Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity.

Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC50 values below or near of 50.0 nM whatever the strain with selectivity index often superior to 100.17b was found as a promising antimalarial candidate with IC50 values of 14.9 nM and 11.0 nM against respectively Pf3D7 and PfW2 and a selectivity index higher than 770 whatever the cell line is. Further experiments were achieved to confirm the safety and to establish the preliminary ADMET profile of compound 17b before the in vivo study performed on a mouse model of P. berghei ANKA infection. The overall data of this study allowed to establish new structure-activity relationships and the development of novel agents with improved pharmacokinetic properties.

Detection of Loa loa Microfilariae in Follicular Fluid During Assisted Reproductive Technology: Case Report and Review of the Literature.

We report on a case of loiasis revealed during an assisted reproductive technology (ART) cycle. Loa loa could limit implantation outcome. We propose to focus on an ART strategy with frozen embryos to treat the patient before any transfer.

Cross-sectional serological survey of human fascioliasis in haiti.

Fasciola hepatica, the aetiological agent of fascioliasis in the Caribbean region, occurs throughout the major islands of the Greater Antilles and in localised zones on two islands (Martinique and Saint Lucia) of the Lesser Antilles. However, apart from Puerto Rico, information regarding human fascioliasis in islands of the Caribbean is out of date or unavailable, or even nonexistent as in Haiti. The authors conducted a retrospective, cross-sectional serological survey in Port-au-Prince using a Western blotting test (LDBIO Diagnostics) on human fascioliasis in Haiti. A total of 216 serum samples obtained from apparently healthy adults were tested. The frequency of antibodies in serum samples of the study population was 6.5% (14/216). The immunodominant bands recognised in Western blots were 27-28 kDa (100%), 42 kDa (64%), 60 kDa, and 8-9 kDa (28%). This is the first survey to reveal a relatively low proportion of asymptomatic F. hepatica-infected humans in Haiti.

Childhood cryptosporidiosis: a case report.

Cryptosporidium has emerged as an important cause of diarrheal illness worldwide, especially amongst young children and patients with infectious or iatrogenic immune deficiencies. The authors describe a case of mild cryptosporidiosis in a well-nourished, immunocompetent, one-year-old child. Rapid clinical and parasitological improvement was observed after a 3-day course of nitazoxanide.

Seroprevalence of human Taenia solium cysticercosis in Haiti.

Human Taenia solium cysticercosis is common in developing countries due to poor sanitary conditions and economics based on breeding livestock, especially pigs, with low hygiene standards. Neurocysticercosis, caused by migration of the larvae of the tapeworm in the nervous system, is the leading cause of acquired epilepsy in adults in Central and South America, sub-Saharan Africa, and East and South Asia. This makes neurocysticercosis a large public health problem in developing countries. Two clinical cases of neurocysticercosis have been observed recently in Haiti. In order to evaluate the prevalence of human T. solium cysticercosis in this country, in 2007 we conducted a cross-sectional serological retrospective survey using a Western blotting test (LDBIO Diagnostics) in Port-au-Prince, where sewage systems are rare and swine usually roam freely throughout the area. A total of 216 serum samples, obtained from healthy adults seen in the work setting of periodical medical visits, were tested after storage at - 20 degrees C. The frequency of antibodies in serum samples of the study population was 2.8% (6/216). The immunodominant bands recognized in Western blots were 23-26 kDa (100%), 39 kDa (67%), 45 kDa and 6-8 kDa (50%), 50-55 kDa (33%). These results confirm for the first time an endemic situation of cysticercosis in humans in Haiti, with similar prevalence as that reported in other Latin American and African countries. It reinforces the urgent need for control and prevention measures to be taken by local public health services.

Dosing accuracy of artesunate and amodiaquine as treatment for falciparum malaria in Casamance, Senegal.

OBJECTIVES: Several products of artesunate plus amodiaquine (AS + AQ) are being deployed in malaria-endemic countries for treating uncomplicated falciparum malaria but dosing accuracy and consequential effects on efficacy and tolerability have not been examined. METHODS: Patients with parasitologically confirmed, uncomplicated falciparum malaria were treated and followed by research teams or local health centre staff in Casamance, Senegal. AS + AQ was given as: (i) loose combination (AS 50 mg, AQ 200 mg), dosed on body weight, or (ii) co-blistered product (AS 50 mg, AQ 153 mg) dosed by weight or age. Target doses were: (i) AS 4 (2-10) mg/kg/day and (ii) AQ 10 (7.5-15) mg/kg/day. Patients receiving therapeutic doses defined dosing accuracy. Treatment-emergent signs and symptoms (TESS) were recorded. RESULTS: A total of 3277 patients were treated with loose (n = 1972, weight-dosed) or co-blistered (n = 1305, 962 age-dosed, 343 weight-dosed) AS + AQ by the research team (n = 966) or clinic staff (n = 2311). AS was dosed correctly in >99% with all regimens. Loose AQ by weight was 98% correct. The co-blister AQ overdosed 18% of patients when dosed by age and underdosed 13% by weight. Low weight was an independent risk factor for overdosing. The co-blister had significantly more TESS than the loose product [117/1305 (9%) vs. 41/1972 (2%), relative risk = 4.3 (95% CI: 3.0-6.1, P < 0.0001)]. Age-based dosing accounted for the difference. TESS occurred mostly within one day (72%) and were mild or moderate (75%). CONCLUSION: Artesunate is easier to dose than AQ. Currently available age-dosed, co-blistered AS + AQ tends to overdose AQ and is less well tolerated than loose tablets. It is not the optimal presentation of AS + AQ.

[Bilharziasis caused by Schistosoma mansoni in a traveler returning from Guinea: failure of serodiagnostic testing]. / Bilharziose à Schistosoma mansoniau retour de Guinée: défaillance du sérodiagnostic.

The purpose of this report is to describe a case of febrile hypereosinophilic syndrome in a traveler three weeks after returning from a sightseeing trip to Guinea. Laboratory testing demonstrated an inflammatory response syndrome and hepatic cytolysis. Parasite serology led to suspicion of toxocariasis that was treated using albendazole. Follow-up tests at two months showed the presence of Schistosoma mansoni eggs in stools despite negative standard serodiagnostic testing (hemagglutination). Secondarily Western blot testing of serum samples at one, two and 14 months after returning from Guinea continued to show only protein bands specific to toxocariasis with no bands specific to bilhariziasis. These findings provide further evidence of the limitations of serological testing for detection of bilharziasis in travelers and the difficulty of diagnosis. Guinea is a high-risk tourist destination. Intestinal and urinary bilharziasis are endemic over three-fourths of country. Travelers planning even short stays in areas where bilharziasis is endemic should be advised on preventive measures.

Plasmodium falciparum in vitro susceptibility to antimalarial drugs in Casamance (southwestern Senegal) during the first 5 years of routine use of artesunate-amodiaquine.

We have monitored the in vitro sensitivities of Plasmodium falciparum isolates predeployment and during the deployment of artesunate plus amodiaquine treatment in Mlomp, Casamance (southwestern Senegal) during 2000 to 2004. Parasites remained susceptible to both drugs. Chloroquine resistance levels were high but stable. Quinine continues to be effective.

Economic evaluation of a policy change from single-agent treatment for suspected malaria to artesunate-amodiaquine for microscopically confirmed uncomplicated falciparum malaria in the Oussouye District of south-western Senegal.

Senegal is changing policy for case management of uncomplicated falciparum malaria, which hitherto is diagnosed clinically and treated with chloroquine or intramuscular quinine. The WHO recommends artemisinin-based combinations for treating falciparum malaria, preferably based on a parasitological diagnosis. There are no economic projections if such a policy were introduced in Senegal. We have conducted a preliminary economic assessment of such a policy change. The study took place in the chloroquine-resistant district of Oussouye in south-western Senegal. We reviewed clinic registers of the district health posts (n=5) from 1996 to 2001, and piloted artesunate combined with amodiaquine (at 4 and 10 mg/kg/day x 3 days respectively) (AS--AQ) for treating slide-proven falciparum malaria during two rainy seasons (2000 and 2001) at one health centre. These data were used to calculate current direct patient costs (clinic visit, diagnosis, drugs) of malaria treatment and project future costs for the district. The robustness of the model was tested by allowing for different drug failure rates and costs of diagnosis. During 1996--2001, the mean number of primary treatments per year was 7654 for a mean, direct cost of 17,452 US dollars to the community. Clinical diagnosis resulted in over-treatment: 56% and 66% in the wet and dry seasons respectively. Current policy leads to substantial drug wastage and excess direct costs for the community. The direct costs of implementing AS-AQ for slide-proven malaria would be 8,150 US dollars (53% less expensive). Studies examining the public health effect and economics of deploying AS--AQ on a wider scale are underway in Senegal.

[Center of multidrug-resistant malaria in a forest zone of Cameroon revisited after 14 years]. / Un foyer de paludisme multi-resistant en zone forestiere au Cameroun revisite 14 ans apres.

In vitro sensitivity of Plasmodium falciparum to chloroquine, amodiaquine, quinine and pyronaridine was assessed using the DELI microtest method in 2000. Isolates were collected on the La Nyé'eté rubber plantations located in a forest zone 45 km southeast of Kribi, Cameroon. Comparison with results of the last survey in 1986 showed that chloroquine resistance has remained stable (61% versus 56%). Sensitivity to amodiaquine and pyronaridine was high (76.5% and 89.5% respectively) in all isolates including chloroquine-resistant isolates. Despite intensive use in the area, quinine remained highly effective (sensitivity, 80%). These results indicate that chloroquine sensitivity has remained relatively stable in this resistant zone and that little cross-resistance with amodiaquine and pyronaridine has developed. These findings hold the promise for an alternative treatment of uncomplicated Plasmodium falciparum malaria in chloroquine-resistance areas.

Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: a randomised, multicentre trial.

BACKGROUND: Increasing drug resistance limits the choice of efficacious chemotherapy against Plasmodium falciparum malaria in Africa. Amodiaquine still retains efficacy against P falciparum in many African countries. We assessed the safety, treatment efficacy, and effect on gametocyte carriage of adding artesunate to amodiaquine in three randomised trials in Kenya, Sénégal, and Gabon. METHODS: We enrolled 941 children (400 in Kenya, 321 in Sénégal, and 220 in Gabon) who were 10 years or older and who had uncomplicated P falciparum malaria. Patients were randomly assigned amodiaquine (10 mg/kg per day for 3 days) plus artesunate (4 mg/kg per day for 3 days) or amodiaquine (as above) and placebo (for 3 days). The primary endpoints were parasitological cure rates at days 14 and 28. Analysis was by intention to treat and by an evaluability method. FINDINGS: Both regimens were well tolerated. Six patients in the amodiaquine-artesunate group and five in the amodiaquine group developed early, drug-induced vomiting, necessitating alternative treatment. By intention-to-treat analysis, the day-14 cure rates for amodiaquine-artesunate versus amodiaquine were: 175/192 (91%) versus 140/188 (74%) in Kenya (D=16.7% [95% CI 9.3-24.1], p<0.0001), 148/160 (93%) versus 147/157 (94%) in Sénégal (-1.1% [-6.7 to 4.5], p=0.7), and 92/94 (98%) versus 86/96 (90%) in Gabon (8.3% [1.5-15.1], p=0.02). The corresponding rates for day 28 were: 123/180 (68%) versus 75/183 (41%) in Kenya (27.3% [17.5-37.2], p<0.0001), 130/159 (82%) versus 123/156 (79%) in Sénégal (2.9% [-5.9 to 11.7], p=0.5), and 80/94 (85%) versus 70/98 (71%) in Gabon (13.7% [2.2-25.2], p=0.02). Similar rates were obtained by evaluability analysis. INTERPRETATION: The combination of artesunate and amodiaquine improved treatment efficacy in Gabon and Kenya, and was equivalent in Sénégal. Amodiaquine-artesunate is a potential combination for use in Africa. Further investigations to assess the potential effect on the evolution of drug resistance, disease transmission, and safety of amodiaquine-artesunate are warranted.

High prevalence of co-factor independent anticardiolipin antibodies in malaria exposed individuals.

Anticardiolipin antibodies (aCL) were investigated in 137 individuals chronically exposed to malaria and living in Africa and Asia. They belonged to several groups according to parasite (Plasmodium falciparum or vivax) and clinical manifestations (i.e. asymptomatic parasite carriers, acute uncomplicated attack or severe malaria episodes). aCL were measured in an enzyme immunoassay (ELISA) performed in the presence of either goat serum (aCLs) or gelatin (aCLg). In a group of 53 patients with autoimmune manifestations (i.e. antiphospholipid syndrome and/or lupus), detection of IgG but not IgM aCL was markedly reduced in the presence of gelatin. In malaria donors, high prevalence of serum co-factor-independent IgG and IgM were detected, and the presence of goat serum in the assay consistently decreased their detection. aCLg levels were found to be related to the clinical/endemic status of donors. IgG aCLg were found to be higher in asymptomatic P. falciparum carriers than in patients with uncomplicated acute or cerebral malaria. IgM aCLg were higher in the cerebral malaria group than in groups with uncomplicated acute malaria patients or asymptomatic individuals. Data suggest that using a serum co-factor independent, sensitive ELISA, aCL are commonly detected during malarial infections and related to malarial infection status.

[Evaluation of in vitro drug sensitivity of antimalarials for Plasmodium falciparum using a colorimetric assay (DELI-microtest)]. / Evaluation de la sensibilité in vitro de Plasmodium falciparum aux antimalariques par un test colorimétrique (DELI-microtest).

The DELI-microtest (Double-Site Enzyme Linked LDH Immunodetection) is a colorimetric method for determination of Plasmodium falciparum in vitro sensitivity to antimalarial drugs. This method is based on the capture of the specific lactate deshydrogenase of Plasmodium falciparum (pLDH) using 2 monoclonal antibodies which recognize 2 different sites of the enzyme. The second monoclonal antibody is biotinylated and may catch a peroxidase-labelled streptavidine and develop a colorimetric reaction in the presence of peroxidase substrate. The level of pLDH released by parasite growth is determined by the measure of optical densities. An excellent correlation has been observed between the IC50's obtained using the DELI-microtest and the classical isotopic microtest, and the high sensitivity of the DELI-microtest can be used to measure the IC50's for isolates with parasitemia as low as 0.005%. It is easier and faster to process than isotopic microtest in field conditions. In addition, due to high sensitivity of the DELI-microtest, isolates with a low parasitemia may be included in the studies.

Sensitivity of Plasmodium falciparum to amodiaquine and chloroquine in central Africa: a comparative study in vivo and in vitro.

A comparative study in vivo of amodiaquine efficacy (35 mg/kg over 3 d) and chloroquine (25 mg/kg over 3 d) was conducted in 1991 and 1992 in Cameroon and Congo in 123 patients with uncomplicated Plasmodium falciparum malaria. Amodiaquine was more effective than chloroquine, with parasite clearance by day 7 in 79.7% of the patients compared with 59.4%. Sixteen of 32 (50%) P. falciparum isolates tested in vitro were resistant to chloroquine and only 3 of 34 (9%) were resistant to amodiaquine. 5.3% of patients treated with amodiaquine complained of pruritus and 18.7% of nausea, compared with 15.7% and 5% respectively of those treated with chloroquine.

[Sensitivity in vivo and in vitro of Plasmodium falciparum to chloroquine and amodiaquine in Bangangte (west Cameroon)]. / Sensibilité in vivo et in vitro de Plasmodium falciparum a la chloroquine et à l'amodiaquine à Bangangte (ouest-Cameroun).

A cross-sectional malaria survey was conducted during the rainy season in Bangangté (West-Cameroon), a town of 90,000 inhabitants located in the high tablelands zone of Cameroon. An in vivo study revealed that 50% of P. falciparum malaria patients were resistant to chloroquine (25 mg/kg over 3 days) and 26.3% to amodiaquine (35 mg/kg over 3 days) at a RII/RIII level. In addition, plasmodial indices indicated that malaria was mesoendemic in this area of Cameroon.

[In vivo resistance of Plasmodium falciparum to chloroquine in Anjouan (Comoros)]. / Résistance in vivo à la chloroquine de Plasmodium falciparum à Anjouan (Comores).

An in vivo study of P. falciparum sensitivity to chloroquine was conducted at Anjouan island (République fédérale islamique des Comores) from December 1990 to March 1991. The 27 patients included in the study were given chloroquine at a dose regimen of 25 mg/kg over 3 days and were followed up 7 days. Six patients (22.2%) still harboured parasites up to day 7, thus showing a RII/RIII level of resistance. This is likely related to an increased chloroquine consumption by the inhabitants of this island since 1987.

A study of onchocerciasis with severe skin and eye lesions in a hyperendemic zone in the forest of southwestern Cameroon: clinical, parasitologic, and entomologic findings.

Prior to the initiation of an onchocerciasis control program based on the mass administration of ivermectin in the rain forest of southwestern Cameroon, a preliminary baseline study of the area was conducted. The results of this study showed that onchocerciasis was hyperendemic in the area. Skin symptoms and signs were observed including pruritus (67.4% of the population examined), onchocerca nodules (51.6%), skin depigmentation (18.5%), and hanging groins (5.7%). Except for pruritus, the prevalence of these symptoms increased with age. Of the eyes examined, 44.9% had microfilariae in the anterior chamber, 33.5% had choroidoretinitis, 28.0% had punctate keratitis, 8.3% had papillary abnormalities, and 3.6% had sclerosing keratitis. Vision in 10.5% of the eyes examined was classified as blind or very poor (visual acuity = 0-0.10), in 15.7% as poor (visual acuity = 0.11-0.39), and in 73.8% as good (visual acuity = 0.4-1.00). Unlike previous reports that have linked serious ocular damage mainly to savanna onchocerciasis, the present study showed that forest onchocerciasis also caused significant ocular pathology, including blindness. Parasitologically, positive skin snips were recorded for 92.7% of the persons examined, with both sexes being equally infected. The parasite load, expressed as the geometric mean number of microfilariae per skin snip, was 53.6, and was much higher in males than in females. The flv vector, Simulium squamosum, had a high infection rate of 7.5% infective females in Bakumba and 6.8% infective females in Ngbandi, the two fly-catching points. The transmission potential was 266 infective larvae per person per month in Bakumba and 189 in Ngbandi.