In Vivo Half-Life Extension of BMP1/TLL Metalloproteinase Inhibitors Using Small-Molecule Human Serum Albumin Binders.

Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivo half-lives are highly desirable. One of the most promising approaches to extend the in vivo half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of AlbuBinder 1, a small-molecule noncovalent HSA binder, to extend the in vivo half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1 with BMP1/TLL inhibitors were prepared. In particular, conjugate c showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to AlbuBinder 1 should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies.

A whole-molecule immunocapture LC-MS approach for the in vivo quantitation of biotherapeutics.

AIM: Large-molecule biotherapeutic quantitation in vivo by LC-MS has traditionally relied on enzymatic digestion followed by quantitation of a 'surrogate peptide' to infer whole-molecule concentration. MS methods presented here measure the whole molecule and provide a platform to better understand the various circulating drug forms by allowing for variant quantitation. RESULTS: An immunocapture LC-MS method for quantitation of a biotherapeutic monoclonal antibody from human plasma is presented. Sensitivity, precision and accuracy for each molecular portion are presented along with an example of glycoform variant quantitation. CONCLUSION: The method is presented as a basic platform to be further developed for Good Practice (GxP) applications, critical quality attribute analysis or general understanding of molecular forms present as required for the wide range of drug development processes.

Menage a quoi? Optimal number of peer reviewers.

Peer review represents the primary mechanism used by funding agencies to allocate financial support and by journals to select manuscripts for publication, yet recent Cochrane reviews determined literature on peer review best practice is sparse. Key to improving the process are reduction of inherent vulnerability to high degree of randomness and, from an economic perspective, limiting both the substantial indirect costs related to reviewer time invested and direct administrative costs to funding agencies, publishers and research institutions. Use of additional reviewers per application may increase reliability and decision consistency, but adds to overall cost and burden. The optimal number of reviewers per application, while not known, is thought to vary with accuracy of judges or evaluation methods. Here I use bootstrapping of replicated peer review data from a Post-doctoral Fellowships competition to show that five reviewers per application represents a practical optimum which avoids large random effects evident when fewer reviewers are used, a point where additional reviewers at increasing cost provides only diminishing incremental gains in chance-corrected consistency of decision outcomes. Random effects were most evident in the relative mid-range of competitiveness. Results support aggressive high- and low-end stratification or triaging of applications for subsequent stages of review, with the proportion and set of mid-range submissions to be retained for further consideration being dependent on overall success rate.

Neuroanatomia Clinica / Clinical Neuroanatomy

este libro ofrece a los estudiantes la posibilidad de comprender la organizacion funcional del sistema nervioso e indica en forma clara el modo en que las lesiones y las enfermedades pueden causar daño neurologico