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Atovaquone and Mefloquine hydrochloride are well known anti-malarial drugs. Literature survey reveals that there was no method available for the selected drug combination. In this way, here an endeavour has been made to develop simple, precise, fast method for simultaneous estimation of atovaquone and mefloquine hydrochloride in bulk drug by using RP-HPLC method. The method was carried out by using gradient HPLC on C18 column using Shimadzu prominence LC 20 AD and mobile phase comprised of Methanol:ACN:Water in the ratio of 85:7.5:7.5 (pH 2.9 was adjusted with OPA). The method was performed with 10µl injection volume. The UV detection was done at 231nm.The retention times of atovaquone and mefloquine hydrochloride were 7.6 and 2.6 min respectively. The proposed method was validated according to ICH guidelines. The validation parameters were linearity, accuracy, precision (inter-day, intra-day and repeatability) and robustness etc. Linearity was in the range of 80-120µg/ml for atovaquone and 40-60µg/ml for mefloquine hydrochloride. The percent recoveries of both drugs were 99.99-100% and 92.05-99.09%. This method is suitable for the routine analysis of atovaquone and mefloquine hydrochloride in bulk drugs either individually or in mixture

Background: Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those without such facilities or 2019-novel coronavirus (2019-nCoV). This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV related coronavirus model. Methods: A 2019-nCoV related pangolin coronavirus GX_P2V/pangolin/2017/ Guangxi was described. Whether GX_P2X uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA) -mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2X infection. The antiviral activities and antiviral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively. Results: The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs-cepharanthine (CEP), selamectin and mefloquine hydrochloride exhibited complete inhibition of cytopathic effects in cell culture at 10 μmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect [EC50] of 0.98 μmol/L. The viral RNA yield in cells treated with 10 μmol/L CEP was 15,393-fold lower than in cells without CEP treatment ([6.48±0.02]×10-4vs. 1.00±0.12, t=150.38, P

The asymmetric (er > 99:1) total synthesis of (+)-anti- and (−)-syn-mefloquine hydrochloride from a common intermediate is described. The Sharpless asymmetric dihydroxylation is the key asymmetric transformation used in the synthesis of this intermediate. It is carried out on an olefin that is accessed in three steps from commercially available materials, making the overall synthetic sequence very concise. The common diol intermediate derived from the Sharpless asymmetric dihydroxylation is converted into either a trans- or cis-epoxide, and these are subsequently converted to (+)-anti- and (−)-syn-mefloquine, respectively. X-ray crystallographic analysis of derivatives of (+)-anti- and (−)-syn-mefloquine is used to lay to rest a 40 year argument regarding the absolute stereochemistry of the mefloquines. A formal asymmetric (er > 99:1) synthesis of (+)-anti-mefloquine hydrochloride is also presented that uses a Sharpless asymmetric epoxidation as a key step.

Given that cancer stem cells (CSC) play a key role in drug resistance and relapse, targeting CSCs remains promising in cancer therapy. Here we show that RAB5/7, which are involved in the endolysosomal pathway, play key roles in the maintenance of CSC survival via regulation of the mitophagic pathway. Inhibition of RAB5/7 efficiently eliminated colorectal CSCs and disrupted cancer foci. In addition, we identified mefloquine hydrochloride, an antimalarial drug, as a novel RAB5/7 inhibitor and promising colorectal CSC-targeting drug. Endolysosomal RAB5/7 and LAMP1/2 mediated parkin-dependent mitochondrial clearance and modulated mitophagy through lysosomal dynamics. In a patient-derived xenograft (PDX) model of colon cancer, treatment with mefloquine resulted in suppression of mitophagic PINK1/PARKIN and increased mitochondrial disorder and mitochondria-induced apoptosis without apparent side effects. These results suggest that the combination of mefloquine with chemotherapeutic agents in the PDX model potentially disrupts the hierarchy of colorectal cancer cells and identify endolysosomal RAB5/7 and LAMP1/2 as promising therapeutic targets in CSCs. Significance: These findings show that endosomal/lysosomal RAB5 and RAB7, which regulate mitophagy, are essential for the survival of colon cancer stem cells.

Albeit widely studied, the structure of the antimalarial drug (±)-mefloquine hydrochloride is still a controversial issue. A combination of X-ray powder diffraction, theoretical calculations and Fourier transform–infrared spectroscopy is used to unambiguously determine the crystal structure of the molecule in its active pharmaceutical ingredient. It is demonstrated that water is incorporated into the structure, leading to a hydrated form and, most importantly, to significant differences in both structure and bonding. Such changes can lead to significant differences in biological activity.

The present study deals with the formulation and evaluation of mefloquine hydrochloride nanoparticles. Mefloquine is a blood schizonticidal quinoline compound, which is indicated for the treatment of mild-to-moderate acute malarial infections caused by mefloquine-susceptible multi-resistant strains of P. falciparum and P. vivax. The purpose of the present work is to minimize the dosing frequency, taste masking toxicity and to improve the therapeutic efficacy by formulating mefloquine HCl nanoparticles. Mefloquine nanoparticles were formulated by emulsion diffusion method using polymer poly(ε-caprolactone) with six different formulations. Nanoparticles were characterized by determining its particle size, polydispersity index, drug entrapment efficiency, drug content, particle morphological character and drug release. The particle size ranged between 100 nm to 240 nm. Drug entrapment efficacy was >95%. The in-vitro release of nanoparticles were carried out which exhibited a sustained release of mefloquine HCl from nanoparticles up to 24 hrs. The results showed that nanoparticles can be a promising drug delivery system for sustained release of mefloquine HCl.

The present study developed and validated an HPLC method for the simultaneous determination of artesunate (AS) and mefloquine hydrochloride (MQ) in fixed-dose combination tablets, according to ICH guidelines. The chromatographic separation was carried out on an XBridge C18 (250 x 4.6 mm i.d., 5 µm particle size, Waters) analytical column. The mobile phase included a 0.05 M monobasic potassium phosphate buffer (pH adjusted to 3.0 with phosphoric acid) and acetonitrile (50 + 50, v/v). The flow rate was 1.0 mL/min, and the run time was 13 minutes. A dual-wavelength approach was employed: AS detection was performed at 210 nm and MQ was detected at 283 nm, using a diode array detector. Stability of sample solutions was evaluated for 8 hours after preparation, during which time the solutions remained stable. Youden's test was employed to evaluate robustness. The method proved to be linear (r²>0.99), precise (RSD0,99), preciso (DPR

The pharmacokinetic properties of mefloquine hydrochloride (15 mg base kg -1) were studied in 12 Karen children (five girls, seven boys) aged between 5 and 10 years presenting with uncomplicated falciparum malaria. The drug was well tolerated. Mean (s.d.) peak blood drug concentrations of 2031 (831) ng ml-1 were reached in a median of 8 (range 6-24) h. Mean (s.d.) estimates for oral clearance and mean residence time were 0.52 (0.27) ml min -1 kg -1 and 15.3 (4.7) days, respectively. These values are similar to those reported previously in adults. In one child parasitaemia failed to clear despite whole blood mefloquine concentrations which peaked at 1744 ng ml -1; parasitaemia rose and fever recurred when blood drug concentrations had fallen to 442 ng ml -1. The prevalence of highly mefloquine resistant parasites such as this can be expected to increase under drug pressure in this area.

A concise asymmetric (

In only three steps and in 21-67% overall yields from the natural trioxane artemisinin, a series of 21 new trioxane C-10 thioacetals was prepared. Upon receiving a single oral dose of only 6 mg/kg of the monomeric trioxane 12c combined with 18 mg/kg of mefloquine hydrochloride, Plasmodium berghei-infected mice survived on average 29.8 days after infection. Two of the four mice in this group had no parasites detectable in their blood on day 30 after infection, and they behaved normally and appeared healthy. One of the mice had 11% blood parasitemia on day 30, and one mouse in this group died on day 29. Of high medicinal importance, the efficacy of this ACT chemotherapy is much better than (almost double) the efficacy under the same conditions using as a positive control the popular trioxane drug artemether plus mefloquine hydrochloride (average survival time of only 16.5 days).

Transition metal complex of Co(II) with Mefloquine hydrochloride (antimalaria drug) was synthesized using template method. Chemical analysis including conductivity measurements and spectroscopic studies were used to propose the geometry and mode of binding of the ligand to metal ion. From analytical data, the stoichiometry of the complex has been found to be 1:1. Infrared spectral data also suggest that the ligand (mefloquine hydrochloride) behaves as a tridentate ligand with N:N:O donor sequence towards the metal ion. The complex generally showed octahedral coordinate geometry. Conductivity measurement of 10-2mol dm-3methanol solution of the complex indicated non-electrolytic nature of metal complex. It also revealed that the ligand anions were covalently bonded to the complex.In-vivoevaluation of antimicrobial studies of the metal complex showed greater activities when compared to the free mefloquine.The complex was screened against malarial parasites (Plasmodium yoelii nigeriensis): It was evident from the results obtained that Co(II) mefloquine has highest clearance of about 80% parasitaemia reduction compared to the free mefloquine. The ligand and metal complex were screened for their toxicological activities at the dose of 0.60 mg/Kg body weight twice daily for seven days on the alkaline phosphatase (ALP), alanine aminotranferase (ALT), and aspartate aminotransferase (AST) activities of rat serum, liver and kidney. Overall, it was revealed that both mefloquine and its metal complex do not showed toxicity particularly on the liver and kidney.

A simple HPLC method for determination of mefloquine hydrochloride in tablets was developed and validated. The separation was carried out on an Xterra RP18 (250 × 4.6 mm id, 5 µm particle size) analytical column. The mobile phase was 0.05 M monobasic potassium phosphate buffer (pH 3.5)–methanol (40 + 60, v/v). The flow rate and wavelength were set to 1 mL/min and 283 nm, respectively. The method was specifc for mefloquine hydrochloride in the presence of hydrolytic, oxidative, and photolytic degradation products. It was also linear, precise, accurate, and robust, being suitable for routine QC analyses and stability studies. The developed HPLC method was compared to a previously described spectrophotometric method.

Mefloquine hydrochloride is an important antimalarial drug. It is currently manufactured and administered in racemic form; however there are indications regarding the biological activity of the two enantiomers that suggest the superiority of the (+)-form. The asymmetric total synthesis of the (+)-enantiomer of mefloquine hydrochloride is described. The key asymmetric transformation utilized is a novel asymmetric Darzens reaction of a chiral α-chloro-N-amino cyclic carbamate hydrazone derived from an N-amino cyclic carbamate (ACC) chiral auxiliary.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing mefloquine hydrochloride as the only active pharmaceutical ingredient (API) are reviewed. The solubility and permeability data of mefloquine hydrochloride as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability studies were taken into consideration. Mefloquine hydrochloride is not a highly soluble API. Since no data on permeability are available, it cannot be classified according to the Biopharmaceutics Classification System with certainty. Additionally, several studies in the literature failed to demonstrate BE of existing products. For these reasons, the biowaiver cannot be justified for the approval of new multisource drug products containing mefloquine hydrochloride. However, scale-up and postapproval changes (HHS-FDA SUPAC) levels 1 and 2 and most EU type I variations may be approvable without in vivo BE, using the dissolution tests described in these regulatory documents.

Pharmaceutical cocrystallization is a promising alternative for improving the solubility and dissolution rate or manipulating other physical properties of active pharmaceutical ingredients. The objective of this investigation was to study the effect of cocrystallization with different cocrystal formers on physicochemical properties of mefloquine hydrochloride.Cocrystals were prepared by solution crystallization method--mefloquine hydrochloride (414.8 mg, 1 mmol) and different cocrystal formers (1/2 mmol) were dissolved in 20 mL of ethanol with warming. Solution was cooled in ice bath for 6 hours. The crystals were isolated by filtration through a membrane (0.45 microm) and dried in the air. The pure drug and the prepared cocrystals were characterized in terms of saturation solubility, drug content, infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, in vitro dissolution studies, and stability studies.The cocrystals showed enhanced solubility and dissolution rate. The cocrystals were found to be stable over the period of 6 months confirmed from stability studies.Cocrystals resist the conversion of anhydrous form of drug into its hydrate which is responsible for the drugs less solubility and dissolution rate.

Three thermally and hydrolytically stable silylamide trioxanes have been prepared from the natural trioxane artemisinin in only five simple chemical steps and in at least 56% overall yield. Two of these new chemical entities completely cured malaria-infected mice at a single oral dose of only 8 mg/kg combined with 24 mg/kg of mefloquine hydrochloride. The high efficacy of this ACT chemotherapy is considerably better than the efficacy using the popular trioxane drug artemether plus mefloquine hydrochloride.

In only five simple steps and 48% overall yield from the natural trioxane artemisinin, the thermally and hydrolytically stable trioxane fluoroanilide 4b has been prepared. Upon one oral dose of only 6.8 mg/kg of monomeric trioxane 4b combined with 20 mg/kg of mefloquine hydrochloride, all of the malaria-infected mice lived until at least day 30 post infection. Of the five mice in this surviving group, four (80%) were completely cured (no parasites in their blood) and one mouse had 4% blood parasitemia. Importantly, the efficacy of this ACT chemotherapy using monomeric trioxane 4b plus mefloquine hydrochloride is considerably better than the efficacy under the same conditions using the popular trioxane drug artemether plus mefloquine hydrochloride.

The asymmetric synthesis of (+)-(11R,12S)-mefloquine hydrochloride, an antimalarial drug, was accomplished from commercially available 2-trifluoromethylaniline, ethyl 4,4,4-trifluoroacetoacetate and cyclopentanone in 7 steps with a 14% overall yield. The key steps were proline-catalyzed asymmetric direct aldol reaction and Beckmann rearrangement. The absolute configuration was assigned by a Mosher's method.

The objective of the present investigation was to reduce the bitterness with improved dissolution, in acidic medium (pH 1.2), of mefloquine hydrochloride (MFL). Microparticles were prepared by coacervation method using Eudragit E (EE) as polymer and sodium hydroxide as precipitant. A 32 full factorial design was used for optimization wherein the drug concentration (A) and polymer concentration (B) were selected as independent variables and the bitterness score, particle size and dissolution at various pH were selected as the dependent variables. The desirability function approach has been employed in order to find the best compromise between the different experimental responses. The model is further cross validated for bias. The optimized microparticles were characterized by FT-IR, DSC, XRPD and SEM. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis revealed that the reduced bitterness of MFL can be obtained by controlling the dissolution of microparticles at pH 6.8 and increasing the EE concentration. The increase in polymer concentration leads to reduction in dissolution of microparticles at pH > 5 due to its insolubility. However the dissolution studies at pH 1.2 demonstrated enhanced dissolution of MFL from microparticles might be due to the high porosity of the microparticles, hydrophilic nature of the EE, and improved wettability, provided by the dissolved EE. The bitterness score of microparticles was decreased to zero compared to 3+ of pure ARM. In conclusion the bitterness of MFL was reduced with improved dissolution at acidic pH.

The long-standing discussion of the absolute configuration of erythro-mefloquine is revisited, showcasing the strength of a combination of experimental and calculated Vibrational Circular Dichroism spectroscopy. The resulting assignment of one of the most important antimalarials is subsequently confirmed by Electronic Circular Dichroism spectroscopy and X-ray diffraction-based structure elucidation of thiourea derivates, adding to the amount of evidence on the absolute configuration that had long remained a matter of debate.

Mefloquine hydrochloride has been used widely in the past few decades for malaria prophylaxis and treatment. However, in recent years, it has fallen out of favor due to reports of exposure being linked to numerous neuropsychiatric effects, including emotional disturbances. In this study we examined the effects of different doses (5, 25, or 100 mg/kg) of mefloquine relative to vehicle on male C57BL/6 J mice in two tests of emotional behavior, the light–dark box and the tail suspension test. It was found that mefloquine exposure reduced anxiety-linked behaviors in the light–dark box and reduced total immobility times in the tail suspension test, especially at higher doses. Our results lend support to the notion that mefloquine exposure could induce emotional disinhibition.

A concise asymmetric (>99:1 e.r.) total synthesis of (+)-anti- and (-)-syn-mefloquine hydrochloride from a common intermediate is described. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless-derived diol is converted into either a trans or cis epoxide, and these are subsequently converted into (+)-anti- and (-)-syn-mefloquine, respectively. The synthetic (+)-anti- and (-)-syn-mefloquine samples were derivatized with (S)-(+)-mandelic acid tert-butyldimethylsilyl ether, and a crystal structure of each derivative was obtained. These are the first X-ray structures for mefloquine derivatives that were obtained by coupling to a known chiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+)-anti- as well as (-)-syn-mefloquine.

A highly enantioselective and cost efficient process for the synthesis of (+)-erythro mefloquine has been developed. The key step is an enantioselective reduction of pyridyl ketone KI using transfer hydrogenation with formic acid as the hydrogen source. The ratio of formic acid to NEt3 was found to be very important to achieving a highly efficient process.

Four 5-carbon-linked trioxane dimer orthoesters (6a-6d) have been prepared in 4 or 5 chemical steps from the natural trioxane artemisinin (1). When administered orally to malaria-infected mice using a single dose of only 6 mg/kg body weight along with 18 mg/kg of mefloquine hydrochloride, trioxane dimer orthoester sulfone 6d completely and safely cured the mice; after 30 days, the cured mice showed no detectable parasitemia, gained at least as much weight as the control mice (no infection), and behaved normally.

The current study was designed to evaluate anti-leishmanial activity of mefloquine hydrochloride (Mephaquin®) and artesunate (Plasmotrium®) which are currently being used as malarial drugs. A total of 17 patients (volunteers) with cutaneous leishmaniasis were treated with these drugs in this study. Of these subjects, 16 were treated by the oral administration of a total dosage of 1, 500mg (I Lactab® each for 6 days) mefloquine, 4.2mg/kg/day for 6 days, and if necessary the dosage was repeated with 3 weeks intervals. The majority of cutaneous lesions healed within 2 to 3 weeks after the commencement of mefloquine treatment, showing an average of 3.6 weeks of healing times with 100% cure rate. One slowly healing within 8 weeks after the commencement was observed; this case grew worse because of infection with Tunga penetrans at the late healing phase of leishrnaniasis. The remaining one patient with an ulcer lesion was treated by the oral administration of a total dosage of 1, 200mg (2 Lactab® each for 3 days) artesunate, e., 6.7mg/kg/day for 3 days, and the same dosage was repeated 2 weeks later. The lesion healed within 6 weeks after the commencement of artesunate treatment. In the present study, all the patients received mefloquine or artesunate were treated without admission, performing their normal daily activities. No specified adverse reaction was noticed.

Objective: The objective of present investigation was to evaluate performance of cocrystals of Mefloquine Hydrochloride (MFL) in tablet dosage form. Our previous investigation showed significant effect of cocrystal formers on improving the solubility and dissolution rate of Mefloquine hydrochloride by cocrystallization method when prepared by solution cocrystallization method.Materials and methods: Prepared cocrystals of MFL with different ratio of cocrystal formers were incorporated in tablet dosage form and evaluated for micrometric properties, drug content, hardness, disintegration test, vitro dissolution studies and stability studies. Performance was compared with laboratory prepared tablet of MFL 250 mg.Results: The considerable improvement in the dissolution rate was observed in case of cocrystals based tablets than pure MFL tablets.Discussion and conclusion: So we can incorporate cocrystals in tablet dosage form to enhance in vitro and in vivo performance. To the best of our knowledge, this is the ...

The aqueous solubility of an active pharmaceutical ingredient (API) is an important property that requires evaluation during early development and prior to formulation of the final product. With general, experimental, solubility testing of different APIs, the question always arises as to whether particle size had been determined beforehand or not. All available literature suggests that particle size, for pharmaceutical powders, does not significantly affect equilibrium solubility. The dissolution rate will differ according to different particle sizes, but the overall results should be identical after equilibrium is established. This study was therefore planned to investigate as to whether different particle size fractions of the same API, dissolving at different rates, would all reach solubility equilibrium within 24 hours. Also, APIs from different solubility classes were investigated, because poorly soluble substances would most likely require a longer period of time to equilibrate. The time period of 24 hours was selected, because many published solubility studies report using that interval and is it the standard for our research group also. Available APIs were selected to determine the influence (if any) of particle size on their equilibrium solubilities and the time required for attaining that status. For the purpose of this investigation, five APIs were selected from compounds at our disposal in-house, ranging from freely soluble to poorly soluble in the order: chloroquine phosphate > pyrazinamide > mefloquine hydrochloride > closantel sodium > roxithromycin. Solubility studies were successfully completed on four of the five APIs selected. For closantel sodium, pyrazinamide and roxithromycin it was demonstrated that the 24 hour test period was sufficient for the attainment of equilibrium solubility, regardless of the particle size fractions tested. Surprisingly, the only API in this study for which 24 hours was an insufficient test period was mefloquine HCl, which was not the least soluble compound tested. Further testing would be required to clarify this anomaly. What was evident from the outcomes of this investigation was that although the ubiquitous 24 hour solubility test may work well in many cases, its suitability should be reviewed on a case-by-case basis and not just for the most poorly soluble compounds. Researchers testing solubility at temperatures lower than 37°C should be especially cautious of using a standardised test period, because equilibrium solubility would take longer to achieve with less energy available to the system. Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

The polymorphic and pseudopolymorphic forms of mefloquine hydrochloride have been characterized by use of X-ray powder diffractometry, thermal analysis, infrared spectral analysis, scanning electron microscopy, and solubility measurements. It was determined that mefloquine hydrochloride can crystallize in at least eight forms, anhydrous forms (A, B′, E and M), solvate forms (B and I) and hydrate forms (C and D). The acetone solvate (form B) and isopropanol solvate (form I) transform into forms B ' and M, respectively, when they are heated on a hot stage. Form E, which was recrystallized from ethanol, showed gradual weight loss on heating, and a small endotherm in the DSC thennogram due to desolvation. However, the X-ray powder diffraction pattern of form E after removal of virtually all the ethanol, showed almost the same pattern. This suggests that ethanol is contained in channels within the crystal lattice of form E. An X-ray powder diffraction study showed that the crystal forms of mefloquine hydrochloride in lots of commercial tablets obtained from two sources were forms E and C. When the tablets were stored at 60°C, 75% R.H., form E was transformed into form D, but form C did not undergo a significant change. A study of the effect of various excipients on the solid-state crystal transformation revealed that microcrystalline cellulose promotes the transformation from form E into form D. However, methylcellulose, hydroxyethylcellulose, β-cyclodextrin, crospovidone and hydrous lactose have no effect on the crystal transformation.

INTRODUCTION: The emergence of drug resistance is one of the main problems concerning malaria treatment. The use of counterfeit and/or substandard antimalarial drugs can contribute to the development of parasite resistance. Thus, the aim of this study was to evaluate the quality of antimalarial drugs distributed in Brazil. METHODS: Samples containing chloroquine phosphate, mefloquine hydrochloride, primaquine phosphate, and quinine sulfate tablets were delivered to the Rio de Janeiro central storeroom (CENADI), state storerooms (SS), and Basic Health Units (BHUs) in the north region of Brazil - a total of 10 sample sets. After 5 months of storage, the samples were collected, and in vitro quality control analyses according to official and published methods were performed. RESULTS: Inadequate drug storage conditions were found in two SS and in all BHUs evaluated. There were no quality deviations found in the chloroquine samples. The quinine samples exhibited weight variation above the allowed limits. The primaquine samples were found to have packaging deficiency. The release of mefloquine in samples from some regions showed a statistically significant difference when compared with the CENADI samples. CONCLUSIONS: It is important to periodically evaluate the quality and storage conditions of essential drugs. The quality deviations found with the primaquine and quinine samples are not related to storage conditions and must be addressed urgently. The decreased mefloquine release from tablets is related to formulation problems or influenced by inadequate storage conditions, prompting further investigation. Even with the mentioned problems, the samples would probably not contribute to resistant parasite selection. INTRODUÇÃO: O aparecimento de resistência aos medicamentos é um dos maiores problemas do tratamento da malária. O uso de medicamentos falsos e/ou de má qualidade pode contribuir para o desenvolvimento de resistência no parasita. Este estudo tem por objetivo avaliar a qualidade dos medicamentos antimaláricos distribuídos no Brasil. MÉTODOS: Amostras contendo comprimidos de difosfato de cloroquina, cloridrato de mefloquina, difosfato de primaquina e sulfato de quinina foram enviadas ao almoxarifado central na Cidade do Rio de Janeiro (CENADI), almoxarifados estaduais (SS) e Unidades Básicas de Saúde (UBS) nos estados da região norte do Brasil, totalizando dez amostras. Após cinco meses de armazenamento, as amostras foram coletadas e analisadas segundo métodos oficiais e da literatura. RESULTADOS: Foram encontradas condições inadequadas de armazenamento de medicamentos em duas SS e em todas as UBS avaliadas. Não foram encontrados problemas de qualidade com as amostras de cloroquina. As amostras de quinina apresentaram variação de peso acima dos limites permitidos. Amostras de primaquina foram encontradas com problemas na embalagem. A cedência de mefloquina de comprimidos, em algumas regiões, apresentou diferença estatisticamente significativa quando comparada com a amostra do CENADI. CONCLUSÕES: É importante avaliar, periodicamente, a qualidade e as condições de armazenamento de medicamentos essenciais. Desvios de qualidade encontrados com as amostras de primaquina e quinina não estão relacionados às condições de armazenamento e devem ser corrigidos urgentemente. O decréscimo na cedência de mefloquina dos comprimidos está relacionado com a formulação ou foi influenciada por condições de armazenamento inadequadas, necessitando de uma investigação posterior. Apesar dos problemas mencionados, as amostras provavelmente não contribuiriam para a seleção de parasitas resistentes.

As part of the ongoing research for more effective antimalarial drug, Fe (III) complex of mefloquine hydrochloride (antimalarial drug) was synthesized using template method. Mefloquine was tentatively found to have coordinated through the hydroxyl and the two nitrogen atoms in the quinoline and piperidine in the structure, respectively. Characterization has been done on the basis of analytical, conductance, atomic absorption, magnetic measurement, electronic and Infra-red spectrometry. From analytical data, the stoichiometry of the complex has been found to be 1:1. Infra-red spectral data also suggest that the ligand (mefloquine) behaves as a tridentate ligand with N:N:O donor sequence towards the metal ion. On the basis of the above physico-chemical data it is proposed that the complex is assigned octahedral geometry. The antimicrobial activities of mefloquine metal complex exhibited greater inhibition than the parent ligand. The ligand and metal complex were screened for their toxicological activities at the dose of 6.66 mg/kg body weight twice daily for seven days on the alkaline phosphatase (ALP), alanine aminotranferase (ALT) and aspartate aminotransferase (AST) activities of rat serum, liver and kidney. Overall, it was revealed that both mefloquine and its metal complex might show mild toxicity particularly on the liver and kidney. Key words: Fe(III) complex, synthesis, anti-malarial drug, antimicrobial, toxicology.

Recent studies of military personnel who have deployed to Iraq and Afghanistan have reported a number of combat-related psychiatric disorders such as posttraumatic stress disorder, depression, and traumatic brain injury. This case report involves a 27-year-old male active-duty US military service member who developed severe depression, psychotic hallucinations, and neuropsychological sequelae following the prophylactic use of the antimalarial medication mefloquine hydrochloride. The patient had a recent history of depression and was taking antidepressant medications at the time of his deployment to the Middle East. Psychiatrists and other health care providers should be aware of the possible neuropsychiatric side effects of mefloquine in deployed military personnel and should consider the use of other medications for malaria prophylaxis in those individuals who may be at increased risk for side effects.

R*, 12S*)-( __. )-a-2-Piperidinyl-2,8-bis- (trifluoromethyl)-4-quinolinemethanol monohydro- chloride, C)7H)vF6N2 O+ .Cl-.0"5CH3OH, Mr = 430.8, tetragonal, P42/n (origin at center of symme- try), a = b = 24.595 (4), c = 6.398 (2) .~,, V = 3870"0A 3, Z =8, Dx = 1.48gcm -3, CuKce, A= 1.54178 A, /x = 24.28 cm-l, F(000) = 1768, room temperature, final R = 7.5% for 2067 reflections with !Fo > 3o-(F). Mefloquine hydrochloride crystallized as a secondary amine salt with channels of dis- ordered methanol solvent. The trifluoromethyl group on the C adjacent to the quinoline N atom exhibited rotational disorder. Each chloride ion accepts three hydrogen bonds, one each from the hydroxyl group and the two H atoms of the amine group of meflo- quine from three separate molecules. The angle between the average plane of the quinoline ring and the average plane of the piperidine ring is 110.5 °. Introduction. (___)-Mefloquine hydrochloride was developed by the Walter Reed Army Institute of Research and Roche Laboratories (Nutley, N J) as an alternative treatment for multi-drug-resistant malaria. ( __+ )-Mefloquine hydrochloride was approved for treating malaria in 1989 by the Food and Drug Administration and is marketed under the trade name Lariam. Not only is malaria a disease of worldwide epidemic proportions with estimated yearly cases in the 100 millions and an estimated yearly death rate in the millions, chloroquine- resistant malaria, first confirmed in South America and Southeast Asia in the 1960's, now resides in malaria endemic areas around the globe (Wyler, 1983; Payne, 1987). Mefloquine is a quinoline-containing amino alco- hol antimalarial whose structure is derived from the

Stability data is used to determine the change the product has undergone over a certain time period at specific temperatures. In the present study, the physical stability characterized by size, pH and entrapment efficacy of mefloquine loaded liposomes and Pheroid™ vesicles were investigated. Size was accurately determined by flow cytometry. Entrapment efficacy, after unentrapped drug was removed was successfully determined by UV-spectrophotometry. The formulations contained 0.5% (m/v) mefloquine and results showed that mefloquine interfered with the formation of lipid bilayer of the liposomes. Liposomes increased in size from 5.22 ± 0.03 μm to 9.71 ± 1.11 μm with accelerated stability and large aggregates were observed. A notable difference in stability testing of Pheroid™ vesicles was seen with no significant increase in size. Entrapment efficacy of 68.72 ± 0.04% (5 °C), 67.45 ± 2.92% (25 °C) and 67.45 ± 2.92% (30 °C) were obtained at the different storage conditions. With these findings the mefloquine loaded Pheroid™ vesicles are stable and should be used investigated for the possible increase in efficacy and bioavailability and decrease toxicity. http://dx.doi.org/10.1016/j.ijpharm.2011.08.031

A new series of 6 dimeric trioxane sulfones has been prepared from the natural trioxane artemisinin in five or six chemical steps. One of these thermally and hydrolytically stable new chemical entities (4c) completely cured malaria-infected mice via a single oral dose of 144 mg/kg. At a much lower single oral dose of only 54 mg/kg combined with 13 mg/kg of mefloquine hydrochloride, this trioxane dimer 4c as well as its parent trioxane dimer 4b also completely cured malaria-infected mice. Both dimers 4c and 4b were potently and selectively cytotoxic toward five cancer cell lines.

Three new 5-carbon-linked trioxane dimer carboxylate esters have been prepared from the natural trioxane, artemisinin in only 3-steps and 40-50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure.

R*, 12S*)-( __. )-a-2-Piperidinyl-2,8-bis- (trifluoromethyl)-4-quinolinemethanol monohydro- chloride, C)7H)vF6N2 O+ .Cl-.0"5CH3OH, Mr = 430.8, tetragonal, P42/n (origin at center of symme- try), a = b = 24.595 (4), c = 6.398 (2) .~,, V = 3870"0A 3, Z =8, Dx = 1.48gcm -3, CuKce, A= 1.54178 A, /x = 24.28 cm-l, F(000) = 1768, room temperature, final R = 7.5% for 2067 reflections with !Fo > 3o-(F). Mefloquine hydrochloride crystallized as a secondary amine salt with channels of dis- ordered methanol solvent. The trifluoromethyl group on the C adjacent to the quinoline N atom exhibited rotational disorder. Each chloride ion accepts three hydrogen bonds, one each from the hydroxyl group and the two H atoms of the amine group of meflo- quine from three separate molecules. The angle between the average plane of the quinoline ring and the average plane of the piperidine ring is 110.5 °. Introduction. (___)-Mefloquine hydrochloride was developed by the Walter Reed Army Institute of Research and Roche Laboratories (Nutley, N J) as an alternative treatment for multi-drug-resistant malaria. ( __+ )-Mefloquine hydrochloride was approved for treating malaria in 1989 by the Food and Drug Administration and is marketed under the trade name Lariam. Not only is malaria a disease of worldwide epidemic proportions with estimated yearly cases in the 100 millions and an estimated yearly death rate in the millions, chloroquine- resistant malaria, first confirmed in South America and Southeast Asia in the 1960's, now resides in malaria endemic areas around the globe (Wyler, 1983; Payne, 1987). Mefloquine is a quinoline-containing amino alco- hol antimalarial whose structure is derived from the

1. The influence of the antifilarial drug diethylcarbamazine citrate (D) and DL-erythro mefloquine hydrochloride (Mf) on PGI2 synthesis by the male rat thoracic aorta and day-20 pregnant rat myometrium was investigated in vitro using a rat platelet antiaggregatory bioassay method. 2. Pretreatment of the tissues with D (25.5-204 microM) or Mf (24-192 microM) for 30 min at 37 degrees C significantly inhibited PGI2 synthesis in a concentration-dependent manner. 3. D exhibited its inhibitory effect even in presence of exogenous arachidonic acid (AA) (16.6 microM) whereas Mf lost its inhibitory effect in presence of AA. 4. Pretreatment of urethane-anaesthetized rats with D (32 mumol kg-1) but not Mf (7.5 mumol kg-1) for 30 min significantly antagonized AA (4 nmol kg-1)-induced hypotension. 5. Furthermore, D (0.25-0.5 microM) antagonized AA-induced aggregation in rabbit platelet-rich plasma without affecting that of ADP. 6. D seemed to interfere with the action of the PG endoperoxide synthase (PG cyclooxygenase) whereas Mf seemed to interfere with the action of phospholipase A2 (PLA2) enzyme. 7. D may have exerted its effect via release of toxic O2 radicals whereas Mf effect may have been due to an interaction with PLA2 substrate phospholipids. 8. The demonstrated inherent property of these two drugs to inhibit the synthesis of the potent vasodilator, platelet antiaggregatory, anticonvulsant and antiinflammatory mediator PGI2 may partly contribute towards better understanding of the biochemical mechanisms that underly some of the previously known but poorly understood actions of these drugs.