The influence of SARS-CoV-2 infection on expression of drug-metabolizing enzymes and transporters in a hACE2 murine model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting Coronavirus disease 2019 emerged in late 2019 and is responsible for significant morbidity and mortality worldwide. A hallmark of severe COVID-19 is exaggerated systemic inflammation, regarded as a "cytokine storm," which contributes to the damage of various organs, primarily the lungs. The inflammation associated with some viral illnesses is known to alter the expression of drug-metabolizing enzymes and transporters. These alterations can lead to modifications in drug exposure and the processing of various endogenous compounds. Here, we provide evidence to support changes in the mitochondrial ribonucleic acid expression of a subset of drug transporters (84 transporters) in the liver, kidneys, and lungs and metabolizing enzymes (84 enzymes) in the liver in a humanized angiotensin-converting enzyme 2 receptor mouse model. Specifically, three drug transporters (Abca3, Slc7a8, Tap1) and the pro-inflammatory cytokine IL-6 were upregulated in the lungs of SARS-CoV-2 infected mice. We also found significant downregulation of drug transporters responsible for the movement of xenobiotics in the liver and kidney. Additionally, expression of cytochrome P-450 2f2 which is known to metabolize some pulmonary toxicants, was significantly decreased in the liver of infected mice. The significance of these findings requires further exploration. Our results suggest that further research should emphasize altered drug disposition when investigating therapeutic compounds, whether re-purposed or new chemical entities, in other animal models and ultimately in individuals infected with SARS-CoV-2. Moreover, the influence and impact of these changes on the processing of endogenous compounds also require further investigation.

Mechanistic Modeling of the Effect of Recombinant Human Hyaluronidase (rHuPH20) on Subcutaneous Delivery of Cetuximab in Rats.

PURPOSE: To evaluate the duration of effect of rHuPH20 on SC absorption of cetuximab and to develop a mechanistic pharmacokinetic model linking the kinetics of rHuPH20 action with hyaluronan (HA) homeostasis and absorption of cetuximab from the SC space. METHODS: Serum pharmacokinetics of cetuximab was evaluated after IV and SC dosing at 0.4 and 10 mg/kg (control groups). In test groups, SC cetuximab was administered simultaneously with rHuPH20 (Co-Injection) or 12 h after injection of rHuPH20 (Pre-Injection). Mechanistic pharmacokinetic model was developed to simultaneously capture cetuximab kinetics in all groups. RESULTS: Administration of rHuPH20 resulted in a faster absorption of cetuximab; the difference between co-injection and pre-injection groups appeared to be dependent on the dose level. The model combined three major components: kinetics of rHuPH20 at SC site; HA homeostasis and its disruption by rHuPH20; and cetuximab systemic disposition and the effect of HA disruption on cetuximab SC absorption. The model provided good description of experimental data obtained in this study and collected previously. CONCLUSIONS: Proposed model can serve as a potential translational framework for capturing the effect of rHuPH20 across multiple preclinical species and in human studies and can be used for optimization of SC delivery of biotherapeutics.

Renoprotective Effects of Melatonin against Vancomycin-Related Acute Kidney Injury in Hospitalized Patients: a Retrospective Cohort Study.

Vancomycin is associated with nephrotoxicity, and the mechanism may in part be related to oxidative stress. In vitro and preclinical studies suggest that melatonin supplementation decreases oxidative stress. The objective of this study was to evaluate concomitant use of melatonin and vancomycin and the incidence of acute kidney injury (AKI). We performed a retrospective cohort study at a large community medical center. All consecutive patients admitted to the medical center between January 2016 and September 2020 who received vancomycin therapy alone or concomitantly with melatonin as part of ordinary care were considered for inclusion. The primary endpoint was the development of AKI, defined as an absolute increase in serum creatinine of ≥0.3 mg/dl or a ≥50% increase in serum creatinine. All data were analyzed using descriptive statistics. A multivariable logistic regression was constructed to account for potential confounding variables. We identified a total of 303 adult patients meeting inclusion and exclusion criteria treated with vancomycin, 101 of which received melatonin concomitantly. Overall baseline characteristics were similar between the two groups except for the incidence of bacteremia/sepsis. After controlling for the vancomycin area under the curve, baseline creatinine clearance, and intensive care unit admission in a multivariable logistic regression analysis, melatonin use was associated with a 63% decrease in AKI (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.14 to 0.96; P = 0.041). Melatonin use was associated with a significant reduction in vancomycin-related AKI. Although this was a retrospective study with a small sample size, given the magnitude of the difference seen, further large prospective studies are warranted.

Simultaneous quantification of ondansetron and tariquidar in rat and human plasma using a high performance liquid chromatography-ultraviolet method.

Ondansetron, a widely used antiemetic agent, is a P-glycoprotein (P-gp) substrate and therefore expression of P-gp at the blood-brain barrier limits its distribution to the central nervous system (CNS), which was observed to be reversed by coadministration with P-gp inhibitors. Tariquidar is a potent and selective third-generation P-gp inhibitor, and coadministration with ondansetron has shown improved ondansetron distribution to the CNS. There is currently no reported bioanalytical method for simultaneously quantifying ondansetron with a third-generation P-gp inhibitor. Therefore, we aimed to develop and validate a method for ondansetron and tariquidar in rat and human plasma samples. A full validation was performed for both ondansetron and tariquidar, and sample stability was tested under various storage conditions. To demonstrate its utility, the method was applied to a preclinical pharmacokinetic study following coadministration of ondansetron and tariquidar in rats. The presented method will be valuable in pharmacokinetic studies of ondansetron and tariquidar in which simultaneous determination may be required. In addition, this is the first report of a bioanalytical method validated for quantification of tariquidar in plasma samples.

Prevention of paclitaxel-induced neuropathy by formulation approach.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse effect of paclitaxel. Several liposome-based products have been approved and demonstrated superior efficacy and safety profiles for other drugs. The first objective of this work was to evaluate the effect of liposome formulation of paclitaxel (L-PTX) on neurotoxicity in-vitro and in-vivo in comparison to the standard Taxol® formulation. The second aim was to investigate the effect of formulation on paclitaxel biodistribution following intravenous administration in an animal model. Free paclitaxel was toxic to cell of neuronal origin (IC50 = 18.4 µg/mL) at a lower concentration than to lung cancer cells (IC50 = 59.1 µg/mL), and L-PTX demonstrated a comparable toxicity in both cell lines (IC50 = 31.8 and 33.7 µg/mL). Administration of L-PTX at 2 mg/kg per dose for a total of 4 doses on day 0, 2, 4, and 6 to rats did not result in increased sensitivity in response to mechanical or thermal stimulation of hind paws, in comparison to Taxol® administration at the same dose level that resulted in neuropathy. Paclitaxel biodisposition was evaluated for two formulations in plasma, liver, lung, brain, spinal cord, skin and muscle of rats after single intravenous dose at 6 mg/kg. The exposure to paclitaxel in brain, spinal cord, muscle, and skin was lower in the L-PTX group compared to Taxol® group. PEGylated liposomes containing paclitaxel were successfully developed and demonstrated reduced neurotoxicity in-vitro in neuronal cells and prevented development of peripheral neuropathy in-vivo. This proof of concept study showed that formulation in nanoparticles is a promising approach for reducing (or preventing) neurotoxicity caused by cancer drugs.

Anticoagulant activity of enoxaparin and unfractionated heparin for venous thromboembolism prophylaxis in obese patients undergoing sleeve gastrectomy.

BACKGROUND: One risk of bariatric surgery is venous thromboembolism and the optimal strategy to reduce risk requires further clarification. OBJECTIVES: The objectives of this study were to identify antiXa goal attainment with the institutional standard chemoprophylaxis, analyze discordance between antiXa and thrombin generation assay (TGA) in terms of adequacy of anticoagulation, and to identify correlations between patient characteristics or covariates and markers of coagulation status. SETTING: Large academic medical center in Northeastern United States. METHODS: A total of 60 sleeve gastrectomy patients were enrolled in this institutional review board-approved, prospective cohort study. Patients received the institutional standard prophylactic therapy (subcutaneous enoxaparin 40 mg twice daily or unfractionated heparin [UFH]). The UFH dose was weight based, 5000 units (<120 kg) or 7500 units (≥120 kg) every 8 hours. Various measures of coagulation status were measured at or near steady state. RESULTS: Patients receiving enoxaparin achieved goal antiXa more frequently compared with the UFH group, and statistical significance was demonstrated (93.8 % versus 4.5%, respectively; P < .0001). Target endogenous thrombin potential reduction from baseline was more frequently obtained in the enoxaparin group versus UFH (50% versus 27.7%, respectively; P = .12). AntiXa was below the limit of detection for the majority of UFH patients; while TGA suggested patients did experience anticoagulation at some level of effectiveness. Endogenous thrombin potential change in the enoxaparin group was correlated to several measures of body composition. CONCLUSIONS: Patients receiving enoxaparin achieved goal antiXa more often versus UFH. There was discordance between antiXa and TGA-based assessment of coagulation status. TGA may provide a more robust assessment of the adequacy of chemoprophylaxis.

Perception of Aesthetics by Different Professionals of Different Communities.

AIM: To evaluate the perception of aesthetics by different professionals of different communities in India by a photographic study. MATERIALS AND METHODS: This was a photographic study conducted among different professionals of different communities to establish an aesthetic norm for Indian population. The communities to which the professionals belonged were North Indian, South Indian, Maharashtrian, Gujarati and Parsi. The subjects photographed were aesthetic profiles with good occlusion. Five different facial photographic views each for male and female were obtained. These photographs were then subjected to changes in increments of 2 mm and 4 mm in retrusive and protrusive profile in Adobe Photoshop CS5 after which they were evaluated by different professionals of different communities according to their preference from most liked to least liked. RESULTS: The aesthetic preferences differed widely among different professionals of different community. CONCLUSION: The established aesthetic norms can be utilized by the dental fraternity in general and Orthodontist's in particular in diagnosis and treatment planning of Samples belonging to different communities to have the treatment outcome in unison with the established soft tissue norm for that particular community.

Characterisation of the n-colour printing process using the spot colour overprint model.

This paper is aimed at reproducing the solid spot colours using the n-colour separation. A simplified numerical method, called as the spot colour overprint (SCOP) model, was used for characterising the n-colour printing process. This model was originally developed for estimating the spot colour overprints. It was extended to be used as a generic forward characterisation model for the n-colour printing process. The inverse printer model based on the look-up table was implemented to obtain the colour separation for n-colour printing process. Finally the real-world spot colours were reproduced using 7-colour separation on lithographic offset printing process. The colours printed with 7 inks were compared against the original spot colours to evaluate the accuracy. The results show good accuracy with the mean CIEDE2000 value between the target colours and the printed colours of 2.06. The proposed method can be used successfully to reproduce the spot colours, which can potentially save significant time and cost in the printing and packaging industry.

Efficacy of planas direct tracks for early treatment of skeletal Class II malocclusion--a clinical and cephalometric study.

OBJECTIVE: To evaluate the efficacy of Planas Direct Tracks in the treatment of skeletal Class II malocclusion due to retrognathic mandible in the intermediate mixed dentition stage clinically and cephalometrically. MATERIALS AND METHOD: A six month cross sectional comparative study consisted of 40 subjects (21 males and 19 females) with a mean age of 9.8 + 1.3 years. The total sample was classified into control group (20 patients which were not subjected to treatment with Planas Direct Tracks (PDT) which were observed over a period of six months) and experimental group (20 patients subjected to treatment with Planas Direct Tracks and were observed over a period of six months). Records were taken before treatment and at the end of six months for comparative analysis. RESULT: The experimental group showed a a significant increase in mandibular length, and a significant improvement in maxillo-mandibular sagittal skeletal relationships. They exhibited a significant reduction in overjet and an improvement in molar relationship. CONCLUSIONS: The PDT protocol is effective in early treatment of skeletal Class II malocclusion.