Administration Of Phosphate Research Articles

COLONOSCOPY-RELATED NEPHROPATHY

Colonoscopy is a widely used tool for the diagnosis and treatment of colon disease [1]. It is the gold standart to visualize the large bowel [2]. Acute phosphate nephropathy (APhN) is a clinical entity which causes acute and subsequent chronic renal failure after exposure to oral sodium phosphate (OSP) bowel purgatives. APhN is seen as a result of oral sodium phosphate use in patients undergoing bowel cleansing before colonoscopy [3]. Generally, patients who will undergo colonoscopy are given 45 ml of OSP twice, starting 12-24 hours before the procedure. After intestinal absorption, elevated urea and creatinine, transient hyperphosphatemia, hypocalcemia, hypernatremia, hyponatremia, hypokalemia and high anion gap metabolic acidosis may also be observed [4]. Advanced age, ACEi/ARB use, acute or chronic kidney disese or the presence of a kidney transplant, retention of OSP resulting from poor bowel motility or colitis, female gender, volume depletion, hypertension, diabetes, and diuretic, lithium, or nonsteroidal anti-inflammatory drug use are considered as risk factors [5]. This case report describes a patient who developed nephropathy and required urgent observation and treatment after phosphate administration before colonoscopy.

Cutting-Edge Approach to Targeted Therapy: Repositioning of Old Drugs in Combination with Standard Clinical Chemotherapeutics Potentiates a Propitious Novel Targeted Therapy for Human Pancreatic Cancer

Metastatic pancreatic cancer leads to a fatal outcome, with a median progression-free survival of approximately six months when utilizing the most successful combination of chemotherapeutic regimens. When drug resistance develops, it facilitates an increase in primary tumor growth and new and growing metastases. Patients inevitably and quickly succumb to their disease and die. Notably, chemotherapy has an unintended impact on the development of drug resistance through the enhancement of EMT development and the enrichment of cancer stem cells (CSC). Recent report discovered that neuraminidase-1 (Neu-1) regulates EMT induction, angiogenesis, and cellular proliferation by the activation of several receptor tyrosine kinases. Here, the continual therapeutic inhibition of Neu-1 through intravenous administration of oseltamivir phosphate (OP) and aspirin (ASA) alongside GEM treatment significantly inhibits tumor progression, crucial compensatory signaling pathways, EMT program, CSC, and metastasis progression in a preclinical RAG2xCy double mutant BALB/c mouse model of human PANC-1 pancreatic cancer. The tumorigenic and metastatic potential of the xenotumors from the animals treated with the experimental protocols were significantly ablated when transferred into the mammary fat pads of NSG (NOD SCID gamma) branded mice. Keywords: pancreatic cancer; chemoresistance; drug repurposing; EMT.

The Impact of Prescription Time Limits on Phosphate Administration in the Intensive Care Unit: A Before-After Quality Improvement Study.

(1) Background: We aim to examine and improve phosphate prescribing as part of a quality assurance program by examining the change in the proportion of patients receiving phosphate with normal or high preceding serum phosphate concentrations before and after the introduction of the 24 h time limit to default phosphate prescription. (2) Methods: This was a quality assurance study conducted across three Australian adult intensive care units (ICUs). All adult patients with ICU lengths of stay greater than or equal to 48 h who had their serum phosphate concentrations measured were included. A 24 h time limit was introduced to the protocolised prescription in the electronic clinical information system for enteral and intravenous phosphate at participating ICUs. Patient characteristics, phosphate administration, and outcomes were compared before and after this time limit was introduced. The primary outcome was the proportion of patients to whom phosphate was prescribed after measurement of a normal or high serum phosphate level. Secondary outcomes were ICU length of stay, mortality, and discharge destination. (3) Results: A total of 1192 patients were included from three ICUs over the two periods. The proportion of patients with a normal or high measured phosphate level who then received phosphate supplementation was significantly lower in the second study period (30.3% vs. 9.9%; p < 0.001). This difference persisted when adjusted for potential confounders in a mixed-effects logistic regression model (an adjusted odds ratio for receiving phosphate with normal or high serum concentration 0.214, 95% confidence interval of 0.132-0.347; p < 0.001). No significant difference was seen in the typical ICU length of stay, in-hospital case-fatality rate, and hospital discharge destination between these groups. (4) Conclusions: This multicentre before-after study has demonstrated that the introduction of a 24 h limit on electronic phosphate prescriptions resulted in significantly fewer patients receiving phosphate when their serum phosphate concentration was normal or high, without any adverse impact on patient outcomes.

Evaluation of a Novel Enteral Phosphorus Therapy with Enteral Nutrition during a National Intravenous Sodium Phosphate Shortage.

The purpose of this study was to evaluate the efficacy and safety of intragastric administration of small volumes of sodium enema solution containing phosphorus as phosphorus replacement therapy in critically ill patients with traumatic injuries who required continuous enteral nutrition. Adult patients (>17 years of age) who had a serum phosphorus concentration <3 mg/dL (0.97 mmol/L) were evaluated. Patients with a serum creatinine concentration >1.4 mg/dL (124 µmol/L) were excluded. Patients were given 20 mL of saline enema solution intragastrically, containing 34 mmol of phosphorus and mixed in 240 mL water. A total of 55% and 73% of patients who received one (n = 22) or two doses (n = 11) had an improvement in the serum phosphorus concentration, respectively. The serum phosphorus concentration increased from 2.5 [2.1, 2.8] mg/dL (0.81 [0.69, 0.90] mmol/L) to 2.9 [2.2, 3.0] mg/dL (0.94 [0.71, 0.97 mmol/L) for those who received two doses (p = 0.222). Excluding two patients with a marked decline in serum phosphorus by 1.3 mg/dL (0.32 mmol/L) resulted in an increase in the serum phosphorus concentration from 2.3 [2.0, 2.8] mg/dL (0.74 [0.65, 0.90] mmol/L) to 2.9 [2.5, 3.2] mg/dL (0.94 [0.81, 1.03] mmol/L; n = 9; p = 0.012). No significant adverse effects were noted. Our data indicated that intragastric phosphate administration using a small volume of saline enema solution improved the serum phosphorus concentrations in most patients.

ДИНАМИКА СОДЕРЖАНИЯ ФОСФОРА СЫВОРОТКИ КРОВИ У ПАЦИЕНТОВ ПРИ КАРДИОХИРУРГИЧЕСКИХ ОПЕРАЦИЯХ

Perioperative phosphorus monitoring should be used to prevent the complications after cardiac surgery and, as a result, to reduce the length of intensive care and hospital stay. The purpose of the study was to describe the change in blood phosphorus concentrations in open heart cardiopulmonary bypass surgery patients over time. Material and methods. A prospective non-randomized cohort study was performed. The change in phosphorus concentrations was assessed in 45 adult patients admitted to the Cardiac Surgery Department for an open heart cardiopulmonary bypass surgery. All patients gave venous blood samples at the following sampling time points: 1 – before the surgery; 2 – at 24 hours after the start of the surgery, 3 and 4 – at 48 hours and 72 hours, respectively. Phosphorus concentrations were assayed by photometry at the clinical biochemistry laboratory. Results. A phase change in phosphorus concentrations was observed during the postoperative period vs. preoperative period. Blood phosphorus levels showed statistically significant increase vs. baseline by 0,193, 0,2 and 0,34 mmol/L at 24-, 48- and 72-hours post-surgery, respectively. In 33.3% of patients, hypophosphataemia of less than 0,8 mmol/L was seen at 48 hours. The change in phosphorus concentrations over time in patients with and without creatine phosphate administration was studied. Intraoperative creatine phosphate therapy did not affect the postoperative phosphorus levels. Conclusions. In the postoperative period of cardiosurgical interventions using cardiopulmonary bypass, it is necessary to control the content of phosphorus in the blood serum and, if hypophosphatemia develops, to perform the introduction of phosphates.

Hepatic phosphate uptake and subsequent nerve-mediated phosphaturia are crucial for phosphate homeostasis following portal vein passage of phosphate in rats

Fibroblast growth factor 23, parathyroid hormone, and 1,25-dihydroxyvitamin D are critical in phosphate homeostasis. Despite these factors’ importance, regulators of phosphaturia in the acute postprandial phase remain largely unknown. This study investigated the mechanism of acute phosphate regulation in the postprandial phase in rats. Duodenal administration of radiolabeled phosphate (32P) showed that 32P levels in the inferior vena cava (IVC) blood were lower than those in the portal vein (PV) blood. Serum phosphate concentration transiently increased 5 min after phosphate solution administration through IVC, while it was maintained after the administration through PV. Phosphate administration through both IVC and PV resulted in increased fractional excretion of phosphate (FEPi) at 10 min without elevation of the known circulating factors, but urinary phosphate excretion during the period was 8% of the dose. Experiments using 32P or partial hepatectomy showed that the liver was one of the phosphate reservoirs. The elevation of FEPi and suppression of sodium-phosphate cotransporter 2a in the kidney at 10 min was attenuated in rats with SCH23390, hepatic denervation, or renal denervation, thus indicating that the liver communicated with the kidney via the nervous system to promote phosphaturia. These results revealed previously unknown mechanisms for serum phosphate maintenance.

Antenatal corticosteroids in Singapore: a clinical and scientific assessment.

Preterm birth (PTB; delivery prior to 37 weeks' gestation) is the leading cause of early childhood death in Singapore today. Approximately 9% of Singaporean babies are born preterm; the PTB rate is likely to increase given the increased use of assisted reproduction technologies, changes in the incidence of gestational diabetes/high body mass index and the ageing maternal population. Antenatal administration of dexamethasone phosphate is a key component of the obstetric management of Singaporean women who are at risk of imminent preterm labour. Dexamethasone improves preterm outcomes by crossing the placenta to functionally mature the fetal lung. The dexamethasone regimen used in Singapore today affords a very high maternofetal drug exposure over a brief period of time. Drawing on clinical and experimental data, we reviewed the pharmacokinetic profile and pharmacodynamic effects of dexamethasone treatment regimen in Singapore, with a view to creating a development pipeline for optimising this critically important antenatal therapy.

Rare causes of Hypophosphatemia: diagnostic approach

Hypophosphatemia is common and may be overlooked due to its asymptomatic nature or non-specific symptoms. Two main mechanisms are at its origin: a shift towards the intracellular sector and an increase in urinary phosphate excretion. A measurement of the urinary phosphate reabsorption threshold allows a diagnostic orientation. Alongside common forms of parathyroid hormone-dependent hypophosphatemia, one should not ignore rare FGF23-mediated forms, in particular X-linked hypophosphatemic rickets. The treatment, above all etiological, also includes the administration of phosphate and, in the event of an excess of FGF23, supplementation with calcitriol. In cases of oncogenic osteomalacia and X-linked hypophosphatemic rickets, the use of burosumab, an anti-FGF23 antibody, must be considered.

PENGARUH INTERAKSI ANTARA PEMBERIAN BIOFOSFAT DENGAN PENGGUNAAN KULTIVATOR LOKAL UBI JALAR TERHADAP PERTUMBUHAN HASIL DAN KANDUNGAN GULA TANAMAN UBI JALAR

This study aims to examine the effect of the interaction between the administration of biophosphate and the use of local Jakar potato cultivars on the growth, yield and sugar content of sweet potato plants. The research method uses (RAK) 4 times. The 1st factor was Biophosphate (B), consisting of two levels: b1 (100 kg/ha biophosphate) and b2 (200 kg/ha biophosphate). The second factor was Sweet Potato Cultivar (K), consisting of three levels: k1 (cilembu), k2 (maja) and k3 (brass and white). Differences in treatment means were tested using Duncan's multiple range test at the 5% level. The results showed that bophosphate and sweet potato cultivars had no interaction effect. Phosphate administration did not have a different effect on all growth and yield variables of sweet potato plants. The use of cultivars had no different effect on growth, yield and sugar content.

Creatine phosphate preconditioning reduces ischemiareperfusion injury in isolated rat heart

Aim . To study the effect of simultaneous administration of creatine phosphate immediately before ischemia on cardiodynamic parameters and biomarkers of oxidative stress in the coronary venous blood flow during retrograde perfusion in an isolated rat heart. Materials and methods . 20 Wistar albino rats were divided into 2 groups: group 1 (control) and group 2 (experimental), 10 rats per group. Cannulation and retrograde perfusion of aorta of an isolated rat heart with Krebs–Henseleit buffered solution by Landendorff was performed. Both groups underwent ischemia-reperfusion injury, which included global ischemia for 20 minutes followed by reperfusion for 30 minutes. The group 2 (experimental) was preconditioned with creatine phosphate at a dose of 0.2 mmol/l for 5 min before ischemia. We registered cardiodynamic parameters and indicators of oxidative stress at the point of stabilization, at the 1st and 30th minutes of reperfusion. Results . With the impact of creatine phosphate at the 30th minute of reperfusion in the group 2 in comparison with group 1, there was found an increase in the maximum and minimum speed of pressure elevation in the left ventricle (1.7 and 1.9 times, respectively), and of systolic and diastolic pressure in the left ventricle (1.5 and 1.6 times, respectively). Biomarkers of oxidative stress (lipid peroxidation index, nitrites, superoxide anion radical and hydrogen peroxide) were also statistically significantly lower in the group 2 after the 1st minute of reperfusion (by 1.2 times, by 1.4 times, by 2.8 times and 1.9 times, respectively), and after the 30th minute (1.3 times, 2.1 times, 1.9 times and 2.1 times, respectively). Conclusion . The administration of creatine phosphate into the coronary flow 5 minutes before the onset of ischemia has a protective effect on myocardial contractility. Reduction of oxidative stress and damage can be considered as a protective effect of creatine phosphate.

Vascular calcification maladaptively participates in acute phosphate homeostasis.

Non-renal extravasation of phosphate from the circulation and transient accumulation into tissues and extracellular fluid is a regulated process of acute phosphate homeostasis that is not well understood. This process is especially relevant in the setting of chronic kidney disease (CKD), where exposure to increased phosphate is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated mineral dysregulation induces pathological accumulation of phosphate causing vascular calcification (VC). Our objective was to determine whether the systemic response to acute phosphate challenges is altered by VC. After bolus phosphate administration, circulating and tissue deposition of this challenge was assessed in two rat models of VC using a radiolabelled phosphate tracer. In an adenine-induced model of CKD (N = 70), animals with VC had a blunted elevation of circulating 33PO4 following oral phosphate administration (P < 0.01), and the discordant deposition could be traced to the calcified arteries (11.4 [7.5-13.1] vs.43.0 [35.5-53.7] pmol/ng tissue, P < 0.001). In a non-CKD model of VC, calcification was induced with 0.5 ug/kg calcitriol and then withdrawn (N = 24). New phosphate uptake by the calcified vasculature correlated to the pre-existing burden of calcification (r = 38, P < 0.001) and was substantially attenuated in the absence of calcification stimulus (P < 0.01). Phosphate accrual was stimulated by the phosphate challenge and not present to the same degree during passive disposition of circulating phosphate. Further, the form of phosphate that deposited to the vasculature was predominately amorphous inorganic phosphate and not that which was bound in matured calciprotein particles. In the process of calcification, arteries acutely deposit substantial amorphous phosphate while blunting the elevation in the circulation, thereby altering the systemic disposition of phosphate and identifying VC as a participatory mineral homeostatic organ. This study demonstrates the negative vascular consequence of acute fluctuations in circulating phosphate, and supports the importance of phosphate bioavailability and diet management in CKD patients as a mediator of cardiovascular risk.

Increased PHOSPHO1 expression mediates cortical bone mineral density in renal osteodystrophy.

Patients with advanced chronic kidney disease (CKD) often present with skeletal abnormalities, a condition known as renal osteodystrophy (ROD). While tissue non-specific alkaline phosphatase (TNAP) and PHOSPHO1 are critical for bone mineralization, their role in the etiology of ROD is unclear. To address this, ROD was induced in both WT and Phospho1 knockout (P1KO) mice through dietary adenine supplementation. The mice presented with hyperphosphatemia, hyperparathyroidism, and elevated levels of FGF23 and bone turnover markers. In particular, we noted that in CKD mice, bone mineral density (BMD) was increased in cortical bone (P < 0.05) but decreased in trabecular bone (P < 0.05). These changes were accompanied by decreased TNAP (P < 0.01) and increased PHOSPHO1 (P < 0.001) expression in WT CKD bones. In P1KO CKD mice, the cortical BMD phenotype was rescued, suggesting that the increased cortical BMD of CKD mice was driven by increased PHOSPHO1 expression. Other structural parameters were also improved in P1KO CKD mice. We further investigated the driver of the mineralization defects, by studying the effects of FGF23, PTH, and phosphate administration on PHOSPHO1 and TNAP expression by primary murine osteoblasts. We found both PHOSPHO1 and TNAP expressions to be downregulated in response to phosphate and PTH. The in vitro data suggest that the TNAP reduction in CKD-MBD is driven by the hyperphosphatemia and/or hyperparathyroidism noted in these mice, while the higher PHOSPHO1 expression may be a compensatory mechanism. Increased PHOSPHO1 expression in ROD may contribute to the disordered skeletal mineralization characteristic of this progressive disorder.

A Drug Repurposing Screen Identifies Fludarabine Phosphate as a Potential Therapeutic Agent for N-MYC Overexpressing Neuroendocrine Prostate Cancers.

Neuroendocrine prostate cancer (NEPC) represents a highly aggressive form of prostate tumors. NEPC results from trans-differentiated castration-resistant prostate cancer (CRPC) with increasing evidence indicating that the incidence of NEPC often results from the adaptive response to androgen deprivation therapy. Recent studies have shown that a subset of NEPC exhibits overexpression of the MYCN oncogene along with the loss of tumor suppressing TP53 and RB1 activities. N-MYC is structurally disordered with no binding pockets available on its surface and so far, no clinically approved drug is available. We adopted a drug-repurposing strategy, screened ~1800 drug molecules, and identified fludarabine phosphate to preferentially inhibit the proliferation of N-MYC overexpressing NEPC cells by inducing reactive oxygen species (ROS). We also show that fludarabine phosphate affects N-MYC protein levels and N-MYC transcriptional targets in NEPC cells. Moreover, enhanced ROS production destabilizes N-MYC protein by inhibiting AKT signaling and is responsible for the reduced survival of NEPC cells and tumors. Our results indicate that increasing ROS production by the administration of fludarabine phosphate may represent an effective treatment option for patients with N-MYC overexpressing NEPC tumors.

Tolerability and Effects of 2-Aminoethyl Dihydrogen Phosphate in Dogs With Mast Cell Tumors.

Canine mast cell tumor is a malignant neoplasm, and a gold standard treatment remains to be determined despite the proposed chemotherapies or other therapies in dogs. This study aimed to determine therapeutic, adverse effects and toxicity, tumor-free, and overall survival times of 10 dogs with surgically excised mast cell tumors evaluated by histopathological/immunohistochemistry and treated with four weekly intravenous administrations of 2-Aminoethyl Dihydrogen Phosphate (70 mg/kg) as adjuvant therapy. No adverse events were noted. Laboratory changes were limited (p < 0.05) in red blood cell, hemoglobin, and platelet counts. Mean tumor-free and overall survival were 599.1 ± 469 and 755.5 ± 423.5 days, respectively. In conclusion, 2-Aminoethyl Dihydrogen Phosphate administration was safe in dogs. However, 2-Aminoethyl Dihydrogen Phosphate was not sufficiently effective to prevent a recurrence, new tumor, or metastasis of canine mast cell tumors with poor immunohistochemical prognostic factors.

Creatine phosphate administration in cardiac ischemia-reperfusion injury in rats: focus on differences between preconditioning, perconditioning, and postconditioning protocols.

The aim of this study was to examine and compare the influence of preconditioning, perconditioning, and postconditioning with creatine phosphate (PCr) on functional recovery and production of prooxidants in isolated rat hearts subjected to ex vivo ischemic-reperfusion (I-R) injury on a Langendorff apparatus. Wistar albino rats (male, n=40) were divided into four groups: control and groups in which PCr (0.5mmol/L, 5 min) was perfused before (Pre group), after (Post group), or during (Per group) ex vivo induced ischemia. PCr application was associated with the great benefits of preserving cardiac contractility (in Pre group 100.96% for +(dP/dt max) and 97.61% for -(dP/dt max), in Per group 96.72% for +(dP/dt max) and 95.60% for -(dP/dt max), and in Post group 143.84% for +(dP/dt max) and 104.36% for -(dP/dt max) in relation to the stabilization). In addition, PCr application prevented the increase in prooxidative markers during I-R injury in all therapeutic modalities. The most intensive benefits in the current investigation were observed when PCr was applied during the period of ischemia because the lowest fluctuations in the parameters of cardiac function and oxidative stress were observed. Overall, the results of this study highlight PCr-induced cardioprotection with promising prospects for future clinical use.

528 Evaluation of phosphate replacement practices in burn patients

IntroductionBurn injury causes acute shifts in phosphorus leading to hypophosphatemia and negative sequelae, such as motor neuropathy, muscle weakness, cardiac failure, and respiratory failure. These patients require frequent phosphorus level monitoring and repletion beyond the needs of a general critical care patient. Data suggests patients with normal phosphorus levels have lower incidence of ventilator wean failure and positive clinical outcomes. There is limited data evaluating phosphate replacement practices in burn patients for their intensive care unit (ICU) length of stay while also evaluating those who concomitantly receive continuous renal replacement therapy (CRRT) as it is the primary mode of renal replacement therapy in this population and further depletes phosphorus levels.MethodsThis was a single-center, retrospective, observational study of patients with a burn injury admitted and discharged from a burn intensive care unit (BICU) from January 1, 2016 to June 30, 2020 who received phosphate. Patients less than 18 years of age and those admitted to the BICU for non-burn injuries were excluded. Burn injury type, number of phosphorus doses per day, and phosphorus levels were collected. Normal phosphorus was defined as 2.5-4.9 mg/dL and hypophosphatemia as < 2.5mg/dL. Patient data was evaluated in 24-hour time intervals as defined as midnight to midnight. Phosphorus lab values were included in data analysis if there was corresponding phosphate administration in that 24-hour interval. The primary objective was to assess the temporal dose-response to phosphate replacement in burn patients.ResultsThere were 291 patients who met criteria, 116 were selected in chronological order by admission date and were included in data analysis. The mean age was 51.51 years and the mean total body surface area burned was 21.48%. Flame burn accounted for 83.6 % (n=97) of patients and 37.06% (n=43) of patients had concomitant inhalation injury. The mean amount of phosphate given to a patient per day was 28.38 mmol and patients on CRRT received a mean amount of phosphate of 33.34 mmol per day. In response to phosphate administration, the mean change in phosphorus was 0.334 ± 1.08 mg/dL. In patients on CRRT, the mean change in phosphorus was 1.4 ± 1.89 mg/dL. Patients experienced hypophosphatemia 69.63% of the days that they received phosphate repletion and patients on CRRT had hypophosphatemia 87.39% of the days they received phosphate repletion.ConclusionsHypophosphatemia is common in the burn injury population and current phosphate replacement practices are insufficient to replete phosphorus in burn injury patients.

Exosomes derived from adipose-derived stem cells alleviate cigarette smoke-induced lung inflammation and injury by inhibiting alveolar macrophages pyroptosis

BackgroundChronic obstructive pulmonary disease (COPD) is a frequently encountered disease condition in clinical practice mainly caused by cigarette smoke (CS). The aim of this study was to investigate the protective roles of human adipose-derived stem cells-derived exosomes (ADSCs-Exo) in CS-induced lung inflammation and injury and explore the underlying mechanism by discovering the effects of ADSCs-Exo on alveolar macrophages (AMs) pyroptosis.MethodsADSCs were isolated from human adipose tissues harvested from three healthy donors, and then ADSCs-Exo were isolated. In vivo, 24 age-matched male C57BL/6 mice were exposed to CS for 4 weeks, followed by intratracheal administration of ADSCs-Exo or phosphate buffered saline. In vitro, MH-S cells, derived from mouse AMs, were stimulated by 2% CS extract (CSE) for 24 h, followed by the treatment of ADSCs-Exo or phosphate buffered saline. Pulmonary inflammation was analyzed by detecting pro-inflammatory cells and mediators in the bronchoalveolar lavage fluid. Lung histology was assessed by hematoxylin and eosin staining. Mucus production was determined by Alcian blue-periodic acid-Schiff staining. The profile of AMs pyroptosis was evaluated by detecting the levels of pyroptosis-indicated proteins. The inflammatory response in AMs and the phagocytic activity of AMs were also investigated.ResultsIn mice exposed to CS, the levels of pro-inflammatory cells and mediators were significantly increased, mucus production was markedly increased and lung architecture was obviously disrupted. AMs pyroptosis was elevated and AMs phagocytosis was inhibited. However, the administration of ADSCs-Exo greatly reversed these alterations caused by CS exposure. Consistently, in MH-S cells with CSE-induced properties modelling those found in COPD, the cellular inflammatory response was elevated, the pyroptotic activity was upregulated while the phagocytosis was decreased. Nonetheless, these abnormalities were remarkably alleviated by the treatment of ADSCs-Exo.ConclusionsADSCs-Exo effectively attenuate CS-induced airway mucus overproduction, lung inflammation and injury by inhibiting AMs pyroptosis. Therefore, hADSCs-Exo may be a promising cell-free therapeutic candidate for CS-induced lung inflammation and injury.

Зміни звивистих канальців нирок при введенні НАДФ на тлі стрептозотоцин-індукованого цукрового діабету в щурів

Мета. Вивчення змін структур звивистих канальців нирок при введенні нікотинамідаденіндинуклеотидфосфату (НАДФ) на тлі індукованого стрептозотоцином цукрового діабету (ЦД) у щурів. Матеріали та методи. Експерименти проведено на самцях білих щурів, яким моделювали ЦД шляхом уведення стрептозотоцину в дозі 70 мг/кг. НАДФ уводили у дозі 30 мг/кг. Вивчали структури нирок на 11-ту, 21-шу та 31-шу добу експерименту. Результати. На противагу класичним методам забарвлення ранні зміни в різних структурах нирки були виявлені за допомогою гістохімічного методу на основі забарвлення гістологічних зрізів бромфеноловим синім за методом Mikel Calvo. Висновки. Загалом структури нирок виявляли позитивну реакцію на введення НАДФ, що може бути пов’язане зі зниженням прямого ушкоджувального впливу гіперглікемії як за рахунок зменшення кількості глікозильованих білків, так і внаслідок прямого безпосереднього його позитивного впливу на стан ендотеліоцитів.

An exploratory first-in-man study to investigate the pharmacokinetics and safety of liposomal dexamethasone at a 2- and 1-week interval in patients with metastatic castration resistant prostate cancer.

Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome‐encapsulated dexamethasone disodium phosphate (liposomal dexamethasone) administration in mCRPC patients.In this exploratory first‐in‐man study, patients in part A received a starting dose of 10 mg followed by five doses of 20 mg liposomal dexamethasone at 2‐week intervals. Upon review of part A safety, patients in part B received 10 weekly doses of 18.5 mg. Primary outcomes were safety and pharmacokinetic profile, secondary outcome was antitumor efficacy.Nine mCRPC patients (5 part A, 4 part B) were enrolled. All patients experienced grade 1–2 toxicity, one (part B) patient experienced grade 3 toxicity (permanent bladder catheter‐related urosepsis). No infusion‐related adverse events occurred. One patient had upsloping glucose levels ≤9.1 mmol/L. Trough plasma concentrations of liposomal‐ and free dexamethasone were below the lower limit of quantification (LLOQ) in part A, and above LLOQ in three patients in part B (t 1/2 ~50 h for liposomal dexamethasone), trough concentrations of liposomal‐ and free dexamethasone increased toward the end of the study. In seven of nine patients (78%) patients, stable disease was observed in bone and/or CT scans at follow‐up, and in one (part B) of these seven patients a >50% PSA biochemical response was observed.Bi‐ and once weekly administrations of IV liposomal dexamethasone were well‐tolerated. Weekly dosing enabled trough concentrations of liposomal‐ and free dexamethasone >LLOQ. The data presented support further clinical investigation in well‐powered studies.Clinical trial registration: ISRCTN 10011715.

Microscopic features of the rat adrenal gland associated with chronic codeine phosphate administration.

Codeine is an opioid analgesic and antitussive that has been widely abused. Some adverse effects noted with its abuse include adrenocortical insufficiency and activation of the hypothalamic-pituitary-adrenal axis. The structural basis for these dysfunctions is not clearly understood. Twenty-five adult male rats were used for the study. They were divided into intervention and control groups that were administered 40 mg/kg of codeine phosphate and normal saline respectively by gavage daily for 50 days. Subsequently, both groups were given normal saline for a further fourteen days to note recovery changes. At day 0, 50 and 64, rats were randomly selected from both groups, euthanized and adrenal glands harvested for histological processing and analysis. At day 50 of codeine administration, the adrenal glands demonstrated an increase in zona fasciculata thickness but a decrease in zona reticularis thickness. Lower values were noted in the volume density of zona reticularis and cells count of the medulla in the experimental compared to the control groups (P-value<0.05). The experimental group also showed an increase in vascularization and connective tissue in the glands. After 14 days of recovery, most of the changes observed in experimental animals were reversed and the adrenal glands in both groups had similar features. A decrease in cell count of the adrenal medulla was however observed (P-value<0.05). In conclusion administration of codeine phosphate causes discernible changes in the microscopic structure of the adrenal gland, most of which appear to be reversed after two weeks recovery period.