Thymoquinone and Curcumin Defeat Aging-Associated Oxidative Alterations Induced by D-Galactose in Rats' Brain and Heart.

D-galactose (D-gal) administration causes oxidative disorder and is widely utilized in aging animal models. Therefore, we subcutaneously injected D-gal at 200 mg/kg BW dose to assess the potential preventive effect of thymoquinone (TQ) and curcumin (Cur) against the oxidative alterations induced by D-gal. Other than the control, vehicle, and D-gal groups, the TQ and Cur treated groups were orally supplemented at 20 mg/kg BW of each alone or combined. TQ and Cur effectively suppressed the oxidative alterations induced by D-gal in brain and heart tissues. The TQ and Cur combination significantly decreased the elevated necrosis in the brain and heart by D-gal. It significantly reduced brain caspase 3, calbindin, and calcium-binding adapter molecule 1 (IBA1), heart caspase 3, and BCL2. Expression of mRNA of the brain and heart TP53, p21, Bax, and CASP-3 were significantly downregulated in the TQ and Cur combination group along with upregulation of BCL2 in comparison with the D-gal group. Data suggested that the TQ and Cur combination is a promising approach in aging prevention.

Preparation of solid dispersion systems for enhanced dissolution of poorly water soluble diacerein: In-vitro evaluation, optimization and physiologically based pharmacokinetic modeling.

Diacerein (DCN), a BCS II compound, suffers from poor aqueous solubility and limited bioavailability. Solid dispersion systems (SD) of DCN were prepared by solvent evaporation, using hydrophilic polymers. In-vitro dissolution studies were performed and dissolution parameters were evaluated. I-Optimal factorial design was employed to study the effect of formulation variables (drug:polymer ratio and polymer type) on the measured responses including; drug content (DC) (%), dissolution efficiency at 15 min (DE (15 min)%) and 60 min (DE (60 min)%) and mean dissolution time (MDT) (min). The optimized SD was selected, prepared and evaluated, allowing 10.83 and 3.42 fold increase in DE (15 min)%, DE (60 min)%, respectively and 6.07 decrease in MDT, compared to plain drug. DSC, XRD analysis and SEM micrographs confirmed complete amorphization of DCN within the optimized SD. Physiologically based pharmacokinetic (PBPK) modeling was employed to predict PK parameters of DCN in middle aged healthy adults and geriatrics. Simcyp® software established in-vivo plasma concentration time curves of the optimized SD, compared to plain DCN. Relative bioavailability of the optimized SD compared to plain drug was 229.52% and 262.02% in healthy adults and geriatrics, respectively. Our study reports the utility of PBPK modeling for formulation development of BCS II APIs, via predicting their oral bio-performance.

Development of orally disintegrating tablets containing solid dispersion of a poorly soluble drug for enhanced dissolution: In-vitro optimization/in-vivo evaluation.

Diacerein (DCN), a potent anti-inflammatory API used to treat osteoarthritis yet, it suffers from poor water solubility which affects its oral absorption. Unabsorbed colonic DCN is converted into rhein, which is responsible for laxation as a main side effect of DCN treatment. Therefore, in this study orally disintegrating tablets (ODTs) loaded with optimized DCN solid dispersion system were prepared using different co-processed excipients (Prosolv® ODT, Pharmaburst® 500 and F-melt®), aiming to achieve improved solubility, rapid absorption and consequently limited amount of rhein reaching the colon. Prepared ODTs were evaluated for physical characteristics, in-vitro drug release, disintegration and wetting times. Dissolution parameters; dissolution efficiency percent at 10 (DE (10 min)%) and 30 (DE (30 min)%) min and mean dissolution time (MDT) were determined. The optimized ODT showed 1.50 and 1.12 fold increase in DE (10 min)% and DE (30 min)%, respectively and 2 fold decrease in MDT, compared to Diacerein® capsules. In-vivo anti-inflammatory effect of optimized ODT, using rat paw edema revealed significant increase in edema inhibition (p < 0.0465) and promoted onset of action compared to Diacerein® capsules at 0.5 hr. It could be concluded that optimized ODT could be promising for enhanced dissolution and rapid absorption of DCN from the oral cavity.

Mechanisms for hemodynamic instability related to renal replacement therapy: a narrative review.

Hemodynamic instability related to renal replacement therapy (HIRRT) is a frequent complication of all renal replacement therapy (RRT) modalities commonly used in the intensive care unit. HIRRT is associated with increased mortality and may impair kidney recovery. Our current understanding of the physiologic basis for HIRRT comes primarily from studies of end-stage kidney disease patients on maintenance hemodialysis in whom HIRRT is referred to as 'intradialytic hypotension'. Nonetheless, there are many studies that provide additional insights into the underlying mechanisms for HIRRT specifically in critically ill patients. In particular, recent evidence challenges the notion that HIRRT is almost entirely related to excessive ultrafiltration. Although excessive ultrafiltration is a key mechanism, multiple other RRT-related mechanisms may precipitate HIRRT and this could have implications for how HIRRT should be managed (e.g., the appropriate response might not always be to reduce ultrafiltration, particularly in the context of significant fluid overload). This review briefly summarizes the incidence and adverse effects of HIRRT and reviews what is currently known regarding the mechanisms underpinning it. This includes consideration of the evidence that exists for various RRT-related interventions to prevent or limit HIRRT. An enhanced understanding of the mechanisms that underlie HIRRT, beyond just excessive ultrafiltration, may lead to more effective RRT-related interventions to mitigate its occurrence and consequences.

Safety Lapses Prior to Initiation of Hemodialysis for Acute Kidney Injury in Hospitalized Patients: A Patient Safety Initiative.

Background: Safety lapses in hospitalized patients with acute kidney injury (AKI) may lead to hemodialysis (HD) being required before renal recovery might have otherwise occurred. We sought to identify safety lapses that, if prevented, could reduce the need for unnecessary HD after AKI; Methods: We conducted a retrospective observational study that included consecutive patients treated with HD for AKI at a large, tertiary academic center between 1 September 2015 and 31 August 2016. Exposures of interest were pre-specified iatrogenic processes that could contribute to the need for HD after AKI, such as nephrotoxic medication or potassium supplement administration. Other outcomes included time from AKI diagnosis to initial management steps, including Nephrology referral; Results: After screening 344 charts, 80 patients were included for full chart review, and 264 were excluded because they required HD within 72 h of admission, were deemed to have progression to end-stage kidney disease (ESKD), or required other renal replacement therapy (RRT) modalities in critical care settings such as continuous renal replacement therapy (CRRT) or sustained low efficiency dialysis (SLED). Multiple safety lapses were identified. Sixteen patients (20%) received an angiotensin converting enzyme inhibitor or angiotensin receptor blocker after AKI onset. Of 35 patients with an eventual diagnosis of pre-renal AKI due to hypovolemia, only 29 (83%) received a fluid bolus within 24 h. For 28 patients with hyperkalemia as an indication for starting HD, six (21%) had received a medication associated with hyperkalemia and 13 (46%) did not have a low potassium diet ordered. Nephrology consultation occurred after a median (IQR) time after AKI onset of 3.0 (1.0⁻5.7) days; Conclusions: Although the majority of patients had multiple indications for the initiation of HD for AKI, we identified many safety lapses related to the diagnosis and management of patients with AKI. We cannot conclude that HD initiation was avoidable, but, improving safety lapses may delay the need for HD initiation, thereby allowing more time for renal recovery. Thus, development of automated processes not only to identify AKI at an early stage but also to guide appropriate AKI management may improve renal recovery rates.

Activation of 2' 5'-oligoadenylate synthetase by stem loops at the 5'-end of the West Nile virus genome.

West Nile virus (WNV) has a positive sense RNA genome with conserved structural elements in the 5' and 3' -untranslated regions required for polyprotein production. Antiviral immunity to WNV is partially mediated through the production of a cluster of proteins known as the interferon stimulated genes (ISGs). The 2' 5'-oligoadenylate synthetases (OAS) are key ISGs that help to amplify the innate immune response. Upon interaction with viral double stranded RNA, OAS enzymes become activated and enable the host cell to restrict viral propagation. Studies have linked mutations in the OAS1 gene to increased susceptibility to WNV infection, highlighting the importance of OAS1 enzyme. Here we report that the region at the 5'-end of the WNV genome comprising both the 5'-UTR and initial coding region is capable of OAS1 activation in vitro. This region contains three RNA stem loops (SLI, SLII, and SLIII), whose relative contribution to OAS1 binding affinity and activation were investigated using electrophoretic mobility shift assays and enzyme kinetics experiments. Stem loop I, comprising nucleotides 1-73, is dispensable for maximum OAS1 activation, as a construct containing only SLII and SLIII was capable of enzymatic activation. Mutations to the RNA binding site of OAS1 confirmed the specificity of the interaction. The purity, monodispersity and homogeneity of the 5'-end (SLI/II/III) and OAS1 were evaluated using dynamic light scattering and analytical ultra-centrifugation. Solution conformations of both the 5'-end RNA of WNV and OAS1 were then elucidated using small-angle x-ray scattering. In the context of purified components in vitro, these data demonstrate the recognition of conserved secondary structural elements of the WNV genome by a member of the interferon-mediated innate immune response.