Micellar solution of [223Ra]RaCl2: Reaching renal excretion, potent efficacy in osteoblastic osteosarcoma in PDX model, biochemistry alterations and pharmacokinetics.

Despite the successful use of the radiopharmaceutical radium-223 dichloride ([223Ra]RaCl2) for targeted alpha therapy of castration-resistant prostate cancer patients with bone metastases, some short-term side effects, such as diarrhea and vomiting, have been documented, causing patient discomfort. Hence, we prepared a nanosized micellar solution of [223Ra]RaCl2 and evaluated its biodistribution, pharmacokinetics, and induced biochemical changes in healthy mice up to 96 h after intraperitoneal administration as an alternative to overcome the previous limitations. In addition, we evaluated the bone specificity of micellar [223Ra]RaCl2 in patient-derived xenografts in the osteosarcoma model. The biodistribution studies revealed the high bone-targeting properties of the micellar [223Ra]RaCl2. Interestingly, the liver uptake remained significantly low (%ID/g = 0.1-0.02) from 24 to 96 h after administration. In addition, the micellar [223Ra]RaCl2 exhibited a significantly higher uptake in left (%ID/g = 0.85-0.23) and right (%ID/g = 0.76-0.24) kidneys than in small (%ID/g = 0.43-0.06) and large intestines (%ID/g = 0.24-0.09) over time, suggesting its excretion pathway is primarily through the kidneys into the urine, in contrast to the non-micellar [223Ra]RaCl2. The micellar [223Ra]RaCl2 also had low distribution volume (0.055 ± 0.003 L) and longer elimination half-life (28 ± 12 days). This nanosystem was unable to change the enzymatic activities of alanine aminotransferase, aspartate aminotransferase, gamma GT, glucose, and liquiform lipase in the treated mice. Finally, microscopic examination of the animals' osteosarcoma tumors treated with micellar [223Ra]RaCl2 indicated regression of the tumor, with large areas of necrosis. In contrast, in the control group, we observed tumor cellularity and cell anaplasia, mitotic figures and formation of neoplastic extracellular bone matrix, which are typical features of osteosarcoma. Therefore, our findings demonstrated the efficiency and safety of nanosized micellar formulations to minimize the gastrointestinal excretion pathway of the clinical radiopharmaceutical [223Ra]RaCl2, in addition to promoting regression of the osteosarcoma. Further studies must be performed to assess dose-response outcomes and organ/tissue dosimetry for clinical translation.

KS-WNK1 is required for the renal response to extreme changes in potassium intake.

Kidney-specific with-no-lysine kinase 1 (KS-WNK1) is an isoform of WNK1 kinase that is predominantly found in the distal convoluted tubule of the kidney. The precise physiological function of KS-WNK1 remains unclear. Some studies have suggested that it could play a role in regulating potassium renal excretion by modulating the activity of the Na+-Cl- cotransporter (NCC). However, changes in the potassium diet from normal to high failed to reveal a role for KS-WNK1, but under a normal-potassium diet, the expression of KS-WNK1 is negligible. It is only detectable when mice are exposed to a low-potassium diet. In this study, we investigated the role of KS-WNK1 in regulating potassium excretion under extreme changes in potassium intake. After following a zero-potassium diet (0KD) for 10 days, KS-WNK1-/- mice had lower plasma levels of K+ and Cl- while exhibiting higher urinary excretion of Na+, Cl-, and K+ compared with KS-WNK1+/+ mice. After 10 days of 0KD or normal-potassium diet (NKD), all mice were challenged with a high-potassium diet (HKD). Plasma K+ levels markedly increased after the HKD challenge only in mice previously fed with 0KD, regardless of genotype. KSWNK1+/+ mice adapt better to HKD challenge than KS-WNK1-/- mice after a potassium-retaining state. The difference in the phosphorylated NCC-to-NCC ratio between KS-WNK1+/+ and KS-WNK1-/- mice after 0KD and HKD indicates a role for KS-WNK1 in both NCC phosphorylation and dephosphorylation. These observations show that KS-WNK1 helps the distal convoluted tubule to respond to extreme changes in potassium intake, such as those occurring in wildlife.NEW & NOTEWORTHY The findings of this study demonstrate that kidney-specific with-no-lysine kinase 1 plays a role in regulating urinary electrolyte excretion during extreme changes in potassium intake, such as those occurring in wildlife. .

Cardiovascular and hidroelectrolytic changes in rats fed with high-fat diet.

Obesity activates the renin-angiotensin and sympathetic systems facilitating hypertension and changes in the hydroelectrolytic balance. In the present study, in rats fed with high-fat diet (HFD), we investigated daily water intake and urinary excretion, prandial consumption of water and the changes in blood pressure and water intake to intracerebroventricular (icv) angiotensin II (ANG II). Male Holtzman rats (290-320 g) were fed with standard diet (SD, 11% calories from fat) or HFD (45% calories from fat) for 6 weeks. Part of the animals received a stainless steel cannula in the lateral ventricle (LV) at the 6th week after the beginning of the diets and the experiments were performed at the 7th week. The pressor effect, but not the dipsogenic response to acute icv injection of ANG II, was potentiated in the HFD rats. Daily water intake and urinary volume were reduced in rats fed with HFD with no significant changes in sodium excretion. Prandial water consumption was also reduced in rats ingesting HFD, an effect almost totally reverted blocking salivation with atropine. These results show a potentiation of the pressor response to icv ANG II in HFD-fed rats, without changing icv ANG II-induced water intake. In addition, prandial and daily water intake and urinary volume were reduced in HFD-fed rats, without changing sodium excretion. Salivation in rats ingesting HFD may play a role in the reduced prandial and daily water intake.

Seizures, Antiepileptic Drugs, and CKD.

There are 2 major categories of patients with seizures and chronic kidney disease (CKD): patients who develop acute symptomatic seizures in the setting of CKD and patients with epilepsy who at some point develop CKD. The incidence of uremic seizures with kidney failure is ∼10%. These seizures are often nonconvulsive and may mimic uremic encephalopathy. Recognition and management of such situations may be challenging for treating physicians who are non-neurologists. Furthermore, practitioners caring for patients with seizures with or without an established diagnosis of epilepsy in the setting of CKD frequently encounter challenges in the selection, loading, titration, and maintenance of antiepileptic drugs (AEDs) due to potentially altered pharmacokinetics of the AEDs. We review the pathophysiology of uremia, uremic seizures, and other neurologic complications of kidney failure; management approaches to the treatment of such complications; the relevant mechanisms of action and pharmacokinetics of AEDs with their use in CKD; and in particular, the management of AEDs in patients requiring hemodialysis therapy.

Gastrointestinal Absorption and Renal Excretion of Fluoride After Ingestion of a High-Fluoride Dentifrice.

This study aimed to evaluate the gastrointestinal absorption and renal excretion of fluoride after the ingestion of high-fluoride dentifrice. Twelve volunteers participated in this in vivo, crossover, and blinded study. In three experimental phases, the volunteers were randomly assigned to one of three treatment groups, who ingested either the following: distilled and deionized water (control), conventional dentifrice (1100 µg/g), or high-fluoride dentifrice (5000 µg/g). Both dentifrices contained fluoride in the form of NaF/SiO2. To determine the rate of fluoride absorption, non-stimulated saliva was collected for up to 120 min after ingestion and the area under the curve of the salivary fluoride concentration was plotted as a function of time and the maximum concentration determined. All urine produced during the 24 h before and after ingestion was collected, and urinary excretion was calculated from the difference between the urinary fluoride concentrations in the two periods. A specific ion electrode coupled to an ion analyzer was used to measure fluoride concentrations. Statistical analysis was performed by ANOVA followed by Tukey's test with p set at 5%. All measured parameters were highest after the ingestion of the dentifrice with 5000 µg/g (p < 0.001), confirming that this has an increased level of bioavailable fluoride compared with the conventional dentifrice. The high-fluoride dentifrice increases the concentration of salivary fluoride, which may explain its greater anticaries effect. However, it poses a potential risk of causing dental fluorosis and so should not be used by children.

Hydrogen peroxide centrally attenuates hyperosmolarity-induced thirst and natriuresis.

Intragastric hypertonic NaCl that simulates the ingestion of osmotically active substances by food intake induces thirst, vasopressin and oxytocin release, diuresis and natriuresis. Reactive oxygen species (ROS) produced endogenously in central areas may act modulating autonomic and behavioral responses. In the present study, we investigated the effects of H2O2 injected centrally on water intake and renal responses induced by increasing plasma osmolality with intragastric (ig) administration of 2M NaCl (2 ml/rat). Male Holtzman rats (280-320 g) with stainless steel cannula implanted in the lateral ventricle (LV) were used. Injections of H2O2 (2.5 µmol/1 µl) into the LV reduced ig 2M NaCl-induced water intake (3.1 ± 0.7, vs. PBS: 8.6 ± 1.0 ml/60 min, p<0.05), natriuresis (769 ± 93, vs. PBS: 1158 ± 168 µEq/120 min, p<0.05) and diuresis (4.1 ± 0.5, vs. PBS: 5.0 ± 0.5 ml/120 min, p<0.05). Injections of H2O2 into the LV also decreased meal associated water intake (4.9 ± 1.5, vs. PBS: 11.0 ± 1.7 ml/120 min). However, H2O2 into the LV did not modify 2% sucrose intake (3.3 ± 1.5, vs. PBS: 5.4 ± 2.3 ml/120 min) or 24h food deprivation-induced food intake (8.2 ± 2.0, vs. PBS: 11.0 ± 1.6g/120 min), suggesting that this treatment does not produce nonspecific inhibition of ingestive behaviors. The data suggest an inhibitory role for H2O2 acting centrally on thirst and natriuresis induced by hyperosmolarity and on meal-associated thirst.

Does the Anesthetic Urethane Influence the Pharmacokinetics of Antifungal Drugs? A Population Pharmacokinetic Investigation in Rats.

The aim of this paper was to analyze the impact of anesthesia induced by urethane on pharmacokinetics (PK) parameters of fluconazole (FCZ), mostly eliminated via renal excretion and voriconazole (VRC), eliminated mainly by hepatic metabolism. FCZ and VRC PK were investigated after administration of 10 mg/kg i.v. and 5 mg/kg i.v. doses to awake and urethane anesthetized Wistar rats (n = 6 per group), respectively. After dosing, blood samples were collected up to 18 h (FCZ) or 12 h (VRC) and the plasma data analysis was performed using the software MONOLIX v. 4.2.2. The population PK parameters and microconstants were determined by fitting plasma concentration-time profiles to two-compartment model for FCZ and three-compartment model for VRC. Fitting of FCZ plasma profiles after dosing to awake and anaesthetized animals resulted in a volume of distribution (V) of 9.3 and 8.1 L/kg, and k10 values of 0.12 and 0.14 h(-1) , respectively. VRC plasma profiles in awake and anaesthetized showed V 8.7 of and 7.6 L/kg, and k10 of 0.15 and 0.16 h(-1) , respectively. No statistical differences between plasma PK parameters and microconstants for the same drug in both animal conditions studied were observed (α = 0.05).

Steviol effect, a glycoside of Stevia rebaudiana, on glucose clearances in rats / O efeito do esteviol, um glicosídeo da Stevia rebaudiana, no clearance da glicose em ratos

Stevia rebaudiana, a South American plant normally used as a natural herbal sweetener, has been suggested as exerting beneficial effects on human health, including as an antihypertensive and antihyperglycemic. The present experiment was undertaken to evaluate the renal excretion of steviol, the aglycone of several natural products extracted from the leaves of S. rebaudiana, and to clarify the actual participation of this compound on the renal excretion of glucose in rats, which has been previously suggested as the preferential action of steviol on the Na+-glucose renal tubular transport system. Steviol was obtained by enzymatic hydrolysis of stevioside with pectinase. Thirty normal male Wistar rats weighing 345 g were used. After a control period, steviol was infused iv at three doses (0.5, 1.0 and 3.0 mg.kg-1/h), according to classical clearance techniques. During all the experiments no significant changes in inulin clearance (Cin) and p-aminohipuric acid clearance (C PAH) were observed. Administration of steviol resulted in a statistically significant increase in the fractional sodium excretion (FeNa+), fractional potassium excretion (FeK+), urinary flow as percent of glomerular filtration rate (V/GFR) and glucose clearance (C G) when compared to controls, but these effects were absent with the dose of 0.5 mg.kg-1/h. The steviol clearance (C S) was higher than the Cin and lower than the C PAH at all the doses employed in this study. The data suggest that steviol is secreted by renal tubular epithelium, causing diuresis, natriuresis, kaliuresis and a fall in renal tubular reabsorption of glucose.

Stevia rebaudiana, uma planta da América do Sul usada como adoçante natural, parece exercer efeitos benéficos para a saúde humana, incluindo ação anti-hipertensiva e anti-hiperglicêmica. No presente trabalho objetivamos avaliar a excreção renal do esteviol, uma aglicona extraída das folhas de S. rebaudiana, e elucidar a participação deste composto na excreção renal de glicose em ratos, o qual foi sugerido agir no sistema de transporte tubular renal Na+-glicose. O esteviol foi obtido por hidrólise enzimática com pectinase. Foram usados 30 ratos Wistar machos e pesando 345 g. Após um período controle, o esteviol foi infundido iv em três doses (0,5, 1,0 e 3,0 mg.kg-1/h) de acordo com técnicas clássicas de clearance. Durante os experimentos não houve alterações significantes no clearance da inulina (Cin) e do ácido-aminohipúrico (C PAH). A administração de esteviol resultou em um aumento estatisticamente significante na excreção fracional de sódio (FeNa+) e potássio (FeK+ ), no fluxo urinário como porcentagem da taxa de filtração glomerular (V/GFR) e do clearance de glicose (C G) quando comparados aos animais controles, embora estes efeitos estivessem ausentes na dose de 0,5 mg.kg-1/h. O clearance de esteviol (C S) foi maior que o Cin e menor que o C PAH em todas as doses usadas nos experimentos. Os dados sugerem a secreção de esteviol pelo epitélio tubular renal, causando diurese, natriurese, caliurese e uma redução na reabsorção tubular renal de excreção de glicose.

Steviol effect, a glycoside of Stevia rebaudiana, on glucose clearances in rats

Stevia rebaudiana, a South American plant normally used as a natural herbal sweetener, has been suggested as exerting beneficial effects on human health, including as an antihypertensive and antihyperglycemic. The present experiment was undertaken to evaluate the renal excretion of steviol, the aglycone of several natural products extracted from the leaves of S. rebaudiana, and to clarify the actual participation of this compound on the renal excretion of glucose in rats, which has been previously suggested as the preferential action of steviol on the Na+-glucose renal tubular transport system. Steviol was obtained by enzymatic hydrolysis of stevioside with pectinase. Thirty normal male Wistar rats weighing 345 g were used. After a control period, steviol was infused iv at three doses (0.5, 1.0 and 3.0 mg.kg-1/h), according to classical clearance techniques. During all the experiments no significant changes in inulin clearance (Cin) and p-aminohipuric acid clearance (C PAH) were observed. Administration of steviol resulted in a statistically significant increase in the fractional sodium excretion (FeNa+), fractional potassium excretion (FeK+), urinary flow as percent of glomerular filtration rate (V/GFR) and glucose clearance (C G) when compared to controls, but these effects were absent with the dose of 0.5 mg.kg-1/h. The steviol clearance (C S) was higher than the Cin and lower than the C PAH at all the doses employed in this study. The data suggest that steviol is secreted by renal tubular epithelium, causing diuresis, natriuresis, kaliuresis and a fall in renal tubular reabsorption of glucose.

Stevia rebaudiana, uma planta da América do Sul usada como adoçante natural, parece exercer efeitos benéficos para a saúde humana, incluindo ação anti-hipertensiva e anti-hiperglicêmica. No presente trabalho objetivamos avaliar a excreção renal do esteviol, uma aglicona extraída das folhas de S. rebaudiana, e elucidar a participação deste composto na excreção renal de glicose em ratos, o qual foi sugerido agir no sistema de transporte tubular renal Na+-glicose. O esteviol foi obtido por hidrólise enzimática com pectinase. Foram usados 30 ratos Wistar machos e pesando 345 g. Após um período controle, o esteviol foi infundido iv em três doses (0,5, 1,0 e 3,0 mg.kg-1/h) de acordo com técnicas clássicas de clearance. Durante os experimentos não houve alterações significantes no clearance da inulina (Cin) e do ácido-aminohipúrico (C PAH). A administração de esteviol resultou em um aumento estatisticamente significante na excreção fracional de sódio (FeNa+) e potássio (FeK+ ), no fluxo urinário como porcentagem da taxa de filtração glomerular (V/GFR) e do clearance de glicose (C G) quando comparados aos animais controles, embora estes efeitos estivessem ausentes na dose de 0,5 mg.kg-1/h. O clearance de esteviol (C S) foi maior que o Cin e menor que o C PAH em todas as doses usadas nos experimentos. Os dados sugerem a secreção de esteviol pelo epitélio tubular renal, causando diurese, natriurese, caliurese e uma redução na reabsorção tubular renal de excreção de glicose.