Pharmacogenetics of Drug Metabolism: The Role of Gene Polymorphism in the Regulation of Doxorubicin Safety and Efficacy.

Breast cancer (BC) is the prevailing malignancy and major cause of cancer-related death in females. Doxorubicin is a part of BC neoadjuvant and adjuvant chemotherapy regimens. The administration of anthracycline derivates, such as doxorubicin, may cause several side effects, including hematological disfunction, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, and cardiotoxicity. Cardiotoxicity is a major adverse reaction to anthracyclines, and it may vary depending on individual differences in doxorubicin pharmacokinetics. Determination of specific polymorphisms of genes that can alter doxorubicin metabolism was shown to reduce the risk of adverse reactions and improve the safety and efficacy of doxorubicin. Genes which encode cytochrome P450 enzymes (CYP3A4 and CYP2D6), p-glycoproteins (ATP-binding cassette (ABC) family members such as Multi-Drug Resistance 1 (MDR1) protein), and other detoxifying enzymes were shown to control the metabolism and pharmacokinetics of doxorubicin. The effectiveness of doxorubicin is defined by the polymorphism of cytochrome p450 and p-glycoprotein-encoding genes. This study critically discusses the latest data about the role of gene polymorphisms in the regulation of doxorubicin's anti-BC effects. The correlation of genetic differences with the efficacy and safety of doxorubicin may provide insights for the development of personalized medical treatment for BC patients.

Prognostic value of proadrenomedullin in patients with COVID-19 pneumonia.

Objective: The aim of the study was to assess the role of mid-regional proadrenomedullin (MR-proADM) in comparison with routine laboratory tests in patients with COVID-19. Materials and methods: 140 hospitalized patients aged 18 and older with COVID-19 pneumonia were included in prospective single-center study. Routine analyses were performed, and MR-proADM level was measured within the first and the third hospital days using Human MR pro-ADM (Mid-regional pro-adrenomedullin) ELISA Kit with a sensitivity of 0.469 pmol/L (immunofluorescence assay). National Early Warning Score (NEWS) was used for primary assessment of the disease severity. According to disease outcome the patients were divided into two groups: discharged patients (n = 110, 78.6%) and deceased patients (n = 30, 21.4%). Results: The groups had no statistically significant difference in sex, comorbidity, body temperature, oxygen saturation level, heart rate, respiratory rate, and C-reactive protein (CRP) level and procalcitonin (PCT). The deceased patients had statistically significant difference in age (median, 76 years; interquartile range, 73.2-78.2 vs. median, 66 years; interquartile range, 62-67; p < 0.0001), NEWS value (median, 5; interquartile range, 3-8 vs. median, 2; interquartile range, 0-6; p <0.05), hospitalization period (median, 17; interquartile range, 7-35 vs. median, 6; interquartile range, 3-14), quantitative CT extent of lung damage > 50% [n = 26 (86.7%) vs. n = 9 (8.2%) p < 0.0001], level of leukocytes (median, 11.4 ×109/L; interquartile range, 6.2-15.5 vs. median, 5.3 ×109/L; interquartile range, 4.7-6.4; p = 0.003), level of neutrophils (median, 80.9%; interquartile range, 73.6-88.6 vs. median, 72.6%; interquartile range, 68.7-76.9; p = 0.027), level of MR-proADM at the first hospital day (median, 828.6 pmol/L; interquartile range, 586.4-1,184.6 vs. median, 492.6 pmol/L; interquartile range, 352.9-712.2; p = 0.02), and level of MR-proADM at the third hospital day (median, 1,855.2 pmol/L; interquartile range, 1,078.4-2,596.5 vs. median, 270.7 pmol/L; interquartile range, 155.06-427.1). Conclusion: Mid-regional proadrenomedullin has a higher prognostic value in patients with COVID-19 in comparison with routine inflammatory markers (leukocyte and neutrophils levels, CRP, and PCT) and NEWS.

Potential factors of Helicobacter pylori resistance to clarithromycin.

OBJECTIVES: A comparative dissolution kinetics test (CDKT) and bioequivalence studies of generic proton pump inhibitors (PPIs) do not model pharmacological acid suppression (PAS) and pathological duodenogastric reflux (PDGR). This study aimed to model them in CDKT to assess drugs stability and potential pantoprazole-clarithromycin interactions. METHODS: In CDKT, PDGR (dissolution medium pH 7.00 ± 0.05, preexposure at pH 1.20 ± 0.05) and PAS (pH 4.00 ± 0.05) were modelled for original pantoprazole (OP) and its generics (GP1-4). In CDKT with high-performance liquid chromatography, dissolution gastric medium in adequate (pH 4.00 ± 0.05) and inadequate (pH 1.20 ± 0.05) PAS were modelled for original clarithromycin (OC) and its generics (GC1-4). RESULTS: After exposure in pH 7.00 ± 0.05, pantoprazole was released from GP1 within 10 min in the amount of 68.8%. In рН 4.00 ± 0.05, 83.0% and 81.5% of pantoprazole were released from GP1 and GP4. When OP, GP2 and GP3 were placed in pH 7.00 ± 0.05, pantoprazole was released in amount: 99.4%, 88.0% and 98.2%. Clarithromycin releasing from OC, GC1, GC2, GC3, GC4 in pH 4.00 ± 0.05 was 93.5%, 91.6%, 92.9%, 79.4% and 83.0%. In pH 1.20 ± 0.05: 9.7%, 6.7%, 8.5%, 33.3%, 28.8%. CONCLUSIONS: Destruction of enteric coats of some local pantoprazole generics in CDKT-models might be a potential factor for inadequate therapy.

Cerium-Containing N-Acetyl-6-Aminohexanoic Acid Formulation Accelerates Wound Reparation in Diabetic Animals.

BACKGROUND: The main goal of our study was to explore the wound-healing property of a novel cerium-containing N-acethyl-6-aminohexanoate acid compound and determine key molecular targets of the compound mode of action in diabetic animals. METHODS: Cerium N-acetyl-6-aminohexanoate (laboratory name LHT-8-17) as a 10 mg/mL aquatic spray was used as wound experimental topical therapy. LHT-8-17 toxicity was assessed in human skin epidermal cell culture using (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A linear wound was reproduced in 18 outbred white rats with streptozotocin-induced (60 mg/kg i.p.) diabetes; planar cutaneous defect was modelled in 60 C57Bl6 mice with streptozotocin-induced (200 mg/kg i.p.) diabetes and 90 diabetic db/db mice. Firmness of the forming scar was assessed mechanically. Skin defect covering was histologically evaluated on days 5, 10, 15, and 20. Tissue TNF-α, IL-1ß and IL-10 levels were determined by quantitative ELISA. Oxidative stress activity was detected by Fe-induced chemiluminescence. Ki-67 expression and CD34 cell positivity were assessed using immunohistochemistry. FGFR3 gene expression was detected by real-time PCR. LHT-8-17 anti-microbial potency was assessed in wound tissues contaminated by MRSA. RESULTS: LHT-8-17 4 mg twice daily accelerated linear and planar wound healing in animals with type 1 and type 2 diabetes. The formulated topical application depressed tissue TNF-α, IL-1ß, and oxidative reaction activity along with sustaining both the IL-10 concentration and antioxidant capacity. LHT-8-17 induced Ki-67 positivity of fibroblasts and pro-keratinocytes, upregulated FGFR3 gene expression, and increased tissue vascularization. The formulation possessed anti-microbial properties. CONCLUSIONS: The obtained results allow us to consider the formulation as a promising pharmacological agent for diabetic wound topical treatment.

The deactivation of acidic sites of NiMo/B2 O3 -Al2 O3 catalysts during vegetable oil hydrodeoxygenation studied by EPR spectroscopy.

This paper presents the study results of NiMo/B2 O3 -Al2 O3 (0-30% wt. of B2 O3 ) catalysts for vegetable oil hydrodeoxygenation before and after catalytic tests by different electron paramagnetic resonance (EPR) methodologies. For the initial catalysts, the concentration of Brønsted acidic sites (BAS) determined by probe EPR with perylene increases linearly with an increase in the modifier (B2 O3 ) content in the samples. It was found that the isomerization activity of the catalysts increases with increasing the concentration of determined BAS. As for the spent catalysts, linear correlation of paramagnetic species concentration with the content of carbon deposits (determined by thermogravimetric analysis [TGA]/differential thermal analysis [DTA]) was found. The main reasons for the NiMo/B2 O3 -Al2 O3 catalysts deactivation over the formation of carbon deposits related to the participation of acidic sites (both Lewis and Brønsted) in the polycondensation of hydrocarbons via radical species are also proposed.

Diseño de sistema para controlar una silla de ruedas mediante señales eléctricas cerebrales / System Design to control a wheelchair using brain electric signals

RESUMEN Fundamento: Las personas con lesiones de la médula espinal pueden presentar parálisis muscular e imposibilidad para realizar movimientos de diferentes partes del cuerpo, en dependencia del nivel de la lesión. En la actualidad, es posible utilizar las corrientes eléctricas generadas en la superficie del cráneo, producto de la actividad cerebral, para mover una silla de ruedas eléctrica, de manera que disminuye la dependencia de esos pacientes. Objetivo: describir el diseño de un sistema para controlar una silla de ruedas, mediante señales eléctricas cerebrales de un paciente con paraplejía. Métodos: estudio de innovación tecnológica, realizado en la Universidad Tecnológica Equinoccial del Ecuador. La aplicación software para detectar las ondas cerebrales se desarrolló en la plataforma LabVIEW, mediante bibliotecas de vínculos dinámicos (edk.dll) de Emotiv y librerías de Arduino. Las señales de electroencefalografía generadas por el usuario (emoción, participación/aburrimiento, frustración y meditación) fueron observadas y medidas usando un waveform. La prueba del sistema se realizó con un paciente de 40 años de edad, con paraplejía espástica causada por una fractura en la columna vertebral. Resultados: se obtuvo un índice de efectividad mayor del 85 %. El índice de carga de trabajo obtenido fue de un 60,33 %, con índices de cargas individuales relevantes: demanda mental con 22,67 % y rendimiento con un 30 %. Conclusión: el desempeño del sistema descrito resultó adecuado para la movilidad del prototipo de silla de ruedas.

ABSTRACT Foundation: People with spinal cord injuries may have muscular paralysis and inability to perform movements of different parts of the body, depending on the injury level. At present, it is possible to use the electric currents generated on the skull surface, resulting from brain activity, to move an electric wheelchair, so that their dependence decreases. Objective: to describe a system for controlling a wheelchair, by means of the brain electric signals of a paraplegic patient. Methods: study of technological innovation, conducted at the Equinoctial Technological University of Ecuador. The software application to detect brain waves was developed on the LabVIEW platform, using Dynamic Link Libraries (edk.dll) from Emotiv and Arduino libraries. The electroencephalography signals generated by the user (emotion, participation / boredom, frustration and meditation) were observed and measured using a waveform. The system test was performed with a 40-year-old patient with spastic paraplegia caused by a fracture in the spine. Results: an effectiveness index greater than 85 % was obtained. The workload index obtained was 60.33 %, with relevant individual load indices: mental demand with 22.67 % and yield with 30 %. Conclusion: the described system performance was adequate for the wheelchair prototype mobility.

Thermal evolution of Mg-Al and Ni-Al layered double hydroxides: the structure of the dehydrated phase.

Simulation of X-ray diffraction patterns on the basis of the models of one-dimensional disordered crystals was used to investigate the structure of the dehydrated phase produced by dehydration of Mg-Al and Ni-Al layered double hydroxides at a temperature of ∼473-498 K. It was found that the removal of water molecules transforms the initial structure, which is a mixture of 3R1 and 2H1 polytypes, into a structure that comprises preferentially fragments of 3R2 and 1H polytypes and has some turbostratic disorder.

Influence of a specific ginger combination on gastropathy conditions in patients with osteoarthritis of the knee or hip.

BACKGROUND: Nonsteroid anti-inflammatory drugs represent an important osteoarthritis (OA) therapy component, but also a leading cause of gastropathy: one of the most frequent and serious OA therapy complications. The aim of the present study was to study the influence of GI health in an OA population receiving either ginger or diclofenac. METHODS: Forty-three (43) patients with confirmed OA (knee and hip) were included in a randomized controlled study. A ginger group of 21 patients (17 women, 4 men) was given a specific ginger combination daily (340 mg EV.EXT 35 Zingiber officinalis extract) for 4 weeks. A diclofenac group (positive control) of 22 patients (18 women, 4 men) received 100 mg diclofenac daily for the same period. Both groups also received 1000 mg glucosamine daily. Gastrointestinal pain and dyspepsia were evaluated according to the severity of dyspepsia assessment (SODA) form. Patients also underwent esophagogastroduodenoscopy (EGDS) including biopsy before and after the treatment. Serum gastrin-17 levels, and stomach mucosa prostaglandins (PG) E1, E2, F2α, and 6-keto PGF1α (PGI2) levels were measured. Arthritic pain was evaluated using the visual analogue scale (VAS) on standing and moving. RESULTS: The ginger group showed a slight but significantly lowered SODA pain and no change of SODA dyspepsia. EGDS showed significantly increased levels of PGE1, PGE2, and PGF2α in the stomach mucosa. This rise in gastric mucosa PG levels correlated with an increase in serum gastrin-17. On the other hand, the diclofenac group showed increased SODA pain and dyspepsia values with a corresponding significant decrease of stomach mucosa prostaglandins and general negative stomach mucosa degeneration. Both groups showed a relevant and significantly lowered VAS pain both on standing and moving. CONCLUSIONS: The ginger combination is as effective as diclofenac but safer in treating OA, being without effect on the stomach mucosa. The increased mucosal PGs synthesis in the ginger group supports an increased mucosa-protective potential. VAS; visual analogue scale, 0-100 mm.