From lab-to-clinic with model informed formulation development: a case study of hydroxyzine SR tablets.

Model Informed Formulation Development (MIFD) uses physiologically based pharmacokinetic (PBPK) modelling and other tools to facilitate new product development. These tools help set target profiles, predict formulation performance, guide iterative development, define dissolution parameters, and convince the regulatory agencies about a drug's safety and efficacy.This study involves development of a sustained release formulation for Hydroxyzine, an anti-histamine with sedation as a significant side effect.

Advancements in Ocular Modelling and Simulations: Key Considerations and Case Studies.

This review paper discusses the key aspects of ocular biopharmaceutics, with emphasis on the crucial role played by ocular compartmental modelling and simulation in deciphering physiological conditions related to various eye diseases. It describes eye's intricate structure and function and the need for precise and targeted drug delivery systems to address prevalent eye conditions. The review categorizes and discusses various formulations employed in ocular drug delivery, delineating their respective advantages and limitations.

Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A modification.

Macrophages exhibit remarkable functional plasticity, a requirement for their central role in tissue homeostasis. During chronic inflammation, macrophages acquire sustained inflammatory 'states' that contribute to disease, but there is limited understanding of the regulatory mechanisms that drive their generation. Here we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human macrophages to uncover regulatory circuits of inflammatory states.

Modeling kinematic variability reveals displacement and velocity based dual control of saccadic eye movements.

Noise is a ubiquitous component of motor systems that leads to behavioral variability of all types of movements. Nonetheless, systems-based models investigating human movements are generally deterministic and explain only the central tendencies like mean trajectories. In this paper, a novel approach to modeling kinematic variability of movements is presented and tested on the oculomotor system.

Evaluating gender effect in the generic bioequivalence studies by physiologically based pharmacokinetic modeling - A case study of dextromethorphan modified release tablets.

The United States Food and Drug Administration guidelines for the bioequivalence (BE) testing of the generic drug products suggests that there should be an equal proportion of male and female population in the BE study. Despite this requirement, many generic drug companies do not maintain the suggested proportion of female population in their studies. Several socio-economic and cultural factors lead to lower participation of the females in the BE studies.

Modelling Based Approaches to Support Generic Drug Regulatory Submissions-Practical Considerations and Case Studies.

Model informed drug development (MiDD) is useful to predict in vivo exposure of drugs during various stages of the drug development process. This approach employs a variety of quantitative tools to assess the risks during the drug development process. One important tool in the MiDD tool kit is the Physiologically Based Pharmacokinetic Modelling (PBPK).

Velocity tracking control best explains the modulation of saccade kinematics during eye-hand coordination.

Fast movements like saccadic eye movements that occur in the absence of sensory feedback are thought to be controlled by internal feedback. Such internal feedback provides an instantaneous estimate of the output, which serves as a proxy for sensory feedback, that can be used by the controller to correct deviations from the desired plan. In the predominant view, the desired plan/input is encoded in the form of a static displacement signal (endpoint model), believed to be encoded in the spatial map of the superior colliculus (SC).

Context-specific early recruitment of small motor units in the shoulder muscle reflects a reach movement plan.

Understanding how motor plans are transformed into appropriate patterns of muscle activity is a central question in motor control. Although muscle activity during the delay period has not been reported using conventional electromyographic (EMG) approaches, we isolated motor unit activity using a high-density surface EMG signal from the anterior deltoid muscle to test whether heterogeneity in motor units could reveal early preparatory activity. Consistent with our previous work (Rungta SP, Basu D, Sendhilnathan N, Murthy A.

Optimized Nonviral Gene Disruption in Primary Murine and Human Myeloid Cells.

Genetically engineered myeloid cells such as monocytes, macrophages, and dendritic cells have broad applications in basic and translational research. Their central roles in innate and adaptive immunity make them attractive as putative therapeutic cell products. However, efficient gene editing of primary myeloid cells presents unique challenges owing to their sensitivity to foreign nucleic acids and poor editing efficiencies using current methodologies (Hornung et al.

Neck muscle activity reflects neural patterns of sequential saccade planning in head-restrained primates.

Goal-directed behavior involves the transformation of neural movement plans into appropriate muscle activity patterns. Studies involving single saccades have shown that a rapid pathway links saccade planning in frontal eye fields (FEFs) to neck muscle activity. However, it is unknown if the rapid connection between FEF and neck muscle is also maintained during sequential saccade planning.

Antigen-derived peptides engage the ER stress sensor IRE1α to curb dendritic cell cross-presentation.

Dendritic cells (DCs) promote adaptive immunity by cross-presenting antigen-based epitopes to CD8+ T cells. DCs process internalized protein antigens into peptides that enter the endoplasmic reticulum (ER), bind to major histocompatibility type I (MHC-I) protein complexes, and are transported to the cell surface for cross-presentation. DCs can exhibit activation of the ER stress sensor IRE1α without ER stress, but the underlying mechanism remains obscure.

A Novel Approach to Justify Dissolution Differences in an Extended Release Drug Product using Physiologically Based Biopharmaceutics Modeling and Simulation.

Dr Reddy's Laboratories Ltd. developed generic version of XYZ extended release tablets (ER) and achieved bioequivalence as per criteria mentioned by USFDA in both fasting and fed conditions for higher strength formulation (1200 mg). However, on comparison of multimedia dissolution profiles in pH 4.

Structure-Based Design of Potent, Selective, and Orally Bioavailable VPS34 Kinase Inhibitors.

VPS34 is a class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation. Inhibitors of VPS34 were believed to have value as anticancer agents, but genetic and pharmacological data suggest that sustained inhibition of VPS34 kinase activity may not be well tolerated. Here we disclose the identification of a novel series of dihydropyrazolopyrazinone compounds represented by compound as potent, selective, and orally bioavailable VPS34 inhibitors through a structure-based design strategy.

Neural mechanisms underlying the temporal control of sequential saccade planning in the frontal eye field.

Sequences of saccadic eye movements are instrumental in navigating our visual environment. While neural activity has been shown to ramp up to a threshold before single saccades, the neural underpinnings of multiple saccades is unknown. To understand the neural control of saccade sequences, we recorded from the frontal eye field (FEF) of macaque monkeys while they performed a sequential saccade task.

Preparatory activity links the frontal eye field response with small amplitude motor unit recruitment of neck muscles during gaze planning.

A hallmark of intelligent behavior is that we can separate intention from action. To understand the mechanism that gates the flow of information between motor planning and execution, we compared the activity of frontal eye field neurons with motor unit activity from neck muscles in the presence of an intervening delay period in which spatial information regarding the target was available to plan a response. Although spatially specific delay period activity was present in the activity of frontal eye field neurons, it was absent in motor unit activity.

Computational Mechanisms Mediating Inhibitory Control of Coordinated Eye-Hand Movements.

Significant progress has been made in understanding the computational and neural mechanisms that mediate eye and hand movements made in isolation. However, less is known about the mechanisms that control these movements when they are coordinated. Here, we outline our computational approaches using accumulation-to-threshold and race-to-threshold models to elucidate the mechanisms that initiate and inhibit these movements.

Murine Monocyte and Macrophage Culture.

Myeloid progenitors in the bone marrow generate monocytes, macrophages, granulocytes and most dendritic cells. Even though these innate immune cells are part of the same lineage, each cell type plays a specific and critical role in tissue development, host defense and the generation of adaptive immunity. Protocols have been developed in the past to differentiate myeloid cell types from bone marrow cells, enabling functional investigation and furthering our understanding about their contribution to mammalian physiology.

Neural correlates of goal-directed and non-goal-directed movements.

What are the cortical neural correlates that distinguish goal-directed and non-goal-directed movements? We investigated this question in the monkey frontal eye field (FEF), which is implicated in voluntary control of saccades. Here, we compared FEF activity associated with goal-directed (G) saccades and non-goal-directed (nG) saccades made by the monkey. Although the FEF neurons discharged before these nG saccades, there were three major differences in the neural activity: First, the variability in spike rate across trials decreased only for G saccades.

Targeting Autophagy to Treat Cancer: Challenges and Opportunities.

Autophagy is a catabolic process that targets its cargo for lysosomal degradation. In addition to its function in maintaining tissue homeostasis, autophagy is recognized to play a context-dependent role in cancer. Autophagy may inhibit tumor initiation under specific contexts; however, a growing body of evidence supports a pro-tumorigenic role of this pathway in established disease.

Perceptual Priming Can Increase or Decrease With Aging.

A decline in declarative or explicit memory has been extensively characterized in cognitive aging and is a hallmark of cognitive impairments. However, whether and how implicit perceptual memory varies with aging or cognitive impairment is unclear. Here, we compared implicit perceptual memory and explicit memory measures in three groups of participants: (1) 59 healthy young volunteers (20-30 years); (2) 269 healthy old volunteers (50-90 years) and (3) 21 patients with mild cognitive impairment, i.

Neutrophil serine protease 4 is required for mast cell-dependent vascular leakage.

Vascular leakage, or edema, is a serious complication of acute allergic reactions. Vascular leakage is triggered by the release of histamine and serotonin from granules within tissue-resident mast cells. Here, we show that expression of Neutrophil Serine Protease 4 (NSP4) during the early stages of mast cell development regulates mast cell-mediated vascular leakage.