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Biomedical subjects

J M Mayer

Publications and source records attributed to J M Mayer.

At least 37 records · Page 2Linked to original sources
PubMed2000

Discrepancy between CYP2D6 phenotype and genotype derived from post-mortem dextromethorphan blood level.

OBJECTIVE: To describe the death of a toddler after a therapeutic dose of dextromethorphan and its investigation. STUDY DESIGN: Case report, cytochrome P450 phenotype and genotype determination in the victim and post-mortem drug redistribution study performed in rats. RESULTS: A 20-month Asian male who received 3 mg of dextromethorphan once at 09:00 h and again at 22:00 h was found dead at 04:35 h. Post-mortem examination showed signs of early bronchopneumonia (bacterial cultures were negative); dextromethorphan and dextrorphan blood concentrations taken from the heart cavity were 500 ng/ml (1. 84 micromol/l) and 200 ng/ml (0.78 micromol/l), respectively. Despite the dextromethorphan level being almost 100-fold higher than expected after therapeutic doses, intentional or unintentional overdose was extremely unlikely; other potential causes were investigated. Post-mortem drug redistribution study performed in rats showed that dextromethorphan does not undergo extensive redistribution after death (6+/-5-fold increase) and could not explain the observed dextromethorphan level. The dextromethorphan/dextrorphan concentration ratio of 2.5 found in this toddler was compatible with a slow CYP2D6 metabolizer phenotype. However, the toddler exhibited a fast metabolizer genotype. Potential reasons for this discrepancy are discussed. CONCLUSION: CYP450 phenotypes derived from post-mortem blood levels should be interpreted with caution and preferably confirmed by a genotype analysis.

Animals↗
PubMed2000

Single doses of FK506 and OKT3 reduce severity in early experimental acute pancreatitis.

OBJECTIVE: To find out if two immunomodulatory drugs used in organ transplantation (FK506 (tacrolimus) and OKT3 (Orthoclone) would reduce early inflammatory complications in experimental acute pancreatitis. DESIGN: Laboratory study. SETTING: University hospital, Germany. ANIMALS: 36 Balb/c mice. INTERVENTIONS: Pancreatitis induced by 7 intraperitoneal injections of cerulein 50 microg/kg at hourly intervals followed by FK506 0.32 mg/kg, OKT3 0.6 mg/kg, or 0.9% sodium chloride (controls) (n = 12 in each group). 12 hours after induction of pancreatitis the animals were killed. MAIN OUTCOME MEASURES: Serum amylase activity and interleukin-6 (IL-6) concentrations; histological damage to pancreas and lungs, apoptotic cells in pancreas; and myeloperoxidase activity in lungs. RESULTS: No animal died during the experiment. At 12h serum amylase activity and IL-6 concentrations were increased in all 3 groups, but highest in the OKT3 group. The pancreatic histological score, apoptosis, and inflammatory infiltration were lower in the two experimental groups than controls, but the degree of vacuolisation of acinar cells was similar. Packed cell volume was higher in the control than the experimental groups, and pulmonary damage and myeloperoxidase activity were less in the experimental groups than the controls. CONCLUSION: Single therapeutic doses of FK506 and OKT3 reduced the early severity of pancreatitis, pulmonary damage, and haemoconcentration in mice. Single doses of FK506 or OKT3 may therefore be effective in preventing the early complications of pancreatitis.

Acute Disease↗
PubMed2000

Local and systemic zymogen activation in human acute pancreatitis.

BACKGROUND: Activation of trypsinogen and phospholipase A(2) is an early event in pancreatic inflammation, but little is known about zymogen activation and the severity of human pancreatitis. METHODS: Using a new fluoroimmunoassay we measured trypsinogen activation peptide (TAP) and phospholipase A(2) activation peptide (PROP) in plasma and ascites in 25 patients with acute pancreatitis. TAP, PROP, Pro-PROP and pancreatic PLA(2)-I were measured in plasma for 14 days and in pancreatic necroses, ascitic fluid and pleural effusions. RESULTS: All 16 patients with severe acute pancreatitis (SAP) had pancreatic necrosis, 10 developed systemic complications like sepsis, pulmonary or renal failure, 6 had infected necrosis, and 4 died. All 9 patients with mild pancreatitis (MAP) survived. Plasma TAP on admission was higher in patients with SAP than in those with MAP and increased in infected necroses. It did not correlate with systemic complications. Systemic PROP was not increased in complicated courses but was significantly higher in patients with MAP than in those with SAP on admission. Pro-PROP was higher in patients with SAP than in those with MAP but was not correlated with systemic complications. Plasma pancreatic PLA(2)-I was increased but not different in patients with SAP and those with MAP. In patients with pancreatic necrosis, TAP and PROP were highest, while in those with post-acute pancreatic abscess, only PROP and Pro-PROP were high. In patients with pleural effusion, TAP was low and PROP/ Pro-PROP were high. CONCLUSION: Trypsinogen and PLA(2)-I activation are early events in acute pancreatitis and the activation peptides can be detected in plasma. In the pancreas, trypsinogen activation is accompanied by PLA(2)-I activation in patients with pancreatic necrosis. However, in our study, organ complications in SAP patients was not associated with increased plasma PROP.

Acute Disease↗
PubMed2000

Very slow chiral inversion of clopidogrel in rats: a pharmacokinetic and mechanistic investigation.

Clopidogrel hydrogen sulfate, a thienopyridine derivative, is an ADP receptor antagonist that inhibits platelet aggregation. Clopidogrel is an enantiopure carboxylic ester of S-configuration. The R-enantiomer is devoid of antithrombotic activity and can provoke convulsions at high doses in animals. During preclinical safety evaluation, the possible chiral inversion of clopidogrel has, therefore, been investigated in vivo after repeated oral administration of different dose levels of clopidogrel to male and female rats. Due to rapid metabolism in the liver and low plasma levels of unchanged drug, possible chiral inversion was assessed by monitoring the plasma concentrations of the carboxylic acid metabolites, i.e., the (S)- and (R)-acid, by means of a stereoselective assay. The production of 4 to 8% of (R)-acid was observed. This could be the result of chiral inversion of either clopidogrel or its main metabolite, the (S)-acid. Thus, the possibility of nonenzymatic and enzymatic inversion of clopidogrel and its carboxylic acid metabolite was studied in vitro by chiral HPLC and (1)H NMR. Nonenzymatic chiral inversion of clopidogrel at 37 degrees C in 0.1 M phosphate buffers could be observed but was found to be slow, with estimated half-lives of 7 to 12 days, depending on the pH. The (S)-acid was configurationally fully stable up to 45 days in phosphate buffers. Neither clopidogrel nor its carboxylic acid metabolites were subject to enzymatic chiral inversion in isolated rat hepatocyte suspensions. We conclude that the nonenzymatic inversion of clopidogrel accounts for the 4 to 8% of chiral inversion seen in vivo in the rat.

Algorithms↗
PubMed1999

Topical use of chitosan in ophthalmology: tolerance assessment and evaluation of precorneal retention.

The mucoadhesive polysaccharide chitosan was evaluated as a potential component in ophthalmic gels for enabling increased precorneal drug residence times. This cationic vehicle was expected to slow down drug elimination by the lacrymal flow both by increasing solution viscosity and by interacting with the negative charges of the mucus. The molecular weight (Mw) and concentration of polysaccharide were studied in four types of chitosan as parameters that might influence ocular tolerability and precorneal residence time of formulations containing tobramycin as therapeutic agent. An ocular irritation test, using confocal laser scanning ophthalmoscopy (CLSO) combined with corneal fluorescein staining, clearly demonstrated the excellent tolerance of chitosan after topical administration onto the corneal surface. Gamma scintigraphic data showed that the clearance of the formulations labelled with 99mTc-DTPA was significantly delayed in the presence of chitosan with respect to the commercial collyrium (Tobrex(R)), regardless of the concentration and of the molecular weight of chitosan in solution. At least a 3-fold increase of the corneal residence time was achieved in the presence of chitosan when compared to Tobrex(R).

Animals↗
PubMed1999

Electromyographic activity of the lumbar extensor muscles: effect of angle and hand position during Roman chair exercise.

OBJECTIVE: To evaluate the effects of angle and hand position during variable-angle Roman chair (VARC) back extension exercise on lumbar paraspinal electromyographic (EMG) activity. DESIGN: Descriptive, repeated measures. SETTING: University-based musculoskeletal research laboratory. PARTICIPANTS: Two female and eight male volunteers recruited from a university setting. INTERVENTION AND OUTCOME MEASURES: Surface integrated EMG activity was recorded from the L3-L4 paraspinal region during 24 10-second repetitions of dynamic back extension exercise, each consisting of a unique VARC angle (six total) and subject hand position (four total). Lumbar paraspinal surface integrated EMG activity measured in millivolts per repetition was used for analysis. RESULTS: Significant lumbar paraspinal EMG activity was evident during each of the 24 repetitions (p < or = .05), with a 104% increase in activity noted between the lowest and highest. EMG activity increased progressively among hand positions and as the VARC angle became more horizontal. VARC angle affected EMG activity more than hand position, but the greatest impact on EMG activity was produced by modifying both angle and hand position. CONCLUSION: Lumbar paraspinal EMG activity can be altered during VARC back extension exercise by changing angle and hand position. Clinicians can use these data to develop progressive resistance exercise programs using the VARC apparatus.

Adult↗
PubMed1999

Ocular tolerance of preservatives on the murine cornea.

We investigated the effects of instilling 13 commonly used preservatives on the murine cornea in vivo. Due to the instillation of preservatives, micro-lesions are formed on the cornea and can be selectively marked by fluorescein. The sum of the resulting fluorescent areas was measured using an episcopic microscope coupled to an image processing system. All the tested preservatives proved to be well-tolerated by the eye at commonly used concentrations. However, in some cases, increased concentrations of preservatives or combinations resulted in significant increase of the amount of corneal damage. With increasing the concentration, corneal lesion increased the most in the case of cetylpyridinium. While a combination of chlorobutanol 0.5% and phenylethylalcohol 0.5% did not result in an increase in corneal damage (when compared to the use of each separately), the associations of thiomersal 0.02% and phenylethylalcohol 0.4% on one hand and of edetate disodium (EDTA) 0.1% and benzalkonium 0.01% on the other, resulted in significant increases in the amount of corneal damage. However, in none of the tested combinations, the increase in the observed damage exceed the limit of ocular intolerance we had defined beforehand: thus, they were all deemed relatively well-tolerated. In the last part of the study, we investigated the effects of combining several preservatives, at usual concentrations, with an anesthetic solution of oxybuprocaine and found no notable increase in ocular damage.

Animals↗
PubMed1998

Early effect of low-dose endotoxin on rat cecal mucosa ex vivo.

It has been suggested that endotoxin triggers translocation of intestinal bacteria in vivo, either by directly damaging intestinal mucosa or by inducing a systemic inflammatory reaction that leads to mucosal disruption. To address this issue, we examined the immediate effect of extraluminal endotoxin on structure and function of isolated rat cecal mucosa without other inflammatory cells in vitro. The cecal mucosa of 12 male Wistar rats was mounted in modified Ussing chambers filled with Dulbecco's modified Eagle's medium and the ampicillin-resistant Escherichia coli HB101:K12 incubated on the mucosal side. Endotoxin was added to the submucosal side at concentrations of 1 and 10 EU/ml, respectively. Under gassing with carbogene at 37 degreesC, the potential difference across the mucosa was measured continuously. Samples of the mucosal and submucosal solutions were removed at 60, 120, and 180 min and plated out on McConkey ampicillin-agar. After 180 min, the mucosal specimens were retrieved and examined by light and scanning electron microscopy. No significant change in potential difference was observed in control or endotoxin-incubated mucosa within the observation period. Neither light nor scanning electron microscopy showed a significant change in the structure of the epithelium, mucosa, or submucosa. No significant translocation of the E. coli across the mucosa was seen. We concluded that endotoxin alone does not induce immediate structural and functional damage to rat cecal mucosa in vitro. Therefore, it seems unlikely that a short endotoxemia alone directly triggers bacterial translocation by disrupting intestinal mucosa, but rather, entotoxin induces a local and systemic inflammatory reaction that leads to mucosal disruption.

Animals↗
PubMed1998

Role of ultrasonographically guided fine-needle aspiration cytology in the diagnosis of infected pancreatic necrosis.

BACKGROUND: Early detection of infected pancreatic necrosis has a major impact on further management and outcome in acute pancreatitis. The aim of this study was to evaluate the clinical value of ultrasonographically guided fine-needle aspiration cytology (FNAC) in patients with necrotizing pancreatitis over an 8-year period. METHODS: From January 1988 to September 1996 193 (mean 2.0 (range 1-9) aspirations per patient) prospectively assessed FNACs guided ultrasonographically were performed in 98 patients with necrotizing pancreatitis proven by contrast-enhanced computed tomography. Aspirates were considered infected if either Gram stain and/or culture revealed micro-organisms. RESULTS: Ultrasonographically guided FNAC correctly diagnosed infection in 29 of 33 patients with infected necrosis a median of 13 days after onset of symptoms. Of 61 patients with sterile necrosis 55 were identified correctly as sterile by FNAC. There were six false-positive and four false-negative aspirates of which nine occurred during the first week of the disease. In four patients who did not undergo operation FNAC revealed Gram-negative organisms; however, in the absence of repeated aspirations, the positive results remained unconfirmed. An overall sensitivity of 88 per cent and a specificity of 90 per cent was obtained. No difference was found in biochemical and clinical parameters indicating systemic inflammatory response syndrome before each FNAC between patients with proven sterile or infected necrosis. All patients tolerated the procedure well and no major complications were observed. CONCLUSION: Ultrasonographically guided FNAC is a fast and reliable technique for the diagnosis of infected necrosis. As complication rates are very low, the procedure can be repeated at short intervals to improve the diagnostic accuracy. Ultrasonographically guided FNAC is recommended for all patients with necrotizing pancreatitis in whom systemic inflammatory response syndrome persists beyond the first week after onset of symptoms.

Adolescent↗
PubMed1998

Stability of diltiazem in whole blood: forensic implications.

The stability of diltiazem (DTZ) in whole blood and in postmortem samples was investigated. In the first study, an aliquot of outdated Red Cross blood with sodium fluoride added as a preservative was spiked with DTZ and stored for one year under three separate conditions: room temperature, 4 degrees C, and -20 degrees C. DTZ and one of its major metabolites, desacetyldiltiazem (DAD), were quantitated at given intervals during this period. In the second study, case postmortem blood samples (n = 36) that exhibited different degrees of putrefaction were spiked in a similar fashion and the stability of DTZ was determined after storage at 4 degrees C for 92 days. DTZ and DAD were extracted as bases, using mild pH conditions to prevent the hydrolysis of DTZ, and quantitated by an HPLC system equipped with a diode array detector and a Supelcosil LCDP column, 5 microns, 250 mm x 4.6 mm inside diameter. Approximately 50% of DTZ was lost in the Red Cross blood stored at room temperature and 4 degrees C, after 19 and 124 days, respectively. This was associated with concomitant appearance and comparable increase in DAD concentration, presumably due to the in vitro hydrolysis of DTZ to DAD. No significant loss of DTZ was observed in the -20 degrees C samples. Similar changes in DTZ and DAD concentrations were seen in postmortem blood samples stored at 4 degrees C for 92 days, though notably, the extent of loss of DTZ varied from complete to negligible. The data suggest that the potential for in vitro conversion of DTZ to DAD should be considered for proper interpretation of postmortem DTZ/DAD findings. Several cases examined in this laboratory will be used to discuss other forensic implications.

Adult↗
PubMed1997

[Phospholipase A2--from basic research to clinical reality].

Phospholipase A2 (PLA2) is a group of secretory as well as intracellular enzymes that release phospholipids as an early step in inflammation and play a physiologic role in digestion. In humans, the group of secretory, low-molecular-weight PLA2 (sPLA2) is differentiated from the cytosolic, high-molecular-weight PLA2 (cPLA2). The two known cPLA2 mediate the intracellular response to inflammation by releasing arachidonic acid from membrane phospholipids. Secretory pancreatic PLA2 (sPLA2-I) is a digestive zymogen secreted from pancreatic acinar cells in its inactive form. Activated by trypsin in the duodenum, it is an important digestive enzyme. In acute pancreatitis, circulating sPLA2-I indicates pancreatic injury but is mostly inactive. Synovial-type secretory PLA2 (sPLA2-II), first isolated from synovial fluid of arthritis patients, is increased in inflammation, after surgery or trauma, and in various inflammatory diseases. Unlike sPLA2-I, its catalytic activity is held responsible for mediating the systemic inflammatory reaction and its complications by regulating the synthesis of prostaglandins, leukotrienes and platelet activating factor. Clinically, sPLA2-II offers new possibilities as an early marker for severe inflammation and predicting systemic complications in severely ill patients.

Acute Disease↗
PubMed1997

Confocal microscopy as a tool for the investigation of the anterior part of the eye.

In recent years, confocal microscopy has become a powerful tool for examining microscopic structures in the living eye. The decisive advantage of this technique is that it permits the investigation of optical sections of relatively thick (> 10 microns) specimens. Because confocal microscopy suppresses the out-of-focus blur, sharp three-dimensional images with excellent resolution can be obtained. Confocal microscopy is therefore able to provide more information than the classic methods--i.e., specular microscopy and slit-lamp biomicroscopy. This paper reviews recent applications of confocal microscopy in three fields of ophthalmology: the observation of the anatomy of the anterior parts of the eye, the investigation of these structures after local administration of drugs and, finally, the use of this technique for the diagnosis of infectious ocular diseases.

Animals↗
PubMed1997

The potential role of procalcitonin and interleukin 8 in the prediction of infected necrosis in acute pancreatitis.

BACKGROUND: Infection of pancreatic necrosis has a major impact on clinical course, management, and outcome in acute pancreatitis. Currently, guided fine needle aspiration is the only means for an early and accurate diagnosis of infected necrosis. Procalcitonin (PCT), a 116 amino acid propeptide of calcitonin, and interleukin 8 (IL-8), a strong neutrophil activating cytokine, are markers of severe inflammation and sepsis. AIMS: To analyse the clinical value of PCT and IL-8 as biochemical parameters for predicting infected necrosis in acute pancreatitis. PATIENTS AND METHODS: Fifty patients with acute pancreatitis entered this prospective study and were stratified into three groups according to morphological and bacteriological findings: 18 patients with oedematous pancreatitis (group I), 14 patients with sterile necrosis (group II), and 18 patients who developed infected necrosis a median of 13.5 days after the onset of symptoms (group III). After admission serum samples were drawn daily for two weeks. Concentrations of PCT and IL-8 were measured by chemoluminescent immunoassays (upper reference range 0.5 ng/ml for PCT and 70 pg/ml for IL-8). The routine parameter C-reactive protein was determined by laser nephelometry (upper reference range 10 mg/l). RESULTS: Median concentrations of PCT and IL-8 were significantly higher in patients with infected necrosis than in those with sterile necrosis during the observation period, whereas there was no difference in C-reactive protein. In oedematous pancreatitis overall median concentrations of all three parameters were low. By receiver operating characteristics best cut off levels for predicting infected necrosis or persisting pancreatic sepsis were 1.8 ng/ml for PCT and 112 pg/ml for IL-8. If these cut off levels were reached on at least two days, sensitivity, specificity, and accuracy for the prediction of infected necrosis were 94%, 91%, and 92% for PCT and 72%, 75%, and 74% for IL-8, respectively. After surgical treatment of infected necrosis median PCT and IL-8 values continued to be significantly higher in patients with persisting pancreatic sepsis (n = 11) compared with those having an uneventful postoperative course (n = 7). For the preoperative differentiation between infected necrosis and sterile necrosis guided fine needle aspiration was performed in 24 patients with necrotising pancreatitis and reached a diagnostic accuracy of 84% compared with 87% for PCT, and 68% for IL-8. There was no correlation between the aetiology of acute pancreatitis or the extent of necrosis and PCT or IL-8. CONCLUSION: PCT and IL-8 are found in high concentrations in infected necrosis and associated systemic complications in patients with acute pancreatitis. The course of PCT shows the closest correlation with the presence of infected necrosis. Monitoring of serum PCT is a potential new marker for the non-invasive and accurate prediction of infected necrosis as well as for the selection of patients with persisting septic complications after surgical debridement.

Adolescent↗
PubMed1997

Esterase-like activity of human serum albumin toward prodrug esters of nicotinic acid.

The esterase-like activity of human serum albumin (HSA) toward esters of nicotinic acid was investigated under a variety of conditions such as protein concentration, temperature, pH, ionic strength, nature of buffers, and presence of organic solvents. Initial rate constants of hydrolysis of 18 nicotinates in the presence of 50 microM HSA were measured at pH 7.4 and 37 degrees C. The substrates displayed half-lifes ranging from less than 15 min (2-butoxyethyl nicotinate) to more than 95 hr (methyl nicotinate). The hydrolysis of tert-butyl nicotinate was too slow to be measurable, whereas 1-carbamoylethyl nicotinate was stabilized against hydrolysis by the presence of HSA. The rate constants of HSA-catalyzed hydrolysis were well correlated (r2 = 0.85; N = 12) with previously published data obtained in human plasma, indicating similar substrate specificities in the two biological preparations. All evidence points to serum albumin as the possible major catalyst of hydrolysis of nicotinate esters in human plasma.

Esterases↗
PubMed1996

[Topographic-anatomic aspects of laparoscopic management of inguinal hernia].

Accidental injury of important anatomic structures is a factor frequently mentioned in the discussion of the sense of laparoscopic hernia repair via the transabdominal or extraperitoneal approach. We describe the topographic anatomy of the inguinal region and point out important structures in this area as found in our anatomic preparations of eight specimens at the Department of Anatomy of the University of Ulm. These observations are correlated with a meta-analysis of published data on complications of this new technique for inguinal hernia repair. It is concluded that complications of laparoscopic inguinal hernia repair can be avoided if the topographic anatomy of the inguinal region is sufficiently taken into consideration.

Hernia, Inguinal↗
PubMed1996

A continuous fluorimetric method to monitor the enzymatic hydrolysis of medicinal esters.

This paper describes a new spectrofluorimetric assay for continuously monitoring the enzymatic hydrolysis of medicinal esters. The procedure is based on the stoichiometric quantity of protons generated by the hydrolysis of the substrate, which produces changes in the fluorescence of a pH-sensitive dye. The pH indicator, 2', 7'-bis(car-boxyethyl)-5(6)-carboxyfluorescein, was selected due to its favourable pKa for studies under physiological conditions. Moreover, the presence of a domain in the spectra (< 442 nm) where fluorescence intensities are independent of pH allows measurements of wavelength ratios that cancel artifacts and lower sample-to-sample variability. The indicator did not affect the catalytic activity of purified hog liver carboxylesterase or human serum albumin. This assay is easy to perform and appears to be especially useful for studying enzymatic reactions with half-lives of the order of minutes or hours.

Animals↗