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Jean Michel Brunel - One of the best experts on this subject based on the ideXlab platform.

  • Polyaminosteroid analogues as potent antibacterial agents against mupirocin-resistant Staphylococcus aureus strains
    Anti-Infective Agents, 2019
    Co-Authors: Adèle Sakr, Jean Michel Brunel, Frédéric Laurent, Tania Nawfal Dagher, Olivier Blin, Jean Marc Rolain
    Abstract:

    Background and Objective: : Nasal carriage of Staphylococcus aureus (S. aureus) constitutes an important risk factor for subsequent infections in some types of patient populations. Decolonization of carriers using intranasal mupirocin is widely used as a preventive measure. However, resistance to this agent has been rising and causing failure in the decolonization, highlighting the need for new alternatives. The objective of our study was to evaluate the antibacterial activity of polyaminosteroid derivatives against S. aureus strains with different levels of mupirocin-resistance. Methods and Results:: Using the broth microdilution method, we evaluated the minimum inhibitory concentration (MIC) of these molecules against S. aureus clinical strains including mupirocin-resistant strains. We found that Squalamine and one of its analogues, named BSQ-1, are active against mupirocin-susceptible and -resistant clinical isolates with MIC values of 3.125 µg/mL. Additionally, long-term and repeated exposure of a susceptible S. aureus strain to Squalamine and BSQ-1 did not lead to the emergence of resistant bacteria, contrarily to mupirocin. Conclusion: : Our study suggests that these molecules constitute promising new alternatives to mupirocin for nasal decolonization and prevention of endogenous infections.

  • anti persister activity of Squalamine against acinetobacter baumannii
    International Journal of Antimicrobial Agents, 2019
    Co-Authors: Marion Nicol, Mohamed Amine Ben Mlouka, Thierry Berthe, Patrick Di Martino, Thierry Jouenne, Jean Michel Brunel, Emmanuelle De
    Abstract:

    ABSTRACT Squalamine is a natural polycationic aminosterol extracted from the shark Squalus acanthias. Squalamine displays remarkable efficacy against antimicrobial-resistant Gram-negative and Gram-positive bacteria. Its membranolytic activity and low cytotoxicity make Squalamine one of the most promising agents to fight nosocomial pathogens such as Acinetobacter baumannii. In the context of chronic diseases and therapeutic failures associated with this pathogen, the presence of dormant cells, i.e. persisters and viable but non-culturable cells (VBNCs), highly tolerant to antimicrobial compounds is problematic. The aim of this study was to investigate the antibacterial activity of Squalamine against this bacterial population of A. baumannii. Bacterial dormancy was induced by cold shock and nutrient starvation in the presence of high doses of either colistin, ciprofloxacin or Squalamine. Persisters and VBNCs induced by these treatments were then challenged with 100 mg/L Squalamine. The efficacy of each treatment was determined by evaluating culturability on agar medium, membrane integrity (LIVE/DEAD® BacLightTM staining) and respiratory activity (BacLightTM RedoxSensorTM CTC staining) of bacteria. A. baumannii ATCC 17978 generated persisters as well as VBNCs in the presence of high doses of ciprofloxacin but not colistin or Squalamine. Squalamine at 100 mg/L (below its haemolytic concentration) was able to kill dormant cells. Squalamine did not induce persister cell or VBNC formation in A. baumannii ATCC 17978. Interestingly, Squalamine was significantly active against this type of dormant population generated by ciprofloxacin, making it a very promising anti-persister agent.

  • A Double-Blind Randomized Placebo-Controlled Clinical Trial of Squalamine Ointment for tinea capitis Treatment
    Mycopathologia, 2015
    Co-Authors: Oumar Coulibaly, Jean Michel Brunel, Mahamadou A Thera, Abdoulaye K Koné, Goïta Siaka, Pierre Traoré, Abdoulaye A Djimdé, Jean Gaudart, Renaud Piarroux, Ogobara K Doumbo
    Abstract:

    Background Novel treatments against for tinea capitis are needed, and the natural aminosterol Squalamine is a potential topical antidermatophyte drug candidate. Objectives This phase II randomized double-blind placebo-controlled clinical trial aimed at testing the efficacy and safety of a three-week Squalamine ointment regimen for the treatment of tinea capitis . Patients Males aged 6–15 years presenting with tinea capitis were treated with either topical Squalamine ointment or placebo for 3 weeks. The primary endpoint was complete clinical cure. The secondary endpoints were the occurrence of local and/or systemic adverse events, mycological cure, and partial clinical response. Prospective follow-up of clinical adverse events was performed daily. Results Five patients were treated with 1 % Squalamine ointment and 15 with placebo. No complete cure was observed. No clinical or biological adverse event was recorded. A significantly ( p  = 0.03) better hair-growth score, indicating a partial clinical improvement of the tinea capitis lesion, was observed in the patients treated with Squalamine compared to those treated with placebo. Conclusion This three-week Squalamine ointment regimen was well tolerated and showed an encouraging partial clinical activity for the treatment of tinea capitis . Further studies are needed to evaluate the efficacy of topical Squalamine alone against tinea corporis or in combination with a systemic antidermatophyte drug against tinea capitis .

  • A double-blind randomized placebo-controlled clinical trial of Squalamine ointment for tinea capitis treatment.
    Mycopathologia, 2014
    Co-Authors: Oumar Coulibaly, Jean Michel Brunel, Mahamadou A Thera, Abdoulaye K Koné, Goïta Siaka, Pierre Traoré, Abdoulaye A Djimdé, Jean Gaudart, Renaud Piarroux, Ogobara K Doumbo
    Abstract:

    Novel treatments against for tinea capitis are needed, and the natural aminosterol Squalamine is a potential topical antidermatophyte drug candidate. This phase II randomized double-blind placebo-controlled clinical trial aimed at testing the efficacy and safety of a three-week Squalamine ointment regimen for the treatment of tinea capitis. Males aged 6-15 years presenting with tinea capitis were treated with either topical Squalamine ointment or placebo for 3 weeks. The primary endpoint was complete clinical cure. The secondary endpoints were the occurrence of local and/or systemic adverse events, mycological cure, and partial clinical response. Prospective follow-up of clinical adverse events was performed daily. Five patients were treated with 1% Squalamine ointment and 15 with placebo. No complete cure was observed. No clinical or biological adverse event was recorded. A significantly (p = 0.03) better hair-growth score, indicating a partial clinical improvement of the tinea capitis lesion, was observed in the patients treated with Squalamine compared to those treated with placebo. This three-week Squalamine ointment regimen was well tolerated and showed an encouraging partial clinical activity for the treatment of tinea capitis. Further studies are needed to evaluate the efficacy of topical Squalamine alone against tinea corporis or in combination with a systemic antidermatophyte drug against tinea capitis.

  • soluble Squalamine tablets for the rapid disinfection of home nebulizers of cystic fibrosis patients
    Journal of Cystic Fibrosis, 2012
    Co-Authors: Lamia Djouhribouktab, Kamel Alhanout, Veronique Andrieu, Nathalie Stremler, Jean Christophe Dubus, Didier Raoult, Jean Marc Rolain, Jean Michel Brunel
    Abstract:

    Abstract Background The bacterial contamination of nebulizers represents a major problem for cystic fibrosis (CF) patients that can lead to reduced nebulizer performance and increase the risk of patient reinfection by the contaminating bacteria. Objective We investigated the potential use of Squalamine, a broad-spectrum antimicrobial compound, as a nebulizer disinfectant. Methods Pari LC nebulizers were artificially contaminated with a suspension of bacteria ( Staphylococcus aureus and Pseudomonas aeruginosa ; 10 8 CFU/mL) and fungi ( Candidida albicans and Aspergilus niger ; 10 7 CFU/mL) and then disinfected by immersion in Squalamine solution for 20min. Glutaraldehyde and Korsolex peracetic acid were used as disinfectant controls. Result We found that 0.5g/L Squalamine reduced the levels of viable S. aureus and P. aeruginosa by 5 log 10 and the level of viable C. albicans by 4 log 10 after 20min. A concentration of 2g/L was needed to reduce the level of A. niger cells by 4 log 10 in 6hours. Finally, a formulation of Squalamine in the form of a soluble disinfecting tablet containing 2.5% (w/w) Squalamine was developed and successfully applied for nebulizer disinfection. Conclusion Our results suggest that aminosterol derivatives may be used by CF patients for rapid and easy home nebulizer disinfection and that soluble tablets may be developed for this purpose.

Jon I Williams - One of the best experts on this subject based on the ideXlab platform.

  • Regression of Retinopathy by Squalamine in a Mouse Model
    Pediatric Research, 2004
    Co-Authors: Rosemary D Higgins, Michael Zasloff, Yixun Geng, Jon I Williams
    Abstract:

    The goal of this study was to determine whether an antiangiogenic agent, Squalamine, given late during the evolution of oxygen-induced retinopathy (OIR) in the mouse, could improve retinal neovascularization. OIR was induced in neonatal C57BL6 mice and the neonates were treated s.c. with Squalamine doses begun at various times after OIR induction. A system of retinal whole mounts and assessment of neovascular nuclei extending beyond the inner limiting membrane from animals reared under room air or OIR conditions and killed periodically from d 12 to 21 were used to assess retinopathy in Squalamine-treated and untreated animals. OIR evolved after 75% oxygen exposure in neonatal mice with florid retinal neovascularization developing by d 14. Squalamine (single dose, 25 mg/kg s.c.) given on d 15 or 16, but not d 17, substantially improved retinal neovascularization in the mouse model of OIR. There was improvement seen in the degree of blood vessel tuft formation, blood vessel tortuosity, and central vasoconstriction with Squalamine treatment at d 15 or 16. Single-dose Squalamine at d 12 was effective at reducing subsequent development of retinal neovascularization at doses as low as 1 mg/kg. Squalamine is a very active inhibitor of OIR in mouse neonates at doses as low as 1 mg/kg given once. Further, Squalamine given late in the course of OIR improves retinopathy by inducing regression of retinal neovessels and abrogating invasion of new vessels beyond the inner-limiting membrane of the retina.

  • Squalamine lactate reduces choroidal neovascularization in a laser injury model in the rat
    Retina-the Journal of Retinal and Vitreous Diseases, 2003
    Co-Authors: Thomas A Ciulla, Jon I Williams, Michael P Mclane, Mark H Criswell, Ronald P Danis, Kenneth J Holroyd
    Abstract:

    PurposeTo determine if systemically administered Squalamine lactate, a novel aminosterol with antineoplastic and antiangiogenic activity, inhibits the development of experimental choroidal neovascularization membranes (CNVMs) induced by laser trauma in a rat model.MethodsTwenty anesthetized male Bro

  • a phase i iia trial of continuous five day infusion of Squalamine lactate msi 1256f plus carboplatin and paclitaxel in patients with advanced non small cell lung cancer
    Clinical Cancer Research, 2003
    Co-Authors: Roy S Herbst, Jon I Williams, Kenneth J Holroyd, Lisa A Hammond, David P Carbone, Hai T Tran, Avinash Desai, Nebiyou B Bekele, Howard Hait, Victoria Allgood
    Abstract:

    Purpose: Squalamine is an antitumor agent that has been shown to have antiangiogenic activity in animal models. This Phase I/IIA study was designed to assess the safety, clinical response, and pharmacokinetics of Squalamine when administered as a 5-day continuous infusion in conjunction with standard chemotherapy every 3 weeks in patients with stage IIIB (pleural effusion) or stage IV non-small cell lung cancer. Experimental Design: Patients with chemotherapy-naive non-small cell lung cancer were treated with escalating doses of Squalamine in combination with standard doses of paclitaxel and carboplatin. Paclitaxel and carboplatin were administered on day 1, followed by Squalamine as a continuous infusion on days 1–5, every 21 days. Results: A total of 45 patients were enrolled (18 patients in the Phase I dose escalation arm and 27 in the Phase IIA arm). The starting dose of Squalamine was 100 mg/m 2 /day and escalated to 400 mg/m 2 /day; two of three patients at 400 mg/m 2 /day had dose-limiting toxicity that included grade 3/4 arthralgia, myalgia, and neutropenia. On the basis of safety and toxicity, 300 mg/m 2 /day was selected as the Phase II dose of Squalamine in this combination regimen. An additional 27 patients (a total of 33) were enrolled according to the protocol treatment schema at 300 mg/m 2 /day. There was no pharmacokinetic evidence of drug interactions for the combination of Squalamine, carboplatin, and paclitaxel. Forty-three patients were evaluable for response. Partial tumor responses were observed in 12 (28%) of these patients; an additional 8 evaluable patients (19%) were reported to have stable disease. For all of the patients treated, the median survival was 10.0 months; and 1-year survival was 40%. Conclusions: The combination of Squalamine given continuously daily for 5 days, with paclitaxel and carboplatin given on day 1, is well tolerated. Patient survival data and the safety profile of this drug combination suggests that the use of Squalamine given at its maximum tolerated dose with cytotoxic chemotherapy should be explored further as a potentially effective therapeutic strategy for patients with stage IIIB or IV non-small cell lung cancer.

  • a phase i and pharmacokinetic study of Squalamine an aminosterol angiogenesis inhibitor
    Clinical Cancer Research, 2003
    Co-Authors: Lisa A Hammond, Gail S Eckhardt, Amita Patnaik, Chris H Takimoto, Garry Schwartz, Andrew Goetz, Anthony W Tolcher, Heather Mccreery, Khalid Mamun, Jon I Williams
    Abstract:

    Purpose: The purpose of this study was to assess the feasibility and characterize the pharmacokinetics of Squalamine administered as a continuous i.v. infusion daily for 5 days every 3 weeks. Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of Squalamine as a 5-day continuous i.v. infusion every 3 weeks. Doses were initially escalated in 100% increments from a starting dose of 6 mg/m 2 /day, with a single patient treated at each dose level until moderate toxicity was observed, at which time additional patients were treated. Results: Thirty-three patients were treated with 73 courses of Squalamine at 13 dose levels ranging from 6 to 700 mg/m 2 /day. Hepatotoxicity, characterized by brief, asymptomatic elevations in transaminases and hyperbilirubinemia, was the principal dose-limiting toxicity of Squalamine. At 700 mg/m 2 /day, two of three patients developed grade 4 hyperbilirubinemia, which precluded further dose escalation. At 500 mg/m 2 /day, one of seven patients experienced dose-limiting grade 4 hyperbilirubinemia and grade 3 neurosensory changes, which resolved soon after treatment. Squalamine pharmacokinetics were dose-proportional. At 500 mg/m 2 /day, the mean (percentage coefficient of variation) clearance, half-life, and volume of distribution of Squalamine were 2.67 liters/h/m 2 (85%), 9.46 h (81%), and 36.84 liters/m 2 (124%), respectively, and steady-state concentrations [20.08 μg/ml (13%)] were well above those that inhibit angiogenesis in preclinical models. Conclusions: At the recommended Phase II dose of 500 mg/m 2 /day, Squalamine is well tolerated and results in plasma concentrations at least an order of magnitude higher than those required for prominent antiangiogenic effects in preclinical studies.

  • effect of Squalamine on iris neovascularization in monkeys
    Retina-the Journal of Retinal and Vitreous Diseases, 2002
    Co-Authors: M Genaidy, Jon I Williams, Kenneth J Holroyd, A A Kazi, G A Peyman, E Passosmachado, H G Farahat, Diane A Blake
    Abstract:

    PURPOSE:To investigate the effect of Squalamine, an antiangiogenic aminosterol, in an experimental model of iris neovascularization. METHODS:Iris neovascularization was created in cynomolgus monkeys by occluding retinal veins with an argon laser and inducing persistent hypotony with a central corneal suture. Twenty-four eyes were treated in three groups. In Group 1, four eyes were injected intravitreally with 3 microg/0.1 mL Squalamine and four eyes with balanced saline solution (controls) immediately after vein occlusion (day 1); injections were repeated every 3 days for 3 weeks. In Group 2, 1 mg/kg Squalamine was administered with intravenous infusion in dextrose 5% in four animals; four control animals received only dextrose. Infusions began on day 1 and were repeated every 3 days for 3 weeks. In Group 3, after development of iris neovascularization on day 7, 1 mg/kg Squalamine was injected systemically in four animals; four control animals received dextrose 5%. Monkeys were examined by slit-lamp biomicroscopy and underwent color photography and fluorescein angiography. RESULTS:Group 1: All eyes, treated and control, developed intense and persistent rubeosis iridis. Group 2: Two of the four treated eyes in this group developed minimal iris neovascularization; the other two had no iris neovascularization. All four control eyes developed intense, persistent iris neovascularization. Group 3: All eyes developed extensive rubeosis iridis; iris neovascularization regressed in all four treated eyes after Squalamine injections. Two of four treated eyes retained minimal iris neovascularization; two showed complete regression of rubeosis iridis. Rubeosis iridis completely regressed in two of the four control eyes; the remaining two control eyes had intense, persistent iris neovascularization. CONCLUSIONS:Intravitreally injected Squalamine did not affect the development of iris neovascularization; however, systemic Squalamine injection inhibited the development of iris neovascularization and caused partial regression of new vessels in a primate model.

Jean Marc Rolain - One of the best experts on this subject based on the ideXlab platform.

  • Polyaminosteroid analogues as potent antibacterial agents against mupirocin-resistant Staphylococcus aureus strains
    Anti-Infective Agents, 2019
    Co-Authors: Adèle Sakr, Jean Michel Brunel, Frédéric Laurent, Tania Nawfal Dagher, Olivier Blin, Jean Marc Rolain
    Abstract:

    Background and Objective: : Nasal carriage of Staphylococcus aureus (S. aureus) constitutes an important risk factor for subsequent infections in some types of patient populations. Decolonization of carriers using intranasal mupirocin is widely used as a preventive measure. However, resistance to this agent has been rising and causing failure in the decolonization, highlighting the need for new alternatives. The objective of our study was to evaluate the antibacterial activity of polyaminosteroid derivatives against S. aureus strains with different levels of mupirocin-resistance. Methods and Results:: Using the broth microdilution method, we evaluated the minimum inhibitory concentration (MIC) of these molecules against S. aureus clinical strains including mupirocin-resistant strains. We found that Squalamine and one of its analogues, named BSQ-1, are active against mupirocin-susceptible and -resistant clinical isolates with MIC values of 3.125 µg/mL. Additionally, long-term and repeated exposure of a susceptible S. aureus strain to Squalamine and BSQ-1 did not lead to the emergence of resistant bacteria, contrarily to mupirocin. Conclusion: : Our study suggests that these molecules constitute promising new alternatives to mupirocin for nasal decolonization and prevention of endogenous infections.

  • soluble Squalamine tablets for the rapid disinfection of home nebulizers of cystic fibrosis patients
    Journal of Cystic Fibrosis, 2012
    Co-Authors: Lamia Djouhribouktab, Kamel Alhanout, Veronique Andrieu, Nathalie Stremler, Jean Christophe Dubus, Didier Raoult, Jean Marc Rolain, Jean Michel Brunel
    Abstract:

    Abstract Background The bacterial contamination of nebulizers represents a major problem for cystic fibrosis (CF) patients that can lead to reduced nebulizer performance and increase the risk of patient reinfection by the contaminating bacteria. Objective We investigated the potential use of Squalamine, a broad-spectrum antimicrobial compound, as a nebulizer disinfectant. Methods Pari LC nebulizers were artificially contaminated with a suspension of bacteria ( Staphylococcus aureus and Pseudomonas aeruginosa ; 10 8 CFU/mL) and fungi ( Candidida albicans and Aspergilus niger ; 10 7 CFU/mL) and then disinfected by immersion in Squalamine solution for 20min. Glutaraldehyde and Korsolex peracetic acid were used as disinfectant controls. Result We found that 0.5g/L Squalamine reduced the levels of viable S. aureus and P. aeruginosa by 5 log 10 and the level of viable C. albicans by 4 log 10 after 20min. A concentration of 2g/L was needed to reduce the level of A. niger cells by 4 log 10 in 6hours. Finally, a formulation of Squalamine in the form of a soluble disinfecting tablet containing 2.5% (w/w) Squalamine was developed and successfully applied for nebulizer disinfection. Conclusion Our results suggest that aminosterol derivatives may be used by CF patients for rapid and easy home nebulizer disinfection and that soluble tablets may be developed for this purpose.

  • antibacterial efficacy of inhaled Squalamine in a rat model of chronic pseudomonas aeruginosa pneumonia
    Journal of Antimicrobial Chemotherapy, 2012
    Co-Authors: Sami Hraiech, Jean Michel Brunel, Veronique Andrieu, Didier Raoult, Jean Marc Rolain, Fabienne Bregeon, Hubert Lepidi, Laurent Papazian, Antoine Roch
    Abstract:

    Objectives: Squalamine is a steroid extracted from sharks with proven in vitro antibacterial activity. We assessed its efficacy in reducing the lung bacterial load and histological lesions when given via inhalation in a rat model of chronic Pseudomonas aeruginosa pneumonia. Methods: Sprague-Dawley rats were inoculated by tracheal intubation with 150 mL of a solution containing 10 8 cfu/mL of agar bead-embedded P. aeruginosa strain PAO1. MICs of Squalamine and colistin for this strain were 2‐8 and 0.5‐1 mg/L, respectively. Starting the day after infection, the animals were treated twice daily with aerosolized Squalamine (3 mg), colistin (160 mg) or 0.9% saline for 6 days. The bacterial load and lung histological lesions were evaluated on the seventh day. Results: Aerosols of Squalamine and colistin resulted in a significant reduction in median (IQR) pulmonary bacterial count compared with saline [10 3 (6×10 2 ‐2×10 3 ), 10 3 (9×10 2 ‐6×10 3 ) and 10 5 (9×10 4 ‐2×10 5 ) cfu/lung, respectively; P,0.001 for both treated groups versus saline]. The lung weight and the lung histological severity score were significantly lower in both treated groups. Conclusions: In a model of chronic P. aeruginosa pneumonia, treatment twice daily with a Squalamine aerosol for 6 days leads to a significant reduction in the pulmonary bacterial count and pneumonia lesions with an efficacy comparable to that of colistin.

  • synthesis of new 3 20 bispolyaminosteroid Squalamine analogues and evaluation of their antimicrobial activities
    Journal of Medicinal Chemistry, 2011
    Co-Authors: Lamia Djouhribouktab, Nicolas Vidal, Jean Marc Rolain, Jean Michel Brunel
    Abstract:

    3,20-Amino- and polyaminosteroid analogues of Squalamine and trodusquemine were synthesized involving a stereoselective titanium reductive amination reaction in high chemical yields in numerous cases. These derivatives were evaluated for their in vitro antimicrobial properties against references and clinical bacterial strains exhibiting minimum inhibitory concentrations of 2.5–40 μg/mL. The mechanism of action of these derivatives was determined using bioluminescence for ATP efflux measurements and fluorescence methods for membrane depolarization assays.

  • Squalamine ointment for staphylococcus aureus skin decolonization in a mouse model
    Journal of Antimicrobial Chemotherapy, 2011
    Co-Authors: Lamia Djouhribouktab, Kamel Alhanout, Veronique Andrieu, Didier Raoult, Jean Marc Rolain, Jean Michel Brunel
    Abstract:

    Objectives: Staphylococcus aureus colonization of the skin and the nostrils remains a major cause of surgical-site infections despite preoperative and preventive procedures. To date, many compounds have been used for S. aureus decolonization, including mupirocin ointments and antiseptics, with variable results. The emergence of mupirocin-resistant S. aureus strains has led to the search for new antimicrobial agents specifically for S. aureus decolonization. In this work we evaluated Squalamine and related parent-derived ointments (1%) as potential new compounds for S. aureus decolonization in a new mouse model. Methods: We report the development and application of Squalamine and related parent-derived ointments in a new mouse skin model. After skin shaving, mice were colonized with an S. aureus suspension that was calibrated to 10 4 -10 6 cfu/mL. The remaining bacterial load was monitored for 2 days after a single application of Squalamine by spreading. Results: We found that S. aureus colonization of the skin was stable for at least 2 days before it was naturally eliminated. Using this model we found that Squalamine ointment (1%) could reduce S. aureus viable cells by up to 4 log with a single, 1 h application of ointment, whereas mupirocin application reduced viable cell numbers by only 1.3 log during that same time (P<0.05). Conclusions: Our results suggest that such compounds may be useful for S. aureus nasal and skin decolonization and may constitute a potent alternative for skin and nasal antisepsis before surgery.

Kamel Alhanout - One of the best experts on this subject based on the ideXlab platform.

  • soluble Squalamine tablets for the rapid disinfection of home nebulizers of cystic fibrosis patients
    Journal of Cystic Fibrosis, 2012
    Co-Authors: Lamia Djouhribouktab, Kamel Alhanout, Veronique Andrieu, Nathalie Stremler, Jean Christophe Dubus, Didier Raoult, Jean Marc Rolain, Jean Michel Brunel
    Abstract:

    Abstract Background The bacterial contamination of nebulizers represents a major problem for cystic fibrosis (CF) patients that can lead to reduced nebulizer performance and increase the risk of patient reinfection by the contaminating bacteria. Objective We investigated the potential use of Squalamine, a broad-spectrum antimicrobial compound, as a nebulizer disinfectant. Methods Pari LC nebulizers were artificially contaminated with a suspension of bacteria ( Staphylococcus aureus and Pseudomonas aeruginosa ; 10 8 CFU/mL) and fungi ( Candidida albicans and Aspergilus niger ; 10 7 CFU/mL) and then disinfected by immersion in Squalamine solution for 20min. Glutaraldehyde and Korsolex peracetic acid were used as disinfectant controls. Result We found that 0.5g/L Squalamine reduced the levels of viable S. aureus and P. aeruginosa by 5 log 10 and the level of viable C. albicans by 4 log 10 after 20min. A concentration of 2g/L was needed to reduce the level of A. niger cells by 4 log 10 in 6hours. Finally, a formulation of Squalamine in the form of a soluble disinfecting tablet containing 2.5% (w/w) Squalamine was developed and successfully applied for nebulizer disinfection. Conclusion Our results suggest that aminosterol derivatives may be used by CF patients for rapid and easy home nebulizer disinfection and that soluble tablets may be developed for this purpose.

  • In vitro activity of aminosterols against dermatophytes
    Medical Mycology, 2012
    Co-Authors: Oumar Coulibaly, Jean Michel Brunel, Mahamadou A Thera, Abdoulaye A Djimdé, Renaud Piarroux, Ogobara K Doumbo, Kamel Alhanout, Coralie L'ollivier, Stéphane Ranque
    Abstract:

    We recently reported that aminosterols are fungicidal due to their disrupting the outer membranes of yeasts and that they have a significant in vitro activity against various mould species. Yet, their activity against dermatophytes had never been tested. This study’s objective was to evaluate the in vitro activity of Squalamine and a synthetic aminosterol derivative (ASD) against various dermatophytes. Susceptibility testing of Squalamine, ASD, terbinafine, and griseofulvin was performed, in triplicate, in accord with the Clinical Laboratory and Standards Institute’s M38-A2 procedure, using an 80% growth inhibition endpoint. The studies included the following dermatophytes: Trichophyton rubrum, T. mentagrophytes, T. soudanense, Microsporum canis, M. audouinii, M. persicolor; M. cookie and M. gypseum. Squalamine and ASD showed significant in vitro activity against these dermatophytes. The minimum inhibitory concentrations (MICs) ranged from 4–16 mg/l and from 2–8 mg/l for Squalamine and ASD, respectively. ...

  • Squalamine ointment for staphylococcus aureus skin decolonization in a mouse model
    Journal of Antimicrobial Chemotherapy, 2011
    Co-Authors: Lamia Djouhribouktab, Kamel Alhanout, Veronique Andrieu, Didier Raoult, Jean Marc Rolain, Jean Michel Brunel
    Abstract:

    Objectives: Staphylococcus aureus colonization of the skin and the nostrils remains a major cause of surgical-site infections despite preoperative and preventive procedures. To date, many compounds have been used for S. aureus decolonization, including mupirocin ointments and antiseptics, with variable results. The emergence of mupirocin-resistant S. aureus strains has led to the search for new antimicrobial agents specifically for S. aureus decolonization. In this work we evaluated Squalamine and related parent-derived ointments (1%) as potential new compounds for S. aureus decolonization in a new mouse model. Methods: We report the development and application of Squalamine and related parent-derived ointments in a new mouse skin model. After skin shaving, mice were colonized with an S. aureus suspension that was calibrated to 10 4 -10 6 cfu/mL. The remaining bacterial load was monitored for 2 days after a single application of Squalamine by spreading. Results: We found that S. aureus colonization of the skin was stable for at least 2 days before it was naturally eliminated. Using this model we found that Squalamine ointment (1%) could reduce S. aureus viable cells by up to 4 log with a single, 1 h application of ointment, whereas mupirocin application reduced viable cell numbers by only 1.3 log during that same time (P<0.05). Conclusions: Our results suggest that such compounds may be useful for S. aureus nasal and skin decolonization and may constitute a potent alternative for skin and nasal antisepsis before surgery.

  • Squalamine ointment for Staphylococcus aureus skin decolonization in a mouse model
    Journal of Antimicrobial Chemotherapy, 2011
    Co-Authors: Lamia Djouhri-bouktab, Kamel Alhanout, Veronique Andrieu, Didier Raoult, Jean Marc Rolain, Jean Michel Brunel
    Abstract:

    Objectives: Staphylococcus aureus colonization of the skin and the nostrils remains a major cause of surgical-site infections despite preoperative and preventive procedures. To date, many compounds have been used for S. aureus decolonization, including mupirocin ointments and antiseptics, with variable results. The emergence of mupirocin-resistant S. aureus strains has led to the search for new antimicrobial agents specifically for S. aureus decolonization. In this work we evaluated Squalamine and related parent-derived ointments (1%) as potential new compounds for S. aureus decolonization in a new mouse model. Methods: We report the development and application of Squalamine and related parent-derived ointments in a new mouse skin model. After skin shaving, mice were colonized with an S. aureus suspension that was calibrated to 10 4 -10 6 cfu/mL. The remaining bacterial load was monitored for 2 days after a single application of Squalamine by spreading. Results: We found that S. aureus colonization of the skin was stable for at least 2 days before it was naturally eliminated. Using this model we found that Squalamine ointment (1%) could reduce S. aureus viable cells by up to 4 log with a single, 1 h application of ointment, whereas mupirocin application reduced viable cell numbers by only 1.3 log during that same time (P

  • Squalamine as an example of a new potent antimicrobial agents class a critical review
    Current Medicinal Chemistry, 2010
    Co-Authors: Kamel Alhanout, J M Rolain, Jean Michel Brunel
    Abstract:

    An important strategy to circumvent the problem of antimicrobial resistance is to search for new compounds with antimicrobial activity. In this context, aminosterols, which include Squalamine-like compounds and ceragenins, have gained interest due to their wide spectrum of antibacterial and antifungal properties. In light of recently reported data, we decided to analyze the mechanism of action of these compounds as well as their antimicrobial properties. Aminosterols are active against both bacterial reference strains and multidrug-resistant antibiotics as they disrupt the integrity of the bacterial membrane. Thus, these compounds could be useful in the development of new topical decontaminants or disinfecting agents.

Kenneth J Holroyd - One of the best experts on this subject based on the ideXlab platform.

  • randomized phase ii trial of weekly Squalamine carboplatin and paclitaxel as first line therapy for advanced non small cell lung cancer
    Journal of Clinical Oncology, 2004
    Co-Authors: V Rose, Joan H Schiller, Kenneth J Holroyd, Avinash Desai, A Wood, E Eskander, M Ahmed
    Abstract:

    7109 Background:Squalamine is an anti-angiogenic aminosterol that acts directly within activated endothelial cells and has acivity in cancer and eye angiogenesis models. Previously a Phase I/II trial in advanced non-small cell lung cancer (NSCLC) of a once every three weeks regimen of Squalamine (given as a five day infusion at doses of 100 to 400 mg/m2/day) combined with carboplatin (AUC=6) and paclitaxel (225 mg/m2) was reported to give a response rate of 28% in 43 patients, with median survival of 10.0 months and one year survival of 40%. In the current study a weekly “metronomic” dosing approach of the Squalamine, carboplatin, and paclitaxel regimen was evaluated. Methods:45 patients with Stage IIIB NSCLC with pleural effusion or Stage IV disease were enrolled. The drug regimen was a weekly three hour infusion of Squalamine (patients randomly assigned 1:1 to a dose of 100 or 200 mg/m2)combined with weekly carboplatin (AUC=2) and paclitaxel (75 mg/m2), for 12 weeks. Patients were eligible to receive ad...

  • Squalamine lactate reduces choroidal neovascularization in a laser injury model in the rat
    Retina-the Journal of Retinal and Vitreous Diseases, 2003
    Co-Authors: Thomas A Ciulla, Jon I Williams, Michael P Mclane, Mark H Criswell, Ronald P Danis, Kenneth J Holroyd
    Abstract:

    PurposeTo determine if systemically administered Squalamine lactate, a novel aminosterol with antineoplastic and antiangiogenic activity, inhibits the development of experimental choroidal neovascularization membranes (CNVMs) induced by laser trauma in a rat model.MethodsTwenty anesthetized male Bro

  • a phase i iia trial of continuous five day infusion of Squalamine lactate msi 1256f plus carboplatin and paclitaxel in patients with advanced non small cell lung cancer
    Clinical Cancer Research, 2003
    Co-Authors: Roy S Herbst, Jon I Williams, Kenneth J Holroyd, Lisa A Hammond, David P Carbone, Hai T Tran, Avinash Desai, Nebiyou B Bekele, Howard Hait, Victoria Allgood
    Abstract:

    Purpose: Squalamine is an antitumor agent that has been shown to have antiangiogenic activity in animal models. This Phase I/IIA study was designed to assess the safety, clinical response, and pharmacokinetics of Squalamine when administered as a 5-day continuous infusion in conjunction with standard chemotherapy every 3 weeks in patients with stage IIIB (pleural effusion) or stage IV non-small cell lung cancer. Experimental Design: Patients with chemotherapy-naive non-small cell lung cancer were treated with escalating doses of Squalamine in combination with standard doses of paclitaxel and carboplatin. Paclitaxel and carboplatin were administered on day 1, followed by Squalamine as a continuous infusion on days 1–5, every 21 days. Results: A total of 45 patients were enrolled (18 patients in the Phase I dose escalation arm and 27 in the Phase IIA arm). The starting dose of Squalamine was 100 mg/m 2 /day and escalated to 400 mg/m 2 /day; two of three patients at 400 mg/m 2 /day had dose-limiting toxicity that included grade 3/4 arthralgia, myalgia, and neutropenia. On the basis of safety and toxicity, 300 mg/m 2 /day was selected as the Phase II dose of Squalamine in this combination regimen. An additional 27 patients (a total of 33) were enrolled according to the protocol treatment schema at 300 mg/m 2 /day. There was no pharmacokinetic evidence of drug interactions for the combination of Squalamine, carboplatin, and paclitaxel. Forty-three patients were evaluable for response. Partial tumor responses were observed in 12 (28%) of these patients; an additional 8 evaluable patients (19%) were reported to have stable disease. For all of the patients treated, the median survival was 10.0 months; and 1-year survival was 40%. Conclusions: The combination of Squalamine given continuously daily for 5 days, with paclitaxel and carboplatin given on day 1, is well tolerated. Patient survival data and the safety profile of this drug combination suggests that the use of Squalamine given at its maximum tolerated dose with cytotoxic chemotherapy should be explored further as a potentially effective therapeutic strategy for patients with stage IIIB or IV non-small cell lung cancer.

  • effect of Squalamine on iris neovascularization in monkeys
    Retina-the Journal of Retinal and Vitreous Diseases, 2002
    Co-Authors: M Genaidy, Jon I Williams, Kenneth J Holroyd, A A Kazi, G A Peyman, E Passosmachado, H G Farahat, Diane A Blake
    Abstract:

    PURPOSE:To investigate the effect of Squalamine, an antiangiogenic aminosterol, in an experimental model of iris neovascularization. METHODS:Iris neovascularization was created in cynomolgus monkeys by occluding retinal veins with an argon laser and inducing persistent hypotony with a central corneal suture. Twenty-four eyes were treated in three groups. In Group 1, four eyes were injected intravitreally with 3 microg/0.1 mL Squalamine and four eyes with balanced saline solution (controls) immediately after vein occlusion (day 1); injections were repeated every 3 days for 3 weeks. In Group 2, 1 mg/kg Squalamine was administered with intravenous infusion in dextrose 5% in four animals; four control animals received only dextrose. Infusions began on day 1 and were repeated every 3 days for 3 weeks. In Group 3, after development of iris neovascularization on day 7, 1 mg/kg Squalamine was injected systemically in four animals; four control animals received dextrose 5%. Monkeys were examined by slit-lamp biomicroscopy and underwent color photography and fluorescein angiography. RESULTS:Group 1: All eyes, treated and control, developed intense and persistent rubeosis iridis. Group 2: Two of the four treated eyes in this group developed minimal iris neovascularization; the other two had no iris neovascularization. All four control eyes developed intense, persistent iris neovascularization. Group 3: All eyes developed extensive rubeosis iridis; iris neovascularization regressed in all four treated eyes after Squalamine injections. Two of four treated eyes retained minimal iris neovascularization; two showed complete regression of rubeosis iridis. Rubeosis iridis completely regressed in two of the four control eyes; the remaining two control eyes had intense, persistent iris neovascularization. CONCLUSIONS:Intravitreally injected Squalamine did not affect the development of iris neovascularization; however, systemic Squalamine injection inhibited the development of iris neovascularization and caused partial regression of new vessels in a primate model.

  • a phase i and pharmacokinetic study of Squalamine a novel antiangiogenic agent in patients with advanced cancers
    Clinical Cancer Research, 2001
    Co-Authors: Pankaj Bhargava, Jon I Williams, Kenneth J Holroyd, Howard Hait, John Marshall, William L Dahut, Naiyer A Rizvi, Nina Trocky, Sharon Song, Michael J Hawkins
    Abstract:

    Purpose: A Phase I study of Squalamine, a novel antiangiogenic agent originally isolated from the dogfish shark Squalus acanthias , was conducted in patients with advanced cancers to: ( a ) determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of Squalamine lactate when given as a 120-h continuous i.v. infusion every two weeks; and ( b ) to obtain information on prolonged (>120-h) continuous i.v. infusions in patients who have tolerated 120-h infusions. Experimental Design: A rapid dose escalation scheme was used that permitted intrapatient dose escalation. Three or more patients were treated at each dose, of which at least one patient started treatment de novo at that dose. Once DLT was encountered, the dose was decreased by one dose level, and the duration of infusion was prolonged from 10 up to 30 days in 5-day increments. Results: Nineteen patients were treated at eight Squalamine dose levels; the number of patients/dose level who received 120-h infusions were [expressed as dose in mg/m 2 /day (number of patients initiated de novo at that dose/total number of patients treated at that dose)]: 6 (3/3), 12 (3/6), 24 (1/5), 48 (2/6), 96 (4/10), 192 (2/6), 384 (3/8), and 538 (1/5). DLT was encountered at 384 mg/m 2 /day (1/3 de novo patients, 5/8 total patients) and 538 mg/m 2 /day (1/1 de novo patients, 4/5 total patients) and consisted of hepatotoxicity, characterized by grade 3 transaminase elevations that resolved 3–11 days after ceasing Squalamine infusion. Three patients did not experience hepatotoxicity when first treated at 384 mg/m 2 /day but developed DLT at the same dose when de-escalated from 538 mg/m 2 /day. Other toxicities included grade 1–3 fatigue, grade 1–2 nausea, anorexia, and neuromuscular symptoms. The maximum duration of continuous i.v. infusion was 20 days at a dose rate of 192 mg/m 2 /day in one patient without adverse effects. Pharmacokinetic calculations revealed a linear relationship between area under the curve or Cmax and Squalamine dose rate up to 384 mg/m 2 /day, with a prolonged terminal Squalamine persistence in patient plasma (median t 1/2 = 18 h; range, 8–48 h). Transient tumor responses were observed in a patient with synovial cell sarcoma and a patient with breast carcinoma with cutaneous metastases. Conclusions: The best tolerated dose rate of Squalamine when administered as a 120-h continuous i.v. infusion was 192 mg/m 2 /day; however, patients without prior exposure to Squalamine appeared to tolerate a dose rate of 384 mg/m 2 /day without DLT. On the basis of preclinical evidence of synergy with cytotoxic agents and demonstration of human safety from this trial, additional clinical trials have been initiated with Squalamine in combination with chemotherapy for patients with late stage lung cancer and ovarian cancer.