Corallopyronin A for short-course anti-wolbachial, macrofilaricidal treatment of filarial infections

Current efforts to eliminate the neglected tropical diseases onchocerciasis and lymphatic filariasis, caused by the filarial nematodes Onchocerca volvulus and Wuchereria bancrofti or Brugia spp., respectively, are hampered by lack of a short-course macrofilaricidal–adult-worm killing–treatment. Anti-wolbachial antibiotics, e.g. doxycycline, target the essential Wolbachia endosymbionts of filariae and are a safe prototype adult-worm-sterilizing and macrofilaricidal regimen, in contrast to standard treatments with ivermectin or diethylcarbamazine, which mainly target the microfilariae. However, treatment regimens of 4–5 weeks necessary for doxycycline and contraindications limit its use. Therefore, we tested the preclinical anti-Wolbachia drug candidate Corallopyronin A (CorA) for in vivo efficacy during initial and chronic filarial infections in the Litomosoides sigmodontis rodent model. CorA treatment for 14 days beginning immediately after infection cleared >90% of Wolbachia endosymbionts from filariae and prevented development into adult worms. CorA treatment of patently infected microfilaremic gerbils for 14 days with 30 mg/kg twice a day (BID) achieved a sustained reduction of >99% of Wolbachia endosymbionts from adult filariae and microfilariae, followed by complete inhibition of filarial embryogenesis resulting in clearance of microfilariae. Combined treatment of CorA and albendazole, a drug currently co-administered during mass drug administrations and previously shown to enhance efficacy of anti-Wolbachia drugs, achieved microfilarial clearance after 7 days of treatment at a lower BID dose of 10 mg/kg CorA, a Human Equivalent Dose of 1.4 mg/kg. Importantly, this combination led to a significant reduction in the adult worm burden, which has not yet been published with other anti-Wolbachia candidates tested in this model. In summary, CorA is a preclinical candidate for filariasis, which significantly reduces treatment times required to achieve sustained Wolbachia depletion, clearance of microfilariae, and inhibition of embryogenesis. In combination with albendazole, CorA is robustly macrofilaricidal after 7 days of treatment and fulfills the Target Product Profile for a macrofilaricidal drug.

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AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1816585116 ◽

2019 ◽

Vol 116 (4) ◽

pp. 1414-1419 ◽

Cited By ~ 18

Author(s):

W. David Hong ◽

Farid Benayoud ◽

Gemma L. Nixon ◽

Louise Ford ◽

Kelly L. Johnston ◽

...

Keyword(s):

Neglected Tropical Diseases ◽

Drug Candidate ◽

Phenotypic Screening ◽

Tropical Diseases ◽

Proof Of Concept ◽

Preclinical Models ◽

Superior Efficacy ◽

Short Course ◽

Filarial Nematodes ◽

Candidate Molecule

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.

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The Potentials of Calotropis procera against Filarial Elephantiasis: An in- silico approach

10.21203/rs.3.rs-418805/v1 ◽

2021 ◽

Author(s):

Aswin Mohan ◽

Shanitha Shaji ◽

Sunitha P ◽

Shahanas Naisam ◽

Nidhin Sreeku

Keyword(s):

Lymphatic Filariasis ◽

Blood Feeding ◽

Calotropis Procera ◽

Drug Candidate ◽

Potential Drug ◽

Glutathione S Transferase ◽

Filarial Nematodes ◽

Detoxification Process

Abstract Lymphatic filariasis is one of the major diseases that belong to the category of neglected tropical illness. Filarial nematodes are the cause of the disease and are transmitted to humans via blood-feeding arthropod vectors. Drugs such as Albendazole, Ivermectin and diethylcarbamazine are administered either individually or in combination to overcome the progress of the lymphatic filariasis. However, these drugs have some disadvantages like temporary hair loss, dizziness, nausea etc. The filarial parasites have multifunctional proteins including the Glutathione-s-transferase (GST) enzyme which plays a major role in detoxification of endogenous electrophilic compounds. This study aims at the identification of a natural molecule that has the potential to bind with the GST enzyme and thus interrupt the detoxification process within the filarial parasite, Brugia malayi. A medicinal plant Calotropis procera, owing to its anthelmintic properties was searched for the presence of potential phytocompounds. The phytocompounds were docked against the homology modeled GST enzyme using the MOE software. The results were screened and analyzed based on the Lipinski rule of 5. N-octanoate was the phytocompound obtained based on molecular docking, subjected to molecular dynamics. These results require further in vitro and in vivo validation to consider n-octanoate as a potential drug candidate for lymphatic filariasis treatment.

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INFLUENCE OF GROWTH REGULATORS AND LED IRRADIATORS ON PINE STRAWBERRY ADAPTATION

Vestnik of the Russian agricultural science ◽

10.30850/vrsn/2019/6/12-15 ◽

1970 ◽

pp. 12-15

Author(s):

M. G. Markova ◽

E. N. Somova

Keyword(s):

Surface Area ◽

Growth Regulators ◽

Leaf Surface ◽

Combined Treatment ◽

Fragaria X Ananassa ◽

Leaf Surface Area ◽

External Conditions ◽

Light Effects ◽

Control Version

Work on going through the adaptation stage of rooted micro-stalks comes down to searching for new growth regulators and studying the influence of external conditions, which include, among other things, light effects. The data of 2018-2019 on the effect of growth regulators Siliplant, EcoFus and experimental LED phytoradiators on the adaptation of rooted micro-stalks of garden strawberries (Fragaria x ananassa duch) in vivo are presented. The object of research is rooted micro-stalks of garden strawberries of the Korona variety. It was revealed that, at the adaptation stage of rooted micro-stalks of strawberries, the most effective was the treatment of plants by spraying with Siliplant at a concentration of 1.0 ml/l and the combined treatment with Siliplant and EcoFus at concentrations of 0.5 ml/l: regardless of lighting, the survival rate averaged 99.4 - 99.7%, the leaf surface area increased significantly from 291.85 mm2 to 334.4 mm2. The number of normally developed leaves of strawberry microplants increased significantly after treatment with all preparations from 3.5 to 6.0, 5.8 and 6.5 pcs/plant, and a significant increase in the height of strawberry rosettes was facilitated by treatment with Siliplant and Siliplant together with EcoFus. Regardless of growth regulators, the most effective was the experimental LED phyto-irradiator with a changing spectrum, which contributed to an increase in leaf surface area, height of rosettes and the number of normally developed leaves in strawberry microplants. When illuminated with a flashing phytoradiator, these indicators are lower than in the control version, but not significantly. By the end of the rooting stage, all microplants of garden strawberries corresponded to GOST R 54051-2010.

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Peculiarities of the course of type I allergic reactions in patients with blood diseases

Terapevt (General Physician) ◽

10.33920/med-12-2004-06 ◽

2020 ◽

pp. 40-50

Author(s):

A. Nikitina

Keyword(s):

Search Engines ◽

Anaphylactic Shock ◽

Type I ◽

Allergic Reactions ◽

Common Cause ◽

Blood Diseases ◽

Treatment Regimens ◽

Modern Methods

Analysis of literature data presented in search engines — Elibrary, PubMed, Cochrane — concerning the risk of developing type I allergic reactions in patients with blood diseases is presented. It is shown that the most common cause of type I allergic reactions is drugs included in the treatment regimens of this category of patients. The article presents statistics on the increase in the number of drug allergies leading to cases of anaphylactic shock in patients with blood diseases. Modern methods for the diagnosis of type I allergic reactions in vivo and in vitro are considered.

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THE ROLE OF BRACHYTHERAPY IN TREATMENT FOR ESOPHAGEAL CANCER

Problems in oncology ◽

10.37469/0507-3758-2017-63-4-660-665 ◽

2017 ◽

Vol 63 (4) ◽

pp. 660-665

Author(s):

Yelena Tyuryaeva

Keyword(s):

Esophageal Cancer ◽

Critical Review ◽

Palliative Treatment ◽

Combined Treatment ◽

Neoadjuvant Treatment ◽

Early Esophageal Cancer ◽

Separate Section ◽

Treatment Regimens ◽

Contradictory Data

The article is devoted to various aspects of the use of intraluminal brachytherapy (IB) in treatment for esophageal cancer (EC). A critical review of the use of IB as a component of combined radiotherapy/chemoradiotherapy in neoadjuvant treatment regimens, for definitive CRT, as well as in palliative treatment of non-operable tumors of this localization is given. The contradictory data on the effectiveness of brachytherapy with locally distributed, inoperable EC are summarized. A separate section relates to the prospects for incorporating brachytherapy into combined treatment of early esophageal cancer. Carried out analysis testifies to the necessity of standardization of summary and daily doses of irradiation depending on the indications to the IB.

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Identification of 2-Fluoropalmitic Acid as a Potential Therapeutic Agent Against Glioblastoma

Current Pharmaceutical Design ◽

10.2174/1381612826666200429092742 ◽

2020 ◽

Vol 26 (36) ◽

pp. 4675-4684 ◽

Cited By ~ 1

Author(s):

Shabierjiang Jiapaer ◽

Takuya Furuta ◽

Yu Dong ◽

Tomohiro Kitabayashi ◽

Hemragul Sabit ◽

...

Keyword(s):

Combination Therapy ◽

Drug Screening ◽

Therapeutic Agent ◽

Gelatin Zymography ◽

Therapeutic Agents ◽

Drug Candidate ◽

Potential Therapeutic Agent ◽

Sphere Formation ◽

Improve Patient

Background: Glioblastomas (GBMs) are aggressive malignant brain tumors. Although chemotherapy with temozolomide (TMZ) can extend patient survival, most patients eventually demonstrate resistance. Therefore, novel therapeutic agents that overcome TMZ chemoresistance are required to improve patient outcomes. Purpose: Drug screening is an efficient method to find new therapeutic agents from existing drugs. In this study, we explored a novel anti-glioma agent by drug screening and analyzed its function with respect to GBM treatment for future clinical applications. Methods: Drug libraries containing 1,301 diverse chemical compounds were screened against two glioma stem cell (GSC) lines for drug candidate selection. The effect of selected agents on GSCs and glioma was estimated through viability, proliferation, sphere formation, and invasion assays. Combination therapy was performed to assess its ability to enhance TMZ cytotoxicity against GBM. To clarify the mechanism of action, we performed methylation-specific polymerase chain reaction, gelatin zymography, and western blot analysis. Results: The acyl-CoA synthetase inhibitor 2-fluoropalmitic acid (2-FPA) was selected as a candidate anti-glioma agent. 2-FPA suppressed the viability and stem-like phenotype of GSCs. It also inhibited proliferation and invasion of glioma cell lines. Combination therapy of 2-FPA with TMZ synergistically enhanced the efficacy of TMZ. 2-FPA suppressed the expression of phosphor-ERK, CD133, and SOX-2; reduced MMP-2 activity; and increased methylation of the MGMT promoter. Conclusion: 2-FPA was identified as a potential therapeutic agent against GBM. To extend these findings, physiological studies are required to examine the efficacy of 2-FPA against GBM in vivo.

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Naphthoquinones and derivatives for chemotherapy: perspectives and limitations of their anti-trypanosomatids activities

Current Pharmaceutical Design ◽

10.2174/1381612826666201109111802 ◽

2020 ◽

Vol 26 ◽

Author(s):

Luíza Dantas-Pereira ◽

Edézio F. Cunha-Junior ◽

Valter V. Andrade-Neto ◽

John F. Bower ◽

Guilherme A. M. Jardim ◽

...

Keyword(s):

Large Scale ◽

Neglected Tropical Diseases ◽

Folk Medicine ◽

Leishmania Species ◽

Parasitic Infections ◽

Mechanistic Analysis ◽

Leishmania Spp ◽

Nanomolar Range

: Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo are essential for the development of a novel, specific and safe derivative, minimizing adverse effects.

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Tamarix articulata (T. articulata) - An Important Halophytic Medicinal Plant with Potential Pharmacological Properties

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190318120103 ◽

2019 ◽

Vol 20 (4) ◽

pp. 285-292 ◽

Cited By ~ 5

Author(s):

Abdullah M. Alnuqaydan ◽

Bilal Rah

Keyword(s):

Medicinal Plant ◽

Biological Activities ◽

Wide Spectrum ◽

Biological Properties ◽

In Vivo Model ◽

Drug Candidate ◽

Phytochemical Analysis ◽

Pharmacological Properties

Background:Tamarix Articulata (T. articulata), commonly known as Tamarisk or Athal in Arabic region, belongs to the Tamaricaece species. It is an important halophytic medicinal plant and a good source of polyphenolic phytochemical(s). In traditional medicines, T. articulata extract is commonly used, either singly or in combination with other plant extracts against different ailments since ancient times.Methods:Electronic database survey via Pubmed, Google Scholar, Researchgate, Scopus and Science Direct were used to review the scientific inputs until October 2018, by searching appropriate keywords. Literature related to pharmacological activities of T. articulata, Tamarix species, phytochemical analysis of T. articulata, biological activities of T. articulata extracts. All of these terms were used to search the scientific literature associated with T. articulata; the dosage of extract, route of administration, extract type, and in-vitro and in-vivo model.Results:Numerous reports revealed that T. articulata contains a wide spectrum of phytochemical(s), which enables it to have a wide window of biological properties. Owing to the presence of high content of phytochemical compounds like polyphenolics and flavonoids, T. articulata is a potential source of antioxidant, anti-inflammatory and antiproliferative properties. In view of these pharmacological properties, T. articulata could be a potential drug candidate to treat various clinical conditions including cancer in the near future.Conclusion:In this review, the spectrum of phytochemical(s) has been summarized for their pharmacological properties and the mechanisms of action, and the possible potential therapeutic applications of this plant against various diseases discussed.

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The Role of nitro (NO2-), chloro (Cl), and fluoro (F) Substitution in the Design of Antileishmanial and Antichagasic Compounds

Current Drug Targets ◽

10.2174/1389450121666201228122239 ◽

2020 ◽

Vol 21 ◽

Author(s):

Boniface Pone ◽

Ferreira Igne Elizabeth

Keyword(s):

Chagas Disease ◽

Mammalian Cells ◽

Neglected Tropical Diseases ◽

New Drugs ◽

Pharmacokinetic Studies ◽

Scientific Publications ◽

Antitrypanosomal Activity ◽

Chemical Groups

: Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas disease are among the most severe NTDs, and are caused by the Leishmania sp, and Trypanosoma cruzi, respectively. Glucantime, pentamidine and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance, and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, which chemical groups are known to improve the biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluoro-synthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth to mention that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro- and chloro-groups in the compound backbone. All in all, nitro and h0alogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts on in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies, and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.

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