Biomedical subjects
Publications and source records attributed to D Mayer.
Cefpirome is a new cephalosporin antibiotic with a broad antimicrobial spectrum in vitro. This includes strains which are frequently resistant to other cephalosporins (Seibert et al., 1983). This report gives a summary of the toxicological investigations on cefpirome.
Hyperoxia has previously been found to increase metabolic rate (oxygen consumption [VO2] and CO2 production [VCO2]) in newborn mammals. We asked whether the same occurs in the newborn infant. Breathing pattern was measured in 25 full-term infants, 1 to 2 days of age, from the spirometric record obtained with a pneumotachograph attached to a face mask. Concentrations of O2 and CO2 were continuously measured at the mouth; VO2 and VCO2 were computed as the product of VE and the difference between inspired and expired concentration of the respective gases, 5 min of air (FIO2 = 0.21) and 5 min of O2 (FIO2 = 1). A bias flow through the mask and pneumotachograph delivered the inspired gas and eliminated the effects of the instrumental dead space. In neither case did measurements at 1 min significantly differ from those taken at 5 min. In hyperoxia VE increased in 22 of the 25 infants, in average +18% (p less than 0.001, paired two-tailed t test). Because of a rise in tidal volume (+35%, p less than 0.001) and a decrease in breathing rate (-11%, p less than 0.005) alveolar ventilation (VA) increased by about 58% (p less than 0.001). VO2 and VCO2 increased by 25% and 17%, respectively (p less than 0.001). The rise in VO2 was too large to be explained by the greater respiratory work of the hyperventilation, whereas that of VCO2 was not large enough to fully explain the increase in VA. We conclude that in newborn humans, as in other newborn species, the normoxic metabolic rate seems to be limited by the availability of O2.(ABSTRACT TRUNCATED AT 250 WORDS)
Intra- or extrapancreatic pseudocysts (PP) are the most common local complication in chronic pancreatitis. Aim of this study was to investigate frequency, localisation and size of pseudocysts in patients with chronic pancreatitis by means of ultrasound (US) and computed tomography (CT). 155 patients (females 35, males 120) with chronic pancreatitis, that underwent simultaneous (within two weeks) CT and US examinations, from January 1982 to June 1989, were included in this study. Cystic lesions were detected in 62% by CT, in 52% by US. Sensitivity in detection of cysts based on intraoperative findings (gold standard) was 98% for CT and 94% for US. 80% of the pseudocysts were smaller than 6 cm. 46% were in the range from 2 to 66 cm and 34% were smaller than 2 cm. The most common localisation was the pancreatic head region (50%), 20 of 102 patients with chronic pancreatitis were found to have a direct communication of a pseudocyst with the ductal system by ERP. No specific clinical or laboratory pattern were associated with the presence of pseudocysts. Increased pancreatic serum amylase concentration was detected in 29% of patients with and in 27% of patients without pseudocysts.
P450-dependent mono-oxygenase and conjugating enzyme activities were studied in rat liver epithelial cells (RLEs) and compared to those in hepatocytes and bile duct cells. Various RLE cell lines were investigated since (a) they are suspected to be derived from cells in the lineage from putative pluripotent stem cells to either hepatocytes or bile duct cells, and (b) they may represent targets of chemical carcinogens. Despite considerable variation between lines, common features were recognized. P450-dependent monooxygenase activities (7-ethoxyresorufin O-deethylase and 7-ethoxycoumarin O-deethylase) were undetectable in all RLEs and bile duct cells, and were uninducible by benz(a)anthracene. In contrast, glucuronosyltransferase (GT), sulfotransferase and GSH transferase activities were clearly detectable. Conjugating enzyme activities increased until confluency of the cell cultures was reached. Under the latter conditions, GT activities towards 4-methylumbelliferone or benzo(a)pyrene-3,6-quinol (substrates of a 3-methylcholanthrene-inducible phenol GT) were similar to those found in hepatocytes or bile duct cells. Using a selective cDNA probe, phenol GT mRNA was clearly detectable in RLE1. In contrast, GT activity towards 4-hydroxybiphenyl was much lower than in hepatocytes or bile duct cells (0.04- and 0.03-fold). Sulfotransferase and GSH transferase activities were also roughly comparable to those found in hepatocytes and in bile duct cells. The results suggest that RLEs and bile duct cells exhibit both high conjugating enzyme activities and a lack of P450-dependent mono-oxygenase activities, a pattern resembling the 'toxin-resistance phenotype' found in putative preneoplastic hepatocyte foci and nodules.
Homogeneous (7.5%) and gradient (10-15%) ultrathin nondenaturating miniaturized polyacrylamide gels (Pharmacia PhastGel media) were used to separate glycogen phosphorylase isoforms from rabbit muscle, rat liver and brain, MH 3924A cells, a dedifferentiated hepatocellular carcinoma of the rat, and C1I cells, a nontumorigenic epithelial rat liver cell line. The enzymes were detected by in situ phosphorylase assay and by immunoblotting. Phosphorylase proteins from the brain, MH 3924A, and C1I exhibited similar electrophoretic mobility, which was different from that of the enzymes from the muscle and normal liver. Molecular weight determination from sodium dodecyl sulfate gels yielded similar data for the subunits of muscle and liver enzymes (98,000 and 96,000), respectively, on one hand, and brain, MH 3924A tumor, and nontumorigenic C1I cells (93,000, 93,000 and 92,000), respectively, on the other. In the native gels the enzymes migrated as dimers: for muscle phosphorylase a, a tetramer was also observed. The a and b forms of the enzymes could not be resolved. An antibody raised against rat liver phosphorylase reacted only with the liver enzyme, whereas an antibody raised against brain phosphorylase stained the brain enzyme and the enzymes from MH 3924A and C1I cells. This indicates that hepatoma cells and immortalized nontumorigenic epithelial liver cells express a phosphorylase isoenzyme that is different from the liver type but similar to the brain type. The PhastSystem provides a rapid, sensitive, and highly reproducible method to resolve the different isoenzymes of glycogen phosphorylase.
The conversion of the ATP-analogue adenylyl(beta,gamma-methylene)diphosphonate (AMPPCP) to cyclic AMP by adenylate cyclase of rat liver membranes was demonstrated using a radioimmunoassay for cyclic AMP. The conversion was only insignificantly lower than with adenylylimidodiphosphate (AMPPNP), another ATP-analogue which is usually used in the histochemical adenylate cyclase assay. The unspecific phosphate production was lower with AMPPCP as compared to AMPPNP. Therefore AMPPCP is considered to be a more suitable substrate for the histochemical assay. Unspecific phosphate deposition in the histochemical assay was due to ATP:pyrophosphatase activity and could be significantly inhibited by 1 mM NAD. However, a residual phosphate deposition due to cleavage of NAD could not be suppressed. Adenylate cyclase activity could be markedly activated by 5 x 10(-5) M forskolin, an activator of the catalytic subunit of the enzyme, and inhibited by 1 mM 2'5'-dideoxyadenosine, a specific inhibitor of adenylate cyclase. Adenylate cyclase was localized predominantly in the sinusoidal part of the plasma membrane, while ATP-pyrophosphatase seemed to be restricted to the canalicular part. It is concluded that at least three parallel assays are necessary for routine histochemical demonstration of adenylate cyclase, namely (1) basal activity (2) activation by forskolin and (3) inhibition by 2'5'-dideoxyadenosine, to demonstrate a specific enzyme reaction.
The detection of undesirable side effects takes place at several stages in the development of a drug. For this purpose all important endpoints such as acute toxicity, local tolerance, allergenicity, genotoxicity, subchronic/chronic toxicity and reproduction toxicity (male and female fertility, teratogenicity, peri- and postnatal studies) serve to establish the major toxicological characteristics. Comparative metabolism studies are carried out in order to optimize the extrapolation of the results obtained in animal experiments to humans. Special, non-routine studies must be adopted for testing cephalosporins and quinolones. Examples of these are provided.
Adaptation course to NaCl was estimated using a flow chamber for stimulus delivery and changes in the perceived taste magnitude as the criterion. The adapting stimulus of different durations was applied to one side of the tongue. Magnitude estimates were made by comparing the intensity of taste at the end of each adaptation time with the perceived intensity of the same stimulus applied briefly to the unadapted side of the tongue. The course of adaptation followed a negatively accelerated decreasing function. The relationship between taste magnitude and the duration of the adapting stimulus can be approximated by a logarithmic equation and, somewhat less accurately, also by an exponential equation, which can be related to the Beidler theory of taste stimulation. Some advantages of the closed flow technique and comparison of taste magnitudes on the adapted and unadapted sides of the tongue are discussed.
A case of bilateral vocal cord hematomas caused by a shoulder harness injury is presented. The patient was restrained by a three-point belt system and was involved in a front-end collision. She presented with mild facial and chest injuries and a contusion of the neck. One hour after injury she began to complain of hoarseness without airway compromise. Fiberoptic laryngoscopy showed bilateral true vocal cord hematomas. The patient had an uneventful hospital course and a full recovery. The importance of the mechanism of injury and associated injuries is discussed.
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The influence of adaptation to taste stimuli of 1 quality on tastants with other qualities was investigated by comparing the reaction time (RT) to a test solution after adapting-solution flow with the RT to the same test solution after water flow. Adapting solutions were strong concentrations of NaCl, HCl, QHCl, and sucrose; test solutions were the same compounds but in lower concentrations. Adaptation to sucrose significantly shortened RT to NaCl and HCl, and to a lesser degree to QHCl. A similar cross-enhancement was found in sucrose when other compounds served as adapting solutions, In all other taste combinations, only a cross-adaptation effect was observed. Results are discussed in relation to some adaptation phenomena, water taste data, and magnitude-estimation data.
The efficacy and toxicity of a shortened tobramycin dosing interval in the treatment of exacerbations of Pseudomonas aeruginosa pulmonary infection in cystic fibrosis patients were evaluated prospectively. Patients ages 13 to 30 years received 34 treatment courses and were randomized by pairs to receive tobramycin administered either every 6 or 8 hours. Peak serum concentrations were adjusted to 8 to 10 micrograms/ml; thus a larger total daily dosage was administered to patients receiving tobramycin every 6 hours. The shorter dosing interval was associated with better pulmonary function at follow-up and significantly longer time before next hospital admission for a pulmonary exacerbation. During the study hospitalization there were no differences in pulmonary function tests, clinical score, sputum carriage of P. aeruginosa, toxicity or necessary length of hospitalization. A 6-hour tobramycin dosing interval was more efficacious than an 8-hour dosing interval in the treatment of cystic fibrosis patients.
Recovery from adaptation to NaCl was tested by comparing some relevant parameters of response to the adapting and test stimuli separated by different recovery intervals. The time course of response was determined using magnitude estimations and using the flow chamber for stimulus delivery. The course of recovery for all parameters used was a negatively accelerated function of the rest time, but the recovery rate of different parameters did not prove to be equal. Recovery was fastest for the initial maximum taste magnitude, followed by the time needed for the taste to disappear. The taste effect summed over time and the time required for the taste magnitude to decrease to 30% of its preadapted maximum were the slowest to recover. Although the recovery processes proceeded at a rapid rate during the initial period, all parameters remained depressed over a rather long period.
omega-Oxidation with subsequent beta-oxidation from the omega-end is the major pathway for inactivation and degradation of leukotrienes. Oxidative degradation of leukotriene E4 (LTE4), N-acetyl-LTE4, and LTB4 was inhibited by the omega-trifluoro analogs of LTE4, omega-trifluoro-LTE4 (omega-F3-LTE4), and (1S,2R)-5-(3-[1-hydroxy-15,15,15-trifluoro-2-(2-1H- tetrazol-5-ylethyl-thio)pentadeca-3(E),5(Z)-dienyl+ ++]phenyl)-1H-tetrazole (LY 245769). The latter substance inhibited the oxidative degradation of LTE4 and N-acetyl-LTE4 in the rat in vivo by 50% at a dose of 7 mumol/kg body weight. In rat hepatocyte cultures both omega-trifluoro analogs interfered with the omega-oxidation of N-acetyl-LTE4 and LTB4 with IC50 values of about 4 microM. Both analogs inhibited the omega-hydroxylation in isolated rat liver microsomes with IC50 values between 16 and 37 microM. This inhibition is apparently competitive. In addition, in liver cytosol, the conversion of the omega-hydroxylated leukotrienes to omega-carboxy-LTE4 and omega-carboxy-LTB4 was inhibited by both compounds. omega-Trifluoro analogs of leukotrienes provide a new tool for interfering with the inactivation of leukotrienes in the omega-oxidation pathway.
In an open, randomized controlled study, the effect of a combined bismuth preparation, bismuth nitrate and bismuth aluminate on the elimination of Helicobacter pylori, inflammatory activity in the gastric mucosa in chronic type B gastritis, and on the patient's symptoms was investigated. Included in the study were 36 patients with non-ulcerous dyspepsia and chronic gastritis. Twelve patients (Group A) received 4 x 1 tablet a day (800 mg total daily dose), 12 patients (Group B) 2 x 2 tablets a day (800 mg total daily dose), 12 patients (Group C) 2 x 1 tablet (400 mg total daily dose) for a period of 4 weeks. Elimination of Helicobacter pylori was observed in 73% of the patients in Group A, in 87% in Group B, but in only 16% in Group C. Inflammatory activity, measured in terms of polymorphonuclear cell infiltration, regressed noticeably in Group A und B (p less than 0.01), but not in Group C. In all patient groups symptoms regressed significantly (p less than 0.01). Bismuth and methemoglobin concentrations in the serum were within the normal range in all patients on conclusion of treatment.
Amperometric methods were used to study the kinetics of intracellular reduction of 2,6-dichlorophenolindophenol (DCIP) in normal and transformed hepatocytes with glucose and succinate as substrates. The curves showing the formation of DCIPred as a function of time were biphasic, the first part obeying the equation of a pseudo-first-order reaction, the final part corresponding to Michaelis-Menten kinetics. A statistical method was used to estimate pseudo-first-order rate constants k as well as Km and Vmax values. At saturating glucose concentrations k, Km and Vmax values were higher in normal compared to transformed cells. Decreasing glucose concentrations revealed lowered saturation concentrations in tumour cells compared to normal cells. With succinate as substrate for hepatocytes, k values were higher than with glucose, while Km and Vmax were about the same. Hepatoma cells did not metabolize succinate. K values could be attributed to intracellular dehydrogenase activities including cytosolic and mitochondrial processes. Differences in pseudo-first-order rate constants between normal and tumour cells may therefore represent characteristic alterations associated with transformation.
The reduction of 2,6-dichlorophenolindophenol (DCIP) was measured by amperometric methods in Morris hepatoma 3924A cells, normal isolated rat hepatocytes and in mitochondria isolated from normal rat liver. The influence of aerobic and anaerobic atmospheres and of various inhibitors of cellular metabolism, especially of the respiratory chain (KCN, NaN3, oligomycin), on DCIP-reduction were studied using glucose, succinate, beta-hydroxybutyrate, alpha-keto-glutarate and oxalacetate as substrates. Under the influence of KCN and oligomycin the velocity of DCIP-reduction was increased in both cell types. Azide showed a similar effect on tumour cells and to a lower extent on hepatocytes. Using isolated mitochondria total DCIPred was increased by KCN and azide using various mitochondrial metabolites as substrates and with ADP/Pi present. The effects of KCN, azide and oligomycin could be explained by taking DCIP as an artificial coupling site in mitochondria which is only used when oxygen is absent or when the respiratory chain is blocked by inhibitors of cytochrome oxidase. Evaluation of the reaction kinetics revealed differences between normal and transformed cells in terms of the pseudo-first-order rate constants and the activity of overall oxidoreductases. The results apparently reflect quantitative differences in enzymatic equipment and the metabolic pathways predominating in normal and neoplastic cells.