Synthesis, characterization and pharmacological evaluation of (E)-N′-(substituted-benzylidene)isonicotinohydrazide derivatives as potent anticonvulsant agents

A series of (E)-N′-(substituted-benzylidene)isonicotinohydrazide derivatives were synthesized by coupling it with different substituted aldehydes, acetophenone, and benzophenones in presence of absolute ethanol along with catalytic amount of glacial acetic acid. All the synthesized compound were confirmed and characterized by using various spectral technique like IR, ¹H NMR, ¹³C NMR, and mass spectroscopy studies. Anticonvulsant evaluations of all the synthesized compounds were done using various seizures models like maximal electroshock-induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) at a dose of 30, 100, and 300?mg/kg body weight and anticonvulsant activity was noted at 0.5?h and 4?h time intervals after the drug administration. Compound 1a (E)-N′-2-benzylidene isonicotinohydrazide, 1g (E)-N′-2-ethoxybenzylidene isonicotinohydrazide, 1k (E)-N′-3-flourobenzylidene isonicotinohydrazide and 3a (E)-N′-diphenylmethylene isonicotinohydrazide showed protection in MES model, which indicates that these compounds have the ability to prevent the spread of seizure at 300?mg/kg dose and showed protection at 0.5?h duration. Compound 3a was also found to be active in scPTZ screen at a dose of 300?mg/kg. In neurotoxicity screen, all the synthesized compounds were found non-toxic except compounds 1n, 2a, and 3b. Further compounds 1a, 1g, 1k, and 3a were also evaluated in the minimal clonic seizure model and exhibited potent anticonvulsant activity with lower neurotoxicity. Among all synthesized derivatives, analogue 3a was found to exhibit protection in MES and scPTZ seizure models. This study proved that isonicotinoyl hydrazides synthesized by condensing isoniazid with various aldehydes and ketones displayed moderate to potent anticonvulsant activity.     

Smoldering mantle cell lymphoma

Background

Mantle cell lymphoma (MCL) is an aggressive disease, with poor prognosis and a limited survival. However, some patients with indolent MCL can survive beyond 7~10 years. These patients remain largely asymptomatic and can be in observation for a long time without any treatment. The process of “wait and watch” leaves these patients with the potential risk of evolution to classic, aggressive MCL. On the other hand, early treatment for these patients may not impact overall survival but rather affects the quality of life. Therefore, it is essential to clearly identify this type of indolent MCL at the time of diagnosis.

Results

Reported findings of indolent presentation of MCL include: lack of B symptoms, normal serum lactic dehydrogenase (LDH) and β2-microglobulin levels (β2M), low MCL-International Prognostic Index (MIPI) score, maximum tumor diameter less than 3 cm, spleen size?<?20 cm, positron emission tomography/computerized tomography with the Standard Uptake Value max <6, Ki-67 less than 30%, with some particular immunophenotype, such as CD5 and CD38 negative, markedly increased CD23 positive lymphocytes proportions, high expression of CD200, kappa light chain restriction, without C-myc, TP53 and NOTCH1/2 mutations, non-blastoid/pleomorphic histology, and no tumor growth on reevaluation every 2~3 months (followed for at least 6 months). Imaging evaluation may only be performed in the presence of disease-related symptoms or organ involvement. Meanwhile, if novel nodal or extranodal lesion is found, biopsy is mandatory to exclude lymphoma.Common clinopathological forms of indolent presentations include monoclonal B lymphocytosis with t (11; 14); “indolent leukemic” presentation of MCL with involvement of peripheral blood, bone marrow involvement, splenomegaly, and minimal lymphadenopathies and in situ lymphoma (often found in lymph nodes removed for other reasons, and in gastrointestinal biopsies).

Conclusions

Considering these distinct indolent clinical presentations with particular features in cytology and gene mutational status, we propose to include these MCL clinical presentations under the umbrella of “Smoldering Mantle Cell Lymphoma”.

     

Endoscopic full thickness resection for gastric tumors originating from muscularis propria

AIM: To do systematic review of current literature for endoscopic full thickness resection(EFTR) technique for gastric tumors originating from muscularis propria.METHODS: An extensive English literature search was done till December 2015; using Pub Med and Google scholar to identify the peer reviewed original and review articles using keywords-EFTR, gastric tumor, muscularis propria. Human only studies were included. The references of pertinent studies were manually searched to identify additional relevant studies. The indications, procedural details, success rates, clinical outcomes, complications and limitations were considered. For the purpose of review, data from individual studies was combined to calculate mean. No other statistical test was applied.RESULTS: A total of 9 original articles were identified. Four articles were from same institute and the time frames of these studies were overlapping. To avoid duplication of data, only the study with patients over the longest time interval was included and other three were excluded. In total six studies were included in the final review. In our systematic review, the mean success rate for EFTR of gastric tumors originating from muscularis propria was 96.8%. The mean procedure time varied from a minimum of 37 min to a maximum of 105 min. There was no reported mortality from the technique itself. The most common histological diagnosis was gastrointestinal stromal tumors and leiomyoma. Gastric wall defect closure by either metallic clips or over the scope clip(OTSC) had similar outcomes although experience with OTSC was limited to smaller lesions(3cm).CONCLUSION: EFTR is a minimally invasive technique to resect gastric submucosal tumors originating from muscularis propria with a high success rate and low complication rate.     

Role of Niacin in Current Clinical Practice: A Systematic Review

Background

Niacin, a potent high-density lipoprotein cholesterol-raising drug, seems an attractive approach to reduce cardiac events in patients with or at risk of atherosclerotic cardiovascular disease. However, previous evidence for niacin has been challenged recently by negative outcomes in 2 large, randomized, controlled trials comparing niacin to placebo with background statin therapy. We studied the currently available evidence for the role of niacin treatment for reducing the risk of cardiovascular events in current practice.

Insurance Coverage of Biologics for Moderate-to-Severe Psoriasis: A Retrospective,Observational 5-Year Chart Review

Background

With the variability in health insurance coverage for psoriasis systemic therapies, recent changes in coverage for biologics have yet to be evaluated.

Purpose

To determine changes in insurance coverage of biologics for moderate-to-severe psoriasis between 2009 and 2014, with a focus on insurance policies as stated in prior authorization (PA) forms, coverage denials, and time course of approval process.

Methods

A retrospective chart review was performed on patients with a diagnosis of psoriasis (International Classification of Diseases [ICD], Ninth Edition, code ICD 696.1) seen at the Department of Dermatology, Medical Faculty Associates, George Washington University between January 1, 2009 and December 31, 2014. Exclusion criteria included <9 % body surface area, loss to follow-up, lack of biologic treatment, biologic treatment via a clinical trial, and lack of health insurance. For all other patients, metrics collected included age, sex, body surface area, health insurance plan, prior therapies, prescribed biologic, PA necessity, time in days between PA submission and coverage decision, and denial justifications.

Results

Eight hundred and sixty-four patients with a diagnosis of psoriasis within the time period were identified, 114 of who met the inclusion criteria. PA requirement increased from 16 % of patients prescribed a biologic in 2009 to 75 % of patients prescribed a biologic in 2014. The mean duration in days between PA submission and coverage decision from the insurance company increased from 3.7 days in 2009 to 6.7 days in 2014. PA denial rates increased from 0 % in 2009 to 19 % in 2014. The most common reason for coverage denial was failure to attempt alternative therapies prior to requesting biologics.

Conclusion

Insurance coverage of biologics for moderate-to-severe plaque psoriasis has become increasingly regulated between 2009 and 2014. Given both the cost burden and potential benefits of these therapies, further examination of healthcare coverage and treatment accessibility is warranted for optimal patient outcomes.