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Judith Berman - One of the best experts on this subject based on the ideXlab platform.
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topical 15 Paromomycin aquaphilic for bolivian leishmania braziliensis cutaneous leishmaniasis a randomized placebo controlled trial
Clinical Infectious Diseases, 2019Co-Authors: Jaime Soto, Paula Soto, Andrea Ajata, Carmelo Luque, Carlos Tintaya, David Paz, Daniela Rivero, Judith BermanAbstract:BACKGROUND Cutaneous leishmaniasis (CL) presents as 1 or more skin lesions, which makes local therapy inherently attractive compared to systemic therapy that exposes the whole body to a drug. For 30 years, 15% Paromomycin topical formulations have been in clinical experimentation. Recently, 15% Paromomycin in Aquaphilic, a complex base to facilitate adsorption into the lesion, was found superior to aquaphilic vehicle for Old World Leishmania major disease. METHODS We performed a randomized trial of 15% Paromomycin in Aquaphilic (40 patients) vs Aquaphilic vehicle (20 patients) vs a positive control (intralesional pentamidine; 20 patients) against L. braziliensis CL in Bolivia. RESULTS Cure rates after 6 months of follow-up were 31 of 40 (77.5%, 95% confidence interval [CI] 62.5-88%) for Paromomycin-Aquaphilic, 2 of 20 (10%, 95% CI 3-30%) for Aquaphilic vehicle (P < .0001 vs Paromomycin-Aquaphilic), and 14 of 20 (70%, 95% CI 48-85.5%) for intralesional pentamidine. Both Paromomycin-Aquaphilic and the Aquaphilic vehicle were very well tolerated, with only grade 1 adverse reactions in 5-10% of patients. CONCLUSIONS Against L. braziliensis CL, a prevalent, aggressive form of New World CL, 15% Paromomycin-aquaphilic was vastly superior to a negative vehicle control and was comparable in efficacy to a positive control. This study enlarges the potential use of 15% Paromomycin-Aquaphilic from one form of Old World CL to CL more generally. CLINICAL TRIALS REGISTRATION NCT03096457.
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Topical 15% Paromomycin-Aquaphilic for Bolivian Leishmania braziliensis Cutaneous Leishmaniasis: A Randomized, Placebo-controlled Trial.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2018Co-Authors: Jaime Soto, Paula Soto, Andrea Ajata, Carmelo Luque, Carlos Tintaya, David Paz, Daniela Rivero, Judith BermanAbstract:BACKGROUND Cutaneous leishmaniasis (CL) presents as 1 or more skin lesions, which makes local therapy inherently attractive compared to systemic therapy that exposes the whole body to a drug. For 30 years, 15% Paromomycin topical formulations have been in clinical experimentation. Recently, 15% Paromomycin in Aquaphilic, a complex base to facilitate adsorption into the lesion, was found superior to aquaphilic vehicle for Old World Leishmania major disease. METHODS We performed a randomized trial of 15% Paromomycin in Aquaphilic (40 patients) vs Aquaphilic vehicle (20 patients) vs a positive control (intralesional pentamidine; 20 patients) against L. braziliensis CL in Bolivia. RESULTS Cure rates after 6 months of follow-up were 31 of 40 (77.5%, 95% confidence interval [CI] 62.5-88%) for Paromomycin-Aquaphilic, 2 of 20 (10%, 95% CI 3-30%) for Aquaphilic vehicle (P < .0001 vs Paromomycin-Aquaphilic), and 14 of 20 (70%, 95% CI 48-85.5%) for intralesional pentamidine. Both Paromomycin-Aquaphilic and the Aquaphilic vehicle were very well tolerated, with only grade 1 adverse reactions in 5-10% of patients. CONCLUSIONS Against L. braziliensis CL, a prevalent, aggressive form of New World CL, 15% Paromomycin-aquaphilic was vastly superior to a negative vehicle control and was comparable in efficacy to a positive control. This study enlarges the potential use of 15% Paromomycin-Aquaphilic from one form of Old World CL to CL more generally. CLINICAL TRIALS REGISTRATION NCT03096457.
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Topical Paromomycin/Methylbenzethonium Chloride Plus Parenteral Meglumine Antimonate as Treatment for American Cutaneous Leishmaniasis: Controlled Study
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 1998Co-Authors: Jaime Soto, P. Fuya, Rogelio Herrera, Judith BermanAbstract:We determined the efficacy of the combination of the topical formulation 15% Paromomycin sulfate/12% methylbenzethonium chloride (MBCL) and a short course (7 days) of parenteral meglumine antimonate (pentavalent antimony [Sb]) as treatment of American cutaneous leishmaniasis in Colombian patients. Patients were randomly assigned in unequal allocation (2:1:1:1) to group 1 (topical Paromomycin/MBCL plus injectable Sb for 7 days), group 2 (topical placebo plus injectable Sb for 7 days), group 3 (topical Paromomycin/MBCL plus injectable Sb for 3 days), and group 4 (injectable Sb for 20 days). Cure was defined as complete reepithelialization of all lesions without relapse. Cure rates among groups were as follows: 58% (34 of 59), group 1; 53% (16 of 30), group 2; 20% (6 of 30), group 3; and 84% (26 of 31), group 4. Seventy-one percent of the organisms identified to the species level were Leishmania braziliensis panamensis. We conclude that 10 days of therapy with Paromomycin/MBCL does not augment the response of cutaneous leishmaniasis (predominately due to L. braziliensis panamensis) to a short course of treatment with meglumine antimonate.
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topical Paromomycin methylbenzethonium chloride plus parenteral meglumine antimonate as treatment for american cutaneous leishmaniasis controlled study
Clinical Infectious Diseases, 1998Co-Authors: Jaime Soto, P. Fuya, Rogelio Herrera, Judith BermanAbstract:We determined the efficacy of the combination of the topical formulation 15% Paromomycin sulfate/12% methylbenzethonium chloride (MBCL) and a short course (7 days) of parenteral meglumine antimonate (pentavalent antimony [Sb]) as treatment of American cutaneous leishmaniasis in Colombian patients. Patients were randomly assigned in unequal allocation (2:1:1:1) to group 1 (topical Paromomycin/MBCL plus injectable Sb for 7 days), group 2 (topical placebo plus injectable Sb for 7 days), group 3 (topical Paromomycin/MBCL plus injectable Sb for 3 days), and group 4 (injectable Sb for 20 days). Cure was defined as complete reepithelialization of all lesions without relapse. Cure rates among groups were as follows: 58% (34 of 59), group 1; 53% (16 of 30), group 2; 20% (6 of 30), group 3; and 84% (26 of 31), group 4. Seventy-one percent of the organisms identified to the species level were Leishmania braziliensis panamensis. We conclude that 10 days of therapy with Paromomycin/MBCL does not augment the response of cutaneous leishmaniasis (predominately due to L. braziliensis panamensis) to a short course of treatment with meglumine antimonate.
Hyouta Himeno - One of the best experts on this subject based on the ideXlab platform.
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Various effects of Paromomycin on tmRNA-mediated trans-translation
Nucleic Acids Symposium Series, 2003Co-Authors: Takayuki Konno, Toshiharu Takahashi, Akira Muto, Hyouta HimenoAbstract:trans-Translation is an unusual translation in which tmRNA plays a dual function as a tRNA and an mRNA to relieve the stalled translation on the ribosome. In this study, we examined the effects of an aminoglycoside antibiotic, Paromomycin, on several tmRNA-related events in vitro. The results of a chemical footprinting study indicated that Paromomycin molecules bind tmRNA at G 332 /G 333 in the tRNA domain and A 316 in the middle of the long helix between tRNA and mRNA do- mains. Paromomycin bound at G 332 /G 333 inhibited ami- noacylation, and the inhibition was suppressed by the addition of SmpB, a tmRNA-binding protein. It was also found that Paromomycin causes a shift of the transla- tion resuming point on tmRNA by 1. The effect on initiation shift was canceled by a mutation at the paro- momycin-binding site in 16 S rRNA but not by mutations in tmRNA. A high concentration of Paromomycin inhib- ited trans-translation, whereas it enhanced the initia- tion-shifted trans-translation when SmpB was exog- enously added or a mutation was introduced at 333. The effect of Paromomycin on trans-translation differs sub- stantially from that on canonical translation, in which it induces miscoding by modulating the A site of the de- coding helix of the small subunit RNA of the ribosome.
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Various effects of Paromomycin on tmRNA-directed trans-translation.
The Journal of biological chemistry, 2003Co-Authors: Toshiharu Takahashi, Takayuki Konno, Akira Muto, Hyouta HimenoAbstract:Abstract trans-Translation is an unusual translation in which tmRNA plays a dual function as a tRNA and an mRNA to relieve the stalled translation on the ribosome. In this study, we examined the effects of an aminoglycoside antibiotic, Paromomycin, on several tmRNA-related events in vitro. The results of a chemical footprinting study indicated that Paromomycin molecules bind tmRNA at G332/G333 in the tRNA domain and A316 in the middle of the long helix between tRNA and mRNA domains. Paromomycin bound at G332/G333 inhibited aminoacylation, and the inhibition was suppressed by the addition of SmpB, a tmRNA-binding protein. It was also found that Paromomycin causes a shift of the translation resuming point on tmRNA by –1. The effect on initiation shift was canceled by a mutation at the Paromomycin-binding site in 16 S rRNA but not by mutations in tmRNA. A high concentration of Paromomycin inhibited trans-translation, whereas it enhanced the initiation-shifted trans-translation when SmpB was exogenously added or a mutation was introduced at 333. The effect of Paromomycin on trans-translation differs substantially from that on canonical translation, in which it induces miscoding by modulating the A site of the decoding helix of the small subunit RNA of the ribosome.
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Various effects of Paromomycin on tmRNA-mediated trans-translation.
Nucleic acids research. Supplement (2001), 2003Co-Authors: Takayuki Konno, Toshiharu Takahashi, Akira Muto, Hyouta HimenoAbstract:Trans-translation is an unusual translation in which tmRNA plays a dual function as a tRNA and an mRNA to relieve the stalled translation on the ribosome. In this study, we examined the effects of an aminoglycoside antibiotic, Paromomycin, on several tmRNA-related events in vitro. A chemical footprinting study revealed that Paromomycins bind tmRNA in the tRNA domain and in the middle of the long helix between tRNA and mRNA domains. Paromomycin bound in the tRNA domain inhibited aminoacylation, and the inhibition was suppressed by the addition of SmpB, a tmRNA binding protein. It was also found that Paromomycin causes a shift of the translation-resuming point on tmRNA by -1. The effect on initiation-shift was canceled by a mutation at the Paromomycin binding site in 16S rRNA, but not by mutations in tmRNA. The effect of Paromomycin on trans-translation differs substantially from that on canonical translation, in which it induces miscoding by modulating the A site of the decoding helix of the small subunit RNA of the ribosome.
Jaime Soto - One of the best experts on this subject based on the ideXlab platform.
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topical 15 Paromomycin aquaphilic for bolivian leishmania braziliensis cutaneous leishmaniasis a randomized placebo controlled trial
Clinical Infectious Diseases, 2019Co-Authors: Jaime Soto, Paula Soto, Andrea Ajata, Carmelo Luque, Carlos Tintaya, David Paz, Daniela Rivero, Judith BermanAbstract:BACKGROUND Cutaneous leishmaniasis (CL) presents as 1 or more skin lesions, which makes local therapy inherently attractive compared to systemic therapy that exposes the whole body to a drug. For 30 years, 15% Paromomycin topical formulations have been in clinical experimentation. Recently, 15% Paromomycin in Aquaphilic, a complex base to facilitate adsorption into the lesion, was found superior to aquaphilic vehicle for Old World Leishmania major disease. METHODS We performed a randomized trial of 15% Paromomycin in Aquaphilic (40 patients) vs Aquaphilic vehicle (20 patients) vs a positive control (intralesional pentamidine; 20 patients) against L. braziliensis CL in Bolivia. RESULTS Cure rates after 6 months of follow-up were 31 of 40 (77.5%, 95% confidence interval [CI] 62.5-88%) for Paromomycin-Aquaphilic, 2 of 20 (10%, 95% CI 3-30%) for Aquaphilic vehicle (P < .0001 vs Paromomycin-Aquaphilic), and 14 of 20 (70%, 95% CI 48-85.5%) for intralesional pentamidine. Both Paromomycin-Aquaphilic and the Aquaphilic vehicle were very well tolerated, with only grade 1 adverse reactions in 5-10% of patients. CONCLUSIONS Against L. braziliensis CL, a prevalent, aggressive form of New World CL, 15% Paromomycin-aquaphilic was vastly superior to a negative vehicle control and was comparable in efficacy to a positive control. This study enlarges the potential use of 15% Paromomycin-Aquaphilic from one form of Old World CL to CL more generally. CLINICAL TRIALS REGISTRATION NCT03096457.
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Topical 15% Paromomycin-Aquaphilic for Bolivian Leishmania braziliensis Cutaneous Leishmaniasis: A Randomized, Placebo-controlled Trial.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2018Co-Authors: Jaime Soto, Paula Soto, Andrea Ajata, Carmelo Luque, Carlos Tintaya, David Paz, Daniela Rivero, Judith BermanAbstract:BACKGROUND Cutaneous leishmaniasis (CL) presents as 1 or more skin lesions, which makes local therapy inherently attractive compared to systemic therapy that exposes the whole body to a drug. For 30 years, 15% Paromomycin topical formulations have been in clinical experimentation. Recently, 15% Paromomycin in Aquaphilic, a complex base to facilitate adsorption into the lesion, was found superior to aquaphilic vehicle for Old World Leishmania major disease. METHODS We performed a randomized trial of 15% Paromomycin in Aquaphilic (40 patients) vs Aquaphilic vehicle (20 patients) vs a positive control (intralesional pentamidine; 20 patients) against L. braziliensis CL in Bolivia. RESULTS Cure rates after 6 months of follow-up were 31 of 40 (77.5%, 95% confidence interval [CI] 62.5-88%) for Paromomycin-Aquaphilic, 2 of 20 (10%, 95% CI 3-30%) for Aquaphilic vehicle (P < .0001 vs Paromomycin-Aquaphilic), and 14 of 20 (70%, 95% CI 48-85.5%) for intralesional pentamidine. Both Paromomycin-Aquaphilic and the Aquaphilic vehicle were very well tolerated, with only grade 1 adverse reactions in 5-10% of patients. CONCLUSIONS Against L. braziliensis CL, a prevalent, aggressive form of New World CL, 15% Paromomycin-aquaphilic was vastly superior to a negative vehicle control and was comparable in efficacy to a positive control. This study enlarges the potential use of 15% Paromomycin-Aquaphilic from one form of Old World CL to CL more generally. CLINICAL TRIALS REGISTRATION NCT03096457.
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Topical Paromomycin/Methylbenzethonium Chloride Plus Parenteral Meglumine Antimonate as Treatment for American Cutaneous Leishmaniasis: Controlled Study
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 1998Co-Authors: Jaime Soto, P. Fuya, Rogelio Herrera, Judith BermanAbstract:We determined the efficacy of the combination of the topical formulation 15% Paromomycin sulfate/12% methylbenzethonium chloride (MBCL) and a short course (7 days) of parenteral meglumine antimonate (pentavalent antimony [Sb]) as treatment of American cutaneous leishmaniasis in Colombian patients. Patients were randomly assigned in unequal allocation (2:1:1:1) to group 1 (topical Paromomycin/MBCL plus injectable Sb for 7 days), group 2 (topical placebo plus injectable Sb for 7 days), group 3 (topical Paromomycin/MBCL plus injectable Sb for 3 days), and group 4 (injectable Sb for 20 days). Cure was defined as complete reepithelialization of all lesions without relapse. Cure rates among groups were as follows: 58% (34 of 59), group 1; 53% (16 of 30), group 2; 20% (6 of 30), group 3; and 84% (26 of 31), group 4. Seventy-one percent of the organisms identified to the species level were Leishmania braziliensis panamensis. We conclude that 10 days of therapy with Paromomycin/MBCL does not augment the response of cutaneous leishmaniasis (predominately due to L. braziliensis panamensis) to a short course of treatment with meglumine antimonate.
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topical Paromomycin methylbenzethonium chloride plus parenteral meglumine antimonate as treatment for american cutaneous leishmaniasis controlled study
Clinical Infectious Diseases, 1998Co-Authors: Jaime Soto, P. Fuya, Rogelio Herrera, Judith BermanAbstract:We determined the efficacy of the combination of the topical formulation 15% Paromomycin sulfate/12% methylbenzethonium chloride (MBCL) and a short course (7 days) of parenteral meglumine antimonate (pentavalent antimony [Sb]) as treatment of American cutaneous leishmaniasis in Colombian patients. Patients were randomly assigned in unequal allocation (2:1:1:1) to group 1 (topical Paromomycin/MBCL plus injectable Sb for 7 days), group 2 (topical placebo plus injectable Sb for 7 days), group 3 (topical Paromomycin/MBCL plus injectable Sb for 3 days), and group 4 (injectable Sb for 20 days). Cure was defined as complete reepithelialization of all lesions without relapse. Cure rates among groups were as follows: 58% (34 of 59), group 1; 53% (16 of 30), group 2; 20% (6 of 30), group 3; and 84% (26 of 31), group 4. Seventy-one percent of the organisms identified to the species level were Leishmania braziliensis panamensis. We conclude that 10 days of therapy with Paromomycin/MBCL does not augment the response of cutaneous leishmaniasis (predominately due to L. braziliensis panamensis) to a short course of treatment with meglumine antimonate.
Nestor Sosa - One of the best experts on this subject based on the ideXlab platform.
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Topical Paromomycin for New World cutaneous leishmaniasis.
PLoS neglected tropical diseases, 2019Co-Authors: Nestor Sosa, Ryan C. Adams, Kendra Lawrence, Juan M. Pascale, Ana Jiménez, Jeanne A. Norwood, Mara Kreishman-detrick, Peter J. Weina, William F. Mccarthy, Charles ScottAbstract:Background: Paromomycin-based topical treatments were shown to be effective in curing cutaneous leishmaniasis (CL) lesions caused by Leishmania major in Tunisia. Cure rates of an index lesion were approximately 80%. As a follow on, we conducted a similar Phase 3 trial in Panama to demonstrate the efficacy of these treatments against New World species. The primary objective was to determine if a combination topical cream (Paromomycin-gentamicin) resulted in statistically superior final clinical cure rates of an index lesion compared to a Paromomycin alone topical cream for the treatment of CL, primarily caused by Leishmania panamensis. Methods: We conducted a randomized, double blind, Phase 3 trial of topical creams for the treatment of CL caused by Leishmania spp. Three hundred ninety nine patients with one to ten CL lesions were treated by topical application once daily for 20 days. The primary efficacy endpoint was percentage of subjects with clinical cure of an index lesion confirmed to contain Leishmania with no relapse. Results: The clinical cure of the index lesion for Paromomycin-gentamicin was 79% (95% CI; 72 to 84) and for Paromomycin alone was 78% (95% CI; 74 to 87) (p = 0.84). The most common adverse events considered related to study cream application were mild to moderate dermatitis, pain, and pruritus. Conclusions: Superiority of Paromomycin-gentamicin was not demonstrated. However, the approximately 80% cure rates for both topical creams were similar to those demonstrated in Tunisia and previously reported with parenteral antimonials. Author summary: Leishmaniasis, a neglected parasitic infection transmitted by the bite of a female sand fly, is endemic in 98 countries or territories with approximately 0.7 to 1.2 million cutaneous leishmaniasis (CL) cases occurring each year. In Panama, most of the CL cases are caused by L. panamensis and, the first line of treatment is pentavalent antimony, given parenterally for 20 days. These systemic regimen is associated with toxicities that can limit the patient from receiving a full course of treatment. Alternative therapies are needed particularly for patients with mild disease, no mucosal involvement, no immunosuppression, and for patients living in areas with scarce infrastructure. Therefore, less toxic, non-parenteral new therapies against CL are urgently needed. We conducted a comparative clinical study that evaluated Paromomycin topical creams (Paromomycin alone versus Paromomycin+Gentamicin) for the treatment of cutaneous leishmaniasis (n = 399) in three sites of country. Our study demonstrated the efficacy of these preparations against New World leishmanial species (mostly L. panamensis) with a cure rate close to 80%.
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Topical Paromomycin for New World cutaneous leishmaniasis
2019Co-Authors: Nestor Sosa, Ryan C. Adams, Kendra Lawrence, Juan M. Pascale, Jeanne A. Norwood, Mara Kreishman-detrick, Peter J. Weina, William F. Mccarthy, Ana I. Jiménez, Charles ScottAbstract:BackgroundParomomycin-based topical treatments were shown to be effective in curing cutaneous leishmaniasis (CL) lesions caused by Leishmania major in Tunisia. Cure rates of an index lesion were approximately 80%. As a follow on, we conducted a similar Phase 3 trial in Panama to demonstrate the efficacy of these treatments against New World species. The primary objective was to determine if a combination topical cream (Paromomycin-gentamicin) resulted in statistically superior final clinical cure rates of an index lesion compared to a Paromomycin alone topical cream for the treatment of CL, primarily caused by Leishmania panamensis.MethodsWe conducted a randomized, double blind, Phase 3 trial of topical creams for the treatment of CL caused by Leishmania spp. Three hundred ninety nine patients with one to ten CL lesions were treated by topical application once daily for 20 days. The primary efficacy endpoint was percentage of subjects with clinical cure of an index lesion confirmed to contain Leishmania with no relapse.ResultsThe clinical cure of the index lesion for Paromomycin-gentamicin was 79% (95% CI; 72 to 84) and for Paromomycin alone was 78% (95% CI; 74 to 87) (p = 0.84). The most common adverse events considered related to study cream application were mild to moderate dermatitis, pain, and pruritus.ConclusionsSuperiority of Paromomycin-gentamicin was not demonstrated. However, the approximately 80% cure rates for both topical creams were similar to those demonstrated in Tunisia and previously reported with parenteral antimonials.
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Pharmacokinetics and Absorption of Paromomycin and Gentamicin from Topical Creams Used To Treat Cutaneous Leishmaniasis
Antimicrobial agents and chemotherapy, 2013Co-Authors: William R. Ravis, Alejandro Llanos-cuentas, Nestor Sosa, Mara Kreishman-deitrick, Karen M. Kopydlowski, Carl J. Nielsen, Kirsten S. Smith, Philip L. Smith, Janet Ransom, Yuh-jing LinAbstract:ABSTRACT This study evaluated the pharmacokinetics of topical creams containing 15% Paromomycin (“Paromomycin alone”) and 15% Paromomycin plus 0.5% gentamicin (WR 279,396) in patients with cutaneous leishmaniasis. The investigational creams were applied topically to all lesions once daily for 20 days. Plasma samples were analyzed for simultaneous quantitation of Paromomycin and gentamicin isomers and total gentamicin. Pharmacokinetic parameters for gentamicin could not be calculated because detectable levels were rarely evident. After one application, the Paromomycin area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) was 2,180 ± 2,621 ng · h/ml (mean ± standard deviation [SD]) for the Paromomycin-alone group and 975.6 ± 1,078 ng · h/ml for the WR 279,396 group. After 20 days of application, the Paromomycin AUC 0–24 and maximum concentration of drug ( C max ) were 5 to 6 times greater than those on day 1 for both treatment groups. For the Paromomycin-alone group, the AUC 0–24 was 8,575 ± 7,268 ng · h/ml and the C max was 1,000 ± 750 ng/ml, compared with 6,037 ± 3,956 ng · h/ml and 660 ± 486 ng/ml for the WR 279,396 group, respectively. Possibly due to large intersubject variability, no differences ( P ≥ 0.05) in the AUC 0–24 or C max were noted between treatment or between sites on day 1 or 20. The percentage of dose absorbed on day 20 was 12.0% ± 6.26% and 9.68% ± 6.05% for Paromomycin alone and WR 279,396, respectively. Paromomycin concentrations in plasma after 20 days of application were 5 to 9% of those after intramuscular administration of 15 mg/kg of body weight/day to adults for the systemic treatment of visceral leishmaniasis. Effective topical treatment of cutaneous leishmaniasis appears to be possible with limited Paromomycin and gentamicin systemic absorption, thus avoiding drug accumulation and toxicity. (The work described here has been registered at ClinicalTrials.gov under registration no. NCT01032382 and NCT01083576.)
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Randomized, Double-Blinded, Phase 2 Trial of WR 279,396 (Paromomycin and Gentamicin) for Cutaneous Leishmaniasis in Panama
The American journal of tropical medicine and hygiene, 2013Co-Authors: Nestor Sosa, Mara Kreishman-deitrick, Karen M. Kopydlowski, Zeuz Capitán, Javier Nieto, Melissa Nieto, José E. Calzada, Hector Paz, Carmenza Spadafora, Diane R. UllmanAbstract:In this randomized, double-blinded Phase 2 trial, 30 patients with Leishmania panamensis cutaneous leishmaniasis were randomly allocated (1:1) to receive once daily topical treatment with WR 279,396 (15% Paromomycin + 0.5% gentamicin) or Paromomycin Alone (15% Paromomycin) for 20 days. The index lesion cure rate after 6 months follow-up was 13 of 15 (87%) for WR 279,396 and 9 of 15 (60%) for Paromomycin Alone (P = 0.099). When all treated lesions were included, the final cure rate for WR 279,398-treated patients was again 87%, but the final cure rate for Paromomycin Alone-treated patients was 8 of 15 (53.3%; P = 0.046). Both creams were well tolerated with mild application site reactions being the most frequent adverse event. The increased final cure rate in the WR 279,396 group in this small Phase 2 study suggests that the combination product may provide greater clinical benefit than Paromomycin monotherapy against L. panamensis cutaneous leishmaniasis.
Toshiharu Takahashi - One of the best experts on this subject based on the ideXlab platform.
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Various effects of Paromomycin on tmRNA-mediated trans-translation
Nucleic Acids Symposium Series, 2003Co-Authors: Takayuki Konno, Toshiharu Takahashi, Akira Muto, Hyouta HimenoAbstract:trans-Translation is an unusual translation in which tmRNA plays a dual function as a tRNA and an mRNA to relieve the stalled translation on the ribosome. In this study, we examined the effects of an aminoglycoside antibiotic, Paromomycin, on several tmRNA-related events in vitro. The results of a chemical footprinting study indicated that Paromomycin molecules bind tmRNA at G 332 /G 333 in the tRNA domain and A 316 in the middle of the long helix between tRNA and mRNA do- mains. Paromomycin bound at G 332 /G 333 inhibited ami- noacylation, and the inhibition was suppressed by the addition of SmpB, a tmRNA-binding protein. It was also found that Paromomycin causes a shift of the transla- tion resuming point on tmRNA by 1. The effect on initiation shift was canceled by a mutation at the paro- momycin-binding site in 16 S rRNA but not by mutations in tmRNA. A high concentration of Paromomycin inhib- ited trans-translation, whereas it enhanced the initia- tion-shifted trans-translation when SmpB was exog- enously added or a mutation was introduced at 333. The effect of Paromomycin on trans-translation differs sub- stantially from that on canonical translation, in which it induces miscoding by modulating the A site of the de- coding helix of the small subunit RNA of the ribosome.
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Various effects of Paromomycin on tmRNA-directed trans-translation.
The Journal of biological chemistry, 2003Co-Authors: Toshiharu Takahashi, Takayuki Konno, Akira Muto, Hyouta HimenoAbstract:Abstract trans-Translation is an unusual translation in which tmRNA plays a dual function as a tRNA and an mRNA to relieve the stalled translation on the ribosome. In this study, we examined the effects of an aminoglycoside antibiotic, Paromomycin, on several tmRNA-related events in vitro. The results of a chemical footprinting study indicated that Paromomycin molecules bind tmRNA at G332/G333 in the tRNA domain and A316 in the middle of the long helix between tRNA and mRNA domains. Paromomycin bound at G332/G333 inhibited aminoacylation, and the inhibition was suppressed by the addition of SmpB, a tmRNA-binding protein. It was also found that Paromomycin causes a shift of the translation resuming point on tmRNA by –1. The effect on initiation shift was canceled by a mutation at the Paromomycin-binding site in 16 S rRNA but not by mutations in tmRNA. A high concentration of Paromomycin inhibited trans-translation, whereas it enhanced the initiation-shifted trans-translation when SmpB was exogenously added or a mutation was introduced at 333. The effect of Paromomycin on trans-translation differs substantially from that on canonical translation, in which it induces miscoding by modulating the A site of the decoding helix of the small subunit RNA of the ribosome.
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Various effects of Paromomycin on tmRNA-mediated trans-translation.
Nucleic acids research. Supplement (2001), 2003Co-Authors: Takayuki Konno, Toshiharu Takahashi, Akira Muto, Hyouta HimenoAbstract:Trans-translation is an unusual translation in which tmRNA plays a dual function as a tRNA and an mRNA to relieve the stalled translation on the ribosome. In this study, we examined the effects of an aminoglycoside antibiotic, Paromomycin, on several tmRNA-related events in vitro. A chemical footprinting study revealed that Paromomycins bind tmRNA in the tRNA domain and in the middle of the long helix between tRNA and mRNA domains. Paromomycin bound in the tRNA domain inhibited aminoacylation, and the inhibition was suppressed by the addition of SmpB, a tmRNA binding protein. It was also found that Paromomycin causes a shift of the translation-resuming point on tmRNA by -1. The effect on initiation-shift was canceled by a mutation at the Paromomycin binding site in 16S rRNA, but not by mutations in tmRNA. The effect of Paromomycin on trans-translation differs substantially from that on canonical translation, in which it induces miscoding by modulating the A site of the decoding helix of the small subunit RNA of the ribosome.