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Biomedical subjects

J Kuhlmann

Publications and source records attributed to J Kuhlmann.

At least 91 records · Page 5Linked to original sources
PubMed1991

Effect of the calcium antagonists nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal motility in man.

Nifedipine has been proven to be effective and safe in the treatment of primary oesophageal motility disorders which can cause angina-like chest pain and/or dysphagia. The effects of the calcium channel blockers nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal smooth muscle function in healthy male volunteers were studied by oesophageal manometry using the rapid pull-through-technique, in two randomized, double-blind crossover studies. Lower oesophageal sphincter pressure, oesophageal contraction amplitude and duration after a wet swallow (measured 5 cm and 10 cm above the lower oesophageal sphincter) were determined 30 min before and at 10 minute intervals up to 90 min after the administration of nimodipine and up to 120 min after nifedipine, nitrendipine and nisoldipine. The plasma drug concentration was measured at baseline (-15 min) and in parallel with the manometric measurements. Compared to placebo, lower oesophageal sphincter pressure was significantly decreased by 24% by nifedipine and 17% by nimodipine, whereas the effects of nitrendipine (decrease of 15%) and nisoldipine (9%) were not significant. Nifedipine significantly decreased by 17% the oral contraction amplitude compared to placebo and nimodipine by 11%. The duration of the contraction amplitudes was not altered. The decrease in sphincter pressure was correlated with the corresponding plasma drug levels of nifedipine r = 0.92, nitrendipine r = 0.80 and nisoldipine r = 0.79. Nimodipine showed no such correlation.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

Transmembrane signalling via HLA-DR molecules on T cells from a Sezary T-cell leukaemia line.

The human Sezary T-cell leukaemia line, HUT.78, represents a population of activated T cells, i.e. they are HLA-DR+ and IL-2R+. We have analysed the capacity of HUT.78 cells (1) to stimulate HLA-DR-specific T-cell lines or clones and (2) to be induced to synthesize IL-2 by anti-HLA-DR monoclonal antibodies. The results of our experiments show that HLA-DR molecules on HUT.78 cells can stimulate at least one HLA-DR-specific T-cell clone and can act as transmembrane signal transmitters.

Antibodies, Monoclonal↗
PubMed1989

Assembly, intracellular processing, and expression at the cell surface of the human alpha beta T cell receptor/CD3 complex. Function of the CD3-zeta chain.

The TCR/CD3 complex is a multimeric protein complex composed of a minimum of seven transmembrane chains (TCR alpha beta-CD3 gamma delta epsilon zeta 2). Whereas earlier studies have demonstrated that both the TCR-alpha and -beta chains are required for the cell surface expression of the TCR/CD3 complex, the role of the CD3 chains for the TCR/CD3 expression have not been experimentally addressed in human T cells. In this study the function of the CD3-zeta chain for the assembly, intracellular processing, and expression of the TCR/CD3 complex in the human leukemic T cell line Jurkat was investigated. The results indicate that: 1) CD3-zeta is required for the cell surface expression of the TCR/CD3 complex; 2) the pentameric form (TCR alpha beta-CD3 gamma delta epsilon) of the TCR/CD3 complex and single TCR chains associated with CD3 (TCR alpha-CD3 gamma delta epsilon and TCR beta-CD3 gamma delta epsilon) are produced in the endoplasmic reticulum in the absence of CD3-zeta; 3) the CD3-zeta does not associate with TCR alpha-CD3 gamma delta epsilon or TCR beta-CD3 gamma delta epsilon complexes; 4) CD3-zeta associate with the pentameric form of the TCR/CD3 complex in the endoplasmic reticulum to form the heptameric complex (TCR alpha beta-CD3 gamma delta epsilon----TCR alpha beta-CD3 gamma delta epsilon 2); and 5) CD3-zeta is required for the export of the TCR/CD3 complex from the endoplasmic reticulum to the Golgi apparatus for subsequent processing.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1989

Fractionation of T cell subsets on Ig anti-Ig columns: isolation of helper T cells from nonresponder mice, demonstration of antigen-specific T suppressor cells, and selection of CD-3 negative variants of Jurkat T cells.

In the present experiments we have explored the possibilities of a modified immunoadsorbent technique to select for (1) mutagenized T cell receptor (Tcr) negative variants of Jurkat T lymphoma cells and (2) purified CD-4+ or CD-8+ T lymphocytes. The basic principle was to make large numbers of immunoglobulin (Ig) negative T cells Ig+ by T cell subset-specific monoclonal antibodies (mAb), and to select such cells on Ig anti-Ig columns. Our results demonstrated that Thy-1+, Fc receptor positive, antigen-specific T cells regulate the immune response in mice nonresponders to pork insulin, and the "autologous" mixed lymphocyte reaction. In addition, the immunoadsorbent method very efficiently selects Tcr/CD-3- variants from mutagenized Jurkat cell populations incubated with anti-CD3 mAb. The described method is easy and quick and can fractionate large numbers of cells; it is the "poor-man's cell sorter." The most important finding is the demonstration of antigen-specific Thy-1+, CD-8+, and Fc receptor+ T suppressor cell that apparently react with antigen in a non-major histocompatibility complex-restricted manner.

Animals↗
PubMed1989

Failure to synthesize the human T-cell CD3-zeta chain and its consequence for the T-cell receptor-CD3 complex expression.

The T-cell antigen receptor is composed of two variable chains (alpha and beta, termed TcR) which confer ligand specificity, and four constant chains (gamma, delta, epsilon, and zeta, collectively termed CD3) whose functions are not fully understood. To explore the role of the individual CD3 components, the human T-cell tumour line Jurkat was chemically mutagenized followed by negative selection with F101.01 (a monoclonal antibody against the TcR-CD3 complex), and cloning. Growing clones were analysed for TcR-CD3 expression by immunofluorescence. One clone, J79, was found to express greatly diminished levels of TcR-CD3. This clone produced all the TcR-CD3 components except the CD3-zeta, as demonstrated by metabolic labelling and immunoprecipitation followed by one- and two-dimensional sodium dodecyl sulphate-polyacrylamide gel electrophoresis. These data indicate that the CD3-zeta determines the normal intracellular fate of the TcR-CD3 complex, and that the CD3-zeta is necessary for the intracellular transport and expression at the cell surface of the TcR-CD3 complex.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1989

Effect of rioprostil, an oral prostaglandin E1 analogue, on lower oesophageal sphincter pressure and on the motility of the distal oesophagus in healthy volunteers.

The influence of rioprostil on the resting pressure of the lower oesophageal sphincter (LESP) and on the bolus-stimulated contraction wave amplitude of primary peristalsis is investigated in 9 healthy male volunteers receiving placebo or 300 micrograms and 600 micrograms of rioprostil orally in a randomized, double-blind, threefold crossover study. Manometry is performed using the low-compliance pneumohydraulic infusion system. The results show that: rioprostil, 600 micrograms, slightly increases LESP (ns) and contraction wave amplitudes, measured 10 cm above the lower oesophageal sphincter (LES) (p = 0.0039); rioprostil in both doses does not change the contraction wave amplitudes of the distal oesophagus, 5 cm above the LES; the duration of the peristaltic contractions is not altered. We conclude that rioprostil, in doses which effectively inhibit gastric acid and pepsin secretion and heal peptic ulcers, has no inhibitory effects on oesophageal motility. Studies are warranted, therefore, to establish the efficacy of rioprostil in the treatment of reflux oesophagitis.

Adult↗
PubMed1988

Increase in plasma atrial natriuretic factor and right atrial area during endogenous and exogenous volume loading in healthy volunteers: effect on plasma renin activity, aldosterone and antidiuretic hormone.

The mechanisms of atrial natriuretic factor (ANF) release and the effects of ANF on plasma renin activity (PRA), plasma aldosterone and plasma antidiuretic hormone were investigated in two groups of normal subjects. One group was studied before and after endogenous volume loading produced by 30 min of head-down tilt. The other group was studied before and after an exogenous volume load in the form of 1 litre of isotonic saline infused over 30 min. Measurements made included right atrial area by two-dimensional echocardiography, PRA, plasma aldosterone, plasma antidiuretic hormone and plasma levels of ANF. There was a significant correlation between the increase in atrial area and plasma ANF concentrations after endogenous and exogenous volume loading. Levels of PRA and plasma aldosterone were suppressed significantly after exogenous volume loading but not after endogenous volume loading. The concentration of plasma antidiuretic hormone was not affected by either procedure. Short-term changes in right atrial pressure appear to regulate the plasma levels of ANF in normal people.

Aldosterone↗
PubMed1987

Effects of quinidine, verapamil and nifedipine on the pharmacokinetics and pharmacodynamics of digitoxin during steady state conditions.

In a prospective clinical study the effects of quinidine (Q), verapamil (V) and nifedipine (N) on the pharmacokinetics and pharmacodynamics of digitoxin (DGT) were studied in 28 subjects achieving steady state conditions. DGT plasma concentration increased continuously up to a new steady state level after 3 to 4 weeks of Q or V coadministration. Mean steady state DGT concentrations were 45% and 27%, respectively, higher than during treatment with DGT alone. Renal DGT clearance and endogeneous creatine clearance were not significantly affected by Q or V coadministration, while nonrenal DGT clearance was significantly reduced by an average of 40.5% and 29%, respectively. Similarly, elimination half-life determined in 4 volunteers once in presence and once in absence of Q was prolonged by 34.5%. The increased plasma DGT concentration seems to be pharmacodynamically active as demonstrated by electrographic measures and systolic time intervals. While the antagonistic effects of Q and V on QT-duration and myocardial performance with increasing DGT plasma levels nearly disappeared, the synergistic effects of DGT and Q or V were continuously intensified. In contrast, N had no clinically significant effect on pharmacokinetics and pharmacodynamics of DGT. From these investigations it could be concluded that Q and V had a clinically significant effect on pharmacokinetics and pharmacodynamics of DGT but to a lesser extent and, at least in part, by different mechanism than shown for digoxin.

Digitoxin↗
PubMed1986

Effects of quinidine on pharmacokinetics and pharmacodynamics of digitoxin achieving steady-state conditions.

Quinidine has been reported to increase digoxin plasma concentrations, which increases the risk of digoxin overdose. The effect of quinidine on digitoxin pharmacokinetics is still controversial because most studies were not performed with subjects achieving definite steady-state conditions. To determine whether quinidine affects digitoxin kinetics and cardiac efficacy, we measured glycoside plasma concentrations and renal excretion as well as ECG parameters and systolic time intervals before and during quinidine dosing in eight healthy subjects at steady state. Mean (+/- SD) digitoxin plasma concentrations and renal excretion increased from 13.6 +/- 2.2 ng/ml and 16.1 +/- 5.8 micrograms/24 hours before dosing to 19.7 +/- 3.1 ng/ml and 23.4 +/- 4.9 micrograms/24 hours, respectively, during quinidine dosing for 32 days. While renal digitoxin clearance was not noticeably changed by quinidine, total digitoxin clearance and extrarenal digitoxin clearance decreased by an average of 32% and 40.5%, respectively. The elimination t1/2 was prolonged from 150.3 +/- 20.6 to 202.6 +/- 37.5 hours. The increased digitoxin plasma level is pharmacodynamically active. We conclude that there is a clinically important interaction between digitoxin and quinidine, but it is to a lesser extent and is caused by different mechanism, in part, than the interaction between digoxin and quinidine.

Administration, Oral↗
PubMed1986

Prevention of the acetylsalicylic acid-induced changes of the gastric potential difference by the new synthetic prostaglandin E1 analogue rioprostil.

The protective effect of 50 and 100 micrograms of the synthetic prostaglandin E1 analogue rioprostil (2-decarboxy-2-hydroxymethyl-15-deoxy-16RS-hydroxy-16-methyl PGE1) against the 0.5 and 1 g acetylsalicylic acid (ASA)-induced changes of gastric potential difference (PD) was compared to that of placebo in a double-blind cross-over study in 8 volunteers. Rioprostil 50 and 100 micrograms reduced significantly (p = 0.45) the intensity (area under baseline) of the 0.5 g ASA-induced PD changes. Both doses reduced highly significantly (p = 0.003) the time taken for PD to return to baseline value (15.1 min with 50 micrograms and 17.2 min with 100 micrograms rioprostil vs 43.5 min with placebo). Both doses of rioprostil also reduced significantly (p = 0.04) the PD maximal drop induced by 1 g ASA and reduced highly significantly (p = 0.006) the time taken for PD to return to baseline value (18.9 min with 50 micrograms and 16.8 min with 100 micrograms rioprostil vs 64.6 min with placebo). This study shows that rioprostil protects the stomach against the ASA-induced alterations of the gastric mucosa even when it is given at the same time as ASA and in doses which have only a small antisecretory effect.

Adult↗
PubMed1985

[Pharmacokinetic and cardiac efficacy of beta-acetyldigoxin and digitoxin in combination therapy with diltiazem].

The effect of diltiazem (D) on the pharmacokinetics and pharmacodynamics of beta-acetyldigoxin (AD; n = 12) and digitoxin (DGT; n = 10) was studied in 22 patients with cardiac insufficiency stages II-III by the New York Heart Association. Glycoside plasma concentration and renal excretion as well as electrocardiogram [heart rate, atrioventricular transconduction time (PQ), duration of electrical systole corrected for heart rate (QTc), mean amplitude of T-waves in leads V2 to V6 (TV2-6)] and systole time intervals [total electromechanical systole index (QS21), left ventricular ejection time index (LVETI), pre-ejection period index (PEPI), PEP/LVET ratio] were recorded repeatedly before and during co-administration of 180 mg/day D. In eight patients digoxin plasma levels increased continuously during additional D administration. After reaching a new steady state at 0.93 +/- 0.35 ng/ml digoxin concentrations were at an average 43% higher than before D administration (0.65 +/- 0.27 ng/ml) with a simultaneous increase in renal glycoside excretion. The other four patients showed neither changes in digoxin concentrations in plasma nor in renal glycoside excretion. Only half the patients treated with DGT and D revealed an increase in DGT plasma levels of 21.4%. Daily renal glycoside excretion was not altered by D administration. In accordance to the increasing AD plasma concentration, PQ-interval was prolonged and T-wave flattening was intensified, whereas the systolic time intervals after concomitant treatment of AD and D did not differ from those after AD alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyldigoxins↗
PubMed1985

Effects of verapamil on pharmacokinetics and pharmacodynamics of digitoxin in patients.

Investigations by various teams have shown that combined treatment with verapamil and digoxin may result in a marked increase in digoxin plasma concentrations, necessitating a reduction in the dose of digoxin. This is mainly due to an impairment of the renal digoxin excretion. Unlike digoxin, the excretion of digitoxin is independent of renal function. A prospective clinical study was therefore planned to investigate the influence of a daily dose of 240 mg of verapamil on pharmacokinetics and the cardiac effect of digitoxin after a single dose (n = 3) and under steady-state conditions (n = 10). While pretreatment with verapamil did not alter pharmacokinetics of digitoxin in the single-dose study, there was a slight rise of digitoxin plasma concentrations (an average of 35% in 8 out of 10 patients) following administration of verapamil for a period of 4 to 6 weeks. Renal excretion of digitoxin, however, was not changed significantly. Simultaneous with a rise of digitoxin plasma concentrations and until a new steady state was reached, PQ interval was prolonged and T wave flattening intensified. On the other hand, the antagonistic effect on contractility which was initially observed after verapamil administration was diminished. Based on these observations, it can be concluded that the risk of digitalis overdose after combined treatment with verapamil and digitoxin may be less pronounced than after digoxin, and that this glycoside can prove a valuable alternative.

Aged↗
PubMed1985

Effects of verapamil, diltiazem, and nifedipine on plasma levels and renal excretion of digitoxin.

To determine whether verapamil, diltiazem, or nifedipine affect digitoxin kinetics, glycoside plasma concentrations and renal excretion were measured before and during steady-state dosing in 30 patients with cardiac insufficiency. The mean (+/- SD) digitoxin plasma concentration was 14.27 +/- 3.66 ng/ml before and 18.15 +/- 5.33 ng/ml during verapamil dosing in 10 patients over a period of 4 to 6 weeks. Renal digitoxin clearance was not influenced by verapamil, but total body clearance and extrarenal clearance of digitoxin were reduced by 27% and 29%, respectively. Diltiazem resulted in a 6% to 31% (mean = 21%) increase in plasma digitoxin concentrations in five of 10 patients because of reduced extrarenal clearance of digitoxin. In contrast to verapamil, the concomitant dosing of nifedipine over 4 to 6 weeks did not alter digitoxin plasma levels or daily renal excretion. Based on these observations, the risk of digitalis intoxication after combined dosing with verapamil and digitoxin is much less pronounced than that after digoxin, and thus this glycoside is a valuable alternative.

Aged↗
PubMed1985

Effects of nifedipine and diltiazem on plasma levels and renal excretion of beta-acetyldigoxin.

To determine whether nifedipine or diltiazem affect digoxin kinetics, glycoside plasma concentrations and renal excretion were measured before and during dosing in 23 patients with cardiac insufficiency achieving steady-state conditions. Mean (+/- SD) digoxin plasma concentration was 0.64 +/- 0.22 before and 0.61 +/- 0.21 ng/ml during nifedipine dosing in 11 subjects over a period of 10 to 14 days. Renal digoxin clearance was not influenced by nifedipine, whereas total body clearance and extrarenal clearance of digoxin increased slightly. In contrast, diltiazem resulted in a 24% to 70% (means = 46%) increase in plasma digoxin concentrations in eight of 12 subjects. Renal digoxin clearance was not influenced by diltiazem, whereas total body clearance and extrarenal clearance of digoxin were reduced 28% and 44% in five of the eight subjects in whom renal digoxin excretion was measured. From these data it was concluded that nifedipine has no significant effects on digoxin kinetics, but that digoxin plasma concentrations should be controlled in subjects receiving digoxin with diltiazem until new steady-state digoxin concentrations are established, and that the digoxin dose be reduced if there is evidence of toxicity.

Acetyldigoxins↗
PubMed1984

[Pharmacokinetics and cardiac effect of beta-acetyldigoxin and digitoxin in combination therapy with nifedipine].

The effect of nifedipine (N) on the pharmacokinetics and pharmacodynamics of beta-acetyldigoxin (AD; n = 11) and digitoxin (DGT; n = 10) was studied in 21 patients with cardiac insufficiency stage II-III NYHA. Glycoside plasma concentration and renal excretion as well as electrocardiogram heart rate, atrioventricular transconduction time (PQ), duration of electrical systole corrected for heart rate (QTc), mean amplitude of T waves in leads V2 to V6 (TV2-6) and systolic time intervals total electromechanical systole index (QS21), left ventricular ejection time index (LVETI), pre-ejection period index (PEPI), PEP/LVET-ratio were recorded repeatedly before and during co-administrations of 40-60 mg/day N. Plasma AD concentrations were 0.64 +/- 0.22 ng/ml (mean +/- SD) before and 0.61 +/- 0.21 ng/ml during co-administration of N over 10-14 days, plasma DGT concentrations 13.9 +/- 4.1 ng/ml before and 13.7 +/- 4.5 ng/ml during co-administration of N over 4-6 weeks. Daily glycoside excretion was not affected by treatment with N. Heart rate and PQ-interval were not significantly changed during co-administration of N whereas T-wave flattening was intensified and QT-duration was lengthened. Concomitant treatment of AD and N led to an increase of PEPI and PEP/LVET compared to AD alone in ten patients whereas the systolic time intervals after concomitant treatment of DGT and N in most patients did not differ from those after DGT alone. From our findings we conclude that N had no clinically significant effect on pharmacokinetics and pharmacodynamics of AD or DGT.

Acetyldigitoxins↗
PubMed1984

[Digitoxin blood picture and renal elimination in long-term therapy with aluminum-magnesium hydroxide gel].

In ten patients in heart failure for which they were on long-term administration of digitoxin, the influence of aluminium-magnesium hydroxide gel (Maaloxan) on steady-state digitoxin plasma concentration and renal glycoside excretion was studied. Compared with control values before antacid medication (13.6 +/- 4.4 ng/ml), the administration of 20 ml aluminium-magnesium hydroxide gel three or four times daily for several weeks caused no significant change in digitoxin plasma levels (15.1 +/- 4.9 ng/ml). Daily renal glycoside excretion, as a further measure of bioavailability of digitoxin, was also unchanged by the antacid. Therapeutic plasma concentrations of digitoxin are not influenced by antacids which contain aluminium-magnesium hydroxide, at least not if the antacid is taken 1-2 hours after the digitoxin dose.

Aged↗