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M Kühl

Publications and source records attributed to M Kühl.

At least 73 records · Page 4Linked to original sources
PubMed1992

Clinical pharmacokinetics of fluorouracil and folinic acid.

This article deals with the pharmacokinetics of fluorouracil (5-FU) and folinic acid (CHO-THF). 5-FU kinetics are characterized by short serum half-life times of 4.5 to 13 minutes. The high body clearance is mainly caused by a rapid catabolism of 5-FU to dihydrofluorouracil (FUH2), alpha-fluoro-ureidopropionic acid (FUPA), and to alpha-fluoro-beta-alanine (FBAL). Due to an incomplete hepatic extraction, systemic 5-FU levels greater than 5 microM are determined even during hepatic artery infusion. 5-FU measurements during isolated liver perfusion revealed different phases of 5-FU clearance. With higher levels (greater than 430 microM) clearance behaves in accordance with zero-order kinetics, with lower concentrations (less than 150 microM) 5-FU is cleared according to first-order kinetics. The impact of 5-FU kinetics on the treatment with 5-FU is discussed. After administration of the commercially available d,l-folinic acid (d,l-CHO-THF), the biologically inactive d-form is cleared very slowly with a median half-life of 438 +/- 63 minutes. l-CHO has short elimination half-lives of 56.5 +/- 10.5 minutes. The high body clearance of 222 +/- 27 mL/min is partially caused by metabolism to l-methyltetrahydrofolic acid (l-CH3-THF). With bolus injection of 200 mg/m2 or short-term infusion of 300 mg d,l-CHO-THF, serum levels greater than 1 microM are attained for approximately 2 to 3 hours. Total reduced l-folates (l-CHO-THF plus l-CH3-THF) are above 5 microM for at least 3 hours. Continuous infusion of CHO-THF affords steady-state levels in the micromolar range for prolonged time periods. After application of the pure l-folinic acid, mean elimination half-live and area under the curve were in the same range as after administration of the d,l-CHO-THF. Higher doses of oral d,l-folinic acid are always absorbed incompletely. Since the amount of l-CHO-THF absorbed is converted rapidly to CH3-THF, serum levels of l-CHO-THF remain always below 0.1 microM. CH3-THF steady-state levels in the micromolar range, however, are attained with different oral d,l-CHO-THF protocols.

Administration, Oral↗
PubMed1990

Pharmacokinetics of reduced folates after short-term infusion of d, 1-folinic acid.

After the use of d,1-folinic acid (d,1-CHO-THF), pharmacokinetic measurements should take into account 1-CHO-THF and its metabolite 1-methyltetrahydrofolic acid (1-CH3-THF) as well as d-CHO-THF. For this purpose, we developed a simple and rapid assay by combining reversed-phase HPLC to determine total levels of d,1-CHO-THF and CH3-THF and chiral HPLC to separate the biologically active 1-CHO-THF from the inactive d-CHO-THF. We investigated the pharmacokinetics after short-term infusion of 300 mg d,1-CHO-THF in ten healthy volunteers. With a mean of 56.5 min, 1-CHO-THF exhibits a rapid body clearance of 222 ml/min, about 60% of which is caused by metabolism to CH3-THF and 40%, by renal excretion. CH3-THF has a terminal half-life of 208 min and a total body clearance of 88.9 ml/min, which is essentially the same as the renal clearance. Due to the lower clearance of CH3-THF, its AUC (2,132 microM x min) exceeds that of 1-CHO-THF (1445 microM x min) by approximately 50%. In contrast to that of the reduced 1-folates, the total body and renal clearance of d-CHO-THF is very low, with values of 13.2 and 12.9 ml/min, respectively. This results in a very high AUC of 24, 269 microM x min, which is higher by factors of 17 and 11 than those of 1-CHO-THF and CH3-THF, respectively. The implications of the distinct kinetics of the reduced 1-folates and d-CHO-THF for the efficacy of folinic acid/5-fluorouracil therapy and adequate protocols for the treatment of advanced colorectal cancer are discussed.

Adult↗
PubMed1988

Role of aspartate 27 in the binding of methotrexate to dihydrofolate reductase from Escherichia coli.

Dihydrofolate reductase from wild-type Escherichia coli (WT-ECDHFR) and from a mutant enzyme in which aspartate 27 is replaced by asparagine have been compared with respect to the binding of the inhibitor methotrexate (MTX). Although the Asp27----Asn substitution causes only small changes in the association rate constants (kon) for the formation of binary and ternary (with NADPH) complexes, the dissociation rate constants for these complexes (koff) are increased for the mutant enzyme by factors of about 5- and 100-fold, respectively, at pH 7.65. In binding experiments, the initial MTX binary and ternary complexes of the mutant enzyme were found to undergo relatively rapid isomerization (kobs approximately 17 and 145 s-1, respectively). Although such rapid isomerization of complexes of WT-ECDHFR could not be detected in binding experiments, evidence of a slow isomerization (k = 4 x 10(-3) s-1) of the ternary WT-ECDHFR.MTX.NADPH complex was obtained from progress of inhibition experiments. This slow isomerization increases binding of MTX to WT-ECDHFR only 2.4-fold (much less than previously estimated). From presently available data, we could not determine the contribution of the rapid isomerization of complexes to the binding of MTX to the mutant enzyme. The Asp27----Asn substitution increases the overall dissociation constant (KD) 9-fold for the binary complex and 85-fold for the ternary complex. When it is also taken into account that a proton ultimately derived from the solvent must be added to MTX bound to the WT enzyme, but not to MTX bound to the mutant enzyme, these increases in KD for the mutant enzyme correspond to decreases in binding energy for MTX of 3.9 and 5.2 kcal/mol at pH 7.65 for the binary and ternary complexes, respectively.

Asparagine↗
PubMed1988

Computer-assisted pacemaker management systems: three years of clinical experience.

The implantation of large numbers of cardiac pacemakers and the increasing sophistication in engineering techniques has resulted in the demand for computer-assisted pacemaker management systems to remain on top of the available programmable features of the pacers as well as being able to access the follow-up data of pacemaker patients. A pacemaker patient management systems is introduced (PA-TIENTLOG) that has been used in the clinical environment for a number of years. The menu-guided program is easy to handle and features a patient card for administration data, an implantation card for the technical data of the pacer, and a follow-up card where a large number of follow-ups can be stored side by side which are easily graphically displayable. An extensive statistical program, letter functions, automatic back-up and on-line communication with external equipment through an RS 232C interphase and a parallel adapter are available. The data base in Frankfurt holds 8,000 patients, 10,000 interventions and more than 30,000 follow-ups, the existing data base needs 20 M bytes storage space. Up to 96 different pacer types with their specific features can be introduced into the system. Software and hardware design complies with the recommendation of the NASPE Computer Committee.

Computers↗
PubMed1983

[Hairy cell leukemia. 2d report on the clinical course, morphology and therapy of 27 patients].

The course of hairy cell leukaemia was observed in 27 patients for a maximum of 97 months. Splenectomy had been performed in 17 patients and improved the haematological situation impressively in most cases. Amongst patients with splenectomy ten are alive with 8 to 88 months postoperatively. In five of them disease manifesting as isolated leucocytosis, deterioration of the overall haematological situation or as intraabdominal lymphomatous growth could be treated successfully. Treatment consisted of leucapheresis, low-dose long-term therapy with chlorambucil, administration of doxorubicin (adriamycin) or a combination of cytostatics containing doxorubicin as well as abdominal localized or overall irradiation.

Adult↗
PubMed1983

[Penetration of chromate ions in damaged and undamaged skin of sensitized and nonsensitized individuals occupationally exposed to chromates].

The importance of oversensitivity to chromate within the framework of occupational dermatoses is sufficiently well known. Questions still remained unanswered as to which substances and solutions in which form and quantity sensitivity to chromate occurs. Further, it is unclear why one worker reacts allergically and another remains unaffected carrying out the same work. In spite of all attempts it is as a rule still impossible to predict who will be affected. By investigating the penetration of chromate ions, we wanted to draw attention to possible dangers those beginning work are exposed to. We are aware that a complex series of questions exists but that only a small part can be approached at once. It appeared appropriate to determine whether the level of penetration of the metal ions differs between individuals, in particular whether the rate is higher in sensitive than in non-sensitive people. To handle this question a method had to be found to determine metal ions with and without exposure in the skin.

Chromates↗
PubMed1982

[The dermatologist's report or/and medical report on well-founded suspicions of occupational disease].

The "Hautarztverfahren" (method of registering occupationally induced dermatoses at an early stage) can be a great help before a real occupational disease occurs. The limits of practising this desirable procedure are relatively small and are to be shown. Section 5 BeKVO (law of occupational diseases) is important for the medical proceedings in case of a well-founded suspicion of an occupational disease no. 5101. The consequences of the started procedures will be shown using examples. Figures will document that 50% of well-founded cases of suspicion concern occupationally induced dermatoses. Of these about 8% receive compensation. For those remaining, measures are normally carried out, according to Section 3.

Dermatitis, Contact↗
PubMed1979

[Cold-induced skin damage].

Two cases of cold-induced skin-damage are reported. In one case cold-induced panniculitis (Adiponecrosis e frigore) in a small child was found. In the other case a Dermo-Hypodermitis in an elderly lady was found, where cold was possibly just one, even if certainly the most important factor of realisation for the disease. In both cases neither the parents, respectively the patient, thought of cold-inducement of the disease, neither were anamnestic circumstances sufficiently explorated by the prior treating doctors, so that it seems justified to demonstrate such events in relation to this subject.

Aged↗