Time course of urinary excretion of intraportal ammonia as uric acid and ammonia in chickens fed low- or high-protein diet

15N-ammonia was intraportally infused for 6 hr into chickens fed 5% or 20% protein diet to examine the time course of urinary excretion of intraportal ammonia and dietary effects on it. Urinary ammonia increased linearly for the first hour to the same extent in both dietary groups and thereafter further in the low-protein group. Urinary uric acid derived from the intraportal ammonia adaptively increased and reached a steady state level within 1.5 hr. This level was four times higher in the high-protein group. The infused ammonia was excreted into urine as both ammonia and uric acid, in relatively high proportions in the chickens fed the low-protein diet but was almost all excreted as uric acid in those fed the high-protein diet.     

Plasma uric acid levels in ethanol-fed turkey poults treated with allopurinol

Plasma uric acid levels were determined in ethanol-fed poults following administration of allopurinol. In young poults, allopurinol at a dose of 50 mg/kg significantly depressed plasma uric acid levels 6 hr post-dosing. At 11 hr post-dosing, plasma uric acid levels were significantly elevated in the allopurinol-treated poults when compared with control poults. During a period of ethanol abstinence, allopurinol at a dose of 40 mg/kg significantly depressed plasma uric acid levels up to 8 hr post-dosing. At a dose of 30 mg/kg, plasma uric acid levels were similar to control values at 4 and 6 hr post-dosing. Data suggest that plasma uric acid levels can be depressed in ethanol poults when allopurinol is administered every 8 hr at a dose of 40-50 mg/kg of body weight.     

Effect of insulin on excretion and retention of infused glutamine amide-N in chickens (Gallus domesticus)

1. The purpose of this study was to examine the effects of insulin on urinary excretion and retention of the intravenously infused glutamine amide-15N in chickens. 2. Insulin pretreatment reduced urinary total 15N excretion (P less than 0.05) and enhanced 15N retention in chicken body (P less than 0.05), but it did not affect non protein-15N retained in the liver and blood. 3. Insulin decreased the incorporation of the infused glutamine amide-15N into urinary uric acid as well as the excretion of other N-derived urinary uric acid (P less than 0.05), which resulted in a significant decrease in total urinary uric acid (P less than 0.05). 4. There was no effect of insulin on urinary appearance of the infused glutamine amide-15N in the form of ammonia.     

Depression of glutamine-stimulated uric acid production and blood glutamine accumulation by insulin in chickens

This experiment was conducted to examine effects of insulin on glutamine accumulation in blood and uric acid production in the chicken infused with glutamine. Insulin pretreatment eliminated the stimulatory effect of glutamine infusion on urinary uric acid excretion in the chicken fed a 5% protein diet, which resulted in no increase in urinary total nitrogen excretion by the infusion. In the chicken fed a 20% protein diet the pretreatment with insulin did not have such clear depressive effects on the increases in urinary uric acid and total nitrogen excretion caused by the glutamine infusion. Insulin tended to depress the increases in plasma glutamine concentration caused by the infusion of glutamine at both levels of dietary protein intake.     

Zea mays L. extracts modify glomerular function and potassium urinary excretion in conscious rats

Diuretic and uricosuric properties have traditionally been attributed to corn silk, stigma/style of Zea mays L. Although the diuretic effect was confirmed, studies of the plant's effects on renal function or solute excretion were lacking. Thus, we studied the effects of corn silk aqueous extract on the urinary excretion of water, Na+, K+, and uric acid. Glomerular and proximal tubular function and Na+ tubular handling were also studied. Conscious, unrestrained adult male rats were housed in individual metabolic cages (IMC) with continuous urine collection for 5 and 3 h, following two protocols. The effects of 25, 50, 200, 350, and 500 mg/kg body wt. corn silk extract on urine volume plus Na+ and K+ excretions were studied in water-loaded conscious rats (2.5 ml/100 g body wt.) in the IMC for 5 h (Protocol 1). Kaliuresis was observed with doses of 350 (100.42 +/- 22.32-120.28 +/- 19.70 microEq/5 h/100 g body wt.; n = 13) and 500 mg/kg body wt. (94.97+/- 29.30-134.32 +/- 39.98 microEq/5h/100 g body wt.; n = 12; p<0.01), and the latter dose resulted in diuresis as well (1.98 +/- 0.44-2.41 +/- 0.41 ml/5 h/100 g body wt.; n = 12; p<0.05). The effects of a 500 mg/kg body wt. dose of corn silk extract on urine volume, Na+, K+ and uric acid excretions, and glomerular and proximal tubular function, were measured respectively by creatinine (Cler) and Li+ (ClLi) clearances and Na+ tubular handling, in water-loaded rats (5 ml/100 g body wt.) in the IMC for 3 h (Protocol 2). Clcr (294.6 +/- 73.2, n = 12, to 241.7 +/- 48.0 microl/ min/100 g body wt.; n = 13; p<0.05) and the Na+ filtered load (41.9 +/- 10.3, n = 12, to 34.3 +/- .8, n = 13, p<0.05) decreased and ClLi and Na+ excretion were unchanged, while K+ excretion (0.1044 +/- 0.0458, n=12, to 0.2289 +/- 0.0583 microEq/min/100 body wt.; n = 13; p<0.001) increased. For Na+ tubular handling, the fractional proximal tubular reabsorption (91.5 +/- 3.5, n = 12, to 87.5 +/- 3.4%; n = 13; p<0.01) decreased, and both fractional distal reabsorptions--I and II--increased (96.5 +/- 1.5, n = 12, to 97.8 +/- 0.9%; n = 13; p<0.01; and 8.2 +/- 3.5, n = 12, to 12.2 +/- 3.4%, n = 13, p<0.01, respectively). To summarize, in water-loaded conscious rats (2.5 ml/100 body wt.), corn silk aqueous extract is diuretic at a dose of 500 mg/kg body wt. and kaliuretic at doses of 350 and 500 mg/kg body wt. In water-loaded conscious rats (5.0 ml/100 g body wt.), corn silk aqueous extract is kaliuretic at a dose of 500 mg/kg body wt., but glomerular filtration and filtered load decrease without affecting proximal tubular function, Na+, or uric acid excretion.     

Febuxostat (TMX‐67), a Novel,Non‐Purine,Selective Inhibitor of Xanthine Oxidase,Is Safe and Decreases Serum Urate in Healthy Volunteers

In order to evaluate the safety, pharmacological properties, and urate‐lowering efficacy of febuxostat, a non‐purine, selective inhibitor of xanthine oxidase, a Phase 1, 2‐week, multiple‐dose, placebo‐controlled, dose‐escalation study was conducted in 154 healthy adults of both sexes. Daily febuxostat doses in the range 10 mg to 120 mg resulted in proportional mean serum urate reductions ranging from 25% to 70% and in proportional increases in maximum febuxostat plasma concentrations and area under plasma concentration versus time curves. Accompanying the hypouricemic effect were increases in serum xanthine concentrations, decreases in urinary uric acid excretion, and increases in urinary xanthine and hypoxanthine excretion, confirming inhibition of xanthine oxidase activity by febuxostat. Hepatic conjugation and oxidative metabolism were the major pathways of elimination of febuxostat from the body, and renal elimination did not appear to play a significant role. Although not uncommon, adverse events were mild and self‐limited, and no deaths or serious adverse events were observed. Febuxostat is a safe and potent hypouricemic agent in healthy humans.     

Efficacy and safety of allopurinol in patients with the Lesch-Nyhan syndrome and partial hypoxanthine- phosphoribosyltransferase deficiency: a follow-up study of 18 Spanish patients

Allopurinol is used widely for the treatment of purine disorders such as gout, but efficacy and safety of allopurinol has not been analyzed systematically in an extensive series of patients with HPRT deficiency. From 1984 to 2004 we have diagnosed 30 patients with HPRT deficiency. Eighteen patients (12 with Lesch-Nyhan syndrome or complete HPRT deficiency, and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.44 mg/Kg of weight per day) and followed-up for at least 12 months (mean follow-up 7,6 years per patient). Mean age at diagnosis was 7 years (range, 5 months to 35 years). Treatment with allopurinol was associated to a mean reduction of serum urate concentration of 50%, and was normalized in all patients. Mean urinary uric acid excretion was reduced by 75% from baseline values, and uric acid to creatinine ratio was close or under 1.0 in all patients. In contrast, hypoxanthine and xanthine urinary excretion rates increased by a mean of 6 and 10 times, respectively, compared to baseline levels. These modifications were similar in patients with complete or partial HPRT deficiency. In 2 patients xanthine stones were documented despite allopurinol dose adjustments to prevent markedly increased oxypurine excretion rates. Neurological manifestations did not appear to be influenced by allopurinol therapy. Allopurinol is a very efficacy and fairly safety drug for the treatment of uric acid overproduction in patients with complete and partial HPRT deficiency. Allopurinol was associated with xanthine lithiasis.     

Efficacy and Safety of Allopurinol in Patients with the Lesch-Nyhan Syndrome and Partial Hypoxanthine- Phosphoribosyltransferase Deficiency: a Follow-up Study of 18 Spanish Patients

Allopurinol is used widely for the treatment of purine disorders such as gout, but efficacy and safety of allopurinol has not been analyzed systematically in an extensive series of patients with HPRT deficiency. From 1984 to 2004 we have diagnosed 30 patients with HPRT deficiency. Eighteen patients (12 with Lesch-Nyhan syndrome or complete HPRT deficiency, and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.44 mg/Kg of weight per day) and followed-up for at least 12 months (mean follow-up 7,6 years per patient). Mean age at diagnosis was 7 years (range, 5 months to 35 years). Treatment with allopurinol was associated to a mean reduction of serum urate concentration of 50%, and was normalized in all patients. Mean urinary uric acid excretion was reduced by 75% from baseline values, and uric acid to creatinine ratio was close or under 1.0 in all patients. In contrast, hypoxanthine and xanthine urinary excretion rates increased by a mean of 6 and 10 times, respectively, compared to baseline levels. These modifications were similar in patients with complete or partial HPRT deficiency. In 2 patients xanthine stones were documented despite allopurinol dose adjustments to prevent markedly increased oxypurine excretion rates. Neurological manifestations did not appear to be influenced by allopurinol therapy. Allopurinol is a very efficacy and fairly safety drug for the treatment of uric acid overproduction in patients with complete and partial HPRT deficiency. Allopurinol was associated with xanthine lithiasis.     

Comparison of urinary creatine with other biomarkers for detection of cadmium induced testicular damage

In this study, biomarkers of testicular damage were compared. In particular, urinary creatine was evaluated as a non-invasive marker of damage. Male rats were exposed to various doses of cadmium chloride, an established testicular toxicant. Pathological damage, testes weights, urinary creatine and creatinine, serum LDH-C4 and serum testosterone were determined. Cadmium chloride caused dose-dependent damage to the testes undetectable at the lowest dose (0.75 mg kg-1) but apparent at a dose of 1.125 mg kg-1. Urinary creatine was significantly raised after doses of 1.125 mg kg-1 and above 24-48 hr after dosing, and at the highest dose within 24 hr after dosing. Testes weight and serum testosterone were significantly decreased, and LDH-C4 significantly increased, at the highest dose (3.0 mg kg-l). Therefore urinary creatine was the most sensitive marker of acute cadmium-induced testicular damage and dysfunction.     

Comparison of urinary creatine with other biomarkers for detection of cadmium induced testicular damage

In this study, biomarkers of testicular damage were compared. In particular, urinary creatine was evaluated as a non-invasive marker of damage. Male rats were exposed to various doses of cadmium chloride, an established testicular toxicant. Pathological damage, testes weights, urinary creatine and creatinine, serum LDH-C4 and serum testosterone were determined. Cadmium chloride caused dose-dependent damage to the testes undetectable at the lowest dose (0.75 mg kg-1) but apparent at a dose of 1.125 mg kg-1. Urinary creatine was significantly raised after doses of 1.125 mg kg-1 and above 24-48 hr after dosing, and at the highest dose within 24 hr after dosing. Testes weight and serum testosterone were significantly decreased, and LDH-C4 significantly increased, at the highest dose (3.0 mg kg-l). Therefore urinary creatine was the most sensitive marker of acute cadmium-induced testicular damage and dysfunction.     

Effects of intranasal administration of atrial natriuretic hormone on spontaneously hypertensive rats

The effects of the intranasal administration of synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) were investigated in 14 anesthetized spontaneously hypertensive rats (SHR; Okamoto-Aoki strain). They were given intranasally synthetic alpha-hANP in distilled water at doses of 10 micrograms/kg, 50 micrograms/kg and 100 micrograms/kg. Intranasal application of 200 microliter of distilled water as a control was also performed in 3 anesthetized SHR. Sixteen anesthetized SHR were examined for the effects of intravenous administration of alpha-hANP at doses of 4 micrograms/kg, 10 micrograms/kg, 20 micrograms/kg and 40 micrograms/kg. Urinary volume and the urinary excretion of sodium increased 2- to 3-fold during the 50 minutes following intranasal administration of a single dose of 50 micrograms/kg or 100 micrograms/kg, although neither the urinary volume nor the urinary excretion of sodium increased after intranasal administration of 10 micrograms/kg of alpha-hANP or 200 microliter of distilled water. There were no significant changes in arterial pressure or heart rate after the intranasal administration of synthetic alpha-hANP or distilled water. In contrast, arterial pressure was decreased and urinary volume and urinary excretion of sodium were increased, in a dose dependent manner, within 5 minutes after intravenous bolus-injection of alpha-hANP and returned to their baseline levels within 20 minutes. These results indicate that intranasal administration of synthetic alpha-hANP exerts its diuretic effect without concomitant changes in arterial pressure or heart rate in SHR.     

Short-term physiological changes in turbot and seabream juveniles exposed to exogenous ammonia

Seabream and turbot juveniles (40-520 g) were exposed to constant exogenous NH5-N concentrations (1.27-4.27 mmol/l; pH, 8.15). In 96 hr acclimated fish, plasma TA-N (total ammonia nitrogen) contents were positively correlated to ambient ammonia concentrations. The LD50 were 2.2-2.5 mmol/l TA-N in both species. There were no marked osmoregulatory disturbances and plasma urea-N, thyroid hormones levels and gill (Na-K)-ATPase activities were only affected at the highest concentrations. Liver GOT, GPT and GIDH activity dose-response were low and species dependent. In cannulated and non-cannulated turbot exposed to half 96 hr LC50 (lethal ambient concentration for 50% of the population), there was a rapid, pronounced and prolonged increase in plasma TA-N, followed by an immediate decline when exogenous ammonia supply was stopped. Maximum loading and unloading were observed within 1-3 hr. Plasma cortisol levels indicated a stressful situation in exposed fish (150 ng/ml) and a quick recovery capacity. In dose and time response experiments, the most relevant physiological indicator of ammonia stress was blood TA-N content. Other parameters tested led either to transient or low amplitude responses except when fish approached death.     

Inhibition of monoamine synthesis by irreversible blockade of aromatic aminoacid decarboxylase with alpha-monofluoromethyldopa.

DL-α-monofluoromethyldopa is a potent enzyme-activated irreversible inhibitor of purified aromatic aminoacid decarboxylase. Single doses from 0.25 to 25 mg/kg cause partial to total inhibition of this enzyme in kidney and heart. Inhibition of brain enzyme becomes significant at doses above 2.5 mg/kg and is complete at 100 mg/kg. Enzyme activity begins to return after 24 hr, so that repetition of a dose at 12 hr intervals markedly increases the inhibition. Single doses of 100–250 mg/kg almost completely deplete kidney, heart and brain of endogenous catecholamines by blocking dopa decarboxylation. Serotonin is also decreased, presumbaly by the same mechanism.     

Febuxostat (TMX-67), a novel, non-purine, selective inhibitor of xanthine oxidase, is safe and decreases serum urate in healthy volunteers

In order to evaluate the safety, pharmacological properties, and urate-lowering efficacy of febuxostat, a non-purine, selective inhibitor of xanthine oxidase, a Phase 1, 2-week, multiple-dose, placebo-controlled, dose-escalation study was conducted in 154 healthy adults of both sexes. Daily febuxostat doses in the range 10 mg to 120 mg resulted in proportional mean serum urate reductions ranging from 25% to 70% and in proportional increases in maximum febuxostat plasma concentrations and area under plasma concentration versus time curves. Accompanying the hypouricemic effect were increases in serum xanthine concentrations, decreases in urinary uric acid excretion, and increases in urinary xanthine and hypoxanthine excretion, confirming inhibition of xanthine oxidase activity by febuxostat. Hepatic conjugation and oxidative metabolism were the major pathways of elimination of febuxostat from the body, and renal elimination did not appear to play a significant role. Although not uncommon, adverse events were mild and self-limited, and no deaths or serious adverse events were observed. Febuxostat is a safe and potent hypouricemic agent in healthy humans.     

Comparison of urinary creatine with other biomarkers for the detection of 2-methoxyethanol-induced testicular damage

This study has compared different biomarkers of testicular damage, in particular evaluating urinary creatine as a non-invasive marker. Male rats were exposed to various doses of 2-methoxyethanol, a known testicular toxicant. Pathological damage, testis weight, urinary creatine and creatinine, serum lactate dehydrogenase, isozyme C4 (LDH-C4), and serum testosterone were determined. 2-Methoxyethanol caused dose-dependent pathological damage to the testes which was detectable at the lowest dose (100 mg kg^-1). Urinary creatine excretion was significantly raised at all doses but testis weight was only significantly decreased at the highest two doses (500, 750 mg kg^-1). Serum testosterone was only significantly decreased at 500 mg kg^-1 and LDH-C4 was not significantly increased at any dose. Therefore urinary creatine was the most sensitive marker of 2-methoxethanol-induced testicular damage and dysfunction.     

Steady state pharmacokinetics, metabolism and pharmacodynamics of theophylline in children after unequal twice-daily dosing of a new sustained-release formulation

This was an open-label study in 19 children aged 9-13 years, weighing 27-44 kg, with bronchial asthma. Twenty-four-hour steady-state concentrations of theophylline and its metabolites 1,3-dimethyl uric acid, 3-methyl xanthine and 1-methyl uric acid were assessed after daily dosing of 600 mg (ca 18 mg/kg/day) of the sustained-release theophylline micro-pellet sprinkle system BY158K, for 4 days. The dosing regimen used was an unequal twice-daily dose of 200 mg in the morning after breakfast and 400 mg in the evening after dinner. Twenty-four-hour peak expiratory flow (PEF) profiles were compared before treatment and at steady-state, along with lung function parameters after bronchial provocation. Mean values +/- SD (n = 16) of the steady-state characteristics were Cmin 6.8 +/- 2.1 mg/l, Cmax 14.5 +/- 4.8 mg/l and Cav 10.5 +/- 2.9 mg/l, the plateau time was 11.7 +/- 4.8 hr and peak-trough fluctuation and swing were 72 +/- 21 and 118 +/- 52%, respectively. There was an excellent reproducibility of theophylline pre-dose levels at corresponding time points of the 24-hr sampling period [r = 0.864 (p less than 0.001)]. Mean values +/- SD of the 24 hr average serum metabolite levels were 0.9 +/- 0.2 mg/1 for 1,3-dimethyl uric acid, 0.6 +/- 0.1 mg/1 for 3-methyl xanthine and 0.4 +/- 0.1 mg/1 for l-methyl uric acid. Lung function (n = 17) following bronchial provocation, improved in 10 children after theophylline treatment of 4 days, remained stable in 2 patients and deteriorated in 5 patients. Serum theophylline profiles and PEF profiles ran largely in parallel over the 24-hr period. Six children exhibited typical theophylline induced side-effects, headache (n = 3), nausea (n = 4), dizziness (n = 1), vomiting (n = 4), sleep disturbances (n = 1), pallor (n = 1) and tremor (n = 1), necessitating in 3 children one dose omission/reduction (n = 2) or subsequent dose reduction (n = 1). It has been shown that a twice daily dosing regimen with unequal doses of anhydrous theophylline (BY158K) is well suited to this population of fast metabolisers. The patients were well protected throughout the day, including the critical early morning hours.     

Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

The main iron chelator used for transfusional iron overload is desferrioxamine, which is expensive, has toxic side effects, and has to be given subcutaneously. An orally active iron chelator is therefore required. The effects of oral 1,2-dimethyl-3-hydroxypyrid-4-one on urinary iron excretion were studied in eight patients who had received multiple transfusions: four had myelodysplasia and four beta thalassaemia major. Different daily doses of the drug up to 100 mg/kg/day, alone or in combination with ascorbic acid, were used. In three patients with thalassaemia the effect of the drug was compared with that of subcutaneous desferrioxamine at the same daily dose. In all eight patients a single dose of oral 1,2-dimethyl-3-hydroxypyrid-4-one resulted in substantial urinary iron excretion, mainly in the first 12 hours. Urinary iron excretion increased with the dose and with the degree of iron loading of the patient. Giving two or three divided doses over 24 hours resulted in higher urinary iron excretion than a single dose of the same amount over the same time. In most patients coadministration of oral ascorbic acid further increased urinary iron excretion. 1,2-Dimethyl-3-hydroxypyrid-4-one caused similar iron excretion to that achieved with subcutaneous desferrioxamine at a comparable dose. In some cases the iron excretion was sufficiently high (maximum 99 mg/day) to suggest that a negative iron balance could be easily achieved with these protocols in patients receiving regular transfusions. No evidence of toxicity was observed on thorough clinical examination or haematological and biochemical testing in any of the patients. None of the patients had any symptoms that could be ascribed to the drug. These results suggest that the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one is as effective as subcutaneous desferrioxamine in increasing urinary iron excretion in patients loaded with iron. Its cheap synthesis, oral activity, and lack of obvious toxicity at effective doses suggest that it should be developed quickly and thoroughly tested for the management of transfusional iron overload.     

Appearance of intraportally infused [15N]urea in blood and urine of domestic fowl

The time course of the occurrence of intraportally infused [15N]urea in blood and urine was investigated in chickens. The infused urea appeared in ureteral urine, mostly in the form of urea, as early as 30 min after the start of infusion and the excretion further increased up to the end of 2 hr infusion. Blood urea concentration rapidly increased and reached about three times the initial level at the end of the experiment (P < 0.05 after 20 min), but no significant effects were observed on uric acid, ammonia and glutamine concentrations. Fifty-seven percent of blood urea N and 3% of blood glutamine-amide N and 1% of blood ammonia N, which were determined at the end of experiment, were derived from the infused urea N. It is concluded that urea, which is rapidly increased in blood and urine after feeding urea to chickens, is mostly derived from dietary urea.     

Influence of oral dehydroepiandrosterone (DHEA) on urinary steroid metabolites in males and females

Oral dehydroepiandrosterone (DHEA) replacement therapy may have a multitude of potential beneficial effects and exerts its action mainly via peripheral bioconversion to androgens (and estrogens). A daily dose of 50-mg DHEA has been shown by us and others to restore low endogenous serum DHEA concentrations to normal youthful levels followed by an increase in circulating androgens and estrogens. As the hepatic first-pass effect may lead to a non physiological metabolism of DHEA after oral ingestion we studied the influence of two single DHEA doses (50 and 100 mg) on the excretion of steroid metabolites in 14 elderly males [age 58.8+/-5.1 years (mean +/- SEM)] with endogenous DHEAS levels <1500 ng/ml and in 9 healthy females (age 23.3+/-4.1 years) with transient suppression of endogenous DHEA secretion induced by dexamethasone (dex) pretreatment (4x0.5 mg/day/4 days). Urinary steroid profiles in the elderly males were compared to the steroid patterns found in 15 healthy young men (age 28.9+/-5.1 years). In the females the results were compared to their individual baseline excretion without dex pretreatment. Urinary steroid determinations were carried out by semiautomatic capillary gas-liquid chromatography. In both genders DHEA administration induced significant increases in urinary DHEA (females: baseline vs. 50 mg vs. 100 mg: 361+/-131 vs. 510+/-264 vs. 1541+/-587 microg/day; males: placebo vs. 50 mg vs. 100 mg: 434+/-154 vs. 1174+/-309 vs. 4751+/-1059 microg/day) as well as in the major DHEA metabolites androsterone (A) and etiocholanolone (Et). Fifty mg DHEA led to an excretion of DHEA and its metabolites only slightly above baseline levels found in young females and in young men, respectively, whereas 100 mg induced clearly supraphysiological values. After 50 mg DHEA the ratios of urinary DHEA metabolites (A/DHEA, Et/DHEA) were not significantly different between elderly males vs. young male volunteers and young healthy females versus their individual baseline levels. In conclusion, an oral dose of 30 to 50 mg DHEA restores a physiological urinary steroid profile in subjects with DHEA deficiency without evidence for a relevant hepatic first-pass effect on urinary metabolites.     

Metabolism of [13N]ammonia in rat lung

Bolus injection of [13N]ammonia into the femoral vein of pentobarbital-anesthetized rats was followed by rapid clearance from the blood and first-pass extraction of nearly 30% by the lungs. Of the label present in the lungs at 6 s after injection (about 27% of the dose), more than 20% was in metabolized form. Of the label present in the lungs at 2 min after injection (about 10% of the dose), 18-25% was in ammonia, about 75% was in glutamine (amide) and less than 1% was in glutamate and aspartate. Thus, despite the presence of significant amounts of glutamate dehydrogenase, the overwhelming route for metabolism of ammonia entering the rat lung in vivo was the glutamine synthetase reaction. Lung tissue that was removed 6 s after intravenous injection of [13N]ammonia and incubated in Krebs-Ringer glucose medium at 37 degrees C for 20 min, showed a significant increase (more than one-third), compared to unincubated lung tissue in the quantity of label in glutamine. Between 6s and 2 min after injection, during which time the total 13N content of the lungs decreased by more than 60%, the maintenance of a quasi-steady state in the concentration of labeled glutamine suggested a short-term balance between formation from extracted ammonia and loss of glutamine into the circulation. Our data support the concept that the lungs are a source of circulating glutamine in the rat. Despite the large fractional extraction of blood-borne [13N]ammonia by the lungs, only minute amounts of tracer (0.2-0.6 ppm of the injected dose) were detected in the expired air within the first 5 min after administration of [13N]ammonia to anesthetized rats, so that pulmonary excretion was not a significant pathway of ammonia elimination. The present findings emphasize the importance of the lungs in the maintenance of whole-body nitrogen homeostasis and suggest the use of [13N]ammonia and 13N-labeled amino acids as non-invasive probes in the study of normal and diseased lung metabolism.