Biomedical subjects
U C Dubach
Publications and source records attributed to U C Dubach.
Use of urinary enzymes as markers of nephrotoxicity.
Urinary excretion of enzymes can be monitored continuously at low cost, with commonly available laboratory equipment; there is little discomfort for the animal or person investigated. Under controlled conditions, the time-course and dose-dependence of some pathophysiological events in the kidney can be followed by measuring urinary enzymes. The activities of enzymes in urine are, however, affected by a large number of parameters, even under physiological conditions. Furthermore, the heterogeneity of the kidney renders application of urinary enzymes for diagnostic purposes difficult. Assessment of renal injury by urinary analysis may be possible only if the pathophysiological mechanisms and the time sequence of the nephrotoxicity are known.
Pharmacokinetics of cefetamet pivoxil (Ro 15-8075) with ascending oral doses in normal healthy volunteers.
The pharmacokinetics of cefetamet pivoxil during administration of ascending oral doses were studied in 16 male normal healthy volunteers (age, 24.5 +/- 2.1 years; weight, 73.5 +/- 8.5 kg). The subjects were randomly assigned to four oral treatments of 500, 1,000, 1,500, and 2,000 mg of cefetamet pivoxil according to a four-by-four Latin square design. After an overnight fast, the drug was administered 10 min after a standard breakfast. It was found that both the rate and extent of prodrug absorption, measured as cefetamet adsorption, were reduced with increasing doses. The time to maximum concentration of cefetamet in serum was delayed from 4.00 +/- 0.81 to 4.88 +/- 0.96 h (P less than 0.05) when the dose of cefetamet pivoxil was increased from 500 to 2,000 mg. The dose-normalized values of area under the curve from 0 h to infinity for cefetamet and fraction of dose excreted as cefetamet were reduced by averages of 10.3 and 12.5%, respectively, over the dose range studied (P less than 0.05). The changes in rate and extent of prodrug absorption are thought to be the main factors contributing to the nonlinear relationship between maximum concentration in serum and dose. The change in absorption characteristics of cefetamet pivoxil with dose is, however, expected to have few clinical consequences because the magnitudes of these changes are comparable with their respective intragroup variations.
Purification and properties of a 5'-nucleotidase from rat renal membranes.
5'-Nucleotidase activity was solubilized from a particulate fraction of rat renal homogenates by Sulphobetaine 14. An 11,430-fold purification was achieved by a two-step chromatographic procedure using concanavalin-A Sepharose and ADP-agarose. SDS-PAGE of the purified material revealed a single polypeptide band with a Mr of 69,000. The enyzme exhibited absolute specificity for 5'-mononucleotides. Among 7 tested substrates, adenosine monophosphate (AMP) showed the highest value of V/Km. The Km for 5'-AMP is 5.1 mumol/l and V is 632 mumol/min/mg. The plot of activity versus pH shows a broad plateau between pH 6.8 and 8.0. The hydrolysis of 5'-AMP was competitively inhibited by adenosine 5'-triphosphate (ATP; Ki = 1.2 mumol/l), adenosine 5'-diphosphate (ADP; Ki = 0.032 mumol/l) and alpha, beta-methyleneadenosine 5'-diphosphate (AOPCP; Ki = 0.005 mumol/l). All of the 5 detergents tested activated the enzyme. Sulphobetaine 14 was the most potent and resulted in a 4-fold stimulation by increasing V without change of Km. Addition of exogenous divalent cations was not required for activity. However, the enzyme was inhibited by EDTA. This inhibition was overcome by the addition of Co2+, Mn2+ and to a lesser extent of Mg2+. Hg2+, Zn2+, Cu2+ and Pb2+ inhibited in the low micromolar range. The properties of this enzyme from the rat kidney are similar to those reported in the literature for ecto 5'-nucleotidases from other sources.
Tests for local toxicity of intramuscular drug preparations. Comparison of in vivo and in vitro findings.
The local tissue tolerance after intramuscular injection caused by two multivitamin preparations, two excipient preparations without vitamins and a reference preparation (glycine 2.5%) was determined in albino rats and volunteers by measuring the creatine phosphokinase activity in the blood. The creatine phosphokinase activity was determined 2 h after the injection in the rats and before, 6, 12, 24, and 48 h after the injection in the volunteers. These measurements were compared to findings from an in vitro test using the haemolytic effect of the preparations in human erythrocytes. The haemolytic potential of the drug and excipient preparations was closely correlated to the creatine phosphokinase elevation in rats. The elevation of creatine phosphokinase in the volunteers was not indicative of any differences between the test preparations. Thus it could be shown that the elevation of the creatine phosphokinase activity is useful in demonstrating muscle damage and that the haemolytic potential of the drug and excipient preparations are closely related to the elevation of the creatine phosphokinase activity in rats. However, the results of the elevation of the creatine phosphokinase activity in humans are inconclusive for determining local muscle damage.
[Psychosomatic factors in angina pectoris].
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[Pneumopathy of unknown etiology in chronic lymphatic leukemia].
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[Phase contrast microscopy demonstration of glomerular erythrocytes in urine: practicable in ambulatory practice?].
The use of phase-contrast microscopy in microhematuria, as proposed in 1979 by Birch and Fairley, renders morphological changes in red cells easily detectable and makes it possible to distinguish glomerular from non-glomerular bleeding. The aim of this study was to evaluate the practicability of this method as a routine laboratory test in ambulatory care. 60 patients with asymptomatic microhematuria (greater than or equal to 2 erythrocytes per high power field) were followed up over a one-year period. All patients were investigated by intravenous pyelography, ultrasound of urinary tract and three cytological examinations of the urine. The description of urine samples was done with phase-contrast microscopy by a first investigator at the beginning of the study and by a second after 12.8 months, blinded to clinical results and previous examinations. In 21 patients a definitive diagnosis was possible. In 18 patients the morphologic descriptions of the two investigators correlated with the clinical results. Only in two patients with established diagnosis there were differences between the urine description of the two investigators, and in one patient the interpretations of both investigators were wrong. These incorrect descriptions concerned patients with low-grade microhematuria. Thus, phase-contrast microscopy is a practicable method for the practitioner's use as a routine laboratory investigation. In low-grade microhematuria the method seems to be of minor value.
[Changes in creatine kinase activity in serum following intramuscular injection].
The effect of intramuscular injections of two multivitamin preparations, two excipient preparations without vitamins, and a placebo preparation (glycine 2.5%) on serum creatine kinase activity (S-CK) in ten healthy volunteers (three female, seven male) aged between 23 and 25 years was investigated. One of the multivitamin preparations contained no lidocaine, the other 1% lidocaine. The one excipient formulation was isoosmotic, while the other contained added saline to bring it to the same degree of hyperosomolarity as the multivitamin formulation without lidocaine. The formulations were administered by deep ventrogluteal injection by means of a standardized injection technique. Blood samples were taken before and 6, 12, 24 and 48 h after injection. Following the administration of all the formulations except that of the glycine 2.5%, a marked increase in S-CK activity (1260 I.U./l) was observed 12 h after injection (normal range: male: 47-243 I.U./l, female: 39-226 I.U./l). The relative standard deviation for the 12 h S-CK value was 66.4-97.3%. On applying a threeway analysis of variance to the parameter S-CKmax, no significant differences (alpha = 5%) were found between the effects of the multivitamin and excipient formulations. There was a difference between these and glycine 2.5%, however. There were significant differences between individual volunteers but no significant differences based on the sequence in which the injections were given. With regard to the parameter S-CK AUC (area under the curve, trapezoidal rule), a significant difference (alpha = 5%) was observed only between glycine 2.5% and the multivitamin formulation containing 1% lidocaine.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of probenecid on the elimination and protein binding of ceftriaxone.
The kinetics and binding parameters of ceftriaxone have been characterized in eight normal subjects who received, in sequence, 1.0 g ceftriaxone and 1.0 g ceftriaxone together with 250 and 500 mg probenecid q.i.d. Probenecid increased the total systemic clearance (CLTS) from 0.244 to 0.312 ml/min/kg, whereas the terminal half-life (t1/2T (beta)) fell from 8.1 to 6.5 h. In contrast, the renal clearance of free ceftriaxone (CLFR) was decreased from 2.09 to 1.67 ml/min/kg, confirming a small but significant contribution of tubular secretion to the renal elimination of ceftriaxone. The final value of CLFR was attained with the lower dose probenecid, whereas the non-renal clearance of free ceftriaxone (CLFNR) fell progressively from 2.78 to 1.90 ml/min/kg with the increasing probenecid dose. The total decrease in the systemic clearance of free ceftriaxone (CLFS) after the higher dose of probenecid was about 30% (4.87 to 3.57 ml/min/kg). As a consequence of a decreased affinity constant (KA), the average free fraction in plasma (f) was increased by 54% after the low dose and by 74% after the high dose of probenecid. The protein binding interaction between probenecid and ceftriaxone appears to be unique. The results are of limited clinical consequence for ceftriaxone but they emphasise the importance of evaluating the kinetics of the free drug when examining interactions involving probenecid.
Pharmacokinetics of cefetamet (Ro 15-8074) and cefetamet pivoxil (Ro 15-8075) after intravenous and oral doses in humans.
This report summarizes the results of three pharmacokinetic studies of cefetamet and cefetamet pivoxil conducted in normal adult male volunteers. In the first study the pharmacokinetics of cefetamet were evaluated after intravenous infusion of doses ranging from 133 to 2,650 mg. Over this dose range, the pharmacokinetics were linear. A dose-proportional increase in the area under the curve from zero to infinity was observed, whereas total clearance (140.3 +/- 23.6 ml/min), renal clearance (130.3 +/- 18.2 ml/min), volume of distribution at steady state (0.288 +/- 0.023 liter/kg), fraction excreted unchanged in the urine (94 +/- 11%), and elimination half-life (2.07 +/- 0.18 h) were independent of dose. In a second study the absolute bioavailability of single 1,500-mg doses of a tablet formulation of the pivaloyloxymethylester of cefetamet was evaluated under conditions of fasting and after a standard breakfast. Administration with food increased the extent of absorption (from 31 +/- 7 to 44 +/- 4%) while decreasing the rate of absorption (time to maximum concentration of drug in plasma increased from 3.0 +/- 0.6 to 4.8 +/- 0.4 h). The third study consisted of multiple oral administration of 1,000 mg of a similar oral tablet formulation twice daily for 10 days. This regimen was preceded and followed by intravenous administration of a 500-mg bolus dose of cefetamet. Oral doses were administered with breakfast and dinner. The absolute bioavailability of the tablet formulation was assessed after the first dose and after both the morning and the evening doses on day 10 of oral therapy. The compound was consistently absorbed to the extent of approximately 50% with no significant differences observed between the morning and evening doses on day 10.
An ATP-inhibited soluble 5'-nucleotidase of rat kidney.
Hydrolysis of 5'-AMP by 5'-nucleotidase is a possible source of adenosine in the kidney. A renal membrane-bound ecto-5'-nucleotidase has been previously described. The present study deals with the catalytic properties of a 5'-AMP phosphohydrolase partially purified from high-speed supernatants of rat kidney homogenates. It exhibits phosphatase activity toward 5'-AMP, 5'-IMP, and 5'-GMP, but not toward 2'- and 3'-AMP and corresponds therefore to a 5'-nucleotidase. The hydrolysis of 5'-AMP by the soluble 5'-nucleotidase requires divalent cations. Maximal activity is reached with 10 microM of either Mn2+ or Co2+, whereas half-maximal activity is obtained with approximately 400 microM Mg2+. The soluble 5'-nucleotidase exhibits Michaelis-Menten kinetics with a Km of 9.5 microM for 5'-AMP. In the presence of 1 mM of free Mg2+, physiological concentrations of ATP provoke an increase of the Km for 5'-AMP and a decrease of Vmax. An increase of the pH of 0.4 units in the pH range 6.4-7.4 roughly doubles the rate of hydrolysis of 5'-AMP. The effects of ATP and of the pH are compatible with a role of the renal soluble 5'-nucleotidase in the hydrolysis of 5'-AMP and in the production of adenosine during hypoxia.
The use of urinary enzymes as markers of nephrotoxicity.
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[The importance of the medical interview in patients with functional chest pains].
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[Prevalence of Blastocystis hominis in refugees].
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[The significance of alkaline phosphatase in an ambulatory internal medicine clinic: clarification, diagnostic results, therapeutic consequences in 207 patients with elevated alkaline phosphatase].
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Cerebral blood flow and calcium antagonists in hypertension.
Antihypertensive treatment reduces the risk of ischaemic strokes and cerebral haemorrhage as complications of excessive or long-standing hypertension. However, neurological dysfunction and brain damage may also accompany acute and, under certain conditions, even chronic antihypertensive treatment. Treatment should therefore be instituted restrictively and cautiously, with special regard to the action of antihypertensive drugs on cerebral perfusion in patients with an increased risk for treatment-induced cerebral ischaemic complications, e.g. patients with hypertensive encephalopathy, patients with autonomic dysfunction or elderly patients with suspected sclerotic stenosis of cerebral or neck arteries. The present study is a review of the structural and functional lesions of cerebral vessels observed in acute and chronic hypertension, together with the effects of antihypertensive drugs on cerebral blood flow. Calcium channel blockers such as nifedipine, nitrendipine and verapamil may have advantages as first-line drugs in the treatment of patients with an elevated risk for cerebral hypoperfusion, because of their selective action on vasoconstricted vessels and their differential effects in different regional vascular beds. The particular efficacy of calcium antagonists in acute antihypertensive treatment, with a significant increase in cerebral blood flow in the case of nifedipine, and also in chronic antihypertensive therapy without decreasing cerebral blood flow, may change the traditional management of hypertensive emergencies, as well as of other patients at risk of treatment-induced complications.
Single-dose investigation of possible interactions between the components of the antimalarial combination Fansimef.
Fansimef is a new oral schizonticide which contains pyrimethamine (P), sulfadoxine (S) and mefloquine (M) in a weight ratio of 1:20:10. This antimalarial combination is highly active against multi-resistant Plasmodium falciparum and in vitro studies showed that the resistance development by plasmodia against this combination is considerably delayed. The single-dose pharmacokinetics of the three Fansimef components were investigated in 10 Caucasian volunteers with special emphasis on possible mutual kinetic interactions. For this reason the same subjects received successively tablets of Fansimef (P + S + M), Fansidar (P + S) and mefloquine alone. Following administration of Fansimef all three components revealed long elimination half-lives (P = 88 h, S = 183 h, M = 437 h) and high binding to plasma proteins (P = 92.5%, S = 87.6%, M = 97.6%). The apparent volume of distribution in the postdistributive phase (VD beta/F) was small for S (0.13 l/kg) but amounted to 2.1 l/kg for P and reached even 11.8 l/kg in the case of M. The systemic clearance (ClTS/F) showed almost identical values for P and M, namely approximately equal to 19 ml/h/kg, while sulfadoxine reached only a value of 0.5 ml/h/kg. Almost identical pharmacokinetic parameters (p greater than 0.05) were found after administration of Fansidar or M alone. Therefore one can exclude any significant interaction between the single components of the Fansimef combination. In addition, animal studies showed that synergism of the toxicity of the three combination partners can be excluded.