Study on development and tissue permeation of different formulations of Fasudil.

OBJECTIVE: The study is intended to formulate Fasudil loaded vesicular system for application in the management of angina. MATERIALS AND METHODS: Fasudil was made into a complex with phospholipid, and other different formulations were made, including Fasudil solution, liposomal form, and Fasudil loaded into the gel. A drug characterization study was conducted and noted. Drug release was quantified and analyzed and, finally, inoculated in Sprague-Dawley rats. These rats underwent anginal induction, and each formulation's effect on angina was evaluated. RESULTS: Drug solution (F-Phos) and F-Phos-Lipo (liposomal dispersion form of the drug) have shown that more than half percent of them have been released within 1.5 hours, and the rapid release occurred from liposomal dispersion in the first hour. The study determined the viscosity of the different formulations, which was significantly (p<0.05) higher than the theoretical sum of the viscosity of each formulation. The study found that the F-Phos-Lipo+P-407HMS formulation is the most effective as its application has the minimum infarct area percentage compared to the other formulations and can also reduce creatine kinase levels significantly as compared to the different formulations (p<0.05). CONCLUSIONS: The study concluded that the typical gel formulation (liposomal Fasudil dispersed in hydroxypropyl methylcellulose solution, which is added to blank poloxamer 407) had been shown to have significantly anti-anginal properties, including easy administration, its application on the infarct area percentage and subsequently its pharmacological effect on the cardiac tissue.

In silico elucidation of plausible anti-obesity activity by Withaferin-A compound targeting alpha-amylase.

OBJECTIVE: The study aimed to evaluate the Withaferin-A against the drug target α-amylase, revealing its plausible mode of action and molecular-level interactions essential for this specific target inhibitory potential computational approach. MATERIALS AND METHODS: In this scenario, we used computational methods, including docking, molecular dynamics simulation, and model-building simulations, to elucidate the atomic-level details responsible for the inhibitory potential of Withaferin-A derived from W. somnifera. The studio visualizer software was used for the visualization of ligands, structures of the receptor, bond length, and rendering of the image. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics of phytochemicals were investigated. Crystal structure of protein receptors and ligands were generated. Semi-flexible docking was done using Autodock software. Docking was performed using the Lamarckian Genetic Algorithm (LGA). Molecular descriptors were evaluated, and the pharmacological properties of the phytochemicals were explored. Molecular dynamic simulations were analyzed at the atomic level. All the simulations were conducted under the same temperature, pressure, and volume circumstances over the simulated time scale. RESULTS: Withaferin-A has shown a strong binding affinity towards α-amylase as demonstrated with -9.79 Kcal/mol with 66.61 estimated nanomolecular IC50 value for plausible anti-obesity activity. Molecular-level relationships and knowledge obtained from this study indicate solid interactions with TYR59, ASP197, and HIS299 residues which are of high importance for future works related to computational screening of target-specific α-amylase inhibitors. The results from the analysis have revealed potential molecular-level interactions useful for further designing/discovering novel α-amylase inhibitors. CONCLUSIONS: The framework of the studied phytochemicals enables the rapid development of subsequent modifications that could result in more lead-like compounds with better inhibitory efficacy and selectivity for α-amylase.

Previously undiagnosed attention-deficit/hyperactivity disorder associated with poor metabolic control in adolescents with type 1 diabetes.

BACKGROUND: Managing modern diabetes treatment requires efficient executive functions. Patients with attention-deficit/hyperactivity disorder (ADHD) and type 1 diabetes have poor metabolic control and present with ketoacidosis more often than patients without ADHD. OBJECTIVE: To assess whether patients with type 1 diabetes and with indications of executive problems met criteria for ADHD, and to investigate whether these patients had difficulties achieving metabolic control. METHODS: In a hospital-based study, including 3 pediatric departments at hospitals in Stockholm and Uppsala, Sweden, questionnaires regarding executive problems had been filled out by 12- to 18-year-old patients with type 1 diabetes and their parents. Out of 166 patients with completed questionnaires, 49 were selected for a clinical study due to reported executive problems/ADHD symptoms. However, 7 already had a diagnosis of ADHD, 21 denied follow-up, 8 did not respond, leaving 13 adolescents for the clinical assessment. RESULTS: Of the clinically assessed adolescents, 9 (6 girls) met criteria for ADHD. Patients who did not respond to the follow-up and patients who were diagnosed with ADHD within the study, showed to a larger extent than the other study groups high HbA1c levels (>70 mmol/mol, 8,6%). HbA1c >70 mmol/mol (8.6%) was associated with diagnosed ADHD (prior to or within the study), odds ratio 2.96 (95% confidence interval 1.02-8.60). CONCLUSION: Patients with type 1 diabetes and poor metabolic control should be assessed with regard to ADHD. There is a need for paying special attention to girls with poor metabolic control.

The effects of repetitive transcranial magnetic stimulation on empathy: a systematic review and meta-analysis.

Empathy is a multi-dimensional concept with affective and cognitive components, the latter often referred to as Theory of Mind (ToM). Impaired empathy is prevalent in people with neuropsychiatric disorders, such as personality disorder, psychopathy, and schizophrenia, highlighting the need to develop therapeutic interventions to address this. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive therapeutic technique that has been effective in treating various neuropsychiatric conditions, can be potentially used to modulate empathy. To our knowledge, no systematic reviews or meta-analyses in this field have been conducted. The aim of the current study was to review the literature on the use of rTMS to modulate empathy in adults. Seven electronic databases (AMED, Cochrane library, EMBASE, Medline, Pubmed, PsycInfo, and Web of Science) were searched using appropriate search terms. Twenty-two studies were identified, all bar one study involved interventions in healthy rather than clinical populations, and 18 of them, providing results for 24 trials, were included in the meta-analyses. Results showed an overall small, but statistically significant, effect in favour of active rTMS in healthy individuals. Differential effects across cognitive and affective ToM were evident. Subgroup analyses for cognitive ToM revealed significant effect sizes on excitatory rTMS, offline paradigms, and non-randomised design trials. Subgroup analyses for affective ToM revealed significant effect sizes on excitatory rTMS, offline paradigms, and non-randomised design trials. Meta-regression revealed no significant sources of heterogeneity. In conclusion, rTMS may have discernible effects on different components of empathy. Further research is required to examine the effects of rTMS on empathy in clinical and non-clinical populations, using appropriate empathy tasks and rTMS protocols.

Determination of occlusal vertical dimension for complete dentures patients: an updated review.

Determination of the occlusal vertical dimension (OVD) is an integral part of complete dentures fabrication. Due to the lack of teeth, the clinician faces the challenge of how to accurately establish the OVD of the new denture. Therefore, the purpose of this review article was to present, discuss and critique the available methods used in determining the OVD for complete dentures patients. This review identified two main streams to determine the OVD: (i) pre-extraction methods and (ii) post-extraction methods. For the pre-extraction methods, the OVD of the natural dentition is transferred to the new dentures mainly by intra-oral measurements, profile tracing and cephalometric analysis. The post-extraction methods rely on mandibular rest position, facial aesthetic appearance, swallowing pattern, craniofacial landmarks measurements, cephalometric analysis, phonetics and existing dentures. In general, all the available techniques have merits and are helpful for routine clinical use. However, they are empirical in nature, controversial and lack the scientific support. Further, there is no single accurate method for OVD determination. To overcome the limitations of the techniques, the clinician will benefit from applying combination of techniques to approximate the OVD.

Individual placement and support (IPS) for patients with offending histories: the IPSOH feasibility cluster randomised trial protocol.

INTRODUCTION: People with involvement in forensic psychiatric services face many obstacles to employment, arising from their offending, as well as their mental health problems. This study aims to assess the feasibility of conducting a randomised controlled trial (RCT) to evaluate the effectiveness of individual placement and support (IPS), in improving employment rates and associated psychosocial outcomes in forensic psychiatric populations. IPS has been found consistently to achieve employment rates above 50% in psychiatric patients without a history of involvement in criminal justice services. METHODS/DESIGN: This is a single-centre feasibility cluster RCT. Clusters will be defined according to clinical services in the community forensic services of Nottinghamshire Healthcare NHS Foundation Trust (NHCT). IPS will be implemented into 2 of the randomly assigned intervention clusters in the community forensic services of NHCT. A feasibility cluster RCT will estimate the parameters required to design a full RCT. The primary outcome is the proportion of people in open employment at 12-month follow-up. Secondary outcome measures will include employment, educational activities, psychosocial and economic outcomes, as well as reoffending rates. Outcome measures will be recorded at baseline, 6 months and 12 months. In accordance with the UK Medical Research Council guidelines on the evaluation of complex interventions, a process evaluation will be carried out; qualitative interviews with patients and staff will explore general views of IPS as well as barriers and facilitators to implementation. Fidelity reviews will assess the extent to which the services follow the principles of IPS prior, during and at the end of the trial. ETHICS AND DISSEMINATION: Ethical approval was obtained from the East Midlands Research Ethics Committee-Nottingham 1 (REC reference number 15/EM/0253). Final and interim reports will be prepared for project funders, the study sponsor and clinical research network. Findings will be disseminated through peer-reviewed journals, conferences and event presentations. TRIAL REGISTRATION NUMBER: NCT02442193; Pre-results.

Synthesis and characterization of some substituted 3, 4-dihydronaphthalene derivatives through different enaminones as potent cytotoxic agents.

A new series of novel substituted 3,4-dihydronaphthalene incorporated to benzo[h]quinoline, benzo[g]indazole, thiazolidin-4-one, pyrazolo[3,4-d]thiazol and thiazolo[4,5-b]pyridine ring systems were synthesized and evaluated for their cytotoxicity against selected human cancer cell lines. Some of the tested compounds exhibited promising carcinoma growth inhibition. The detailed synthesis, spectroscopic data and biological activities of the tested compounds were reported.

Roles of NMDA and dopamine D1 and D2 receptors in the acquisition and expression of flavor preferences conditioned by oral glucose in rats.

Animals learn to prefer flavors associated with the intake of sugar (sucrose, fructose, glucose) and fat (corn oil: CO) solutions. Conditioned flavor preferences (CFP) have been elicited for sugars based on orosensory (flavor-flavor: e.g., fructose-CFP) and post-ingestive (flavor-nutrient: e.g., intragastric (IG) glucose-CFP) processes. Dopamine (DA) D1, DA D2 and NMDA receptor antagonism differentially eliminate the acquisition and expression of fructose-CFP and IG glucose-CFP. However, pharmacological analysis of fat (CO)-CFP, mediated by both flavor-flavor and flavor-nutrient processes, indicated that acquisition and expression of fat-CFP were minimally affected by systemic DA D1 and D2 antagonists, and were reduced by NMDA antagonism. Therefore, the present study examined whether systemic DA D1 (SCH23390), DA D2 (raclopride) or NMDA (MK-801) receptor antagonists altered acquisition and/or expression of CFP induced by oral glucose that should be mediated by both flavor-flavor and flavor-nutrient processes. Oral glucose-CFP was elicited following by training rats to drink one novel flavor (CS+, e.g., cherry) mixed in 8% glucose and another flavor (CS-, e.g., grape) mixed in 2% glucose. In expression studies, food-restricted rats drank these solutions in one-bottle sessions (2 h) over 10 days. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 2% glucose occurred 0.5 h after systemic administration of vehicle (VEH), SCH23390 (50-800 nmol/kg), raclopride (50-800 nmol/kg) or MK-801 (50-200 µg/kg). Rats displayed a robust CS+ preference following VEH treatment (94-95%) which was significantly though marginally attenuated by SCH23390 (67-70%), raclopride (77%) or MK-801 (70%) at doses that also markedly reduced overall CS intake. In separate acquisition studies, rats received VEH, SCH23390 (50-400 nmol/kg), raclopride (50-400 nmol/kg) or MK-801 (100 µg/kg) 0.5 h prior to ten 1-bottle training trials with CS+/8%G and CS-/2%G training solutions that was followed by six 2-bottle CS+ vs. CS- tests in 2% glucose conducted without injections. The significant and persistent CS+ preferences observed in the VEH (94-98%) group was significantly reduced by rats receiving SCH23390 at 400 nmol/kg (65-73%), raclopride at 200 or 400 nmol/kg (76-82%) or MK-801 at 100 µg/kg (68-69%). Thus, systemic DA D1 and DA D2 receptor antagonism produced smaller reductions in the expression of oral glucose-CFP relative to fructose-CFP or IG-glucose-CFP. Correspondingly, systemic DA D1, DA D2 and NMDA receptor antagonism also produced smaller reductions in the acquisition of oral glucose-CFP relative to fructose-CFP or IG-glucose-CFP. These data suggest, but do not prove, that the magnitude and persistence of these receptor antagonist effects upon sugar-CFP might depend upon the individual or combined engagement of flavor-flavor and flavor-nutrient processes.

Critical role of NMDA but not opioid receptors in the acquisition of fat-conditioned flavor preferences in rats.

Animals learn to prefer flavors associated with the intake of dietary fats such as corn oil (CO) solutions. We previously reported that fat-conditioned flavor preferences in rats were relatively unaffected by systemic treatment with dopamine D1 and D2 antagonsits. The present study examined whether systemic opioid (naltrexone, NTX) or NMDA (MK-801) receptor antagonists altered the acquisition and/or expression of CO-CFP. The CFP was produced by training rats to drink one novel flavor (CS+, e.g., cherry) mixed in a 3.5% CO solution and another flavor (CS-, e.g., grape) in a 0.9% CO solution. In expression studies, food-restricted rats drank these solutions in one-bottle sessions (2 h) over 10 d. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 0.9% CO solutions occurred 0.5h after systemic administration of vehicle (VEH), NTX (0.1-5 mg/kg) or MK-801 (50-200 µg/kg). Rats displayed a robust CS+ preference following VEH treatment (85-88%) which was significantly though moderately attenuated by NTX (69-70%). The lower doses of MK-801 slightly reduced the CS+ preference; the high dose blocked the CS+ preference (49%) but also markedly reduced overall CS intake. In separate acquisition studies, rats received VEH or NTX (0.1, 0.5, 1mg/kg) or MK-801 (100 µg/kg) 0.5h prior to 1-bottle training trials with CS+/3.5% CO and CS-/0.9% CO training solutions. Additional Limited VEH groups were trained with intakes limited to that of the NTX and MK-801 groups. Subsequent two-bottle CS+ vs. CS- tests were conducted without injections. Significant and persistent CS+ preferences were observed in VEH (77-84%) and Limited VEH (88%) groups. NTX treatment during training failed to block the acquisition of CO-CFP although the magnitude of the CS+ preference was reduced by 0.5 (70%) and 1.0 (72%) mg/kg doses relative to the Limited VEH treatment (88%). In contrast, MK-801 (100 µg/kg) treatment during training blocked the acquisition of the CO-CFP. These data suggest a critical role for NMDA, but not opioid receptor signaling in the acquisition of a fat conditioned flavor preferences, and at best limited involvement of NMDA and opioid receptors in the expression of a previously learned preference.

Adrenocortical tumors in children: a Kuwait experience.

INTRODUCTION: Adrenocortical tumors (ACT) are rare tumors of childhood. The majority of these tumors is hormone-producing and cause virilization and Cushing syndrome or feminization. METHODOLOGY: The authors describe 6 cases of adrenal cortical tumors treated at the Kuwait Cancer Center which were presented over a period of 20 years (1989-2009). RESULTS: The mean age was 5.5 years (range 15 months - 12 years). All had signs of virilization. One child had hypertension, while 2 had a metastatic disease at presentation. The diagnosis was made by clinical signs and symptoms, high levels of relevant adrenal hormones and imaging. Two children were not fit for surgery; one was too sick for any treatment and died shortly after diagnosis, while the other died after receiving one cycle of palliative chemotherapy. Four patients underwent complete surgical resection and achieved complete remission, three of whom later had recurrence (distant in one and local in two patients) and succumbed due to progressive disease. Mitotane was used in two children. Only one patient is currently surviving and well nearly 13 years after her surgery. In our series, the long-term outcome of children with adrenocortical tumors was very poor. CONCLUSIONS: Virilization is an important clue to the diagnosis of ACT. Early diagnosis and complete surgical resection are important for survival. Metastasis at presentation or as recurrence carries very dismal prognosis.