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[Absorption, distribution, metabolism and excretion of bacmecillinam. III. Absorption, metabolism and excretion of 14C-bacmecillinam following oral administration to dogs].

The pharmacokinetics (i.e., blood level, biological half-lives and excretion) of bacmecillinam (KW-1100) was investigated. KW-1100 was orally administered to dogs at the dose of 20 mg/kg (as mecillinam). Biological half-lives (radioactivity) of 14C-KW-1100 in plasma were 1.2 hours (T1/2 alpha) and 52 hours (T1/2 beta). The Cmax and Tmax were 8.4 micrograms/ml and 2 hours. The biological half-life (microbiological activity) of KW-1100 in plasma was 0.9 hour. The Cmax and Tmax were 5.6 micrograms/ml and 1 hour. The urinary and fecal excretion of 14C-KW-1100 were approximately 46% and 49% (0 approximately 72 hours), respectively. The major metabolites in the urine (0 approximately 8 hours) were mecillinam, 5,5-dimethyl-2-(1'-formamidomethyl)-thiazolidine-1',4-dicarboxy lat e (M-1) and 6-beta-[(hexahydro-1 H-azepin-1-yl)-methyleneamino]penicilloic acid (M-6), each distribution ratio of which was 57.2, 24.2 and 12.0% of the total radioactivity in the sample, respectively. The major metabolite in the plasma at peak time (2 hours) was mecillinam (56.2%).

Administration, Oral↗

Virus excretion in smallpox. 2. Excretion in the throats of household contacts.

Throat swabs of 34 of 328 family contacts of 52 smallpox cases, examined 4-8 days after the onset of the disease in the family, were positive for variola virus. The log titre of virus per swab ranged from 2 to 3.95. A higher proportion of unvaccinated than of vaccinated contacts excreted the virus. Only 4 of the virus-positive contacts developed clinical smallpox; this occurred 5-7 days after their swabs were examined. Excretion of virus in the throats of these contacts, a few of whom were in the incubation period of the disease, suggests the possibility that they could have spread the infection. This possibility, if kept in mind, may help in tracing the source of infection or in determining the incubation period in a few instances when difficulty is experienced.

Adolescent↗

Excretion of free and conjugated steroids in rainbow trout (Oncorhynchus mykiss): evidence for branchial excretion of the maturation-inducing steroid, 17,20 beta-dihydroxy-4-pregnen-3-one.

The goal of this study was to identify excretory routes of three main steroids produced by sexually mature male and female rainbow trout: 17,20 beta-dihydroxy-4-pregnen-3-one (17,20 beta-P), sulfated 17,20 beta-P (17,20 beta-P-S), and testosterone glucuronide (TG). Spermiating males or maturing trout were cannulated via the dorsal aorta and urinary bladder and injected with tritiated steroids. Blood, water, and urine were sampled over the next 12 hr when the fish were killed and bile was collected. The identities of the excreted products were determined by anion-exchange chromatography, reverse-phase high-performance liquid chromatography, enzyme hydrolysis, acid solvolysis, microchemical modification, and thin-layer chromatography. Following the injection of tritiated 17,20 beta-P, 25% of the radioactivity rapidly appeared unmodified in the water; 15% appeared slowly in the urine, mainly as 17,20 beta-P-S; and 40% was recovered in the bile, mainly as 17,20 beta-P-glucuronide. 17,20 beta-P was shown to be released into the water via the gills. Over the 12-hr sampling period, 20% of the 17,20 beta-P released into the water was taken up again by the fish (also branchially). A mathematical analysis showed that 40% of the 17,20 beta-P would have been released into the water in the absence of uptake. Following the injection of tritiated 17,20 beta-P-S, 63% appeared very rapidly, in an unmodified form, in the urine, and 15% was recovered in the bile. Following the injection of tritiated TG, 9% appeared slowly, mainly untransformed, in the urine, and 59% was recovered in the bile. These results show that the three types of steroids are released into the water by three different routes: free steroids, gills; sulfated steroids, urine; and glucuronidated steroids, bile.

Animals↗

Defective renal water excretion in nephrotic syndrome: the relationship between renal water excretion and kidney function, arginine vasopressin, angiotensin II and aldosterone in plasma before and after oral water loading.

An oral water load of 20 ml (kg body wt)-1 was given to seventeen patients with the nephrotic syndrome and fifteen healthy control subjects. Diuresis (D), free water clearance (CH2O), plasma concentrations of arginine vasopressin (AVP), angiotensin II (AII) and aldosterone (Aldo) were determined before and 3 times during the first 4 h after loading. In the nephrotic syndrome D was significantly lower 1-2 h after loading than in the control subjects, predominantly due to a lower CH2O (2.61 and 7.01 ml min-1 (medians), P less than 0.01). Creatinine clearance and the maximum increase in CH2O were significantly correlated in patients with the nephrotic syndrome (rho = 0.721, n = 17, P less than 0.01) and the control subjects (rho = 0.596, n = 15, P less than 0.01). AVP was reduced in both groups during loading, but AVP was clearly elevated in the patients with the nephrotic syndrome when compared to the control subjects both before (3.0 and 1.9 pmol 1(-1), P less than 0.01) and during loading. There was a significantly negative correlation between CH2O and AVP in both groups. AII and Aldo were reduced during loading, but the levels were the same in the patients and in the control group, and AII and Aldo were not correlated to CH2O. It is concluded that patients with the nephrotic syndrome excrete an oral water load more slowly than healthy control subjects, and that this phenomenon partly is due to reduced glomerular filtration rate and partly to increased AVP.

Adult↗

Renal tubular excretion of triethylcholine (TEC) in the chicken: enhancement and inhibition of renal excretion of choline and acetylcholine by TEC.

1. [3H]-triethylcholine (TEC) was actively transported by the renal tubule of the chicken at a rate 85% that of simultaneously administered p-aminohippuric acid (PAH). 2. TEC was demonstrated to be transported by the organic cation transport system in the kidney through inhibition with quinine and the bio-cation choline. 3. When the infusion of TEC was increased to 2 times 10(-6) mol kg(-1) min(-1) reaching the infused kidney, the transport of [3H]-TEC was inhibited, suggesting that an excretory transport maximum for TEC in the renal tubules had been reached. 4. The excretion of both choline and acetylcholine was enhanced by TEC loads as low as 1 times 10(-18) mol kg(-1) min(-1). Enhancement continued as TEC infusion was increased up to approximately 1 times 10(-7) mol kg(-1) min(-1) at which point this enhancement was converted to inhibition. 5. Possible mechanisms for the biphasic effect of TEC on organic cation transport are discussed.

Acetylcholine↗

Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure.

Diuretics are frequently required to treat fluid retention in patients with congestive heart failure (CHF). Unfortunately, they can lead to a decline in renal function, electrolyte depletion, and neurohumoral activation. Arginine vasopressin (AVP) promotes renal water reabsorption via the V2 receptor, and its levels are increased in CHF. This study was designed to assess the effects of a single oral dose of tolvaptan, a selective V2-receptor blocker, in the absence of other medications, on renal function in human CHF and to compare this to the effects of a single oral dose of furosemide. We hypothesized that V2-receptor antagonism would yield a diuresis comparable to furosemide but would not adversely affect renal hemodynamics, plasma electrolyte concentration, or neurohumoral activation in stable human CHF. Renal and neurohumoral effects of tolvaptan and furosemide were assessed in an open-label, randomized, placebo-controlled crossover study in 14 patients with NYHA II-III CHF. Patients received placebo or 30 mg of tolvaptan on day 1 and were crossed over to the other medication on day 3. On day 5, all subjects received 80 mg of furosemide. Tolvaptan and furosemide induced similar diuretic responses. Unlike tolvaptan, furosemide increased urinary sodium and potassium excretion and decreased renal blood flow. Tolvaptan, furosemide, and placebo did not differ with respect to mean arterial pressure, glomerular filtration rate, or serum sodium and potassium. We conclude that tolvaptan is an effective aquaretic with no adverse effects on renal hemodynamics or serum electrolytes in patients with mild to moderate heart failure.

Antidiuretic Hormone Receptor Antagonists↗

[Excretion of p-chloroaniline metabolites into urine. Excretion of 2,4-dichloroaniline and p-chloroformanilide].

Previously, we identified by gas chromatography/mass spectrometry (GC/MS) urinary metabolites of p-chloroaniline (p-CA) in a patient with acute p-CA poisoning. Among these metabolites there is a possibility that 2,4-dichloroaniline (2,4-DCA) and p-chloroformanilide (p-CFA) are produced through some unknown metabolic pathways in human. In order to clarify whether 2,4-DCA and p-CFA were produced within the human body or not, an attempt was made to detect these metabolites in the patient's urine samples prepared by various pretreatments, using both GC/MS and high performance liquid chromatograph. In addition, the detection of these metabolites in non-exposed person's urine samples spiked with p-CA and 2-amino-5-chlorophenol was attempted by GC/MS using same the procedures in order to examine whether p-CA and 2-amino-5-chlorophenol excreted as metabolites were further changed to 2,4-DCA or p-CFA in the urine or not. 2,4-DCA was found abundantly in the ethereal extracts from the patient's urine samples hydrolyzed with hydrochloric, sulfuric and nitric acids, but only small amounts from intact urine samples by GC/MS. No 2,4-DCA was detected in the urine samples to which were added p-CA and 2-amino-5-chlorophenol. p-CFA was found in the ethereal samples which were extracted at acidic conditions from the patient's urine samples by GC/MS at the injection port temperature of 250 degrees C of the gas chromatograph, but the p-CFA peak disappeared at the injection port temperature of 150 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Aniline Compounds↗

Impaired renal water excretion in early hepatic cirrhosis. Lack of relationship between renal water excretion and plasma levels of arginine vasopressin, angiotensin II, and aldosterone after water loading.

An oral water load of 20 ml per kg body weight was given to 9 patients with hepatic cirrhosis and 11 healthy controls. Urinary output, free water clearance, and plasma concentrations of arginine vasopressin, angiotensin II and aldosterone were determined before and three times during the first 4 h after loading. In the cirrhotic patients urinary output was significantly lower after loading than in the control subjects, mainly because of a lower free water clearance, and, in contrast to the healthy controls, the cirrhotic patients did not have natriuresis after water loading. No differences were found between patients and controls in arginine vasopressin, angiotensin II, aldosterone, or creatinine clearance. It is concluded that patients with well-compensated cirrhosis of the liver have an impaired ability to excrete sodium and water. This phenomenon does not seem to be due to increased arginine vasopressin secretion, activation of the renin-angiotensin-aldosterone system, or a decreased glomerular filtration rate.

Adult↗

[Excretion of nitrates with saliva and urine and nitrite excretion with saliva in patients with chronic gastritis and duodenal ulcer].

The study assessed excretion of nitrates in urine and saliva and that of nitrites with saliva of patients suffering gastric and duodenal ulcer. In both study groups, a positive correlation was established between nitrate concentration in saliva, on the one hand, and that in urine, and nitrite level in urine, on the other. The groups failed to show a difference in nitrate concentrations in either urine or saliva. Since retention of nitrates in the body of chronic gastritis patients held as precancer of the stomach proved no higher than that in patients with duodenal ulcer, the authors cast doubt on endogenous nitroso compounds as a cause of gastric cancer in cases of chronic gastritis.

Adolescent↗

[Effects of new antihypertensive agent, 2-[4-(n-butyryl)-homopiperazine-1-ul]-4-amino-6, 7-dimethoxy-quinazoline (E-643), on blood pressure, urinary sodium excretion and urinary norepinephrine excretion rate in stroke-prone, spontaneously hypertensive rats].

Present study was undertaken to elucidate the effects of E-643, on blood pressure, urinary electrolyte (U-Na, U-K) and catecholamines excretion rates in stroke-prone spontaneously hypertensive rats (SHRSP). An attempt was also made to clarify the effects of E-643 on plasma catecholamine concentration and sympathetic efferent nerve discharges including renal and adrenal nerve activity. E-643 (10 mg/kg/day X 4 weeks, p.o.) administered SHRSP (E-643 SHRSP) produced a significant hypotensive effect as compared with sex-age matched nondrug control SHRSP (control SHRSP). Both U-Na and U-K in E-643 SHRSP increased significantly as compared with those of control SHRSP. Urinary norepinephrine content (U-NE) also increased significantly in E-643 SHRSP. Plasma NE concentration tended to increase in E-643 SHRSP. While, plasma epinephrine (E) concentration decreased significantly in E-643 SHRSP. E-643 did not produce any significant effects on both sympathetic renal nerve activity and adrenal nerve activity in SHR. The changes induced by exogenous administered NE (blood pressure rise, tachycardia and the change in sympathetic nerve activity) were antagonized by pretreatment of E-643 in SHR. It was demonstrated that therapeutic doses of E-643 did not seem to produce any significant effect on central nervous system. These findings suggest that E-643 is a peripherally acting alpha 1 antagonist with natriuretic effect.

Animals↗

Studies on the excretion of endogenously formed N-nitrosoproline. I. Percutaneous excretion of N-nitrosoproline in humans.

N-Nitrosoproline (NPRO) formed intragastrically after ingestion of 8 mg/kg body weight sodium nitrate and the same amount of proline was determined in the sweat of six volunteers during intensive sweating in a Finnish sauna (60-80 degrees C). The amounts of sweat and NPRO and the concentrations of this compound varied between individual volunteers and in the same subjects in consecutive experiments. Females excreted higher concentrations of NPRO in smaller amounts of sweat. During the second hour after the start of intragastric nitrosation of proline, the concentrations and amounts of NPRO in sweat decreased rapidly.

Adult↗