Nanotechnology-mediated nose to brain drug delivery for Parkinson's disease: a mini review

Nose to brain delivery of neurotherapeutics have been tried by several researchers to explore the virtues of this route viz. circumvention of BBB, avoidance of hepatic metabolism, practicality, safety, ease of administration and non-invasiveness. Nanoparticle (NP) therapeutics is an emerging modality for the treatment of Parkinson's disease (PD) as it offers targeted delivery and enhances the therapeutic efficacy and/or bioavailability of neurotherapeutics. This review presents a concise incursion into the nanomedicines suitable for PD therapy delivered via naso-brain transport. Clinical signs of PD, its pathophysiology, specific genetic determinants, diagnosis and therapy involved have been hashed out. Properties of brain-targeting NPs, transport efficacy and various nanocarriers developed so far also been furnished. In our opinion, nanotechnology-enabled naso-brain drug delivery is an excellent means of delivering neurotherapeutics and is a promising avenue for researchers to develop new formulations for the effective management of PD.     

Design and Synthesis of Butenolide‐based Novel Benzyl Pyrrolones: Their TNF‐α based Molecular Docking with In vivo and In vitro Anti‐inflammatory Activity

A focused library of novel benzyl pyrrolones has been synthesized and their in silico molecular docking studies carried out against TNF‐α target. Among all the docked molecules, compound 3f showed best glide score of ?6.89. All the synthesized compounds were evaluated for in vivo anti‐inflammatory activity by carrageenan‐induced paw edema model. Compounds showing significant anti‐inflammatory activity were further tested for their in vitro TNF α expression. Compounds 3b and 2b were found to show significant inhibition of 76.22% and 71.47%, respectively after 5 h in comparison with standard drug indomethacin, which showed 80.98% inhibition of inflammation. Compounds 3b and 2b also suppressed TNF α level by 65.03% and 60.90% as compared indomethacin, which showed 68.84% of inhibition. Compound 3b showed significant analgesic activity of 60.04%, and its activity was comparable with indomethacin (64.04%). Compounds 3b and 2b were also tested for their effect on protein expression of COX‐2 and NF‐κB in the liver tissues. Compounds 3b and 2b were further evaluated for their gastric risk and lipid peroxidation action and showed superior GI safety along with reduction of LPO as compared to indomethacin. Hepatotoxicity study showed that these two compounds did not cause any damage to liver.     

Duloxetine Hydrochloride-Induced Oral Lichenoid Reaction: A Case Report

Objective

To report the first case of duloxetine hydrochloride (DH)-induced oral lichenoid drug reaction (OLDR).

Clinical Presentation and Intervention

A 57-year-old male patient presented with painful ulcerative lesions on the bilateral buccal mucosa of 2-year duration. The patient was on multiple drug therapy for his systemic ailments. After thorough evaluation for possible medical ailments and with the physician''s consent, withdrawal of DH was done. The oral lesions were resolved after 2 weeks.

Conclusion

In this case, DH induced OLDR.Key Words: Duloxetine hydrochloride, Drug-induced oral lichenoid reaction, Oral lichen planus     

ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis

The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of β-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.     

Histamine 3 receptor activation mediates inhibition of acid secretion during Helicobacter-induced gastritis

AIM: To test the hypothesis that histamine 3 receptor (H3R) activation during Helicobacter infection inhibits gastric acid secretion in vivo and in vitro.METHODS: Helicobacter felis (H. felis) infected and uninfected C57Bl/6 mice were infused with either PBS or the H3 receptor antagonist thioperamide (THIO) for 12 wk. After treatment, mice were analyzed for morphological changes and gastric acid content. Total RNA was prepared from the stomachs of each group and analyzed for changes in somatostatin and gastrin mRNA abundance by real time-polymerase chain reaction (RT-PCR). Location of H3 receptors in the stomach was analyzed by co-localization using antibodies specific for the H3 receptor and parietal cell marker H⁺, K⁺-ATPase β subunit.RESULTS: Inflammation and parietal cell atrophy was observed after 12 wk of H. felis infection. Interestingly, treatment with the H3R antagonist thioperamide (THIO) prior to and during infection prevented H. felis-induced inflammation and atrophy. Compared to the uninfected controls, infected mice also had significantly decreased gastric acid. After eradication of H. felis with THIO treatment, gastric acidity was restored. Compared to the control mice, somatostatin mRNA abundance was decreased while gastrin gene expression was elevated during infection. Despite elevated gastric acid levels, after eradication of H. felis with THIO, somatostatin mRNA was elevated whereas gastrin mRNA was suppressed. Immunofluorescence revealed the presence of H3 receptors on the parietal cells, somatostatin-secreting D-cells as well as the inflammatory cells.CONCLUSION: This study shows that during H. felis infection, gastric acidity is suppressed as a consequence of an inhibitory effect on the parietal cell by H3R activation. The stimulation of gastric mucosal H3Rs increases gastrin expression and release by inhibiting release of somatostatin.     

Volar plating for intra-articular fracture of the base of the proximal phalanx

Comminuted fractures involving the articular surface of the base of the proximal phalanx are relatively rare and pose a challenging problem for hand surgeons because of the difficulty in achieving an accurate reduction and secure fixation of the articular surface. These fractures usually comprise a volar base fracture associated with a central depression of the articular surface. We describe a technique for open reduction and plate fixation of intra-articular fractures of the base of the proximal phalanx through a volar A1 pulley approach. Compared with the dorsal approach, this technique offers the advantages of direct visualization of the volar base fragment and the depressed central fragment, allowing for a more accurate reduction and rigid internal fixation using a volar buttress plate. In addition, there is no interference with extensor apparatus. Although our experience is limited to 4 patients, we have had a positive experience with this technique. The technique is useful for internal fixation of intra-articular fractures of the base of the proximal phalanx.     

Functional compressive mechanics of a PVA/PVP nucleus pulposus replacement

Emerging techniques as an alternative to the current treatments of lower back pain include nucleus replacement by an artificial material, which aims to relieve pain and restore the normal spinal motion. The compressive mechanical behavior of the PVA/PVP hydrogel nucleus implant was assessed in the present study. PVA/PVP hydrogels were made with various PVP concentrations. The hydrogels were loaded statically under unconfined and confined conditions. Hydrogels were tested dynamically up to 10 million cycles for a compression fatigue. Also, hydrogel nucleus implants with a line-to-line fit, were implanted in the human cadaveric intervertebral discs (IVD) to determine the compressional behavior of the implanted discs. Hydrogel samples exhibited typical non-linear response under both unconfined and confined compressions. Properties of the confinement ring dictated the observed response. Hydrogel moduli and polymer content were not different pre- and post-fatigues. Slight geometrical changes (mostly recoverable) were observed post-fatigue. In cadavers, hydrogels restored the compressive stiffness of the denucleated disc when compared with equivalent condition of the IVD. The results of this study demonstrate that PVA/PVP hydrogels may be viable as nucleus pulposus implants. Further studies under complex loading conditions are warranted to better assess its potential as a replacement to the degenerated nucleus pulposus.     

Endoscopic third ventriculostomy in infants

BACKGROUND: Endoscopic third Ventriculostomy (ETV) is one of the surgical options for obstructive hydrocephalus. There are varying opinions about results of ETV in infants. We are therefore presenting the results of ETV in 54 infants. MATERIALS AND METHODS: A prospective study of 54 infants undergoing ETV in our institution in the last 2 years was carried out. There were 48 cases of congenital hydrocephalus with aqueductal stenosis, 6 of post tubercular meningitis hydrocephalus. Average follow up was 18 months. RESULTS: There was 83.3% (45 cases) clinical success rate in our study. Infection, persistent cerebro-spinal fluid (CSF) leak and bleeding occurred in 4 (8%) cases each while blockage of stoma was observed in 8 (14.8%) patients. Majority of ETV stoma closure (6 out of total 8) occurred following infection (4) or bleeding during surgery (2). One patient (2%) had transient diabetes insipidus. Overall failure rate in our study was 16.7% (8 stoma blocks and 1 procedure abandoned). Low birth weight pre mature infants had higher failure rate (3 out of 5 infants 60%) compared to full term infants with normal birth weight (12.3%). Age did not have any impact on the success rate (P>0.05). Success rates were not significanlty different in patients with aqueductal stenosis (85.4%) and TBM (66.6%) (Fisher's exact test, P=0.3). CONCLUSION: ETV was fairly safe and effective in full term normal birth weight infants while the results in low birth weight pre mature infants were poor.