In-vitro/in-vivo correlation of pulsatile drug release from press-coated tablet formulations: a pharmacoscintigraphic study in the beagle dog.

The aim of the current study was to investigate the in-vitro and in-vivo performance of a press-coated tablet (PCT) intended for time delayed drug release, consisting of a rapidly disintegrating theophylline core tablet, press-coated with barrier granules containing glyceryl behenate (GB) and low-substituted hydroxypropylcellulose (L-HPC). The PCTs showed pulsatile release with a lag time dependent upon the GB and L-HPC composition of the barrier layer. In-vivo gamma-scintigraphic studies were carried out for PCTs containing GB:L-HPC at 65:35 w/w and 75:25 w/w in the barrier layer in four beagle dogs, in either the fed or fasted state. The in-vivo lag time in both the fed and fasted states did not differ significantly (p>0.05) from the in-vitro lag time. Additionally, no significant difference (p<0.05) between in-vivo fed and fasted disintegration times was observed, demonstrating that in-vivo performance of the PCT was not influenced by the presence or absence of food in the gastrointestinal tract. A distinct lag time was obtained prior to the appearance of drug in plasma and correlated (R2=0.98) with disintegration time observed from scintigraphic images. However, following disintegration, no difference in pharmacokinetic parameters (AUC(0-6 dis), K(el), Cmax) was observed. The current study highlighted the potential use of these formulations for chronopharmaceutical drug delivery.     

Sociodemographic Patterns of Exclusive,Dual, and Polytobacco Use Among U.S. High School Students: A Comparison of Three Nationally Representative Surveys

PurposeThis study examines sociodemographic patterns of exclusive/dual/polytobacco use among U.S. high school students using multiple national surveys.MethodsUsing three national youth surveys (Population Assessment of Tobacco and Health [PATH] Wave 4 [2016–2017], 2017 Youth Risk Behavior Survey, and 2017 National Youth Tobacco Survey), we classified tobacco products into four groups: (1) electronic nicotine delivery systems (ENDS), (2) conventional cigarettes (CCs), (3) other combustible tobacco products, and (4) smokeless tobacco products. We created 16 categories of non/exclusive/dual/polytobacco use within the past 30 days using the four product groups and calculated weighted population prevalence by sex and race/ethnicity (all surveys) and parental education and income (PATH), based on variable availability.ResultsThe results from 9,331, 12,407, and 9,699 high school students in PATH, Youth Risk Behavior Survey, and National Youth Tobacco Survey, respectively, largely agreed and pointed to similar conclusions. ENDS was the most prevalent exclusive use product (3.8%–5.2% across surveys), with CCs falling to second or third (1.2%–2.0% across surveys). By sex, exclusive, dual, and poly smokeless tobacco product use were more common for males, whereas exclusive CC use was more common for females. By race/ethnicity, non-Hispanic Whites had a higher prevalence of exclusive ENDS use and ENDS/CC dual use than non-Hispanic Blacks. As income and parental education levels increased from low to high, the prevalence of exclusive CC use decreased, whereas the prevalence of exclusive ENDS use increased.ConclusionUnderstanding sociodemographic patterns of tobacco use can help identify groups who may be at greater risk for tobacco-related health outcomes.     

A framework for considering the risk‐benefit trade‐off in designing noninferiority trials using composite outcome approaches

When a new treatment regimen is expected to have comparable or slightly worse efficacy to that of the control regimen but has benefits in other domains such as safety and tolerability, a noninferiority (NI) trial may be appropriate but is fraught with difficulty in justifying an acceptable NI margin that is based on both clinical and statistical input. To overcome this, we propose to utilize composite risk‐benefit outcomes that combine elements from domains of importance (eg, efficacy, safety, and tolerability). The composite outcome itself may be analyzed using a superiority framework, or it can be used as a tool at the design stage of a NI trial for selecting an NI margin for efficacy that balances changes in risks and benefits. In the latter case, the choice of NI margin may be based on a novel quantity called the maximum allowable decrease in efficacy (MADE), defined as the marginal difference in efficacy between arms that would yield a null treatment effect for the composite outcome given an assumed distribution for the composite outcome. We observe that MADE: (1) is larger when the safety improvement for the experimental arm is larger, (2) depends on the association between the efficacy and safety outcomes, and (3) depends on the control arm efficacy rate. We use a numerical example for power comparisons between a superiority test for the composite outcome vs a noninferiority test for efficacy using the MADE as the NI margin, and apply the methods to a TB treatment trial.     

Wooden foreign body impalement through the right shoulder region – an unusual penetrating injury: A case report

BACKGROUNDImpalement of the body is a rare injury and comes with varied presentation. There is no set classification or defined protocols for managing this injury. This case report aims to create awareness among trauma surgeons about unusual presentation and management of such case. CASE SUMMARYA 45-year-old man presented to the emergency department with a sharp penetrating wooden plank at right clavicular region between the neck and shoulder following a road traffic accident. The vehicle had crashed into a roadside wooden hut, thus causing an impalement injury. He was meticulously worked up and taken to emergency theatre. The wooden plank was removed and the wound healed uneventfully. Postoperatively, he had fairly good shoulder function and was able to return back to work successfully.CONCLUSIONEach impalement injury brings in challenges in management as no two cases are the same. The varied presentation and risks involved should be known to medical professionals handling the emergency. Coordinated multidisciplinary team approach is needed for successful outcome.     

Antioxidant and antigenotoxic properties of Alpinia galanga,Curcuma amada,and Curcuma caesia

Objective: To compare the antioxidant and anti-genotoxic properties of Alpinia (A.) galanga, Curcuma (C.) amada, and C. caesia. Methods: Cytotoxicity of ethanol...     

GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis

Rhabdomyosarcoma (RMS) typically arises from skeletal muscle. Currently, RMS in patients with recurrent and metastatic disease have no successful treatment. The molecular pathogenesis of RMS varies based on cancer sub-types. Some embryonal RMS but not other sub-types are driven by sonic hedgehog (Shh) signaling pathway. However, Shh pathway inhibitors particularly smoothened inhibitors are not highly effective in animals. Here, we show that Shh pathway effectors GLI1 and/or GLI2 are over-expressed in the majority of RMS cells and that GANT-61, a specific GLI1/2 inhibitor dampens the proliferation of both embryonal and alveolar RMS cells-derived xenograft tumors thereby blocking their growth. As compared to vehicle-treated control, about 50% tumor growth inhibition occurs in mice receiving GANT-61 treatment. The proliferation inhibition was associated with slowing of cell cycle progression which was mediated by the reduced expression of cyclins D1/2/3 & E and the concomitant induction of p21. GANT-61 not only reduced expression of GLI1/2 in these RMS but also significantly diminished AKT/mTOR signaling. The therapeutic action of GANT-61 was significantly augmented when combined with chemotherapeutic agents employed for RMS therapy such as temsirolimus or vincristine. Finally, reduced expression of proteins driving epithelial mesenchymal transition (EMT) characterized the residual tumors.     

Multimodality Imaging of Submitral Left Ventricular Aneurysm

Submitral left ventricular aneurysms are a rare nonischemic aneurysm thought to be developmental in origin. These aneurysms invariably occur at the site of posterior mitral annulus and lead to mitral valve incompetence. We hereby describe a case of a 30‐year‐old adult with a rare form of submitral left ventricular aneurysm involving whole of the posterior mitral annulus. Multimodality imaging with two‐dimensional echocardiography, three‐dimensional echocardiography, computed tomography and invasive left ventriculography helped the patient to undergo successful resection of the aneurysm along with mitral valve replacement.