Quinine

Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.

BackgroundThe Lives Saved Tool (LiST) model was developed to estimate the impact of the scale-up of child survival interventions on child mortality. New advances in antimalarials have improved their efficacy of treating uncomplicated and severe malaria. Artemisinin-based combination therapies (ACTs) for uncomplicated Plasmodium falciparum malaria and parenteral or rectal artemisinin or quinine for severe malaria syndromes have been shown to be very effective for the treatment of malaria in children. These interventions are now being considered for inclusion in the LiST model. However, for obvious ethical reasons, their protective efficacy (PE) compared to placebo is unknown and their impact on reducing malaria-attributable mortality has not been quantified.MethodsWe performed systematic literature reviews of published studies in P. falciparum endemic settings to determine the protective efficacy (PE) of ACT treatment against malaria deaths among children with uncomplicated malaria, as well as the PE of effective case management including parenteral quinine against malaria deaths among all hospitalized children. As no randomized placebo-controlled trials of malaria treatment have been conducted, we used multiple data sources to ascertain estimates of PE, including a previously performed Delphi estimate for treatment of uncomplicated malaria.ResultsBased on multiple data sources, we estimate the PE of ACT treatment of uncomplicated P. falciparum malaria on reducing malaria mortality in children 1-23 months to be 99% (range: 94-100%), and in children 24-59 months to be 97% (range: 86-99%). We estimate the PE of treatment of severe P. falciparum malaria with effective case management including intravenous quinine on reducing malaria mortality in children 1-59 months to be 82% (range: 63-94%) compared to no treatment.ConclusionsThis systematic review quantifies the PE of ACT used for treating uncomplicated malaria and effective case management including parenteral quinine for treating severe P. falciparum malaria for preventing malaria mortality in children <5. These data will be used in the Lives Saved Tool (LiST) model for estimating the impact of scaling-up these interventions against malaria. However, in order to estimate the reduction in child mortality due to scale-up of these interventions, it is imperative to develop standardized indicators to measure population coverage of these interventions.

The emergence of drug-resistant parasites is a serious threat faced by malaria control programs. Understanding the genetic basis of resistance is critical to the success of treatment and intervention strategies. A novel locus associated with antimalarial resistance, ap2-mu (encoding the mu chain of the adaptor protein 2 [AP2] complex), was recently identified in studies on the rodent malaria parasite Plasmodium chabaudi (pcap2-mu). Furthermore, analysis in Kenyan malaria patients of polymorphisms in the Plasmodium falciparum ap2-mu homologue, pfap2-mu, found evidence that differences in the amino acid encoded by codon 160 are associated with enhanced parasite survival in vivo following combination treatments which included artemisinin derivatives. Here, we characterize the role of pfap2-mu in mediating the in vitro antimalarial drug response of P. falciparum by generating transgenic parasites constitutively expressing codon 160 encoding either the wild-type Ser (Ser160) or the Asn mutant (160Asn) form of pfap2-mu. Transgenic parasites carrying the pfap2-mu 160Asn allele were significantly less sensitive to dihydroartemisinin using a standard 48-h in vitro test, providing direct evidence of an altered parasite response to artemisinin. Our data also provide evidence that pfap2-mu variants can modulate parasite sensitivity to quinine. No evidence was found that pfap2-mu variants contribute to the slow-clearance phenotype exhibited by P. falciparum in Cambodian patients treated with artesunate monotherapy. These findings provide compelling evidence that pfap2-mu can modulate P. falciparum responses to multiple drugs. We propose that this gene should be evaluated further as a potential molecular marker of antimalarial resistance.

The genetic basis of Plasmodium falciparum resistance to quinine, a drug used to treat severe malaria, has long been unclear. To investigate this, here we used a human liver-chimaeric mouse model to conduct a P. falciparum genetic cross between quinine-partially resistant and quinine-sensitive parasites. Drug profiling and quantitative trait loci analyses of 120 unique recombinant progeny mapped resistance to segments on chromosomes 7 and 12, indicating a polygenic basis. The chloroquine resistance transporter PfCRT and a structurally similar putative drug/metabolite transporter, DMT1, were identified as primary chromosome 7 candidates based on gene-editing studies. In a proteoliposome assay, both mutant DMT1 and PfCRT transported more quinine than their wild-type isoforms. DMT1 localized to the P. falciparum digestive vacuole, lipid bodies, parasitophorous vacuolar membrane and structures associated with vesicular trafficking. An ATP-dependent zinc metalloprotease (FtsH1) on chromosome 12 also modulated quinine and chloroquine resistance. We suggest that genotypic surveillance of these markers should be performed in clinical settings of quinine use.