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BackgroundThe experience from clinical trials indicates that anti-Aβ immunotherapy could be effective in early/pre-clinical stages of AD, whereas at the late stages promoting the clearing of Aβ alone may be insufficient to halt the disease progression. At the same time, pathological tau correlates much better with the degree of dementia than Aβ deposition. Therefore, targeting pathological tau may provide a more promising approach for the treatment of advanced stages of AD. Recent data demonstrates that the N-terminal region of tau spanning aa 2-18 termed "phosphatase activation domain" that is normally hidden in the native protein in 'paperclip'-like conformation, becomes exposed in pathological tau and plays an essential role in the inhibition of fast axonal transport and in aggregation of tau. Hence, we hypothesized that anti-Tau2-18 monoclonal antibodies (mAb) may recognize pathological, but not normal tau at very early stages of tauopathy and prevent or decrease the aggregation of this molecule.MethodsMouse mAbs were generated using standard hybridoma methodology. CDR grafting was used for humanization of mouse mAb. Humanized mAb (Armanezumab) was characterized and tested in vitro/ex vivo/in vivo using biochemical and immunological methods (HPLC, Biacore, ELISA, IHC, FRET, etc.). Stable DG44 cell line expressing Armanezumab was generated by clone selection with increased concentrations of methotrexate (MTX).ResultsA panel of mouse mAbs was generated, clone 1C9 was selected based on binding to pathological human tau with high affinity and humanized. Fine epitope mapping revealed conservation of the epitope of human tau recognized by the parent murine mAb and Armanezumab. Importantly, Armanezumab (i) bound to tau with high affinity as determined by Biacore; (ii) bound pathological tau in brains from AD, FTD and Pick's disease cases; (iii) inhibited seeding effect of aggregated tau from brain lysate of P301S Tg mice; (iv) inhibited cytotoxic effect of tau oligomers; (v) reduced total tau (HT7) and AT100, PHF1, AT8, AT180, p212, p214-positive tau species in brains of tau transgenic mice after intracranial injection. A stable CHO cell line producing >1.5 g/l humanized mAb, Armanezumab was generated.ConclusionThese findings suggest that Armanezumab could be therapeutic in clinical studies for treatment of AD.

The Krebs Cycle is a highly taught biochemical pathway that is traditionally difficult to learn. Twenty-seven undergraduate students were randomized to a rote memorization arm or to a mnemonic arm. They were given a pre-test, then shown a lecture corresponding to their assigned method, and then given an immediate Week 0 post-test and a Week 4 post-test. Groups scored comparably low on the pre-test (p = 0.7113). Students in the mnemonic arm performed better on the Week 0 post-test than those using rote (p = 0.0055). By Week 4, there was evidence of knowledge decay, with both arms' having comparably low scores (mnemonic vs. rote, p = 0.3739). The mnemonic assists in rapid acquisition of knowledge but probably has to be reviewed iteratively over time to demonstrate its full potential over rote memorization. A limited number of students from only one school was used.

The objective of this study was to compare the potencies of two topical corticosteroid products (TCPs) using the Emax model to fit the skin blanching responses obtained from the US FDA's vasoconstrictor assay (VCA) and to illustrate the influence of formulation on potency. The potencies of two marketed TCPs, Dermovate® cream containing clobetasol propionate (CP) and Elocon® cream containing mometasone furoate (MF), were assessed using healthy human subjects. In order to investigate the influence of formulation and associated vehicle properties, the creams were compared with their respective topical corticosteroids (TCs) from a previously published study wherein the inherent potencies of those TCs were assessed using a validated VCA method. Whereas the inherent potency of MF (Emax = −94.45 ± 0.21) was found to be greater than CP (Emax = −58.80 ± 15.65), when formulated as creams, the TCP containing CP had a higher potency (Emax = −86.15 ± 0.17) than that containing MF (Emax = −42.61 ± 26.04). This reversal of potency may be attributed to the effect of formulation factors. The comparison of the potencies of TCPs with inherent potencies of their corresponding TCs confirmed the influence of formulation parameters on the potency of those products. [ABSTRACT FROM AUTHOR]

Abstract: Class III antiarrhythmics are preferred therapy for managing atrial fibrillation/flutter. Dofetilide 0.5‐mg capsules were US Food and Drug Administration (FDA) approved in 1999 to treat atrial fibrillation/flutter. Bioequivalence of generic dofetilide is important for treating arrhythmias because drug concentrations must be consistent to maintain normal sinus rhythm. Generic dofetilide 0.5‐mg capsule pharmacokinetics were compared with branded product in 2 open‐label, 2‐way crossover, single‐dose studies — 1 study each in fasted and fed healthy subjects. Blood samples were collected before and up to 48 hours after dosing. Safety was assessed by tabulating adverse events and vital signs. Seventy‐three subjects were enrolled; 59 completed the studies. In fasted subjects, the 90% confidence intervals (CIs) for generic dofetilide 0.5 mg versus the reference formulation were 0.996–1.026 for the area under the plasma concentration–time curve from 0 to infinity (AUC) and 0.974–1.066 for the maximum observed concentration (Cmax). In fed subjects, the 90%CIs for AUC and Cmax were 0.988–1.015 and 0.928–0.992, respectively. All ratios were within the FDA‐established bioequivalence range. Twenty‐six subjects experienced 37 adverse events (generic, 15; reference, 22); all but 1 were mild or moderate in severity. Generic dofetilide 0.5‐mg capsules can be considered bioequivalent to the reference product. [ABSTRACT FROM AUTHOR]

The article offers information on optimization of clinical end- point bioequivalence (CEBE) studies for the new drug application submissions in U.S. Topics discussed include CEBE studies are commonly used to demonstrate bioequivalence between prospective generic and reference product formulations; importance of new drug trials in patient enrichment strategies; and replication strategy for controlling sample size.

The widespread use of topical corticosteroids (TCs) in dermatotherapy requires a consideration of their potency and benefit/risk ratios. Although there are a variety of topical corticosteroid products (TCPs) available on the market and their potencies are ranked using different classification systems, to our knowledge, no classification system to rank the inherent potencies of TC active pharmaceutical ingredients (APIs) currently exists. Most of the published classification systems for TCPs are based on randomized clinical comparative studies and/or vasoconstrictor assay (VCA) data. The objective was to apply the US FDA's VCA to classify the inherent potencies of several TCs using standardized doses to make appropriate comparisons of the relevant APIs in solutions of the same molar concentrations. Six TC APIs were assessed for their relative potencies using healthy human participants. The E max model was used to fit skin blanching data following application of the respective TCs, and the parameters, E max and ED 50 , were derived. E max values were used as the metric to assess potency. Statistical analyses of the data revealed that the inherent potencies of fluticasone propionate, mometasone furoate, and hydrocortisone butyrate were similar. However, there was no significant difference between hydrocortisone butyrate and clobetasol propionate, while there was a significant difference between clobetasol propionate, fluticasone propionate, and mometasone furoate. Hence, the potency of hydrocortisone butyrate appears to overlap two potency classes. Furthermore, the potencies of betamethasone valerate and methylprednisolone aceponate were similar but lower than those of all of the other APIs. The application of the VCA to classify inherent potency provides a reliable method to establish a classification system for TCs. Inherent potency assessment of TCs provides information that will be useful when choosing an appropriate TC for the development of a TCP for a specific clinical indication.