Total hydroxyproline in urine of 4 to 6 year-old children--an investigation on its relationship to growth and nutrition

We analysed over a period of 30-32 days the daily total hydroxyproline and creatinine excretine in urine from 9 healthy, normally fed 4 to 6 year-old children (2 girls, 7 boys). The average urinary hydroxyproline excretion was 45.6 mg/24 hr, with a coefficient of variation of 25.6%. Urinary hydroxyproline for individual children showed distinct differences from day to day, which were independent of urine volume. There were significant differences between the mean values for urine hydroxyproline in individual children, which were independent of age. The average creatinine in urine was 346/24 hr with a coefficient of variation of 17.7%. The hydroxyproline-index did not define the nutritional state of these normally developed children on a normal diet. Dietary hydroxyproline contributed 7.4% to the total urinary hydroxyproline in our investigation. There was a close correlation between urine hydroxyproline excretion and growth velocity in each child.     

Urinary creatinine excretion in the ICU: low excretion does not mean inadequate collection

BACKGROUND: It has been assumed that a urinary creatinine excretion rate of less than 10 mg/kg per day means an inadequately collected urine sample. OBJECTIVE: To determine the frequency of a urinary creatinine excretion rate of less than 10 mg/kg per day in intensive care unit patients with an adequately collected urine sample. METHOD: In a prospective study of creatinine excretion rates, 24-hour urine samples were evaluated for urinary creatinine in 209 critically ill patients with indwelling Foley catheters. Patients from three adult intensive care units in New York City were divided into two groups. Group 1 patients excreted less than 10 mg/kg per day of urinary creatinine, and group 2 patients excreted at least 10 mg/kg per day. Groups 1 and 2 were first evaluated by dividing the creatinine excretion data by actual body weight. Since actual body weight may overestimate body weight in the critically ill patient, data from groups 1 and 2 were also evaluated using lean body weight. RESULTS: Urinary creatinine excretion was less than 10 mg/kg per day in 36.8% of patients using actual body weight and 29.7% of patients adjusted for lean body weight. The average age of patients in group 1 was 74 +/- 17 years for both actual body weight and lean body weight. The average age of group 2 patients was 60 +/- 19 years for actual body weight and 62 +/- 19 years for lean body weight. There was a significant difference in age between group 1 and group 2 patients for both actual body weight and lean body weight. The proportion of female vs male patients with reduced creatinine excretion was significantly greater, whether the actual body weight or lean body weight adjustment was used. CONCLUSIONS: A urinary creatinine excretion rate of less than 10 mg/kg per day occurs in about one third of critically ill patients, who are more likely to be elderly and female.     

Serum and urinary boron levels in rats after single administration of sodium tetraborate

The pharmacokinetics of boron was studied in rats by administering a 1 ml oral dose of sodium tetraborate solution to several groups of rats (n=20) at eleven different dose levels ranging from 0 to 0.4 mg/100 g body weight as boron. Twenty-four-hour urine samples were collected after boron administration. After 24 h the average urinary recovery rate for this element was 99.6+/-7.9. The relationship between boron dose and excretion was linear (r=0.999) with a regression coefficient of 0.954. This result suggests that the oral bioavailability (F) of boron was complete. Another group of rats (n=10) was given a single oral injection of 2 ml of sodium tetraborate solution containing 0.4 mg of boron/100 g body wt. The serum decay of boron was followed and found to be monophasic. The data were interpreted according to a one-compartment open model. The appropriate pharmacokinetic parameters were estimated as follows: absorption half-life, t1/2a=0.608+/-0.432 h; elimination half-life, t1/2=4.64+/-1.19 h; volume of distribution, Vd = 142.0+/-30.2 ml/100 g body wt.; total clearance, Ctot=0.359+/-0.0285 ml/min per 100 g body wt. The maximum boron concentration in serum after administration (Cmax) was 2.13+/-0.270 mg/l, and the time needed to reach this maximum concentration (Tmax) was 1.76+/-0.887 h. Our results suggest that orally administered boric acid is rapidly and completely absorbed from the gastrointestinal tract into the blood stream. Boric acid in the intravascular space does not have a strong affinity to serum proteins, and rapidly diffuses to the extravascular space in proportion to blood flow without massive accumulation or binding in tissues. The main route of boron excretion from the body is via glomerular filtration. It may be inferred that there is partial tubular resorption at low plasma levels. The animal model is proposed as a useful tool to approach the problem of environmental or industrial exposure to boron or in cases of accidental acute boron intoxication.     

Arsenic trioxide absorption and excretion in industry

1. A study of 24 smelter workers routinely exposed to arsenic trioxide was conducted to evaluate some characteristics of its absorption and excretion. A statistically significant correlation was found between airborne arsenic trioxide concentrations below 300 mug/m3 and urinary arsenic values below 500 mug/liter. These men wore personal monitors for five consecutive work days and were determined to have been exposed to average airborne arsenic concentrations of 53 mug/m3 (70 mug/m3 of arsenic trioxide) which increased their urinary arsenic values from 152 mug/liter to 200 mug/liter (an average gain on 32%). 2. The background average urinary arsenic value for adult males not exposed to arsenic trioxide in industry was determined to be 52.6 mug/liter for 204 men during preemployment examinations. 3. After removal from industrial arsenic trioxide exposure, the rate of fall in urinary arsenic values varies with the magnitude of the urinary arsenic level. An initial decrease of 9.5% per day was measured for workers having urinary arsenic values below 200 mug/liter. The initial decrease is about 21% per day for workers with urinary arsenic values over 600 mug/liter. 4. It was determined that arsenic in seafood can alter, in a dramatic fashion, the urinary arsenic values determined for smelter workers within 24 hours following consumption. It is recommended, therefore, that the absorption of arsenic trioxide due to industrial exposure is best evaluated from urine samples collected at least two days after seafood has been eaten.     

Glutamine transaminase K intranephron localization in rats determined by urinary excretion after treatment with segment-specific nephrotoxicants

Glutamine transaminase K(GTK) excretion assessed in urine and by kidney histology was evaluated in rats after single treatment with 1.0 mg/kg i.p. of mercuric chloride, 100 mg/kg i.p. of hexachloro-1:3-butadiene (both S3, pars recta, segment-specific nephrotoxicants) and 25 mg/kg s.c. of potassium dichromate (S1-S2, pars convoluta, segment-specific nephrotoxicant). The aim was to correlate segment-specific injury and enzyme excretion in order to assess, using non-vasive methods, localization of GTK along the proximal tubule. Mercuric chloride and hexachloro-1:3-butadiene produced early focal damage in the pars recta (focal necrosis was shown 10 h after treatment, and diffuse necrosis appeared later at 34 and 24 h after treatment). Changes of the pars convoluta were occasional and delayed (72 h after treatment for both substances). On the contrary, potassium dichromate induced damage of the pars convoluta (vacuolar degeneration and focal necrosis were evident 24 h and 48 h after treatment, respectively), whereas the pars recta was affected later (focal vacuolar degeneration was observed 72 h after treatment). Increase urinary GTK excretion was early after treatment with mercuric chloride and hexachloro-1:3-butadiene (significant increase was observed within 10 h), with a peak for both substances 24 h after treatment, in agreement with the necrosis of the pars recta. Potassium dichromate induced a significant increase of enzyme excretion in urine also 24 h after injection, according to histological features showing vacuolar degeneration of the pars convoluta; the peak of excretion was reached 48 h after treatment (delay was due, probably, to s.c. administration). The results show that GTK increased in urine after treatment with S3 and S1-S2 specific nephrotoxicants; the combination of histological examination and urinary enzyme supports the evidence that the enzyme is distributed along the whole of the proximal tubule.     

Effect of oral calcium loading on intact PTH and calcitriol in idiopathic renal calcium stone formers and healthy controls

The calciuric response after an oral calcium load (1000 mg elemental calcium together with a standard breakfast) was studied in 13 healthy male controls and 21 recurrent idiopathic renal calcium stone formers, 12 with hypercalciuria (UCa x V > 7.50 mmol/24 h) and nine with normocalciuria. In controls, serum 1,25(OH)2 vitamin D3 (calcitriol) remained unchanged 6 h after oral calcium load (50.6 +/- 5.1 versus 50.9 +/- 5.0 pg/ml), whereas it tended to increase in hypercalciuric (from 53.6 +/- 3.2 to 60.6 +/- 5.4 pg/ml, P = 0.182) and fell in normocalciuric stone formers (from 45.9 +/- 2.6 to 38.1 +/- 3.3 pg/ml, P = 0.011). The total amount of urinary calcium excreted after OCL was 2.50 +/- 0.20 mmol in controls, 2.27 +/- 0.27 mmol in normocalciuric and 3.62 +/- 0.32 mmol in hypercalciuric stone formers (P = 0.005 versus controls and normocalciuric stone formers respectively); it positively correlated with serum calcitriol 6 h after calcium load (r = 0.392, P = 0.024). Maximum increase in urinary calcium excretion rate, delta Ca-Emax, was inversely related to intact PTH levels in the first 4 h after calcium load, i.e. more pronounced PTH suppression predicted a steeper increase in urinary calcium excretion rate. Twenty-four-hour urine calcium excretion rate was inversely related to the ratio of delta calcitriol/deltaPTHmax after calcium load (r = -0.653, P = 0.0001), indicating that an abnormally up-regulated synthesis of calcitriol and consecutive relative PTH suppression induce hypercalciuria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of phenobarbital pretreatment on in vitro enzyme kinetics and in vivo biotransformation of benzene in the rat

Phenobarbital pretreatment (50 mg/kg/day for 3 days orally) of male Wistar rats increased Vmax of benzene in vitro hepatic microsomal biotransformation about 6-fold without changing Km. However, benzene blood levels after oral, intraperitoneal, or subcutaneous benzene administration (3-3.5 mmoles/kg) were not influenced by phenobarbital pretreatment. The phenol blood levels after oral or intraperitoneal benzene were increased by phenobarbital pretreatment, but less than expected from in vitro data and only 3 h after benzene administration. Phenol elimination in urine after subcutaneous benzene was not affected by phenobarbital. After oral or intraperitoneal benzene administration, phenol urine excretion closely followed the levels of phenol in blood, i.e., rate of phenol urine excretion was significantly, but shortly increased, and the cumulative urine excretion of phenol increased very little or remained unchanged. Differences between the in vitro and in vivo observations of the effect of phenolbarbital on benzene biotransformation may partly be explained by distribution of benzene, which apparently limited benzene availability for biotransformation (Vd = 5.5) and caused rapid decrease of benzene concentrations in blood. Conditions for enzyme activity may have been substantially different in vitro vs. in vivo: in vitro concentrations of benzene were at least by an order of magnitude higher than phenol concentrations, while in vivo, an opposite relation prevailed making a competition for microsomal monooxygenase possible. Cofactor availability may be another rate-limiting step or factor of in vivo benzene biotransformation, as benzene ring hydroxylation requires high energy. The rate of in vitro hepatic microsomal benzene biotransformation proved to be of limited value when predicting benzene quantitative biotransformation in vivo in contradistinction to various substrates where the in vitro and in vivo biotransformation data are in good agreement.     

Ceftezole, a new cephalosporin C derivative II. Distribution and excretion in parenteral administration

The distribution of ceftezole in blood and tissues and its excretion after intramuscular or intravenous administration of single doses of 10 and 20 mg/kg were compared with those of cefazolin, cephaloridine and cephalothin. Blood levels of ceftezole in rats and rabbits were lower than those of cefazolin, and higher than those of cephaloridine and cephalothin. Retention time of ceftezole in the blood was somewhat shorter than that of cefazolin. However, blood levels of ceftezole in dogs were nearly the same as those of cefazolin and cephaloridine. The rate of urinary excretion of ceftezole in 24-hour urine after administration in rats and rabbits was found to be higher than those of the other antibiotics tested. In dogs, however, the rate of urinary excretion of ceftezole was nearly the same as that of cefazolin and higher than those of cephaloridine and cephalothin. The biliary excretion of ceftezole in rats and dogs was much higher than those of cephaloridine and cephalothin, but lower than that of cefazolin. Tissue distribution of ceftezole in rats was compared with that of the other antibiotics by intramuscular and intravenous administration. The initial level of ceftezole in the kidneys was found to be substantially higher than those of the other antibiotics. The initial level of ceftezole in the liver and lungs was also slightly higher than those of the other drugs when administered intramuscularly. Tissue levels of ceftezole were somewhat lower than those of cefazolin in rabbits after intravenous administration. Ceftezole attained a higher maximum level in rat lymph by intramuscular administration than the other antibiotics tested. The maximum concentration of ceftezole present in the exudate in the rat inflammatory pouch was higher than that of cefazolin. In rabbits with cerebrospinal meningitis induced by infection of Streptococcus pyogenes, the level of ceftezole in the cerebrospinal fluid was several times higher than that in normal rabbits. The serum level and urinary excretion of ceftezole was examined in 6 healthy male volunteers after intramuscular administration of a single dose of 500 mg. Ceftezole attained a mean maximum serum level of 22.9 mug/ml 30 minutes after administration and disappeared from the blood in about 6 hours. It was excreted rapidly in the urine. The concentration in 1-hour urine was the highest (mean level: 2,667 mug/ml) and the total excretion rate was 92.6%. No metabolites with antimicrobial activity were observed in the urine. No changes in the pattern of plasma level and urinary excretion and no accumulation in the tissues were observed after repeated intramuscular administration of 20 mg/kg of ceftezole in rabbits, 26 times, for 14 days.     

Formic acid excretion in rats exposed to trichloroethylene: a possible explanation for renal toxicity in long-term studies

Rats exposed to trichloroethylene, either by gavage or by inhalation, excreted large amounts of formic acid in urine which was accompanied by a change in urinary pH, increased excretion of ammonia, and slight increases in the excretion of calcium. Following a single 6-h exposure to 500 ppm trichloroethylene, the excretion of formic acid was comparable to that seen after a 500 mg/kg dose of formic acid itself, yet the half-life was markedly different. Formate excretion in trichloroethylene treated rats reached a maximum on day 2 and had a half-life of 4-5 days, whereas urinary excretion was complete within 24 h following a single dose of formic acid itself. Formic acid was shown not to be a metabolite of trichloroethylene. When rats were exposed to 250 or 500 ppm trichloroethylene, 6 h/day, for 28 days, the only significant effects were increased formic acid and ammonia excretion, and a change in urinary pH. There was no evidence of morphological liver or kidney damage. Long-term exposure to formic acid is known to cause kidney damage suggesting that excretion of this acid may contribute to the kidney damage seen in the long-term studies with trichloroethylene.     

Urinary excretion of phenols as an indicator of occupational exposure in the coke-plant industry

OBJECTIVE: In the present study the relationship between the level of exposure to o-cresol and of 2,4- +2,5-, 3,4-, and 3,5-xylenols and the urinary excretion of their metabolites was examined. The mixed exposure to phenolic derivatives of exposed workers during their work shift was monitored by personal air sampling of the breathing-zone air and by measurements of phenol, o-cresol, and xylenol isomer concentrations in shift-end urine. METHODS: The study subjects were 76 men working at a coke plant who were 22-58 years old and 34 nonexposed subjects. Concentrations of phenolic compounds were determined in the breathing-zone air during the work shift, whereas concentrations of phenol, cresol, and xylenol isomers were measured in urine collected after the work shift. Concentrations of phenols in air and urine were determined by gas chromatography with flame-ionization detection. Urine samples were extracted after acid hydrolysis of glucuronides and sulfates by solid-phase extraction. The gas chromatography-mass spectrometry method was applied to identify metabolites in urine samples. RESULTS: The time-weighted average concentrations of phenol, cresol, and xylenol isomers detected in breathing-zone air showed that the exposure level of the workers was relatively low. The geometric mean values were as follows: 0.26 mg/m3 for phenol, 0.09 mg/m3 for o-cresol, 0.13 mg/m3 for p- and m-cresol, and 0.02-0.04 mg/m3 for xylenols at the tar-distillation process. Corresponding urinary concentrations were 10.39, 0.53, and 0.25-0.88 mg/g creatinine for phenol, o-cresol, and xylenol isomers, respectively. The correlation coefficients between the o-cresol and 2,4-, 2,5-, 3,4-, and 3,5-xylenol concentrations measured in urine and in the breathing-zone air were statistically significant, varying in the range of 0.54-0.74 for xylenol isomers and being 0.69 for o-cresol. CONCLUSION: We have found that the presence of o-cresol and xylenol isomers in urine can be used as a biomarker for phenol exposure. Analysis performed on workers at the tar-distillation process showed that they were exposed to relatively low concentrations of phenolic compounds.     

Concentration of 14C-1-butylbiguanide in plasma of diabetic patients and its elimination after administration of a new Galenical formulation (author's transl)

The time course of 1-butylbiguanide concentration in plasma and the urinary and fecal elimination of the substance were measured in six female elimination of the substance were measured in six female diabetic patients after oral administration of 100 mg of 14C-1-butylibiguanide hydrochloride as Sindiatil. The mean maximum plasma concentration was 37 mug/100 ml and was reached after about 2 1/2 h. At least semi-maximum plasma concentrations (greater than or equal 18 mug/100 ml) were maintained between the 1st and 8th h after administration. Within 24 h 64% of the administered dose were eliminated (36% via the kidneys, 28% with the faeces). After 3 days a total of 80% had been eliminated, one-half each in urine and faeces, respectively. The average time taken for 50% of maximum renal elimination, and thus of the absorbed quantity, to be excreted was 7.2 h.     

The pharmacokinetics and metabolism of 14C/13C-labeled ortho-phenylphenol formation following dermal application to human volunteers

1. The pharmacokinetics and metabolism of uniformly labeled 14C/13C-ortho-phenylphenol (OPP) were followed in six human male volunteers given a single 8 h dermal dose of 6 microg OPP/kg body weight formulated as a 0.4% (w/v) solution in isopropyl alcohol. The application site was covered with a non-occlusive dome allowing free movement of air, but preventing the loss of radioactivity due to physical contact. At 8 h post-exposure the non-occlusive dome was removed, the dose site was wiped with isopropyl alcohol containing swabs and the skin surface repeatedly stripped with tape. Blood specimens, urine, and feces were collected from each volunteer over a 5 day post-exposure period and were analyzed for radioactivity and metabolites (urine only). 2. Following dermal application, peak plasma levels of radioactivity were obtained within 4 h post-exposure and rapidly declined with virtually all of the absorbed dose rapidly excreted into the urine within 24 h post-exposure. A one-compartment pharmacokinetic model was used to describe the time-course of OPP absorption and clearance in male human volunteers. Approximately 43% of the dermally applied dose was absorbed through the skin with an average absorption half-life of 10 h. Once absorbed the renal clearance of OPP was rapid with an average half-life of 0.8 h. The rate limiting step for renal clearance was the relatively slower rate of dermal absorption; therefore the pharmacokinetics of OPP in humans was described by a 'flip-flop' single compartment model. Overall, the pharmacokinetics were similar between individuals, and the model parameters were in excellent agreement with the experimental data. 3. Approximately 73% of the total urinary radioactivity was accounted for as free OPP, OPP-sulfate and OPP-glucuronide conjugates. The sulfate conjugate was the major metabolite (approximately 69%). Therefore, total urinary OPP equivalents (acid-labile conjugates+free OPP) can be used to estimate the systemically absorbed dose of OPP. 4. The rapid excretion of OPP and metabolites into the urine following dermal exposure indicates that OPP is unlikely to accumulate in humans upon repeated exposure. Based on these data, blood and/or urinary OPP concentration (acid-labile conjugates) could be utilized to quantify the amount of OPP absorbed by humans under actual use conditions.     

Lymphatic absorption and metabolism of orally administered testosterone undecanoate in man

[3H]-testosterone undecanoate ([3H]TU) was administered orally to 4 patients with a thoracic duct catheter after neck dissection surgery. Appearance of radioactivity in lymph, plasma and urine was measured at different times. Metabolites of TU in these fluids were investigated. Peak levels of radioactivity appeared simultaneously in lymph and plasma (2.5-5 h after administration) while the excretion in urine was highest approximately 2 h after the plasma and lymph peak. The main compounds appearing in the lymph were TU and 5alpha-dihydrotestosterone undecanoate (5alpha-DHTU), but 5beta-DHTU could not be detected. In plasma almost all metabolites were probably conjugated. During the first 24 h approximately 40% of the administered radioactivity was excreted in the urine. The total amount of radioactivity excreted in the urine during the first week was 45-48%. The predominant urinary metabolites were testosterone- and androsterone-glucuronide. The results indicate that TU is metabolized partly in the intestinal wall. The remaining TU and newly-formed 5alpha-DHTU, at least partly, are absorbed via the lymphatic system.     

Biliary excretion of cobalt in rats

The excretion of 58Co2+ via bile, urine and intestinal wall after intravenous administration of 58CoCl2 in two doses (177 and 1770 micrograms of Co2+ per kg B. Wt.) was studied in rats. The cumulative biliary excretion reached 24 hours after administration of lower dose 2.67 +/- 1.98% and higher dose 7.33 (4.6-10.9) % of the amount given. The highest excretion rate of 58Co was detected between 10 and 30 minutes after administration. After administration of higher dose of 58Co the lower urinary excretion was observed [73.6 +/- 4.0% resp. 47.9% (45.5-52.5)] of the amount given. There were no differences between both doses studied in the excretion of 58Co via the wall of gastrointestinal tract.     

Replica cytology in cancer of the larynx: an evaluation of a replica method in the diagnosis of laryngeal malignancy

Dopamine, noradrenaline and adrenaline were measured in plasma and in urine, using double-isotope derivative techniques, in 46 normal subjects and in 17 tetraplegic patients with physiologically complete cervical spinal cord transections above the sympathetic outflow. Dopamine was present in plasma in normal subjects in a concentration of 0.33 mug/l +/- 0.06 (SEM). Twenty-four hour urinary excretion of dopamine averaged 248 mug +/- 22. There was a significant correlation between the 24 h urinary excretion of dopamine and of noradrenaline. In the normal subjects plasma dopamine and the urinary excretion of dopamine did not change during three days of fasting while urinary excretion of adrenaline increased twofold. In the normal subjects exercise significantly increased plasma dopamine from 0.25 mug/l to 0.43 mug/l, but significantly decreased the urinary excretion of dopamine. Exercise significantly increased the excretion of noradrenaline. In the tetraplegic patients the plasma dopamine concentration and the urinary excretion of dopamine were lower but not significantly different from the corresponding values in the normal subjects. Plasma noradrenaline and the urinary excretion of noradrenaline and adrenaline were significantly lower in the tetraplegic patients. It is concluded that dopamine is present in human plasma in concentrations similar to that of noradrenaline. Free dopamine in plasma and urine of normal subjects is not dependent on foot intake. Urinary dopamine may be derived from circulating dopamine. Urinary dopamine does not necessarily appear to reflect changes in plasma dopamine. The relationship between plasma dopamine and changes in adrenergic nervous activity deserves further investigation.     

Micromanipulation and cloning studies on buffalo oocytes and embryos using nucleus transfer

1. Nine male volunteers were exposed to the pyrethroid insecticide cyfluthrin. The study was performed in an exposure room, where an aerosol containing cyfluthrin was sprayed to obtain atmospheres with mean cyfluthrin concentrations of 160 and 40 micrograms/m3. Four volunteers were exposed for 10, 30 and 60 min at 160 micrograms/m3 and another five volunteers were exposed for 60 min at 40 micrograms/m3. For 160 micrograms/m3 exposure urine samples were collected before and immediately after exposure as well as for the periods 1-2, 2-3, 3-4, 4-5, 5-6, 6-12 and 12-24 h after exposure. For 40 micrograms/m3 exposure urine samples were collected before and 2 h after exposure. 2. The main urinary cyfluthrin metabolites, cis-/trans-3-(2,2-dichlorovinyl)-2,2-dimethylycyclopropane carboxylic acid (DCCA) and 4-fluoro-3-phenoxybenzoic acid (FPBA), were determined. The limit of detection (LOD) for all metabolites was 0.0025 microgram in an urine sample of 5 ml (0.5 microgram/l). After inhalative exposure of 40 micrograms cyfluthrin/m3 air for 60 min, the amount of metabolites in urine collected in the first 2 h after exposure was less than the LOD, namely 0.14 microgram for cis-DCCA, 0.15-0.28 microgram for trans-DCCA and 0.12-0.23 microgram for FPBA. 3. Of the metabolites, 93% was excreted within the first 24 h (peak excretion rates between 0.5 and 3 h) after inhalative exposure of 160 micrograms/m3. The mean half-lives were 6.9 h for cis-DCCA, 6.2 h for trans-DCCA and 5.3 h for FPBA. 4. The mean trans-:cis-DCCA ratio was 1.9 for the time course as well as for each subject. 5. The amount of metabolites in urine depends on the applied dose, on the exposure time and shows interindividual differences.     

Urinary excretion of free cystine and the tiopronin-cysteine-mixed disulfide during long term tiopronin treatment of cystinuria

We report the results of a biochemical evaluation of long-term treatment of cystinuria with the SH compound tiopronin (2-mercaptopropionylglycine). The effects of tiopronin were studied by monitoring the urinary excretion of free cysteine and the mixed disulfide between tiopronin and cysteine. Thirty-one patients with homozygous cystinuria were treated with tiopronin for 0.4-12 years (mean 7.8 years). The urinary concentration of free cysteine was used to adjust the tiopronin dose. In 28 of the 31 patients a mean urinary cystine concentration of less than 1,200 mumol/1(288 mg/l) was achieved with the final dose. The final daily doses of tiopronin ranged from 250 mg (1.5 mmol) to 3,000 mg (18.4 mmol; mean 1,540 mg; 9.4 mmol). In a majority of the patients the treatment reduced the 24-hour urinary free cystine excretion effectively, on average by 0.61 mumol (0.15 mg)/mg of tiopronin administered. No changes in the efficacy of tiopronin over time were observed, and the frequency of adverse effects was acceptable. To evaluate the effects of tiopronin on the metabolism of cystine we calculated the total urinary excretion of cystine as the sum of free cystine and the amount of cystine corresponding to the cysteine content of the tiopronin-cysteine disulfide. At low doses of tiopronin there was an increase in urinary excretion of the mixed disulfide as well as of total cystine. Monitoring urinary cystine concentration is necessary to achieve adequate individualized doses of tiopronin. Assessment of the mixed tiopronin-cysteine disulfide and the urinary excretion of total cystine shows that tiopronin may interfere with cystine metabolism in a more complex way than through a simple disulfide exchange reaction with urinary cystine.     

Diuretic response to cyclophosphamide in rats bearing a matrix metalloproteinase-9-producing tumour

When cyclophosphamide (CY) (100-120 mg kg(-1)) was administered intravenously (i.v.) to normal F-344 rats, oliguria occurred over the 5-day observation period. Conversely, in rats bearing matrix metalloproteinase-9 (MMP-9) producing 13762NF mammary adenocarcinoma (MTLn3 clone), polyuria occurred chiefly during the first 24 h after CY treatment. In parallel with urine volume, a decrease in the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) was observed during the first 5 days after CY treatment in normal rats, but it increased in MTLn3-bearing rats. No elevation in blood urea nitrogen (BUN) or serum creatinine (Cr) values was observed for either group. Both urine volume and urinary excretion of NAG after CY treatment were lower in rats bearing the MTC clone (lower production of MMP-9) than for those bearing the MTLn3 clone. In the case of treatment with cisplatin (CDDP, 4-6 mg kg(-1)), urine volume, urinary NAG excretion and BUN and serum Cr values all increased in normal rats and were all found to be higher in MTLn3-bearing rats than in normal rats. The diuretic response to these drugs in tumour-bearing (TB) rats may be associated with MMP-9 produced by the tumour cells. This report suggests that the nephrotoxicity due to anti-cancer drugs may change when the drugs are used for the treatment of patients bearing a MMP-9-producing tumour.     

An increase in renal dopamine production after the administration of radiographic contrast agents

Renal vasoconstriction and anti-natriuresis conditioned by radiographic contrast agents (CA) may be antagonised by the administration of exogenous dopamine. However, the influence of CA on the activity of renal synthesis of dopamine has not been studied. This study assessed the daily urinary excretion of dopamine, its precursor. L-3, 4-dihydroxyphenylaline (L-DOPA), and its metabolites (acid 3, 4-dihydroxyphenylacetic, DOPAC; homovanillic acid, HVA) 24 hours before and 48 hours following administration of a non ionic and hyposmolar (lopromide) CA in patients (n = 10; average age 61.3 +/- 4.3 years) submitted to coronary angiography. Urinary excretion of noradrenalin, a marker of sympathetic activity, was also assessed during the same period. The deputation of creatinine (Ccr) and the urinary excretion of sodium (UNa+) lowered after the administration of the CA (Ccr, 79.2 +/- 10.2 vs 72.2 +/- 9.6 ml/min/1.73 m2, p < 0.05; UNa+, 112.8 +/- 9.6 vs 61.7 +/- 25.1 mmol/24 h, p < 0.05). On the contrary, the urinary excretion of potassium increased in the period of 24 h following the administration of the AC (31.7 +/- 5.2 vs 103.8 +/- 10.8 mmol/24 h, p < 0.05). There was an increase in the urinary excretion of dopamine as well as noradrelalin during the 24 hour period following the administration of the CA (dopamine, 1260.2 +/- 196.8 vs 1571.5 +/- 170.2 mmol/24 h p < 0.5; noradrenalin, 186 +/- 36.6 mmol/24 h, p < 0.05). On the contrary, the urinary excretion of L-DOPA lowered after the administration of the CA (115.4 +/- 25.5 vs 80.5 +/- 13.2 mmol/24 h, p < 0.05). These results conditioned an increase in the dopamine/L-DOPA ratio in the urine, after the administration of the CA (12.2 +/- 1.5 vs 22.2 +/- 4.5 mmol/24 h, p < 0.05). In conclusion, the administration of CA is accompanied by an increase in the renal production of dopamine which, in these conditions, may act as a compensatory natriuretic hormone.     

Effects of gemcitabine on renal function in patients with non-small cell lung cancer

Gemcitabine is a novel fluorine-substituted cytarabine (Ara-C) analogue with activity against a range of solid tumours. Besides dose-limiting haematological toxicity, renal side-effects were observed from phase I and II studies concerning elevations of serum creatinine, proteinuria and erythrocyturia. The aim of this study was to investigate the effect of gemcitabine on renal function in 11 untreated patients with non-small cell lung cancer (NSCLC). Gemcitabine was given as weekly infusions of 1250 mg/m2 for 3 weeks, followed by 1 week rest. This comprised one cycle (maximum of six cycles). The glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured simultaneously with a constant infusion of 125I-iothalamate and 131I-hippuran, respectively. Tubular damage was monitored by excretion of tubular enzymes (lactic dehydrogenase (LDH), alkaline phosphatase (ALP), gamma-glutamyltransferase (GT) and beta 2-microglobulin); glomerular damage was monitored by excretion of albumin in the urine. In 9 patients, the effect of the first infusion was evaluated. After the first infusion of gemcitabine, no change was observed in renal function. After two, three, and six cycles of treatment, no significant changes in GFR and ERPF were noticed in 9 evaluable patients. However, in 3 patients, a decrease in GFR of > 10% was observed after multiple cycles. In one of them this was accompanied with albuminuria (360 mg/24 h) and erythrocyturia. There were no significant changes in urinary excretion of tubular enzymes or albumin. In conclusion, we did not observe acute renal toxicity with gemcitabine. No significant cumulative effects of gemcitabine on renal function could be detected, although 3 patients, treated with multiple cycles of gemcitabine, showed a moderate decrease in renal function. Glomerular damage might play a role in the development of renal function loss.