Modernizing the World Health Organization List of Essential Medicines for Preventing and Controlling Cardiovascular Diseases

Kishore, Sandeep P.; Blank, Evan; Heller, David J.; Patel, Amisha; Peters, Alexander W.; Price, Matthew J.; Vidula, Mahesh K.; Fuster, Valentín; Onuma, Oyere; Huffman, Mark D.; Vedanthan, Rajesh

doi:10.1016/j.jacc.2017.11.056

Cited by 41 publications

(29 citation statements)

References 50 publications

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“…To complement the single-marker mapping described above, we performed a gene-burden approach to map BZ resistance [ 33 , 34 ]. Compared to the single-marker approach that includes SNVs with a minimum 5% minor allele frequency among all strains, the gene-burden approach incorporates all rare strain-specific variation within a gene for association testing [ 34 , 38 ]. With this alternative mapping strategy, we identified the same two QTL on chromosome II that we identified with the single-marker approach.…”

Section: Resultsmentioning

confidence: 99%

Extreme allelic heterogeneity at a Caenorhabditis elegans beta-tubulin locus explains natural resistance to benzimidazoles

et al. 2018

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Benzimidazoles (BZ) are essential components of the limited chemotherapeutic arsenal available to control the global burden of parasitic nematodes. The emerging threat of BZ resistance among multiple nematode species necessitates the development of novel strategies to identify genetic and molecular mechanisms underlying this resistance. All detection of parasitic helminth resistance to BZ is focused on the genotyping of three variant sites in the orthologs of the β-tubulin gene found to confer resistance in the free-living nematode Caenorhabditis elegans. Because of the limitations of laboratory and field experiments in parasitic nematodes, it is difficult to look beyond these three sites to identify additional mechanisms that might contribute to BZ resistance in the field. Here, we took an unbiased genome-wide mapping approach in the free-living nematode species C. elegans to identify the genetic underpinnings of natural resistance to the commonly used BZ, albendazole (ABZ). We found a wide range of natural variation in ABZ resistance in natural C. elegans populations. In agreement with known mechanisms of BZ resistance in parasites, we found that a majority of the variation in ABZ resistance among wild C. elegans strains is caused by variation in the β-tubulin gene ben-1. This result shows empirically that resistance to ABZ naturally exists and segregates within the C. elegans population, suggesting that selection in natural niches could enrich for resistant alleles. We identified 25 distinct ben-1 alleles that are segregating at low frequencies within the C. elegans population, including many novel molecular variants. Population genetic analyses indicate that ben-1 variation arose multiple times during the evolutionary history of C. elegans and provide evidence that these alleles likely occurred recently because of local selective pressures. Additionally, we find purifying selection at all five β-tubulin genes, despite predicted loss-of-function variants in ben-1, indicating that BZ resistance in natural niches is a stronger selective pressure than loss of one β-tubulin gene. Furthermore, we used genome-editing to show that the most common parasitic nematode β-tubulin allele that confers BZ resistance, F200Y, confers resistance in C. elegans. Importantly, we identified a novel genomic region that is correlated with ABZ resistance in the C. elegans population but independent of ben-1 and the other β-tubulin loci, suggesting that there are multiple mechanisms underlying BZ resistance. Taken together, our results establish a population-level resource of nematode natural diversity as an important model for the study of mechanisms that give rise to BZ resistance.

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Section: Resultsmentioning

confidence: 99%

Extreme allelic heterogeneity at a Caenorhabditis elegans beta-tubulin locus explains natural resistance to benzimidazoles

et al. 2018

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“…Low‐ and middle‐income countries have already included several of these treatments on their lists of national essential medicines to inform priorities for procurement, reimbursement, and central distribution . The scale‐up of WHO essential medicines for hypertension protocols follows the success of adapting national level scale‐up priorities for other medication types …”

Section: Laboratory Monitoringmentioning

confidence: 99%

Recommended treatment protocols to improve management of hypertension globally: A statement by Resolve to Save Lives and the World Hypertension League (WHL)

Jaffe

Frieden

Campbell

et al. 2018

J of Clinical Hypertension

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| INTRODUC TI ONCardiovascular disease (CVD) is the world's leading cause of death, killing 18 million people per year-about one-third of all deaths. 1 Hypertension is the leading cause of CVD and contributes to 10 million deaths per year-the same number of people killed by all infectious diseases combined. 2 Whereas the burden of hypertension and CVD afflict predominantly older aged persons in high-income countries, younger populations are disproportionately affected in lowand middle-income countries. 1 It is estimated that CVD costs 2%-4% of gross national income in these countries. 3 Hypertension is amenable to treatment with generic, oncedaily, low-cost medications that are safe and effective, yet currently, fewer than 15% of adults with hypertension worldwide have their blood pressure controlled to 140/90 or lower. 4 Some countries and health systems have achieved control rates approaching 70%; 5,6 accomplishing this on a global basis could save millions of lives. The Resolve to Save Lives Cardiovascular Health Initiative has been established to help improve hypertension management. Resolve to Save Lives -a 5-year, $225 million initiative based at Vital Strategies, a global health nonprofit organization, is supporting key organizations and engaging new partners to help low-and middle-income countries accelerate and scale-up implementation of proven tools and strategies to prevent CVD. 7 These tools, together with the elimination of artificial trans-fats and a reduction of sodium consumption, could improve hypertension management and save 100 million lives over the next 30 years.

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“…A similar P2Y 2 R agonist, denufosol, improved lung function relative to placebo in cystic fibrosis patients during phase 2 clinical trials, but failed to achieve its primary endpoints during phase 3 follow-up trials (Accurso et al, 2011). Notably, the FDA-approved anti-coagulant Plavix (clopidogrel), a P2Y 12 receptor (P2Y 12 R) antagonist, was the 2 nd most prescribed drug in the world in 2010 and is currently on the World Health Organization's List of Essential Medicines (Topol and Schork, 2011;Kishore et al, 2018). However, the therapeutic potential of targeting purinergic receptors has not been wellinvestigated in the context of human salivary dysfunction.…”

Section: Introductionmentioning

confidence: 99%

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

et al. 2020

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Although often overlooked in our daily lives, saliva performs a host of necessary physiological functions, including lubricating and protecting the oral cavity, facilitating taste sensation and digestion and maintaining tooth enamel. Therefore, salivary gland dysfunction and hyposalivation, often resulting from pathogenesis of the autoimmune disease Sjögren's syndrome or from radiotherapy of the head and neck region during cancer treatment, severely reduce the quality of life of afflicted patients and can lead to dental caries, periodontitis, digestive disorders, loss of taste and difficulty speaking. Since their initial discovery in the 1970s, P2 purinergic receptors for extracellular nucleotides, including ATP-gated ion channel P2X and G protein-coupled P2Y receptors, have been shown to mediate physiological processes in numerous tissues, including the salivary glands where P2 receptors represent a link between canonical and non-canonical saliva secretion. Additionally, extracellular nucleotides released during periods of cellular stress and inflammation act as a tissue alarmin to coordinate immunological and tissue repair responses through P2 receptor activation. Accordingly, P2 receptors have gained widespread clinical interest with agonists and antagonists either currently undergoing clinical trials or already approved for human use. Here, we review the contributions of P2 receptors to salivary gland function and describe their role in salivary gland dysfunction. We further consider their potential as therapeutic targets to promote physiological saliva flow, prevent salivary gland inflammation and enhance tissue regeneration.

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Modernizing the World Health Organization List of Essential Medicines for Preventing and Controlling Cardiovascular Diseases

Cited by 41 publications

References 50 publications

Extreme allelic heterogeneity at a Caenorhabditis elegans beta-tubulin locus explains natural resistance to benzimidazoles

Extreme allelic heterogeneity at a Caenorhabditis elegans beta-tubulin locus explains natural resistance to benzimidazoles

Recommended treatment protocols to improve management of hypertension globally: A statement by Resolve to Save Lives and the World Hypertension League (WHL)

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

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