Malaria Therapy Research Articles

Reduced Exposure to Piperaquine, Compared to Adults, in Young Children Receiving Dihydroartemisinin-Piperaquine as Malaria Chemoprevention.

Dihydroartemisinin (DHA)-piperaquine is being evaluated as intermittent preventive therapy for malaria, but dosing has not been optimized for children. We assessed exposure to DHA and piperaquine in Ugandan children at two ages during infancy. Intensive sampling was performed in 32 children at 32weeks of age, 31 children at 104weeks, and 30 female adult controls. Compared with adults, DHA area under the concentration-time curve (AUC0-8 hr ) was 52% higher at 32weeks and comparable at 104weeks. Compared with adults, piperaquine AUC0-21 d was 35% lower at 32weeks and 53% lower at 104weeks. Terminal piperaquine concentrations on days 7, 14, and 21 were lower in children compared with adults and lower at 104 compared with 32weeks. Piperaquine exposure was lower in young children compared with adults, and lower at 104 compared with 32weeks of age, suggesting a need for age-based DHA-piperaquine dose optimization for chemoprevention.

Ethnobotanical survey of the plants used for the management of malaria in Ondo State, Nigeria

An ethnobotanical survey of the plants used for the traditional management of malaria by the residents of Ondo State, Nigeria was carried out. Data was collected by interviews using a semi-structured questionnaire. A total of 162 indigenous people were interviewed [male, 110 (68%); female, 52(32%)]. A total of 97 plant species belonging to 52 different families were identified. Detailed information about their vernacular names, modes of preparation and previous investigations of their antiplasmodial/antimalarial effects was also compiled. Of the plants identified, the family Euphorbiaceae is predominant while Mangifera indica, Anacardium occidentale and Cymbopogon citratus are the most cited species. Only a few (37%) of the plants identified have been subjected to scientific investigations, most of which are only preliminary. Of the tested plants, some have shown in vivo activities comparable with that of orthodox antimalarial drugs. There is, therefore, a need to scientifically investigate the antimalarial potential of these plants as they serve as potential source of lead compounds for malaria therapy.

Ferroquine-derived polyamines that target resistant Plasmodium falciparum

Rising resistance to conventional therapies for malaria has led to the search for novel drugs and strategies with distinct mechanisms of action that may overcome this. Ferroquine is currently the gold standard as far as antimalarial metal-based drugs are concerned and is currently in phase IIb clinical trials as part of the MMV pipeline (in partnership with Sanofi) of antimalarials. It is assumed to inhibit haemozoin formation like chloroquine and maintain its activity in the resistant strain. Here we report two ferroquine-derived polyamines that target a resistant strain of Plasmodium falciparum. Furthermore, upon treatment of Plasmodium falciparum with a ferroquine-derived polyamine, cellular haem fractionation experiments reveal that the inhibition of haemozoin formation is likely not the mechanism responsible for their activity, an important result to aid further clinical development.

A randomized controlled trial of azithromycin and sulphadoxine–pyrimethamine as prophylaxis against malaria in pregnancy among human immunodeficiency virus–positive women

Malaria and human immunodeficiency virus (HIV) infections in pregnancy are important and major contributing factors to maternal morbidity and mortality in sub-Saharan Africa. Prevention of malaria in HIV-positive pregnant woman will reduce the burden of malaria-HIV comorbidity. The objective of this study was to compare effects and safety of azithromycin (AZ) with sulphadoxine-pyrimethamine (SP) for intermittent preventive therapy for malaria in HIV-positive pregnant women. We performed a randomized, controlled, open-label pregnancy trial of 140 HIV-positive pregnant patients attending antenatal clinics at the University College Hospital and Adeoyo Maternity Teaching Hospital, Ibadan, Nigeria. Participants were enrolled from a gestational age of 16 weeks and randomized to receive AZ or SP. The primary outcome was peripheral parasitaemia at delivery. Secondary outcomes were drug tolerability, foetal outcome and birthweight. The χ2 test (or Fisher's exact test, as appropriate) and Student's t test were used in the per-protocol analysis. The level of statistical significance was p<0.05. A total of 123 participants (87.9%) completed the study: 60 participants received AZ and 63 received SP. The incidence of malaria parasitaemia at delivery in the AZ group was 6 (10.0%), compared with 7 (11.1%) in the SP group (relative risk 0.89 [95% confidence interval 0.28 to 2.82], p=0.84). Placental parasitization was demonstrated in 1 (1.6%) participant in the SP group compared with 3 (5.0%) in the AZ group (p=0.36). The findings suggest that AZ is comparable to SP in malaria prevention and safety in HIV-positive pregnant women.

Development and Evaluation of a Novel HNB Based Isothermal Amplification Assay for Fast Detection of Pyrimethamine Resistance (S108N) in Plasmodium falciparum.

Sulphadoxine and pyrimethamine (SP) have been used as long-acting partner antimalarial drugs in artemisinin combination therapy (ACT) for falciparum malaria. The emergence and increasing spread of SP resistance in malaria-endemic areas have become a challenge for the control of malaria. Therefore, regular monitoring of the mutation status of partner drugs is important for the better management of drug policy. There are limitations with traditional molecular methods and there is an urgent need for an easy method for diagnosis of drug resistance. In this study we have introduced and developed a novel single nucleotide polymorphism loop-mediated isothermal amplification (SNP–LAMP) approach based on a hydroxynaphthol blue (HNB) indicator for the easier and quicker detection of pyrimethamine resistance in Plasmodium falciparum malaria. To implement this novel approach, many sets of LAMP primers were designed and tested. Finally, one set of forward inner primer M1 (FIPM1) of LAMP primer was selected that specifically distinguishes pyrimethamine-resistant P. falciparum malaria. The LAMP reactions were optimized at 60–66 °C for 45 min. High sensitivity (7 parasites/µL) was observed with 10−4 fold dilutions (<2 ng DNA) of genomic DNA. Moreover, this approach has the potential to be applied even in laboratories unfamiliar with PCR or other molecular methods, and in future, this can be helpful for the better management of anti-malarial policy.

MANNOSYLATED MULTIWALLED CARBON NANOTUBES ASSISTED ARTESUNATE DELIVERY FOR CEREBRAL MALARIA

Objective: The present investigation focused on the novel approach using artesunate (AS) loaded mannosylated conjugated multi-walled carbon nanotubes (M-MWCNTs) for site-specific delivery to the brain in the treatment of cerebral malaria (CM).&#x0D; Methods: The raw MWCNTs were purified by selective oxidation method and then exposed to sequential chemical functionalization according to the following steps: carboxylation, acylation, amine modification and finally, D-mannose conjugation. The AS was loaded via the equilibrium dialysis method in the molar ratio 1:3 of various functionalized sonicated MWCNTs. The functionalized MWCNTs were characterized for elemental analysis, FTIR, TEM, zeta potential and percentage drug entrapment efficiency. The in vitro drug release study was performed on AS conjugated purified MWCNTs (AS-P-MWCNT) and AS conjugated M-MWCNTs. Bio-distribution study was performed on albino rat for quantitative measurement of AS in different organs and blood.&#x0D; Results: The TEM images of M-MWCNTs indicated their open tubular nature and AS-M-MWCNTs suggests the entrapment of AS. The percent drug entrapment of AS-M-MWCNT was found to be 80.29±3.4 %. In vitro AS release from AS-M-MWCNTs was found in a controlled manner at pH 7.4. The bio-distribution studies clearly indicate the superiority of the AS-M-MWCNTs, as compared to the plain drug towards increasing the accumulation of AS in brain.&#x0D; Conclusion: The results suggest that AS-M-MWCNTs could be employed as an efficient nano-carrier for antimalarial therapy in cerebral malaria.

Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil.

Emerging Plasmodium vivax resistance to chloroquine (CQ) may undermine malaria elimination efforts in South America. CQ-resistant P. vivax has been found in the major port city of Manaus but not in the main malaria hot spots across the Amazon Basin of Brazil, where CQ is routinely coadministered with primaquine (PQ) for radical cure of vivax malaria. Here we randomly assigned 204 uncomplicated vivax malaria patients from Juruá Valley, northwestern Brazil, to receive either sequential (arm 1) or concomitant (arm 2) CQ-PQ treatment. Because PQ may synergize the blood schizontocidal effect of CQ and mask low-level CQ resistance, we monitored CQ-only efficacy in arm 1 subjects, who had PQ administered only at the end of the 28-day follow-up. We found adequate clinical and parasitological responses in all subjects assigned to arm 2. However, 2.2% of arm 1 patients had microscopy-detected parasite recrudescences at day 28. When PCR-detected parasitemias at day 28 were considered, response rates decreased to 92.1% and 98.8% in arms 1 and 2, respectively. Therapeutic CQ levels were documented in 6 of 8 recurrences, consistent with true CQ resistance in vivo In contrast, ex vivo assays provided no evidence of CQ resistance in 49 local P. vivax isolates analyzed. CQ-PQ coadministration was not found to potentiate the antirelapse efficacy of PQ over 180 days of surveillance; however, we suggest that larger studies are needed to examine whether and how CQ-PQ interactions, e.g., CQ-mediated inhibition of PQ metabolism, modulate radical cure efficacy in different P. vivax-infected populations. (This study has been registered at ClinicalTrials.gov under identifier NCT02691910.).

Effect of Plasmodium falciparum sulfadoxine-pyrimethamine resistance on the effectiveness of intermittent preventive therapy for malaria in pregnancy in Africa: a systematic review and meta-analysis

Resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine threatens the antimalarial effectiveness of intermittent preventive treatment during pregnancy (IPTp) in sub-Saharan Africa. We aimed to assess the associations between markers of sulfadoxine-pyrimethamine resistance in P falciparum and the effectiveness of sulfadoxine-pyrimethamine IPTp for malaria-associated outcomes. For this systematic review and meta-analysis, we searched databases (from Jan 1, 1990 to March 1, 2018) for clinical studies (aggregated data) or surveys (individual participant data) that reported data on low birthweight (primary outcome) and malaria by sulfadoxine-pyrimethamine IPTp dose, and for studies that reported on molecular markers of sulfadoxine-pyrimethamine resistance. Studies that involved only HIV-infected women or combined interventions were excluded. We did a random-effects meta-analysis (clinical studies) or multivariate log-binomial regression (surveys) to obtain summarised dose-response data (relative risk reduction [RRR]) and multivariate meta-regression to explore the modifying effects of sulfadoxine-pyrimethamine resistance (as indicated by Ala437Gly, Lys540Glu, and Ala581Gly substitutions in the dhps gene). This study is registered with PROSPERO, number 42016035540. Of 1097 records screened, 57 studies were included in the aggregated-data meta-analysis (including 59 457 births). The RRR for low birthweight declined with increasing prevalence of dhps Lys540Glu (ptrend=0·0060) but not Ala437Gly (ptrend=0·35). The RRR was 7% (95% CI 0 to 13) in areas of high resistance to sulfadoxine-pyrimethamine (Lys540Glu ≥90% in east and southern Africa; n=11), 21% (14 to 29) in moderate-resistance areas (Ala437Gly ≥90% [central and west Africa], or Lys540Glu ≥30% to <90% [east and southern Africa]; n=16), and 27% (21 to 33) in low-resistance areas (Ala437Gly <90% [central and west Africa], or Lys540Glu <30% [east and southern Africa]; n=30; ptrend=0·0054 [univariate], I2=69·5%). The overall RRR in all resistance strata was 21% (17 to 25). In the analysis of individual participant data from 13 surveys (42 394 births), sulfadoxine-pyrimethamine IPTp was associated with reduced prevalence of low birthweight in areas with a Lys540Glu prevalence of more than 90% and Ala581Gly prevalence of less than 10% (RRR 10% [7 to 12]), but not in those with an Ala581Gly prevalence of 10% or higher (pooled Ala581Gly prevalence 37% [range 29 to 46]; RRR 0·5% [-16 to 14]; 2326 births). The effectiveness of sulfadoxine-pyrimethamine IPTp is reduced in areas with high resistance to sulfadoxine-pyrimethamine among P falciparum parasites, but remains associated with reductions in low birthweight even in areas where dhps Lys540Glu prevalence exceeds 90% but where the sextuple-mutant parasite (harbouring the additional dhps Ala581Gly mutation) is uncommon. Therapeutic alternatives to sulfadoxine-pyrimethamine IPTp are needed in areas where the prevalence of the sextuple-mutant parasite exceeds 37%. US Centers for Disease Control and Prevention, the Malaria in Pregnancy Consortium (funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine), Worldwide Antimalarial Resistance Network, European and Developing Countries Clinical Trials Partnership.

Spray drying OZ439 nanoparticles to form stable, water-dispersible powders for oral malaria therapy

BackgroundOZ439 is a new chemical entity which is active against drug-resistant malaria and shows potential as a single-dose cure. However, development of an oral formulation with desired exposure has proved problematic, as OZ439 is poorly soluble (BCS Class II drug). In order to be feasible for low and middle income countries (LMICs), any process to create or formulate such a therapeutic must be inexpensive at scale, and the resulting formulation must survive without refrigeration even in hot, humid climates. We here demonstrate the scalability and stability of a nanoparticle (NP) formulation of OZ439. Previously, we applied a combination of hydrophobic ion pairing and Flash NanoPrecipitation (FNP) to formulate OZ439 NPs 150 nm in diameter using the inexpensive stabilizer hydroxypropyl methylcellulose acetate succinate (HPMCAS). Lyophilization was used to process the NPs into a dry form, and the powder’s in vitro solubilization was over tenfold higher than unprocessed OZ439.MethodsIn this study, we optimize our previous formulation using a large-scale multi-inlet vortex mixer (MIVM). Spray drying is a more scalable and less expensive operation than lyophilization and is, therefore, optimized to produce dry powders. The spray dried powders are then subjected to a series of accelerated aging stability trials at high temperature and humidity conditions.ResultsThe spray dried OZ439 powder’s dissolution kinetics are superior to those of lyophilized NPs. The powder’s OZ439 solubilization profile remains constant after 1 month in uncapped vials in an oven at 50 °C and 75% RH, and for 6 months in capped vials at 40 °C and 75% RH. In fasted-state intestinal fluid, spray dried NPs achieved 80–85% OZ439 dissolution, to a concentration of 430 µg/mL, within 3 h. In fed-state intestinal fluid, 95–100% OZ439 dissolution is achieved within 1 h, to a concentration of 535 µg/mL. X-ray powder diffraction and differential scanning calorimetry profiles similarly remain constant over these periods.ConclusionsThe combined nanofabrication and drying process described herein, which utilizes two continuous unit operations that can be operated at scale, is an important step toward an industrially-relevant method of formulating the antimalarial OZ439 into a single-dose oral form with good stability against humidity and temperature.

Artesunate-heparin conjugate based nanocapsules with improved pharmacokinetics to combat malaria

Artesunate-heparin conjugate (ART-HEP) based nanocapsules as drug delivery vehicle was developed for intracellular release of ART in malaria therapy. Owing both hydrophobic and hydrophilic moieties, the conjugate was successfully self-assembled into artesunate-heparin nanocapsules (ART-HEP-NCPs) with lower critical micelle concentration (CMC) of about 20 µg/mL. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed that ART-HEP-NCPs has an average hydrodynamic diameter of 112.1 nm with a negatively charged surface (−11.2 mV) and typical micellar nanostructure, respectively. Interestingly, such modification achieved high drug loading efficiency (DLE) of ART (29.3 wt%), which is significantly higher than already reported conventional ART-loaded nanoparticles. The nanocapsules demonstrated lower in vitro ART release under neutral physiological environment (33.81%) but higher release rate was observed in simulated acidic microenvironment (92.74%) in 70 h test. This behavior of ART-HEP-NCPs will facilitate the intracellular release of ART under slightly acidic parasitic food vacuole for effective antimalarial effect. Storage stability and hemolytic studies exhibited that ART-HEP based nanocapsules were stable and safe for intravenous (i.v) injection. Notably, ART-HEP-NCPs has promising internalization into Plasmodium infected red blood cells (iRBCs) and also displayed in vitro inhibitory effect against P. falciparum 3D7 with half-maximal inhibitory concentration (IC50) of 10.16 nM, which was slightly higher than free ART (IC50 6.27 nM). This expected slightly lower inhibitory effect of polymeric prodrug could be ascribed to the gradual release of ART from the polymer chain over time. More importantly, the in vivo pharmacokinetics study indicated that the nanoscale characteristic of nanocapsules substantially contributed to the extended circulation of ART in blood. In conclusion, such multifunctional ART-HEP-NCPs with higher ART loading and extended half-life could be a promising platform for targeted antimalarial drug delivery.

Impact of Ferroquine on the Solubilization of Artefenomel (OZ439) during in Vitro Lipolysis in Milk and Implications for Oral Combination Therapy for Malaria.

Milk is an attractive lipid-based formulation for the delivery of poorly water-soluble drugs to pediatric populations. We recently observed that solubilization of artefenomel (OZ439) during in vitro intestinal lipolysis was driven by digestion of triglycerides in full-cream bovine milk, reflecting the ability of milk to act as an enabling formulation in the clinic. However, when OZ439 was co-administered with a second antimalarial drug, ferroquine (FQ) the exposure of OZ439 was reduced. The current study therefore aimed to understand the impact of the presence of FQ on the solubilization of OZ439 in milk during in vitro intestinal digestion. Synchrotron small-angle X-ray scattering was used for in situ monitoring of drug solubilization (inferred via decreases in the intensity of drug diffraction peaks) and polymorphic transformations that occurred during the course of digestion. Quantification of the amount of each drug solubilized over time and analysis of their distributions across the separated phases of digested milk were determined using high-performance liquid chromatography. The results show that FQ reduced the solubilization of OZ439 during milk digestion, which may be due to competitive binding of FQ to the digested milk products. Interactions between the protonated FQ-H+ and ionized liberated free fatty acids resulted in the formation of amorphous salts, which removes the low-energy crystalline state as a barrier to dissolution of FQ, while inhibiting the solubilization of OZ439. We conclude that although milk could enhance the solubilization of poorly water-soluble OZ439 during in vitro digestion principally due to the formation of fatty acids, the solubilization efficiency was reduced by the presence of FQ by competition for the available fatty acids. Assessment of the solubilization of both drugs during digestion of fixed-dose combination lipid formulations (such as milk) is important and may rationalize changes in bioavailability when compared to that of the individual drugs in the same formulation.

Identification of antiplasmodial triterpenes from Keetia species using NMR-based metabolic profiling

IntroductionThe increase in multidrug resistance and lack of efficacy in malaria therapy has propelled the urgent discovery of new antiplasmodial drugs, reviving the screening of secondary metabolites from traditional medicine. In plant metabolomics, NMR-based strategies are considered a golden method providing both a holistic view of the chemical profiles and a correlation between the metabolome and bioactivity, becoming a corner stone of drug development from natural products.ObjectiveCreate a multivariate model to identify antiplasmodial metabolites from 1H NMR data of two African medicinal plants, Keetia leucantha and K. venosa.MethodsThe extracts of twigs and leaves of Keetia species were measured by 1H NMR and the spectra were submitted to orthogonal partial least squares (OPLS) for antiplasmodial correlation.ResultsUnsupervised 1H NMR analysis showed that the effect of tissues was higher than species and that triterpenoids signals were more associated to Keetia twigs than leaves. OPLS–DA based on Keetia species correlated triterpene signals to K. leucantha, exhibiting a higher concentration of triterpenoids and phenylpropanoid-conjugated triterpenes than K. venosa. In vitro antiplasmodial correlation by OPLS, validated for all Keetia samples, revealed that phenylpropanoid-conjugated triterpenes were highly correlated to the bioactivity, while the acyclic squalene was found as the major metabolite in low bioactivity samples.ConclusionNMR-based metabolomics combined with supervised multivariate data analysis is a powerful strategy for the identification of bioactive metabolites in plant extracts. Moreover, combination of statistical total correlation spectroscopy with 2D NMR allowed a detailed analysis of different triterpenes, overcoming the challenge posed by their structure similarity and coalescence in the aliphatic region.

Extracellular methemoglobin promotes cyto-adherence of uninfected RBC to endothelial cells: Insight into cerebral malaria pathology.

The endothelial cell barrier is tightly regulated, and disruption or the leaky behavior of the barrier leads to pathology. Disturbance of blood-brain barrier is observed during viral infection, cerebral malaria, and acute hemorrhagic encephalitis. Red blood cells (RBCs) bind to the endothelial cells (ECs) and their affinity towards ECs enhances in the presence of Plasmodium falciparum infection. ECs stimulated with methemoglobin (MetHb; 20 µM) for 1 hour exhibit high levels of cyto-adherence receptors CD36 and ICAM-1 on their cell surface compared with unstimulated cells. These ECs have acquired affinity towards uninfected RBCs in flow at arterial shear stress. SEM analysis indicates that EC-RBC cyto-adherence involved multiple attachment points. Initially, ECs bind single layer of RBCs and the number of RBCs increases over time to give high-order cyto-adherence with more than 30 RBCs adhered to each endothelial cell. The cyto-adherence complexes are stable to high shear stress and can withstand shear stress up to 450 dyne/cm 2 . MetHb-treated ECs exhibited high reactive oxygen species level, and preincubation of ECs with antioxidant (NAC or mannitol) abolished the formation of EC-RBC cyto-adherence complexes. In addition, gallic acid (present in red wine) and green tea extract has inhibited the formation of EC-RBC cyto-adherence complex. A better understanding of gallic acid and tea polyphenol targeting pathological cyto-adherence may allow us to develop a better adjuvant therapy for cerebral malaria and other noninfectious diseases.

Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria

BackgroundTafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed “radical cure.”MethodsWe performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin.ResultsA protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, −4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96).ConclusionsAmong patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123.)

Donatien Raffegeau (1855–1931), fondateur de la clinique « La Villa des Pages » au Vésinet ; ses collaborateurs et successeurs : B.-A. Casalis, H. Leulier, P.-M. Leulier, R. Leulier et H. Mignon

Donatien Raffegeau (1855–1931) was born in Vendée. He studied medicine in Nantes and Angers. He was successively the intern of Aurèle Petrucci (1880–1906), medical director at Saint-Gemmes-sur-Loire asylum, Ambroise-Eusebe Mordret (1822–1904), head doctor at the mental asylum of Le Mans and Jules Christian (1847–1907) during 15 months at the National House of Charenton. In 1884, he qualified as a medical doctor. Raffegeau worked for a short period of time in a private asylum located at 130 rue Glacière in Paris and then he found a house of health in 1890. Its name was “Hydrotherapeutic Institute of Vésinet” and called later “La Villa des Pages”. It was a winter and summer sanatorium for cases of convalescents and all nervous disorders. The insane were not admitted. Raffegeau promoted a treatment approach by the hydrotherapy, the thermotherapy and the massotherapy. He used the electrotherapy, the light therapy and the suggestion according to Liebeault’ method. The gymnastic or the fencing were used as therapeutic adjuvants. Raffegeau prescribed for specific patients a therapeutic stay at the “Villa des Charmilles” (Castle of Port-Cé) near Saint-Nazaire (Loire Atlantique). In 1908, he acquired this peacefull place located on the waterfront. Member of various societies: medico-psychological society, anthropology society, hypnotism society, astronomy society and vice-president of the psychotherapy society, he was elected Mayor of his native city from 1908 to 1931 and Vésinet municipal counsellor. In the flow of mental hygienist school, he insisted on the important role of the school doctor on the mental and physic health. After the Great War, Raffegeau was the first to prescribe the Gardénal epilepsy treatment (Luminal of the Germans), which became a classic treatment. The quality of social and professional life of the patients has been improved. This treatment was developed at the Villa des Pages clinic (Le Vésinet). Over the years, the Villa des Pages has opened its doors to the psychiatric patients. The physiotherapy had to give way partially to the new therapeutic approaches developed in public hospitals: malaria therapy, insulin shock therapy, electroshock, caradiazol therapy. No psychiatric doctor could not ignore them in their practice. They have been introduced by the doctors Henri Mignon (1870–1854), Pierre-Maximin Leulier (1884–1952), Bernard-Alfred Casalis (1902–1975) as proved their articles published in “Annales Médico-Psychologiques”. From 1947 to 1981, their successors Roger Leulier (1913–1998) and Hélène Leulier (1913–) trained by pioneers of modern psychiatry (J. Delay, P. Guiraud, G. Heuyer, J. Rondepierre) have assumed the medical direction. The latter was a member of the Psychiatric Evolution (1946) and an adherent member of the Psychoanalytic Society of Paris (1953). She introduced the psychoanalysis in the Villa des Pages. After having been directed by two psychiatrists (A. Campagne and A. Sonnier), this old “Hydrotherapy Institute of Vésinet” is an establishment whose destiny is in the hands of the ORPEA group since 2002. We acknowledge that the renewal of the clinic's doctors since being set up in 1890 who took account of therapeutic advances in the field of psychiatric by integrating them into their practice had allowed that this Health Home survived throughout the centuries and to maintain in the world of French psychiatric.

Effect of artemisinin-piperaquine treatment on the electrocardiogram of malaria patients.

Concern regarding the cardiotoxicity of antimalarials has been renewed because of their potential to cause QT/QTc interval prolongation related to torsade de pointes (TdP). Artemisinin-piperaquine (AP) is considered an effective artemisinin-based combination therapy (ACT) for malaria. This study involved a retrospective analysis of clinical data of 93 hospitalized malaria patients who had received AP orally. Electrocardiograms (ECGs) were obtained at specific time points in the original study. Some cases of QT prolongation were observed. However, no TdP was found. AP may cause QT interval prolongation in some malaria patients but may not lead to TdP.

Antimalarial activities of butanol and ethylacetate fractions of Combretum nigricans leaf

Objective: To evaluate the antimalarial activity of the ethylacetate and butanol fractions of Combretum nigricans (C. nigricans) leaf extract in mice. Methods: C. nigricans solvent (butanol and ethylacetate) fractions were screened for their phytochemical constituents using standard procedures illustrated by Harborne and Evans. The Peters’ 4-day suppressive test against early malaria infection, Rane’s curative test against established malaria and prophylactic test for residual activity were employed for evaluating the antimalarial potential in mice. Results: The phytochemical screening revealed the presence of alkaloids, terpenoids, saponins, and flavonoids in both fractions at different intensity. Both fractions exhibited significant antimalarial activity in all test models (P Conclusions: Both solvent fractions of C. nigricans possess antimalarial activity, and may be useful at different stages of malaria therapy.

Inhibition of Cytomegalovirus Replication with Extended-Half-Life Synthetic Ozonides.

Artesunate (AS), a semisynthetic artemisinin approved for malaria therapy, inhibits human cytomegalovirus (HCMV) replication in vitro, but therapeutic success in humans has been variable. We hypothesized that the short in vivo half-life of AS may contribute to the different treatment outcomes. We tested novel synthetic ozonides with longer half-lives against HCMV in vitro and mouse cytomegalovirus (MCMV) in vivo Screening of the activities of four ozonides against a pp28-luciferase-expressing HCMV Towne recombinant identified OZ418 to have the best selectivity; its effective concentration inhibiting viral growth by 50% (EC50) was 9.8 ± 0.2 µM, and cytotoxicity in noninfected human fibroblasts (the concentration inhibiting cell growth by 50% [CC50]) was 128.1 ± 8.0 µM. In plaque reduction assays, OZ418 inhibited HCMV TB40 in a concentration-dependent manner as well as a ganciclovir (GCV)-resistant HCMV isolate. The combination of OZ418 and GCV was synergistic in HCMV inhibition in vitro Virus inhibition by OZ418 occurred at an early stage and was dependent on the cell density at the time of infection. OZ418 treatment reversed HCMV-mediated cell cycle progression and correlated with the reduction of HCMV-induced expression of pRb, E2F1, and cyclin-dependent kinases 1, 2, 4, and 6. In an MCMV model, once-daily oral administration of OZ418 had significantly improved efficacy against MCMV compared to that of twice-daily oral AS. A parallel pharmacokinetic study with a single oral dose of OZ418 or AS showed a prolonged plasma half-life and higher unbound concentrations of OZ418 than unbound concentrations of AS. In summary, ozonides are proposed to be potential therapeutics, alone or in combination with GCV, for HCMV infection in humans.

Artemether and Praziquantel: Origin, Mode of Action, Impact, and Suggested Application for Effective Control of Human Schistosomiasis.

The stumbling block for the continued, single-drug use of praziquantel (PZQ) against schistosomiasis is less justified by the risk of drug resistance than by the fact that this drug is inactive against juvenile parasites, which will mature and start egg production after chemotherapy. Artemisinin derivatives, currently used against malaria in the form of artemisinin-based combination therapy (ACT), provide an opportunity as these drugs are not only active against malaria plasmodia, but surprisingly also against juvenile schistosomes. An artemisinin/PZQ combination would be complementary, and potentially additive, as it would kill two schistosome life cycle stages and thus confer a transmission-blocking modality to current chemotherapy. We focus here on single versus combined regimens in endemic settings. Although the risk of artemisinin resistance, already emerging with respect to malaria therapy in Southeast Asia, prevents use in countries where ACT is needed for malaria care, an artemisinin-enforced praziquantel treatment (APT) should be acceptable in regions of North Africa (including Egypt), the Middle East, China, and Brazil that are not endemic for malaria. Thanks to recent progress with respect to high-resolution diagnostics, based on circulating schistosome antigens in humans and molecular approaches for snail surveys, it should be possible to keep areas scheduled for schistosomiasis elimination under surveillance, bringing rapid response to bear on problems arising. The next steps would be to investigate where and for how long APT should be applied to make a lasting impact. A large-scale field trial in an area with modest transmission should tell how apt this approach is.

Monocyte phagocytosis of malaria β-haematin in the presence of artemisinin, amodiaquine, chloroquine, doxycycline, primaquine, pyrimethamine and quinine

The intraerythrocytic malaria parasite digests haemoglobin to provide amino acids for metabolism and releases toxic haem that is sequestered into haemozoin, a non-toxic, insoluble, crystalline pigment. Following erythrocyte rupture, haemozoin is released into circulation and phagocytosed by monocytes. Phagocytosed haemozoin and antimalarial drugs have both been reported to modulate monocyte functions. This study determined the effects of therapeutic concentrations of seven antimalarial drugs; amodiaquine, artemisinin, chloroquine, doxycycline, primaquine, pyrimethamine and quinine, on the phagocytosis of β-haematin (synthetic haemozoin) by two monocytic cell lines, J774A.1 and U937, and human peripheral blood mononuclear cells. A novel spectrophotometric method based on the absorbance (O.D 400 nm) of alkali/SDS treated monocytes containing β-haematin was developed to complement counting phagocytosis with microscopy. The method has potential use for the large scale screening of monocyte phagocytic activity. Artemisinin, quinine, primaquine and pyrimethamine activated β-haematin phagocytosis by 12% or more, whereas amodiaquine, chloroquine and doxycyline inhibited β-haematin phagocytosis. In contrast, antimalarial drugs had minimal inhibitory effects on the phagocytosis of latex beads with only quinine resulting in more than 20% inhibition. Antimalarial drugs appear to alter monocyte phagocytic activity which has implications for the treatment, pathogenicity and adjunct therapies for malaria.