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Peptides, despite their therapeutic potential, face challenges with undesirable pharmacokinetic (PK) properties and biodistribution, including poor oral absorption and cellular uptake, and short plasma elimination half-lives. Lipidation of peptides is a common strategy to improve their physicochemical and PK properties, making them viable drug candidates. For example, the plasma half-life of peptides has been extended via conjugation to lipids that are proposed to promote binding to serum albumin and thus protect against rapid clearance. Recent work has shown that lipid conjugation to oligodeoxynucleotides, polymers and small molecule drugs results in association not only with albumin, but also with lipoproteins, resulting in half-life prolongation and transport from administration sites via the lymphatics. Enhancing delivery into the lymph increases the efficacy of vaccines and therapeutics with lymphatic targets such as immunotherapies. In this study, the plasma PK, lymphatic uptake, and bioavailability of the glucagon-like peptide-1 (GLP-1) receptor agonist peptides, liraglutide (lipidated) and exenatide (non-lipidated), were investigated following subcutaneous (SC) administration to rats. As expected, liraglutide displayed an apparent prolonged plasma half-life (9.1 versus 1 h), delayed peak plasma concentrations and lower bioavailability (∼10 % versus ∼100 %) compared to exenatide after SC administration. The lymphatic uptake of both peptides was relatively low (<0.5 % of the dose) although lymph to plasma concentration ratios were greater than one for several early timepoints suggesting some direct uptake into lymph. The low lymphatic uptake may be due to the nature of the conjugated lipid (a single-chain C16 palmitic acid in liraglutide) but suggests that other peptides with similar lipid conjugations may also have relatively modest lymphatic uptake. If delivery to the lymph is desired, conjugation to more lipophilic moieties with higher albumin and/or

Peptides, despite their therapeutic potential, face challenges with undesirable pharmacokinetic (PK) properties and biodistribution, including poor oral absorption and cellular uptake, and short plasma elimination half-lives. Lipidation of peptides is a common strategy to improve their physicochemical and PK properties, making them viable drug candidates. For example, the plasma half-life of peptides has been extended via conjugation to lipids that are proposed to promote binding to serum albumin and thus protect against rapid clearance. Recent work has shown that lipid conjugation to oligodeoxynucleotides, polymers and small molecule drugs results in association not only with albumin, but also with lipoproteins, resulting in half-life prolongation and transport from administration sites via the lymphatics. Enhancing delivery into the lymph increases the efficacy of vaccines and therapeutics with lymphatic targets such as immunotherapies. In this study, the plasma PK, lymphatic uptake, and bioavailability of the glucagon-like peptide-1 (GLP-1) receptor agonist peptides, liraglutide (lipidated) and exenatide (non-lipidated), were investigated following subcutaneous (SC) administration to rats. As expected, liraglutide displayed an apparent prolonged plasma half-life (9.1 versus 1 h), delayed peak plasma concentrations and lower bioavailability (∼10 % versus ∼100 %) compared to exenatide after SC administration. The lymphatic uptake of both peptides was relatively low (<0.5 % of the dose) although lymph to plasma concentration ratios were greater than one for several early timepoints suggesting some direct uptake into lymph. The low lymphatic uptake may be due to the nature of the conjugated lipid (a single-chain C16 palmitic acid in liraglutide) but suggests that other peptides with similar lipid conjugations may also have relatively modest lymphatic uptake. If delivery to the lymph is desired, conjugation to more lipophilic moieties with higher albumin and/or

TOPIC: An evaluation of the efficacy and tolerability of generic prostaglandin analogues (PGAs) compared with their original counterpart.CLINICAL RELEVANCE: This systematic review was initiated to enlighten ophthalmologists and patients in the use of original and generic ophthalmic solutions.METHODS: A literature search was conducted on PubMed, EMBASE, MEDLINE, Clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform, along with a manual search, from the marketing of the first PGA, latanoprost, in 1995 to the present. Randomized controlled trials comparing an original PGA with its generic counterpart were included. The last literature search was conducted in June 2019. Risk of bias was assessed by 2 independent reviewers using the Cochrane Handbook for Systematic Reviews Tool. The primary outcome was reduction of intraocular pressure (IOP) from baseline. Secondary outcomes included tolerability, ocular surface health, quality of life, disease progression, and cost-effectiveness. Meta-analysis of the primary outcome was planned.RESULTS: Of 385 screened articles, 6 were included in a broad characterization and in the meta-analysis. A total of 619 patients were enrolled. The duration of the studies ranged from 3 to 16 weeks. Meta-analysis of all 6 studies denied any clinically significant difference in efficacy, and the 95% confidence interval included nil (-0.50 to 0.04 mmHg). The evidence was of moderate certainty because of unclear or high risk of bias in all studies. There were no reported differences in tolerability.CONCLUSIONS: Trials comparing original and generic PGAs did not show a clinically significant difference in IOP-lowering effect or tolerability. However, the quality of the trials is suboptimal. Overall, there is uncertainty, and further research is needed to confirm equivalence.

The lymphatic system plays an integral role in the development and progression of a range of disease conditions, which has impelled medical researchers and clinicians to design, develop and utilize advanced lymphatic drug delivery systems. Following interstitial administration, most therapeutics and molecules are cleared from tissues via the draining blood capillaries. Macromolecules and delivery systems > 20 kDa in size or 10-100 nm in diameter are, however, transported from the interstitium via draining lymphatic vessels as they are too large to cross the blood capillary endothelium. Lymphatic uptake of small molecules can be promoted by two general approaches: administration in association with synthetic macromolecular constructs, or through hitchhiking on endogenous cells or macromolecular carriers that are transported from tissues via the lymphatics. In this paper we review the latter approach where molecules are targeted to lymph by hitchhiking on endogenous albumin transport pathways after subcutaneous, intramuscular or intradermal injection. We describe the properties of the lymphatic system and albumin that are relevant to lymphatic targeting, the characteristics of drugs and delivery systems designed to hitchhike on albumin trafficking pathways and how to further optimise these properties, and finally the current applications and potential future directions for albumin-hitchhiking approaches to target the lymphatics.

Research synthesis seeks to gather, examine and evaluate systematically research reports that converge toward answering a carefully crafted research question, which states the problem patient population, the intervention under consideration, and the clinical outcome of interest. The product of the process of systematically reviewing the research literature pertinent to the research question thusly stated is the "systematic review".The objective and transparent approach of the systematic review aims to minimize bias. Most systematic reviews yield quantitative analyses of measurable data (e.g., acceptable sampling analysis, meta-analysis). Systematic reviews may also be qualitative, while adhering to accepted standards for gathering, evaluating, and reporting evidence. Systematic reviews provide highly rated recommendations for evidence-based health care; but, systematic reviews are not equally reliable and successful in minimizing bias.Several instruments are available to evaluate the quality of systematic reviews. The 'assessment of multiple systematic reviews' (AMSTAR) was derived from factor analysis of the most relevant items among them. AMSTAR consists of eleven items with good face and content validity for measuring the methodological quality of systematic reviews, has been widely accepted and utilized, and has gained in reliability, reproducibility. AMSTAR does not produce quantifiable assessments of systematic review quality and clinical relevance. In this study, we have revised the AMSTAR instrument, detracting nothing from its content and construct validity, and utilizing the very criteria employed in the development of the original tool, with the aim of yielding an instrument that can quantify the quality of systematic reviews. We present validation data of the revised AMSTAR (R-AMSTAR), and discuss its implications and application in evidence-based health care.

Research synthesis seeks to gather, examine and evaluate systematically research reports that converge toward answering a carefully crafted research question, which states the problem patient population, the intervention under consideration, and the clinical outcome of interest. The product of the process of systematically reviewing the research literature pertinent to the research question thusly stated is the "systematic review".The objective and transparent approach of the systematic review aims to minimize bias. Most systematic reviews yield quantitative analyses of measurable data (e.g., acceptable sampling analysis, meta-analysis). Systematic reviews may also be qualitative, while adhering to accepted standards for gathering, evaluating, and reporting evidence. Systematic reviews provide highly rated recommendations for evidence-based health care; but, systematic reviews are not equally reliable and successful in minimizing bias.Several instruments are available to evaluate the quality of systematic reviews. The 'assessment of multiple systematic reviews' (AMSTAR) was derived from factor analysis of the most relevant items among them. AMSTAR consists of eleven items with good face and content validity for measuring the methodological quality of systematic reviews, has been widely accepted and utilized, and has gained in reliability, reproducibility. AMSTAR does not produce quantifiable assessments of systematic review quality and clinical relevance. In this study, we have revised the AMSTAR instrument, detracting nothing from its content and construct validity, and utilizing the very criteria employed in the development of the original tool, with the aim of yielding an instrument that can quantify the quality of systematic reviews. We present validation data of the revised AMSTAR (R-AMSTAR), and discuss its implications and application in evidence-based health care.

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

IDSIA-06-05, info:eu-repo/semantics/published

IDSIA-06-05, info:eu-repo/semantics/published

IDSIA-07-04, info:eu-repo/semantics/published

Lugano, Switzerland, IDSIA-06-04, info:eu-repo/semantics/published

SCOPUS: ar.k, info:eu-repo/semantics/published

IDSIA-07-04, info:eu-repo/semantics/published

Lugano, Switzerland, IDSIA-06-04, info:eu-repo/semantics/published

SCOPUS: ar.k, info:eu-repo/semantics/published

Darmstadt, Germany, AIDA-03-04, info:eu-repo/semantics/published

Darmstadt, Germany, AIDA-03-05, info:eu-repo/semantics/published

Practice and Theory of Automated Timetabling IV, Proceedings of 4th International Conference (PATAT 2002), E. Burke & P. D. Causmaecker (Eds.), info:eu-repo/semantics/published

Darmstadt, Germany, AIDA-03-04, info:eu-repo/semantics/published

Darmstadt, Germany, AIDA-03-05, info:eu-repo/semantics/published

Practice and Theory of Automated Timetabling IV, Proceedings of 4th International Conference (PATAT 2002), E. Burke & P. D. Causmaecker (Eds.), info:eu-repo/semantics/published

Lugano, Switzerland, IDSIA-18-02, info:eu-repo/semantics/published

info:eu-repo/semantics/published

Lugano, Switzerland, IDSIA-18-02, info:eu-repo/semantics/published

info:eu-repo/semantics/published

The Group Shop Scheduling Problem (GSP) is a generalization of the classical Job Shop and Open Shop Scheduling Problems. In the GSP there are m machines and n jobs. Each job consists of a set of operations, which must be processed on specified machines without preemption. The operations of each job are partitioned into groups on which a total precedence order is given. The problem is to order the operations on the machines and on the groups such that the maximal completion time (makespan) of all operations is minimized. The main goal of this paper is to provide a fair comparison of five metaheuristic approaches (i.e. Ant Colony Optimization, Evolutionary Algorithm, Iterated Local Search, Simulated Annealing, and Tabu Search) to tackle the GSP. We guarantee a fair comparison by a common definition of neighborhood in the search space, by using the same data structure, programming language and compiler, and by running the algorithms on the same hardware., SCOPUS: cp.k, info:eu-repo/semantics/published