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Background and Objectives: Intrathecal morphine is a widely used method for postoperative pain relief after major abdominal surgery. The aim of this randomized, double-blinded study was to compare intrathecal morphine and intravenous PCA morphine for postoperative analgesia and recovery course after major colorectal surgery in elderly patients.Methods: After written informed consent, patients >70 years of age were prospectively and randomly assigned to receive either preoperative intrathecal morphine (0.3 mg) and postoperative patient-controlled (PCA) intravenous morphine (IT morphine) or PCA alone (group control). Results are presented as mean +/- SD (95% confidence interval).Results: Twenty-six patients successfully completed the study in each group. In the IT morphine group, rate of awakening was delayed. Pain intensity and daily intravenous morphine consumption were significantly reduced 1 and 2 days after surgery in the IT morphine group (P < .01). Mental function (assessed by Mini Mental State and Digit Symbol Substitution Test) was similar in both groups. Episodes of postoperative delirium/confusion occurred similarly in both groups. Time to ileus resolution and time to ambulation without assistance did not differ between the 2 groups. The duration of hospitalization was 8.4 +/- 1.7 (7-11) days and 7.9 +/- 2.0 (6-9.9) days for control and IT morphine, respectively (nonstatistical difference). Patients in the IT morphine group had longer time to awakening from anesthesia and experienced more sedation.Conclusions: Intrathecal morphine, as compared with intravenous PCA morphine alone, improves immediate postoperative pain and reduces parenteral morphine consumption but does not improve postoperative recovery in elderly patients after major colorectal surgery. [ABSTRACT FROM AUTHOR]

Aims Whether all patients with congestive heart failure (CHF) need to reach the target dose of beta-blocker to obtain a benefit in terms of survival remains uncertain.Methods and results We classified by tertile the 2647 patients enrolled in CIBIS II according to the last tolerated dose: low dose (LD: 1.25, 2.5 or 3.75mg/day, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(n=434\) \end{document}), moderate dose (MD: 5 or 7.5mg/day, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(n=328\) \end{document}) and high dose (HD: 10mg/day, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(n=565\) \end{document}) of bisoprolol or placebo (LD=234, MD=278 and HD=808). In both groups, patients tolerating only low doses were significantly older with more severe New York Heart Association (NYHA) functional class and higher frequency of co-morbidities. Treatment withdrawal was associated with a significant increase of mortality in the bisoprolol group (relative hazard (RH)=2.13, 95% confidence interval (CI)=1.43–3.17, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(p=0.0002\) \end{document}). After adjustment, all-cause mortality was significantly reduced in the bisoprolol group compared to placebo regardless of the dose level considered: LD (RH=0.66, 95% CI=0.48–0.92), MD (RH=0.33, 95% CI=0.21–0.51) or HD (RH=0.59, 95% CI=0.40–0.89).Conclusions Bisoprolol reduces mortality in CHF patients at all tolerated dose levels and its withdrawal increases the risk of mortality. Efforts should be made to maintain bisoprolol therapy based on the individual patient's tolerability. [ABSTRACT FROM PUBLISHER]

Examines the age-associated changes over time of plasma paraxanthine/caffeine (PAX/CAF) ratios used as a probe for CYP1A2 activity. Comparison between the ratio of PAX/CAF in aged and young subjects; Relation of PAX/CAF ratio to the smoking status of subjects; Lack of influence of age on the CYP1A2 activity.

Discusses the antiarrhythmic drug, propafenone, its characteristics and recent research concerning its effectiveness. Results of the Cardiac Arrhythmia Suppression Trial. Flecainide and encainide; Conclusions.

The arrhythmogenic effects of exercise tests are often unpredictable, sometimes paradoxical, and usually poorly reproducible. This explains why they are rather neglected by rhythmologists in studying the mechanisms of arrhythmias and the effects of antiarrhythmic drugs and why their prognostic value is a matter of controversy. At the same time the induced, supposedly ischaemia-related arrhythmias are usually not prevented by revascularization procedures. All these discrepancies are probably explained by the complex interactions between the time-limited stimulation of the sympathetic drive and the arrhythmia mechanisms.During the exercise test the sympathetic drive is increased via the neurogenic and humoral routes, and the post-exercise period is characterized by a vagally-induced deceleration of the heart rate which intervenes in the setting of a persistent high level of sympathetic activity. The arrhythmia components formed by potential triggers (isolated premature beats) and substrates (repetitive activity) do not react in the same way to those different phases. Extrasystoles are mainly rate-dependent, so that they often tend to disappear as the sinus rate accelerates. The repetitive ventricular activity directly depends on the sympathetic drive, but necessitates the presence of the trigger to become manifest. Conceivably, many different situations may result from the complex interplay between these distinct parameters, so that the apparent clinical effect of exercise may be either arrhythmogenic or antiarrhythmic in apparently identical diseases, or even in the same patients. [ABSTRACT FROM PUBLISHER]

1. Quinidine is a potent inhibitor of the genetically-determined debrisoquine 4-hydroxylation. Oxidation reactions of several other drugs, including the 5-hydroxylation of the new antiarrhythmic drug propafenone, depend on the isozyme responsible for debrisoquine 4- hydroxylation. 2. The effect of quinidine on the debrisoquine phenotype- dependent 5-hydroxylation and the pharmacological activity of propafenone was studied in seven 'extensive' metabolizers and two 'poor' metabolizers of the drug receiving propafenone for the treatment of ventricular arrhythmias. 3. In patients with the extensive metabolizer phenotype, quinidine increased mean steady-state plasma propafenone concentrations more than two fold, from 408 +/- 351 (mean +/- s.d.) to 1096 +/- 644 ng ml-1 (P less than 0.001), decreased 5- hydroxypropafenone concentrations from 242 +/- 196 to 125 +/- 97 ng ml- 1 (P less than 0.02) and reduced propafenone oral clearance by 58 +/- 23%. 4. Despite these changes in plasma concentrations, electrocardiographic intervals and arrhythmia frequency were unaltered by quinidine coadministration, indicating that 5-hydroxypropafenone contributes to the pharmacologic effects of propafenone therapy in extensive metabolizers. 5. In contrasts, plasma concentrations of propafenone and 5-hydroxypropafenone remained unchanged in the two patients with the poor metabolizer phenotype. 6. Biotransformation of substrates for the debrisoquine pathway can be markedly perturbed by even low doses of quinidine; interindividual variability in drug interactions may have a genetic component. [ABSTRACT FROM AUTHOR]

Drug interactions involving macrolides have been mainly reported in subjects receiving troleandomycin and in a few receiving erythromycin derivatives. In rats and in humans, troleandomycin, erythromycin and erythromycin derivatives induce microsomal enzymes; the induced isozymes of cytochrome P-450 have a high activity for these macrolides but a poor activity with several other substrates. These isozymes actively demethylate and oxidize these macrolides into nitrosoalkanes which form stable, inactive complexes with the iron of cytochrome P-450. Eventually, the oxidative metabolism of other drugs may be decreased. These effects are marked after administration of troleandomycin, moderate after administration of erythromycin derivatives and absent (or negligible) after administration of spiramycin, josamycin or midecamycin.A second adverse effect of the administration of troleandomycin or erythromycin derivatives is the possible occurrence of hepatitis. Mild hepatic dysfunction is fairly frequent and may be toxic in type. In contrast, jaundice is common, is frequently associated with hypersensitivity, and promptly recurs when the drug is readministered. Troleandomycin and erythromycin derivatives, which form nitrosoalkanes, produce hepatitis, whereas josamycin, midecamycin and spiramycin, which do not form cytochrome P-450-nitrosoalkane complexes, rarely, if ever, produce hepatitis. Nitrosoalkanes are unstable intermediates which react with glutathione but also with cysteine and might covalently bind to the SH-groups of proteins.The following mechanism might be proposed as a hypothetical attempt to link up these various observations. The macrolide (or its reactive metabolite) may have discrete toxicity; in several subjects, this may produce minor liver lesions and a mildly raised aminotransferase activity. Necrosis of a few hepatocytes may release into the circulation plasma membrane proteins altered by the covalent binding of metabolites. Such modified liver antigens may be recognized as foreign and may trigger, in an exceptional subject, an immunoallergic type of clinical hepatitis. [ABSTRACT FROM PUBLISHER]

A patient with congestive heart failure and moderate renal insufficiency developed severe reversible non-oliguric renal failure while on frusemide and enalapril. Renal failure developed when enalapril was given in the presence of pronounced sodium depletion. When positive sodium balance was restored the plasma creatinine concentration began to fall while angiotensin converting enzyme inhibition remained effective and blood pressure was stable. These observations suggest that the degree of sodium depletion plays an important role in the tendency for angiotensin converting enzyme inhibitors to induce renal failure in patients with congestive heart failure and moderate renal insufficiency. Restoration of a positive sodium balance promotes the recovery of renal function after the combined administration of angiotensin converting enzyme inhibitors and diuretics. [ABSTRACT FROM PUBLISHER]

A 60 year old hypertensive patient suffered several cerebral infarctions. A phaeochromocytoma was suspected because the excretion rates of vanillylmandelic acid and its methoxy derivatives were raised and the patient had hypertensive crises. No tumour was found, however, by 131mI-iodobenzylguanidine scintigraphy and computed tomography of the abdomen. Moreover, the enhanced orthostatic plasma catecholamine response suggested that the high excretion rates of catecholamine metabolites were more likely to be caused by the syndrome of raised catecholamines after cerebrovascular accidents than a phaeochromocytoma. A phaeochromocytoma should not be diagnosed within several months of cerebral infarction without first excluding the possibility of a hyperadrenergic state induced by cerebral infarction. [ABSTRACT FROM PUBLISHER]