Sodium Furosemide Research Articles

Targeting gut microbial nitrogen recycling and cellular uptake of ammonium to improve bortezomib resistance in multiple myeloma

The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C.freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C.freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance.

Preparation of an amorphous sodium furosemide salt improves solubility and dissolution rate and leads to a faster Tmax after oral dosing to rats

Amorphous forms of furosemide sodium salt and furosemide free acid were prepared by spray drying. For the preparation of the amorphous free acid, methanol was utilised as the solvent, whereas the amorphous sodium salt was formed from a sodium hydroxide-containing aqueous solvent in equimolar amounts of NaOH and furosemide. Information about the structural differences between the two amorphous forms was obtained by Fourier Transform Infrared Spectroscopy (FTIR), and glass transition temperature (Tg) was determined using Differential Scanning Calorimetry (DSC). The stability and devitrification tendency of the two amorphous forms were investigated by X-ray Powder Diffraction (XRPD). The apparent solubility of the two amorphous forms and the crystalline free acid form of furosemide in various gastric and intestinal stimulated media was determined. Moreover, the dissolution characteristics of the two amorphous forms and of crystalline free acid were investigated.FTIR confirmed molecular differences between the amorphous free acid and salt. The amorphous salt showed a Tg of 101.2°C, whereas the Tg for the amorphous free acid was found to be 61.8°C. The amorphous free acid was physically stable for 4days at 22°C and 33% relative humidity (RH), while the amorphous salt exhibited physical stability for 291days at the same storage conditions. When storing the amorphous forms at 40°C and 75% RH both forms converted to crystalline forms after 2days.The apparent solubility of the amorphous salt form was higher than that of both amorphous and crystalline free acid in all media studied. All three forms of furosemide exhibited a greater solubility in the presence of biorelevant media as compared to buffer, however, an overall trend for a further increase in solubility in relation to an increase in media surfactant concentration was not seen. The amorphous salt demonstrated an 8- and 20-fold higher intrinsic dissolution rate (IDR) when compared to amorphous and crystalline free acid, respectively.The promising properties of the amorphous salt in vitro were further evaluated in an in vivo study, where solid dosage forms of the amorphous salt, amorphous and crystalline free acid and a solution of furosemide were administered orally to rats. The amorphous salt exhibited a significantly faster Tmax compared to the solution and amorphous and crystalline free acid. Cmax for the solution was significantly higher compared to the three furosemide forms. No significant difference was found in AUC and absolute bioavailability for the solution, crystalline free acid and the two amorphous forms of furosemide. It can be concluded that the higher IDR and higher apparent solubility of the amorphous salt resulted in a faster Tmax compared to the amorphous and crystalline free acid.

Positively Charged Polyethersulfone Membranes: The Influence of Furosemide on the Zeta Potential

The aim of the present work is to measure changes in the Zeta potential of uncharged (PES0) and positively charged (PES+) polyethersulfone membranes, and to investigate their chemical composition. Endotoxin-retentive filters with a 0.2 μm PES0 and PES+ membranes are used for filtration of a furosemide sodium solution, with an increasing concentration up to 60 μmol/l. To analyze the chemical composition of both membranes, X-Ray photoelectron spectroscopy (XPS) was used. The Zeta potential was determined by a streaming current electrokinetic analyzer. The positive charge of the PES+ membrane corresponding to a positive Zeta potential decreased with increasing furosemide sodium concentration. In contrast, the Zeta potential of PES0 membranes hardly changes with increasing drug concentration. XPS allows the determination of the chemical composition of the investigated membranes. Both membranes only contain oxygen, carbon, sulfur and nitrogen. On the surface of the PES+ membrane, the positive charge is caused by ammonium nitrogen. No ionic additives could be detected. The manufacturer’s intended period of PES+ filter use (96 h), should only be applied to nonionic infusion solutions. Hence, information should be given on the maximum period of filter use, if ionic infusion solutions are applied.

Compatibility and Stability of Furosemide and Dexamethasone Combined in Infusion Solutions

The goal of palliative care is the achievement of the best quality of life for patients and their families. For this, the administration of drugs by subcutaneous infusion is frequently used since many patients have great difficulties in taking drugs orally and regular intramuscular injections are painful. Usually, drugs are combined in infusion solutions. The objective was therefore to study the compatibility and stability of dexamethasone sodium phosphate (CAS 2392-39-4) and sodium furosemide (CAS 54-31-9) combined in solutions destined to subcutaneous administration in palliative medicine. Twelve different solutions were assessed during 15 days. Drug admixtures were prepared in polypropylene syringes using 0.9 % saline as diluent and stored at 4 degrees C and 25 degrees C in the dark. Initial concentrations were 3.33-10.0 mg/ ml for sodium furosemide (dose range 40-120 mg/day) and 0.33-3.33 mg/ml (dose range 4-40 mg/day) for dexamethasone sodium phosphate. Quantification of both drugs was performed by high-performance liquid chromatography. After 5 days of storage at both temperatures, the maximum losses obtained were lower than 10 % for both drugs. However, after 15 days, slight precipitation/turbidity was observed in all mixtures. At this time, maximum losses of 20 % were obtained for both drugs. These results confirm the stability of mixtures prepared with sodium furosemide (< or = 120 mg/day) and dexamethasone sodium phosphate (< or = 40 mg/day) for a period of 5 days and with independence of their storage at 4 degrees C or 25 degrees C.

Availability of a rich source of sodium during the perinatal period programs the fluid balance restoration pattern in adult offspring

Osmoregulatory mechanisms can be vulnerable to electrolyte and/or endocrine environmental changes during the perinatal period, differentially programming the developing offspring and affecting them even in adulthood. The aim of this study was to evaluate whether availability of hypertonic sodium solution during the perinatal period may induce a differential programming in adult offspring osmoregulatory mechanisms. With this aim, we studied water and sodium intake after Furosemide–sodium depletion in adult offspring exposed to hypertonic sodium solution from 1week before mating until postnatal day 28 of the offspring, used as a perinatal manipulation model [PM-Na group]. In these animals, we also identified the cell population groups in brain nuclei activated by Furosemide–sodium depletion treatment, analyzing the spatial patterns of Fos and Fos–vasopressin immunoreactivity.In sodium depleted rats, sodium and water intake were significantly lower in the PM-Na group vs. animals without access to hypertonic sodium solution [PM-Ctrol group]. Interestingly, when comparing the volumes consumed of both solutions in each PM group, our data show the expected significant differences between both solutions ingested in the PM-Ctrol group, which makes an isotonic cocktail; however, in the PM-Na group there were no significant differences in the volumes of both solutions consumed after Furosemide–sodium depletion, and therefore the sodium concentration of total fluid ingested by this group was significantly higher than that in the PM-Ctrol group.With regard to brain Fos immunoreactivity, we observed that Furosemide–sodium depletion in the PM-Na group induced a higher number of activated cells in the subfornical organ, ventral subdivision of the paraventricular nucleus and vasopressinergic neurons of the supraoptic nucleus than in the PM-Ctrol animals. Moreover, along the brainstem, we found a decreased number of sodium depletion-activated cells within the nucleus of the solitary tract of the PM-Na group.Our data indicate that early sodium availability induces a long-term effect on fluid drinking and on the cell activity of brain nuclei involved in the control of hydromineral balance. These results also suggest that availability of a rich source of sodium during the perinatal period may provoke a larger anticipatory response in the offspring, activating the vasopressinergic system and reducing thirst after water and sodium depletion, as a result of central osmosensitive mechanism alterations.

Drug retention by inline filters – Effect of positively charged polyethersulfone filter membranes on drug solutions with low concentration

Objective The use of infusion filters in pediatrics is controversially discussed. Their application is an excellent opportunity to prevent complications, but there are researchers, who do not see any advantage in using inline filters. This paper describes the interaction of five different drugs with a positively charged as opposed to an uncharged polyethersulfone (PES + versus PES 0) membrane. Methods To measure the extent and the mechanism of interaction, PES + versus PES 0 membranes and furosemide sodium, potassium canrenoate, digitoxin, digoxin and adenosine, each 30 μmol/l, were investigated. Salt ions with different hydrodynamic radii and different concentrations have been used in the eluents. Results During furosemide sodium and potassium canrenoate filtration with PES +, the onset of UV absorption depends on the electrolyte concentration in the eluent: the lower the electrolyte concentration the later the onset of UV absorption. A correlation between the hydrodynamic volume of the different salt ions used and the onset of UV absorption could be proven for both substances: The larger the hydrodynamic volume of the extrinsic ion, the later the onset of the UV absorption if the same electrolyte concentration was used. Due to a higher structural density of PES + than PES 0 a delayed onset of UV absorption during filtration of digitoxin and digoxin with the PES + membrane could be observed. No correlation between the hydrodynamic volume of the different salt ions used and the onset of UV absorption could be seen. With adenosine neither the filter type nor the electrolyte concentration or the hydrodynamic volume of the salt ions had an influence on the onset time of absorption. Conclusion The results obtained with the anionic drugs investigated are particularly relevant if low drug concentrations in a saltless infusion solution are applied in combination with a charged filter membrane. Therefore, for each infusion formulation, a careful selection of the filter material is essential.

Repeated sodium depletion affects gustatory neural responses in the nucleus of the solitary tract of rats.

Furosemide sodium depletions were induced repeatedly to determine the effects on gustatory neural responses in the nucleus of the solitary tract (NST) of chronically prepared, but lightly anesthetized, rats. Sodium-replete and sodium-deplete conditions were alternated four times in each rat. When rats were under depleted conditions, the responses to NaCl were significantly greater than in sodium-replete conditions. This effect was attributable primarily to an increase in the magnitude of response of those neurons that responded better to NaCl than to the other standard stimuli (sucrose, citric acid, and quinine hydrochloride). In addition, the largest change in responsiveness of the NaCl-best neurons occurred during the third and fourth sodium depletions. These results are essentially opposite to those reported for NST neurons when sodium appetite is induced by dietary sodium restriction. This suggests that the coding of intensity in the gustatory system is dependent not only on the animal's deprivation condition, but also the method through which the deprivation is produced.