Clonidin-supplementierte postoperative Analgesie bei kieferchirurgischen Patienten

Methods

After approval by the local Ethics Commitee and after informed consent had been given, 40 patients scheduled for elective maxillofacial surgery were included in this double-blind, randomized study. As a supplement to standardized general anaesthesia (isoflurane, N₂O), the patients received either clonidine 5 μg/kg or placebo during the last hour of the operation. Blood pressure, heart rate, time of recovery, and sedation and pain scores were measured postoperatively. The occurrence of nausea, vomiting or shivering was noted, as were the requirements of piritramide for analgesia, which was administered on demand in titrating dosages, and of nifedipine for systolic blood pressure exceeding 180 mm Hg.

Results

The two groups were comparable regarding biometric parameters, ASA-classification and duration of anaesthesia. Clonidinetreated patients were later in opening their eyes (22.5±11.9 min vs 17.9±10.9; n.s.) and the ability to state their dates of birth returned later (32.2±11.6 min vs. 25.7±12.8;P<0.05). Pain was more frequent in the placebo group (P<0.05 after 30 min), and there-fore, these patients required much more piritramid (P<0.01). The sedation scores showed no significant differences. No vomiting occurred in the clonidine group, and shivering was less frequent (P<0.01). The placebo group received more nifedipine (P<0.05) because the rate-pressure product was higher (P<0.01).

Discussion

Opiates are frequently used as analgesics after maxillofacial surgery, even though their most common side effect—respiratory depression, nausea and vomiting—are particularly dangerous in these patients because of the obstruction of the upper respiratory tract. Self-titration of the opiate dosage on demand can decrease the incidence of serious side effects. Clonidine administered intraoperatively caused a profound reduction in analgesic requirements in this study. Additional opiate administration in the postoperative period was unnecessary in nearly all clonidine-treated patients. The attenuating effect on sympathoadrenergic reactions leads to lowering of the rate-pressure product and may be of advantage for patients suffering from arterial hypertension, angina pectoris or bronchial asthma. The slower emergence from anaesthesia following clonidine administration is probably caused by double-blind study properties preventing full consideration of the decreased isoflurane requirements after clonidine.     

The pharmacokinetics of high-dose epirubicin and of the cardioprotector ADR-529 given together with cyclophosphamide, 5-fluorouracil,and tamoxifen in metastatic breast-cancer patients

A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-m silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i.v. administration of different doses of ADR-529 (600–1000 mg/m²) together with different doses of epirubicin (E, 60–100 mg/m²), fixed-dose cyclophosphamide (C, 600 mg/m²), fixed-dose 5-fluorouracil (F, 600 mg/m²), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m². We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity.     

Response of multicellular tumor spheroids to liposomes containing TNF-α

Summary This publication describes a new model to investigate the influence of tumor necrosis factor- (TNF-) on a three-dimensional glial cell aggregate under defined, standardized, reproducible conditions using the glioma cell line A 172.The cells are initially grown as normal monolayer culture until they reach a cell density of up to 1×10⁶. Subsequently they are grown as spheroids by the liquid overlay technique. Spheroids grown in this way were divided into ten groups of more than 50 cell aggregates. Three groups were coincubated with free TNF- in increasing dosages (100 ng/ml, 200 ng/ml and 1000 ng/ml); three groups were incubated with empty liposomes (0.2 mg/ml, 0.4 mg/ml and 2 mg/ml); three groups received liposomes which had been loaded with TNF-, and one group, which received no treatment, served as control.The diameter of the spheroids ranged from 80 m to 350 m. There was no significant difference in growth between the 3 groups treated with free TNF-. Comparing spheroids treated with TNF- with those which had been coincubated with empty liposomes, there was a significant difference (p<0.001) in growth, which correlated with the amount of liposomes. Similarly, free TNF- had a significantly (P<0.001) stronger growth-inhibiting effect as compared to liposomes loaded with TNF-. Comparing the groups treated with liposomes only to those treated with liposomes loaded with TNF-, the latter exhibited a more marked (although not significantly) growth-inhibiting effect.The preliminary conclusion is that the major growth-inhibiting effect seems to be mediated by the liposomes. This phenomenon is in agreement with results obtained in monolayer cultures.     

Involvement of calyculin A-sensitive phosphatase(s) in the differentiation of Trypanosoma cruzi trypomastigotes to amastigotes

Differentiation of the non-dividing trypomastigote form of Trypanosoma cruzi, the causative agent of Chagas disease, to the dividing amastigote form normally occurs in cytoplasm of infected cells. Here we show that calyculin A. a potent inhibitor of protein phosphatases 1 and 2A, induces at pH 7.5 extracellular transformation of long slender trypomastigotes to round amastigote-like forms which acquire characteristic features observed after the normal differentiation process: repositioning and structural changes of the kinetoplast, release of surface neuraminidase, and expression of amastigote-specific epitopes. Calyculin A inhibits parasite phosphatases and changes in the phosphorylation of specific proteins occur during the transformation process. As an exposure of trypomastigotes to calyculin A concentrations as low as 1 nM and for only 1-2 h is sufficient to induce transformation, the inhibition of calyculin A-sensitive phosphatase(s) appears to play a major role in initiating the trypomastigote differentiation.     

Use of limited color-flow duplex for a carotid screening project.

BACKGROUND: Although the efficacy of carotid endarterectomy for asymptomatic carotid stenosis has been established, no cost-effective approach for identification of these patients has yet been devised. The purpose of this study was to develop a limited carotid duplex screening examination to be utilized for the detection of asymptomatic carotid stenoses. METHODS: Carotid screening examinations employed rapid identification of the carotid bifurcation using color-flow duplex imaging and an immediate Doppler-derived velocity of the segment of the internal carotid artery with the most turbulent flow. Complete examinations were then finished using well-established protocols in our accredited vascular laboratory. A total of 512 patients were referred for complete studies based upon standard indications. Criteria for at least a 50% internal carotid artery stenosis on the complete examination was defined as a peak systolic velocity (PSV) of at least 125 cm/sec. Receiver operator characteristic (ROC) curves were then constructed to identify the optimal screening velocity criteria as compared with the final results on the complete examination. RESULTS: Five screening examinations were technically limited yielding a total of 507 patients with 1,014 carotid arteries available for analysis. Comparison of screening examinations versus complete examinations for a PSV of 125 cm/sec yielded sensitivity 86%, specificity 98%, positive predictive value (PPV) 95%, and a negative predictive value (NPV) 93%. ROC analysis identified a "cut point" of 115 cm/sec on the screening examinations to achieve sensitivity 91%, specificity 95%, PPV 89%, and NPV 96%. Time to perform screening examinations averaged 3.2 minutes per patient. Three patients had common carotid lesions not identified on the limited internal carotid screening examinations. CONCLUSIONS: Screening carotid examinations are a rapid, reliable, and relatively inexpensive method for detection of patients with asymptomatic internal carotid artery stenosis. Limited screening examinations should be developed in each vascular laboratory and utilized in high-risk patients.     

MRI findings in Hirayama’s disease: flexion-induced cervical myelopathy or intrinsic motor neuron disease?

Hirayama’s disease is a benign juvenile form of focal amyotrophy affecting the upper limbs. Previous studies have suggested that the disorder is a neck flexion induced cervical myelopathy. We report clinical and magnetic resonance imaging findings in nine patients with Hirayama’s disease. Cervical imaging of seven patients revealed spinal cord changes consisting of focal atrophy and foci of signal alterations. On neck flexion a forward movement and mild reduction in the anteroposterior diameter of the lower cervical cord against the vertebral bodies was noted in affected individuals as well as in five normal controls. In contrast to earlier reports, none of our patients showed complete obliteration of the posterior subarachnoid space. Measurement of the anteroposterior spinal cord diameter in each vertebral segment (C4–C7) revealed no significant differences in the degree of spinal cord flattening between the two groups. Furthermore, two of our patients had significant degenerative changes in the cervical spine (disc herniation, retrospondylosis) contralateral to the clinically affected side. These degenerative changes resulted in a marked cord compression on neck flexion but were not associated with ipsilateral clinical abnormalities or spinal cord alterations. Our results argue against a flexion-induced cervical myelopathy and support the view that Hirayama’s disease is an intrinsic motor neuron disease. Received: 15 March 1999 Received in revised form: 25 May 1999 Accepted: 1 June 1999