Leo Einck - Academia.edu (original) (raw)

Papers by Leo Einck

The most evident challenge to treatment of Helicobacter pylori, a bacterium responsible for gastr... more The most evident challenge to treatment of Helicobacter pylori, a bacterium responsible for gastritis, peptic ulcers and gastric cancer, is the increasing rate of resistance to all currently used therapeutic antibiotics. Thus, the development of novel therapies is urgently required. N-geranyl-N'-(2-adamantyl) ethane-1, 2-diamine (SQ109) is an ethylene diamine-based antitubercular drug that is currently in clinical trials for the treatment of tuberculosis (TB). Previous pharmacokinetic studies of SQ109 revealed that persistently high concentrations of SQ109 remain in the stomach 4 hours post oral administration in rats. This finding, combined with the need for new anti-Helicobacter therapies, prompted us to define the in vitro efficacy of SQ109 against H. pylori. Liquid broth micro-dilution was used for susceptibility studies to determine the antimicrobial activity of SQ109 against a total of 6 laboratory strains and 20 clinical isolates of H. pylori; the clinical isolates inclu...

doi:10.1093/jac/dki319 Identification of a new antitubercular drug candidate, SQ109, from a combi... more doi:10.1093/jac/dki319 Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines

Expert review of vaccines, Sep 7, 2016

Is the US ready for a biological attack using Ebola virus or Anthrax? Will vaccine developers be ... more Is the US ready for a biological attack using Ebola virus or Anthrax? Will vaccine developers be able to produce a Zika virus vaccine, before the epidemic spreads around the world? A recent report by The Blue Ribbon Study Panel on Biodefense argues that the US is not ready for these challenges, however, technologies and capabilities that could address these deficiencies are within reach. Vaccine technologies have advanced and readiness has improved in recent years, due to advances in sequencing technology and computational power making the 'vaccines on demand' concept a reality. Building a robust strategy to design effective biodefense vaccines from genome sequences harvested by real-time biosurveillance will benefit from technologies that are being brought to bear on the cancer cure 'moonshot'. When combined with flexible vaccine production platforms, vaccines on demand will relegate expensive and, in some cases, insufficiently effective vaccine stockpiles to the du...

Journal of Antimicrobial Chemotherapy, 2016

Objectives: Clostridium difficile infection (CDI) is a primary cause of antibiotic-associated dia... more Objectives: Clostridium difficile infection (CDI) is a primary cause of antibiotic-associated diarrhoeal illness. Current therapies are insufficient as relapse rates following antibiotic treatment range from 25% for initial treatment to 60% for treatment of recurrence. In this study, we looked at the efficacy of SQ641 in a murine model of CDI. SQ641 is an analogue of capuramycin, a naturally occurring nucleoside-based compound produced by Streptomyces griseus. Methods: In a series of experiments, C57BL/6 mice were treated with a cocktail of antibiotics and inoculated with C. difficile strain VPI10463. Animals were treated orally with SQ641 for 5 days at a dose range of 0.1-300 mg/kg/day, 20 mg/kg/day vancomycin or drug vehicle. Animals were monitored for disease severity, clostridial shedding and faecal toxin levels for 14 days post-infection. Results: Five day treatment of CDI with SQ641 resulted in higher 14 day survival rates in mice compared with either vancomycin or vehicle alone. CDI survival rates were 100% (13 of 13) and 94% (32 of 34), respectively, in the 1 and 10 mg/kg/day SQ641 treatment groups, 37% (7 of 19) with vancomycin treatment at 20 mg/kg/day and 32% (14 of 44) in the vehicle-only control group. Secondary measures of efficacy, such as prevention of weight loss, decreased disease severity, decreased C. difficile shedding and decreased toxin in faeces, were observed with SQ641 and vancomycin treatment. Conclusions: SQ641 is effective for CDI treatment with prevention of relapse in the murine model of CDI.

While tuberculosis (TB) is a curable intracellular disease, it remains a global health issue with... more While tuberculosis (TB) is a curable intracellular disease, it remains a global health issue with over 1 million deaths reported in 2007. Causes of failed treatment include patient non-compliance and the emergence of drug resistance over the 6 month therapeutic course. Advanced technologies are needed to improve the efficiency of drug delivery to reduce dosing frequency and limit drug resistance, while ensuring patient compliance. Block copolymer directed rapid precipitations by Flash NanoPrecipitation enable formation of nanoparticles which have two unique advantages: (1) multiple drugs can be simultaneously assembled in the same nanoparticle and (2) targeting ligands can be introduced efficiently in drug formulations. Using nanoparticles as a drug delivery platform, we have created nanoscale drug cocktails to colocalize a novel, potent anti-tubercular drug with an efflux pump blocker to ensure therapeutic doses are achieved intracellularly. Targeted polyethylene glycol protected n...

Molecular pharmaceutics, Jan 17, 2015

Tuberculosis (TB) remains a major global health concern, and new therapies are needed to overcome... more Tuberculosis (TB) remains a major global health concern, and new therapies are needed to overcome the problems associated with dosing frequency, patient compliance, and drug resistance. To reduce side effects associated with systemic drug distribution and improve drug concentration at the target site, stable therapeutic nanocarriers (NCs) were prepared and evaluated for efficacy in vitro in Mycobacterium tuberculosis-infected macrophages. Rifampicin (RIF), a current, broad-spectrum antibiotic used in TB therapy, was conjugated by degradable ester bonds to form hydrophobic prodrugs. NCs encapsulating various ratios of nonconjugated RIF and the prodrugs showed the potential ability to rapidly deliver and knockdown intracellular M. tuberculosis by nonconjugated RIF and to obtain sustained release of RIF by hydrolysis of the RIF prodrug. NCs of the novel antibiotic SQ641 and a combination NC with cyclosporine A were formed by flash nanoprecipitation. Delivery of SQ641 in NC form resulte...

The most evident challenge to treatment of Helicobacter pylori, a bacterium responsible for gastr... more The most evident challenge to treatment of Helicobacter pylori, a bacterium responsible for gastritis, peptic ulcers and gastric cancer, is the increasing rate of resistance to all currently used therapeutic antibiotics. Thus, the development of novel therapies is urgently required. N-geranyl-N'-(2-adamantyl) ethane-1, 2-diamine (SQ109) is an ethylene diamine-based antitubercular drug that is currently in clinical trials for the treatment of tuberculosis (TB). Previous pharmacokinetic studies of SQ109 revealed that persistently high concentrations of SQ109 remain in the stomach 4 hours post oral administration in rats. This finding, combined with the need for new anti-Helicobacter therapies, prompted us to define the in vitro efficacy of SQ109 against H. pylori. Liquid broth micro-dilution was used for susceptibility studies to determine the antimicrobial activity of SQ109 against a total of 6 laboratory strains and 20 clinical isolates of H. pylori; the clinical isolates inclu...

doi:10.1093/jac/dki319 Identification of a new antitubercular drug candidate, SQ109, from a combi... more doi:10.1093/jac/dki319 Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines

Expert review of vaccines, Sep 7, 2016

Is the US ready for a biological attack using Ebola virus or Anthrax? Will vaccine developers be ... more Is the US ready for a biological attack using Ebola virus or Anthrax? Will vaccine developers be able to produce a Zika virus vaccine, before the epidemic spreads around the world? A recent report by The Blue Ribbon Study Panel on Biodefense argues that the US is not ready for these challenges, however, technologies and capabilities that could address these deficiencies are within reach. Vaccine technologies have advanced and readiness has improved in recent years, due to advances in sequencing technology and computational power making the 'vaccines on demand' concept a reality. Building a robust strategy to design effective biodefense vaccines from genome sequences harvested by real-time biosurveillance will benefit from technologies that are being brought to bear on the cancer cure 'moonshot'. When combined with flexible vaccine production platforms, vaccines on demand will relegate expensive and, in some cases, insufficiently effective vaccine stockpiles to the du...

Journal of Antimicrobial Chemotherapy, 2016

Objectives: Clostridium difficile infection (CDI) is a primary cause of antibiotic-associated dia... more Objectives: Clostridium difficile infection (CDI) is a primary cause of antibiotic-associated diarrhoeal illness. Current therapies are insufficient as relapse rates following antibiotic treatment range from 25% for initial treatment to 60% for treatment of recurrence. In this study, we looked at the efficacy of SQ641 in a murine model of CDI. SQ641 is an analogue of capuramycin, a naturally occurring nucleoside-based compound produced by Streptomyces griseus. Methods: In a series of experiments, C57BL/6 mice were treated with a cocktail of antibiotics and inoculated with C. difficile strain VPI10463. Animals were treated orally with SQ641 for 5 days at a dose range of 0.1-300 mg/kg/day, 20 mg/kg/day vancomycin or drug vehicle. Animals were monitored for disease severity, clostridial shedding and faecal toxin levels for 14 days post-infection. Results: Five day treatment of CDI with SQ641 resulted in higher 14 day survival rates in mice compared with either vancomycin or vehicle alone. CDI survival rates were 100% (13 of 13) and 94% (32 of 34), respectively, in the 1 and 10 mg/kg/day SQ641 treatment groups, 37% (7 of 19) with vancomycin treatment at 20 mg/kg/day and 32% (14 of 44) in the vehicle-only control group. Secondary measures of efficacy, such as prevention of weight loss, decreased disease severity, decreased C. difficile shedding and decreased toxin in faeces, were observed with SQ641 and vancomycin treatment. Conclusions: SQ641 is effective for CDI treatment with prevention of relapse in the murine model of CDI.

While tuberculosis (TB) is a curable intracellular disease, it remains a global health issue with... more While tuberculosis (TB) is a curable intracellular disease, it remains a global health issue with over 1 million deaths reported in 2007. Causes of failed treatment include patient non-compliance and the emergence of drug resistance over the 6 month therapeutic course. Advanced technologies are needed to improve the efficiency of drug delivery to reduce dosing frequency and limit drug resistance, while ensuring patient compliance. Block copolymer directed rapid precipitations by Flash NanoPrecipitation enable formation of nanoparticles which have two unique advantages: (1) multiple drugs can be simultaneously assembled in the same nanoparticle and (2) targeting ligands can be introduced efficiently in drug formulations. Using nanoparticles as a drug delivery platform, we have created nanoscale drug cocktails to colocalize a novel, potent anti-tubercular drug with an efflux pump blocker to ensure therapeutic doses are achieved intracellularly. Targeted polyethylene glycol protected n...

Molecular pharmaceutics, Jan 17, 2015

Tuberculosis (TB) remains a major global health concern, and new therapies are needed to overcome... more Tuberculosis (TB) remains a major global health concern, and new therapies are needed to overcome the problems associated with dosing frequency, patient compliance, and drug resistance. To reduce side effects associated with systemic drug distribution and improve drug concentration at the target site, stable therapeutic nanocarriers (NCs) were prepared and evaluated for efficacy in vitro in Mycobacterium tuberculosis-infected macrophages. Rifampicin (RIF), a current, broad-spectrum antibiotic used in TB therapy, was conjugated by degradable ester bonds to form hydrophobic prodrugs. NCs encapsulating various ratios of nonconjugated RIF and the prodrugs showed the potential ability to rapidly deliver and knockdown intracellular M. tuberculosis by nonconjugated RIF and to obtain sustained release of RIF by hydrolysis of the RIF prodrug. NCs of the novel antibiotic SQ641 and a combination NC with cyclosporine A were formed by flash nanoprecipitation. Delivery of SQ641 in NC form resulte...