The Experts below are selected from a list of 54 Experts worldwide ranked by ideXlab platform
Niroshini Nirmalan - One of the best experts on this subject based on the ideXlab platform.
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lead optimisation of Dehydroemetine for repositioned use in malaria
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Priyanka Panwar, Kepa K Burusco, Muna Abubaker, Holly Matthews, Andrey Gutnov, Elena Fernandezalvaro, Richard A Bryce, James A Wilkinson, Niroshini NirmalanAbstract:: Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent in vitro inhibitor of the multidrug-resistant strain K1 of Plasmodium falciparum (50% inhibitory concentration [IC50], 47 nM ± 2.1 nM [mean ± standard deviation]). Dehydroemetine, a synthetic analogue of emetine dihydrochloride, has been reported to have less-cardiotoxic effects than emetine. The structures of two diastereomers of Dehydroemetine were modeled on the published emetine binding site on the cryo-electron microscopy (cryo-EM) structure with PDB code 3J7A (P. falciparum 80S ribosome in complex with emetine), and it was found that (-)-R,S-Dehydroemetine mimicked the bound pose of emetine more closely than did (-)-S,S-dehydroisoemetine. (-)-R,S-Dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multidrug-resistant K1 strain of P. falciparum compared with (-)-S,S-dehydroisoemetine (IC50, 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1'. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compound exhibited gametocidal properties with no cross-resistance against any of the multidrug-resistant strains tested. Drug interaction studies showed (-)-R,S-Dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride and (-)-R,S-Dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity affecting the mitochondrial membrane potential, indicating a possible multimodal mechanism of action.
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lead optimisation of Dehydroemetine for repositioned use in malaria
bioRxiv, 2019Co-Authors: Priyanka Panwar, Kepa K Burusco, Muna Abubaker, Holly Matthews, Andrey Gutnov, Elena Fernandezalvaro, Richard A Bryce, James A Wilkinson, Niroshini NirmalanAbstract:Abstract Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC50: 47 nM + 2.1 nM). 2,3-Dehydroemetine, a synthetic analogue of emetine dihydrochloride has been claimed to have less cardiotoxic effects than emetine. The structures of two diastereoisomers of 2,3-Dehydroemetine were modelled on the reported emetine binding site on cryo-EM structure 3J7A and it was found that (-)-R,S-Dehydroemetine mimicked the bound pose of emetine more closely than (-)-S,S-dehydroisoemetine. (-)-R,S-Dehydroemetine was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison with (-)-S,S-dehydroisoemetine, which loses its potency due to the change of configuration at C-1’. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug resistant strains tested. Drug interaction studies showed (-)-R,S-Dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride, and (-)-R,S-Dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed atovoquone-like activity on the mitochondrial membrane potential.
K. Rajender Reddy - One of the best experts on this subject based on the ideXlab platform.
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Amebiasis
Current Treatment Options in Gastroenterology, 1999Co-Authors: Salvatore Badalamenti, Jennifer E. Jameson, K. Rajender ReddyAbstract:More than 80% of cases of amebic liver abscess can be managed with a 14-day course of intravenous or oral metronidazole. In cases of suspected amebic liver abscess, treatment should be started before diagnostic confirmation. If no clinical improvement is evident by 72 to 96 hours, treatment should be changed to Dehydroemetine and chloroquine. Invasive treatment is necessary only in patients in whom medical treatment fails within 5 days or in whom signs of clinically severe disease are present. A 10-day course with a luminal agent such as paromomycin to eliminate intestinal cysts, which are resistant to imidazoles, should always follow treatment of the liver abscess. Percutaneous catheter drainage is indicated in patients with impending rupture, with a lesion 6 cm or more in diameter, with an abscess located in the left lobe or high in the dome of the right lobe, or in whom medical treatment fails. Although sympathetic pleural effusion is not an indication for drainage, direct pulmonary involvement or spread to pleural or lung tissues requires drainage. Intraperitoneal rupture and peritonitis necessitate open surgical drainage. Only a small minority of amebic liver abscesses are secondarily infected by other organisms. Because relapses are possible, feces should be checked for cysts monthly for several months after therapy.
Priyanka Panwar - One of the best experts on this subject based on the ideXlab platform.
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lead optimisation of Dehydroemetine for repositioned use in malaria
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Priyanka Panwar, Kepa K Burusco, Muna Abubaker, Holly Matthews, Andrey Gutnov, Elena Fernandezalvaro, Richard A Bryce, James A Wilkinson, Niroshini NirmalanAbstract:: Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent in vitro inhibitor of the multidrug-resistant strain K1 of Plasmodium falciparum (50% inhibitory concentration [IC50], 47 nM ± 2.1 nM [mean ± standard deviation]). Dehydroemetine, a synthetic analogue of emetine dihydrochloride, has been reported to have less-cardiotoxic effects than emetine. The structures of two diastereomers of Dehydroemetine were modeled on the published emetine binding site on the cryo-electron microscopy (cryo-EM) structure with PDB code 3J7A (P. falciparum 80S ribosome in complex with emetine), and it was found that (-)-R,S-Dehydroemetine mimicked the bound pose of emetine more closely than did (-)-S,S-dehydroisoemetine. (-)-R,S-Dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multidrug-resistant K1 strain of P. falciparum compared with (-)-S,S-dehydroisoemetine (IC50, 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1'. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compound exhibited gametocidal properties with no cross-resistance against any of the multidrug-resistant strains tested. Drug interaction studies showed (-)-R,S-Dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride and (-)-R,S-Dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity affecting the mitochondrial membrane potential, indicating a possible multimodal mechanism of action.
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lead optimisation of Dehydroemetine for repositioned use in malaria
bioRxiv, 2019Co-Authors: Priyanka Panwar, Kepa K Burusco, Muna Abubaker, Holly Matthews, Andrey Gutnov, Elena Fernandezalvaro, Richard A Bryce, James A Wilkinson, Niroshini NirmalanAbstract:Abstract Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC50: 47 nM + 2.1 nM). 2,3-Dehydroemetine, a synthetic analogue of emetine dihydrochloride has been claimed to have less cardiotoxic effects than emetine. The structures of two diastereoisomers of 2,3-Dehydroemetine were modelled on the reported emetine binding site on cryo-EM structure 3J7A and it was found that (-)-R,S-Dehydroemetine mimicked the bound pose of emetine more closely than (-)-S,S-dehydroisoemetine. (-)-R,S-Dehydroemetine was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison with (-)-S,S-dehydroisoemetine, which loses its potency due to the change of configuration at C-1’. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug resistant strains tested. Drug interaction studies showed (-)-R,S-Dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride, and (-)-R,S-Dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed atovoquone-like activity on the mitochondrial membrane potential.
Salvatore Badalamenti - One of the best experts on this subject based on the ideXlab platform.
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Amebiasis
Current Treatment Options in Gastroenterology, 1999Co-Authors: Salvatore Badalamenti, Jennifer E. Jameson, K. Rajender ReddyAbstract:More than 80% of cases of amebic liver abscess can be managed with a 14-day course of intravenous or oral metronidazole. In cases of suspected amebic liver abscess, treatment should be started before diagnostic confirmation. If no clinical improvement is evident by 72 to 96 hours, treatment should be changed to Dehydroemetine and chloroquine. Invasive treatment is necessary only in patients in whom medical treatment fails within 5 days or in whom signs of clinically severe disease are present. A 10-day course with a luminal agent such as paromomycin to eliminate intestinal cysts, which are resistant to imidazoles, should always follow treatment of the liver abscess. Percutaneous catheter drainage is indicated in patients with impending rupture, with a lesion 6 cm or more in diameter, with an abscess located in the left lobe or high in the dome of the right lobe, or in whom medical treatment fails. Although sympathetic pleural effusion is not an indication for drainage, direct pulmonary involvement or spread to pleural or lung tissues requires drainage. Intraperitoneal rupture and peritonitis necessitate open surgical drainage. Only a small minority of amebic liver abscesses are secondarily infected by other organisms. Because relapses are possible, feces should be checked for cysts monthly for several months after therapy.
Muna Abubaker - One of the best experts on this subject based on the ideXlab platform.
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lead optimisation of Dehydroemetine for repositioned use in malaria
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Priyanka Panwar, Kepa K Burusco, Muna Abubaker, Holly Matthews, Andrey Gutnov, Elena Fernandezalvaro, Richard A Bryce, James A Wilkinson, Niroshini NirmalanAbstract:: Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent in vitro inhibitor of the multidrug-resistant strain K1 of Plasmodium falciparum (50% inhibitory concentration [IC50], 47 nM ± 2.1 nM [mean ± standard deviation]). Dehydroemetine, a synthetic analogue of emetine dihydrochloride, has been reported to have less-cardiotoxic effects than emetine. The structures of two diastereomers of Dehydroemetine were modeled on the published emetine binding site on the cryo-electron microscopy (cryo-EM) structure with PDB code 3J7A (P. falciparum 80S ribosome in complex with emetine), and it was found that (-)-R,S-Dehydroemetine mimicked the bound pose of emetine more closely than did (-)-S,S-dehydroisoemetine. (-)-R,S-Dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multidrug-resistant K1 strain of P. falciparum compared with (-)-S,S-dehydroisoemetine (IC50, 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1'. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compound exhibited gametocidal properties with no cross-resistance against any of the multidrug-resistant strains tested. Drug interaction studies showed (-)-R,S-Dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride and (-)-R,S-Dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity affecting the mitochondrial membrane potential, indicating a possible multimodal mechanism of action.
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lead optimisation of Dehydroemetine for repositioned use in malaria
bioRxiv, 2019Co-Authors: Priyanka Panwar, Kepa K Burusco, Muna Abubaker, Holly Matthews, Andrey Gutnov, Elena Fernandezalvaro, Richard A Bryce, James A Wilkinson, Niroshini NirmalanAbstract:Abstract Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC50: 47 nM + 2.1 nM). 2,3-Dehydroemetine, a synthetic analogue of emetine dihydrochloride has been claimed to have less cardiotoxic effects than emetine. The structures of two diastereoisomers of 2,3-Dehydroemetine were modelled on the reported emetine binding site on cryo-EM structure 3J7A and it was found that (-)-R,S-Dehydroemetine mimicked the bound pose of emetine more closely than (-)-S,S-dehydroisoemetine. (-)-R,S-Dehydroemetine was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison with (-)-S,S-dehydroisoemetine, which loses its potency due to the change of configuration at C-1’. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug resistant strains tested. Drug interaction studies showed (-)-R,S-Dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride, and (-)-R,S-Dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed atovoquone-like activity on the mitochondrial membrane potential.