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The Journal of Organic Chemistry Aug 2021Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino- alkaloids. Most effectively, 11-aminomefloquine with an...
Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino- alkaloids. Most effectively, 11-aminomefloquine with an configuration was obtained by conversion of 11-alcohol into azide and hydrogenation. Alkylation of a secondary amine unit was needed to arrive at diastereomeric -11-aminomefloquine and to introduce diversity. Most of the substitution reactions of the hydroxyl group to azido group proceeded with net retention of the configuration and involved actual aziridine or plausible aziridinium ion intermediates. Enantiomerically pure products were obtained by the resolution of either the initial mefloquine or one of the final products. The evaluation of the efficacy of the obtained vicinal diamines in enantioselective transformations proved that -11-aminomefloquine is an effective catalyst in the asymmetric Michael addition of nitromethane to cyclohexanone (up to 96.5:3.5 er) surpassing -aminoquinine in terms of selectivity.
Topics: Amines; Diamines; Mefloquine; Molecular Structure; Stereoisomerism
PubMed: 34314190
DOI: 10.1021/acs.joc.1c01316 -
ChemMedChem Oct 2023In antimalarial drug development research, overcoming drug resistance has been a major challenge for researchers. Nowadays, several drugs like chloroquine, mefloquine,... (Review)
Review
In antimalarial drug development research, overcoming drug resistance has been a major challenge for researchers. Nowadays, several drugs like chloroquine, mefloquine, sulfadoxine, and artemisinin are used to treat malaria. But increment in drug resistance has pushed researchers to find novel drugs to tackle drug resistance problems. The idea of using transition metal complexes with pharmacophores as ligands/ligand pendants to show enhanced antimalarial activity with a novel mechanism of action has gained significant attention recently. The advantages of metal complexes include tunable chemical/physical properties, redox activity, avoiding resistance factors, etc. Several recent reports have successfully demonstrated that the metal complexation of known organic antimalarial drugs can overcome drug resistance by showing enhanced activities than the parent drugs. This review has discussed the fruitful research works done in the past few years falling into this criterion. Based on transition metal series (3d, 4d, or 5d), the antimalarial metal complexes have been divided into three broad categories (3d, 4d, or 5d metal-based), and their activities have been compared with the similar control complexes as well as the parent drugs. Furthermore, we have also commented on the potential issues and their possible solution for translating these metal-based antimalarial complexes into the clinic.
Topics: Humans; Antimalarials; Coordination Complexes; Malaria; Chloroquine; Mefloquine; Drug Resistance; Plasmodium falciparum; Malaria, Falciparum
PubMed: 37436090
DOI: 10.1002/cmdc.202300326 -
BMJ Military Health Nov 2020
Topics: Antimalarials; Humans; Malaria; Mefloquine; Military Personnel; Pre-Exposure Prophylaxis
PubMed: 32086266
DOI: 10.1136/jramc-2019-001295 -
The Cochrane Database of Systematic... Aug 2014Urinary schistosomiasis is caused by an intravascular infection with parasitic Schistosoma haematobium worms. The adult worms typically migrate to the venous plexus of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Urinary schistosomiasis is caused by an intravascular infection with parasitic Schistosoma haematobium worms. The adult worms typically migrate to the venous plexus of the human bladder and excrete eggs which the infected person passes in their urine. Chronic infection can cause substantial morbidity and long-term complications as the eggs become trapped in human tissues causing inflammation and fibrosis. We summarised evidence of drugs active against the infection. This is new edition of a review first published in 1997.
OBJECTIVES
To evaluate the efficacy and safety of drugs for treating urinary schistosomiasis.
SEARCH METHODS
We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, CENTRAL, EMBASE and LILACS and reference lists of articles up to 23 May 2014.
SELECTION CRITERIA
Randomized controlled trials (RCTs) of antischistosomal drugs and drug combinations compared to placebo, no intervention, or each other.
DATA COLLECTION AND ANALYSIS
Two researchers independently screened the records, extracted the data and assessed risk of bias. The primary efficacy outcomes were parasitological failure (defined as the continued presence of S. haematobium eggs in the urine at time points greater than one month after treatment), and percent reduction of egg counts from baseline. We presented dichotomous data as risk ratios (RR), and continuous data as mean difference (MD), alongside their 95% confidence intervals (CIs). Where appropriate we combined trials in meta analyses or tables. We assessed the quality of evidence using the GRADE approach.
MAIN RESULTS
We included 30 RCTs enrolling 8165 participants in this review. Twenty-four trials were conducted in children in sub-Saharan Africa, and 21 trials were over 20 years old. Many studies were assessed as being at unclear risk of bias due to inadequate descriptions of study methods. PraziquantelOn average, a single 40 mg/kg dose of praziquantel reduced the proportion of people still excreting eggs in their urine by around 60% compared to placebo at one to two months after treatment (treatment failure: RR 0.42, 95% CI 0.29 to 0.59, 864 participants, seven trials, high quality evidence). The proportion of people cured with praziquantel varied substantially between trials, from 22.5% to 83.3%, but was higher than 60% in five of the seven trials. At one to two months following praziquantel treatment at 40 mg/kg, the mean number of schistosome eggs in the urine was reduced by over 95% in five out of six trials (678 participants, six trials, high quality evidence).Splitting praziquantel 40 mg/kg into two doses over 12 hours probably has no benefits over a single dose, and in a single trial of 220 participants the split dose caused more vomiting (RR 0.5, 95% CI 0.29 to 0.86) and dizziness (RR 0.39, 95% CI 0.16 to 0.94). MetrifonateA single dose of metrifonate 10 mg/kg reduced egg excretion (210 participants, one trial, at eight months), but was only marginally better than placebo at achieving cure at one month (RR 0.83, 95% CI 0.74 to 0.94, 142 participants, one trial). In a single trial comparing one, two and three doses, the absolute number of participants cured improved from 47% after one dose to 81% after three doses (93 participants, one trial, low quality evidence).Two small trials compared 40 mg/kg single dose praziquantel with two or three doses of 10 mg/kg metrifonate and found no clear evidence of differences in cure (metrifonate 2 x 10 mg/kg at one month: RR 1.03, 95% CI 0.8 to 1.34, 72 participants, one trial; metrifonate 3 x 10 mg/kg at three months: RR 0.33, 95% CI 0.07 to 1.57, 100 participants, one trial. In one trial both drugs performed badly and in one trial both performed well. Other drugsThree trials have evaluated the antimalarial artesunate; with inconsistent results. Substantial antischistosomal effects were only seen in one of the three trials, which was at unclear risk of bias due to poor reporting of the trial methods. Similarly, another anti-malarial mefloquine has been evaluated in two small trials with inconsistent effects.Adverse events were described as mild for all evaluated drugs, but adverse event monitoring and reporting was generally of low quality.
AUTHORS' CONCLUSIONS
Praziquantel 40 mg/kg is the most studied drug for treating urinary schistosomiasis, and has the strongest evidence base.Potential strategies to improve future treatments for schistosomiasis include the combination of praziquantel with metrifonate, or with antimalarial drugs with antischistosomal properties such as artesunate and mefloquine. Evaluation of these combinations requires rigorous, adequately powered trials using standardized outcome measures.
Topics: Adult; Anthelmintics; Artemisinins; Artesunate; Child; Humans; Mefloquine; Praziquantel; Randomized Controlled Trials as Topic; Schistosomiasis haematobia; Trichlorfon
PubMed: 25099517
DOI: 10.1002/14651858.CD000053.pub3 -
Tropical Diseases, Travel Medicine and... 2016Recreational diving occurs annually in areas of the world where malaria is endemic. The safety and efficacy of antimalarials for travelers in a hyperbaric environment is... (Review)
Review
BACKGROUND
Recreational diving occurs annually in areas of the world where malaria is endemic. The safety and efficacy of antimalarials for travelers in a hyperbaric environment is unknown. Of particular concern would be medications with adverse effects that could either mimic diving related illnesses such as barotrauma, decompression sickness (DCS) and gas toxicities, or increase the risk for such illnesses.
METHODS
We conducted a review of PubMed and Cochrane databases to determine rates of neurologic adverse effects or other effects from antimalarials that may be a problem in the diving environment.
RESULTS
One case report was found on diving and mefloquine. Multiple case reports and clinical trials were found describing neurologic adverse effects of the major chemoprophylactic medications atovaquone/proguanil, chloroquine, doxycycline, mefloquine, and primaquine.
CONCLUSIONS
Of the available literature, atovaquone/proguanil and doxycycline are most likely the safest agents and should be preferred; atovaquone/proguanil is superior due to reduced rates of sunburn in the marine environment. Primaquine also appears to be safe, but has reduced efficacy against ; mefloquine possesses the highest rate of neurologic side effects and therefore these agents should be limited to extreme cases of patients intolerant to other agents. Chloroquine appears unsafe in the hyperbaric environment and should be avoided. More studies are required to include database reviews of returned divers traveling to malaria endemic areas and randomized controlled trials in the hyperbaric environments.
PubMed: 28883967
DOI: 10.1186/s40794-016-0041-x -
PLoS Neglected Tropical Diseases Jul 2014Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel. Hence, there is a pressing need to develop additional therapeutics against... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel. Hence, there is a pressing need to develop additional therapeutics against schistosomiasis. The antimalarial drug mefloquine shows antischistosomal activity in animal models and clinical trials, which calls for further investigations.
METHODOLOGY
We comparatively assessed the efficacy and tolerability of the following treatments against Schistosoma haematobium in school-aged children in Côte d'Ivoire: (i) praziquantel (40 mg/kg; standard treatment); (ii) mefloquine (25 mg/kg) combined with praziquantel (40 mg/kg); and (iii) mefloquine-artesunate (3× (100 mg artesunate +250 mg mefloquine)) combined with praziquantel (40 mg/kg) (treatments administered on subsequent days). Two urine samples were collected before, and on days 21-22 and 78-79 after the first dosing.
PRINCIPAL FINDINGS
Sixty-one children were present on all examination time points and had complete datasets. No difference in efficacy was observed between the three treatment groups on either follow-up. On the 21-22 day posttreatment follow-up, based on available case analysis, cure rates of 33% (95% confidence interval (CI) 11-55%), 29% (95% CI 8-50%), and 26% (95% CI 5-48%) were observed for praziquantel, mefloquine-artesunate-praziquantel, and mefloquine-praziquantel, respectively. The corresponding egg reduction rates were 94% and above. On the second follow-up, observed cure rates ranged from 19% (praziquantel) to 33% (mefloquine-artesunate-praziquantel), and egg reduction rates were above 90%. Praziquantel monotherapy was the best tolerated treatment. In the mefloquine-artesunate-praziquantel group, adverse events were reported by 91% of the participants, and in the mefloquine-praziquantel group, 95% experienced adverse events. With the exception of abdominal pain at moderate severity, adverse events were mild.
CONCLUSIONS/SIGNIFICANCE
The addition of mefloquine or mefloquine-artesunate does not increase the efficacy of praziquantel against chronic S. haematobium infection. Additional studies are necessary to elucidate the effect of the combinations against acute schistosomiasis.
Topics: Adolescent; Animals; Anthelmintics; Artemisinins; Artesunate; Child; Cote d'Ivoire; Drug Therapy, Combination; Female; Humans; Male; Mefloquine; Praziquantel; Schistosoma haematobium; Schistosomiasis haematobia
PubMed: 25033291
DOI: 10.1371/journal.pntd.0002975 -
International Journal For Parasitology.... Dec 2014Helminth infections are responsible for a considerable public health burden, yet the current drug armamentarium is small. Given the high cost of drug discovery and... (Review)
Review
Helminth infections are responsible for a considerable public health burden, yet the current drug armamentarium is small. Given the high cost of drug discovery and development, the high failure rates and the long duration to develop novel treatments, drug repurposing circumvents these obstacles by finding new uses for compounds other than those they were initially intended to treat. In the present review, we summarize in vivo and clinical trial findings testing clinical candidates and marketed drugs against schistosomes, food-borne trematodes, soil-transmitted helminths, Strongyloides stercoralis, the major human filariases lymphatic filariasis and onchocerciasis, taeniasis, neurocysticercosis and echinococcosis. While expanding the applications of broad-spectrum or veterinary anthelmintics continues to fuel alternative treatment options, antimalarials, antibiotics, antiprotozoals and anticancer agents appear to be producing fruitful results as well. The trematodes and nematodes continue to be most investigated, while cestodal drug discovery will need to be accelerated. The most clinically advanced drug candidates include the artemisinins and mefloquine against schistosomiasis, tribendimidine against liver flukes, oxantel pamoate against trichuriasis, and doxycycline against filariasis. Preclinical studies indicate a handful of promising future candidates, and are beginning to elucidate the broad-spectrum activity of some currently used anthelmintics. Challenges and opportunities are further discussed.
PubMed: 25516827
DOI: 10.1016/j.ijpddr.2014.07.002 -
Infectious Diseases of Poverty Mar 2017The current approach of morbidity control of schistosomiasis, a helminth disease of poverty with considerable public health and socioeconomic impact, is based on... (Review)
Review
The current approach of morbidity control of schistosomiasis, a helminth disease of poverty with considerable public health and socioeconomic impact, is based on preventive chemotherapy with praziquantel. There is a pressing need for new drugs against this disease whose control entirely depends on this single drug that has been widely used over the past 40 years. We argue that a broader anthelminthic approach supplementing praziquantel with new antischistosomals targeting different parasite development stages would not only increase efficacy but also reduce the risk for drug resistance. Repositioning drugs already approved for other diseases provides a shortcut to clinical trials, as it is expected that such drugs rapidly pass the regulatory authorities. The antischistosomal properties of antimalarial drugs (e.g., semisynthetic artemisinins, synthetic trioxolanes, trioxaquines and mefloquine) and of drugs being developed or registered for other purposes (e.g., moxidectin and miltefosin), administered alone or in combination with praziquantel, have been tested in the laboratory and clinical trials. Another avenue to follow is the continued search for new antischistosomal properties in plants. Here, we summarise recent progress made in schistosomiasis chemotherapy, placing particular emphasis on repositioning of existing drugs against schistosomiasis.
Topics: Animals; Anthelmintics; Antimalarials; Drug Repositioning; Drug Resistance; Drug Therapy, Combination; Humans; Praziquantel; Public Health; Schistosoma; Schistosomiasis
PubMed: 28351414
DOI: 10.1186/s40249-017-0286-2 -
Acta Tropica Jan 2021Conventional anthelmintics such as albendazole could not achieve complete cure of trichinellosis till now. The antimalarial mefloquine mediates oxidative stress and...
Conventional anthelmintics such as albendazole could not achieve complete cure of trichinellosis till now. The antimalarial mefloquine mediates oxidative stress and disrupts lysosomal functions leading to cell death. Therefore, the aim of this work was to investigate the effect of mefloquine on experimental acute and chronic trichinellosis and to clarify the possible mechanisms of such effects. Mice were divided into four groups; Group I: Uninfected untreated control (20 mice); Group II: Infected untreated control (40 mice); Group III: infected and treated with albendazole (400 mg/kg) (40 mice); Group IV: infected and treated with mefloquine (300 mg/kg) (40 mice). All infected treated groups were equally subdivided into 2 subgroups; (a) treated on the 2 day post infection (dpi) for 3 days, (b) treated on the 35 dpi for 5 days. Parasitological adults and larvae counting besides immunohistopathological examination of intestines and muscles were done. Biochemical assay of oxidant/antioxidant status, apoptotic, cytoprotective and inflammatory biomarkers in intestinal and muscle homogenates were achieved. Results showed that both albendazole and mefloquine significantly reduced adults and larvae counts with higher efficacy of albendazole in the intestinal phase and superiority of mefloquine in the muscle phase. The superiority of mefloquine was indicated by increased inflammatory immune infiltration and decreased anti-apoptotic immunohistochemical markers expression in both jejunal and muscle tissues. Biochemically, mefloquine treatment showed highly significant oxidative, apoptotic and inflammatory effects. So, our results suggest that mefloquine might be a superior treatment for chronic trichinellosis.
Topics: Albendazole; Animals; Anthelmintics; Apoptosis; Disease Models, Animal; Jejunum; Larva; Male; Mefloquine; Mice; Muscles; Oxidative Stress; Reactive Oxygen Species; Trichinella spiralis; Trichinellosis
PubMed: 33221280
DOI: 10.1016/j.actatropica.2020.105760 -
Biochemical and Biophysical Research... Nov 2021Angiogenesis, the formation of new blood vessels from the pre-existing ones, is a hallmark characteristic of glioblastoma, making it an appealing target for treatment...
Angiogenesis, the formation of new blood vessels from the pre-existing ones, is a hallmark characteristic of glioblastoma, making it an appealing target for treatment development. Given potent anti-cancer efficacy of mefloquine, FDA-approved anti-malarial drug, there is increasing interest in repurposing mefloquine for treatment of cancers, including glioblastoma. In line with these efforts, our work is the first to demonstrate that mefloquine is also an inhibitor of glioblastoma angiogenesis. Using glioblastoma microvascular endothelial cell (GMEC) isolated from glioblastoma patients, we show that mefloquine at clinically achievable concentration inhibits GMEC differentiation, capillary network formation, adhesion to Matrix, growth and survival. Mefloquine also inhibits growth and induces apoptosis in glioblastoma cells regardless of cellular origin and genetic background. We further show that mefloquine significantly inhibits glioblastoma growth but not formation, and this is associated with decreased glioblastoma angiogenesis in mice. Mechanistically, mefloquine disrupted lysosomal integrity and function in GMECs, leading to oxidative stress and lysosomal lipid damage. Rescue studies confirm that mefloquine acts on GMECs in a lysosomal disruption-dependent manner. Our findings demonstrate the anti-angiogenic activity of mefloquine via disrupting lysosomal function. The dual inhibitory role of mefloquine in glioblastoma angiogenesis and glioblastoma displays its advantage over other anti-cancer drugs for glioblastoma treatment. Our work also highlights the essential role of lysosome in both glioblastoma and its angiogenesis.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Humans; Male; Mefloquine; Mice, SCID; Neovascularization, Pathologic; Mice
PubMed: 34607260
DOI: 10.1016/j.bbrc.2021.09.069