Biomedical subjects
J C Frölich
Publications and source records attributed to J C Frölich.
[Comments on the contribution by Prof. Dr. S. H. Hohnloser. Sotalol].
Explore the source record for details and available documents.
[Legal liability in drug trials].
Studies on humans are carried out in all nations with scientific trials. These studies are concerned with all kinds of goals, i.e. pharmacological treatment procedures. This necessitates clinical and pharmaceutical testing on healthy volunteers or patients. Lawyers watch over the activities of the clinical drug testing. The participation on human tests requires voluntariness and information. The documentation of the voluntariness and the information about goals, methods, and risks are very important.
Differential effects of two calcium channel blockers on bronchial smooth muscle.
The effects of the new Ca(2+)-entry blocker SK&F 96365 (1-¿beta-[4-methoxyphenyl)propoxy]-4-methoxy-phenethyl¿-1H- imidazole hydrochloride, [sequence: see text] CAS 130495-35-1) and nifedipine on the contractile response of guinea-pig trachea to KCl and histamine are described. Diameter changes of cannulated, perfused tubes of guinea-pig trachea were recorded by a computerized video-microscopy bioassay system. In order to determine whether the capacitive calcium entry is the major mechanism in the guinea-pig trachea, the effects of SK&F 96365, an antagonist of the second-messenger operated channel, were studied. The results of experiments in Ca(2+)-free medium containing EGTA (0.1 mmol l-1) indicate that KCl- and histamine evoked contractions are mainly due to an influx of extracellular Ca2+ rather than due to release from intracellular stores. SK&F 96365 (10 mumol l-1) showed a more effective antispasmogenic activity on histamine-induced contraction of guinea-pig trachea than the voltage-operated channel (VOC)-blocker nifedipine (10 mumol l-1). Nifedipine is only effective in inhibiting KCl induced contraction. These results may have significance for the use of agents such as SK&F 96365 in the treatment of asthma.
Quantification of nitrite and nitrate in human urine and plasma as pentafluorobenzyl derivatives by gas chromatography-mass spectrometry using their 15N-labelled analogs.
For the quantification of nitrite and nitrate, the stable metabolites of L-arginine-derived nitric oxide (NO) in human urine and plasma, we developed a gas chromatographic-mass spectrometric (GC-MS) method in which [15N]nitrite and [15N]nitrate were used as internal standards. Endogenous nitrite and [15N]nitrite added to acetone-treated plasma and urine samples were converted into their pentafluorobenzyl (PFB) derivatives using PFB bromide as the alkylating agent. For the analysis of endogenous nitrate and [15N]nitrate they were reduced to nitrite and [15N]nitrite, respectively, by cadmium in acidified plasma and urine samples prior to PFB alkylation. Reaction products were extracted with toluene and 1-microliter aliquots were analyzed by selected-ion monitoring at m/z 46 for endogenous nitrite (nitrate) and m/z 47 for [15N]nitrite ([15N]nitrate). The intra- and inter-assay relative standard deviations for the determination of nitrite and nitrate in urine and plasma were below 3.8%. The detection limit of the method was 22 fmol of nitrite. Healthy subjects (n = 12) excreted into urine 0.49 +/- 0.25 of nitrite and 109.5 +/- 61.7 of nitrate (mean +/- S.D., mumol/mmol creatinine) with a mean 24-h output of 5.7 mumol for nitrite and 1226 mumol for nitrate. The concentrations of nitrite and nitrate in the plasma of these volunteers were determined to be (mean +/- S.D., mumol/l) 3.6 +/- 0.8 and 68 +/- 17, respectively.
Enhanced synthesis of cysteinyl leukotrienes in juvenile rheumatoid arthritis.
OBJECTIVE: Endogenous synthesis of cysteinyl leukotrienes in juvenile rheumatoid arthritis (JRA) was investigated. METHODS: Cysteinyl leukotriene synthesis was assessed by measuring the excretion of leukotriene E4 (LTE4) in urine by radioimmunoassay. The identity of urinary LTE4 was investigated by gas chromatography-mass spectrometry (GC-MS), and 2,3-dinor-thromboxane B2 was measured with GC-MS. RESULTS: Excretion of LTE4 into urine was significantly (P < 0.05) enhanced in children with JRA compared with that in healthy children (n = 10). Aspirin, in a dosage of 2.5 gm/day, had no effect on urinary LTE4 levels, but it reduced urinary 2,3-dinorthromboxane B2 levels by more than 85% in healthy adults. There was a positive correlation between LTE4 excretion and the number of affected joints. CONCLUSION: This study demonstrates a markedly enhanced cysteinyl leukotriene synthesis and a positive correlation between LTE4 excretion and the number of affected joints in children with JRA.
Comments from chairs of institutes of clinical pharmacology in Germany.
Explore the source record for details and available documents.
L-arginine infusion decreases peripheral arterial resistance and inhibits platelet aggregation in healthy subjects.
1. L-Arginine is the physiological precursor of nitric oxide which induces vasodilatation and inhibits platelet aggregation by the formation of cyclic GMP. 2. In the present study we investigated the effects of an intravenous infusion of L-arginine (30 g, 30 min) compared with placebo on blood pressure, heart rate and peripheral haemodynamics in ten healthy male subjects. Cyclic GMP, NO2- and NO3- were determined in plasma and urine to assess NO production in vivo by a new, highly specific and sensitive gas chromatography-mass spectrometry method. 3. L-Arginine significantly decreased mean arterial blood pressure and increased heart rate. The effect was more pronounced on diastolic than on systolic blood pressure. This was due to a decreased peripheral arteriolar resistance, as in femoral artery Doppler sonography the arterial diameter was unchanged but blood flow was increased. These haemodynamic effects were not observed after placebo administration. 4. Urinary excretion of cyclic GMP increased by 65.4% after L-arginine and by 25.1 after placebo. Urinary NO2- excretion was near the threshold of detection. Urinary NO3- excretion increased by 79.7% after L-arginine. Plasma arginine levels increased nearly ten-fold after the L-arginine infusion, and plasma cyclic GMP increased by a similar rate as in urine. However, plasma NO2- and NO3- remained unchanged after both treatments, as did plasma alpha-atrial natriuretic peptide levels. 5. Platelet aggregation was inhibited by 32.7% after L-arginine (P < 0.05), but was unchanged after placebo. Platelet intracellular cyclic GMP was increased by 43.0% after L-arginine, but not after placebo (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Long-term administration of L-arginine, L-NAME, and the exogenous NO donor molsidomine modulates urinary nitrate and cGMP excretion in rats.
OBJECTIVE: The effects of long term oral administration of L-arginine, NG-nitro-L-arginine methyl-ester (L-NAME), or molsidomine v placebo on blood pressure and the urinary excretion rates of NO3- and cyclic GMP were studied in Munich Wistar Frömter (MWF) rats. METHODS: L-arginine (2 g.kg-1 body weight, n = 8), NG-nitro-L-arginine methylester (L-NAME; 5 mg.kg-1, n = 8), or molsidomine (3 mg.kg-1, n = 8) were given in drinking water and compared with placebo (n = 8) over a period of five months. Urinary excretion rates of NO3- (by gas chromatography) and cyclic GMP (by radioimmunoassay) were assessed in monthly intervals, as well as systolic blood pressure (tail plethysmography). RESULTS: Mean basal blood pressure was 143.5(SEM 2.2) mm Hg. It was unaffected by L-arginine or molsidomine, but continuously and significantly increased during L-NAME treatment to 199.3(6.4) mm Hg (p < 0.05). Urinary excretion of NO3- increased by 20-41% v controls in L-arginine and molsidomine treated rats (p < 0.05), and decreased by 5-15% in L-NAME treated rats (p < 0.05). Urinary excretion of cyclic GMP increased by 9-38% v controls in the L-arginine and molsidomine treated groups and decreased by 5-20% in the L-NAME treated animals. Consistent with their higher blood pressure, L-NAME treated animals displayed cardiac hypertrophy. CONCLUSIONS: Determination of urinary NO3- excretion by gas chromatography is a sensitive and specific method to assess NO formation in vivo. Long term oral administration of L-arginine in MWF rats increases NO production (as assessed by the urinary excretion rates of NO3- and cyclic GMP), but does not significantly influence systolic blood pressure, whereas L-NAME induces sustained hypertension and cardiac hypertrophy due to inhibition of NO formation.
Vascular release of superoxide radicals is enhanced in hypercholesterolemic rabbits.
Production/release of superoxide anions from aortic rings was measured by a modified lucigenin-enhanced chemiluminescence (CL) technique. The aortic rings were obtained from control and cholesterol-fed (1% for 12 weeks) rabbits. The CL signal was significantly increased in aortic wall of cholesterol-fed rabbits. Pretreatment with oxypurinol, an inhibitor of xanthine oxidase, had a slight but insignificant effect on the CL response produced by aortic rings from control animals but significantly reduced CL response to aortic rings from cholesterol-fed rabbits. Pretreatment with diethyldithiocarbamate (DETC), an inhibitor of intrinsic superoxide dismutase (SOD), increased the CL signal for both animal groups, but this increase was greatly aggravated in aortic rings from hypercholesterolemic rabbits. Addition of phorbol 12-myristate 13 acetate (PMA) to stimulate the respiratory burst of wall-adherent and/or resident leukocytes had only slight effect on the CL response to aortic rings from control animals but extensively stimulated photon emission of aortic rings from cholesterol-fed rabbits. These findings are in agreement with the concept that the arterial wall in hypercholesterolemia and/or atherosclerosis is under increased "oxidative stress."
Increased urinary nitrate excretion in rats with adjuvant arthritis.
OBJECTIVES: In rats with adjuvant arthritis measurements were taken of the urinary excretion of nitrate, reflecting endogenous nitric oxide (NO) formation, and cyclic guanosine monophosphate (cGMP). METHODS: Urinary nitrate was determined by gas chromatography, cGMP by radioimmunoassay. RESULTS: A significant (p < 0.001), more than three fold increase of urinary nitrate excretion was found in rats 20 days after induction of adjuvant arthritis compared with non-arthritic rats. There was no significant difference in urinary cGMP excretion between arthritic rats and control animals. CONCLUSION: The data suggest that the dramatic increase of urinary nitrate excretion is due to increase of NO synthesis by the inducible form of NO synthase.
Impaired degradation of prostaglandins and thromboxane in Zellweger syndrome.
Cyclooxygenase products are metabolized by omega-oxidation as well as beta-oxidation. Children with Zellweger syndrome (ZS) are characterized by peroxisome deficiency. To evaluate the role of peroxisomal beta-oxidation on cyclooxygenase metabolites, the degradation of endogenous prostaglandin (PG) E2, prostacyclin, and thromboxane (Tx) A2 was assessed in children with ZS (n = 7) and in healthy children (n = 7). PGE2, prostacyclin, TxB2, and their major urinary metabolites 7 alpha-hydroxy-5,11-dioxo-tetranor-prosta-1,16-dioic acid, 2,3-dinor-6-oxo-PGF1 alpha, and 2,3-dinor-TxB2, respectively, were measured in urine by gas chromatography-mass spectrometry/mass spectrometry. The median excretion of healthy children was 17.9 ng of 7 alpha-hydroxy-5,11-dioxo-tetranor-prosta-1,16-dioic acid/mg creatinine (interquartile range, 6.3 to 19.4 ng/mg), 0.38 ng of 2,3-dinor-6-oxo-PGF1 alpha/mg creatinine (interquartile range, 0.34 to 0.70 ng/mg), and 0.36 ng of 2,3-dinor-TxB2/mg creatinine (interquartile range, 0.14 to 0.54 ng/mg). In contrast, none of these metabolites could be detected in urine of children with ZS (p < 0.002). However, we identified in the urine of these children a new metabolite of PGE2 as 11-hydroxy-9,15-dioxo-prost-5-en-1,20-dioic acid by gas chromatography-mass spectrometry, and we confirmed the presence of 9,11-dihydroxy-15-oxo-prost-5-en-1,20-dioic acid the main urinary metabolite of PGF2 alpha in ZS. Importantly, these two metabolites were only detectable in urine of children with ZS.(ABSTRACT TRUNCATED AT 250 WORDS)
Exercise increases systemic nitric oxide production in men.
BACKGROUND: Our aim was to compare the effects of exercise on systemic nitric oxide formation, assessed from the urinary excretion rates of nitrate and of cyclic GMP, in endurance-trained and untrained men. METHODS: Ten endurance-trained and six untrained men underwent a submaximal exercise test for 30 min at 60% of their individual maximal work capacity. Urinary excretion rates of nitrate (measured using gas chromatography) and cyclic GMP (measured using a radioimmunoassay) were assessed at hourly intervals. RESULTS: Urinary nitrate excretion was comparable at rest in the two groups (104 +/- 35 and 110 +/- 19 mumol/mmol creatinine; NS), more than doubled during exercise in both groups (236 +/- 88 mumol/mmol creatinine in untrained and 252 +/- 39 mumol/mmol creatinine in trained participants; P < 0.01 for both groups) and decreased rapidly after the completion of the exercise test. Excretion of urinary cyclic GMP at rest was four times higher in the endurance-trained than in the untrained men (21 +/- 5 compared with 6 +/-1 nmol/mmol creatinine; P < 0.05). During the exercise test, GMP excretion approximately doubled in both groups (52 +/- 12 and 10 +/- 1 nmol/mmol creatinine, respectively; P < or = 0.01 for both groups) and returned to baseline at the end of the test. Urinary cyclic GMP and nitrate excretion correlated well in both groups (p < 0.05). Atrial natriuretic factor is also a stimulator of cyclic GMP formation but resting plasma levels of atrial natriuretic factor did not differ between the groups (22 +/- 3 compared with 21 +/- 4 pmol/l; NS). CONCLUSION: An acute submaximal exercise test increases the formation of nitric oxide, reflected in the increase in urinary excretion of nitrate and cyclic GMP. This increase may contribute to vasodilatation during physical exercise and at least partly explain the beneficial effects of physical training in patients with vascular diseases.
Assessment of cysteinyl leukotriene synthesis in man.
We have developed methods to measure LTE4, the index metabolite of cysteinyl leukotrienes, by HPLC/RIA and GC/MS. Urinary LTE4 appears to be a reliable parameter to assess whole body cysteinyl leukotriene synthesis in man from all evidence available at this time. Measurement of this metabolite can be used to monitor effects of diseases and drugs on cysteinyl leukotriene synthesis in man.
Gas chromatographic-mass spectrometric determination of leukotriene E4 in human urine using deuterium-labelled leukotriene E4 standards.
The utility of two deuterium-labelled leukotriene (LT) E4 analogs, e.g. [20,20,20-2H3]LTE4 and [14,15,17,17,18,18-2H6]LTE4, as internal standards for the determination of LTE4 in human urine by gas chromatography-mass spectrometry (GC-MS) was investigated. 2H-Exchange during hydrogenation occurred both in [20,20,20-2H3]LTE4 and [14,15,17,17,18,18-2H6]LTE4 in an extent of 9.4 +/- 0.5% and 67.3 +/- 0.6% (mean +/- S.D., n = 6), respectively. The lower extent of 2H-exchange in [20,20,20-2H3]LTE4 allowed a more accurate quantitation than the use of [14,15,17,17,18,18-2H6]LTE4. Applying [20,20,20-2H3]LTE4 as internal standard the coefficients of variation for the intra- and inter-assay determination of LTE4 in human urine were 5.7% and 6.2% (n = 4), respectively. The inter-assay coefficient of variation for [14,15,17,17,18,18-2H6]LTE4 was 15%. Using [20,20,20-2H3]LTE4 as internal standard and GC-MS, healthy volunteers were found to excrete 17 +/- 10 nmol LTE4 per mol creatinine (mean +/- S.D., n = 11). Similar excretion rates for LTE4 in urine of healthy volunteers were found using GC-tandem MS with [1,1-18O2]LTE4 as internal standard. Our results demonstrate that [20,20,20(-2)H3]LTE4 is a suitable internal standard for the GC-MS determination of urinary LTE4.
[Volume replacement therapy with human albumin. Basic principles, differential indications, alternatives].
Explore the source record for details and available documents.
[Therapeutic drug monitoring in general practice--indications and interpretation].
Explore the source record for details and available documents.
Analysis of leukotrienes, prostaglandins, thromboxane B2 and their metabolites by capillary isotachophoresis.
An analytical capillary isotachophoretic method for the analysis of the eicosanoids leukotriene E4, leukotriene B4, prostaglandins E1 and E2, 6-keto-prostaglandin F1 alpha, thromboxane B2, and their metabolites of omega- and/or beta-oxidation is described. The method is based on anionic separation and detection by UV absorbance (254 nm) and conductivity and allows simultaneous analysis of the primary compounds and their corresponding major urinary metabolites. The method was applicable to the qualitative and quantitative analysis of prostaglandin E1 in a drug preparation.