疟疾药物预防的现状与进展

近年来,疟疾的发病率已明显下降,但仍然是全球最重要的公共卫生负担。目前预防用药可以大大降低其发病率、病死率,控制传播,但长时间服药带来的不良反应及耐药等问题亟待解决,新的药物或组合方案应具有良好的耐受性、安全性和有效性。本文就疟疾预防用药的现状及进展作一综述。     

Effectiveness of chemoprophylaxis and other determinants of malaria in travellers to Kenya

Summary objective  To investigate the effectiveness of chemoprophylaxis and the determinants of malaria importation from Kenya.
method  In a population-based case-control study, 51 travellers from Bavaria diagnosed with falciparum malaria imported from Kenya (cases) and a sample of 383 healthy Bavarian travellers returning from Kenya (controls) were interviewed. Data were analysed by multiple logistic regression.
results  Mefloquine (OR = 0.055; 95% Cl 0.019-0.16) and chloroquine combined with proguanil (OR = 0.128; 95% CI 0.039-0.419) were highly protective against P. falciparum malaria, whereas other drugs were ineffective (OR = 1.225; 95% CI 0.536-2.803). Ineffective prophylaxis (10.4%) and non-prophylaxis (11.2%) were the main reasons for malaria importation. Travelling alone or with friends, male sex, and travel duration over 4 weeks could be identified as additional risk factors. The main reason for inadequate chemoprophylaxis was inappropriate medical advice (87.5%). Prophylaxis refusal occurred frequently despite correct advice (58.1%). Diagnosis was often delayed unnecessarily (27.5%).
conclusion  Malaria importation from Kenya could be reduced substantially (34%) by eliminating inappropriate medical advice.     

Compliance with malaria chemoprophylaxis and preventative measures against mosquito bites among Dutch travellers.

Summary Self-reported compliance with a malaria chemoprophylaxis regimen of proguanil (PG) plus chloroquine (CQ) was assessed in a cohort of 547 Dutch travellers who visited a single travel clinic when travelling to various areas endemic for falciparum malaria. 503 (92%) had taken PG/CQ prophylaxis, but only 326 (60%) reported regular and uninterrupted use throughout the journey and 4 weeks afterwards. Compliance differed by travel destination and was 45% in South America, 52% in West Africa, 53% in South-east Asia, 60% in the Indian Subcontinent and 78% in East Africa. Parasitologically confirmed falciparum malaria occurred in 5 travellers (0.9%), including 3 of 24 non-compliant travellers to West Africa (12.5%). Apart from destination, independent risk factors for non-compliance were young age, extensive travel experience and adventurous travel. Compliance with protection against mosquito bites was 80% for wearing long-sleeved shirts and long-legged trousers after sunset, 73% for use of repellents, 56% for sleeping under bednets and 37% for keeping the sleeping quarters free of mosquitoes. Although 440 travellers (80%) reported to have taken two or more of these measures at least once, only 88 (16%) had done so on a daily basis. Daily use of bednets was reported more frequently among subjects who were non-compliant with chemoprophylaxis. Compliance regarding malaria chemoprophylaxis should be improved, particularly in high-risk areas such as Sub-saharan Africa, with extra attention to young, adventurous travellers. More emphasis should be placed on prevention of Anopheles bites.     

Compliance with and tolerance of mefloquine and chloroquine + proguanil malaria chemoprophylaxis in French short-term travellers to sub-Saharan Africa

To compare the compliance with and tolerance of mefloquine (MQ) and chloroquine + proguanil (CQ-PRO) chemoprophylaxis, we conducted a study using a self-reported questionnaire in 2 groups of native French adult visitors to Senegal or Kenya. CQ (100 mg daily) + PRO (200 mg daily) prophylaxis was prescribed for all patients travelling to Senegal and for those going to Kenya when MQ was contraindicated; MQ (250 mg weekly) was prescribed for the other subjects. There were no significant differences in age, sex, exposition and measures of protection against mosquito bites, concomitant drug use or mean duration of chemoprophylaxis between the 2 groups, and compliance during travel was excellent in both. Chemoprophylaxis was more frequently interrupted prematurely in the MQ group. The rates of overall side-effects attributed to malaria chemoprophylaxis were 16% for MQ against 12% for CQ-PRO (not significant). However, nonserious neuropsychiatric adverse events are more frequent with MQ: 11.5% compared to 2% with CQ-PRO. MQ should be used with caution.     

Tolerability of amodiaquine and sulphadoxine-pyrimethamine, alone or in combination for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan adults

OBJECTIVE: To assess the tolerability and efficacy of amodiaquine (AQ)+sulphadoxine-pyrimethamine (SP), the first-line malaria treatment in Rwanda. METHOD: Randomized, double-blind trial in 2003 in Kigali town. A total of 351 adult patients with uncomplicated Plasmodium falciparum malaria were randomly allocated to one of the following treatments: AQ+SP, AQ or SP. We followed patients until day 14 after treatment and recorded adverse events (AEs) and clinical and parasitological outcomes. RESULTS: One hundred and eighteen patients reported at least one AE: 40% in the AQ, 39% in the AQ+SP and 21% in the SP groups. The AE was classified as possibly related to the antimalarial treatment for 86 patients. The Risk Ratio for at least one AE after treatment was significantly and about fourfold higher in patients receiving AQ or AQ+SP than in patients receiving SP. Pruritus and fatigue were significantly more frequent in patients treated with AQ or AQ+SP than in those receiving SP. Severe AEs, such as fatigue, nausea, dizziness and vomiting, were observed in four patients treated with AQ, in 10 treated with AQ+SP and in one patient treated with SP. CONCLUSION: Amodiaquine+SP is not well tolerated and a substantial proportion of patients experienced pruritus and fatigue, thus decreasing their compliance and compromising the first line treatment implementation at national level. This renders AQ-containing regimens sub-optimal; better-tolerated treatments should be identified.     

Evidence for undetected malaria infection in non-immune Australian travellers not taking chemoprophylaxis

To determine whether travellers from malaria-free countries can develop unrecognised or asymptomatic malaria after visiting endemic areas, we analysed data from 751 prospective blood donors who had visited or resided in malaria-risk areas in the previous 3 years. Malarial antibodies were measured using an established commercial enzyme-linked immunoassay incorporating four recombinant blood-stage plasmodial antigens and with published sensitivity > or =83% and specificity 100%. Details of countries visited and antimalarial chemoprophylaxis used were obtained by questionnaire. Among the 606 subjects resident in malaria-free countries and with no past history of malaria, 176 had visited high-risk countries as categorised by the World Health Organisation (WHO). Of these, 89 took no chemoprophylaxis including 6 (6.7%) who were antibody-positive; there were no antibody-positive subjects in the 87 who took chemoprophylaxis (P=0.029), which was that recommended by WHO in 84% of cases. These data underscore the value of effective antimalarial prophylaxis in non-immune travellers visiting high malaria-risk areas but also suggest that unrecognised infections can occur in those unprotected by chemoprophylaxis.     

Epidemiological features and case management practices of imported malaria in northern Italy 1991-1995

We report the results of a retrospective analysis of the clinical charts of imported malaria cases notified during the period 1991-95 in the Lombardy region of northern Italy. We analysed 694 admissions related to 683 individuals. The proportion of immigrants increased during the observation period from 34.4% in 1991 to 59.9% in 1995 (P = 0.002). P. falciparum was the causative species in 534 cases (78. 2%), and 591 (90.1%) of 656 cases with a full travel history had travelled to Africa. Information on chemoprophylaxis was available in 604 cases: 429 (71.0%) reported no drug intake, 140 (23.2%) an incomplete, and 35 (5.8%) a complete chemoprophylactic course. The proportion of subjects who had initiated malaria chemoprophylaxis was significantly lower among immigrants (7.4%) than nonimmigrants (50.2%) (P < 0.001). Severe disease was diagnosed in 26 (4.7%) of 551 cases of falciparum malaria, with a significantly lower incidence among immigrants (1.3% vs. 9.2%; P < 0.001). Eight deaths were recorded, all among nonimmigrants, whose fatality rate was significantly higher (P = 0.02). Mefloquine treatment of cases of uncomplicated falciparum malaria was associated with a significantly shorter fever clearance time (2.8 days +/- 1.5 vs. 3.5 days +/- 1.9; P < 0.001) and mean hospital stay (5.9 days +/- 4.4 vs. 8.3 days +/- 5.1; P < 0.001) compared to quinine treatment.     

A randomized open study to assess the efficacy and tolerability of dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Cambodia

OBJECTIVES: To compare the efficacy and tolerability of dihydroartemisinin-piperaquine (DHA-PQP) with that of a 3-day regimen of mefloquine and artesunate (MAS3) for the treatment of uncomplicated falciparum malaria in Cambodia. METHOD: Randomized open-label non-inferiority study over 64 days. RESULTS: Four hundred and sixty-four patients were included in the study. The polymerase chain reaction genotyping-adjusted cure rates on day 63 were 97.5% (95% confidence interval, CI, 93.8-99.3) for DHA-PQP and 97.5% (95% CI, 93.8-99.3) for MAS3, P = 1. There were no serious adverse events, but significantly more episodes of vomiting (P = 0.03), dizziness (P = 0.002), palpitations (P = 0.04), and sleep disorders (P = 0.03) reported in the MAS3 treatment group, consistent with the side-effect profile of mefloquine. CONCLUSIONS: DHA-PQP was as efficacious as MAS3, but much better tolerated, making it more appropriate for use in a routine programme setting. This highly efficacious, safe and more affordable fixed-dose combination could become the treatment of choice for Plasmodium falciparum malaria in Cambodia.     

Intramuscular artemether vs intravenous quinine: an open,randomized trial in Malawian children with cerebral malaria

objectives To compare artemether (by intramuscular injection) and quinine (by intravenous infusion) as treatments for cerebral malaria in African children.methods An open, randomized trial conducted at the Queen Elizabeth Central Hospital in Blantyre, Malawi. This trial was part of a multicentre study designed to determine if treatment with artemether would significantly lower mortality rates compared with quinine. Data from 83 artemether recipients and 81 quinine recipients are reported here.results Overall mortality rates and coma resolution times were not significantly different in the two treatment groups. Parasite and fever clearance times were significantly more rapid in the artemether recipients. Analyses which took into account the possible confounding variables did not significantly alter the findings of these unadjusted analyses.conclusion These results do not suggest that treatment with artemether would confer a survival advantage in children with life-threatening malaria. The power and precision of the estimated treatment effects of artemether would be enhanced by a meta-analysis of all relevant clinical trials.     

Subacute clinical forms of Plasmodium falciparum malaria in travelers receiving chloroquine-proguanil prophylaxis.

We have observed 4 French travelers, returning from African countries, who were not immune to malaria and were receiving chloroquine-proguanil prophylaxis, in whom the diagnosis of malaria could easily have been missed because the clinical signs were uncommon. These cases suggest that chloroquine-proguanil prophylaxis is not always effective and that travelers with unexplained symptoms should be monitored closely for malaria.     

Substantial increase of malaria in inland areas of eastern French Guiana

This study includes malaria cases diagnosed by the Parasitology Unit of the Cayenne Hospital (French Guiana) using the same procedure from 1996 to 2003. We provide data for two main rural communities in slightly inland areas of eastern French Guiana (Cacao, Regina) and for Cayenne, the capital of this French department. The frequency of bouts of malaria has been increasing rapidly since mid-2001, in these regions that were virtually considered to be malaria-free. This substantial increase of malaria appears mainly to involve Plasmodium vivax and recent Brazilian immigrants. Other plausible explanations which could account for the observed trend are discussed.     

Open randomized study of artesunate-amodiaquine vs. chloroquine-pyrimethamine-sulfadoxine for the treatment of uncomplicated Plasmodium falciparum malaria in Nigerian children

BACKGROUND: Artemisinin-based combination antimalarials are currently considered effective alternatives for the treatment of malaria in Africa, but there are few studies of such combinations in Nigerian children. We assessed the safety, treatment efficacy and effects on gametocyte carriage of the combination of artesunate plus amodiaquine and chloroquine plus pyrimethamine-sulfadoxine in children. METHODS: We evaluated 153 children who were aged 12 years or younger who had uncomplicated Plasmodium falciparum malaria. Patients were randomly assigned a combination of artesunate (4 mg/kg of body weight daily for 3 days) plus amodiaquine (30 mg/kg over 3 days), or chloroquine (25 mg/kg over 3 days) plus pyrimethamine-sulfadoxine (25 mg/kg of the sulfadoxine component at presentation). The primary endpoints were the proportions of children with adequate clinical and parasitological response, late parasitological failure, late clinical failure and early treatment failure. The parasitological cure rates on days 14-28 were also used as the primary endpoints. RESULTS: Both regimens were well tolerated; no child was withdrawn because of drug intolerance. All children treated with artesunate plus amodiaquine had adequate clinical and parasitological response (ACPR), while all but five children treated with chloroquine plus pyrimethamine-sulfadoxine had similar response. Fever clearance times were similar in the two treatment groups. However, the proportion of patients whose parasitaemia cleared by day 2 was significantly higher (100 vs. 50%, P = 0.00001) and parasite clearance was significantly faster (1.7 +/- 0.4 vs. 2.5 +/- 0.8 days, P = 0.0001) in children treated with artesunate plus amodiaquine. The cure rates on days 21 (100%vs. 94%, P = 0.03) and 28 (100%vs. 90%, P = 0.003) were also significantly higher in children treated with artesunate plus amodiaquine than in those treated with chloroquine plus pyrimethamine-sulfadoxine. Overall, a significantly higher proportion of children treated with chloroquine plus pyrimethamine-sulfadoxine carried gametocytes at least once during follow-up compared with those treated with artesunate plus amodiaquine [5 of 50 (10%) vs. 1 of 103 (0.97%), P = 0.01]. CONCLUSION: The combination of artesunate plus amodiaquine is therapeutically superior to a combination of chloroquine plus pyrimethamine-sulfadoxine, and significantly reduced gametocyte carriage following treatment.     

Impact of malaria control on childhood anaemia in Africa -- a quantitative review

OBJECTIVE: To review the impact of malaria control on haemoglobin (Hb) distributions and anaemia prevalences in children under 5 in malaria-endemic Africa. METHODS: Literature review of community-based studies of insecticide-treated bednets, antimalarial chemoprophylaxis and insecticide residual spraying that reported the impact on childhood anaemia. Anaemia outcomes were standardized by conversion of packed cell volumes into Hb values assuming a fixed threefold difference, and by estimation of anaemia prevalences from mean Hb values by applying normal distributions. Determinants of impact were assessed in multivariate analysis. RESULTS: Across 29 studies, malaria control increased Hb among children by, on average, 0.76 g/dl [95% confidence interval (CI): 0.61-0.91], from a mean baseline level of 10.5 g/dl, after a mean of 1-2 years of intervention. This response corresponded to a relative risk for Hb < 11 g/dl of 0.73 (95% CI: 0.64-0.81) and for Hb < 8 g/dl of 0.40 (95% CI: 0.25-0.55). The anaemia response was positively correlated with the impact on parasitaemia (P = 0.005, P = 0.008 and P = 0.01 for the three outcome measures), but no relationship with the type or duration of malaria intervention was apparent. Impact on the prevalence of Hb < 11 g/dl was larger in sites with a higher baseline parasite prevalence. Although no age pattern in impact was apparent across the studies, some individual trials found larger impacts on anaemia in children aged 6-35 months than in older children. CONCLUSION: In malaria-endemic Africa, malaria control reduces childhood anaemia. Childhood anaemia may be a useful indicator of the burden of malaria and of the progress in malaria control.     

Open randomized study of pyrimethamine-sulphadoxine vs. pyrimethamine-sulphadoxine plus probenecid for the treatment of uncomplicated Plasmodium falciparum malaria in children

BACKGROUND: Increasing drug resistance in Plasmodium falciparum has necessitated renewed search for cheap, effective alternatives to commonly available antimalarials, chloroquine and pyrimethamine-sulphadoxine, for the treatment of malaria in Africa. Probenecid, an inhibitor of organic anion transporters and multiresistance-associated proteins, can chemosensitize P. falciparum to pyrimethamine and sulphadoxine in vitro, but the clinical significance is unclear. We assessed the safety, treatment efficacy, and effects on gametocyte carriage of adding probenecid to pyrimethamine-sulphadoxine. METHODS: We evaluated 151 children aged 12 years or younger who had uncomplicated P. falciparum malaria. Patients were randomly assigned pyrimethamine-sulphadoxine (25 mg/kg of the sulphadoxine component) or pyrimethamine-sulphadoxine as above plus probenecid 20-25 mg/kg of bodyweight in two divided doses daily for 3 days. The primary endpoints were parasitological cure rates on days 14 and 28. RESULTS: Both regimens were well tolerated; no child was withdrawn because of drug intolerance. Fever (1.9 +/- 1.1 vs. 2.4 +/- 1.2 days, P = 0.02) and parasite clearance (2.3 +/- 0.9 vs. 2.7 +/- 1.1 days, P = 0.04) were significantly shorter, and the parasitological cure rate on day 14 (96.2%vs. 83.5%, P = 0.02) but not day 28 (79.4%vs. 72.6%, P = 0.4), was significantly higher in children treated with pyrimethamine-sulphadoxine-probenecid than in those treated with pyrimethamine-sulphadoxine. Gametocyte carriage was similar with both treatment regimens. CONCLUSIONS: The combination of pyrimethamine-sulphadoxine, and probenecid, at a relatively moderate dose, improved treatment efficacy but had no effect on gametocyte carriage. The pyrimethamine-sulphadoxine-probenecid combination merits further evaluation as a potential treatment for use in Nigeria.     

Improving adherence to malaria treatment for children: the use of pre-packed chloroquine tablets vs. chloroquine syrup

Malaria is a major cause of morbidity and mortality among children under five in sub-Saharan Africa. Prompt diagnosis and adequate treatment of acute clinical episodes are essential to reduce morbidity and prevent complications and mortality. In many countries, chloroquine syrup is the mainstay of malaria treatment for children under five. Not only is syrup more expensive than tablets, adherence to the prescribed dose at home is a problem because mothers use wrongly sized measuring devices or have difficulty with the instructions. We investigated the impact of introducing pre-packed tablets for children on adherence to treatment and compared the total cost of the tablets with that of syrup. Children aged 0--5 years diagnosed with malaria at the clinic over a 6-week period received either pre-packed tablets or syrup by random assignment. The principal caregivers were interviewed at home on day 4 after attending the clinic. Of the 155 caregivers given pre-packed tablets, 91% (n=141) adhered to the recommended dosage, while only 42% (n=61) of 144 who were provided syrup did. Only 20% of caregivers who received syrup used an accurate 5 ml measure. The cost of treatment with tablets was about one-quarter that of syrup and 62% (n=96) of caregivers preferred tablets. Pre-packed chloroquine tablets are a viable alternative to syrup.     

Tolerability of beta-blockers in elderly patients with chronic heart failure: the COLA II study

BACKGROUND: Beta-blockers are recommended therapy for patients with chronic heart failure (CHF). However, there remains concern regarding tolerability of these agents in the elderly, which has contributed to the limited uptake of these agents in clinical practice. AIMS: We conducted a multi-national, prospective evaluation of tolerability to carvedilol in 1030 CHF patients aged >70 years selected by their treating physician to receive this agent in everyday practice. METHODS AND RESULTS: NYHA Class II-IV CHF patients were assessed at baseline for key demographic parameters that may predict tolerability, then followed for 6 months after starting carvedilol. Tolerability was defined as being on >or=6.25 mg bd of carvedilol at 6 months having received a total of >or=3 months therapy. Tolerability overall was 80% with age 70-75 years 84.3%, 76-80 years 76.8% and >80 years 76.8%. Mean carvedilol dose achieved was 31.2 mg. In multivariate analysis, advanced age, low diastolic BP, LVEF, obstructive airways disease and presence of diabetes were predictors of tolerability. CONCLUSIONS: Carvedilol appears to be well tolerated in this elderly CHF patient cohort. Therefore, elderly CHF patients should not be denied treatment with carvedilol because of concerns regarding tolerability.     

An open label randomized comparison of mefloquine-artesunate as separate tablets vs. a new co-formulated combination for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand

BACKGROUND: Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium falciparum. A lower tablet burden should also facilitate adherence to treatment. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant falciparum malaria. METHODS: On the north-western border of Thailand 500 adults and children with uncomplicated falciparum malaria were randomized to receive either the new fixed combination or separate tablets. They were followed up weekly for 63 days. RESULTS: The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2-95.6) in the fixed combination group and 89.2% (85.0-93.4) in the loose tablets group (P=0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination. CONCLUSION: This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer.     

Azithromycin vs doxycycline in the treatment of non-gonococcal urethritis.

Azithromycin is a novel azalide macrolide active against Chlamydia trachomatis and Ureaplasma urealyticum. High persistent tissue concentrations allow short courses or even single doses to be considered. Sixty-two patients were studied, 19 received azithromycin 1 g in a single dose, 22 received azithromycin 500 mg in a single dose on day 1 followed by 250 mg once daily for 2 days and 21 received doxycycline 200 mg in a loading dose followed by 100 mg every 12 h for 7 days. Efficacy of these 3 regimens was compared in the treatment of non-gonococcal urethritis (NGU). Clearance of C. trachomatis from post-treatment cultures was satisfactory with all regimens. Response defined as the absence of symptoms and reduction in polymorphonuclear leucocytes in a Gram stained smear of urethral secretion to less than 5 cells per hpf (x 100 objective) was statistically better for the 3 day regimen of azithromycin than for the other 2 regimens. All treatments were well tolerated. Three days or single doses of azithromycin compared to 7 days of tetracycline (or 10-14 days as is often prescribed) have obvious advantages for patient compliance.