子孢子，表明此种按配伍治疗后，会引起恶     

复方蒿甲醚片治疗抗药性恶性疟临床研究

复方蒿甲醚片是由抗疟新药苯芴醇与蒿甲醚配伍的新制剂，在抗药性恶性疟流行区治疗恶性疟现症病人５７例，临床治愈率１００％；平均退热时间３５．７±１８．２ｈ，原虫无性体转阴时间４０．１±１０．８ｈ，２８ｄ根治率９４．６％。用药后无不良反应，原虫配子体出现率２．１％。它对原虫在蚊体内孢子增殖有抑制效果。对减少疟疾传播有益，适宜于抗药性恶性疟的治疗。     

2001-2008年海南省恶性疟发病率与大劣按蚊捕获数关系

目的分析海南省恶性疟发病率与大劣按蚊捕获数的相关性,为有针对性地开展海南省恶性疟防控工作提供依据。方法计算2001-2008年五指山市和琼中县恶性疟发病率和捕获的大劣按蚊数,采用Cochran-Armitage趋势检验分析两个地区恶性疟发病率的变化趋势;采用Spearman秩相关分析,探讨两个地区恶性疟发病率与大劣按蚊数量的相关性。结果 2001-2008年两个地区恶性疟发病率存在波动,但总体呈显著下降的趋势（Z五指山=-6.16,P〈0.01;Z琼中=-7.17,P〈0.01）;两个地区大劣按蚊捕获量均存在较大波动,并且恶性疟发病率与大劣按蚊捕获量均无显著相关性（r五指山=0.36,P〉0.05;r琼中=0.67,P〉0.05）。结论恶性疟的防控不仅要加强灭蚊工作,更要从环境治理、易感人群保护等多个角度入手,开展全方位的防控工作。     

东南亚抗药性恶性疟的发生和扩散的流行病学

东南亚柬、泰边境拜林的药盐计划证明,当大批恶性疟患者面临严重传播时,在强烈的药物压下,能发生药物抗性,特别是氯喹抗性。抗性原虫的选育因无免疫人群的输入而增强。药物抗性的产生是由于恶性疟原虫对乙胺嘧啶和氯喹连续、长期大量接触,导致抗性突变型的选育。这种选育如果在原虫反复通过无免疫力宿主期间,多次与很高药物剂量接触,将增加抗性的程度。通过已感染抗药性恶性疟的临时移民的流动,抗性扩散到柬埔寨和其它邻近国家的可接受性地区。在巴拉巴按蚊地区,氯喹抗性的迅速和早期扩散不是一个巧合,而是与这个按蚊种团对疟疾传播有关的生物学优势的结果。在澳大拉西亚,与巴布亚新几内亚接界的伊里安查亚执行的药盐计划,也导致了抗药性恶性疟的发生。     

库态按蚊是奥里萨地区的传疟媒介

奥里萨位于印度东海岸,地形可分为丘陵、平原和滨海三类。该地区恶性疟发病率很高,1984年有283 927个疟疾病例,其中恶性疟226 279例,占印度当年恶性疟病例总数的35%。由于该地区蚊相复杂,早期对传疟媒介的判定相互矛盾,因此在1982～1985年对当地常见蚊种进行了胃和唾腺解剖,检查疟原虫感染情况。在奥里萨的丘陵、平原和滨海地区捕获环斑按蚊、库态按蚊、溪流按蚊和吉甫按蚊共     

成都市主要媒介蚊种对常用杀虫剂抗药性监测结果

本文报告了用区分剂量法、半数致死浓度法连续5年监测成都市主要媒介蚊种对化学杀虫剂（溴氰菊酯、氯菊酯、马拉硫磷、DDT）抗药性。致倦库蚊对所测杀虫剂均有明显抗药性；三带喙库蚊对马拉硫磷的抗药性明显，对溴氰菊酯和DDT存在初级抗性；中华按蚊对溴氰菊酯抗药性波动较大，但敏感性处于回升趋势，对马拉硫磷是相当敏感的，而对DDT有明显抗药性；嗜人按蚊对溴氰菊酯和DDT均敏感。     

肯尼亚西部按蚊幼虫的空间分布和孳生地特点

在肯尼亚当地恶性疟在人群中的流行率大于50％。重要的传播媒介有冈比亚按蚊种团和催命按蚊,其中在肯尼亚同一地区出现了3种冈比亚种团的按蚊,包括冈比亚按蚊,阿拉伯按蚊和纯净按蚊。许多研究表明,在肯尼亚西部和沿海地带媒介密度有明显差异。     

CSNC方案治疗抗药性恶性疟41例分析

ＣＳＮＣ方案治疗抗药性恶性疟４１例分析河北医学院附属第二医院（石家庄０５００００）王彦，薛新平，石克勋，高志钧扎伊尔金沙萨地区的抗药性恶性疟病人十分常见￣［１］，且相当难治，作者于１９９１～１９９２年应用ＣＳＮＡ方案（氯喹、复方新诺明￣［２］、心痛定...     

广东省1980—1987年疟疾流行状况

1980—1987年,疟疾年平均发病率3.65±0.40‰,较解放初期下降99.25%。年平均死亡率0.11/100万。1987年发病率≥5‰的尚有14个县(市),约450多万人口,其中发病率较高的有90余万人口。疟疾流行主要发生在海南岛少数民族地区和大陆人口流动频繁的地区。海南岛的恶性疟和混合疟病例减少,恶性疟、间日疟和三日疟的比例由抗疟前的0.623:0.365:0.012变化为0.383:0.617:0。大陆地区的恶性疟只见外地输入病例,三日疟均由输血引起,目前只见间日疟流行。1983—1987年,大陆地区共出现暴发点379个,其中336个点(88.7%)由外地传染源输入引起。在临时民工住棚解剖中华按蚊、嗜人按蚊和微小按蚊,发现子孢子阳性感染。海南岛的恶性疟原虫在体内对氯喹、喹哌、氨盼喹产生抗药性,在体外对奎宁、甲氟喹亦显示轻度抗药性。     

DDT滞留喷洒防制雷氏按蚊嗜人亚种控制恶性疟的实验研究

1983年6～10月在安徽省舒城县芦镇公社进行DDT室内滞留喷洒,对雷氏按蚊嗜人亚种有良好的防制效果,叮人率下降99.5％,疟疾传播强度明显下降,以恶性疟为显著,其发病率等各项考核指标下降幅度均在85％以上。说明在以雷氏按蚊嗜人亚种为主要传疟媒介地区的疟疾防治,采用DDT室内滞留喷洒,结合现症病人治疗,即能有效地控制恶性疟的发病与传播。     

Sensitivity of Plasmodium falciparum to mefloquine-sulphadoxine-pyrimethamine (Fansimef) in vivo and to mefloquine alone in vitro in Nigeria

In Nigeria chloroquine remains the drug of choice for the treatment of falciparum malaria, since chloroquine resistance is not yet a problem. Nevertheless, in view of the rapid spread of multi-resistant Plasmodium falciparum in Africa it is desirable to test alternative drugs for efficacy and safety. To this end, we undertook a comparative controlled trial of the new triple combination, mefloquine-sulphadoxine-pyrimethamine (MSP, Fansimef) with chloroquine in a group of Nigerian children with symptomatic falciparum malaria. Our results showed that Fansimef was an effective blood schizontocide against the Nigerian strain of P. falciparum and was well tolerated. In particular, sinus bradycardia, which was frequently observed with Fanismef in the trials conducted in Zambia, was not seen in any of the Nigerian patients. In vitro sensitivity tests done on 26 P. falciparum isolates showed that all isolates were susceptible to complete inhibition by mefloquine, but the minimum concentration which produced complete inhibition in some isolates was higher than expected for fully sensitive parasites.     

Antimalarial and toxic effect of triple combination of pyronaridine, sulfadoxine and pyrimethamine

The triple combination of pyronaridine, sulfadoxine and pyrimethamine which has been proven to be efficient in delaying emergence of drug resistance of rodent malarial parasites was further studied for potential application to malaria control. The antimalarial effect of the triple combination on Plasmodium berghei ANKA-infected mice and the toxic effects in mice and rats were additive. A single dose of pyronaridine 500 mg in combination with sulfadoxine, 1000 or 1500 mg, and pyrimethamine, 50 or 75 mg, given to 72 acute falciparum malaria patients resulted in a 100% cure rate with nil or mild side effects, and no recrudescence of asexual parasite over 4-week follow-up. Preliminary experiments on the drug effect on sporogony showed that the drug combination at the dose used could not completely interrupt the sporozoite formation although many retarded oocysts were found.     

The chemotherapy of rodent malaria XXXV. Further studies on the retardation of drug resistance by the use of a triple combination of mefloquine, pyrimethamine and sulfadoxine in mice infected with P. berghei and 'P. berghei NS'

In the face of an increasing prevalence of Plasmodium falciparum resistant to chloroquine and to pyrimethamine-sulphonamide or -sulphone mixtures, the need for a new, effective blood schizontocide for treatment of acute malaria is urgent. The only such compound that is almost ready for release is mefloquine (M) but there is already a danger that parasites may become resistant to this compound if it is used extensively alone. Earlier studies using a rodent model indicated that mefloquine could be 'protected' by administering it with a pyrimethamine-sulfadoxine (PS) mixture, but the experimental technique used was open to criticism. The present experiments, using a relapse technique to develop drug resistance, more closely parallel the way antimalarials are likely to be deployed in human communities. They confirm that the development of resistance to the individual components in the P. berghei N line is delayed by the triple combination, and more so in the slightly chloroquine-resistant 'P. berghei NS' line. The combination did not prevent the development of resistance in a line initially resistant to PS, but the level reached was much less than those seen when P. berghei N or 'P. berghei NS' were exposed to MPS or to M alone. It was concluded that the use of a triple combination of M, P and S against P. falciparum would be of value in 'protecting' these compounds, and thus gain time while new agents against malaria are being developed.     

Chlorproguanil-dapsone (LAPDAP) for uncomplicated falciparum malaria

The synergistic antifolate combination of chlorproguanil with dapsone (CPG-DDS; LAPDAP) is being developed by a public-private partnership as a low-cost treatment for uncomplicated falciparum malaria. LAPDAP is rapidly eliminated from the body, giving it low selection pressure for drug resistance. Clinical cases with sulphadoxine-pyrimethamine (SP)-resistant infections acquired in Africa have been predicted to be responsive to LAPDAP, and clinical evidence is available to support this. A regulatory dossier is being prepared for simultaneous submission to the UK Medicines Control Agency and African licencing authorities. The team working on LAPDAP has also started to develop the triple combination of chlorproguanil-dapsone-artesunate (CDA) as a low-cost combination therapy for uncomplicated falciparum malaria. Although LAPDAP does not have regulatory approval (and development of CDA is at an early stage), the development team is keen to communicate with public health scientists to try to anticipate the policy and implementation hurdles that lie ahead. This short paper outlines the current stages that LAPDAP and CDA have reached, and sketches the anticipated public health issues.     

Comparative drug trial of a sulfadoxine/pyrimethamine and a sulfalene/pyrimethamine combination against Plasmodium falciparum infections in semi-immune populations of Burma

The antiplasmodial effect of a single dose treatment with a sulfadoxine/pyrimethamine combination as compared to a sulfalene/pyrimethamine combination against falciparum malaria was assessed in semi-immune populations in Burma in early 1980. Parasite clearance rates on Day 7 after treatment were 99.2% for the sulfadoxine/pyrimethamine combination and 98.6% for the sulfalene/pyrimethamine combination for all age-groups. The earlier recrudescence rates within one month were 3.7% and 9.2% respectively, while the later recrudescence rates between 1 and 2 months were 9% and 8.3% respectively. Hence, both combinations were equally effective for treatment of falciparum malaria as no significant difference in the parasite clearance rates was observed. However, the earlier recrudescence rates showed a significant difference with a higher rate for the sulfalene/pyrimethamine combination. This is thought to be due to the shorter half-life of sulfalene compared to sulfadoxine and to its being unable therefore to suppress the falciparum infections for as long a period as sulfadoxine. But there was not much difference in the later recrudescence rates. These combinations have a stimulating effect on the production of falciparum gametocytes; and, in order to minimize transmission, an effective gametocytocide such as primaquine should be given along with them, as well as with the chloroquine/pyrimethamine combination, in areas with efficient malaria vectors. Recrudescence rates and gametocyte rates were highest among children in the 1-4 years age-group and this could be attributed to their lower level of acquired immunity compared to the older children and adults. Vivax malaria was also found to be effectively suppressed for about 4 weeks with both combinations.(ABSTRACT TRUNCATED AT 400 WORDS)     

A clinical trial of combination of artesunate and mefloquine in the treatment of acute uncomplicated falciparum malaria: a short and practical regimen

The difficulties in treating drug-resistant falciparum malaria in Thailand are compounded by the necessity of giving antimalarials over long periods of time. The resultant fall in patient compliance not only lowers cure rates but also predisposes to the further spread of drug-resistance. Sequential treatment with artesunate given over 5 days followed by mefloquine produced 100% cure rates in previous study, but might not be a suitable regimen for field treatment. We conducted a clinical trial of a combination of artesunate and mefloquine given twice daily for 2 days in 150 patients with acute uncomplicated falciparum malaria. The dose of artesunate (200 mg) and mefloquine (312.5 mg) were given simultaneously in a separate package. All patients were admitted to a hospital in Bangkok for 28 days to exclude re-infection and monitor the possible adverse effects. One hundred and thirty patients completed the study with 28 days follow up. Twenty patients (13%) left the hospital prior to completion of follow-up for reasons unrelated to their treatment. Cure rate was 97% (126/130). There were no RII or RIII failures and all four patients with treatment failures were of the RI type. The mean parasite clearance time and fever clearance time were 46.4 and 42.5 hours, respectively. All patients were tolerated the combination drugs well and there were no serious toxic adverse reactions. The results indicate that combination of artesunate and mefloquine given twice daily for 2 days is effective and well tolerated in patients with acute, uncomplicated falciparum malaria and suitable as an alternative treatment for multidrug resistant falciparum malaria.     

A randomized trial of artesunate-sulfamethoxypyrazine-pyrimethamine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali.

The choice of artemisinin-based combination that is being adopted for malaria treatment in sub-Saharan Africa may depend on several factors, including cost, efficacy, side effects, and simplicity of administration. We tested the hypothesis that artesunate-sulfamethoxypyrazine-pyrimethamine is as efficacious as the four-dose regimen of artemether-lumefantrine for treatment of Plasmodium falciparum malaria. The study was carried out during two transmission seasons (2003 and 2004) in Sotuba, Mali. Participants at least 6 months of age with uncomplicated P. falciparum malaria were randomly assigned to receive artesunate-sulfamethoxypyrazine-pyrimethamine or artemether-lumefantrine. Treatment efficacy was assessed using the World Health Organization 28-day protocol. A total of 606 (303 in each arm) patients were enrolled. The cure rate was higher for artesunate-sulfamethoxypyrazine-pyrimethamine than for artemether-lumefantrine (98.7% versus 89.6%; P < 0.0001). After correction for cases of re-infection, the cure rates were 100% and 99.0%, respectively (P = 0.08). No serious adverse events occurred. Artesunate-sulfamethoxypyrazine-pyrimethamine is well-tolerated and effective against P. falciparum malaria. It showed an additional benefit of preventing new infections.     

The efficacy of combined mefloquine-artesunate versus mefloquine-primaquine on subsequent development of Plasmodium falciparum gametocytemia

An open randomized controlled study of mefloquine-artesunate and mefloquine-primaquine for the treatment of uncomplicated Plasmodium falciparum malaria was carried out in Kanchanaburi in the Saiyok District in western Thailand. Weekly parasite counts from thick and thin blood films were done for six weeks. The gametocyte carriage rate was calculated and compared between the two treatment groups. Gametocytes on presentation, recrudescent infection, and reinfection were the significant factors associated with subsequent development of gametocytemia. It is the increased propensity of recrudescent infections to produce gametocytes that drives drug resistance. The results of this study confirmed that the complete eradication of a sexual forms of P. falciparum by effective antimalarial treatment, but not by combination treatment with primaquine, is the most effective means to prevent subsequent gametocytemia.     

Low efficacy of amodiaquine or chloroquine plus sulfadoxine-pyrimethamine against Plasmodium falciparum and P. vivax malaria in Papua New Guinea

Because of increasing resistance to 4-aminoquinolines in Papua New Guinea, combination therapy of amodiaquine (AQ) or chloroquine (CQ) plus sulfadoxine-pyrimethamine (SP) was introduced as first-line treatment against uncomplicated malaria in 2000. The purpose of this study was to monitor in vivo efficacy of the current standard combination therapy against Plasmodium falciparum and P. vivax malaria. Studies were conducted between 2003 and 2005 in the Simbu, East Sepik, and Madang Provinces in Papua New Guinea according to the revised protocol of the World Health Organization (WHO) for assessment of antimalarial drug efficacy. Children between six months and seven years of age with clinically overt and parasitologically confirmed P. falciparum or P. vivax malaria were treated according to the new policy guidelines (i.e., AQ plus SP given to patients weighing < 14 kg and CQ plus SP given to patients weighing < 14 kg). Children were monitored up to day 28 and classified according to clinical and parasitological outcome as adequate clinical and parasitological response (ACPR), early treatment failure (ETF), late clinical failure (LCF), or late parasitological failure (LPF). For P. falciparum malaria, polymerase chain reaction (PCR)-corrected treatment failure rates up to day 28 ranged between 10.3% and 28.8% for AQ plus SP and between 5.6% and 28.6% for CQ plus SP, depending on the region and the year of assessment. Overall treatment failure rate with AQ or CQ plus SP for P. vivax malaria was 12%. Our results suggest that the current first-line treatment in Papua New Guinea is not sufficiently effective. According to the new WHO guidelines for the treatment of malaria, a rate of parasitological resistance greater than 10% in the two dominant malaria species in the country justifies a change in treatment policy.     

Artesunate reduces but does not prevent posttreatment transmission of Plasmodium falciparum to Anopheles gambiae

Combination therapy that includes artemisinin derivatives cures most falciparum malaria infections. Lowering transmission by reducing gametocyte infectivity would be an additional benefit. To examine the effect of such therapy on transmission, Gambian children with Plasmodium falciparum malaria were treated with standard regimens of chloroquine or pyrimethamine-sulfadoxine alone or in combination with 1 or 3 doses of artesunate. The infectivity to mosquitoes of gametocytes in peripheral blood was determined 4 or 7 days after treatment. Infection of mosquitoes was observed in all treatment groups and was positively associated with gametocyte density. The probability of transmission was lowest in those who received pyrimethamine-sulfadoxine and 3 doses of artesunate, and it was 8-fold higher in the group that received pyrimethamine-sulfadoxine alone. Artesunate reduced posttreatment infectivity dramatically but did not abolish it completely. The study raises questions about any policy to use pyrimethamine-sulfadoxine alone as the first-line treatment for malaria.