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J C Frölich

Publications and source records attributed to J C Frölich.

At least 73 records · Page 4Linked to original sources
PubMed1998

Effect of selective inhibition of the inducible cyclooxygenase on renin release in healthy volunteers.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) can block renin release via inhibition of cyclooxygenase (COX). The responsible COX-isoenzyme in man is unknown. Therefore, we assessed the effects of meloxicam, a selective inhibitor of COX-2, and indomethacin, an unselective inhibitor of COX-1 and COX-2, on furosemide stimulated plasma renin activity (PRA). METHODS: In a randomized cross-over design 15 healthy female volunteers received no NSAID or meloxicam 7.5 mg/d for 6 days or indomethacin 25 mg tid for 2 days and 25 mg on the 3rd day. On the control day and on the last day of each treatment the following parameters were evaluated before and after furosemide 20 mg i.v.: PRA measured by RIA, urinary excretion of prostaglandin E2 (PGE2) assessed by gas chromatography-tandem mass spectrometry, urine volume and urinary excretion of sodium, potassium, and creatinine, and serum concentrations of sodium, potassium, and creatinine. RESULTS: Furosemide led to a more than two-fold rise of PRA. Indomethacin as well as meloxicam had no significant effect on basal PRA but inhibited the furosemide-stimulated PRA increase. PGE2 excretion on the control day rose two-fold after furosemide. Meloxicam had no effect on basal PGE2 excretion, whereas indomethacin reduced this parameter by 30%. Both drugs inhibited the increase of urinary PGE2 after furosemide. No drug effects on urine flow nor on electrolytes and creatinine in serum and urine could be observed. CONCLUSION: Meloxicam inhibited furosemide stimulated renin release, suggesting that in man COX-2 is responsible for prostaglandin synthesis mediating renin release.

Adolescent↗
PubMed1997

Dietary L-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits: comparison with lovastatin.

BACKGROUND: We investigated whether L-arginine induces regression of preexisting atheromatous lesions and reversal of endothelial dysfunction in hypercholesterolemic rabbits, whether similar effects can be obtained by cholesterol-lowering therapy with lovastatin, and which mechanism leads to these effects. METHODS AND RESULTS: Rabbits were fed 1% cholesterol for 4 weeks and 0.5% cholesterol for an additional 12 weeks. Two groups of cholesterol-fed rabbits were treated with L-arginine (2.0% in drinking water) or lovastatin (10 mg/d) during weeks 5 through 16. Systemic nitric oxide (NO) formation was assessed as the urinary excretion rates of nitrate and cGMP in weekly intervals. Cholesterol feeding progressively reduced urinary nitrate excretion to approximately 40% of baseline (P<.05) and increased plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous NO synthesis inhibitor. Dietary L-arginine reversed the reduction in plasma L-arginine/ADMA ratio and partly restored urinary excretion of nitrate and cGMP (each P<.05 vs cholesterol) but did not change plasma cholesterol levels. L-Arginine completely blocked the progression of carotid intimal plaques, reduced aortic intimal thickening, and preserved endothelium-dependent vasodilator function. Lovastatin treatment reduced plasma cholesterol by 32% but did not improve urinary nitrate or cGMP excretion or endothelium-dependent vasodilation. Lovastatin had a weaker inhibitory effect on carotid plaque formation and aortic intimal thickening than L-arginine. L-Arginine inhibited but lovastatin potentiated superoxide radical generation in the atherosclerotic vascular wall. CONCLUSIONS: Dietary L-arginine improves NO-dependent vasodilator function in cholesterol-fed rabbits and completely blocks the progression of plaques via restoration of NO synthase substrate availability and reduction of vascular oxidative stress. Lovastatin treatment has a weaker inhibitory effect on the progression of atherosclerosis and no effect on vascular NO elaboration, which may be due to its stimulatory effect on vascular superoxide radical generation.

Animals↗
PubMed1997

Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease.

BACKGROUND: We studied urinary nitrate and cGMP excretion rates, indices of systemic NO formation, and plasma concentrations of L-arginine and the endogenous NO synthase inhibitor asymmetrical dimethylarginine (ADMA) and its inactive stereoisomer, symmetrical dimethylarginine, in 77 patients with peripheral arterial occlusive disease (PAOD) in Fontaine stages IIb through IV and in 47 young and 37 elderly healthy control subjects. METHODS AND RESULTS: Urinary nitrate excretion was 182.0+/-11.4 micromol/mmol creatinine and cGMP excretion was 186.2+/-13.0 nmol/mmol creatinine in young healthy control subjects. In elderly control subjects, both excretion rates were slightly lower (nitrate, 156.0+/-7.8 micromol/mmol creatinine; cGMP, 150.0+/-8.3 nmol/mmol creatinine; P=NS). In PAOD patients, there was a significant, progressive reduction of urinary nitrate (IIb, 138.4+/-11.9; III, 128.6+/-11.3; and IV, 91.9+/-8.0 micromol/mmol creatinine; P<.05) and cGMP (IIb, 139.9+/-25.2; III, 115.6+/-13.1; and IV, 76.9+/-7.9 nmol/mmol creatinine; P<.05) excretion rates related to the Fontaine stage of PAOD. These changes were independent of changes in renal excretory function. Plasma L-arginine concentrations were not significantly different between the groups, but ADMA concentrations were elevated in PAOD patients (young control subjects, 1.25+/-0.11; elderly control subjects, 1.01+/-0.05 micromol/L; IIb, 2.62+/-0.24; III, 3.06+/-0.48; and IV, 3.49+/-0.26 micromol/L; P<.05 for PAOD versus control subjects). There was a significant linear correlation between urinary nitrate and cGMP excretion rates and a significant negative linear correlation between plasma ADMA concentrations and urinary nitrate excretion. CONCLUSIONS: In PAOD patients, there is a progressive reduction in urinary nitrate and cGMP excretion rates, which may be caused in part by accumulation of ADMA, an endogenous inhibitor of NO synthase.

Adult↗
PubMed1997

Measurement of nitrite and nitrate in biological fluids by gas chromatography-mass spectrometry and by the Griess assay: problems with the Griess assay--solutions by gas chromatography-mass spectrometry.

Assay methods based on the Griess reaction are frequently used to measure nitrite and nitrate in urine, plasma, and other biological fluids. With minor exceptions, careful attention has not been paid in extending the Griess assay from aqueous solutions to biological fluids, In the present study, parallel measurements of nitrite and nitrate were performed in urine, plasma, and aqueous solutions with a published batch assay based on the Griess reaction and with gas chromatography-mass spectrometry (GC-MS). We report here further interferences by free reduced thiols, proteins, and other plasma constituents in the Griess assay but not in GC-MS. The best correlation (r2 = 0.985) between the Griess assay and GC-MS was observed for aqueous solutions in the absence of thiols. Unlike GC-MS, the Griess assay was not applicable to whole human plasma and urine samples. For the measurement of nitrate in diluted human urine samples, reduction by cadmium was performed both under acidic (pH 2 or 5) and alkaline (pH 8.8) conditions. The mean recovery rate of nitrate from urine samples was quantitative in the GC-MS but amounted to only 30-80% in the Griess assay. Measurement of nitrate in human urine samples (n = 33) resulted in an excellent correlation between two GC-MS techniques (r2 = 0.979) but only in a poor correlation (r2 < 0.64) between the Griess assay and GC-MS. Unlike GC-MS, the batch Griess assay is associated with many problems in measuring nitrate in biological fluids.

Chromatography, High Pressure Liquid↗
PubMed1997

A classification of NSAIDs according to the relative inhibition of cyclooxygenase isoenzymes.

Non-steroidal anti-inflammatory drugs (NSAIDs) are, as a group, the most frequently consumed drugs worldwide. They also cause the most, and often dangerous, side-effects reported to the US Food and Drug Administration, the majority of which are owing to damage of the gastrointestinal tract and kidneys. This explains the continuous interest of pharmacologists, clinical pharmacologists and pharmacoepidemiologists in this group of drugs. Based on an increasing body of data, J. Frölich proposes a simple alternative to the usual chemical classification of NSAIDs, allowing one to predict a drug's major effects according to its relative inhibition of the constitutive and inducible cyclooxygenase isoenzymes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Dose-related effect of intravenous L-arginine on muscular blood flow of the calf in patients with peripheral vascular disease: a H215O positron emission tomography study.

1. Endothelium-derived nitric oxide (NO) contributes to the regulation of vascular tone and blood pressure. Infusion of L-arginine produces systemic vasodilatation via stimulation of endogenous NO formation. Vasodilatation is accompanied by an increase in peripheral arterial blood flow. However, it is not known whether capillary nutritive blood flow increases as well. The time course and dose-response pattern of this effect remain to be elucidated. 2. Two groups of ten patients with peripheral vascular disease (PVD) received an intravenous infusion of 8 g or 30 g of L-arginine over a period of 40 min. Blood pressure and heart rate were monitored non-invasively. Muscular blood flow (MBF) of the calf was determined at 0, 20, 40, 60, 80 min by positron emission tomography with H215O as flow tracer. Plasma L-arginine and cyclic GMP (cGMP) levels were determined at the same time points. 3. L-arginine induced a dose-related decrease in blood pressure during the infusion period. MBF and plasma cGMP levels during and after the infusion of 8 g of L-arginine did not change significantly. In the patients receiving 30 g of L-arginine, MBF was enhanced significantly from 1.56 +/- 0.14 to 2.09 +/- 0.21 ml min-1 100 ml-1 at 40 min and 2.23 +/- 0.15 ml min-1 100 ml-1 after 80 min (+43.0%). The increase in MBF was paralleled by an increase in plasma cGMP from 4789.8 +/- 392.2 nmol/l at baseline to 9223.2 +/- 1233.6 nmol/l at 40 min. 4. We conclude that intravenous L-arginine enhances nutritive capillary MBF in patients with PVD via the NO-cGMP pathway in a dose-related manner. This effect might be therapeutically beneficial in patients with PVD.

Aged↗
PubMed1997

Cigarette smoking stimulates cysteinyl leukotriene production in man.

Chronic cigarette smoking is an important risk factor for pulmonary and cardiovascular diseases. An increased production of cysteinyl leukotrienes has been shown in asthma and in cardiac ischaemia. The effect of cigarette smoking on cysteinyl leukotriene biosynthesis is, however, not known. Urinary leukotriene E4 (LTE4) was measured in 30 habitual smokers and in 30 non-smokers. In a further 12 non-smokers urinary LTE4 excretion was assessed before and after smoking six cigarettes. In addition, the effect of transdermal nicotine on urinary LTE4 excretion was studied in seven non-smokers. There was a close correlation (r = 0.92, P < 0.0001) between urinary excretion of LTE4 and the number of cigarettes smoked daily by habitual smokers. Smoking six cigarettes within 12h resulted in a significant (P = 0.0047), twofold increase in the mean individual LTE4 excretion in non-smokers. Transdermal nicotine had no effect on LTE4 excretion in non-smokers. In conclusion, cigarette smoke causes a dose-related increase in cysteinyl leukotriene production in habitual smokers. Some of the adverse effects of smoking may be related to an enhanced leukotriene synthesis.

Administration, Cutaneous↗
PubMed1997

Nitric oxide inhibits the secretion of T-helper 1- and T-helper 2-associated cytokines in activated human T cells.

Mechanisms regulating the balance of T-helper 1 (Th1) and T-helper 2 (Th2) immune responses are of great interest as they may determine the outcome of allergic and infectious diseases. Recently, in mice, nitric oxide (NO), a powerful modulator of inflammation, has been reported to preferentially down-regulate Th1-mediated immune responses. In the present study, we investigated the effect of NO on the production of Th1- and Th2-associated cytokines by activated human T cells and human T-cell clones. Cytokine secretion was measured in the presence of the NO-donating agents 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP). Both NO-donors markedly inhibited the release of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-5, IL-10 and IL-4 by anti-CD3 activated T cells. A preferential inhibition of Th1-associated cytokines was not observed. Neither was nitrite found in the supernatants of activated T cells, nor was specific mRNA for inducible and constitutive NO synthase detectable, indicating that T cells themselves did not contribute to the observed effect of the NO donors. Costimulation with anti-CD28 monoclonal antibodies (mAb) prevented SIN-1/SNAP-mediated down-regulation of cytokine production only in part. In contrast, when T cells were stimulated by phorbol-ester and ionomycin, they were refractory to SIN-1-induced inhibition of cytokine production. When SIN-1 was added after the onset of anti-CD3 stimulation, the inhibitory effect was found to be less pronounced, indicating that SIN-1 may interfere with early signal transduction events. The addition of superoxide dismutase (SOD) and catalase did not restore the effects of SIN-1, demonstrating that the inhibition of cytokines was due to NO and not to oxygen intermediates. Furthermore, 8-Br-cGMP-mediated increase of intracellular cGMP caused the same pattern of cytokine inhibition as observed with SIN-1 and SNAP. Using a single cell assay, these agents were shown to reduce the frequency of IFN-gamma-producing T cells, suggesting that not all T cells are susceptible to SIN-1/SNAP. However, cytokine production by purified T-cell subpopulations (CD4+, CD8+, CD45RA+, and CD45RO+) was equally impaired by NO donors. In conclusion, in contrast to the murine system, our results do not provide evidence that NO preferentially inhibits Th1-cytokine secretion of activated human T cells in vitro.

CD3 Complex↗
PubMed1997

Euthanasia.

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Attitude of Health Personnel↗
PubMed1997

Effects of meloxicam and indomethacin on cyclooxygenase pathways in healthy volunteers.

BACKGROUND: Meloxicam is a new NSAID with selectivity for the inducible cyclooxygenase (COX-2) in vitro. We compared the effects of therapeutically equivalent doses of meloxicam and indomethacin, a preferential inhibitor of the constitutive cyclooxygenase (COX-1), on platelet aggregation and platelet thromboxane formation, which are exclusively COX-1 dependent, physiological renal, and total body prostaglandin E2 (PGE2) production. METHODS: In a randomized cross-over design, 14 healthy female volunteers received meloxicam 7.5 mg per day for 6 days or indomethacin 25 mg three times per day for 3 days; the wash-out period was 5 days, and drug intake was adapted to the menstrual cycle. On the day before treatment and on the last day of each treatment period the following parameters were evaluated: maximum platelet aggregation and thromboxane B2 (TXB2) formation in response to 1.0 mmol/L arachidonic acid; 24-hour urinary excretion of PGE2 and 7 alpha-hydroxy-5, 11-diketo-tetranor-prosta-1, 16-dionic acid (PGE-M), the index metabolites of renal and total body PGE2 synthesis, respectively, were assessed by gas chromatography/tandem mass spectrometry. RESULTS: Maximum platelet aggregation and TXB2 formation were almost completely inhibited by indomethacin (-87% and -99%, respectively; p < 0.001, each) as compared to control (100%), but remained unaffected by meloxicam (-1% and +4%, respectively). Meloxicam showed no significant effects on urinary PGE2 excretion (-13%) and only slight effects on PGE-M excretion (-22%; p < 0.05), whereas indomethacin reduced urinary PGE2 excretion (-43%; p < 0.05) as well as PGE-M excretion (-36%; p < 0.001). CONCLUSIONS: Our data show, that meloxicam 7.5 mg per day is COX-1 sparing in humans in vivo.

Adult↗
PubMed1997

[Prostaglandins].

Prostaglandin research has led to a plethora of discoveries on pathophysiology. Remarkable examples are arteriosclerosis and its complications, where the role of thromboxane and prostacyclin was discovered and led to the development of strategies for the prevention of myocardial infarction by acetylsalicylic acid. Nephrology has gained new insights into the role of prostaglandins in kidney function under physiological and pathological conditions. The action of various drugs on kidney function has led to the understanding of interactions between non-steroidal antiinflammatory drugs and antihypertensive drugs and lithium. Systematic research on the role of prostaglandins and leukotrienes in inflammation and in asthma has led to the development of new drugs for both diseases. The original idea to use prostaglandins themselves for various indications has not been realized. As observed often in the past in biological and technological research the most important discoveries came unexpected and as a surprise to the specialists: The use of acetylsalicylic acid for primary and secondary prevention of myocardial infarction and the development of a new generation of non-steroidal antiinflammatory drugs with much better gastrointestinal and renal tolerance.

Animals↗
PubMed1997

[Positive lists/negative lists from the viewpoint of clinical pharmacology].

Drug lists reduce freedom of choice, but are a logical consequence when drugs are prescribed, which are of no proven value. The current prescribing behaviour is the consequence of insufficient training in clinical pharmacology in medical schools and postgraduate education. Positive lists have shown to be of significant value for hospitals in order to reduce the number of drugs available, which brings safety advantages for the patient, improves in depth knowledge of the physician and reduces stock keeping for the pharmacy.

Curriculum↗
PubMed1997

[Special therapeutic processes from the viewpoint of clinical pharmacology].

Special therapies comprise homeopathic drugs, anthroposophic medicine and phytotherapy a heterogenous mixture, which consists partly on authorities (Hahnemann, Steiner) and partly describes the origin of the drug (herbal drugs). The field, therefore, is open to new additions (Chinese traditional medicine, American Indian drug therapy etc.). These drugs do not meet the requirements for safety and efficacy required for modern drugs and this is not required, because according to German lawyers this would be inadequate. We demonstrate examples where the health of patients has been severely damaged by this kind of medical therapies and point out that these problems continue. Reasons are presented, why the public has the right to demand proof of efficacy and safety of all drugs.

Adverse Drug Reaction Reporting Systems↗
PubMed1996

Is S-nitroso-N-acetyl-L-cysteine a circulating or an excretory metabolite of nitric oxide (NO) in man? Assessment by gas chromatography-mass spectrometry.

S-Nitroso-L-cysteine has been shown to be a circulating metabolite of the L-arginine-derived nitric oxide (NO.) in mammals. We describe here a highly sensitive gas chromatographic-mass spectrometric (GC-MS) method for the measurement of S-nitroso-N-acetyl-L-cysteine, the potential mercapturic acid of S-nitroso-L-cysteine, in human plasma and urine. For use as internal standard (I.S.) in this method we synthesized S-[15N]nitroso-N-[2H3]acetyl-L-cysteine. In plasma (n = 10) and urine (n = 30) samples of healthy humans no S-nitroso-N-acetyl-L-cysteine was detected (detection limit approximately 1 nM). Injecting the I.S. in the rat showed a good recovery of the I.S. but no endogenous S-nitroso-N-acetyl-L-cysteine. Our results suggest that renal N-acetylation of S-nitroso-L-cysteine does not represent a metabolic pathway in man.

Animals↗
PubMed1996

Elevated L-arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits.

Dietary supplementation of L-arginine, the precursor of endogenous NO, has been shown to enhance endothelial function in the cholesterol-fed rabbits. However, the mechanism by which dietary L-arginine accomplishes these effects has been unclear. In the present study we have assessed the plasma concentrations of L-arginine and of asymmetrical dimethylarginine (ADMA), a known endogenous inhibitor of NO synthase, in cholesterol-fed rabbits with or without dietary supplementation of L-arginine. Urinary nitrate excretion rates were assessed as an index of endogenous NO formation. Plasma L-arginine levels were not different between control and cholesterol-fed rabbits, but they were elevated nearly threefold in rabbits fed cholesterol + L-arginine. Plasma ADMA concentration increased about two-fold in hypercholesterolemia, but was unaffected by dietary L-arginine. Thus, dietary L-arginine elevated the plasma L-arginine/ADMA ratio above the normal level, and partly restored urinary nitrate excretion, which was decreased by hypercholesterolemia. We conclude that elevation of the L-arginine/ADMA ratio may at least partly explain the restored NO formation by exogenous L-arginine in hypercholesterolemia.

Arginine↗