The Effect of Tadalafil on Renal Fibrosis Induced by Ureteral Obstruction / Efecto del Tadalafil en la Fibrosis Renal Inducida por Obstrucción Uretral

ABSTRACT Objective: It has been reported that phosphodiesterase-5 (PDE-5) inhibitors improve kidney function during acute and chronic renal failure. This study aimed to determine the possible therapeutic effects of tadalafil, a specific PDE-5 inhibitor, on renal fibrosis induced by unilateral ureteral obstruction (UUO). Methods: Male Sprague-Dawley rats were used and randomly divided into three groups (n = 6) as sham-operated, UUO and tadalafil-treated (10 mg/72 hours, ig) UUO (UUO+T) groups. Unilateral ureteral obstruction was induced by complete ligation of the left ureter and 14 days after surgery creatinine clearance, urinary cyclic guanosine monophosphate (cGMP), renal alpha-smooth muscle actin (α-sma) and transforming growth factor βeta (TGF-β) levels, as well as histologic changes, were observed in all the animals. Results: Unilateral ureteral obstruction-induced renal fibrosis was confirmed by increased α-sma level, collagen deposition, tubular dilation, inflammatory cell infiltration and necrosis. An increased renal TGF-β level and decreased urinary cGMP level was also observed in obstructed animals in addition to reduced creatinine clearance. Tadalafil treatment, which restored the animals 'urinary cGMP level, significantly attenuated the fibrotic changes and TGF-β increase in their kidneys. Conclusion: This study suggests that tadalafil treatment ameliorates renal fibrosis by reducing TGF-β expression and may have important clinical relevance since tadalafil is currently used clinically to treat erectile dysfunction and pulmonary hypertension.

RESUMEN Objetivo: Se ha reportado que los inhibidores de la fosfodiesterasa-5 (PDE-5) mejoran las funciones renales durante la insuficiencia renal aguda y crónica. Este estudio tuvo por objetivo determinar los posibles efectos terapéuticos del tadalafil - un inhibidor específico de la PDE-5 - sobre la fibrosis renal inducida por una obstrucción ureteral unilateral (OUU). Métodos: Se utilizaron ratas machos Sprague-Dawley, divididas de manera aleatoria en tres grupos (n = 6): operación simulada, OUU y tratamiento con tadalafil (10 mg/72 horas, IG), y OUU (OUU+T). La obstrucción uretral unilateral fue inducida por una ligadura completa del uréter izquierdo y 14 días después de la cirugía, se observaron niveles de monofosfato de guanosina cíclico (GMP) urinario, alfa-actina de músculo liso (α-SMA), y factor de crecimiento transformante βeta (FCT-β), así como cambios histológicos en todos los animales. Resultados: La fibrosis renal inducida por obstrucción uretral unilateral fue confirmada por un aumento del nivel de α-SMA, deposición de colágeno, dilatación tubular, infiltración de células inflamatorias y necrosis. También se observó un aumento del nivel de FCT-β renal y una disminución del nivel de GMP urinario en los animales con obstrucción, además de una reducción del aclaramiento de la creatinina. El tratamiento con tadalafil, que restauró el nivel de GMP urinario de los animales, atenuó significativamente los cambios fibróticos y el aumento de FCT-β en los riñones. Conclusión: Este estudio sugiere que el tratamiento con tadalafil mejora la fibrosis renal al reducir la expresión de FCT-β y puede tener una importante relevancia clínica por cuanto el tadalafil se usa hoy día clínicamente para tratar la disfunción eréctil y la hipertensión pulmonar.

Formulation of lyophilized single vial kit of N-N-Ethylene-L-Dicysteine 99m [EC] for labeling with Tc. II: Radiochemical and clinical evaluation 99mr as a renal tubular agent in comparison with Tc-MAG[3]

A Technetium[99m]Tc labeled lyophilized single component kit of N-N-ethylene-I-dicysteine [EC] is developed to replace multiple step kit developed by others. The aim of study is to formulate a radionuclide that is easy to prepare, has rapid plasma clearance, produce high quality images and is an affective alternative to radioiodine labeled orthoiodohippurate, which has been remained the physiological 'gold standard' since long time. To achieve this goal, the systematically varied key parameters such as pH, the use of reducing agents, stabilizers and additives are optimized to obtain maximum radiochemical purity and optimum bio distribution in non human and human primates. Various pH levels of EC showed equally good results in animal experiments but only pH 10 was suitable for human use. Dynamic and renal Scintigraphic studies are carried out with[99m]Tc-EC at pH 8 in 12 volunteers and at pH 10 in 18 volunteers and compared with[99m]Tc-MAG[3], Background ratios, renograms, relative renal function and semi quantitative parameters are available in all studies. The background ratios [mean +/- SD] at 30[th] minute are 0229+/-0.024 and 0.236+/-0.018 for[99m]Tc-EC at pH 10 and[99m]c-MAG[3] respectively. The mean +/- standard error of mean [SEM] values of T[M]X and time to half activity [T[12]] for[99m]Tc-EC [pHIO] are 3.7+/-0.6 and 7.3+/-1.0 respectively while for [99m]Tc-MAG[3], they are 4.0+/-0.8 and 7.9+/-1.4 with p values 0.001 and 0.049 respectively. The values of relative renal function [RRF] for[99m]Tc-EC and[99m]Tc-MAG[3] are 50.8+/-3.11 and 51.2+/-3.4 respectively with p value of 0.822. The residual activity at 25[th] minute [A[25] / A[MAX]] and renal uptake are 0. 209+/-12.67+/-2.80 for[99m]Tc-EC and 0.218+/-0.035 and 1053+/-2.98 for[99m]Tc-MAG[3] [p=0.031 an 0.0003] respectively. The correlation coefficient [R] for T[max], T1/2, A[2]5/A[Max] and renal uptake are 0.96, 0.69, 0.93 and 0.85 respectively

Nephroprotective activity of Solanum xanthocarpum fruit extract against gentamicin-induced nephrotoxicity and renal dysfunction in experimental rodents

OBJECTIVE@#To evaluate nephroprotective potential of Solanum xanthocarpum (S. xanthocarpum) fruit extract(SXE) against gentamicin (GM) induced nephrotoxicity and renal dysfunction.@*METHODS@#Twenty-four Wistar rats were divided into four groups (n=6). Control rats that received normal saline (i.p.) and 0.5% carboxymethyl cellulose (p.o.) per day for 8 d. Nephrotoxicity was induced in rats by intraperitoneal administration of GM (100 mg/kg/d for 8 d) and were treated with SXE (200 and 400 mg/kg/d (p.o.) for 8 d). Plasma and urine urea and creatinine, kidney weight, urine output, blood urea nitrogen, renal enzymatic and non-enzymatic antioxidants and lipid peroxidation was evaluated along with histopathological investigation in various experimental groups of rats.@*RESULTS@#It was observed that the GM treatment induced significant elevation (P<0.001) in plasma and urine urea, creatinine, kidney weight, blood urea nitrogen, renal lipid peroxidation along with significant decrement (P<0.001) in urine output, renal enzymatic and non-enzymatic antioxidants. SXE 200 and 400 mg/kg treatment to GM treated rats recorded significant decrement (up to P<0.001) in plasma and urine urea and creatinine, renal lipid peroxidation along with significant increment (up to P<0.001) in renal enzymatic and non-enzymatic antioxidants. Histological observations of kidney tissues too correlated with the biochemical observations.@*CONCLUSIONS@#These finding powerfully supports that S. xanthocarpum fruit extract acts in the kidney as a potent scavenger of free radicals to prevent the toxic effects of GM both in the biochemical and histopathological parameters and thus validates its ethnomedicinal use.

Suplementación con antioxidantes no previene nefrotoxicidad por cisplatino en pacientes con cáncer cérvico uterino avanzado / Anti oxidant agent does not prevent nefro-toxicity in advance cervical cancer patients

En México el cáncer cérvico uterino al igual que en otros países de América representa un grave problema de salud pública. El tratamiento depende de su extensión; los estadios localmente avanzados son tratados con una combinación de quimioterapia con cisplatino y radioterapia. Ambas terapias utilizadas son consideradas oxidativas y por ello son capaces de influir en las toxicidades del propio tratamiento, el objetivo de este trabajo es determinar la eficacia de la suplementación con antioxidantes y su efecto sobre la prevención de la toxicidad renal por cisplatino. Ensayo clínico aleatorizado que incluyó a pacientes con cáncer cérvico uterino en estadios localmente avanzados cuyo tratamiento antineoplásico consistió en radioterapia y quimioterapia con cisplatino. Se asignó aleatoriamente a las pacientes a recibir un suplemento antioxidante diariamente o bien un placebo. Se determinó la función renal mediante la depuración de creatinina antes de iniciar el tratamiento y al término del mismo. Se realizaron pruebas t-Student inter e intra grupales a fin de determinar el efecto de la suplementación sobre los parámetros evaluados. No se encontraron diferencias estadísticamente significativas entre ambos grupos; en cambio, existió una disminución significativa en ambos grupos al finalizar el tratamiento. La suplementación con antioxidantes no es capaz de prevenir la toxicidad a nivel renal producida por la quimioterapia con cisplatino.

In Mexico, our country, the pathology of cervical cancer is a major public health issue, the same situation is present in other American countries. The treatment for this pathology depends on its extension; for locally advanced stages, a combination of radiotherapy and chemotherapy with cisplatin drug is common used. The both therapies are considered to be pro oxidative and this can be implied in the toxicities of the treatment. The objective of this work was to determine the efficacy of antioxidant supplementation on the prevention of cisplatin drug in the renal toxicity. We conducted a randomized clinical trial in the patients with locally advanced stage cervical cancer whose antineoplastic treatment consisted in radiation therapy and chemotherapy with the cisplatin drug. The patients were randomly assigned to receive either an antioxidant supplement or the placebo. We assessed renal function as creatinine clearance before and after concluding the oncologic treatment. We performed inter and intragroupal t-Student tests in order to determine the effect of the antioxidant supplementation on the evaluated parameters. No statistically significant differences we were found between the groups; however, there was a significant decrease in renal function in the both groups after finalizing the oncologic treatment. The antioxidant supplementation does not prevent the renal toxicity from the cisplatin drug chemotherapy.

Medicamentos excepcionais para doença renal crônica: gastos e perfil de utilização em Minas Gerais, Brasil / Dispensing of exceptional drugs for chronic renal failure: expenditures and patients' profile in Minas Gerais State, Brazil

No Brasil, os medicamentos para o tratamento da doença renal crônica são disponibilizados gratuitamente pelo Sistema Único de Saúde (SUS). Este estudo teve como objetivos descrever os gastos públicos com esses medicamentos em Minas Gerais, Brasil, e o perfil dos usuários; objetivou, também, analisar os fatores associados ao gasto médio mensal individual. Observou-se que o gasto total com os medicamentos estudados (R$ 41,6 milhões) representa uma parcela significativa do gasto total com procedimentos ambulatoriais no SUS (9,6 por cento). A maioria dos usuários é do sexo masculino, adultos jovens e teve como causa principal de doença renal crônica a hipertensão arterial. A análise multivariada indicou tendência de menor gasto entre indivíduos que eram mais idosos, que tinham como causa principal da doença o diabetes, que fizeram uso de hidróxido de ferro e que residiam em municípios de menor IDH-M (p < 0,05). Finalmente, o estudo indicou a importância de ferramentas gerenciais que permitam visualizar a trajetória dos pacientes no sistema de saúde, as quais sejam capazes de subsidiar o processo de formulação de políticas de saúde.

In Brazil, medicines for treatment of chronic renal failure are available free of cost from the Unified National Health System (SUS). This study's objectives were to describe government spending on these drugs in Minas Gerais State, Brazil, and the patients' profile, as well as to analyze the factors associated with individual average monthly costs. Spending on medication for chronic renal failure (R$ 41.6 million, or U$25 million) represents a significant portion of total spending on outpatient procedures in the National health System (9.6 percent). Most patients are young adult males with arterial hypertension as the main cause of chronic renal failure. Multivariate analysis showed a trend towards lower spending on elderly patients, those with diabetes as the main underlying disease, those using iron hydroxide, and in municipalities with a lower human development index, or HDI (p < 0.05). Finally, the study indicated the importance of management tools that allow monitoring the trajectory of individual patients in the health system and support appropriate health policymaking.

Effects of Chinese kidney-tonifying drugs on bone mineral density (BMD), biomechanics, 25-hydroxy vitamin D3 and 1,25-dihydroxy vitamin D3 of ovariectomized osteoporosis rats / 中国骨伤

<p><b>OBJECTIVE</b>To investigate the effects of Chinese kidney-tonifying drugs on bone mineral density, biomechanics, 25-hydroxy Vitamin D3 and 1,25-dihydroxy Vitamin D3 of ovariectomized osteoporosis rats, and explore the mechanism of treating osteoporosis with the drugs.</p><p><b>METHODS</b>Thirty-six female SD rats (four months) were randomly divided into model group, sham group and treatment group. All the rats had been ovariectomied except those in sham group. Selecting 4, 8, 12 weeks in the experiment, the value of bone mineral density (BMD) was measure by dual energy X-ray absorptiometry (DEXA) of femoral head, while the biomechanics machine was applied to analysis femoral head biomechanics index and ELISA method was used to detect the content of 25-hydroxy Vitamin D3 and 1,25-dihydroxy Vitamin D3 discern in blood-serum, liver and kidney.</p><p><b>RESULTS</b>Treatment group rats' BMD of femoral head was enhance compared with model group, significant differences were absent (P<0.05), and the maximal load and maximal stress measurement were improved, significant differences were absent (P<0.05). As the content of 25-hydroxy Vitamin D3 and 1,25-dihydroxy Vitamin D3 discern in blood-serum, liver and kidney were elevate, furthmore there were significant differences in group comparison, all significant differences were absent (P<0.05). But those compared with sham group, there was no significant difference (P>0.05).</p><p><b>CONCLUSION</b>In the early period in absence of estrogenic hormone, the Chinese kidney-tonifying drugs could activate bone metabolism to raise BMD and reinforce quality of bone through up-regulating expression of 25-hydroxy Vitamin D3 and 1,25-dihydroxy Vitamin D3 at protein level.</p>

Síndrome poliúrico / Poliuric syndrome

Se sospecha Síndrome Poliúrico (SP) cuando el volumen urinario excede en 2 a 3 veces lo esperado para la edad o cuando a raíz de una deshidratación o restricción hídrica no se produce concentración urinaria adecuada. El volumen y la osmolaridad de los líquidos orgánicos se regulan con gran precisión gracias a la actividad de la hormona antidiurética (HAD), producida en el eje hipotálamo hipofisiario, que maneja la permeabilidad del agua de los túbulos distales y colectores renales. El SP se clasifica en dos grandes grupos: 1) con niveles plasmáticos bajos de HAD (diabetes insípida central DIC o neurogénica y polidipsia primaria) y 2) con niveles plasmáticos normales de HAD (diuresis osmótica y diabetes insípida nefrogénica DIN). El diagnóstico diferencial se hace con la prueba de deprivación acuosa y el tratamiento consiste en reemplazo hormonal con HAD en DIC y en la DIN reducción del aporte calórico proteico con la ingesta libre de agua, más diuréticos tiazídicos y antiinflamatorios. En el presente artículo se hace una revisión actualizada del SP.

Renoprotective effects of matrine on experimental glomerulosclerosis in rats / 中华儿科杂志

<p><b>OBJECTIVE</b>Matrine has an anti-fibrosis effect, such as hepatic cirrhosis and derma fibrosis, while its effect on glomerulosclerosis is unknown. The purpose of this study was to analyze the renoprotective effects of matrine on experimental glomerulosclerosis in rats and inquire into its mechanisms.</p><p><b>METHODS</b>The rats were randomly assigned to following groups: normal control group, model control group, benazepril treatment group, matrine 100 mg/kg treatment group and matrine 50 mg/kg treatment group. The rats of normal control group were subjected to sham operation and were injected with normal saline via the tail vein one week later. The rats of the other groups were uninephrectomized and injected with adriamycin (5 mg/kg) via the tail vein one week later. The dose of benazepril was 6 mg/kg. Both matrine and benazepril were given by gastric perfusion from the first day after the operation. The level of urinary protein was measured at the 2nd, 4th and 6th week after the operation. The serum total protein and albumin, serum creatinine, blood urea nitrogen (BUN) were tested only at the 6th week after operation. Renal pathology changes were evaluated at the 6th week as well. Immunohistochemistry was used to detect the expression of fibronectin (FN), laminin (LN), connective tissue growth factor (CTGF) and transforming growth factor-beta1 (TGF-beta1) in glomeruli.</p><p><b>RESULTS</b>Matrine and benazepril not only reduced the excretion of urinary protein and the level of serum creatinine and BUN, but also significantly ameliorated glomerular mesangial proliferation and glomerular sclerosis (P < 0.05, respectively). Immunohistochemical staining indicated that there was an increasing FN, LN, CTGF and TGF-beta1 expression in model control group as compared to the three treatment groups (P < 0.05). Matrine 100 mg/kg treatment group and benazepril treatment group showed much more advantages than matrine 50 mg/kg treatment group (P < 0.05), but there was no significant difference between the former two groups (P > 0.05).</p><p><b>CONCLUSION</b>Matrine has a renoprotective effect on experimental glomerulosclerosis in rats, the possible mechanism might relate to the reduction of the TGF-beta1 negative function via CTGF, which will inhibit the activation and proliferation of glomerular intrinsic cells, decrease the secretion of ECM accordingly.</p>

Nocturnal enuresis.

Childhood enuresis is a common socially disruptive problem. The possible pathophysiological factors include a disorder of sleep arousal, nocturnal polyuria, and low bladder capacity. The evaluation of a patient with nocturnal enuresis is aimed to exclude any organic pathology, UTI and voiding dysfunction. An approach to management of this common disorder is outlined.

Effect of selective angiotensin antagonists on the antidiuresis produced by angiotensin-(1-7) in water-loaded rats

In the present study we evaluated the nature of angiotensin receptors involved in the antidiuretic effect of angiotensin-(1-7) (Ang-(1-7)) in water-loaded rats. Water diuresis was induced in male Wistar rats weighing 280 to 320 g by water load (5 ml/100 g body weight by gavage). Immediately after water load the rats were treated subcutaneously with (doses are per 100 g body weight): 1) vehicle (0.05 ml 0.9 percenr NaCl); 2) graded doses of 20, 40 or 80 pmol Ang-(1-7); 3) 200 nmol Losartan; 4) 200 nmol Losartan combined with 40 pmol Ang-(1-7); 5) 1.1 or 4.4 nmol A-779; 6) 1.1 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 7) 4.4 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 8) 95 nmol CGP 42112A, or 9) 95 nmol CGP 42112A combined with 40 pmol Ang-(1-7). The antidiuretic effect of Ang-(1-7) was associated with an increase in urinary Na+ concentration, an increase in urinary osmolality and a reduction in creatinine clearance (CCr: 0.65 ñ 0.04 ml/min vs 1.45 ñ 0.18 ml/min in vehicle-treated rats, P<0.05). A-779 and Losartan completely blocked the effect of Ang-(1-7) on water diuresis (2.93 ñ 0.34 ml/60 min and 3.39 ñ 0.58 ml/60 min, respectively). CGP 42112A, at the dose used, did not modify the antidiuretic effect of Ang-(1-7). The blockade produced by Losartan was associated with an increase in CCr and with an increase in sodium and water excretion as compared with Ang-(1-7)-treated rats. When Ang-(1-7) was combined with A-779 there was an increase in CCr and natriuresis and a reduction in urine osmolality compared with rats treated with Ang-(1-7) alone. The observation that both A-779, which does not bind to AT1 receptors, and Losartan blocked the effect of Ang-(1-7) suggests that the kidney effects of Ang-(1-7) are mediated by a non-AT1 angiotensin receptor that is recognized by Losartan.

Estudo prospectivo controlado comparando lomefloxacina e ampicilina mais probenecide em dose única oral no tratamento de uretrite gonocócica aguda no homem / Controlled prospective study comparing lomefloxacin and ampicilin more probenecid in a single dose in the treatment of acute gonococcal urethritis in the man

As infecçöes gonocócicas há muito constituem um fator de importância para a saúde pública, devido à sua alta prevalência na populaçäo. Torna-se, portanto, imperioso a obtençäo de tratamentos eficazes e práticos, visando a observância completa do paciente ao tratamento, a cura clínica e a interrupçäo do ciclo de transmissäo. Neste estudo comparou-se lomefloxacina e ampicilina, quanto a sua eficácia clínica, laboratorial e seus efeitos colaterais, administradas em dose única. A lomefloxacina mostrou-se superior quanto à eficácia e apresentou menos efeitos adversos em relaçäo à ampicilina.