A method to improve the efficacy of topical eflornithine hydrochloride cream

Kumar, Amit; Naguib, Youssef W.; Shi, Yan; Cui, Zhengrong

doi:10.3109/10717544.2014.951746

Cited by 34 publications

(26 citation statements)

References 39 publications

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“…Lastly, to our knowledge, spironolactone has not been studied in the context of T. brucei infection, although it has been tested for its effects on myocardial protection in a model of Chagas disease [48]. Spironolactone is used for the treatment of hirsutism, as is eflornithine, which is one of the most important anti-trypanosomal drugs in current use [49].…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

et al. 2020

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Trypanosoma brucei are unicellular parasites endemic to Sub-Saharan Africa that cause fatal disease in humans and animals. Infection with these parasites is caused by the bite of the tsetse fly vector, and parasites living extracellularly in the blood of infected animals evade the host immune system through antigenic variation. Existing drugs for Human and Animal African Trypanosomiasis are difficult to administer and can have serious side effects. Resistance to some drugs is also increasing, creating an urgent need for alternative trypanosomiasis therapeutics. We screened a library of 1,585 U.S. or foreign-approved drugs and identified 154 compounds that inhibit trypanosome growth. As all of these compounds have already undergone testing for human toxicity, they represent good candidates for repurposing as trypanosome therapeutics. In addition to identifying drugs that inhibit trypanosome growth, we wished to identify small molecules that can induce bloodstream form parasites to differentiate into forms adapted for the insect vector. These insect stage parasites lack the immune evasion mechanisms prevalent in bloodstream forms, making them vulnerable to the host immune system. To identify drugs that increase transcript levels of an invariant, insect-stage specific surface protein called procyclin, we engineered bloodstream reporter parasites that express Green Fluorescent Protein (GFP) following induction or stabilization of the procyclin transcript. Using these bloodstream reporter strains in combination with automated flow cytometry, we identified eflornithine, spironolactone, and phenothiazine as small molecules that increase abundance of procyclin transcript. Both eflornithine and spironolactone also affect transcript levels for a subset of differentiation associated genes. While we failed to identify compounds that increase levels of procyclin protein on the cell surface, this study is proof of principle that these fluorescent reporter parasites represent a useful tool for future small molecule or genetic screens aimed at identifying molecules or processes that initiate remodeling of the parasite surface during life cycle stage transitions.

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Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

et al. 2020

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“…Spironolactone is used for the treatment hirsutism, as is eflornithine, which is one of the most important anti-trypanosomal drugs in current use (27).…”

Section: A Proof Of Principle Screen Shows That the Reporter Strain Cmentioning

confidence: 99%

Identification of clinically approved small molecules that inhibit growth and promote surface remodeling in the African trypanosome

Walsh

Naudzius

Diaz

et al. 2019

Preprint

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Trypanosoma brucei are unicellular parasites endemic to Sub-Saharan Africa that cause fatal disease in humans and animals. Infection with these parasites is caused by the bite of the tsetse fly vector, and parasites living extracellularly in the blood of infected animals evade the host immune system through antigenic variation. Existing drugs for Human and Animal African Trypanosomiasis are difficult to administer and can have serious side effects. Resistance to some drugs is also increasing, creating an urgent need for alternative trypanosomiasis therapeutics. In addition to identifying drugs that inhibit trypanosome growth, we wish to identify small molecules that can induce bloodstream form parasites to differentiate into forms adapted for the insect vector. These insect stage parasites do not vary proteins on their cell surface, making them vulnerable to the host immune system. To identify drugs that trigger differentiation of the parasite from bloodstream to insect stages, we engineered bloodstream reporter parasites that express Green Fluorescent Protein (GFP) following induction of the invariant insect-stage specific procyclin transcript. Using these bloodstream reporter strains in combination with high-throughput flow cytometry, we screened a library of 1,585 U.S. or foreignapproved drugs and identified eflornithine, spironolactone, and phenothiazine as small molecules that induce transcription of procylin. Both eflornithine and spironolactone also affect transcript levels for a subset of differentiation associated genes. We further identified 154 compounds that inhibit trypanosome growth. As all of these compounds have already undergone testing for human toxicity, they represent good candidates for repurposing as trypanosome therapeutics. Finally, this study is proof of principle that fluorescent reporters are a useful tool for small molecule or genetic screens aimed at identifying molecules or processes that initiate remodeling of the parasite surface during life cycle stage transitions. Author SummaryAfrican trypanosomes are unicellular parasites that infect humans and animals, causing a fatal disease known as sleeping sickness in humans and nagana in cattle. These diseases impose a severe economic burden for people living in Sub-Saharan Africa, where parasites are transmitted to humans and animals through the bite of the tsetse fly. Parasites living outside cells in humans and animals are attacked by the antibodies of the host immune system, but they can evade this attack by varying the proteins on their cell surface. In contrast, because flies do not have an antibody-mediated immune response, parasites living in flies do not vary the proteins on their cell surface. In this study, we performed a small molecule screen to identify compounds that might force bloodstream parasites to move forward in their life cycle to become more similar to parasites living in flies, causing them to express a protein on their cell surface that does not vary. This invariant protein on the surface of bloodstream parasites ...

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“…Microneedles for drug delivery Various types of microneedle devices, either alone or in combination with other therapies, such as radiofrequency [4], iontophoresis [5], photodynamic therapy [6] and laser, have been used for the treatment of skin conditions, such as wrinkles, melasma, photo damaging, hirsutism [7] and scars [8]. The most common forms of the microneedle devices are dermal rollers, microinjections, solid microneedles and drug-laden microneedles.…”

Section: Micro and Nanoneedles For Drug Deliverymentioning

confidence: 99%

Micro and Nanoneedles for Drug Delivery and Biosensing

Kathuria

Kochhar²,

Kang

2018

Ther. Deliv.

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Delivering therapeutics in a painless manner is one of the many objectives for the treatment of clinical conditions. Micro and nanoneedles are small-scale devices that can help overcome the resistance encountered during drug diffusion by creating conduits of small dimensions through biomembranes. Microneedles for drug delivery applications were manually produced until the 1990s and after this the high precision technology from the semiconductor industry was adopted for their production [ 1 ]. Over the last decade or so, microneedles for transdermal applications have been widely studied. Currently, microneedle patches, mainly based on hyaluronates, are available over the counter for cosmetic applications. On the other hand, nanoneedles are used in atomic force microscopy, which has been explored for drug delivery and biosensing over the last two decades [ 2 , 3 ]. Micro and nanoneedle-based biosensing also poses potential for environment-responsive drug delivery. In this article, the current research, clinical studies and future perspectives of micro and nanoneedle-based systems are discussed for drug delivery and biosensing applications.

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A method to improve the efficacy of topical eflornithine hydrochloride cream

Cited by 34 publications

References 39 publications

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome

Identification of clinically approved small molecules that inhibit growth and promote surface remodeling in the African trypanosome

Micro and Nanoneedles for Drug Delivery and Biosensing

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