10 research outputs found
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Preparation of Tacrolimus-loaded Biodegradable Nanoparticles for Sustained Drug Delivery
Tacrolimus is an immunosuppressant drug approved by the FDA for the prevention of organ transplant rejection. However, the use of this drug is hindered by its narrow therapeutic window and extreme insolubility in water. Due to these properties, the currently used tacrolimus preparations must be administered once or twice daily to minimize peak and trough effects and maintain a therapeutic concentration in the subject. In this study, biodegradable polymeric nanoparticles are explored as an alternative delivery vehicle. First, a method was developed for formulating tacrolimus-loaded nanoparticles. Seven different polymers were used to prepare the nanoparticles, and their size, polydispersity index (PDI), and drug loading was quantified. The stability of the best formulations was assessed at room temperature and in a refrigerated environment. The drug release profiles of these formulations were also studied and plotted. Though these nanoparticles did not demonstrate significant extended release properties, they were successful in increasing the tacrolimus solubility in water by over a factor of 100 compared to the free drug. Furthermore, the results of this study reflect the importance of PEGylated polymers for developing tacrolimus-loaded nanoparticles.
Key words: tacrolimus, immunosuppressant, nanoparticles, drug deliver
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Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation.
Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity-a phenomenon known as paradoxical excitation. Previous studies have identified GABAA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABAA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish
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In Situ Gelling Polyvalerolactone-Based Thermosensitive Hydrogel for Sustained Drug Delivery
Biodegradable poly(ethyleneglycol)-poly(valerolactone)-poly(ethyleneglycol) [PEG-PVL-PEG] copolymers were synthesized through ring opening polymerization of ÎŽ-valerolactone (VL) followed by the coupling of monomethoxy poly(ethyleneglycol-poly(valerolactone) (mPEG-PVL) with hexamethylene diisocyanate (HDI). The copolymers were characterized by ÂčH NMR, FT-IR, and GPC. Block copolymers of PEG and PVL with different VL/PEG molar ratios were successfully synthesized. One of the copolymers (Copolymer 2, PEGâ
â
â-PVLââââ-PEGâ
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â) displayed a sol-gel transition at a physiological temperature based on the test tube inverting method and rheological studies. The thermogelling copolymer demonstrated a characteristic crystalline peak for PVL block as determined by DSC and XRD analysis. In vitro release from the copolymer hydrogel matrix indicated that dexamethasone (DEX), a hydrophobic model drug, released comparatively slower than 5-fluoruracil (5-FU), a hydrophilic model drug, due to the potential partitioning of DEX into the PVL core. 5-FU in vitro release from copolymer 2 was 86% in 22 hr, whereas only 14% of DEX was released in 24 hr. Cell viability studies confirmed that hydrogels composed of block copolymers are biocompatible. Copolymer 2 showed more than 80% relative cell viability at all concentrations, including concentrations greater than 200 fold CMC. In vivo gel formation studies indicate that gel integrity was maintained for 7 days upon subcutaneous injection into mice. These results indicate that PEG-PVL-PEG copolymers are suitable for drug delivery applications.Keywords: Biodegradable, In situ gelling, Thermosensitive hydrogel, Polyester, In vitro drug release, ÎŽâvalerolacton
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No straight lines â young womenâs perceptions of their mental health and wellbeing during and after pregnancy: a systematic review and meta-ethnography
Background: Young mothers face mental health challenges during and after pregnancy including increased rates of depression compared to older mothers. While the prevention of teenage pregnancy in countries such as the United States and the United Kingdom has been a focus for policy and research in recent decades, the need to understand young womenâs own experiences has been highlighted. The aim of this meta-ethnography was to examine young womenâs perceptions of their mental health and wellbeing during and after pregnancy to provide new understandings of those experiences.
Methods: A systematic review and meta-ethnographic synthesis of qualitative research was conducted. Seven databases were systematically searched and forward and backward searching conducted. Papers were included if they were from Organisation for Economic Co-operation and Development countries and explored mental health and wellbeing experiences of young mothers (age under 20 in pregnancy; under 25 at time of research) as a primary research question â or where evidence about mental health and wellbeing from participants was foregrounded. Nineteen papers were identified and the Critical Appraisal Skills Programme checklist for qualitative research used to appraise the evidence. Following the seven-step process of meta-ethnography, key constructs were examined within each study and then translated into one another.
Results: Seven translated themes were identified forming a new line of argument wherein mental health and wellbeing was analysed as relating to individual bodily experiences; tied into past and present relationships; underpinned by economic insecurity and entangled with feelings of societal surveillance. There were âno straight linesâ in young womenâs experiences, which were more complex than dominant narratives around overcoming adversity suggest.
Conclusions: The synthesis concludes that health and social care professionals need to reflect on the operation of power and stigma in young womenâs lives and its impact on wellbeing. It adds to understanding of young womenâs mental health and wellbeing during and after pregnancy as located in physical and structural factors rather than individual capacities alone
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Developing zebrafish behavioral assays for high-throughput psychoactive drug discovery
Neurological and psychiatric disorders (such as depression, neurodegeneration, and drug addiction) are among the greatest challenges faced by modern medicine. Though they are some of the most prevalent and debilitating illnesses in the world, current treatment options leave much to be desired due to limited efficacy or intolerable side effects. Our understanding of the nervous system is still rudimentary, preventing the development of new drugs that precisely target the pathogenic mechanisms of disease. Instead, most neuroactive drugs in clinical use were either developed decades ago or are chemical derivatives of these legacy drugs. Typical target-based approaches to drug screening have had limited success in psychiatric drug discovery due to inadequate mechanistic understanding and the multifactorial nature of the disorders they aim to treat. As a result, neuroactive drug development has stagnated while pharmaceutical companies focus their resources on less risky endeavors.
How can we overcome these challenges to accelerate psychoactive drug discovery in the future? One approach is phenotypic drug screening based on observations of animal behavior. This strategy has the potential to uncover behaviorally active compounds with unprecedented mechanisms but is limited by the difficulty of efficiently measuring animal behaviors at scale. This dissertation documents contributions to phenotypic drug screening utilizing the zebrafish model organism, including the identification of meaningful behavioral phenotypes which are accessible in a large-scale context and new methods to automate the quantification of these behaviors.
In Chapter 1, the influence of neuroactive drugs on zebrafish buoyancy is investigated using a computational method to approximate the depth of larvae in a 96-well plate. This approach is easily scaled up, allowing us to rapidly screen thousands of molecules to discover new ligands for adrenergic and serotonergic receptors which alter behavior in vivo. In Chapter 2, we explore phenotypes related to paradoxical excitation during early-stage general anesthesia â a complex and poorly understood behavioral state that would be very difficult to study in systems other than intact animals. By identifying compounds from a behavioral screen that phenocopy the response of zebrafish to anesthetics like etomidate and propofol, we uncovered new GABAA receptor modulators with potential anesthetic activity in vivo. In summary, the work included in this dissertation provides new methods to quantify zebrafish behavior on a high-throughput scale and demonstrates their use by identifying several new behavior-modifying small molecules
Direct Electrochemical Detection of Glutamate, Acetylcholine, Choline, and Adenosine Using Non-Enzymatic Electrodes
Non-electroactive neurotransmitters such as glutamate, acetylcholine, choline, and adenosine play a critical role in proper activity of living organisms, particularly in the nervous system. While enzyme-based sensing of this type of neurotransmitter has been a research interest for years, non-enzymatic approaches are gaining more attention because of their stability and low cost. Accordingly, this focused review aims to give a summary of the state of the art of non-enzymatic electrochemical sensors used for detection of neurotransmitter that lack an electrochemically active component. In place of using enzymes, transition metal materials such as those based on nickel show an acceptable level of catalytic activity for neurotransmitter sensing. They benefit from fast electron transport properties and high surface energy and their catalytic activity can be much improved if their surface is modified with nanomaterials such as carbon nanotubes and platinum nanoparticles. However, a general comparison reveals that the performance of non-enzymatic biosensors is still lower than those that use enzyme-based methods. Nevertheless, their excellent stability demonstrates that non-enzymatic neurotransmitter sensors warrant additional research in order to advance them toward becoming an acceptable replacement for the more expensive enzyme-based sensors