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H Heidemann

Publications and source records attributed to H Heidemann.

At least 19 recordsLinked to original sources
PubMed1996

Antipyrine as a probe for human oxidative drug metabolism: identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation.

BACKGROUND AND OBJECTIVE: Antipyrine has been widely used as a probe drug for human oxidative drug metabolism. To evaluate the role of antipyrine as a model drug, we have identified the cytochrome P450 enzymes involved in 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine formation. METHODS: We used the following methods for this study: (1) determination of enzyme kinetics for antipyrine metabolite formation in human liver microsomes, (2) inhibition studies with antibodies and inhibitors, and (3) formation of metabolites by stable expressed human P450 enzymes. RESULTS: Antipyrine biotransformation could be described by Michaelis-Menten kinetics: norantipyrine: maximum rate of metabolite formation (Vmax), 0.91 +/- 0.04 nmol . mg-1 . min-1; Michaelis-Menten constant (Km), 19.0 +/- 0.8 mmol/L; 4-hydroxyantipyrine: Vmax, 1.54 +/- 0.08 nmol . mg-1 . min-1;Km,39.6 +/- 2.5 mmol/L. Antibodies against CYP3A4 inhibited the formation of 4-hydroxyantipyrine by 25% to 65%. LKM-2 antibodies (anti-CYP2C) caused a 75% to 100% inhibition of norantipyrine and a 58% to 80% inhibition of 3-hydroxymethylantipyrine formation. Sulfaphenazole inhibited the formation of 3-hydroxymethylantipyrine and norantipyrine by about 50%. Furafylline and fluvoxamine inhibited norantipyrine, 4-hydroxyantipyrine, and 3-hydroxymethylantipyrine formation by about 30%, 30%, and 50%, respectively. Ketoconazole reduced formation of norantipyrine, 3-hydroxymethylantipyrine, and 4-hydroxyantipyrine by up to 80%. Formation in stable expressed enzymes indicated involvement of CYP1A2, CYP2B6, CYP2C, and CYP3A4 in metabolite formation. CONCLUSION: Antipyrine metabolites are formed by at least six hepatic cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP3A4). 4-Hydroxylation is mainly catalyzed by CYP3A4 and, to a lesser extent, by CYP1A2. The CYP2C subfamily contains the predominant enzymes for norantipyrine formation, and CYP1A2 is also involved. Formation of 3-hydroxymethylantipyrine is mediated by CYP1A2 and CYP2C9. Because several cytochrome P450 enzymes are involved in the formation of each metabolite, antipyrine is not well suited as a probe for distinct human cytochrome P450 enzymes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Effect of amphotericin B on hepatic cytochrome P-450 and glucose-6-phosphatase in the rat.

The effect of amphotericin B on hepatic microsomal cytochrome P-450 (P-450) concentration was measured in vitro, in vivo and ex vivo in the rat. In vitro, both amphotericin B (0-500 micrograms/ml) and its vehicle, sodium deoxycholate (0-410 micrograms/ml), caused similar dose-dependent decreases of P-450 concentrations and glucose-6-phosphatase activity. Intravenous amphotericin B (3 mg/kg) given daily for 3 days decreased antipyrine clearance from control values of 1.24 +/- 0.24 ml/min to 0.67 +/- 0.12 ml/min (p less than 0.001); whereas antipyrine clearance was unchanged by sodium deoxycholate. The P-450 concentration on the third day was reduced from 0.74 +/- 0.14 nmol/mg protein in control rats to 0.33 +/- 0.09 nmol/mg protein in rats treated with amphotericin B (p less than 0.001). Sodium deoxycholate had no effect on P-450 concentration. In contrast, amphotericin B had no effect on either antipyrine clearance or P-450 concentration following enzyme induction by phenobarbital. Amphotericin B had no effect on microsomal glucose-6-phosphatase activity in vivo. Neither amphotericin B nor sodium deoxycholate induced lipid peroxidation, measured as malondialdehyde production. These results show that amphotericin B decreases hepatic cytochrome P-450 content and function in the rat. These effects can not be observed in the enzyme induced state. Amphotericin B has no effect on glucose-6-phosphatase in vivo, the key enzyme of the gluconeogenesis, indicating selective effects on hepatic microsomal function.

Amphotericin B↗
PubMed1992

Predictability of the in vivo metabolism of verapamil from in vitro data: contribution of individual metabolic pathways and stereoselective aspects.

In vitro studies of drug metabolism with human liver microsomes can be performed in the early stages of drug development. Such experiments may reflect the in vivo metabolism of drugs in humans and thus allow for a prediction of drug disposition before the compound is administered to humans. We tested this hypothesis for the example of verapamil, which is a calcium channel blocker that undergoes extensive metabolism. Moreover, the drug is administered as a racemate, and stereoselective first-pass metabolism favoring the extraction of the more potent S-verapamil is observed after p.o. administration. To evaluate the in vitro metabolism, microsomes prepared from 10 human livers were incubated with both S- and R-verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

[In vivo 31-phosphorus magnetic resonance spectroscopy of liver diseases].

31P-MR spectroscopy was performed in 12 patients with focal and diffuse liver disease and in ten normal controls, using surface coils. Results so far show a significantly increased concentration of PME/beta-ATP and of PDE/beta-ATP in patients with liver metastases and in one patient with hepatic involvement by malignant lymphoma. The spectra of liver cirrhosis and fatty livers showed no characteristic changes.

Adult↗
PubMed1987

Amphotericin-B nephrotoxicity in humans decreased by sodium supplements with coadministration of ticarcillin or intravenous saline.

Previous observations suggest that salt loading can help reverse amphotericin-B induced nephrotoxicity. Evidence is presented indicating that sodium supplements provide prophylaxis against the development of amphotericin-B nephrotoxicity. In a retrospective study at Vanderbilt University, 14/21 patients receiving amphotericin B (target dose, 25 mg/day) without salt supplements developed impaired renal function; in 10 instances amphotericin B was temporarily withdrawn. In contrast, only 2/17 patients who received amphotericin B with ticarcillin (with its obligatory sodium supplement) developed nephrotoxicity (P less than 0.01). All four patients, who were receiving the combination of amphotericin B and ticarcillin and who had their ticarcillin therapy stopped, developed nephrotoxicity in the subsequent week. In a prospective observational study at Essen, 20 patients had 24 courses of amphotericin B (target dose, 40 mg/day) with routine supplementation of 1 liter of 0.9% sodium chloride daily. Only two patients showed evidence of nephrotoxicity and no dosage modification of amphotericin B was required in any patient. Four patients with initial evidence of mildly impaired renal function received full supplements without adverse effects or the development of nephrotoxicity. These observations suggest that routine parenteral administration of sodium supplements can help minimize the nephrotoxic potential of amphotericin B.

Amphotericin B↗
PubMed1987

Nitrendipine/digoxin interaction.

The effect of nitrendipine in two different dosages on digoxin plasma levels, urinary recovery, and systolic time intervals was investigated in eight healthy volunteers. Following an adequate loading dose of the glycoside, 0.25 mg digoxin twice daily was given alone for 2 weeks orally. After that, 0.25 mg digoxin twice daily was administered for two 1-week periods combined with nitrendipine, 10 mg or 20 mg once daily. The study was completed with a second digoxin monotherapy phase lasting seven days. Nitrendipine, 20 mg daily, led to a significant increase of the digoxin plasma concentration and of its area under the plasma concentration-time curve (AUC0-12) compared with digoxin monotherapy. Thus, AUC0-12 was 9.7 +/- 0.75 ng ml-1 h (X +/- SEM) when digoxin was given alone and was 11.2 +/- 0.92 ng ml-1 h under coadministration of the calcium antagonist (p less than 0.05). Nitrendipine in the dosage of 10 mg once daily caused a small, insignificant tendency to elevate digoxin plasma levels. In conclusion, nitrendipine, 20 mg daily, causes a significant increase of digoxin plasma concentration and of its AUC, which in certain patients might be of clinical relevance.

Adult↗
PubMed1987

[Prevention of nephrotoxicity of amphotericin B during the treatment of deep candidiasis].

Previous observations suggest that tubulo-glomerular feedback could be involved in amphotericin B nephrotoxicity. We then investigated the influence of sodium status on the occurrence of renal damage during amphotericin B therapy. A retrospective survey demonstrated that impaired renal function occurred during therapy in 67 per cent of the patients who received amphotericin B alone and in 12 per cent of the patients who received amphotericin B and ticarcillin (parenteral sodium supplement of 100-150 meq per day). Prospective studies were then undertaken both in adults and children. Intravenous sodium supplement was given intravenously as routine prophylaxis with amphotericin B therapy. In all courses amphotericin B was successfully administered without deterioration in renal function. These results support the hypothesis that parenteral sodium supplementation reduces the frequency of developing impaired renal function during amphotericin B therapy.

Adult↗
PubMed1986

Effect of two different doses of nitrendipine on steady-state plasma digoxin level and systolic time intervals.

The effect of two different doses of nitrendipine on plasma digoxin levels, urinary recovery and systolic time intervals was investigated in 8 healthy volunteers. Following a loading dose, digoxin 0.25 mg b.d.p.o. was given alone for 2 weeks. Then 0.25 mg digoxin b.d. was administered for two 1-week periods combined with nitrendipine 10 mg or 20 mg once daily. The study was completed with another digoxin monotherapy phase lasting 7 days. Nitrendipine 20 mg daily led to a significant increase in plasma digoxin levels and in its area under the plasma concentration-time curve AUC (0-12) was 9.7 ng ml-1h when digoxin alone was given and 11.2 ng ml-1h on co-administration of the calcium antagonist. Urinary recovery and renal clearance of digoxin were slightly but not significantly increased by nitrendipine. Nitrendipine 10 mg once daily caused a small, insignificant tendency to elevate the plasma digoxin level. Nitrendipine co-administration (10 and 20 mg once daily) did not significantly alter systolic time intervals, as non-invasively measured haemodynamic parameters, compared to digoxin treatment alone. Thus, nitrendipine 20 mg daily caused a significant increase in plasma digoxin concentrations and in its AUC, which would rarely be of clinical relevance.

Adult↗
PubMed1986

Quantitative study of cell interaction with collagen and fibronectin.

The interaction of BHK-fibroblasts with collagen or fibronectin-collagen complex was investigated quantitatively. For that purpose an improved method for production of defined cell substrata was developed. The method permitted reproducible coupling of different ligands to glass via an amino or carboxyl group. BHK-cells grown on collagen required a minimum density of 15-20 ng collagen/cm2 for spreading. When grown on fibronectin adsorbed on collagen the cells were found to remove fibronectin from the substratum at a rate of 0.15 pg/(cell X h).

Animals↗
PubMed1985

[High-dose cytarabine treatment: a promising therapy modality in acute resistant myeloid leukemias in recurrence].

High dose Cytarabin in relapsed and refractory acute leukaemia. High dose cytarabin can be very effective for the treatment of acute leukaemia resistent to conventional cytarabin doses. Therefore 10 patients (6 males, 4 females) with ages ranging from 18 to 58 years (median: 34 years) refractory to conventional induction therapy were treated with 1 hour infusions of high dose cytarabin (3 g/m2 q 12 h for 6 days) 2 patients got additional 20 mg/m2 doxorubicin on days 7 to 9. According to this treatment, in 5 of the 10 patients complete remissions could be achieved. Without further treatment 3 patients relapsed after 4, 7 and 15 months leading to death in 2 or 3 months. 19 months after treatment 1 patient is in complete remission, though demonstrating meningosis leukaemica 5 months after high dose cytarabin. Another patient relapsed 14 months after high dose cytarabin, reaching another complete remission after treatment according to a ALL/AUL protocol [7]. 2 patients died in bone marrow aplasia and 2 patients did not show any response, dying 11 months after high dose cytarabin application. All patients demonstrated vomiting, nausea, diarrhea and allopecia. Bone marrow was profoundly depressed in all patients with severe granulocytopenia and thrombocytopenia for periods from 7 to 34 days. 3 to 5 days after the end of high dose cytarabin therapy 3 patients developed acute ceratitis and 2 patients conjunctivitis. 3 patients showed erythrodermia of their skin with epidermolysis in 2 of these patients.

Adolescent↗
PubMed1984

[Climatotherapy in chronic inflammations of the uvea].

Treatment of uveitis depends on the inhibition of the inflammatory reaction by corticosteroids or immunosuppressive agents. "Climatotherapy" remains a controversial subject and is generally not accepted. To test its efficacy a pilot study was undertaken. Children with chronic iridocyclitis or intermediate uveitis were sent to Israel for 3 weeks. During the follow-up period of 26 months there was an initial regression of the inflammatory reaction in most cases, followed by varied courses depending on the severity of the disease. Although no definite conclusions can be drawn owing to the small number of patients (5) there might been a beneficial effect. It seems very difficult to prove the efficacy of such "treatment", since not only the climate but also many other environmental factors were changed.

Adolescent↗
PubMed1984

Drug interactions with nitrendipine.

Interactions between calcium channel blockers like nifedipine and concurrently administered drugs like digoxin or cimetidine have been described in the literature. Therefore, possible interactions of the new calcium channel blocker nitrendipine (20 mg daily) with digoxin (0.5 mg daily), digitoxin (0.1 mg daily), cimetidine (1,000 mg daily), ranitidine (300 mg daily), atenolol (100 mg daily), metoprolol (200 mg daily), and acebutolol (400 mg daily) were studied following 1 week of combined treatment of nitrendipine with each of these drugs. Six healthy volunteers were investigated (mean age, 30.2 +/- 2.1 years; mean body weight, 69.7 +/- 4.7 kg; means +/- SEM). Under nitrendipine monotherapy, maximum plasma levels (Cmax) averaged 41.6 +/- 12.8 ng/ml, and they were reached after 2 h. Mean area under the curve was 131.5 +/- 40 ng ml-1 h, and "oral" plasma clearance (Clpl) amounted to 80.8 +/- 27.5 L/h. The H2 receptor antagonists cimetidine and ranitidine and the digitalis glycosides like digoxin or digitoxin did not alter nitrendipine kinetics significantly. Also simultaneous treatment with beta-blockers did not significantly influence kinetic values of the calcium channel blocker, but atenolol showed a tendency to increase Cmax of nitrendipine to 54.2 +/- 19.7 ng/ml, when its Clpl was distinctly lowered to 42.7 +/- 10.4 L/h (p greater than 0.05 compared with 80.8 +/- 27.5 L/h under nitrendipine monotherapy). Increased digoxin plasma levels and digoxin-induced side-effects were seen under nitrendipine co-administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1984

HLA typing of nonviable tissues with a multiple microabsorption method.

HLA typing is usually performed by directly measuring complement-dependent cytotoxicity on viable peripheral blood lymphocytes as target cells. To overcome the limitations inherent to viable targets, absorption inhibition techniques have been developed. The main drawbacks of most of these techniques are, however, that they are not very feasible and require relatively large amounts of absorbing material and rare antisera. Therefore, we adjusted the multiple microabsorption method (MMA) and tested simultaneously for 16 HLA specificities of the A, B, and C locus on 6 different nonviable tissues. The results of the MMA, when compared with those of the usual microlymphocytotoxicity test (LCT) that was run in parallel, correspond in 96% of the 28 comparable antigen pairs. Only one false negative and no false positive result was found. The absorbing quality of the individual organs differed, as was to be expected: lymph node and spleen rank on the top, followed by liver and kidney, whereas brain and muscle show several negative reactions. Altogether, the MMA proves to be a reliable and practical method for typing nonviable tissues, eg, in hematological diseases or in certain forensic situations.

Brain↗
PubMed1983

[Effect of cimetidine and ranitidine on the pharmacokinetics and anti-hypertensive effect of nifedipine].

Simultaneous administration of cimetidine and nifedipine to six healthy volunteers produced an about 80% rise in maximal plasma levels and the area under the plasma level-time curve of nifedipine compared with results on nifedipine administration alone (P less than 0.05). After treatment for one week with 4 X 10 mg nifedipine daily and 3 X 200 mg cimetidine daily and 400 mg at night plasma level peaks of nifedipine averaged 87.7 +/- 19.1 ng/ml, while after 4 X 10 mg nifedipine alone they were only 46.1 +/- 10.6 ng/ml. Ranitidine produced an approximately 25%, nonsignificant, rise in plasma level-time curve and peak plasma levels of nifedipine. Seven hypertensives (WHO stage I and II) had a mean arterial blood pressure level of 127 +/- 2.5 mm Hg after two-week placebo administration, and of 109 +/- 2.38 mm Hg after four weeks of nifedipine alone at 4 X 10 mg daily (P less than 0.01). After additional administration of 1 g cimetidine daily for two weeks the mean blood pressure fell significantly to 95 +/- 3.1 mm Hg (P = 0.02), while blood pressure fell to 103 +/- 3.88 mm Hg after two weeks of additional administration of 300 mg ranitidine daily, a fall which was not significant (P greater than 0.05). The interaction of nifedipine and cimetidine is thus of clinical significance because of its pharmacodynamic effect.

Adult↗