A validated micellar LC method for simultaneous determination of furosemide, metoprolol and verapamil in human plasma

An accurate and precise micellar LC method coupled with UV and fluorimetric detectors was developed and validated for the simultaneous analysis of furosemide, metoprolol and verapamil in human plasma. The total analysis time was 25 min (12 min for sample preparation and 13 min for drug separation). All drugs possessed linear behavior (r > 0.999 for calibration curves) in their therapeutic concentrations. The mean drug recoveries were 101.9, 100.1 and 100.2% for furosemide, metoprolol and verapamil, respectively. The accuracies (relative error %) were less than 15% for all drugs. Intra- and inter-day precisions (RSD%) were less than 15% and the stability data were acceptable according to the US FDA guideline for bioanalytical method validation.     

Evaluation serum levels of Insulin Growth Factor-1 (IGF-1) and its association with clinical parameters in severe COVID-19

Inflammopharmacology - Severe coronavirus disease-2019 (COVID-19) is associated with dysregulated immune response and extreme inflammatory injury. Considering the role of insulin growth factor-1...     

Improved MR-based characterization of engineered cartilage using multiexponential T2 relaxation and multivariate analysis

Noninvasive monitoring of tissue quality would be of substantial use in the development of cartilage tissue engineering strategies. Conventional MR parameters provide noninvasive measures of biophysical tissue properties and are sensitive to changes in matrix development, but do not clearly distinguish between groups with different levels of matrix development. Furthermore, MR outcomes are nonspecific, with particular changes in matrix components resulting in changes in multiple MR parameters. To address these limitations, we present two new approaches for the evaluation of tissue engineered constructs using MR, and apply them to immature and mature engineered cartilage after 1 and 5 weeks of development, respectively. First, we applied multiexponential T(2) analysis for the quantification of matrix macromolecule-associated water compartments. Second, we applied multivariate support vector machine analysis using multiple MR parameters to improve detection of degree of matrix development. Monoexponential T(2) values decreased with maturation, but without further specificity. Much more specific information was provided by multiexponential analysis. The T(2) distribution in both immature and mature constructs was qualitatively comparable to that of native cartilage. The analysis showed that proteoglycan-bound water increased significantly during maturation, from a fraction of 0.05 ± 0.01 to 0.07 ± 0.01. Classification of samples based on individual MR parameters, T(1), T(2), k(m) or apparent diffusion coefficient, showed that the best classifiers were T(1) and k(m), with classification accuracies of 85% and 84%, respectively. Support vector machine analysis improved the accuracy to 98% using the combination (k(m), apparent diffusion coefficient). These approaches were validated using biochemical and Fourier transform infrared imaging spectroscopic analyses, which showed increased proteoglycan and collagen with maturation. In summary, multiexponential T(2) and multivariate support vector machine analyses provide improved sensitivity to changes in matrix development and specificity to matrix composition in tissue engineered cartilage. These approaches show substantial potential for the evaluation of engineered cartilage tissue and for extension to other tissue engineering constructs.     

Evaluation of Myocardial Function by Pulsed Tissue Doppler in Kawasaki Disease

Myocarditis is a well-recognized component of Kawasaki disease, with left ventricular dysfunction occurring in more than half of patients during the acute phase. The purpose of this study was to evaluate myocardial function in patients with Kawasaki disease using pulsed tissue Doppler imaging (TDI). Twenty-five patients with the diagnosis of acute Kawasaki disease were enrolled in the study. All patients underwent echocardiographic studies at the time of diagnosis of the disease, in its acute phase, prior to treatment, and then 4 weeks later. For an aged-matched control group with fever and no cardiac disease, the same echocardiographic evaluations were performed. Peak velocities of systolic (Sa), early diastolic (Ea), and late diastolic (Aa) motion of the annulus were obtained at the lateral and septal sides in apical four-chamber view, and TDI-derived myocardial performance index (TDI-MPI) was also calculated. Peak Ea velocity of lateral mitral annulus was decreased significantly during the acute phase of illness (14 ± 4.40 vs. 17.67 ± 4.41; P = 0.028). In seven patients with carditis, changes in Ea-to-Aa ratio of septum (1.28 ± 0.278 vs. 1.78 ± 0.49; P = 0.018) and lateral mitral annulus (1.23 ± 0.496 vs. 2.11 ± 0.822; P = 0.014) were statistically significant but TDI-MPI showed no statistically significant changes. This study showed that peak mitral annular Ea velocities obtained by TDI were significantly altered in the acute phase of Kawasaki disease. TDI- MPI does not add an incremental benefit to other indexes of myocardial performance for comprehensive myocardial function in the acute phase of Kawasaki disease.     

Effects of metformin on autoimmune immunoglobins and interferon-γ in patients with early diagnosed pemphigus vulgaris: a prospective clinical trial

The management of pemphigus vulgaris (PV) is challenging. This study aimed to evaluate the immunomodulating effects of metformin on PV. The study was conducted in two phases: in the first phase, patients received routine first-line treatment (prednisolone plus azathioprine) for 2 months, then in the second phase, metformin was added to this regimen for another 2 months. After addition of metformin to the first-line medications, significant reductions were seen in serum IgG1 (reduced from 534.92 ± 134.83 mg/dL to 481.58 ± 130.46 mg/dL, P < 0.001), IgG4 (51.83 ± 27.26 mg/dL to 44.50 ± 26.05 mg/dL, P < 0.001) and interferon-γ (277.99 ± 108.71 pg/mL to 45.05 ± 17.080 pg/mL, P = 0.03) concentrations. The suppressant effect of metformin was greatest on IgG4 (coefficient of variation 1.28), the dominant subclass of IgG involved in PV. Metformin could have immunomodulating effects on PV with controlling effects on steroid complications.     

An overview of aldehyde oxidase: an enzyme of emerging importance in novel drug discovery

Introduction: Given the rising trend in medicinal chemistry strategy to reduce cytochrome P450-dependent metabolism, aldehyde oxidase (AOX) has recently gained increased attention in drug discovery programs and the number of drug candidates that are metabolized by AOX is steadily growing.

Areas covered: Despite the emerging importance of AOX in drug discovery, there are certain major recognized problems associated with AOX-mediated metabolism of drugs. Intra- and inter-species variations in AOX activity, the lack of reliable and predictive animal models using the common experimental animals, and failure in the predictions of in vivo metabolic activity of AOX using traditional in vitro methods are among these issues that are covered in this article. A comprehensive review of computational human AOX (hAOX) related studies are also provided.

Expert opinion: Following the recent progress in the stem cell field, the authors recommend the application of organoids technology as an effective tool to solve the fundamental problems associated with the evaluation of AOX in drug discovery. The recent success in resolving the hAOX crystal structure can too be another valuable data source for the study of AOX-catalyzed metabolism of new drug candidates, using computer-aided drug discovery methods.     

The antitumor efficiency of combined electrochemotherapy and single dose irradiation on a breast cancer tumor model

Background

The aim of this study was to investigate the antitumor effectiveness of electrochemotherapy with cisplatin combined with suboptimal radiotherapy doses. Tumor radiosensitization was evaluated on large invasive ductal carcinoma tumors in Balb/C mice.

Materials and methods

Tumors of an average volume of 630 mm³ were treated with cisplatin, electric pulses, radiotherapy, electrochemotherapy, alone as well as in appropriate combinations. Tumors were irradiated with Cobalt-60 γ-rays at doses 3 Gy and 5 Gy in combination with electrochemotherapy using cisplatin. Controls included each of the treatments alone as well as the combination of the radiotherapy with electric pulses alone or with cisplatin alone. Antitumor effectiveness was evaluated by tumor growth delay, tumor-doubling time, inhibition ratio and the objective response rates.

Results

As anticipated, electrochemotherapy was more effective than the treatment with cisplatin alone or the application of the electric pulses alone. When treatments were combined with tumor irradiation at either 3 or 5 Gy, the combination with electrochemotherapy was more effective: at 5 Gy, 2 animals out of 8 were in complete remission 100 days later. In general the higher 5 Gy dose of γ-radiation was more effective than the lower one of 3 Gy.

Conclusions

The results of our study demonstrate that irradiation doses, 3 Gy or 5 Gy, increase the antitumor effectiveness of electrochemotherapy with cisplatin on invasive ductal carcinoma tumors. Good antitumor results were achieved in experimental tumors with a size comparable to clinical lesions, demonstrating that this three-modality combined treatment is useful for the treatment of large lesions even at sub-optimal radiotherapy doses.