The Experts below are selected from a list of 2646 Experts worldwide ranked by ideXlab platform
Gianpaolo Candiani - One of the best experts on this subject based on the ideXlab platform.
-
pharmacological properties of nai 603 a well tolerated Semisynthetic Derivative of ramoplanin
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Daniela Jabes, Gianpaolo Candiani, Gabriella Romano, Cristina Brunati, Simona Riva, Sonia I Maffioli, Rosaria Rossi, Matteo Simone, Eleonora Gaspari, Stefano DonadioAbstract:NAI-603 is a ramoplanin Derivative designed to overcome the tolerability issues of the parent drug as a systemic agent. NAI-603 is highly active against aerobic and anaerobic Gram-positive bacteria, with MICs ranging from 0.008 to 8 μg/ml. MICs were not significantly affected by pH (range, 6 to 8), by inoculum up to 108 CFU/ml, or by addition of 50% human serum. Against staphylococci and enterococci, NAI-603 was rapidly bactericidal, with minimum bactericidal concentration (MBC)/MIC ratios never exceeding 4. The frequency of spontaneous resistance was low at 2× to 4× MIC (≤1 × 10−6 to ≤1 × 10−8) and below the detection limit (about ≤1 × 10−9) at 8× MIC. Serial subcultures at 0.5× MIC yielded at most an 8-fold increase in MICs. In a systemic infection induced by methicillin-resistant Staphylococcus aureus (MRSA), the 50% effective dose (ED50) of intravenous (i.v.) NAI-603 was 0.4 mg/kg, lower than that of oral (p.o.) linezolid (1.4 mg/kg) and subcutaneous (s.c.) teicoplanin (1.4 mg/kg) or vancomycin (0.6 mg/kg). In neutropenic mice infected with vancomycin-resistant enterococci (VRE), the ED50s for NAI-603 were 1.1 to 1.6 mg/kg i.v., compared to 0.5 mg/kg i.v. of ramoplanin. The bactericidal activity was confirmed in vivo in the rat granuloma pouch model induced by MRSA, where NAI-603, at 40 mg/kg i.v., induced about a 2- to 3-log10-reduction in viable bacteria in the exudates, which persisted for more than 72 h. The pharmacokinetic (PK) profiles of NAI-603 and ramoplanin at 20 mg/kg show similar half-lives (3.27 and 3.80 h, respectively) with the maximum concentration (Cmax) markedly higher for NAI-603 (207 μg/ml versus 79 μg/ml). The favorable pharmacological profile of NAI-603, coupled with the absence of local tolerability issues, supports further investigation.
-
in vitro and in vivo antibacterial activity of bi 397 a new semi synthetic glycopeptide antibiotic
Journal of Antimicrobial Chemotherapy, 1999Co-Authors: Gianpaolo Candiani, Gabriella Romano, Monica Abbondi, Monica Borgonovi, Franco ParentiAbstract:: BI 397 (formerly A-A-1) is a Semisynthetic Derivative of the teicoplanin-like glycopeptide A40926. It was more active in vitro against staphylococci (including some teicoplanin-resistant strains) than teicoplanin and vancomycin. Against streptococci (including penicillin-resistant strains) BI 397 has activity comparable with that of teicoplanin and better than vancomycin. BI 397, when administered to rats by the i.v. route, gives high and long lasting blood levels. It shows excellent activity in models of acute septicaemia in immunocompetent and neutropenic mice. In a rat staphylococcal endocarditis model it is as effective as teicoplanin and vancomycin at reducing bacterial loads in the heart, but at lower dosages and with a reduced number of daily treatments compared with the two glycopeptide controls. BI 397 is highly efficacious in clearing penicillin-susceptible and -resistant pneumococci from lungs of immunocompetent and neutropenic rats. The data from these studies show that BI 397 combines an excellent in-vitro antibacterial activity with favourable pharmacokinetic behaviour resulting in potent in-vivo activity.
-
antimicrobial activity of mdl 63 246 a new Semisynthetic glycopeptide antibiotic
Antimicrobial Agents and Chemotherapy, 1995Co-Authors: Beth P. Goldstein, Marisa Berti, Gianpaolo Candiani, T M Arain, Gabriella Romano, Ismaela Ciciliato, Matt Mainini, Monica Abbondi, Roberto Scotti, Francesco RipamontiAbstract:MDL 63,246 is a Semisynthetic Derivative of the naturally occurring glycopeptide antibiotic MDL 62,476 (A40926). It was more active in vitro against Staphylococcus aureus and coagulase-negative staphylococci than MDL 62,476, teicoplanin, and vancomycin and was more active than mideplanin (MDL 62,873) against some isolates. MDL 63,246 had excellent activity against streptococci and teicoplanin-susceptible enterococci, and it also had in vitro activity against some VanA enterococcal isolates. It was more active than teicoplanin and vancomycin against acute staphylococcal, streptococcal, and enterococcal septicemia in immunocompetent and neutropenic mice. It was highly efficacious in reducing the bacterial load in the hearts of rats in staphylococcal endocarditis experiments and the bacterial load of Staphylococcus epidermis in a high infection model in neutropenic mice. The excellent in vivo activity of MDL 63,246 appears to correlate both with its in vitro antibacterial activity and with its long half-life in rodents.
-
antimicrobial activity of mdl 62 873 a Semisynthetic Derivative of teicoplanin in vitro and in experimental infections
Antimicrobial Agents and Chemotherapy, 1992Co-Authors: Marisa Berti, Gianpaolo Candiani, Francesco Ripamonti, Roberto Scotti, M Borgonovi, P Landini, L Cavenaghi, Maurizio Denaro, Beth P. GoldsteinAbstract:MDL 62,873 is an amide Derivative of teicoplanin A2-2. Like those of natural glycopeptides, its antibacterial activity is mediated by inhibition of cell wall peptidoglycan synthesis. Against streptococci and enterococci, the in vitro activity of MDL 62,873 was similar to that of teicoplanin and greater than that of vancomycin. Against staphylococci, it has activity similar to that of vancomycin, and it was significantly more active than teicoplanin against coagulase-negative isolates. Like teicoplanin and vancomycin, MDL 62,873 had slow but significant bactericidal activity (99 to 99.9% killing in 24 h) against staphylococci at concentrations near the MIC. In murine septicemia studies with Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae, the 50% effective doses were lower than those of vancomycin. In staphylococcal endocarditis in rats, MDL 62,873 at 20 mg/kg of body weight and vancomycin at 40 mg/kg, both doses given intravenously twice daily, had similar efficacies in reducing the heart bacterial load. These results probably reflect the longer half-life of MDL 62,873, which has a pharmacokinetic profile in rats similar to that of teicoplanin.
Fabiana Volpe Zanutto - One of the best experts on this subject based on the ideXlab platform.
-
Semisynthetic Derivative of artemisia annua loaded transdermal bioadhesive for the treatment of uncomplicated malaria caused by plasmodium falciparum in children
Journal of Pharmaceutical Sciences, 2019Co-Authors: Uno Fonsecasantos, Fabiana Volpe Zanutto, Emma Mcaliste, Marcelo Marucci Pereira Tangerina, Tais Helena Costa Salles, Ilza Maria Oliveira Souza, Andi Isibe, Wagne Vilegas, Marlus ChorilliAbstract:Abstract According to the most recent World Health Organization statistics, malaria infected approximately 219 million people in 2017, with an estimate of 435,000 deaths (World Health Organization, 2018). Communities isolated from cities are the most deprived of access to the necessary hospital facilities. Herein we report the development of a transdermal bioadhesive containing artemether (ART), an alternative, potentially lifesaving, treatment regimen for malaria in low-resource settings. Bioadhesives were prepared from an aqueous blend of hydroxyethylcellulose (4.5% w/w), ART, propoxylated-ethoxylated-cetyl-alcohol, polysorbate 80, propyleneglycol, glycerine, mineral oil, and oleic acid. In this study, the average pore size of bioadhesive 5.5b was 52.6 ± 15.31 μm. Differential scanning calorimetry and thermogravimetric analyses confirm the thermal stability of ART bioadhesives at room temperature. Tensile tests indicated good mechanical properties for bioadhesive 5.5b, when compared to 5.5a, where 5.5b showed elastic modulus 0.19 MPa, elongation at break 204%, tensile stress 0.31 MPa, tensile strength at break 0.23 MPa. Bioadhesion assays suggested that formulations containing surfactants had higher detachment forces. Permeation studies demonstrated that the best outcome was achieved with a bioadhesive containing 25 mg ART (5.5b) that after 24 h released 6971 ± 125 μg, which represents approximately 28% of drug permeation. Data reported presents a promising candidate for a new antimalarial transdermal formulation.
Michael J Kelner - One of the best experts on this subject based on the ideXlab platform.
-
Synergy of irofulven in combination with other DNA damaging agents: synergistic interaction with altretamine, alkylating, and platinum-derived agents in the MV522 lung tumor model
Cancer Chemotherapy and Pharmacology, 2008Co-Authors: Michael J Kelner, Leita A. Estes, Trevor C Mcmorris, Rafael Rojas, Pharnuk SuthipinijthamAbstract:Purpose Irofulven (MGI 114, NSC 683863) is a Semisynthetic Derivative of illudin S, a natural product present in the Omphalotus illudins (Jack O’Lantern) mushroom. This novel agent produces DNA damage, that in contrast to other agents, is predominately ignored by the global genome repair pathway of the nucleotide excision repair (NER)2 system. The aim of this study was to determine the antitumor activity of irofulven when administered in combination with 44 different DNA damaging agents, whose damage is in general detected and repaired by the genome repair pathway.
-
Enhanced antitumor activity of irofulven in combination with thiotepa or mitomycin C
Cancer Chemotherapy and Pharmacology, 2002Co-Authors: Michael J Kelner, Rafael J. Rojas, Nicole A. Trani, Trevor C Mcmorris, Leita EstesAbstract:Purpose: Irofulven (6-hydroxymethylacylfulvene, MGI 114, NSC 683863) is a Semisynthetic Derivative of illudin S, a toxin present in the Omphalotus mushroom. Irofulven has demonstrated activity against a broad range of solid tumors in both xenograft models and human trials. The potential application of administering irofulven in combination with aziridine-containing chemotherapeutic agents was evaluated in this study. Methods: Human lung carcinoma MV522 cells and BALB/c athymic mice bearing the human lung carcinoma MV522 xenograft were used to evaluate the activity of irofulven in combination with aziridine-containing drugs. Results: Irofulven in combination with either thiotepa or mitomycin C demonstrated a strong synergistic (supraadditive) activity both in vitro and in vivo, that exceeded results obtained with monotherapy at the same or higher doses of these agents. The majority of xenograft-bearing animals that received subtoxic doses of irofulven, and either thiotepa or mitomycin C, demonstrated a complete cure. In contrast, there was no detectable synergistic activity between irofulven and other aziridine-containing drugs, including AZQ and thiotepa metabolites such as TEPA or AZD. Conclusions: These results indicate that the therapeutic activity of irofulven is enhanced when combined with mitomycin C or thiotepa, and further evaluation of these combinations is therefore warranted.
-
preclinical antitumor activity of 6 hydroxymethylacylfulvene a Semisynthetic Derivative of the mushroom toxin illudin s
Cancer Research, 1997Co-Authors: John R Macdonald, Michael J Kelner, Trevor C Mcmorris, Charles C Muscoplat, Daniel L Dexter, Gina Mangold, Shih Fong Chen, Daniel D Von HoffAbstract:Abstract 6-Hydroxymethylacylfulvene (HMAF; MGI 114) is a novel Semisynthetic antitumor agent derived from the sesquiterpene mushroom toxin illudin S. In vitro cytotoxicity determinations produced IC50 concentrations (concentrations required for 50% inhibition of growth) ranging from 160 nm in sensitive MCF-7 human mammary carcinoma cells to 17 µm in relatively insensitive murine B16 melanoma cells. In vivo antitumor activity was consistent with in vitro sensitivity. HMAF was very effective in human tumor xenograft models, including MX-1 breast carcinoma, MV522 lung adenocarcinoma, and HT-29 colon carcinoma, but not murine B16 melanoma or P388 leukemia. Excellent responses were observed in animals bearing MX-1 tumors administered i.v. or i.p. doses of 3–7.5 mg/kg daily for 5 days, with complete regression recorded in 29 of 30 animals administered i.v. HMAF. Extensive tumor shrinkage was also observed with MV522, and significant tumor growth inhibition was obtained with HT-29 when animals received 5 daily i.p. doses ranging from 3.75 to 7.5 mg/kg. Complete regressions were also observed in individual animals with MV522 and HT-29. The excellent activity of HMAF in several human solid tumor xenografts, including the more refractory MV522 and HT-29 models, warrants the further investigation of this novel agent in clinical trials.
-
Reaction of antitumor hydroxymethylacylfulvene (HMAF) with thiols
Tetrahedron, 1997Co-Authors: Trevor C Mcmorris, Leita A. Estes, Michael J KelnerAbstract:Abstract Hydroxymethylacylfulvene (HMAF) is a Semisynthetic Derivative of the toxic sesquiterpene illudin S. HMAF (also designated MGI-114) has potent antitumor properties and is currently in clinical trials. It reacts with thiols at neutral and acidic pH forming novel products in which the primary allylic hydroxyl is displaced by thiol. These Derivatives retain antitumor activity.
-
Efficacy of HMAF (MGI-114) in the MV522 metastatic lung carcinoma xenograft model nonresponsive to traditional anticancer agents
Investigational New Drugs, 1996Co-Authors: Michael J Kelner, Leita Estes, Trevor C Mcmorris, Wen Wnag, Kyra M. Samson, Raymond TaetleAbstract:Illudin analogs are cytotoxic to a variety of multidrug resistant cell lines, and display an unusual toxicity towards DNA helicase-deficient cell lines. Earlier illudin analogs demonstrated efficacy in several xenograft models, including a metastatic MV522 lung cancer model, resistant to conventional anticancer agents. These illudin analogs prolonged life span as compared to conventional agents, but did not induce complete remission of primary tumors. In vitro screening studies identified a Semisynthetic Derivative, hydroxymethylacylfulvene (HMAF, MGI-114), with increased selective cytotoxicity towards carcinoma cells. The HMAF analog was markedly effective in the experimental MV522 metastasizing lung carcinoma xenograft system, a model refractory to treatment with existing anticancer agents. Treatment with paclitaxel, doxorubicin, or cisplatin failed to significantly inhibit primary tumor growth or prolong life span of MV522 tumor-bearing animals. Treatment with mitomycin C at the LD_20 increased life span in surviving animals up to 61% (p = 0.04). Treatment with HMAF induced primary tumor regression in all animals and increased life span greater than 150% (p
Marlus Chorilli - One of the best experts on this subject based on the ideXlab platform.
-
Semisynthetic Derivative of artemisia annua loaded transdermal bioadhesive for the treatment of uncomplicated malaria caused by plasmodium falciparum in children
Journal of Pharmaceutical Sciences, 2019Co-Authors: Uno Fonsecasantos, Fabiana Volpe Zanutto, Emma Mcaliste, Marcelo Marucci Pereira Tangerina, Tais Helena Costa Salles, Ilza Maria Oliveira Souza, Andi Isibe, Wagne Vilegas, Marlus ChorilliAbstract:Abstract According to the most recent World Health Organization statistics, malaria infected approximately 219 million people in 2017, with an estimate of 435,000 deaths (World Health Organization, 2018). Communities isolated from cities are the most deprived of access to the necessary hospital facilities. Herein we report the development of a transdermal bioadhesive containing artemether (ART), an alternative, potentially lifesaving, treatment regimen for malaria in low-resource settings. Bioadhesives were prepared from an aqueous blend of hydroxyethylcellulose (4.5% w/w), ART, propoxylated-ethoxylated-cetyl-alcohol, polysorbate 80, propyleneglycol, glycerine, mineral oil, and oleic acid. In this study, the average pore size of bioadhesive 5.5b was 52.6 ± 15.31 μm. Differential scanning calorimetry and thermogravimetric analyses confirm the thermal stability of ART bioadhesives at room temperature. Tensile tests indicated good mechanical properties for bioadhesive 5.5b, when compared to 5.5a, where 5.5b showed elastic modulus 0.19 MPa, elongation at break 204%, tensile stress 0.31 MPa, tensile strength at break 0.23 MPa. Bioadhesion assays suggested that formulations containing surfactants had higher detachment forces. Permeation studies demonstrated that the best outcome was achieved with a bioadhesive containing 25 mg ART (5.5b) that after 24 h released 6971 ± 125 μg, which represents approximately 28% of drug permeation. Data reported presents a promising candidate for a new antimalarial transdermal formulation.
Gabriella Romano - One of the best experts on this subject based on the ideXlab platform.
-
pharmacological properties of nai 603 a well tolerated Semisynthetic Derivative of ramoplanin
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Daniela Jabes, Gianpaolo Candiani, Gabriella Romano, Cristina Brunati, Simona Riva, Sonia I Maffioli, Rosaria Rossi, Matteo Simone, Eleonora Gaspari, Stefano DonadioAbstract:NAI-603 is a ramoplanin Derivative designed to overcome the tolerability issues of the parent drug as a systemic agent. NAI-603 is highly active against aerobic and anaerobic Gram-positive bacteria, with MICs ranging from 0.008 to 8 μg/ml. MICs were not significantly affected by pH (range, 6 to 8), by inoculum up to 108 CFU/ml, or by addition of 50% human serum. Against staphylococci and enterococci, NAI-603 was rapidly bactericidal, with minimum bactericidal concentration (MBC)/MIC ratios never exceeding 4. The frequency of spontaneous resistance was low at 2× to 4× MIC (≤1 × 10−6 to ≤1 × 10−8) and below the detection limit (about ≤1 × 10−9) at 8× MIC. Serial subcultures at 0.5× MIC yielded at most an 8-fold increase in MICs. In a systemic infection induced by methicillin-resistant Staphylococcus aureus (MRSA), the 50% effective dose (ED50) of intravenous (i.v.) NAI-603 was 0.4 mg/kg, lower than that of oral (p.o.) linezolid (1.4 mg/kg) and subcutaneous (s.c.) teicoplanin (1.4 mg/kg) or vancomycin (0.6 mg/kg). In neutropenic mice infected with vancomycin-resistant enterococci (VRE), the ED50s for NAI-603 were 1.1 to 1.6 mg/kg i.v., compared to 0.5 mg/kg i.v. of ramoplanin. The bactericidal activity was confirmed in vivo in the rat granuloma pouch model induced by MRSA, where NAI-603, at 40 mg/kg i.v., induced about a 2- to 3-log10-reduction in viable bacteria in the exudates, which persisted for more than 72 h. The pharmacokinetic (PK) profiles of NAI-603 and ramoplanin at 20 mg/kg show similar half-lives (3.27 and 3.80 h, respectively) with the maximum concentration (Cmax) markedly higher for NAI-603 (207 μg/ml versus 79 μg/ml). The favorable pharmacological profile of NAI-603, coupled with the absence of local tolerability issues, supports further investigation.
-
in vitro and in vivo antibacterial activity of bi 397 a new semi synthetic glycopeptide antibiotic
Journal of Antimicrobial Chemotherapy, 1999Co-Authors: Gianpaolo Candiani, Gabriella Romano, Monica Abbondi, Monica Borgonovi, Franco ParentiAbstract:: BI 397 (formerly A-A-1) is a Semisynthetic Derivative of the teicoplanin-like glycopeptide A40926. It was more active in vitro against staphylococci (including some teicoplanin-resistant strains) than teicoplanin and vancomycin. Against streptococci (including penicillin-resistant strains) BI 397 has activity comparable with that of teicoplanin and better than vancomycin. BI 397, when administered to rats by the i.v. route, gives high and long lasting blood levels. It shows excellent activity in models of acute septicaemia in immunocompetent and neutropenic mice. In a rat staphylococcal endocarditis model it is as effective as teicoplanin and vancomycin at reducing bacterial loads in the heart, but at lower dosages and with a reduced number of daily treatments compared with the two glycopeptide controls. BI 397 is highly efficacious in clearing penicillin-susceptible and -resistant pneumococci from lungs of immunocompetent and neutropenic rats. The data from these studies show that BI 397 combines an excellent in-vitro antibacterial activity with favourable pharmacokinetic behaviour resulting in potent in-vivo activity.
-
antimicrobial activity of mdl 63 246 a new Semisynthetic glycopeptide antibiotic
Antimicrobial Agents and Chemotherapy, 1995Co-Authors: Beth P. Goldstein, Marisa Berti, Gianpaolo Candiani, T M Arain, Gabriella Romano, Ismaela Ciciliato, Matt Mainini, Monica Abbondi, Roberto Scotti, Francesco RipamontiAbstract:MDL 63,246 is a Semisynthetic Derivative of the naturally occurring glycopeptide antibiotic MDL 62,476 (A40926). It was more active in vitro against Staphylococcus aureus and coagulase-negative staphylococci than MDL 62,476, teicoplanin, and vancomycin and was more active than mideplanin (MDL 62,873) against some isolates. MDL 63,246 had excellent activity against streptococci and teicoplanin-susceptible enterococci, and it also had in vitro activity against some VanA enterococcal isolates. It was more active than teicoplanin and vancomycin against acute staphylococcal, streptococcal, and enterococcal septicemia in immunocompetent and neutropenic mice. It was highly efficacious in reducing the bacterial load in the hearts of rats in staphylococcal endocarditis experiments and the bacterial load of Staphylococcus epidermis in a high infection model in neutropenic mice. The excellent in vivo activity of MDL 63,246 appears to correlate both with its in vitro antibacterial activity and with its long half-life in rodents.
