FORMULATION AND IN VITRO EVALUATION OF METOPROLOL SUCCINATE FLOATING TABLETS

Gastroretentive dosage forms extend significantly the period of time over which the drug may be released. This prolonged gastric retention improves bioavailability, decrease drug waste and improve solubility of drugs that are less soluble in a high pH environment due to their availability in gastric pH for longer duration of time.Floating drug delivery systems have a bulk density less than gastric fluids and hence remain buoyant in the stomach. The main objective of the present study was to develop Gastroretentive (GR) controlled release ormulations of Metoprolol to prolong the gastric retention time so that its bioavailability can be improved. The formulations were prepared by using swellable polymers like HPMC K4M, HPMC K15M, HPMC K100M, Guar Gum, Xanthan Gum, Sodium carboxymethyl cellulose and various effervescent compounds, e.g. sodium bicarbonate, and citric acid by the direct compression method. All the formulations were evaluated for different parameters like floating lag time, total floating time, hardness, weight variation, density measurements, drug content and water uptake/swelling index. Dissolution studies were done for all formulations in 0.1N HCl (pH 1.2). Formulations F3, F4 and F10 were found to provide maximum sustained release of metoprolol s uccinate up to 24 h with optimum floating properties.Key words : Controlled release; Gastro retentive; HPMC; Guargum; Xantham gu

Management of Class II Division 1 Subdivision malocclusion using unilateral bicuspid extractions and fixed functional appliance: A Two Year Follow-Up

Introduction: Management of Class II Subdivision cases pose a clinical dilemma and require a careful diagnosis to ascertain the source of asymmetry. Various treatment modalities involving: different protocols of tooth extractions; molar distalization; fixed functional appliances, or orthognathic surgery have been proposed for the same.Case presentation: This article reports a unique approach for management of a severe skeletal Class II with Angle’s Class II Division 1 subdivision malocclusion using unilateral bicuspid extractions in mandibular and maxillary arches and a fixed functional appliance.Results: A 13 year 1-month-old male in CVMI transition stage was successfully treated. Extraction of #44 was done to alleviate crowding in the mandibular anterior region and #15 was extracted to protract #16 to achieve a Class II molar relationship. A pre-functional Class II molar and canine relationship with co-incident midlines were achieved. The functional phase consisted of a fixed functional appliance (Forsus FRD) for mandibular advancement to correct the severe skeletal Class II. Class I molar and canine relationships were achieved with the reduction of facial convexity and overjet. The result remained stable 24 months after treatment. The improvement can be quantified by the reduction in scores of orthodontic indices measured pre and post-treatment.Conclusions: Management of Class II subdivision malocclusion requires careful planning. This paper presents a unique approach utilizing unilateral extractions and fixed functional appliances to address severe skeletal Class II discrepancy and the subdivision dilemma

Substrate-bound crystal structures reveal features unique to Mycobacterium tuberculosis N-acetyl-glucosamine 1-phosphate uridyltransferase and a catalytic mechanism for acetyl transfer

N-Acetyl-glucosamine-1-phosphate uridyltransferase (GlmU), a bifunctional enzyme involved in bacterial cell wall synthesis is exclusive to prokaryotes. GlmU, now recognized as a promising target to develop new antibacterial drugs, catalyzes two key reactions: acetyl transfer and uridyl transfer at two independent domains. Hitherto, we identified GlmU from Mycobacterium tuberculosis (GlmUMtb) to be unique in possessing a 30-residue extension at the C terminus. Here, we present the crystal structures of GlmUMtb in complex with substrates/products bound at the acetyltransferase active site. Analysis of these and mutational data, allow us to infer a catalytic mechanism operative in GlmUMtb. In this SN2 reaction, His-374 and Asn-397 act as catalytic residues by enhancing the nucleophilicity of the attacking amino group of glucosamine 1-phosphate. Ser-416 and Trp-460 provide important interactions for substrate binding. A short helix at the C-terminal extension uniquely found in mycobacterial GlmU provides the highly conserved Trp-460 for substrate binding. Importantly, the structures reveal an uncommon mode of acetyl-CoA binding in GlmUMtb; we term this the U conformation, which is distinct from the L conformation seen in the available non-mycobacterial GlmU structures. Residues, likely determining U/L conformation, were identified, and their importance was evaluated. In addition, we identified that the primary site for PknB-mediated phosphorylation is Thr-418, near the acetyltransferase active site. Down-regulation of acetyltransferase activity upon Thr-418 phosphorylation is rationalized by the structures presented here. Overall, this work provides an insight into substrate recognition, catalytic mechanism for acetyl transfer, and features unique to GlmUMtb, which may be exploited for the development of inhibitors specific to GlmU

Small extracellular vesicles in plasma reveal molecular effects of modified Mediterranean-ketogenic diet in participants with mild cognitive impairment

Extracellular vesicles (EV) have emerged as a less-invasive nano-tool for discovering biomarkers of Alzheimer’s disease and related dementia. Here, we analyzed different neuron-enriched EV from plasma to predict response and molecular mechanisms of ketogenic diet’s efficacy in mild cognitive impairment participants. The study was a randomized crossover design in which cognitively normal and mild cognitive impairment participants consumed a modified Mediterranean-ketogenic diet (MMKD) or American Heart Association diet (AHAD) for six weeks, followed by other diet after washout. L1 cell adhesion molecule (L1CAM), synaptophysin, and neural cell adhesion molecule (NCAM) surface markers were used to enrich for neuron-secreted small EV (sEVL1CAM, sEVSYP, and sEVNCAM). For the first time, we have presented multiple evidences, including immunogold labeling/Transmission electron microscopy, CD63 (clusters of differentiation 63)-ELISA based assay, confocal microscopy fluorescent images, and flow cytometry data confirming the presence of L1CAM on the surface of sEVL1CAM, validating purity and relative abundance of sEVL1CAM in the plasma. Cargo analysis of sEVL1CAM showed that MMKD intervention reduces amyloid beta 1-42 (50.3%, p = 0.011), p181-tau (34.9%, p = 0.033) and neurofilament light (54.2%, p = 0.020) in mild cognitive impairment participants. Moreover, sEVL1CAM showed better sensitivity compared to CSF in analyzing increased glutamate (6 folds, p < 0.0001) from mild cognitive impairment participants following MMKD intervention. sEVL1CAM characterization also suggested that MMKD differentially targets the expression of various glutamate receptors - glutamate receptor ionotropic NMDA1 (GRIN1), glutamate receptor ionotropic NMDA2A (GRIN2A), glutamate receptor ionotropic NMDA2B (GRIN2B) and glutamate receptor ionotropic AMPA type subunit 1 (GRIA1). Importantly, these sEVL1CAM measures strongly correlated with corresponding clinical CSF biomarkers (neurogranin, amyloid beta 1-42, neurofilament light, and tau). Furthermore, sEVL1CAM were loaded with less advanced-glycation endproducts and exhibited anti-inflammatory activity following MMKD intervention. Most importantly, the expression of monocarboxylate transporter 2 on the surface of sEVL1CAM predicted the amyloid beta 1-42 response to MMKD intervention (Area under the curve = 0.87, p = 0.0044) and offered a novel screening tool to identify participants responsive to this dietary intervention. Finally, sEVL1CAM, sEVSYP, and sEVNCAM showed significantly high concordance in analyzing amyloid beta 1-42 (Pearson correlation coefficient ≥ 0.63, p < 0.01) and neurofilament light (Pearson correlation coefficient ≥ 0.49, p < 0.05). Together, sEV in plasma offers promise in assessing the efficacy of dietary/therapeutic intervention against mild cognitive impairment/Alzheimer’s disease

Angiopreventive Efficacy of Pure Flavonolignans from Milk Thistle Extract against Prostate Cancer: Targeting VEGF-VEGFR Signaling

The role of neo-angiogenesis in prostate cancer (PCA) growth and metastasis is well established, but the development of effective and non-toxic pharmacological inhibitors of angiogenesis remains an unaccomplished goal. In this regard, targeting aberrant angiogenesis through non-toxic phytochemicals could be an attractive angiopreventive strategy against PCA. The rationale of the present study was to compare the anti-angiogenic potential of four pure diastereoisomeric flavonolignans, namely silybin A, silybin B, isosilybin A and isosilybin B, which we established previously as biologically active constituents in Milk Thistle extract. Results showed that oral feeding of these flavonolignans (50 and 100 mg/kg body weight) effectively inhibit the growth of advanced human PCA DU145 xenografts. Immunohistochemical analyses revealed that these flavonolignans inhibit tumor angiogenesis biomarkers (CD31 and nestin) and signaling molecules regulating angiogenesis (VEGF, VEGFR1, VEGFR2, phospho-Akt and HIF-1α) without adversely affecting the vessel-count in normal tissues (liver, lung, and kidney) of tumor bearing mice. These flavonolignans also inhibited the microvessel sprouting from mouse dorsal aortas ex vivo, and the VEGF-induced cell proliferation, capillary-like tube formation and invasiveness of human umbilical vein endothelial cells (HUVEC) in vitro. Further studies in HUVEC showed that these diastereoisomers target cell cycle, apoptosis and VEGF-induced signaling cascade. Three dimensional growth assay as well as co-culture invasion and in vitro angiogenesis studies (with HUVEC and DU145 cells) suggested the differential effectiveness of the diastereoisomers toward PCA and endothelial cells. Overall, these studies elucidated the comparative anti-angiogenic efficacy of pure flavonolignans from Milk Thistle and suggest their usefulness in PCA angioprevention

Asiatic Acid Inhibits Pro-Angiogenic Effects of VEGF and Human Gliomas in Endothelial Cell Culture Models

Malignant gliomas are one of the most devastating and incurable tumors. Sustained excessive angiogenesis by glioma cells is the major reason for their uncontrolled growth and resistance toward conventional therapies resulting in high mortality. Therefore, targeting angiogenesis should be a logical strategy to prevent or control glioma cell growth. Earlier studies have shown that Asiatic Acid (AsA), a pentacyclic triterpenoid, is effective against glioma and other cancer cells; however, its efficacy against angiogenesis remains unknown. In the present study, we examined the anti-angiogenic efficacy of AsA using human umbilical vein endothelial cells (HUVEC) and human brain microvascular endothelial cells (HBMEC). Our results showed that AsA (5–20 µM) inhibits HUVEC growth and induces apoptotic cell death by activating caspases (3 and 9) and modulating the expression of apoptosis regulators Bad, survivin and pAkt-ser473. Further, AsA showed a dose-dependent inhibition of HUVEC migration, invasion and capillary tube formation, and disintegrated preformed capillary network. AsA also inhibited the VEGF-stimulated growth and capillary tube formation by HUVEC and HBMEC. Next, we analyzed the angiogenic potential of conditioned media collected from human glioma LN18 and U87-MG cells treated with either DMSO (control conditioned media, CCM) or AsA 20 µM (AsA20 conditioned media, AsA20CM). CCM from glioma cells significantly enhanced the capillary tube formation in both HUVEC and HBMEC, while capillary tube formation in both endothelial cell lines was greatly compromised in the presence of AsA20CM. Consistent with these results, VEGF expression was lesser in AsA20CM compared to CCM, and indeed AsA strongly inhibited VEGF level (both cellular and secreted) in glioma cells. AsA also showed dose-dependent anti-angiogenic efficacy in Matrigel plug assay, and inhibited the glioma cells potential to attract HUVEC/HBMEC. Overall, the present study clearly showed the strong anti-angiogenic potential of AsA and suggests its usefulness against malignant gliomas

An interplay between dermatology and ophthalmology: a systematic review and meta-analysis on intense pulsed light therapy for Meibomian gland dysfunction: A systematic review and meta-analysis on intense pulsed light therapy for Meibomian gland dysfunction

Objectives: To examine the effectiveness of intense pulsed light therapy (IPL) in treating Meibomian gland dysfunction (MGD) and dry eye symptoms. Methods: This study was conducted following the PRISMA statement guidelines. Literature sources included MEDLINE, Embase, Cochrane Library and meeting abstracts from COS and ARVO. Articles underwent 3 stages of screening before data extraction and meta-analysis. Results: 493 studies were found. 50 remained after title screening, 23 after abstract screening and 8 progressed to data extraction. Meta-analysis indicated a significant increase in tear break-up time (TBUT) post-IPL in the less than 1-month follow-up (SMD=1.45; CI:[0.33, 2.57]), 1.5–2 months follow-up (SMD=2.08; CI: [1.14, 3.01]), and 3-months follow-up (SMD=3.28; CI:[2.78, 3.78]) groups and a non-significant increase in TBUT in the 6-month follow-up  (SMD=1.90; CI:[-0.18, 3.98]) and at 12-months follow-up (SMD=0.0; CI:[-0.48, 0.48]) groups. Meta-analysis also indicated a significant increase in Schirmer’s test values during the less than 1-month (SMD=0.91; CI:[0.50, 1.31]) and 6-month (SMD=0.65; CI:[0.25, 1.04]) follow-up periods and a non-significant increase in Schirmer’s test values during the 1.5–2 month follow-up period (SMD=0.41; CI:[-0.93, 1.75]). Conclusions: The results suggested a significant increase up to 5-months and a non-significant increase at 6-months post-IPL for TBUT. They also suggested a significant increase in Schirmer’s test values during the less than 1-month and 6-month follow-up periods and a non-significant increase in Schirmer’s test values during the 1-month follow-up period. Ultimately, IPL seems to be a promising therapy for MGD, but we recommend future studies with longer follow-up periods

An interplay between dermatology and ophthalmology: a systematic review and meta-analysis on intense pulsed light therapy for Meibomian gland dysfunction: A systematic review and meta-analysis on intense pulsed light therapy for Meibomian gland dysfunction

Objectives: To examine the effectiveness of intense pulsed light therapy (IPL) in treating Meibomian gland dysfunction (MGD) and dry eye symptoms. Methods: This study was conducted following the PRISMA statement guidelines. Literature sources included MEDLINE, Embase, Cochrane Library and meeting abstracts from COS and ARVO. Articles underwent 3 stages of screening before data extraction and meta-analysis. Results: 493 studies were found. 50 remained after title screening, 23 after abstract screening and 8 progressed to data extraction. Meta-analysis indicated a significant increase in tear break-up time (TBUT) post-IPL in the less than 1-month follow-up (SMD=1.45; CI:[0.33, 2.57]), 1.5–2 months follow-up (SMD=2.08; CI: [1.14, 3.01]), and 3-months follow-up (SMD=3.28; CI:[2.78, 3.78]) groups and a non-significant increase in TBUT in the 6-month follow-up  (SMD=1.90; CI:[-0.18, 3.98]) and at 12-months follow-up (SMD=0.0; CI:[-0.48, 0.48]) groups. Meta-analysis also indicated a significant increase in Schirmer’s test values during the less than 1-month (SMD=0.91; CI:[0.50, 1.31]) and 6-month (SMD=0.65; CI:[0.25, 1.04]) follow-up periods and a non-significant increase in Schirmer’s test values during the 1.5–2 month follow-up period (SMD=0.41; CI:[-0.93, 1.75]). Conclusions: The results suggested a significant increase up to 5-months and a non-significant increase at 6-months post-IPL for TBUT. They also suggested a significant increase in Schirmer’s test values during the less than 1-month and 6-month follow-up periods and a non-significant increase in Schirmer’s test values during the 1-month follow-up period. Ultimately, IPL seems to be a promising therapy for MGD, but we recommend future studies with longer follow-up periods

Interaction entre la dermatologie et l’ophtalmologie : méta-analyse et recension systématique des écrits sur la lumière pulsée intense utilisée pour traiter le dysfonctionnement des glandes de Meibomius

Objectifs : Examiner, au moyen d’une méta-analyse, l’efficacité de la thérapie à lumière pulsée intense dans le traitement des symptômes de la sécheresse oculaire. Méthodologie : Cette étude a été réalisée en suivant la grille PRISMA. Les sources documentaires consultées comprennent MEDLINE, Embase, la bibliothèque Cochrane et des résumés de réunions de la SCO, d’ARVO, de l’American Academy of Optometry et de l’American Academy of Ophthalmology. Les articles ont subi trois étapes de tri avant l’extraction des données et la méta-analyse. Résultats : Au départ, nous avons recensé 495 études. Nous en avons retenu 52 après la présélection des titres et 23 après la présélection des résumés. Huit ont été sélectionnées en vue de l’extraction des données. La méta-analyse indique une augmentation importante du temps de rupture du film lacrymal (TRFL) après une thérapie à lumière pulsée (TLP) dans le suivi à moins d’un mois (différence moyenne standardisée [DMS]=1,45; IC :[0,33, 2,57]), le suivi à 1,5 ou 2 mois (DMS=2,08; IC : [1,14, 3,01]) et le suivi à 3 mois (DMS=3,28; IC :[2,78, 3,78]) et aucun changement significatif dans le TRFL dans le suivi à 6 mois (DMS=1,90; IC :[-0,18, 3,98]) ou le suivi à 12 mois des groupes d’une seule étude (DMS=0,0; IC :[-0,48, 0,48]). La méta-analyse indique également une augmentation importante des valeurs du test de Schirmer pendant la période de suivi à moins d’un mois (DMS = 0,91; IC : [0,50, 1,31]) et à six mois (DMS = 0,65; IC : [0,25, 1,04]) et aucun changement significatif des valeurs du test de Schirmer pendant la période de suivi à 1,5 ou 2 mois (DMS=0,41; IC :[-0,93, 1,75]). Conclusions : Les résultats indiquent une augmentation importante du TRFL jusqu’à 5 mois et aucun changement important à 6 mois après une TLP. Ils indiquent également une augmentation importante des valeurs du test de Schirmer au suivi à moins d’un mois et à six mois et aucun changement important de ces valeurs au suivi à un mois. Au bout du compte, la TLP semble prometteuse pour soulager les symptômes de la sécheresse oculaire, mais d’autres études comprenant des périodes de suivi plus longues sont nécessaires