The uptake and O-methylation of 3H-(±)-isoprenaline in rat cerebral cortex slices

Summary The O-methylation and accumulation of ³H-isoprenaline in slices of the rat cerebral cortex were studied before and after inhibition of COMT. 1. Inhibition of COMT by mol/l U-0521 virtually abolished the O-methylation and increased the accumulation of ³H-isoprenaline; hence, there is evidence for the existence of a central O-methylating system (with a transport mechanism and intracellular COMT). 2. Experiments were carried out with selective uptake inhibitors for uptake, (cocaine and desipramine) or uptake2 (corticosterone and OMI), with phenoxybenzamine (known to inhibit both carriers) and with changes in the ionic composition of the incubation medium. They revealed that the central carrier differed from both, uptake, and uptake2, although exhibiting some resemblance with uptake₂ (lack of dependence on Na⁺ and Cl^–, sensitivity to K⁺ and phenoxybenzamine, ability to transport ³H-isoprenaline). 3. Although the central carrier was rather sensitive to inhibition by beta-adrenoceptor antagonists (propranolol, carteolol), the effect of propranolol was not stereoselective; hence, beta-adrenoceptors do not seem to be involved. 4. Virtually identical IC₃₀-values were obtained for inhibitors, when determined with or without inhibition of COMT. Only OMI was found to inhibit COMT as well as the central transport system; hence it was more potent in inhibiting the O-methylation than the accumulation of ³H-isoprenaline. 5. IC₅₀-values (against initial rates of accumulation of ³H-isoprenaline; COMT inhibited) were determined for various substrates and inhibitors of peripheral uptake₂. There was no correlation with the IC₅₀-values determined earlier for uptake2 in rat heart (Grohmann and Trendelenburg 1984). 6. Unlabelled catecholamines half saturated the intracellular COMT when slices were incubated with 0.22 mol/l [(±)-dobutamine] to 4.9 mol/l [(–)-noradrenaline]. As the presence of unlabelled catecholamines increased tissue levels of ³H-isoprenaline, catecholamines are substrates of the central carrier. 7. The carrier of the central O-methylating system differs from uptake₂ of peripheral organs, although it resembles the peripheral carrier in some respects.Abbreviations COMT catechol-O-methyl transferase - DOPEG dihydroxyphenylglycol - MAO monoamine oxidase - OMI 3-Omethyl-isoprenaline Supported by the Deutsche Forschungsgemeinschaft (Tr 96 and SFB 176) and by a scholarship of the Royal Society for V. G. Wilson. Some of the results were presented to the British Pharmacological Society (Trendelenburg and Wilson 1986)     

Preauricular pilomatrixoma: a diagnostic pitfall

Although pilomatrixomas are well known to dermatologists and dermatopathologists, surgeons encountering these lesions over the parotid gland frequently do not consider this benign neoplasm in the differential diagnosis. Presentation of a subcutaneous preauricular lesion, coupled with an erroneous cytologic diagnosis of malignancy, can potentially result in histologic "overdiagnosis" and more aggressive therapy than is required for these benign hair follicle neoplasms. A case is reported to illustrate this potential diagnostic trap, and a series of 206 cases collected at the University Hospital of Zurich from 1975 to 1987 is reviewed.     

Comparison of the chelating capacity of EDTA and EGTA, a new demineralized agent, on molars in vitro

Recent morphologic studies have shown qualitative, how demineralizing substances clean teeth roots. In this work we attempt to describe quantitatively the "chelation process" and pH evolution of the quelator solution in-vitro inside the teeth during the reaction. These results indicate that Ca++ coming from hydroxyapatite release protons from EDTAH under neutral conditions. This is the most likely mechanism of the "self-limitation". Furthermore, it allow us to explain why EDTA Im and EGTA Im were more efficient than EDTA Na and EGTA Na upon demineralizing the tooth. EGTA Im turn out to be the fastest demineralizing agent as compared to EDTA Na which is currently employed in endodontic therapy.     

Relative sensitivity of four noninvasive methods in assessing systolic cardiovascular effects of isoproterenol in healthy volunteers.

STUDY OBJECTIVE: The study was performed to evaluate the relative sensitivity of various noninvasive methods to detect and describe the systolic cardiovascular effects of stepwise increasing doses of isoproterenol: two-dimensional left ventricular echocardiography (main variable, ejection fraction), ACVF (attenuation compensated volume flow)--dual-beam Doppler echoaortography (time-averaged mean velocity), electrical impedance cardiography [(dZ/dtmax)/RZ index], and systolic time intervals from mechanocardiography (PEP and QS2c). METHODS: Isoproterenol was administered by constant rate intravenous infusion in consecutive steps of 0.1, 0.2, 0.4, 0.75, and 1.5 micrograms/min (each for 15 minutes). Saline control infusions were given in analog fashion. The treatments (isoproterenol and saline solution) were administered in a period-balanced two-way crossover design with randomly allocated sequences. The subjects, observers, and analysts were blinded to the treatment protocol. Study subjects were 10 healthy male volunteers (age range, 23 to 31 years; mean age, 26.6 years). RESULTS: Compared with saline solution, isoproterenol caused a dose-related increase in ejection fraction, (dz/dt)/RZ index, and time-averaged mean velocity and a dose-related shortening of PEP and QS2c. The responses are congruent with an enhancement of cardiac systolic performance caused by a positive inotropic stimulation and an afterload reduction ("inodilatory" response). The effects on systolic time intervals reached statistical significance (alpha = 0.05) at the first isoproterenol dose step, the effects on the impedance cardiography and the Doppler echoaortography variables reached statistical significance at the second dose step, and the effects on the two-dimensional echocardiography reached statistical significance at the third dose step. CONCLUSIONS: All methods allowed to detect isoproterenol-related changes. Systolic time intervals were the most sensitive, followed by impedance cardiography, ACVF--dual-beam Doppler echoaortography, and two-dimensional echocardiography. The practical convenience and high sensitivity of the systolic time intervals makes them suitable to evaluate investigational systolic inodilatory changes in humans.     

Haemostyptic preparations on the basis of collagen alone and as fixed combination with fibrin glue

Preparations containing collagen play a prominent role among local haemostyptic agents in surgery. Sheets of collagen are used as degradable haemostyptic tampons. Various investigations have shown better haemostasis with collagen compared to other degradable materials, although the haemostyptic effect of these collagen preparations is limited. Concerning the mechanism of haemostasis, not all the reactions stimulated, e.g. by the collagen of an injured vessel wall, may be activated by a haemostyptic tampon from collagen. This depends very much on the kind of preparation. The combined application of a sheet of collagen with fibrin glue improved local haemostasis to a great extent. Large areas of capillary bleeding can be treated successfully with this method. Despite the very good results, this method has not been applied on a broad scale. This is due to the necessary skill and experience and the relatively cumbersome preparation required at the operation site. These drawbacks have been overcome with the latest development in this field--a sheet of collagen covered with a fixed layer of the solid components of a fibrin glue (fibrinogen, thrombin and aprotinin). The performance of this new local haemostyptic agent is described with special emphasis on the results of clinical trials. Haemostasis of large areas of capillary bleeding was very efficient and safe with the new material. Moreover, bile leakage and liquor, pancreatic and aerial fistulae could be sealed without problems.     

Serum interleukin 6 levels become elevated in acute myocardial infarction.

We have examined serum interleukin 6 (IL-6) levels in 12 patients with acute myocardial infarction (AMI). IL-6 levels became elevated in all patients, following the rise of serum creatine kinase (CK) activity. Peak IL-6 levels showed a good correlation with peak serum C-reactive protein (CRP) levels, while there was no direct relationship between peak IL-6 levels and peak CK activity. IL-6 mRNA was not detected in unstimulated "quiescent" rat cardiocytes cultured in serum-free medium, but its expression was induced by exposure of the cells to serum or ionomycin. These results show that IL-6 is synthesized in the myocardium and serum IL-6 levels become elevated in AMI, suggesting that IL-6 could affect the progression and/or healing processes of AMI.     

Human dignity and human rights of severely disabled persons. On the significance of the current "quality of life discussion" for treatment and care of elderly incurable patients]

Concurrent with a nursing shortage and the increasing indigent requiring care in Germany preliminary discussions are emerging about quality of life and the rights of this socioeconomic group. This contribution shows which effects such a discussion may have on the care of a most defenseless segment of our society. It counters those who deny these rights and opposes their view of human dignity, which is characterized by categories of self-consciousness and intellectual ability. According to the christian view, dignity is a transcendental state and cannot be categorized as an empirical matter by virtue of its presence or absence. Exaggerated ideals of health have overshadowed realities of incurable disease, lingering illness, and dying, and is easily leading us to discount such people as being "unworthy to live". According to the view presented nursing carers are valued.     

Steady-state pharmacokinetics of idebenone in patients with moderate renal impairment

Idebenone (45 mg twice daily) was administered to 7 patients with moderate renal impairment (creatinine clearance 21-40 ml/min) for 10 days. Standard pharmacokinetic parameters were computed on day 1 (single administration) and on day 10. On day 1 the mean of the maximum plasma concentration values (C(max)) was 364 ng/ml (standard deviation (S.D.) 100); time to C(max) (t(max)) was in the range of 1-2 h for 6 patients and 12 h for the remaining patient: the mean was 3 h (S.D. 3.99); the mean area under the plasma concentration vs. time curve (AUC) was 3005 ng h/ml (S.D. 1152). On day 10 the mean C(max) was 531 ng/ml (S.D. 355.3), the mean t(max) was 0.07 h (S.D. 0.19), the mean AUC was 3167 ng/ml (S.D. 2944) and the mean elimination half-life (t(1/2)) was 4.9 h (S.D. 1.1). Idebenone metabolites (QS-4, QS-6 and QS-10) showed a kinetic profile similar to the parent compound, with pharmacokinetic parameters comparable to idebenone for QS-4 and lower than idebenone for QS-6 and QS-10. Idebenone was metabolized and easily excreted and no accumulation was observed for the compound and its metabolites. No significant modification of the biohumoral indexes and vital signs and no adverse reactions were observed.