Impact of the CYP2D6 genotype on the clinical effects of metoprolol: a prospective longitudinal study.

After administration of metoprolol, plasma concentrations of the drug are markedly higher in CYP2D6 poor metabolizers (PMs) than in non-PMs. In a prospective double-blind 3-month study, we investigated whether this translates into differences in metoprolol's effects after initiation of therapy. Despite administering equal doses to PMs and non-PMs, metoprolol plasma concentrations were 4.9-fold higher in the PM group. Metoprolol evoked significantly and persistently greater reductions in heart rate, diastolic blood pressure, and mean arterial pressure in PMs than in non-PMs. It appears, therefore, that the CYP2D6 genotype contributes to interindividual differences in metoprolol response.

Valdecoxib does not interfere with the CYP2D6 substrate metoprolol.

OBJECTIVE: We reported recently that celecoxib inhibits the metabolism of the cytochrome P450 (CYP)2D6 substrate metoprolol in volunteers. Valdecoxib, the active metabolite of parecoxib, has also been claimed to interfere with the metabolism of CYP2D6 substrates. However, little support for this contention is available despite the intensive use of parecoxib in the perioperative setting. Therefore, the objective of this study was to examine the effect of valdecoxib on the pharmacokinetics of the clinically relevant CYP2D6 substrate metoprolol. METHODS: An open, randomized, 3-period crossover study was performed in 15 healthy male volunteers. Metoprolol (50 mg) was given in all 3 periods without, or following a 7-day pre-treatment with valdecoxib (20 mg, o.d.) or rofecoxib (25 mg, o.d.), to achieve steady state conditions of COX-2 inhibitors in Periods 2 and 3. In a small group of extensive metabolizers (EM/EM), short-term application of twice the dose was investigated. RESULTS: No effect of valdecoxib (20 mg/d) or rofecoxib (25 mg/d) were detected on the area under the plasma concentration-time curve of metoprolol (323 +/- 333 to 324 +/- 296 or 309 +/- 256 microg x h/l) or at a higher dose. No significant changes of pharmacokinetic or pharmacodynamic parameters of metoprolol were apparent. CONCLUSION: We conclude that, at therapeutic doses, valdecoxib and rofecoxib do not influence the CYP2D6 substrate metoprolol.

Prospective crossover comparison of carvedilol and metoprolol in patients with chronic heart failure.

OBJECTIVES: This study investigates the effects of a change of beta-adrenergic blocking agent treatment from metoprolol to carvedilol and vice versa in patients with heart failure (HF). BACKGROUND: Beta-blockers improve ventricular function and prolong survival in patients with HF. It has recently been suggested that carvedilol has more pronounced effects on left ventricular ejection fraction (LVEF) compared with metoprolol. It is uncertain whether a change from one beta-blocker to the other is safe and leads to any change of left ventricular function. METHODS: Forty-four patients with HF due to ischemic (n = 17) or idiopathic cardiomyopathy (n = 27) that had responded well to long-term treatment with either metoprolol (n = 20) or carvedilol (n = 24) were switched to an equivalent dose of the respective other beta-blocker. Before and six months after crossover of treatment, echocardiography, radionuclide ventriculography and dobutamine stress echocardiography were performed. RESULTS: Six months after crossover of beta-blocker treatment, LVEF had further improved with both carvedilol and metoprolol (carvedilol: 32 +/- 3% to 36 +/- 4%; metoprolol: 27 +/- 4% to 30 +/- 5%; both p < 0.05 vs. baseline), without interindividual differences. There were no changes in either New York Heart Association functional class or any other hemodynamic parameters at rest. Dobutamine stress echocardiography revealed a more pronounced increase of heart rate after dobutamine infusion in metoprolol- compared with carvedilol-treated patients. After dobutamine infusion, LVEF increased in the carvedilol- but not in the metoprolol-treated group. CONCLUSIONS: When switching treatment from one beta-blocker to the other, improvement of LVEF in patients with HF is maintained. Despite similar long-term effects on hemodynamics at rest, beta-adrenergic responsiveness is different in both treatments.

[Stimulation of endogenous TSH secretion and endocrine orbitopathy]. / Stimulation der endogenen TSH-Sekretion und endokrine Orbitopathie.

In 81 patients the thyrotoxicosis was controlled with antithyroid drugs only. Ophthalmopathy was seen in 53 patients when therapy was started. Patients with ophthalmopathy stage V or VI were excluded from this study. Maximal pathological eye signs were seen in 24 patients before starting therapy. Worsening occurred during treatment in 16 patients and some months after therapy was stopped in 13 patients. In summary, 40 patients passed a phase of subnormal thyroid hormone levels. Although stimulated, thyrotrophin secretion during this phase of antithyroid drug treatment took place in 19 patients a time related, reversible progression of endocrine ophthalmopathy was seen only in one subject. During medical treatment of a relapse in this patient worsening of eye signs had been seen once more despite thyrotrophin secretion was suppressed. The results are discussed in view of an immunologic concept of the pathogenesis of Graves' disease.

[Radiation therapy of endocrine orbitopathy. 1st communication: clinical results (author's transl)]. / Zur Strahlentherapie der endokrinen Orbitopathie. 1. Mitteilung: Klinische Ergebnisse.

Ten patients with serious endocrine orbitopathy underwent radiation therapy of the retrobulbar orbital tissue. Between the 2nd and the 13th week preceding radiotherapy, exacerbation of the clinical symptoms had appeared in all the patients, and distinct symptoms of infiltrative tissular processes were seen beside bulbar protrusion. Of the cases, 5 suffered from marked extra-ocular myopathy, 6 from corneal lesions, and one patient had lost his visual faculty. Index numbers for the degree of the orbitopathy (4-11, average 6.7) were established in all cases, and a total focal dose amounting to maximally 1000 cGy for each retrobulbar target volume was administered in one series. The pituitary gland was not included in the radiation field. Indices for the degree of ophthalmopathy were reduced by at least 3 points (average 3.7). Swelling of soft tissue and bulbar protrusion were decreased primarily. No improvement of myopathy was obtained but aggravation also did not occur. Recurrences appeared in 4 patients, at the earliest 4 months, at the latest 24 months after the end of the therapy. The present findings have shown orbital irradiation as an effective method for the treatment of endocrine orbitopathy.

[The normal liver-spleen scintigram with the gamma camera (author's transl)]. / Das normale Leber-Milz-Szintigramm mit der Gammakamera.

In 104 patients without liver disease, liver spleen scintigrams were analysed according to uniform criteria. The scintigrams were taken after application of 99mTc-sulfur colloid in at least six projections with the gamma camera and coupled data processing. As a significant difference compared to scanner scintigraphy, a non-homogeneous storage pattern is frequently also found in the healthy liver, especially in the ventral projection. Superimpositions or impressions caused by extra- or intrahepatic structures were also more frequent and more pronounced than with scanner scintigraphy. As expected, there were no appreciable differences with regard to the liver forms. The following quantitative parameters were determined (mean +/- SD): maximum vertical diameter of the liver: 199 +/- 20.0 mm, maximum horizontal diameter: 219 +/- 19.8 mm; liver area (ventral projection): 187 +/- 27.3 cm2; spleen area (dorsal projection): 55.3 +/- 15.9 cm2; index of liver size (liver area divided by the normal weight of the patient as determined from a given table): mean +/- SD = 2.69 +/- 0.58 (ventral projection); spleen area index (spleen area divded by body surface): mean = 3.03 +/- 0.81 (dorsal projection). The choice of projection did not have any appreciable effect on the area dimensions and indices, so that with super-imposition of organs these values can be determined with sufficient accuracy even from oblique projections.

[Effective out-patient treatment of gastric ulcer with proglumide: preliminary results (author's transl)]. / Wirksame ambulante Therapie des Ulcus ventriculi mit Proglumid. Vorläufige Mitteilung.

In a double-blind trial 16 persons with gastric ulcer and 35 with duodenal ulcer were treated as out-patients with 1200 mg proglumide daily or 1320 mg magnesium tricilicate daily (as an "active placebo") for four weeks. The ulcers were assessed by endoscopy before and after treatment. The gastric ulcers disappeared in 75% of patients receiving proglumide (six of eight subjects) but in only 25% of those on the placebo (two of eight). There was no significant effect of proglumide on duodenal ulcers (17 in the proglumide and 18 in the placebo groups). Proglumide failed to affect either basal or maximally stimulated acid secretion, nor was there any change in the serum gastrin level. There were no side effects during proglumide administration. This underlines its therapeutic value in the treatment of gastric ulcer, in comparison with cimetidine or carbenoxolone.

[Pathogenesis of Basedow's disease]. / Zur Pathogenese der Basedow' schen Erkrankung.

Thyroid antibodies and thyroid-stimulating factors (LATS and LATS-Protector) have been controlled 53 patients with Graves' disease during antithyroid drug treatment. It has been demonstrated that dosage is higher and duration of treatment has been more protracted in antibody-positive thyrotoxicosis than in patients without these antibodies. Thyroid antibodis have been found only in patients with detectable thyroid-stimulating factors, which are identified as immunglobulins. These results indicate the importance of immunologic processes. Suppressibility of thyroid function proved 2 months after stopping medical treatment, was negative in 19 and positive in 17 patients. Thyroid-stimulating factors remained positive up to this time in 20 patients and disappeared in 18. In 8 patients the suppression-test was positive indicating a normal function of the thyroid stimulating hormone (TSH), but thyroid-stimulating factors still have been detected in these patients. These results are controversial to the autoimmune-concept of the pathogenesis of Graves' disease. As this concept cannot be refused, changes in the effectivity of LATS or LATS protector by crude serum factors or by changes of the receptor structures are discussed.

[Embolism by ultrasound-thrombolysis (author's transl)]. / Die Emboliegefahr bei der Ultraschall-Thrombolyse

By ultrasound it is possible to destroy thrombi intravascular and remove them by a hollow flexible probe at the same time. Experiments were now performed in 6 dogs with 2-9 days old thromboses in the femoral or iliac veins, to detect embolisation during ultrasound-thrombolysis. Parameters were pulmonary angiograms and lung scans. Only in one dog with a floating thrombus in the iliac vein signs of pulmonary embolism were found after thrombolysis. The controls of the other 5 dogs were normal.

[Effect of experimentally induced hyperthyroidism on zona glomerulosa from adrenal cortex of the rat (author's transl)]. / Beeinflussbarkeit der Zona glomerulosa der Nebennierenrinde der Ratte durch Schilddrüsenhormone

By histochemical and histometrical methods the the effect of l-triiodothyronine on the zona glomerulosa from rat adrenal cortex was investigated. Glucose-6-phosphatedehydrogenase and 3-beta-OH-steroiddehydrogenase activities were determined in slices of adrenal cortex. No increase in activities of these enzymes was observed after treatment with l-triiodothyronine. In contrast, histometrical studies showed a significant enlargement of nuclei in the zona glomerulosa as well as in the zona fasciculata. This observation suggests enhanced secretory activity of both zones of the adrenal cortex of the rat.

[Clinical significance of serum magnesium concentration in thyrotoxicosis (author's transl)]. / Magnesiumkonzentration im Serum bei Hyperthyreose. Klinische Bedeutung

Thyrotoxicosis is associated with hypomagnesemia. Therapy leads to restoration of serum magnesium concentration. The clinical significance of the disturbance in magnesium metabolism is discussed on results of two groups of patients with hyperthyroidism. One group of 7 patients with high serum thyroxine levels and mild clinical signs of thyrotoxicosis showed a normal magnesium concentration in serum. In a second group with further 7 patients serum magnesium level did not increase during therapy while thyroxine decreased in spite of lack of clinical improvement. The results suggest that serum magnesium concentration is primarily determined by 1-triiodothyronine.

Circular DNA in chromoplasts of Tulipa gesneriana.

Circular DNA has been extracted from isolated globulous chromoplasts of Tulipa gesneriana L. The isolated DNA molecules occur in the form of "open circles" and have a contour length of about 43.6 µm, corresponding to a molecular weight of about 92 kdaltons.