Inhibitory effects of procainamide and probenecid on renal excretion of sultopride enantiomers in rats

The effects of the coadministration of procainamide and probenecid on the pharmacokinetic behavior of sultopride, an antipsychotic agent, after intravenous administration were studied with rats. The areas under the concentration-time curve for and renal clearances of (+)-sultopride and (-)-sultopride, which exist as organic cations under physiological pH conditions, were significantly decreased (p < 0.01) by the coadministration of procainamide, an organic cation under physiological pH conditions. The renal clearance of (-)-sultopride was partially decreased (p < 0.05) by the coadministration of probenecid, an organic anion under physiological pH conditions. The results suggest that drug-drug interactions between organic cations and organic anions occur to a certain extent during the tubular secretion process in rats.     

Different inhibitory effects of 2,4-dinitrophenol, iodoacetate, and probenecid on renal excretion of p-aminohippurate, cyclopenthiazide, and sulfamethoxypyridazine in rats

A novel series of acidic cycloalkanoindoles comprising tetrahydrocarbazole-, cyclopentindole-, and cycloheptindole-1-acetic acids has been synthesized via the Fischer indolization between a phenylhydrazine and a 1-alkyl-2-oxocycloalkaneacetic acid ester. These compounds were evaluated, orally, for their capacities to decrease estabished adjuvant arthritis in rats. The most active compound of the series was 1-ethyl-8-n-propyl-1,2,3,4-tetrahydrocarbazole-1-acetic acid (AY-24 873),which had an ED50 of 1.1 +/- 0.2 mg/kg. AY-24 873 was also studied orally in rats for its effect on the acute inflammatory response in the carrageenin paw edema test. It was found that AY-24 873 was about ten times more active against the chromic than against the acute models of inflammation used.     

Moment analysis of stereoselective biliary excretion and chiral inversion of ketoprofen enantiomers in perfused rat liver

The stereoselective local disposition of ketoprofen was evaluated by the single-pass perfusion experiment following a bolus injection of R(-)- or S(+)-ketoprofen into the liver from the portal vein. The elution time profiles of enantiomers into the hepatic vein and the excretion time profiles into the bile were kinetically assessed by local moment analysis. The hepatic recovery ratios (FH) of both enantiomers were < 1%, and the mean hepatic transit times (tH) were approximately 7 s. After the injection of S-ketoprofen into the liver, the biliary excretion ratio (Fb) of total S-ketoprofen was 68% (15% S-ketoprofen and 53% glucuronide) and the mean biliary transit time (tb) of S-ketoprofen was 10 min. R-Ketoprofen inversion from S-ketoprofen was not observed in either the perfusate or in the bile. After the injection of R-ketoprofen, the Fb of total R-ketoprofen was 12% (3% R-ketoprofen and 9% glucuronide), and tb of R-ketoprofen was 8 min. The Fb of total S-ketoprofen inverted from R-ketoprofen was 24% (7% S-ketoprofen and 17% glucuronide), and the tb of inverted S-ketoprofen was 17 min. Forty-six percent of R-ketoprofen was inverted to S-ketoprofen during a single pass through the rat liver, and the mean inversion time was 7.5 min. It was concluded that the unidirectional chiral inversion of ketoprofen was stereospecific, and the hepatic uptake and biliary excretion were stereo-nonspecific.     

Albumin excretion with urine in a population of healthy individuals

Increased urine albumin excretion is the significant prognostic factor for diabetes, hypertension and coronary artery disease. Divergences of the evaluation of albuminuria in different ethnic groups were found. The aim of our study was to evaluate albumin excretion in large group of healthy individuals. 301 healthy subjects (110 female and 191 male), age 20-60 years (mean 32.9 +/- 9.7), were admitted. A questionnaire including data concerning familial history, smoking habits was fulfilled. Subsequently nighttime urine sample was collected in all examined subjects and albumin to creatinine ratio (A/K) was counted. A/K value varied between 0.03-14.1 mg/mmol of creatinine median 1.18. Significantly higher albuminuria in female v male group was found (respectively 1.39; 0.14-14.1 and 1.03; 0.03-11.4 p < 0.05). Reference value for albuminuria was estimated at 3.35 mg/mmol in whole group, and respectively 4 mg/mmol in female and 2.6 mg/mmol in male. There were not differences in A/K ratio in relation to familial history however smoking men excreted more albumin v non smoking (respectively 1.27, 0.03-11.4 and 0.95, 0.14-14.1 mg/mmol p < 0.005). Performed analysis allowed to calculate the value for albuminuria in healthy subjects. Analysis also showed significant influence of gender and smoking habits and no influence of familial history for albumin excretion.     

Urinary excretion of epidermal growth factor and Tamm-Horsfall protein in three rat models with increased renal excretion of urine

This study was conducted to assess the predictive value of different variables including the response to dexamethasone suppression test (DST), in 105 patients with resistant depression after the addition of lithium (600 to 800 mg/day) for 4 weeks to antidepressant medication. Clinical remission was observed in 57 patients and no improvement in 48. A dramatic and rapid relief of depression occurred in 12 patients. Variables with significant or marginally significant differences between responders and non-responders were included in a stepwise logistic regression model. Weight loss (P = 0.0013) and depressive psychomotor activity (P = 0.045) in the Newcastle diagnostic index (NDI) scale, and overall score of the Hamilton Rating Scale for Depression (HRSD) before adding the lithium (P = 0.0039) were significantly associated with clinical remission. The difference in post-DST cortisol plasma levels between both groups was marginally significant. The logistic equation resulted in a sensitivity of 78% and a specificity of 65% and total correct classification of the lithium-added response of 72%. The clinical profile of patients who improve with the addition of lithium may include significant weight loss, psychomotor retardation and possibly, poor control of cortisol secretion. Partial remission before adding lithium as well as endogenomorphic traits according to NDI may also be considered additional criteria for response.     

Pyrithyldione excretion in the urine. Methods and results from various collectives

A simple thinlayer chromatographic method for the detection of pyrithyldion in 5 ml of urine per analysis is described. Sensitivity (0.01 mug of pyrithyldion) and specificity (reaction still positive 5-6 days after injection of 50 mg of pyrithyldion) of the method are considered acceptable. The duration of elimination for pyrithyldion is relatively long (5-6 days). Epidemiological investigations were conducted in two different patient groups to analyze spontaneously voided urine samples. The incidence of positive urine samples in 204 ambulatory internal medicine patients was only 0.5% for pyrithyldion and N-acetyl-p-amino-phenol (the main metabolite of phenacetin). In contrast, the incidence in a specially selected group of 600 working women with regular intake of analgesics was much higher (between 17.7% and 28%) in the period 1969 to 1972.     

Activity of cathepsin B and collagenase in urine and excretion of fibronectin and TGF-beta 1 in urine of patients with membranous glomerulonephritis

In 30% cases nephrotic syndrome is due to membranous glomerulonephritis (MG). Fifty percent of patients reveal end stage renal disease in 15 years follow-up. The another 50% gain persistent remission. The pathogenesis of disease is not known. Protein accumulation in glomeruli leads to progressive loss of kidney structure and function in MG. Also the role of tissue proteolytic systems and growth factors in this process is not known. We aimed to estimate urine cathepsin B, collagenase activity and urine excretion of TGF-beta 1 and fibronectin in MG. MG patients revealed increased urine cathepsin B activity (10.58 +/- 8.73 pmol AMC/mg creatinine/min. vs. control 7.11 +/- 2.05 pmol AMC/mg creatinine/min. [p < 0.05]), urine collagenase activity (8.59 +/- 4.26 pmol AMC/mg creatinine/min. vs. control 3.84 +/- 2.09 pmol AMC/mg creatinine/min. [p > 0.02]) and increased urine excretion of fibronectin (214 +/- 335 ng/mg creatinine vs. control 12.7 +/- 6.7 ng/mg creatinine [p < 0.05]) and increased urine excretion of TGF-beta 1 (283.55 +/- 248.13 pg/ml vs. control 36.11 +/- 48.01 pg/ml [p < 0.05]). The results indicates on glomerular overproduction of TGF-beta 1 and urinary leak of proteolytic enzymes which may exacerbate glomerular proteolytic activity in MG. This may lead to glomerular protein accumulation and progressive loss of kidney function and structure in MG. Increased urine fibronectin excretion in MG patients seems to confirm the hypothesis.     

Effects of centrally administered insulin on urine output and sodium excretion in dogs

Ribosomal RNA (rRNA) synthesis, the initiation of which is an early major event during the transformation of iris into lens in the newt, was characterized in the TVI cell-line derived from the eastern North-American newt Notophthalmus viridescens. Employing the technique of polyacrylamide gel electrophoresis, molecular-weight measurements were made on newt rRNAs using Xenopus laevis and E. coli rRNAs as standards. The molecular weights of N. viridescens 28S and 18S rRNA were found to be 1.4 X 10(6) and 0.7 X 10(6) respectively. The precursor to these RNAs had a molecular weight of 3.1 X 10(6). Three probable intermediates in the processing of precursor to mature rRNA were also identified. On the basis of the molecular weights of all species of RNA identified, a processing pathway, similar to that of Xenopus, has been suggested. Some unusual features in the kinetics of precursor rRNA labelling and processing suggest the possibility that newt-cell rRNA synthesis may be controlled by the availability of essential amino acids in a manner similar to that observed in mammalian cells. A possible relationship between the availability of essential amino acids, the initiation of rRNA synthesis in the newt iris, and the control of lens regeneration is discussed.     

Changes in estriol excretion in the urine and kidney function during Partusisten infusion

In a random controlled trial the effects of a betamimetic infusion (Fenoterol 2 micrograms/min) on the estriol excretion and the renal function were analysed in 30 patients in the 28.-34. weeks of pregnancy. It was stated that the estriol excretion in urine during the Partusisten infusion significant decreases (from 663 micrograms/2 h to 376 micrograms/2 h, i.e. to 56%). The diuresis and the creatinine-clearance showed a significant diminishing too (from 218 ml/2 h to 154 ml/2 h and from 131 ml/min to 88 ml/min). The decrease of estriol excretion is caused on the one hand by the diminution of GFR, on the other by a direct effect of betamimetics on the kidney. From the results obtained in this study the following consequences can be drawn: 1. The determination of urinary estriol during tocolytic treatment is not a suitable method for the monitoring the fetoplacental unit. 2. Applying the tocolysis in an infusion a possible reduction of water intake and a strict control of water balance is of great importance. 3. The betamimetic therapy in patients having an impaired renal function can be applied only with great precaution.     

Stereoselective determination of unchanged and glucuroconjugated eliprodil, a new anti-ischaemic drug, in human plasma and urine by precolumn derivatization and column-switching high-performance liquid chromatography with fluorescence detection

An HPLC method was developed and validated for the determination in human plasma and urine of the enantiomers of eliprodil, (+/-)-alpha-(4-chlorophenyl)-4[(4-fluorophenyl) methyl]piperidine-1-ethanol hydrochloride, a new anti-ischaemic agent administered as a racemate. Both enantiomers are present in human plasma in unchanged and glucuroconjugated form, whereas only the glucuroconjugated form is excreted into urine; as a consequence, such metabolites in human plasma and urine should be submitted to enzymatic deconjugation with beta-glucuronidase (Escherichia coli) before being extracted. The general method involves a liquid-liquid extraction of eliprodil and internal standard from alkalinized plasma or urine with n-hexane, evaporation of the organic phase and derivatization with (S)-(+)-naphthylethyl isocyanate to give carbamate diastereoisomeric derivatives of (S)-(+)- and (R)-(-)-eliprodil and internal standard; after evaporation of the derivatizing mixture and dissolution of the residue in a small volume of phosphate buffer-acetonitrile (60:40, v/v), an aliquot is injected into a column-switching HPLC system. The derivatized sample extract is purified on a precolumn filled with C8-bonded silica material, which is flushed with acetonitrile-water, then diastereoisomers of eliprodil and the internal standard are automatically transferred by the mobile phase to the analytical column. The analytical column is a C8 type, specially deactivated for basic compounds, the mobile phase is 0.025 M phosphate buffer (pH 2.6)-methanol-acetonitrile (42:2:56) at a flow-rate of 1.2 ml min-1 and fluorimetric detector operating at lambda ex = 275 nm and lambda em = 336 nm is used. The retention times, under these conditions, are about 16 and 17 min for (S)-(+)- and (R)-(-)-eliprodil diastereoisomers, respectively, and about 19 min for the first-eluted diastereoisomer of the internal standard. During the analysis time, the precolumn, reset in a different path from that of the analytical column, is back-flushed with different solvents, then re-equilibrated with acetonitrile-water before the next injection. Linearity in plasma, for unchanged eliprodil enantiomers, was assessed in the range 0.15-10 ng ml-1 and for total eliprodil enantiomers (unchanged + conjugated) in the range 0.75-500 ng ml-1; the limit of quantitation (LOQ) is 0.15 ng ml-1 for each unchanged enantiomer and 0.75 ng ml-1 for each total enantiomer. Linearity was also assessed in urine for total (conjugated) eliprodil enantiomers in the range 50-25 000 ng ml-1; the LOQ is 50 ng ml-1 for each enantiomer. The intra- and inter-day precision and accuracy of the method were investigated in plasma and urine and found to be satisfactory for pharmacokinetic studies. The method has been extensively used in pharamcokinetic studies in man treated with a 20-mg dose of eliprodil racemate and some results of this application are reported.     

Characteristics of delayed excretion of flavonoids in human urine after administration of Shosaiko-to, a herbal medicine

There has been little explanation of herbal medicines by modern medical sciences, including pharmacokinetics, whereas physicians follow empirical indications written in classical literature. Recent reports of herb-induced adverse reactions compelled us to proceed the investigation of a herbal medicine Shosaiko-to (TJ-9) from a pharmacokinetic point of view. To five healthy volunteers, a single 5 g dose of TJ-9, consisting of 7 herbs, was administered. We conducted HPLC analysis of the timed-urine specimens to disclose the type and amount of compounds excreted. Excretion rate-time curves were analyzed individually. Four flavonoids, liquiritigenin, baicalein, wogonin and oroxylin A, were found both in the urine and TJ-9. The glycosides in TJ-9 were absorbed after microflora hydrolysis. Davidigenin, which was not found in TJ-9, was an intestinal metabolite of liquiritigenin. Also, two flavanones, S-dihydrowogonin and S-dihydrooroxylin A, were identified as the metabolites of wogonin and oroxylin A, respectively. Excretion rate-time curves of the flavonoids were divided into three types of structure-dependent absorption, i.e. (1) the fast absorption of herbal-origin aglycons, (2) the moderately-delayed absorption of aglycons derived from herbal glycosides, and (3) markedly-delayed absorption after the molecular transformation of herbal compounds. Individual excretion profiles seemed to depend on microflora activities. Two types of flavanones, S-dihydrowogonin and S-dihydrooroxylin A, were found in a half of the volunteers, suggesting there might be two kinds of volunteers, namely, rapid and poor metabolizers of flavonoids.     

Suberylglycine excretion in the urine from a patient with dicarboxylic aciduria

Suberylglycine (HOOC(CH2)6CONHCH2COOH) was found in the urine from a patient with C6-C10-omega-dicarboxylic aciduria and unexplained episodes of lethargy and unconsciousness. The total excretion of adipic, suberic and sebacic acid ranged from 0.77 to 1.3 mg/mg creatinine after episodes of acute attack of the disease. Suberylglycine, identified by gas chromatography/mass spectrometry, was repeatedly found in the urine samples. The amount of this conjugate ranged from 0.2 to 0.5 mg/mg creatinine. The precursors of the dicarboxylic acids are suggested to be long chain monocarboxylic acids, oxidized through omega- and beta-oxidation to adipic, suberic and sebacic acid. Suberylglycine is subsequently formed by glycine-N-acylase catalyzed conjugation.     

Negligible and non-negligible risks in radiodiagnostic examination of patients

Ionizing radiation is regarded as a health hazard, but one is prepared to neglect this factor on the basis of certain motives. In 1975, KNOX published an analysis of these motives, none of which proved tenable. He concluded that a situation which in daily usage is described as safe, is one which entails risks considered to be negligible so that no safety measures are taken. It can be empirically established that in various health-endangering situations a health hazard of less than 1 X 10(-5) is being neglected. This article studies the risk factors to the individual patient in radiodiagnostic examinations involving low, medium and high radiation exposures. The estimates show that radiohygenic measures on behalf of the patient are advisable.     

Correlation between morning urine estriol concentration and 24-hour estriol excretion

In an attempt to circumvent the need for 24-hour urine collections for estriol analyses in assessment of fetal status, the possibility of using morning urine samples was investigated. Results indicate 1) good correlation between 24-hour estriol excretion and morning estriol concentration, and between corresponding E/C ratios, 2) similar morning and 24-hour estriol concentrations, 3) high dependence of estriol and creatinine excretion on 24-hour urine volume but not on morning volume, 4) larger variations in 24-hour than in morning urine volume, and 5) better consistency of values in morning than in 24-hour samples in pathologic pregnancy. The use of serial morning urine concentrations at least as an outpatient monitoring procedure is suggested.     

Comparative pharmacodynamics of flunixin, ketoprofen and tolfenamic acid in calves

The pharmacodynamics of the non-steroidal anti-inflammatory drugs flunixin, tolfenamic acid and ketoprofen were studied in calves after intravenous administration. An acute inflammatory reaction was induced in tissue cages by the intracaveal injection of the mild irritant carrageenan, and the inhibition of inflammatory mediators and enzymes was investigated. The substances measured in the exudate included the enzymes (active and total metalloproteases, serine and cysteine proteases, acid phosphatase [AP], lactate dehydrogenase [LDH] and beta-glucuronidase) and the eicosanoids (prostaglandin [PG]E2 and leukotriene [LT]B4). Studies were also made of inhibition of the synthesis of serum thromboxane (Tx)B2 ex vivo, of bradykinin-induced oedema in vivo and of the generation of superoxide anions (O2-) in vitro. None of the drugs affected the concentration of LTB4, or the activities of metalloproteases, cysteine and serine proteases, AP or LDH in the exudate. All the drugs inhibited the synthesis of serum TxB2 and exudate PGE2 and inhibited the release of beta-glucuronidase. They also decreased the oedematous response to intradermally injected bradykinin and inhibited the generation of O2- ions by neutrophils in vitro. These actions may contribute to the anti-inflammatory effects of the drugs and hence to their clinical efficacy.     

Excess urate excretion correlates with severely acidic urine in patients with renal hypouricemia

OBJECTIVE: To evaluate how the extreme poverty of the patients and the poor salaries of the staff combined to increase the cost of treatment to patients within the subsidised national tuberculosis programme in Sierra Leone. DESIGN/SETTING: From September to December of 1994, semi-structured interviews were conducted with 72 patients and 17 staff of the National Leprosy and Tuberculosis Control Programme of Sierra Leone, a screening and treatment programme funded by international donors. RESULTS: Although some extra costs were indeed incurred within the subsidized national tuberculosis treatment programme, they were much lower than those incurred during the pre-programme period when the patients sought intermittent help from a wide range of traditional and biomedical sources within the plural healing continuum. The national politico-economic crisis, and the consequent poverty of most patients, impeded compliance with and sustainability of treatment, even within the formal subsidised treatment programme. CONCLUSIONS: More money was spent by patients on treatment in the months/years preceding entry into the national tuberculosis programme. Many factors retarded entry, including poor communications, misinformation, malpractice by health professionals, and displacement resulting from chronic internal warfare. The war intensified all factors that predispose to tuberculosis and retarded access to treatment. Supra-programme cost, or 'corruption,' was minimal due to the poverty of health professionals, with a few salient exceptions.     

Effects of smoking on the urine excretion of oral 51Cr EDTA in ulcerative colitis

BACKGROUND: Smokers have a reduced risk and ex-smokers an increased risk of ulcerative colitis (UC). Stopping smoking often precedes onset and relapses. Smoking reduces the 24 hour urine excretion of oral chromium-51 labelled EDTA in healthy individuals. AIMS: To estimate the effects of smoking on the urine excretion of oral 51Cr EDTA in well characterised patients with UC. SUBJECTS: Sixteen smoking and 16 non-smoking patients with UC in remission were studied. The non-smokers had never smoked. Most were taking 5-aminosalicylic acid. No patient took steroids or immunosuppressants. The control group comprised 25 smoking healthy volunteers and 25 who had never smoked. The median cigarette consumption was equal in the patients and volunteers. METHODS: The 24 hour urine excretion of oral 51Cr EDTA was measured and the results were correlated with smoking habits, number of cigarettes, and disease extent. RESULTS: Patients with UC had significantly higher 24 hour urine recoveries than healthy controls (p = 0.04). This difference was more pronounced when patients who smoked were compared with healthy smokers (p = 0.005) No significant differences were found when comparing non-smoking patients with non-smoking controls or when comparing smoking and non-smoking patients. Urine recoveries did not correlate with number of cigarettes or disease extent. Smoking was more prevalent in patients with a more limited disease extent (p = 0.033). CONCLUSIONS: Effects of smoking on the urine excretion of 51Cr EDTA in health were abolished by the presence of UC. The protective effects of smoking in established UC are not due to a moderating effect of smoking on intestinal permeability.