ALBERT

All Library Books, journals and Electronic Records Telegrafenberg

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • Articles  (786)
Collection
  • Articles  (786)
Publisher
Years
Journal
  • 1
    Publication Date: 2018-03-14
    Description: New drug development is both resource and time intensive, where later clinical stages result in significant costs. We analyze recent late-stage failures to identify drugs where failures result from inadequate scientific advances as well as drugs where we believe pitfalls could have been avoided. These can be broadly classified into two categories: 1) where science is mature and the failures can be avoided through rigorous and prospectively determined decision-making criteria, scientific curiosity, and discipline to follow up on emerging findings; and 2) where problems encountered in Phase 3 failures cannot be explained at this time, as the science is not sufficiently advanced and companies/investigators need to recognize the possibility of deficiency of our knowledge. Through these case studies, key themes critical for successful drug development emerge—understanding the therapeutic pathway including receptor and signaling biology, pharmacological responses related to safety and efficacy, pharmacokinetics of the drug and exposure at target site, optimum dose, and dosing regimen; and identification of patient sub-populations likely to respond and will have a favorable benefit-risk profile, design of clinical trials, and a quantitative framework that can guide data-driven decision making. It is essential that the right studies are conducted early in the development process to answer the key questions, with the emphasis on learning in the early stages of development, whereas Phase 3 should be reserved for confirming the safety and efficacy. Utilization of innovative technology in identifying patients based on molecular signature of their disease, rapid assessment of pharmacological response, mechanistic modeling of emerging data, seamless operational processes to reduce start-up and wind-down time for clinical trials through use of electronic health records and data mining, and development of novel and objective clinical efficacy endpoints are some concepts for improving the success rate.
    Electronic ISSN: 1550-7416
    Topics: Chemistry and Pharmacology
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
  • 2
    Publication Date: 2018-03-14
    Description: In ligand binding assays (LBA), the concentration to response data is a nonlinear relationship driven by the law of mass action. Four parameter logistic (4PL) and five parameter logistic (5PL) curve fitting models are two widely accepted and validated models for LBA calibration curve data. Selection of the appropriate regression model and weighting function are key components of LBA development. Assessment of selected model and weighting function should be performed during assay development and confirmed later during validation. There has been limited published work on practical approaches to determining an appropriate weighting function and selection of a regression model for ligand binding assays. Herein, a structured scheme is presented to determine both. By applying commonly available software, assay performance data were analyzed to determine weighting functions and associated choice of a curve fitting model in three presented case studies. As a result, assay ranges of quantification were improved by reducing lower limit of quantification (from 1.00 to 0.317 ng/mL in one case study and from 2.06 to 1.37 ng/mL in another) or extending both low and upper limits of quantification(e.g., 1.04 to 48.3 ng/mL improved to 0.602 to 145 ng/mL). In addition, assay calibration curve performance demonstrated improved assay accuracy (%RE) and precision (%CV). Recommendations on decision flow when determining appropriate weighting function and curve fit model are presented.
    Electronic ISSN: 1550-7416
    Topics: Chemistry and Pharmacology
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
  • 3
    Publication Date: 2018-03-12
    Description: The final step of peptidoglycan (PG) synthesis in all bacteria is the formation of cross-linkage between PG-stems. The cross-linking between amino acids in different PG chains gives the peptidoglycan cell wall a 3-dimensional structure and adds strength and rigidity to it. There are two distinct types of cross-linkages in bacterial cell walls. D,D-transpeptidase (D,D-TPs) generate the classical 4➔3 cross-linkages and the L,D-transpeptidase (L,D-TPs) generate the 3➔3 non-classical peptide cross-linkages. The present study is aimed at understanding the nature of drug resistance associated with L,D-TP and gaining insights for designing novel antibiotics against multi-drug resistant bacteria. Penicillin and cephalosporin classes of β-lactams cannot inhibit L,D-TP function; however, carbapenems inactivate its function. We analyzed the structure of L,D-TP of Mycobacterium tuberculosis in the apo form and in complex with meropenem and imipenem. The periplasmic region of L,D-TP folds into three domains. The catalytic residues are situated in the C-terminal domain. The acylation reaction occurs between carbapenem antibiotics and the catalytic Cys-354 forming a covalent complex. This adduct formation mimics the acylation of L,D-TP with the donor PG-stem. A novel aspect of this study is that in the crystal structures of the apo and the carbapenem complexes, the N-terminal domain has a muropeptide unit non-covalently bound to it. Another interesting observation is that the calcium complex crystallized as a dimer through head and tail interactions between the monomers.
    Electronic ISSN: 1550-7416
    Topics: Chemistry and Pharmacology
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
  • 4
    Publication Date: 2018-03-09
    Description: Design of phase 1 combination therapy trials is complex compared to single therapy trials. In this work, model-based adaptive optimal design (MBAOD) was exemplified and evaluated for a combination of paclitaxel and a hypothetical new compound in a phase 1 study to determine the best dosing regimen for a phase 2 trial. Neutropenia was assumed as the main toxicity and the dose optimization process targeted a 33% probability of grade 4 neutropenia and maximal efficacy (based on preclinical studies) by changing the dose amount of both drugs and the dosing schedule for the new drug. Different starting conditions (e.g., initial dose), search paths (e.g., maximal change in dose intensity per step), and stopping criteria (e.g., “3 + 3 rule”) were explored. The MBAOD approach was successfully implemented allowing the possibility of flexible designs with the modification of doses and dosing schedule throughout the trial. The 3 + 3 rule was shown to be highly conservative (selection of a dosing regimen with at least 90% of the possible maximal efficacy in less than 21% of the cases) but also safer (selection of a toxic design in less than 2% of the cases). Without the 3 + 3 rule, better performance was observed (〉67% of selected designs were associated with at least 90% of possible maximal efficacy) while the proportion of DLTs per trial was similar. Overall, MBAOD is a promising tool in the context of dose finding studies of combination treatments and was showed to be flexible enough to be associated with requirements imposed by clinical protocols.
    Electronic ISSN: 1550-7416
    Topics: Chemistry and Pharmacology
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
  • 5
    Publication Date: 2018-03-09
    Description: The selection of therapeutic dose for the most effective treatment of tumours is an intricate interplay of factors. Molecular imaging with positron emission tomography (PET) or single–photon emission computed tomography (SPECT) can address questions central to this selection: Does the drug reach its target? Does the drug engage with the target of interest? Is the drug dose sufficient to elicit the desired pharmacological effect? Does the dose saturate available target sites? Combining functional PET and SPECT imaging with anatomical imaging technologies such as magnetic resonance imaging (MRI) or computed tomography (CT) allows drug occupancy at the target to be related directly to anatomical or physiological changes in a tissue resulting from therapy. In vivo competition studies, using a tracer amount of radioligand that binds to the tumour receptor with high specificity, enable direct assessment of the relationship between drug plasma concentration and target occupancy . Including imaging studies in early drug development can aid with dose selection and suggest improvements for patient stratification to obtain higher effective utility from a drug after approval. In this review, the potential value of including translational receptor occupancy studies and molecular imaging strategies early on in drug development is addressed.
    Electronic ISSN: 1550-7416
    Topics: Chemistry and Pharmacology
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
  • 6
    Publication Date: 2018-03-09
    Description: Current cancer diagnostic methods are challenged by low sensitivity, high false positive rate, limited tumor information, uncomfortable or invasive procedures, and high cost. Liquid biopsy that analyzes circulating biomarkers in body fluids represents a promising solution to these challenges. Exosomes are one of the promising cancer biomarkers for liquid biopsy because they are cell-secreted, nano-sized, extracellular vesicles that stably exist in all types of body fluids. Exosomes transfer DNAs, RNAs, proteins, and lipids from parent cells to recipient cells for intercellular communication and play important roles in cancer initiation, progression, and metastasis. Many liquid biopsy biosensors have been developed to offer non- or minimally-invasive, highly sensitive, simple, rapid, and cost-effective cancer diagnostics. This review summarized recent advances of liquid biopsy biosensors with a focus on the detection of exosomal proteins as biomarkers for cancer screening, diagnosis, and prognosis. We reviewed six major types of liquid biopsy biosensors including immunofluorescence biosensor, colorimetric biosensor, surface plasmon resonance (SPR) biosensor, surface-enhanced Raman scattering (SERS) biosensor, electrochemical biosensor, and nuclear magnetic resonance (NMR) biosensor. We shared our perspectives on future improvement of exosome-based liquid biopsy biosensors to accelerate their clinical translation.
    Electronic ISSN: 1550-7416
    Topics: Chemistry and Pharmacology
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
  • 7
    Publication Date: 2018-03-09
    Description: The number of new psychoactive substances keeps on rising despite the controlling efforts by law enforcement. Although metabolism of the newly emerging drugs is continuously studied to keep up with the new additions, the exact structures of the metabolites are often not identified due to the insufficient sample quantities for techniques such as nuclear magnetic resonance (NMR) spectroscopy. The aim of the study was to characterise several metabolites of the synthetic cannabinoid (1-pentyl-1H-indol-3-yl) (2,2,3,3-tetramethylcyclopropyl) methanone (UR-144) by NMR spectroscopy after the incubation with the fungus Cunninghamella elegans . UR-144 was incubated with C. elegans for 72 h, and the resulting metabolites were chromatographically separated. Six fractions were collected and analysed by NMR spectroscopy. UR-144 was also incubated with human liver microsomes (HLM), and the liquid chromatography-high resolution mass spectrometry analysis was performed on the HLM metabolites with the characterised fungal metabolites as reference standards. Ten metabolites were characterised by NMR analysis including dihydroxy metabolites, carboxy and hydroxy metabolites, a hydroxy and ketone metabolite, and a carboxy and ketone metabolite. Of these metabolites, dihydroxy metabolite, carboxy and hydroxy metabolites, and a hydroxy and ketone metabolite were identified in HLM incubation. The results indicate that the fungus is capable of producing human-relevant metabolites including the exact isomers. The capacity of the fungus C. elegans to allow for NMR structural characterisation by enabling production of large amounts of metabolites makes it an ideal model to complement metabolism studies.
    Electronic ISSN: 1550-7416
    Topics: Chemistry and Pharmacology
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
  • 8
    Publication Date: 2018-03-09
    Description: This article provides an overview of four case studies to demonstrate the utility of pharmacometric analysis in biosimilar development to help design sensitive clinical pharmacology studies for the demonstration of biosimilarity. The two major factors that determine the sensitivity of a clinical pharmacokinetic/pharmacodynamic (PK/PD) study to demonstrate biosimilarity are the size of the potential difference to be detected (signal) and the inter-subject variability (noise), both of which can be characterized and predicted using pharmacometric approaches. To maximize the chance to detect any potential difference between the proposed biosimilar and the reference drug, the dose selected for the clinical pharmacology study should fall on the steep part of the dose-response curve. Pharmacometric analysis can be used to characterize the dose-response relationship using PD- or PK/PD-linked models. The understanding of the PD endpoints in terms of dynamic range of the response and the location of the studied dose on the dose-response curve can provide strategic advantage in the trial design. To reduce the inter-subject variability (noise), pharmacometric analysis can help avoid high variability associated with low doses, and decrease variability by controlling certain covariates in the inclusion/exclusion criteria. Pharmacometric analysis also can help select or justify margins for the equivalence test of PD endpoints. Pharmacometric analysis will assume an ever-increasing role in the clinical development of biosimilar drugs, as it helps to ensure that sufficient sensitivity is built into the study design to detect potential PK and PD differences.
    Electronic ISSN: 1550-7416
    Topics: Chemistry and Pharmacology
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
  • 9
    Publication Date: 2018-03-05
    Description: Extracellular vesicles (EVs) are cell membrane-derived compartments that regulate physiology and pathology in the body. Naturally secreted EVs have been well studied in their biogenesis and have been exploited in targeted drug delivery. Due to the limitations on production of EVs, nitrogen cavitation has been utilized to efficiently generate EV-like drug delivery systems used in treating inflammatory disorders. In this short review, we will discuss the production and purification of EVs, and we will summarize what technologies are needed to improve their production for translation. We describe the drug-loading processes in EVs and their applications as drug delivery systems for inflammatory therapies, focusing on a new type of EVs made from neutrophil membrane using nitrogen cavitation.
    Electronic ISSN: 1550-7416
    Topics: Chemistry and Pharmacology
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
  • 10
    Publication Date: 2018-03-05
    Description: The healing professions have only about four main therapeutic tools at their disposal—surgery, drugs, physical therapy, and psychotherapy. For the general profession of internal medicine, drug therapy is its primary tool. Providing an understanding of the state-of-the-art in therapeutic methods, grounded in solid scientific and mathematical rigor, is therefore of the utmost clinical importance for both physicians and clinical pharmacists. This is particularly true where rapidly evolving scientific changes require an up-to-date education upon which students can rely. Unfortunately, relatively little attention has been paid to training clinical pharmacokineticists and physicians to manage drug therapy optimally for patients under their care in their everyday practice. In this paper, we discuss one of these basic deficiencies from the perspective of the longstanding controversy in pharmacokinetic modeling: whether the volume and clearance approach or the volume and rate constant approach is somehow “better”. We examine this controversy using the mathematical principle of invariance, which to our knowledge has not been done before. The conclusion of this analysis is that both approaches are rigorously proven mathematically to be equally valid. We also discuss some implications of these equally valid approaches from the framework of mechanistic and non-compartmental models. Ultimately, the conclusion is that the choice of one parameterization over the other is based on preference or usefulness for research or clinical practice, but no longer, because of this analysis, on science.
    Electronic ISSN: 1550-7416
    Topics: Chemistry and Pharmacology
    Location Call Number Expected Availability
    BibTip Others were also interested in ...