Significant Decrease In Urinary Excretion Research Articles

A food ingredient containing phytoecdysteroids and polyphenols from quinoa grain: technology and physiological and biochemical evaluation in vivo

An effective technological approach to produce adaptogenic microingredients is to concentrate plant biologically active substances via sorption on various matrices. The aim was to develop and evaluate in vivo the phytoecdysteroids and flavonoids concentrate extracted from quinoa grain and sorbed on the coagulated chicken egg protein. The consecutive extraction of phytoecdysteroids and flavonoids was conducted followed by sorption on the protein. The in vivo experiment was performed during 37 days using Wistar male rats. The developed concentrate was added into the diet of experimental animals in the dose 0.59±0.02 g/100 g of diet. As a stress model we used daily 40-min immobilization and exhaustive 3-hour immobilization at the end of the experiment. Urinary catecholamines content was determined, blood corticosterone, malon dialdehyde, glutathione reductase and superoxide dismutase content was determined. Phytoecdysteroids and flavonoids were concentrated 20 and 80 times respectively compared to the initial raw materials. The concentrate consumption neutralized negative effect of immobilization stress on anxiety level of Wistar rats. The significant decrease in urinary excretion of adrenaline and noradrenaline shows the pronounced adaptogenic effect of the concentrate, whereas phytoecdysteroids and flavonoids act as prostressors activating body antioxidant protection system, what is substantiated by significantly increased blood superoxide dismutase level of experimental animals.

Pirfenidone prevents acute kidney injury in the rat

BackgroundPirfenidone is an orally active drug used for the treatment of idiopathic pulmonary fibrosis to slow loss of lung function; it acts mainly through an antifibrotic effect but also possesses antioxidant and anti-inflammatory properties. We assessed the effect of prophylactic administration of pirfenidone on acute kidney injury due to bilateral renal ischemia.MethodsEighteen rats were included and divided in: 1) sham-operated rats (S), 2) rats underwent bilateral renal ischemia for 20 min (I/R), and 3) rats treated with pirfenidone 700 mg/kg/day 24 h before surgery and subjected to bilateral renal ischemia for 20 min (I/R + PFN). All the rats were euthanized and studied 24 h after renal reperfusion.ResultsAs was expected, the I/R group exhibited a significant reduction in creatinine clearance, urinary output and renal blood flow, as well as extensive tubular injury. These alterations were associated with a significant decrease in urinary excretion of nitrites and nitrates (UNO2/NO3V). In the I/R + PFN group, recovery of renal function and UNO2/NO3V was observed, together with lesser histological signs of tubular injury compared to the I/R group.ConclusionsThis study shows that prophylactic administration of pirfenidone prevented acute kidney injury due to bilateral ischemia in the rat. Recovery of NO production appears to be one of the mechanism of pirfenidone renoprotective effect. Our findings suggest that pirfenidone is a promising drug to reduce renal injury induced by I/R.

A Recombinant Humanized Anticocaine Monoclonal Antibody Alters the Urinary Clearance of Cocaine and Its Metabolites in Rats.

A recombinant humanized anticocaine monoclonal antibody, h2E2, has shown potential in the preclinical phases for the treatment of cocaine abuse. The standard tests for cocaine usage are the detection of benzoylecgonine (BE) and cocaine in the urine. This includes workplace drug screens as well as in clinical trials for potential treatments of cocaine abuse. By sequestering cocaine into the plasma compartment, h2E2 prevents cocaine from entering the brain. Due to the altered disposition of cocaine in the presence of h2E2, we investigated the effects of h2E2 on cocaine and metabolite levels in the urine of rats to clarify the use of BE as an endpoint measurement for effectiveness in future clinical trials. The urine concentrations of cocaine and metabolites were considerably altered in the presence of h2E2. After a single injection of h2E2 (120 mg/kg) and cocaine hydrochloride (0.56 mg/kg), the concentration of cocaine and BE excreted into the urine of rats decreased by 92% and 91%, respectively, from vehicle controls. Due to the significant decrease in urinary excretion, BE is not an appropriate indicator of cocaine usage in the presence of h2E2. Another endpoint measurement must be selected for the measurement of cocaine usage in the upcoming clinical trials of h2E2. In contrast to the effects on cocaine and BE urinary excretion, there was a 3-fold increase in ecgonine methyl ester (EME) in the presence of h2E2. Therefore, we conclude that EME is a more appropriate measurement of cocaine intake in the presence of h2E2.

Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics.

Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assessing the role of OATP1B transporters in modulating hydroxyurea PK. Using wild-type and Oatp1b knockout (Oatp1b(-/-)) mice, hydroxyurea PK was analyzed in vivo by measuring [(14)C]hydroxyurea distribution in plasma, kidney, liver, urine, or the exhaled (14)CO2 metabolite. Plasma levels were significantly reduced by 20% in Oatp1b(-/-) mice compared with wild-type (area under the curve of 38.64 or 48.45 μg·h(-1)·ml(-1), respectively) after oral administration, whereas no difference was observed between groups following intravenous administration. Accumulation in the kidney was significantly decreased by twofold in Oatp1b(-/-) mice (356.9 vs. 748.1 pmol/g), which correlated with a significant decrease in urinary excretion. Hydroxyurea accumulation in the liver was also decreased (136.6 vs. 107.3 pmol/g in wild-type or Oatp1b(-/-) mice, respectively) correlating with a decrease in exhaled (14)CO2. These findings illustrate that deficiency of Oatp1b transporters alters the absorption, distribution, and elimination of hydroxyurea thus providing the first in vivo evidence that cell membrane transporters may play a significant role in modulating hydroxyurea PK. Future studies to investigate other transporters and their role in hydroxyurea disposition are warranted for understanding the sources of variation in hydroxyurea's PK.

Genistein in Sanfilippo disease: A randomized controlled crossover trial

Sanfilippo disease (mucopolysaccharidosis type III [MPS III]) is a rare neurodegenerative metabolic disease caused by a deficiency of 1 of the 4 enzymes involved in the degradation of heparan sulfate (HS), a glycosaminoglycan (GAG). Genistein has been proposed as potential therapy but its efficacy remains uncertain. We aimed to determine the efficacy of genistein in MPS III. Thirty patients were enrolled. Effects of genistein were determined in a randomized, crossover, placebo-controlled intervention with a genistein-rich soy isoflavone extract (10mg/kg/day of genistein) followed by an open-label extension study for patients who were on genistein during the last part of the crossover. Genistein resulted in a significant decrease in urinary excretion of total GAGs (p = 0.02, slope -0.68 mg GAGs/mmol creatinine/mo) and in plasma concentrations of HS (p = 0.01, slope -15.85 ng HS/ml/mo). No effects on total behavior scores or on hair morphology were observed. Parents or caregivers could not predict correctly during which period of the crossover a patient was on genistein. Genistein at 10mg/kg/day effectively reduces urinary excretion of GAGs and plasma HS concentration in patients with MPS III. However, the absolute reduction in GAGs and in HS is small and values after 12 months of treatment remain within the range as observed in untreated patients. No clinical efficacy was detected. Substantially higher doses of genistein might be more effective as suggested by recent studies in animal models.

Metabolomics analysis reveals elevation of 3-indoxyl sulfate in plasma and brain during chemically-induced acute kidney injury in mice: Investigation of nicotinic acid receptor agonists

An investigative renal toxicity study using metabolomics was conducted with a potent nicotinic acid receptor (NAR) agonist, SCH 900424. Liquid chromatography-mass spectrometry (LC–MS) and gas chromatography-mass spectrometry (GC–MS) techniques were used to identify small molecule biomarkers of acute kidney injury (AKI) that could aid in a better mechanistic understanding of SCH 900424-induced AKI in mice. The metabolomics study revealed 3-indoxyl sulfate (3IS) as a more sensitive marker of SCH 900424-induced renal toxicity than creatinine or urea. An LC–MS assay for quantitative determination of 3IS in mouse matrices was also developed. Following treatment with SCH 900424, 3IS levels were markedly increased in murine plasma and brain, thereby potentially contributing to renal- and central nervous system (CNS)-related rapid onset of toxicities. Furthermore, significant decrease in urinary excretion of 3IS in those animals due to compromised renal function may be associated with the elevation of 3IS in plasma and brain. These data suggest that 3IS has a potential to be a marker of renal and CNS toxicities during chemically-induced AKI in mice. In addition, based on the metabolomic analysis other statistically significant plasma markers including p-cresol-sulfate and tryptophan catabolites (kynurenate, kynurenine, 3-indole-lactate) might be of toxicological importance but have not been studied in detail. This comprehensive approach that includes untargeted metabolomic and targeted bioanalytical sample analyses could be used to investigate toxicity of other compounds that pose preclinical or clinical development challenges in a pharmaceutical discovery and development.

Unexpected Effect of Furosemide on Radioiodine Urinary Excretion in Patients with Differentiated Thyroid Carcinomas Treated with Iodine 131

In patients receiving (131)I for therapeutic purposes, diuretics are frequently used in an attempt to accelerate elimination of unbound radioiodine, reduce its adverse effects, and shorten the hospital stay. The aims of our study were to investigate the influence of furosemide therapy on urinary excretion of (131)I in patients with differentiated thyroid cancer (DTC), referred to radioiodine ablation after thyroidectomy, and to investigate whether diuretics are useful in daily practice in patients with DTC. Forty-three patients with DTC who had normal renal function and low (131)I uptake in cervical region (3.55 +/- 3.45%) were included in this study. The furosemide (20 mg) and potassium chloride (250 mg) were given orally to 23 patients 3 hours after the (131)I administration, and then q8h for 3 days. Twenty patients did not receive either furosemide or potassium chloride. After (131)I administration, the patients collected their urine for 3 days, and radioactivity of urine sample from each micturition was expressed as percentage of the administered dose. Radioactivity of blood samples was measured after 72 hours, and the values were corrected for decay of (131)I and expressed in relation to the administered dose. Initial whole-body measurement (immediately after (131)I administration) and the whole-body measurement after 72 hours were recorded for all patients. The 72-hour whole-body measurement was corrected for decay of (131)I, and expressed as a percentage of the initial whole-body measurement. Urinary excretion of (131)I was significantly lower in the patients who were taking furosemide and potassium chloride compared with the control group. The whole-body measurements after 72 hours (13.22 +/- 6.55% vs. 8.24 +/- 3.39% of the initial; p < 0.01, respectively) and the blood radioactivity (34.66 +/- 24.84 vs. 11.64 +/- 8.32 cpm/mL per 1 MBq of administered (131)I, p < 0.01) were found to be unexpectedly higher in the patients who were taking furosemide and potassium chloride compared with the control group. Our results demonstrated that furosemide given as an adjuvant medication in patients with DTC causes a significant decrease in urinary excretion of radioiodine and its higher blood concentration. Therefore, furosemide should not be recommended as an adjuvant therapy to radioiodine ablation in patients with DTC previously iodine depleted by low-iodine diet.

The influence of aminophylline on uretic beta 2 microglobulin in neonates with asphyxia

Objective To study the renal protection of aminophylline on neonates with asphyxia. Methods 52 neonates with perinatal asphyxia were random divided into experimental group (27 cases) that receive a single dose aminophylline (5mg/kg,) intervenous drop infusion and control group (25 cases) that reveived aqua proinjectione intervenous drop infusion during the first hour of life. The urinary excretion beta 2 micr- oglobulin ( β 2M) was detected for consecutive three days after birth in neonates with asphyxia. Data from two groups were analyzed by statistics.Results There was no statistically significance difference in the levels of β 2 M at 24 hours and 48 hour after birth ( P < 0.05 ) but a statistical significance of 72h after birth (P < 0.01 ) between the experiental group and control group.Conclusios A single dose of aminophylline ( 5mg/kg ) within the first hour of birth in neonates with perinatal asphyxia results in a significant decrease in urinary excretion of β2M. Key words: Newborn infant; Asphyxia; Aminophylline; Renal injury

Validation of lactose[15N,15N]ureide as a tool to study colonic nitrogen metabolism

In vitro experiments have shown that fermentation of carbohydrates prevents accumulation of nitrogen in the colon. Variable results have been obtained on modulation of dietary intakes in vivo. Lactose[15N,15N]-labeled ureide has been proposed as a tool to study colonic nitrogen metabolism. However, on oral administration of the marker, different urinary excretion patterns of the 15N label have been found. In this study, 50 mg lactose[15N,15N]ureide was directly instilled in the colon through an orocecal tube to investigate the colonic handling of this molecule in a direct way. In basal conditions, 42% (range, 37-48%) of labeled nitrogen administered as lactose[15N,15N]ureide was retrieved in urine after 72 h. A substantial variability in total urinary excretion of the label was found, but the urinary excretion pattern of the label was similar in all volunteers. When inulin, a fermentable carbohydrate, was administered together with the labeled marker, a significant decrease in urinary excretion of 15N after 72 h was found, to 29% (range, 23-34%). The effect of a smaller dose of inulin (250 mg) on colonic handling of lactose[15N,15N]ureide (50 mg), was investigated in another group of volunteers, and this time, fecal excretion of the marker was also evaluated. The results seem to indicate that fermentation of inulin causes an increased fecal excretion of the marker, thereby reducing urinary excretion but not retention in the human nitrogen pool. This instillation study shows that lactose[15N,15N]ureide is a tool with good properties to investigate the effect of different types of carbohydrates on nitrogen metabolism in the proximal colon in vivo.

Human heme oxygenase-1 gene transfer lowers blood pressure and promotes growth in spontaneously hypertensive rats.

Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin, with release of free iron and carbon monoxide. Both heme and carbon monoxide have been implicated in the regulation of vascular tone. A retroviral vector containing human HO-1 cDNA (LSN-HHO-1) was constructed and subjected to purification and concentration of the viral particles to achieve 5x10(9) to 1x10(10) colony-forming units per milliliter. The ability of concentrated infectious viral particles to express human HO-1 (HHO-1) in vivo was tested. A single intracardiac injection of the concentrated infectious viral particles (expressing HHO-1) to 5-day-old spontaneously hypertensive rats resulted in functional expression of the HHO-1 gene and attenuation of the development of hypertension. Rats expressing HHO-1 showed a significant decrease in urinary excretion of a vasoconstrictor arachidonic acid metabolite and a reduction in myogenic responses to increased intraluminal pressure in isolated arterioles. Unexpectedly, HHO-1 chimeric rats showed a simultaneous significant proportionate increase in somatic growth. Thus, delivery of HHO-1 gene by retroviral vector attenuates the development of hypertension and promotes body growth in spontaneously hypertensive rats.

Choline Supplementation Alters Carnitine Homeostasis in Humans and Guinea Pigs

We have previously shown that supplementary choline causes significant decreases in urinary excretion of carnitine in humans. The objectives of the present work were to study this interaction in a different human population and on other body pools of carnitine in an animal model. In young adult women, daily choline supplementation (20 mg/kg body wt) resulted in a 75% lower urinary carnitine excretion than in controls, without significantly altering plasma carnitine concentrations. Supplementary choline was added to the ground diet of Sprague-Dawley rats (2.5 g/kg diet) and guinea pigs (3 g/kg diet). Choline supplementation had no effect on plasma concentrations or urinary excretion of carnitine in the rats. In guinea pigs, however, choline supplementation resulted in a significantly lower urinary excretion and higher plasma total carnitine concentrations. The skeletal muscle carnitine concentration was higher in the choline-supplemented guinea pigs, but not significantly higher in other tissues. These studies demonstrated that choline supplementation results in decreased urinary excretion of carnitine in young adult women, that guinea pigs are a suitable animal model for studying the effect of choline supplementation on carnitine status in humans, and that choline results in a conservation of carnitine in guinea pigs and perhaps in humans.

Soy of dietary source plays a preventive role against the pathogenesis of prostatitis in rats

This study examined the effects of diet on the development of prostatitis in male rats. Adult male rats were placed on either of two specially formulated diets which differed from one another by the presence or absence of soy as the protein source. A third group of rats (control) was fed standard laboratory rat chow which also includes soy as a source of protein. After 11 weeks, it was found that rats maintained on soy-free diet developed prostatitis mainly in the lateral lobe of the prostate. Increased severity and incidence of prostatitis in rats maintained on the soy-free diet coincided with a significant decrease in urinary excretion of various phytoestrogens. There was no evidence of prostatitis in rats maintained on soy-containing diets. Urinary excretion of phytoestrogens in rats maintained on soy-containing diet was also not different from controls. These results suggest that soy as a dietary source plays a protective role against the development of prostatitis in rats, and indicate that the ventral, lateral and dorsal lobes of the rat prostate have differnt sensitivities to alterations in dietary factors.

Prostaglandin E2 in renal transplant recipients.

The concentrations of prostaglandin E2 (PGE2), sodium, potassium and creatinine were determined in the blood and urine of 50 renal transplant recipients treated with cyclosporine A or azathioprine, as immunosuppressive agents, for at least one year post transplantation. Fourteen healthy subjects served as control group. The urinary PGE2 excretion was significantly decreased in all treated renal transplant recipients and this reduction was associated with significant decrease in urinary excretion of sodium and potassium. On the other hand, a high elevation in blood PGE2 concentration was observed while no significant changes were seen in sodium and potassium levels in the blood of these renal transplant recipients. The observations suggest an association between urinary PGE2 reduction and immunosuppressive treatments in renal transplant recipients; also, PGE2 may regulate intra-renal haemodynamics and influence the renal tubular electrolyte excretion. Moreover, urinary PGE2 can be used as an indicator of successful renal transplantation.

The Impact of Liver Cirrhosis and Cholelithiasis on Phase I and II Reactions Using Antipyrine and Trimethadione as a Model Substrate.

Five male patients with extrahepatic cholelithasis and ten male patients with liver cirrhosis were administered simultaneously 4mg/kg trimethadione (TMO) and 500mg/man antipyrine (AP). Changes in phase I (AP and TMO) and phase II (AP) reactions of the model substrates in liver disease were examined. The patients with liver cirrhosis exhibited prolonged half-life (t1/2) and decreased metabolic clearance (CL) of AP when compared with cholelithasis patients, while no change was found in the apparent volume of distribution (Vd). The serum dimethadione (DMO)/TMO ratio at 4hr after oral administration of TMO was apparently decreased in the cirrhotic patients. The cirrhotic patients also exhibited significant decreases in urinary excretion and clearance for production of three major AP metabolites (4-hydroxyantipyrine, 3-hydroxymethyl-3-norantipyrine, and 3-hydroxymethylantipyrine), while no significant differences between the cirrhotic patients and cholelithasis patients were noted in percentages of either total or individual glucuronidation of these metabolites. These findings suggest that AP and TMO metabolisms (phase I) are severely impaired in cirrhotic patients, whereas glucuronidation of AP is unaffected (phase II).

Sex differences in salicylic acid metabolism in streptozotocin induced diabetes in rats

The metabolism of salicylic acid was studied in male and female streptozotocin-induced diabetic Wistar rats. Results obtained showed that in both sexes there was a significant increase in urinary excretion of salicyluric acid in diabetic rats when compared to controls (P less than or equal to 0.001). Within the diabetic groups, there was a significant increase in the urinary excretion of salicyluric acid in the female in comparison to the male rats (P less than or equal to 0.01). A statistically significant increase was observed in urinary excretion of salicyl-glucuronic acid in diabetic female compared to control female rats (P less than or equal to 0.01) while comparison of diabetic male to control male showed a significant decrease in urinary excretion of salicyl-glucuronic acid (P less than or equal to 0.01). Comparison of the diabetic female and male groups showed a high statistically significant difference in urinary excretion of salicyl-glucuronic acid. The diabetic ration, ie diabetic/control was significantly higher in female than in male rats with respect to salicyl-glucuronic acid (P less than or equal to 0.001) and total urinary excretion (P less than or equal to 0.01). The diabetic ratio may likely reflect the true significance of the roles played by the two metabolic pathways. The results suggest sex differences in the metabolism of salicylic acid; this may also be the case in other disease states.

Renal excretion of an angiotensin I converting enzyme inhibitor (SA-446) in dogs

The renal excretory mechanism of an orally active inhibitor of angiotensin converting enzyme (SA-446) was examined in anesthetized dogs. Parenteral administration of this compound resulted in production of constant levels of about 2 mg/l in the plasma (PSA) and the urine concentration was 726 +/- 200 mg/l, a level significantly higher than that in the plasma. Renal clearance of SA-446 (CSA) was 2.24 +/- 0.34 ml/g X min and was significantly higher than GFR. The clearance ratio (CSA/GFR) of over 1.0 was indicative of a net tubular secretion. Administration of probenecid resulted in a significant rise in PSA and in a significant decrease in urinary excretion but with no change in the plasma protein binding ratio. CSA decreased significantly from 2.24 +/- 0.34 to 0.71 +/- 0.14 ml/g X min. The inhibitory action of SA-446 (0.02 mg/kg, i.v.) on the pressor response to angiotensin I disappeared at about 50 min, this action being maintained for about 2 h in the probenecid pretreated dog. Since probenecid is a competitive inhibitor of organic anion secretory transport, our results show the net tubular secretion of SA-446, via organic anion transport systems. Prolongation of the action of SA-446, as induced by probenecid may be due to the increase of plasma concentration, by the inhibition of tubular secretion.

Decreased Prostaglandin E2 Renal Synthesis in Women with Phaeochromocytoma

1. Urinary excretion of prostaglandins E2 and F2α were determined in 11 women with phaeochromocytoma and in 23 healthy women. 2. In patients with phaeochromocytoma a significant decrease in urinary excretion of PGE2 and a significant increase in urinary excretion of PGF2α were observed in comparison with controls. 3. Decreased urinary PGE2 and increased urinary PGF2α excretion suggest impaired renal prostaglandin synthesis or metabolism. 4. High PGF2α excretion in association with reduced PGE2 excretion may reflect enhanced activity of 9-ketoreductase, probably caused by excess catecholamines.

The Effect of Mental Stress on Prostaglandin F2α in Patients with Essential Hypertension and in Healthy Subjects

1. The influence of mental stress, 30 min Kraepelin's arithmetic test under noise on the plasma concentration and urinary excretion of prostaglandin (PG) F2 alpha was studied in patients with essential hypertension and in healthy subjects. 2. Before the arithmetic test the plasma PGF2 alpha in hypertensive patients was significantly higher than in healthy subjects. The mental stress produced a significant increased in plasm PGF2 alpha in healthy subjects but not in patients with essential hypertension. 3. Three hour urine excretion of PGF2 alpha before stress was about two times lower in hypertensive patients than in healthy subjects. After exposure to stress a significant decrease in urinary excretion of PGF2 alpha was found in healthy subjects, but not in hypertensive patients. 4. The stress-induced increase in plasma PGF2 alpha of healthy subjects may reflect elevated brain PGF2 alpha synthesis. The individual differences in response to stress in hypertensive patients may result from specific impairments in synthesis and/or prostaglandin turnover.

The effect of gentamicin on liver glucuronyl transferase

Summary The effect of gentamicin on the liverenzyme glucuronyl transferase activity in vitro and on salicylamide glucuronide excretion in vivo was investigated. Little or no inhibition of the enzyme activity was observed after the addition of gentamicin to the substrate in concentrations similar to those observed in blood after the therapeutic administration of this agent. Only in concentrations greater than those produced by therapeutic doses was significant inhibition of the enzyme glucuronyl transferase activity observed. A significant decrease in urinary excretion of salicylamide glucuronide was observed after the administration of gentamicin. No reduction in the binding capacity of a 4 Gm. per cent crystalline human albumin solution for HBABA was observed in any of the drug dilutions.

EFFECT OF ETHANOL ON FORMATION OF HIPPURIC ACID BY THE LIVER.

SummaryThe effect of ethanol on the formation of hippuric acid was determined in studies on non-fasting human males without renal or hepatic disease after oral or intravenous administration of sodium benzoate and premedication with glycine by mouth. Ethanol, given orally or intravenously, resulted in significant decreases in urinary excretion of hippuric acid in all subjects tested. Each subject served as his own control. In similar studies, intravenous administration of sorbitol produced no significant changes in urinary excretion of hippuric acid. The results suggest that the hepatic processes that conjugate benzoate with glycine to form hippurate are impaired during oxidation of ethanol.