A Scientific Roadmap for Antibiotic Discovery: A Sustained and Robust Pipeline of New Antibacterial Drugs and Therapies is Critical to Preserve Public Health

In recent decades, the discovery and development of new antibiotics have slowed dramatically as scientific barriers to drug discovery, regulatory challenges, and diminishing returns on investment have led major drug companies to scale back or abandon their antibiotic research. Consequently, antibiotic discovery—which peaked in the 1950s—has dropped precipitously. Of greater concern is the fact that nearly all antibiotics brought to market over the past 30 years have been variations on existing drugs. Every currently available antibiotic is a derivative of a class discovered between the early 1900s and 1984.At the same time, the emergence of antibiotic-resistant pathogens has accelerated, giving rise to life-threatening infections that will not respond to available antibiotic treatment. Inevitably, the more that antibiotics are used, the more that bacteria develop resistance—rendering the drugs less effective and leading public health authorities worldwide to flag antibiotic resistance as an urgent and growing public health threat

Thorough QT study of the effect of intravenous amisulpride on QTc interval in Caucasian and Japanese healthy subjects.

AIM: The D2 /D3 antagonist amisulpride has shown promising efficacy against postoperative nausea and vomiting (PONV) at low doses. We investigated whether intravenous amisulpride has an effect on the QTc interval in a formal Thorough QT study (TQT). METHODS: This was a randomized, double-blind, placebo and positive-controlled, four-way crossover study. Forty healthy Caucasian and Japanese subjects were included to receive a single administration of 5 mg and 40 mg of i.v. amisulpride or a single oral dose of moxifloxacin or placebo per period. RESULTS: The therapeutic dose of 5 mg amisulpride was associated with a slight, transient increase in mean ΔΔQTcF, from 2.0 ms prior to dosing to a peak of 5 ms (90% CI: 2.8, 7.1 ms) at 8 min, decreasing to 2.1 ms at 30 min after dosing. The supra-therapeutic dose of 40 mg given at twice the infusion rate was associated with prolongation in ΔΔQTcF peaking at 23.4 ms (90% CI: 21.3, 25.5 ms) at the end of infusion (8 min), returning below 10 ms within 1.5 h. Assay sensitivity was confirmed; ΔΔQTcF had increased by 12.3 ms (90% CI 10.1, 14.6 ms) at 4 h post-dose. The PK-PD relationship revealed no differences between Caucasian and Japanese subjects (p-value > 0.5). CONCLUSIONS: Amisulpride has a plasma concentration-dependent effect on the QTc interval. The proposed therapeutic dose for management of PONV does not lead to a prolongation of QTcF above the threshold of regulatory concern, while such effect could not be excluded for the supratherapeutic dose

Phase II Clinical Trial With Pegylated Liposomal Doxorubicin (CAELYX®/Doxil®) and Quality of Life Evaluation (EORTC QLQ-C30) in Adult Patients With Advanced Soft Tissue Sarcomas: A study of the Spanish Group for Research in Sarcomas (GEIS)

Background: Pegylated liposomal doxorubicin (PLD), a formulation with pharmacokinetic differences with respect to doxorubicin (DXR), might benefit patients with advanced soft tissue sarcoma (STS) pretreated with DXR

Liposomes in Biology and Medicine

Drug delivery systems (DDS) have become important tools for the specific delivery of a large number of drug molecules. Since their discovery in the 1960s liposomes were recognized as models to study biological membranes and as versatile DDS of both hydrophilic and lipophilic molecules. Liposomes--nanosized unilamellar phospholipid bilayer vesicles--undoubtedly represent the most extensively studied and advanced drug delivery vehicles. After a long period of research and development efforts, liposome-formulated drugs have now entered the clinics to treat cancer and systemic or local fungal infections, mainly because they are biologically inert and biocompatible and practically do not cause unwanted toxic or antigenic reactions. A novel, up-coming and promising therapy approach for the treatment of solid tumors is the depletion of macrophages, particularly tumor associated macrophages with bisphosphonate-containing liposomes. In the advent of the use of genetic material as therapeutic molecules the development of delivery systems to target such novel drug molecules to cells or to target organs becomes increasingly important. Liposomes, in particular lipid-DNA complexes termed lipoplexes, compete successfully with viral gene transfection systems in this field of application. Future DDS will mostly be based on protein, peptide and DNA therapeutics and their next generation analogs and derivatives. Due to their versatility and vast body of known properties liposome-based formulations will continue to occupy a leading role among the large selection of emerging DDS

An investigation of modified metabolic regulation in streptomycin-dependent Escherichia coli

The acetohydroxy acid synthetase levels in streptomycin-sensitive, -dependent and -resistant mutants have been studied in four different strains of Escherichia coli. The activity of the ∝-acetolactate-forming system was found to be greater both at pH 6.0 and at pH 8.0 in streptomycin-dependent mutants than in the corresponding streptomycin-sensitive cultures. In general, streptomycin-resistant mutants demonstrated enzyme activities within the range found for streptomycin-sensitive organisms regardless of whether they were grown in the presence or absence of antibiotic. The acetohydroxy acid synthetase activity of streptomycin-sensitive and -resistant revertants was observed to be lower than that of the dependent Escherichia coli culture from which they were derived by back-mutation. Mutation to streptomycin-resistance or -dependence had no effect on glucokinase and glutamic dehydrogenase activities. The addition of the coenzyme flavin adenine dinucleotide to the incubation mixtures markedly stimulated the activities of all the extracts. This enhancement of acetohydroxy acid synthetase activity had little or no effect on the ratio of activities of this enzyme in the dependent and sensitive Escherichia coli strains investigated. ∝-Acetohydroxybutyrate formation was found to be greater in extracts from the streptomycin-dependent organism than in extracts prepared from the same strain of sensitive and resistant Escherichia coli. The degree of elevation of ∝-acetohydroxybutyrate paralleled that of ∝-acetolactate formation in the dependent mutant. It was concluded from these observations that excretion of L-valine by streptomycin-dependent Escherichia coli was a consequence of the elevated acetohydroxy acid synthetase activity of these mutants. In the dependent organism, it was postulated that streptomycin functioned as a wde-repressorw of acetohydroxy acid synthetase thus permitting the biosynthetic pathway leading to L-valine to serve as an important route of pyruvate dissimilation.Medicine, Faculty ofBiochemistry and Molecular Biology, Department ofGraduat