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Biomedical subjects

N Rietbrock

Publications and source records attributed to N Rietbrock.

At least 91 records · Page 5Linked to original sources
PubMed1985

Influence of palmitate and oleate on the binding of warfarin to human serum albumin: stopped-flow studies.

The rate of transition from an unstable to a stable complex and the dependence of this on the number of fatty acid ligands present was determined for the binding of warfarin on human serum albumin. When oleate or palmitate was added in amounts up to 2:1 excess to human serum albumin solutions the measured rate constant for the transition (k2) was increased in comparison with fatty acid free albumin. When the fatty acid concentration is further increased, k2 decreases. When the fatty acid level is 2 to 3 mol per mol albumin, the affinity constant (KA) is higher than for fatty acid free solutions. With higher ratios the value for KA is reduced. According to the observed changes in kinetic parameters, the binding of warfarin is apparently affected allosterically. A reduced plasma protein binding of coumarins should be expected when fatty acid levels are raised over a prolonged period.

Humans↗
PubMed1984

Beta-blocker induced changes in the cholesterol: high-density lipoprotein cholesterol ratio and risk of coronary heart disease.

The lowering of blood pressure with beta-blocking drugs has had a low impact on coronary heart disease (CHD) mortality and the question has been raised whether adverse changes in plasma lipoproteins offset the benefits of blood pressure reduction. Comparison of plasma lipoprotein concentrations in hypertensive patients treated with commonly used beta-blockers with lipoprotein concentrations in patients with coronary heart disease shows that these drugs cause clinically important shifts in the cholesterol ratio [total cholesterol (TC): high-density lipoprotein cholesterol (HDLC)] and reductions in the atheroprotective lipoprotein HDLC. The magnitude of these changes is sufficient to increase the risk of heart attack two- to four-fold depending on the initial cholesterol ratio and the duration of treatment. Only beta-blockers with marked intrinsic sympathomimetic agonist activity (pindolol) or combined alpha-beta-blocking properties (Labetalol) appear free of adverse effects on plasma lipoproteins and triglycerides. Chronic treatment with other beta-blockers should be accompanied by cholesterol and HDLC measurements at the beginning of therapy. Plasma lipoprotein measurements at 3-6 month intervals seem mandatory in patients with cholesterol values greater than 6 mmol/1 (230 mg/dl) and (TC):HDLC ratios above 5 at the start of treatment. The risk of a coronary event must be regarded as unacceptable when the cholesterol ratio exceeds a critical value of about 6. Further controlled studies are needed to evaluate the effects of beta-blockers in hypertension when administered for periods of up to a year or more. More information is required on the behaviour of lipoprotein subspecies and apoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1984

[Elucidation and chemical identification of a heart strength and heart rate-increasing substance from human kidney extracts].

Bioassays involving the measurement of cardioactivity have been used in the past to determine glycoside concentration in post-mortem specimens following glycoside poisoning. This paper describes the presence of a cardioactive principle in alcoholic extracts of kidney that could interfere with these bioassays and which has been identified as tyramine. For the analysis of tyramine a combination of purification methods was employed, including cation exchange with Sephadex CM C-25, gel filtration and HPLC. Detection was achieved using mass spectrometry after careful cation-exchange treatment. The fragmentation pattern with and without prior formation of the TFA-derivative corresponded to that tyramine. IR and UV spectra also indicated the presence of tyramine. Under suitable experimental conditions, positive inotropic and positive chronotropic effects on the right guinea-pig atrium and positive inotropic effect on the left guinea-pig atrium produced by the kidney extract can be shown to differ from those cardiac glycosides. These investigations bring into question earlier court decisions made in legal processes which have been based upon the results of bioassays for the evaluation of cardiac glycoside toxicity.

Animals↗
PubMed1984

Verapamil disposition and effect on PQ-intervals after buccal, oral and intravenous administration.

The absorption, pharmacokinetics and effect on PQ-intervals of verapamil (Isoptin) administered as buccal tablet (20 mg), oral capsule (80-120 mg) and as an intravenous injection (5 mg) have been determined in 7 healthy subjects. Hysteresis plots of the percentage change in PQ-interval and serum concentration indicate that the efficacy of verapamil after buccal and intravenous application, as in earlier findings with sublingual verapamil tablets, was higher than after oral application. Thus the serum concentration-response curve after oral application is displaced towards the right reflecting lower potency. This phenomenon has been attributed by other workers to a stereospecific metabolism of the more active L-isomer during first pass through the liver, but competition at the receptor with metabolites cannot yet be ruled out. The rate of absorption, T1/2(alpha), terminal elimination half-life T1/2(gamma), and tmax of the buccal tablet was not significantly different from the oral capsule. The absolute bioavailability of the buccal preparation (37%) was slightly greater than the oral capsule (33%) and both had higher bioavailability than observed in earlier studies on verapamil dragees (10-20%). Thus, although the buccal tablet was alkalinised and had a rapid disintegration in vitro, characteristics thought to increase buccal uptake, the bioavailability is still much less then 100%.

Absorption↗
PubMed1984

[Gitoformate and digitoxin as alternatives to kidney-dependent glycosides in the therapy of cardiac insufficiency].

Kidney independent glycosides offer a high measure of therapeutic safety in comparison with kidney dependent glycosides. The intoxication rate lies between 4 and 6%. The pharmacokinetic properties of pentaformylgitoxin (INN: gitoformate) are comparable with those for digitoxin. The active glycoside 16-formylgitoxin (INN: gitaloxin) is formed by rapid deformylation of the formyl residue on the sugar chain. The maintenance dose of 0.06 mg daily, based on the half-life, produces therapeutic concentrations in the range 6-30 ng/ml. The required loading dose, as for digitoxin, amounts to 10 times the maintenance dose.

Cardiac Glycosides↗
PubMed1983

On the pharmacokinetics of pengitoxin and its cardioactive derivative 16-acetyl-gitoxin.

The pharmacokinetics of pengitoxin has been studied in 28 healthy subjects after intravenous and oral administration. The mean plasma concentration 24 h after 0.5 mg i.v. was 5.2 ng X ml-1. Following an open two-compartment model a mean elimination half-life of 60.5 h (24.9 to 103.5 h) and a mean volume of distribution (Vdarea) of 66.91 (31.8 to 109.61) were calculated. Absorption calculated by comparison of the AUC0-infinity-values amounted to 99%. Within 4 days, 16.7% (11.7 to 21.1%) or 27.8% (18.4 to 33.7%) (0.5 mg i.v. or 1.2 mg p.o.) was excreted in urine. After pengitoxin 0.5 mg i.v. total body clearance and renal clearance were 13.3 ml X min-1 (7.0 to 18.6 ml X min-1) and 3.0 ml X min-1 (1.9 to 3.9 ml X min-1) respectively. The elimination half-life of pengitoxin is longer than that of digoxin and distinctly shorter than that of digitoxin, whilst its distribution volume and clearance are closer to those of digitoxin than of digoxin.

Acetyldigoxins↗
PubMed1983

[Release, absorption and elimination of theophylline from fast and slowly released oral formulations].

Each 2 tablets of four tablet formulations with 150 mg theophylline were administered to 6 and 5 volunteers, respectively, as single oral dose. 8 volunteers received 256 mg theophylline as a solution and as a sustained released formulation, as well as 176 mg theophylline as short intravenous bolus infusion. The elimination was independent of the examined formulations, but differences occurred between the experiments with the different groups of volunteers. The invasion parameters (t1/2i) of the four fast released tablet formulations corresponded to the values (t1/2a) of the oral theophylline solution. Furthermore, no difference existed concerning the mean times (Tsys). The mean time (theophylline) for the body model, Tvss, is 9.9 h; the mean time, which is attributed to the absorption process (Tabs) is 0.7 h; the mean in vivo dissolution time (Tdiss-vivo) for the sustained release formulation is 6.3 h. The mean time after oral administration of the theophylline solution (Tbiol) is 10.6 h. General conditions for a comparison between the in vitro and the in vivo release data are reported.

Administration, Oral↗
PubMed1982

Stopped-flow studies on drug-protein binding. Analog-computer analysis of the pH-dependent binding kinetics of warfarin and human serum albumin.

Binding curves obtained by the stopped-flow method for the association of warfarin and human serum albumin (HSA) at pH 6.0 and 9.0 have been analysed with digital- and analog computers. The first association product (WHSA') at pH 6-9 does not contribute to the observed fluorescence enhancement during warfarin-HSA complex formation. A similar consecutive relaxation process leads to a more stable warfarin-HSA complex, with HSA in the neutral (N)-form (pH 6) and base (B)-form (pH 9). This rearrangement can be measured by stopped-flow (k 2 = 31 s-1 at pH 6; K'2 = 63 s-1 at pH 9). At pH 6 a further concentration dependent relaxation process has been observed indicating that the complex of warfarin with the N-form of HSA gets partially converted into its B-form with a half-time for this N leads to B transition in the range of 0.2-0.4 s. A drug such as warfarin can act as effector molecule for conformational changes of the HSA tertiary and quaternary structure during the formation of a high affinity complex.

Computers, Analog↗
PubMed1982

Dihydroergotoxine kinetics in healthy men after intravenous and oral administration.

The kinetics of intravenous and oral dihydroergotoxine mesylate determined in eight healthy male subjects with a radioimmunoassay method incorporating a plasma extraction step to obtain maximal sensitivity and specificity. The intravenous plasma concentration-time curve showed an initial rapid decline (half-life[t1/2] = 3.5 min) and could be fitted to a three-compartment model. The high systemic clearance (20.2 to 28.8 ml x min-1 x kg-1) and large distribution volume, (9.9 to 20.41 x kg-1) were associated with a terminal t1/2 of 9.5 to 18.4 hr. The oral absorption was rapid. (t1/2 = 14.8 min). Absolute bioavailability was 5.3% to 12.4%. The terminal t1/2 and bioavailability were considerably lower than earlier estimates and this can be attributed to the use in these investigations of a more sensitive and specific dihydroergotoxine assay method.

Administration, Oral↗
PubMed1982

Cytostatic drugs are without significant effect on digitoxin plasma level and renal excretion.

In three patients with malignant lymphoma who received 0.5 mg digitoxin before and 24 hr after combination therapy with cyclophosphamide, Oncovin, procarbazine, and prednisone (COPP) or cyclophosphamide, Oncovin, and prednisone (COP), plasma glycoside concentrations and renal excretion were measured 0 to 168 hr after digitoxin and the areas under plasma concentration-time curves *(AUCs) were calculated. In 10 patients receiving 0.1 mg digitoxin, daily plasma glycoside concentration and daily renal excretion were measured before and after COPP, COP, or cyclophosphamide, Oncovin, cytosine-arabinoside, and prednisone (COAP) treatment schemes. In contrast to previous reports on digoxin, cytostatic drug therapy does not lead to a reduction in steady-state digitoxin plasma levels and daily renal excretion. During cytostatic therapy attainment of peak digitoxin level was delayed after a single dose, showing that the rate of digitoxin absorption was reduced, but that the AUCs and renal excretion of digitoxin (parameters of the extent of digitoxin absorption) were not diminished. Since the absorption rate is not clinically relevant in patients on long-term glycoside therapy, our results indicate that digitoxin is preferable to digoxin in such patients.

Adolescent↗