Antimuscarinic properties of vamicamide,a novel compound for the treatment of pollakiuria

The antimuscarinic profile of vamicamide, a novel compound for the treatment of pollakiuria, was investigated in both in vitro and in vivo preparations. Vamicamide (10 nM–10 μM) inhibited the contractile response of isolated guinea-pig detrusor muscle to transmural electrical stimulation. In isolated guinea-pig detrusor muscle, vamicamide also inhibited contractile response to carbachol with an IC₅₀ value of 0.71 μM, whereas it had little or no effect on detrusor contractions induced by KCl, BaCl₂, or α, β-methylene ATP. In binding studies with dog membrane preparations, the dissociation constant (Ki) of vamicamide against tritiated N-methylscopolamine ([³H]NMS) binding was 172 ± 8 nM for the urinary bladder, which was lower (P < 0.01) than those for the heart (322 ± 31 nM), stomach (317 ± 29 nM), and salivary gland (321 ± 32 nM). The Ki value for the cerebral cortex (95 ± 4 nM) tended to be lower than that for the urinary bladder. In binding studies with cloned human muscarinic receptor subtypes (m1–m3), the dissociation constant (Ki) of vamicamide against [³H]NMS binding was 89.0 ± 3.5 nM for the m3 receptor subtype, which was lower than those for the m1 (235 ± 5 nM, P < 0.05) and m2 (593 ± 49 nM, P < 0.01) receptor subtypes. In anesthetized dogs, vamicamide (3.2–100 μg/kg; 11–336 nmol/kg, iv) inhibited the carbachol-induced contractile responses of the urinary bladder with an ID₅₀ value of 16.1 μg/kg (54 nmol/kg), the stomach with a value of 31.3 μg/kg (105 nmol/kg), the descending colon with a value of 10.1 μg/kg (34 nmol/kg), and secretory response of the salivary gland to carbachol with a value of 43.3 μg/kg (146 nmol/kg); the inhibitory effects of the compound on the stomach and salivary gland were weaker (P < 0.01) than that on the urinary bladder. Furthermore, duration of the action of vamicamide was longer on the urinary bladder and descending colon than those on the stomach and salivary gland. These results suggest that vamicamide has a selective binding affinity to the muscarinic m3 receptor subtype and exhibits greater and longer inhibitory action on the urinary bladder than the other organs examined. © Wiley-Liss, Inc.     

ACUTE EFFECT OF PHYSIOLOGICAL CONCENTRATIONS OF VASOPRESSIN ON RAT RENAL FUNCTION

1. The antidiuretic, pressor and electrolyte transport effects of arginine vasopressin (AVP) were simultaneously evaluated in the anaesthetized water diuretic rat. Increasing concentrations of AVP (7.5, 75 and 750 ng/kg bolus and per h), were used to produce plasma levels which approximate the physiological range (4.8 ± 2.4, 35.7 ± 12.5, 85.2 ± 16.1 pg/mL respectively). 2. Administration of a minimally effective antidiuretic dose (7.5 ng) increased mean urine osmolality (from 101 ± 7 to 312 ± 89 mosmol/kg) without altering mean arterial pressure (MAP), renal plasma flow (RPF) or glomerular filtration rate (GFR). A maximal antidiuretic dose of AVP (75 ng) increased mean urine osmolality to 2002 ± 109 mosmol/kg and was associated with significant mean increases in MAP (9 mmHg), RPF and GFR (25%) by 30–60 min. A further ten-fold increase in AVP (750 ng) produced a greater increase in MAP (116 ± 6 to 134 ± 7 mmHg; P < 0.01) as well as increasing RPF and GFR by 35.5 and 38.9% respectively. 3. Increasing concentrations of AVP also progressively increased the fractional excretion of sodium, potassium and phosphate. However, fractional calcium and magnesium excretion was significantly decreased with maximal and supramaximal concentrations. 4. These studies support evidence that AVP is a pressor hormone in physiological concentrations in baroreceptor intact animals. Its role in renal electrolyte transport is unclear. Measured increases in RPF and GFR with the maximal and supramaximal AVP concentrations appear to be correlated with the increase in MAP.     

HAEMODYNAMIC, RENAL AND HORMONAL RESPONSES TO ENALKIREN IN FOUR PATIENTS WITH POST-SURGICAL OLIGURIA

1. The haemodynamic and hormonal responses of four patients with acute post-surgical oliguria (urine output <0.5 mL/kg perh) were measured in response to the renin inhibitor enalkiren. Enalkiren was infused at 0.01 up to 0.1 mg/kg perh for up to 4h. 2. Enalkiren infusion was associated with a progressive fall in blood pressure, clinically significant in three of the four patients. Systemic vascular resistance fell in proportion to blood pressure fall. Cardiac output and pulse rate remained unchanged. Effective renal plasma flow rose in all four cases (236 ± 19 to 327± 38). There was no change in urine flow rate, or urinary sodium excretion. 3. Plasma renin activity (ng angiotensin I/mL perh) fell from 1.9 ± 0.5 to 0.02 ± 0.01 (P<0.04), plasma angiotensin II (pg/mL) fell from 104 ± 93 to 7.7 ± 1.5, and plasma aldosterone (ng/dL) fell from 32 ± 8 to 21 ± 9 (P= 0.03) at the highest infusion dose. 4. Enalkiren inhibited plasma renin activity with reduced plasma angiotensin II and aldosterone concentrations. This was associated with vasodilation, reduced blood pressure and maintained cardiac output. There was no beneficial effect on renal function in these patients with post-surgical oliguria.     

隔附子饼灸联合生物反馈刺激对脊髓损伤后尿潴留病人膀胱功能、膀胱压力及尿路感染的影响

目的 探究隔附子饼灸联合生物反馈刺激对脊髓损伤后尿潴留病人膀胱功能、膀胱压力及尿路感染的影响。方法 选取河北省沧州中西医结合医院2020年6月至2022年6月收治的76例脊髓损伤后尿潴留病人进行研究,按照随机数字表法分为对照组（38例）和联合组（38例）。其中对照组给予生物反馈刺激,联合组给予隔附子饼灸联合生物反馈刺激。比较两组尿流动力学（最大膀胱压力、膀胱功能、最大膀胱测量容量）,膀胱残余尿量,临床疗效,尿路感染发生率及生活自理能力。结果两组干预前、干预4周、8周后MHU评分、膀胱残余尿量依次降低（P<0.05）,且干预4周、8周后,联合组[（2.45±0.26）分、（216.46±23.72）mL、（1.87±0.19）分、（114.37±11.58）mL]均明显低于对照组[（2.79±0.28）分、（242.75±26.84）mL、（2.14±0.22）分、（162.75±16.49）mL](P<0.05);两组干预前、干预4周、8周MBI评分、膀胱压力依次升高（P<0.05）,且干预4周、8周后,联合组[（38.57±3.46）分、（12.67±1.27）分、...     

异帕米星的临床评价60例

呼吸系和泌尿系感染60例(男性27例,女性33例;平均年龄52±15a),用异帕米星0.4-0.8g/d,分2次静滴或肌注,疗程9±3d。结果临床有效率为82％,细菌清除率75％。对19例血药浓度监测,峰浓度为17±7mg/L,谷浓度2±3mg/L。异帕米星和其他15种药物对53株临床分离菌的MIC测定提示该药对肠杆菌科、绿脓杆菌和葡萄球菌属等均具良好抗菌活性。     

Pharmacokinetic and pharmacodynamic effects of YM087, a combined V1/V2 vasopressin receptor antagonist in normal subjects

Objective: The pharmacokinetic and pharmacodynamic properties of YM087, (4′-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride), a new orally active, dual V₁/V₂ receptor antagonist were characterised in healthy normotensive subjects. Methods: Six subjects were randomly allocated to receive, at 1-week intervals, a single oral dose of 60 mg YM087 and a single i.v. dose of 50 mg YM087 in an open-label, crossover study. Results: YM087 had an oral bioavailability of 44% and a short half-life. Upon oral and i.v. administration of YM087, a significant sevenfold increase in urine flow rate and a fall in urinary osmolality (from 600 mosmol/l to less than 100-mosmol/l) were observed with a peak effect 2 h after drug intake suggesting effective vasopressin V₂ receptor blockade. Simultaneously, significant increases in plasma osmolality (from 283 ± 1.3 mosmol/l to 288 ± 1.0 mosmol/l after i.v. and from 283 ± 2.1 mosmol/l to 289 ± 1.7-mosmol/l after oral administration) and vasopressin levels (from 1.5 ± 0.3 pg/ml to 3.7 ± 0.6 pg/ml after i.v. and from 0.9 ± 0.1 pg/ml to 3.9 ± 0.7 pg/ml after oral administration) were found. When administered i.v., YM087 inhibited the vasopressin-induced skin vasoconstriction, suggesting a blockade of V₁ receptors. However, the YM087-induced antagonism of V₁ receptors was less pronounced than V₂ receptor blockade. Conclusion: These data show that YM087 is an effective dual V₁/V₂ receptor antagonist in man. Received: 17 February 1999 / Accepted in revised form: 18 August 1999     

Proteinuria in adults with sickle-cell disease: the role of hydroxycarbamide(hydroxyurea) as a protective agent

Background Renal abnormalities are often seen in sickle cell disease (SCD). Objective To investigate the role of hydroxycarbamide as a protective agent in sickle cell nephropathy. Setting Patients with SCD followed at a Hematology outpatients clinic. Methods Prospective study with 26 SCD patients. Renal function evaluation was performed and a comparison between patients and control group was done. Patients using hydroxycarbamide were compared to those not taking this drug. Main outcome measure Effect of hydroxycarbamide on renal function. Results Patients mean age was 32.1 ± 9.9 years, and 16 (61 %) were males. Glomerular hyperfiltration was found in nine patients with SCD (34.6 %). GFR < 60 mL/min/1.73 m² was observed in three cases (11.5 %). Microalbuminuria (30–300 mg/day) was found in seven cases (27 %) and macroalbuminuria (>300 mg/dia) in one patient (3.8 %). All patients had urinary concentrating deficit, and inability to acidify urine was found in ten cases (38.4 %). The comparison of patients according to the use of hydroxycarbamide showed lower levels of serum creatinine in those using the drug (0.6 ± 0.1 vs. 0.8 ± 0.3 mg/dL, p = 0.03), as well as lower levels of 24 h-proteinuria (226 ± 16 vs. 414 ± 76 mg/dL, p = 0.0001), but not microalbuminuria (79 ± 15 vs. 55 ± 86 mg/dL, p = 0.35). Conclusion SCD is associated with important renal abnormalities. Hydroxycarbamide seems to protect kidney function in SCD by decreasing proteinuria but not microalbuminuria.     

Functional Teratogens of the Rat Kidney: II. Nitrofen and Ethyienethiourea

Functional Teratogens of the Rat Kidney. II. Nitrofen and Ethylenethiourea.Daston, G. P., REHNBERG, B. F., CARVER, B., AND KAVLOCK, R.J. (1988). Fundam Appl. Toxicol 11, 401–415. Nitrofenand ethylenethiourea (ETU), agents known to prenatally inducehydronephrosis in rats, were assessed for their effects on postnatalrenal functional maturation. Both were given by gavage to pregnantSprague-Dawley rats on Gestation Day 11. Nitrofen was givenat concentrations of 50 or 100 mg/kg, and ETU at 20, 40, or60 mgg/kg. Renal function was examined in the oflspring frombirth until after weaning, the period of renal functional maturationin the rat. Maximal urine concentrating ability was measuredafter DDAVP (desmopressin acetate, a vasopressin analog) challengeor water deprivation. Proximal tubule transport was measuredin renal cortical slices. Various urinary parameters were measured.Both prenatal nitrofen and ETU exposure caused a large numberof neonatal deaths at the high dose, and hydronephrosis wasobserved. The severity of the lesion increased with age. Hydronephroticanimals were deficient in urine concentrating ability, whichbecame more pronounced after weaning. A few other urinary parameterswere altered, but cortical function appeared to be unaffected.Rats prenatally exposed to nitrofen, but with apparently normalkidneys, were significantly compromised in their ability toproduce a concentrated urine in response to DDAVP challenge,on Postnatal Days (PDs) 6 and 14. By PD 30, they were not differentfrom controls in urine concentrating response. Rats prenatallyexposed to the higher doses of ETU, but with grossly normalkidneys, had significantly decreased plasma clearances of certainelectrolytes early in life, but by PD 27, they were not differentfrom controls. Proximal tubule transport of PAH was increasedon PD 7 in ETU-exposed pups, but this effect did not persist.     

Comparative hemodynamic and renal effects of the low Km cGMP phosphodiesterase inhibitors cicletanine and zaprinast in anesthetized dogs

Cicletanine, a vasorelaxant/natriuretic agent, inhibits low K_m cGMP/phosphodiesterase (PDE) (IC₅₀ = 300 μ). The objectives of this study were to compare the cardiovascular and renal effects of cicletanine with another cGMP-PDE inhibitor, zaprinast (IC₅₀ = 0.3 μ), at intravenous dosages of 0.3–3 mg/kg, and to examine the influence of β-adreno-receptor blockade (nadolol, 1 mg/kg, i.v.) upon the responses to cicletanine in anesthetized dogs. Cicletanine (3 mg/kg) and zaprinast (0.3?3 mg/kg) decreased mean arterial pressure (?21.2±3.9 mm Hg [mean±SEM, max. change] at 3 mg/kg and ?64.7 ± 4.8 mm Hg at 0.3 mg/kg, respectively). The response curve of zaprinast was negatively related to the dosages. Cardiac output was increased or tended to increase by approximately 0.3 liter/min by both cicletanine and zaprinast at 3 mg/kg. Renal, but not femoral, blood flow was increased by both cicletanine and zaprinast (18.8±3.7 ml/min at 3 mg/kg and 17.0±4.6 ml/min at 1 mg/kg, respectively). These agents did not have major effects upon heart rate, left ventricular end diastolic pressure, and maximum rates of rise and decline in left ventricular pressure. These agents also did not affect pulmonary systolic, mean and diastolic arterial pressures, nor arterial blood p^O₂, p^CO₂, and pH. Both cicletanine and zaprinast increased or tended to increase urinary output (0.66±0.05 and 0.43±0.22 ml/min, respectively, both at 3 mg /kg) and urinary Na⁺ excretion (150.4±19.7 and 67.0±30.9 μEq/min, respectively, both at 3 mg/kg). Neither agents affected urinary K⁺ excretion. None of the responses to cicletanine were altered by β-, suggesting that β- adrenoreceptors were not in volved in mediating the affects of cicletanine. In conclusion, the cGMP-PDE inhibitors cicletanine and zaprinast vasodilate, increase renal blood flow, and induce diuresis and natrluresis in anesthetized dogs. However, the differences in the natriuretic and vasodilator effects of these agents cannot be explained by the difference in their potencies in PDE inhibition, suggesting that their effects in these dogs may involve additional mechanisms of action.     

Changes in Steady State Digoxin Pharmacokinetics during Quinidine Therapy in Cardiac Patients: Influence of Plasma Quinidine Concentration

Abstract: In seven cardiac patients on long-term digoxin therapy, digoxin kinetics were investigated — in the absence and presence of quinidine — after simultaneous administration of an oral digoxin dose and an intravenous ³H-digoxin bolus injection. From ³H-digoxin data quinidine was found to decrease both renal (from 1.19 ±0.35 to 0.86 ±0.21 ml/min./kg) (P<0.02) and extrarenal clearances of digoxin (from 0.85 ±0.24 to 0.49±0.23 ml/min./kg) (P<0.02), and to diminish the steady state distribution volume of the drug (from 6.78 ± 1.23 to 5.63 ± 1.64 l/kg) (P<0.02). Plasma half-life increased from 51.5 ±5.4 to 64.4±14.8 hrs (P<0.05), while urinary excretion half-life increased from 54.4±3.9 to 78.5± 14.1 hrs (P<0.01). Pharmacokinetic parameters derived from plasma and urinary digoxin data showed similar changes during quinidine therapy. Reduction in renal ³H-digoxin clearance occurred at subtherapeutic plasma quinidine levels and was independent of plasma quinidine, whereas reductions in extrarenal ³H-digoxin clearance and ³H-digoxin distribution volume were positively correlated to plasma quinidine concentrations (P<0.05).     

Effect of a diaza-polyoxa-macrobicyclic complexing agent on the urinary elimination of lead in lead-poisoned rats

The acute toxicity in the mouse and the Wistar rat of 13,16,21,24-hexaoxa-1,10-diazabicyclo-(8,8,8) hexacosane (ligand 222) was determined. LD50 values of 32 ± 1 mg/kg (iv) and 153 ± 16 mg/kg (ip) were obtained for the mouse and 35 ± 2 mg/kg (iv) and 110 ± 5 mg/kg (ip) for the rat. In another experiment, urinary elimination of lead in a group of five male Wistar rats, previously poisoned by ingestion of a solution of lead acetate, was studied. Continuous collection of urine before and after treatment with the new complexing agent (10 mg/kg, iv) was effected after catheterization of the ureters. It was concluded that the urinary elimination of lead is considerably and rapidly augmented by ligand 222, the 10-mg/kg dose increasing the concentration of lead in urine by an average factor of 40. We also noticed the diuresis is induced when ligand 222 is administered but that effect remains unexplained.     

EFFECT OF ARGININE VASOPRESSIN AND PARATHYROID HORMONE-RELATED PROTEIN ON RENAL FUNCTION IN THE OVINE FOETUS

1. The effects of intravenous infusions of arginine vasopressin (AVP), parathyroid hormone-related protein (PTHrP) and AVP + PTHrP on renal function in intact ovine foetuses at 100–125 days of gestation were examined. 2. A low dose of AVP (5.5 ± 0.9 pmol/h) increased plasma AVP concentrations from 0.6 pmol/L to 2.1 ± 0.4 pmol/L (mean ± s.e.m; n= 8). This dose caused a significant reduction in free water clearance (C_H2O; P<0.001), without any significant change in fetal arterial blood pressure, glomerular filtration rate (GFR), or the urinary excretion rates of sodium, calcium or 3', 5'-cyclic adenosine monophosphate (CAMP). 3. Infusions of PTHrP (1 nmol/h), with or without 1 nmol bolus dose, significantly increased (P<0.05) urine osmolality (Uosm), but did not synergize with AVP in reducing C_H2O. 4. It is concluded that AVP and PTHrP do not act synergistically on the kidney of the intact ovine foetus.     

Pamidronate distribution in pediatric renal and rheumatologic patients

Objective To evaluate the distribution and elimination of pamidronate in a population of pediatric patients with renal and rheumatologic disease.Methods Pamidronate whole blood levels were collected for the first 4 h after first exposure in 7 patients. The relationship between the rate of urinary excretion of pamidronate and bone formation or resorption was examined in 18 patients while receiving pamidronate at a total dose of 1 mg/kg/dose infused intravenously over a 4-h period. The urinary pamidronate clearances were correlated with renal function, calcium levels and measures of bone formation and resorption.Results Pamidronate levels reached steady state concentrations of 0.9–1.5 μg/ml within 30 min and the clearance of the drug (mean±SE) from blood was 180.0±64.2 ml/kg/h with an elimination half-life of less than 1 h. The mean urinary excretion of 31.5±2.2% of the administered dose indicated that about 68% of the drug was incorporated into bone, confirming the uptake of pamidronate into bone was similar in pediatric patients compared to that previously reported for adults. Bone specific alkaline phosphatase, which is a marker for bone growth and formation, had significant correlation with the uptake of pamidronate into bone (p=0.002). No correlation was demonstrated with a marker for bone resorption (urinary N-telopeptide/creatinine ratio), or with creatinine clearance or calciuria when assessed 2 months after treatment.Conclusion Pamidronate at a dose of 1 mg/kg/dose every 2 months appears safe in the short term for pediatric patients, achieves relatively low whole blood pamidronate levels, and has similar skeletal uptake of pamidronate compared to adults.     

High sodium intake increases the urinary excretion of L-3,4-dihydroxyphenylalanine but fails to alter the urinary excretion of dopamine and amine metabolites in wistar rats

• 1.1. The present study has examined the daily urinary excretion of L-DOPA, dopamine and its metabolites (DOPAC, 3-MT and HVA) during normal salt (NS) and high salt (HS) diets.
• 2.2. Daily urinary excretion of L-DOPA, DA, DOPAC, 3-MT and HVA during the 4-day period of NS diet averaged, respectively, 7.6±0.4, 71±5,217±22, 570±90and1217±110 nmol/kg/day. The slight increase in the urinary excretion of DA, DOPAC and 3-MT (16% to 42% increase), when rats were fed a HS diet, did not achieve statistical significance.
• 3.3. In contrast, the urinary levels of L-DOPA during the HS diet period (11 ± 1 nmol/kg/day) were found to be significantly higher than during the NS diet period; the maximal increase in the urinary excretion of L-DOPA (93% increase) was observed in the first day and then a progressive decline was observed towards the end of the HS intake period.
• 4.4. During the first 5 days of the HS intake period, the urine output of noradrenaline (NA) was found to increase (27% to 83%) and then to progressively decline to baseline values (13.5±0.7 nmol/kg/day).
• 5.5. Urinary excretion of adrenaline (AD) during the HS intake period was found to increase (72% to 146%); the mean daily urinary excretion of AD during the NS diet period averaged 2.5±0.4 nmol/kg/day. NA and DA contents in the kidney of rats on a NS diet were not significantly different from that of rats in a HS diet.
• 6.6. It is concluded that long-term HS intake in Wistar rats fails to change the urinary excretion of DA and of its metabolites (DOPAC, 3-MT and HVA). Furthermore, the discrepant profile in the urinary excretion of L-DOPA and DA during HS intake might be related to a reduction in the tubular uptake of the amino acid, rather than reflecting a decrease in its decarboxylation.

     

美洛西林与头孢呋辛治疗细菌性感染的成本-效果分析

目的 :探讨不同抗生素治疗细菌性感染所产生的经济效果。方法 :根据文献选择各种细菌性感染的病人 12 0例 ,随机分为美洛西林组和头孢呋辛组分别给予治疗 ,运用药物经济学的成本 效果分析方法进行分析评价。结果 :美洛西林在治疗呼吸道感染和泌尿道感染其成本 /效果比 (治愈率 :51±11和 36± 8;有效率 :39± 8和 2 8± 7)均低于头孢呋辛 (治愈率 :57± 16和 52± 8;有效率 :4 1± 11和 30± 5)。结论 :美洛西林在治疗呼吸道和泌尿道感染方面优于头孢呋辛 ,是一种成本 效果较好的药物。     

尿微量白蛋白与尿肌酐比值对 2型糖尿病合并非酒精性脂肪肝的影响

目的 检测2型糖尿病(T2DM)病人尿微量白蛋白、尿肌酐、血脂、血清总胆固醇水平,探讨尿微量蛋白与尿肌酐比值对2型糖尿病合并非酒精性脂肪肝的影响.方法 选取2018年6月至2019年9月池州市人民医院收治的2型糖尿病病人120例,根据是否合并脂肪肝分为观察组(T2DM合并非酒精性脂肪肝)及对照组(单纯T2DM),其中观察组47例,对照组73例,检测并比较两组血液指标、血生化指标、尿微量白蛋白、尿肌酐(UCr)、三酰甘油(TG)、总胆固醇(TC)及尿微量白蛋白/UCr比值.采用Pearson相关性分析血脂指标与高尿微量蛋白/UCr比值的关系.按照病人是否合并脂肪肝进行赋值(合并脂肪肝=1,不合并脂肪肝=0),绘制尿微量白蛋白与UCr比值对脂肪肝诊断价值的ROC曲线.结果 观察组尿微量白蛋白[45.48(32.57,49.38)mg/L比32.84(25.68,36.34)mg/L]、尿微量白蛋白/UCr[(56.42±10.35)mg/g比(37.57±9.28)mg/g]、TG[(3.12±1.05)mmol/L比(2.05±1.84)mmol/L]、TC[(6.28±2.35)mmol/L比(4.96±2.14)mmol/L]、HOMA-IR[3.89(1.86,4.29)比2.74(1.51,3.75)]、HDL-C[(1.98±0.68)mmol/L比(0.96±0.49)mmol/L]、尿酸[(354.36±25.39)mmol/L比(249.63±26.14)mmol/L]显著高于对照组,差异有统计学意义(P<0.05).经Pearson相关性分析,TG、TC、HDL-C与高尿微量蛋白/UCr比值呈正相关(r值分别为0.770、0.694、0.765,P<0.05).LDL-C高尿微量蛋白/UCr值无相关性(P>0.05).ROC曲线结果显示AUC=0.892,95％CI(0.754～0.915),因AUC>0.6,说明尿微量白蛋白/UCr诊断脂肪肝具有一定价值.结论 尿酸、尿微量蛋白/UCr、肥胖、脂质代谢紊乱、胰岛素抵抗与T2DM病人非酒精性脂肪肝的发生相关,高尿微量蛋白/UCr对于诊断T2DM病人发生非酒精性脂肪肝具有一定价值.     

他克莫司联合激素的免疫调节作用及其对儿童激素耐药难治性肾病的疗效研究

目的：观察他克莫司联合激素对激素耐药难治性肾病患儿调节性T（Treg）细胞的影响及其临床疗效。方法：选取2012年8月至2014年12月余姚市第二人民医院儿科常规激素治疗无效的肾病综合征患儿40例,另选取我院保健中心体检的健康儿童40例作为正常对照。Treg细胞使用流式细胞仪检测,对比治疗前后24 h尿蛋白定量、血肌酐、血清白蛋白、丙氨酸转氨酶、天门冬氨酸转氨酶、胆固醇、甘油三脂等临床指标的变化。结果：健康儿童、患儿治疗前和治疗后Treg细胞在外周血的比例分别为7.12%±1.64%、1.84%±0.51%、6.08%±1.23%,三组比较差异有统计学意义（P<0.05）。他克莫司治疗后患儿24 h尿蛋白定量从（113.2±24.3）mg/kg减少至（24.2±3.6）mg/kg（P<0.01）,血清白蛋白从(19.2±2.5) g/L升高至(34.8±4.7) g/L（P<0.01）,差异均有统计学意义;血肌酐治疗前后比较差异无统计学意义（P>0.05）。他克莫司治疗后患儿胆固醇和甘油三脂分别从（12.1±2.3）mmol/L和（5.9±1.2）mmol/L下降至（4.3±1.1）mmol/L和（2.8±0.6）mmol/L,差异均有统计学意义（P<0.01）。他克莫司治疗前后患儿丙氨酸转氨酶和天门冬氨酸转氨酶水平比较差异无统计学意义（P>0.05）。40例激素耐药难治性肾病患儿经他克莫司治疗后临床缓解率为82.5%,不良反应发生率为12.5%。结论：他克莫司可以显著升高激素耐药肾病患儿Treg细胞的比例,调节患儿的免疫失衡,对激素耐药肾病患儿具有显著临床疗效,使用安全,有一定的临床推广使用价值。     

Targeting of Doxorubicin to the Urinary Bladder of the Rat Shows Increased Cytotoxicity in the Bladder Urine Combined With An Absence of Renal Toxicity

Targeting of anti-tumor drugs to the urinary bladder for the treatment of bladder carcinoma may be useful, since these agents generally have a low degree of urinary excretion and are highly toxic elsewhere in the body. The anti-tumor drug doxorubicin was coupled to the low-molecular weight protein lysozyme via the acid-sensitive cis -aconityl linker. All free amino groups of the lysozyme were used for drug attachment to achieve intact excretion of the doxorubicin-aconityl-lysozyme conjugate into the bladder. In the bladder, the cytotoxic drug should be regenerated through acidification of the urine. First, the doxorubicin-aconityl-lysozyme conjugate was tested in rats for its target specificity and general toxicity. Wistar rats were injected intravenously with 2 mg/kg free doxorubicin or 10 mg/kg lysozyme-conjugated doxorubicin. Total urinary excretion of doxorubicin was about 10 times higher if the drug was coupled to lysozyme (39 ± 3% versus 4.4 ± 0.4%) . Free doxorubicin had no detectable toxic effects on heart, liver and lung but caused severe renal damage (proteinuria, N -acetyl-glucosaminidase excretion and glomerulosclerosis). None of the rats injected with doxorubicin-lysozyme conjugate showed such renal toxicity. Second, we tested whether doxorubicin could be released from the conjugate in the bladder through acidification of the urine and if the released doxorubicin could still exert a cytotoxic effect. Doxorubicin-aconityl-lysozyme (2 mg/kg conjugated doxorubicin, i.v.) was administered in rats with acidified urine (pH 6.1 ± 0.1) and in rats with a high urinary pH (8.2 ± 0.4). Ten times more doxorubicin was released from the conjugate in the group with acidified urine (15 ± 7% versus 1.7 ± 0.1%) . In agreement with this, cytotoxicity was also higher in the low pH group (IC 50 of 255 ± 47 nM versus 684 ± 84 nM doxorubicin). In conclusion, a specific delivery of doxorubicin to the urinary bladder combined with a reduced toxicity of doxorubicin in the kidneys can be achieved by coupling this anti-tumor drug to the low-molecular weight protein lysozyme via an acid-labile linker. A release of cytotoxic doxorubicin in the urinary bladder can be achieved by acidification of the urine. This technology, after further optimization, may provide an interesting tool for the treatment of bladder carcinoma.     

Comparison of Acute Cardiovascular Effects of Cadmium and Captopril in Relation to Oxidant and Angiotensin Converting Enzyme Activity in Rats

Abstract

Cadmium (0.1, 0.32, 1.0 mg/kg i.v.) produced dose dependent hypertensive response in pentobarbitone anesthetized Sprague-Dawley (S-D) rats. The peak hypertensive effect was observed within 15 min of cadmium administration. This response gradually decreased over 1-h observation period. Heart rate did not change significantly. Serum malondialdehyde (MDA) levels increased with cadmium administration. The lower dose of cadmium (0.1 mg/kg i.v.) increased serum MDA to 0.14 ± 0.02 nmol/mL as compared to 0.12 ± 0.01 nmol/mL in the control group and was not statistically significant. However, mid (0.32 mg/kg i.v.) and high doses (1.0 mg/kg i.v.) raised serum MDA levels significantly (P<0.01). Cadmium inhibited serum angiotensin converting enzyme (ACE) levels at all the three tested doses and was statistically significant (P<0.01). Captopril (1.0, 3.2 mg/kg i.v.) produced a dose dependent mild hypotensive response. The peak effect was observed within 5 min. Cadmium produced inhibition of serum ACE levels, however, a dose response effect was not observed. Captopril (3.2 mg/kg i.v.) decreased serum ACE levels to 5.4 ± 1.1 U/mL (control levels 10.7 ± 1.4 U/mL). Serum MDA levels were decreased by captopril treatment. A correlation between serum ACE and MDA following higher dose of cadmium was found. These results indicate that acute administration of cadmium, an inorganic blocker of ACE and calcium channels cadmium produced hypertensive response while captopril produced mild hypotensive response in rats.     

Urinary Excretion and Diuretic Action of Furosemide in Rats: Increased Response to the Urinary Excretion Rate of Furosemide in Rats with Acute Renal Failure

A urinary excretion–response curve representing the urinary excretion rate of furosemide versus the urinary excretion rate of (Na⁺ + K⁺) was used to analyze furosemide action in rats with uranyl nitrate-induced acute renal failure (ARF) with and without dopamine coadministration. Urinary excretion of furosemide, but not its serum concentration, was the determinant for the diuretic action of furosemide. Increased diuretic response was observed in ARF rats, although the total diuretic response and urinary recovery of furosemide within 2 hr decreased. Dopamine enhanced furosemide-induced diuresis in ARF rats in terms of the total urine output and urinary electrolyte excretion, although the urinary excretion–response curves were not different. This enhancement by dopamine was found to be caused by the augmented urinary excretion of furosemide and the increased response to this drug in ARF rats. These findings suggest the contribution of decreased concentrating ability along the nephron and/or increased sensitivity of cells at the site of action to this drug.