FORMULATION AND EVALUATION OF METRONIDAZOLE TABLETED MICROSPHERES FOR COLON DRUG DELIVERY

Objective: The need of this study was to develop tableted microspheres that can be targeted to colon because metronidazole (MNZ) has good solubilityat pH 1.2; hence, coating of the drug with the suitable pH dependent is done to prevent its release in the gastric region.Methods: Colon targeted tablets of MNZ were prepared with enteric coated microspheres using pH dependent polymers such as cellulose acetatephthalate, hydroxypropyl methylcellulose phthalate, and Eudragit S 100 by solvent evaporation method. All the formulations were prepared bychanging drug-polymer ratio from 1:1 to 1:5 and the interactions of the drug with polymers were studied by Fourier transform infrared and thermalanalysis.Results: Formulations F5, F8, and F were found to best optimized in percentage yield, drug entrapment efficiency, mean particle size and in vitrodrug release. The result obtained were found in the desired ranges where % yield ranging from 52.56% to 98.253%, drug entrapment efficiency from42.17% to 99.017%, and mean particle size from 36.774 to 229.961 µm. Then, tablet of optimized formulations was prepared by direct compressionmethod and in vitro drug release was performed. All the parameters of tablets were found acceptable as per IP guideline. Around 4-10% drug releasewas in 0.1 N HCl after 2 hrs, 50% release at pH 7.4 phosphate buffer within 5 hrs, maximum retardation was found in the formulation of Eudragit S100. Scanning electron microscopy permitted a surface topographical analysis.14Conclusion: The MNZ tableted microspheres showed their release at pH 7.4 thus this experimental work can be used to improve absorption of drugin colon for successful treatment of the disease.Keywords: Metronidazole, Tableted microspheres, Solvent evaporation method, Direct compression method

Glial cell line-derived neurotrophic factor receptor REarranged during transfection agonist supports dopamine neurons in Vitro and enhances dopamine release In Vivo

Background Motor symptoms of Parkinson's disease (PD) are caused by degeneration and progressive loss of nigrostriatal dopamine neurons. Currently, no cure for this disease is available. Existing drugs alleviate PD symptoms but fail to halt neurodegeneration. Glial cell line-derived neurotrophic factor (GDNF) is able to protect and repair dopamine neurons in vitro and in animal models of PD, but the clinical use of GDNF is complicated by its pharmacokinetic properties. The present study aimed to evaluate the neuronal effects of a blood-brain-barrier penetrating small molecule GDNF receptor Rearranged in Transfection agonist, BT13, in the dopamine system. Methods We characterized the ability of BT13 to activate RET in immortalized cells, to support the survival of cultured dopamine neurons, to protect cultured dopamine neurons against neurotoxin-induced cell death, to activate intracellular signaling pathways both in vitro and in vivo, and to regulate dopamine release in the mouse striatum as well as BT13's distribution in the brain. Results BT13 potently activates RET and downstream signaling cascades such as Extracellular Signal Regulated Kinase and AKT in immortalized cells. It supports the survival of cultured dopamine neurons from wild-type but not from RET-knockout mice. BT13 protects cultured dopamine neurons from 6-Hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+)-induced cell death only if they express RET. In addition, BT13 is absorbed in the brain, activates intracellular signaling cascades in dopamine neurons both in vitro and in vivo, and also stimulates the release of dopamine in the mouse striatum. Conclusion The GDNF receptor RET agonist BT13 demonstrates the potential for further development of novel disease-modifying treatments against PD. (c) 2019 International Parkinson and Movement Disorder SocietyPeer reviewe

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

PTPRA Phosphatase Regulates GDNF-Dependent RET Signaling and Inhibits the RET Mutant MEN2A Oncogenic Potential

The RET proto-oncogene encodes receptor tyrosine kinase, expressed primarily in tissues of neural crest origin. De-regulation of RET signaling is implicated in several human cancers. Recent phosphatome interactome analysis identified PTPRA interacting with the neurotrophic factor (GDNF)-dependent RET-Ras-MAPK signaling-axis. Here, by identifying comprehensive interactomes of PTPRA and RET, we reveal their close physical and functional association. The PTPRA directly interacts with RET, and using the phosphoproteomic approach, we identify RET as a direct dephosphorylation substrate of PTPRA both in vivo and in vitro. The protein phosphatase domain-1 is indispensable for the PTPRA inhibitory role on RET activity and downstream Ras-MAPK signaling, whereas domain-2 has only minor effect. Furthermore, PTPRA also regulates the RET oncogenic mutant variant MEN2A activity and invasion capacity, whereas the MEN2B is insensitive to PTPRA. In sum, we discern PTPRA as a novel regulator of RET signaling in both health and cancer.Peer reviewe

Adult-onset Still’s Disease: A Case Report

Pyrexia of unknown origin refers to a fever of over 38.3°C on multiple occasions for at least three weeks without a known aetiology, even after a week of hospitalization. Adult-onset Still’s disease is a rare systemic auto-inflammatory disorder with a prevalence of 0.6/100,000 population characterized by spiking fever, arthralgia or arthritis and maculopapular rash. Here, we present a case of 19 years-old female with pyrexia of unknown origin. With no identifiable cause and fulfilled criteria of Yamaguchi, a diagnosis of adult-onset Still’s disease was made. She was treated with IV steroid therapy followed by oral steroids and non-steroidal anti-inflammatory drugs. This case highlights the awareness of the possible adult-onset Still’s disease patients with pyrexia of unknown origin. However, one should remain cautious and exclude all other differentials before making this diagnosis, as the actual disease may masquerade as adult-onset Still’s disease criteria

Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats

Background: Parkinson's disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF's receptor, the transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo. Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons fromMPP+-induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and seemed to protect dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying, therapy for PD.Peer reviewe