Bernard A. MacLeod

Intraarticular bupivacaine (Marcaine) after arthroscopic meniscectomy: a randomized double-blind controlled study.

In this study, 79 patients undergoing arthroscopic meniscectomy were entered into a randomized double-blind controlled trial in which intraarticular bupivacaine (Marcaine), was compared with a saline placebo. Intraarticular bupivacaine was shown to be an effective and safe method of achieving analgesia after arthroscopic meniscectomy.

An improved perfusion apparatus for small animal hearts.

A perfusion apparatus for mechanical and electrophysiological studies in small animal (e.g., rat, guinea pig) hearts is described. The apparatus consists of a number of individual perfusion chambers connected to the aortic perfusion cannula of a Langendorff perfused heart. The aortic root perfusion pressure is controlled by the oxygenating gas (usually 5% CO2 in O2) at a range of 0-200 mmHg. Different solutions can be placed in different individual chambers. Pressure in the left ventricle is monitored by means of a special compliant, but nonelastic, balloon while special atraumatic electrodes allow high-voltage, noise-free ECG recordings to be made from all parts of the epicardium. The apparatus keeps hearts beating for hours while the multichamber allows multiple drug applications to be made rapidly. Thus, the apparatus can be used for all types of pharmacodynamic analysis.

Antiarrhythmic properties of tedisamil (KC8857), a putative transient outward K+ current blocker

1 Rats were used to evaluate the antiarrhythmic properties of tedisamil, a novel agent with the electrophysiological properties of a Class III antiarrhythmic drug. Tedisamil was tested against coronary artery occlusion‐induced arrhythmias in conscious animals. 2 The actions of tedisamil on the ECG, as well as responses to electrical stimulation, were compared with those on the configuration of epicardial intracellular action potentials recorded in vivo. 3 Tedisamil (1–4 mg kg−1, i.v.) caused bradycardia, elevated blood pressure and dose‐dependently reduced ventricular fibrillation (VF) induced by occlusion of the left anterior descending coronary artery. Other ischaemia‐associated arrhythmias were not so well suppressed. Antiarrhythmic activity was greatest when the tedisamil‐induced bradycardia was prevented by electrically‐pacing the left ventricle. 4 Tedisamil dose‐dependently lengthened the effective refractory period and prevented electrically‐induced VF. In vivo, tedisamil (0.5–4 mg kg−1, i.v.) prolonged the duration of epicardial intracellular action potentials by up to 400%. 5 Results showed that tedisamil possessed antifibrillatory actions in rats that were related to Class III electrophysiological actions as revealed by electrical stimulation and electrophysiological analyses.

Liposomal bupivacaine. Extended duration nerve blockade using large unilamellar vesicles that exhibit a proton gradient.

Background There is a clinical requirement for longer-acting local anesthetics, particularly for the management of postoperative and chronic pain. In this regard, liposomes have been suggested to represent a potentially useful vehicle for sustained drug release after local administration. In the current study, the authors used a transmembrane pH gradient to efficiently encapsulate bupivacaine within large unilamellar vesicles. They report on the kinetics of drug uptake and release and the duration of nerve blockade. Methods The rate and extent of bupivacaine uptake into large unilamellar vesicles that exhibit a pH gradient (interior acidic) were determined and compared to drug association with control liposomes that did not exhibit a proton gradient. In subsequent studies, researchers examined the kinetics of bupivacaine release from these liposome systems in vitro. Using the guinea pig cutaneous wheal model, the rate of clearance of the liposome carrier was monitored after intradermal administration, using a radiolabelled lipid marker, and the duration of nerve blockade produced by free and liposomal bupivacaine was compared. Results Bupivacaine was rapidly and efficiently accumulated within liposomes that exhibited a pH gradient (interior acidic) with trapping efficiencies of 64-82% of total drug, depending on the initial bupivacaine:phospholipid ratio. Little uptake was seen, however, for control vesicles that did not exhibit a transmembrane proton gradient. Using an in vitro model of drug clearance, liposomally encapsulated bupivacaine was found to be slowly released for a longer period of time compared with either the free drug or bupivacaine associated with control (no pH gradient liposomes). In the guinea pig cutaneous wheal model, more than 85% of the liposomal carrier was found to remain at the site of administration for 2 days. The sustained drug release afforded by liposomes that exhibited a pH gradient resulted in an increase in the duration of nerve blockade of as much as threefold compared with either the free drug or bupivacaine in the presence of control (no pH gradient) liposomes. Recovery of half maximal response (R2.5) after administration of 0.75% free bupivacaine, for example, was approximately 2 h, whereas the same dose of bupivacaine in pH gradient liposomes exhibited a R2.5 of approximately 6.5 h. Conclusions Large unilamellar vesicles that exhibit a pH gradient can efficiently encapsulate bupivacaine and subsequently provide a sustained-release system that greatly increases the duration of neural blockade.

Anaesthesia by intravenous emulsified isoflurane in mice

An emulsion of isoflurane in Intralipid™ for intravenous (iv) injection was formulated and its anaesthetic properties determined in mice. The major advantage of iv delivery of volatile agents is to accelerate the induction of anaesthesia by circumventing the anaesthetic circuitry and the lung’s functional residual capacity. Isoflurane was added to Intralipid™ in varying concentrations. The ED50 (n = 34) and LD50 (n = 20) were determined by a single iv bolus injection. Anaesthesia was also induced and maintained for 30 min (n = 5) by continuous infusion and the time to emergence was measured. The ED50 and LD50 were 0.7 ± 0.2 μl and 2.4 ± 0.2 μl of isoflurane equivalent respectively. An average infusion rate of 1.6 ± 0.4 μl · min−1 of isoflurane equivalent was required for maintenance following which the average emergence time was 193 ± 35 secs. The only negative effect was local skin ulceration with an inadvertent interstitial injection. We conclude that iv induction and maintenance with emulsified isoflurane in Intralipid™ can be carried out with safety and reproducibility in the mouse. Further larger animal studies are warranted assessing the haemodynamic, toxicological, physiochemical and pharmacokinetic characteristics of these and other similar preparations.RésuméUne émulsion d’isoflurane dans l’Intralipid™ pour injection intraveineuse est préparée et ses propriétés anesthésiques sont déterminées chez la souris. L’avantage principal de l’administration iv d’agents volatils est d’accélérer la vitesse d’induction de l’anesthésie en court-circuitant le circuit anesthésique et la capacité résiduelle fonctionnelle pulmonaire. De l’isoflurane est ajouté à l’Intralipid™ en variant les concentrations. L’ED50 (n = 34) et la LD50 (n = 20) sont déterminées pour une injection unique en bolus. De plus, l’anesthésie est induite et entretenue pendant 30 min (n = 5) par perfusion continue et le temps de récupération mesuré. L’ED50 et la LD50 sont respectivement de 0,7 ± 0,2 μl et de 2,4 ± 0,2 μl d’équivalent isoflurane. En moyenne, une vitesse de perfusion de 1,6 ± 0,4 μl · min−1 est nécessaire pour l’entretien; par la suite, le temps moyen de récupération est de 193 ± 35 sec. Le seul effet négatif consiste en une ulcération locale au site d’une injection interstitielle accidentelle. Nous concluons que l’induction et l’entretien iv avec une émulsion d’isoflurane dans l’Intralipid™ peuventêtre réalisés avec sécurité et reproducibilité chez la souris. Des études ultérieures chez des animaux plus gros sont justifiées pour évaluer les caractéristiques hémodynamiques, toxicologiques, physicochimiques et pharmacocinétiques de ce type de préparation.

Antiarrhythmic actions of verapamil against ischaemic arrhythmias in the rat

1 The actions of intravenous verapamil against arrhythmias induced by occlusion of a coronary artery were investigated in conscious rats. 2 Verapamil (2–20 mg kg−1, i.v. given pre‐occlusion) dose‐dependently reduced arrhythmias in rats with either large or small occluded zones at an ED50 of 6 mg kg−1. This dose was effective when given immediately post‐occlusion. 3 Severe arrhythmias, as opposed to PVC, were preferentially reduced. 4 In conscious, and pentobarbitone‐anaesthetized rats, verapamil (6 mg kg−1) had different effects on electrically‐induced arrhythmias, and the ECG, from an equi‐effective anti‐arrhythmic dose of quinidine (20 mg kg−1, i.v.). Quinidine decreased following frequency, but increased threshold current and pulse width, whereas verapamil did not. Both drugs increased P‐R interval, but only quinidine increased QRS and Q‐T intervals. 5 Thirty minutes post‐occlusion, the verapamil content of tissue and blood was determined after a 6 mg kg−1 dose given pre‐ or post‐occlusion. Measurable levels of verapamil were found in both normal and ischaemic myocardium. Plasma and plasma water concentrations were 3.6 ± 0.8 μmol l−1 and 0.6 ± 0.1 μmol l−1 (x̄ ± s.e.mean), respectively following post‐occlusion administration vs. 2.7 ± 1.2 and 0.24 ± 0.04 for pre‐occlusion administration. 6 Plasma water concentrations were close to IC50 values for inhibition of contractility in rat atria and ventricles. Similar concentrations depressed slow action potentials induced in rat ventricles by raised K+ 7 We suggest that the ability of verapamil to prevent severe ventricular arrhythmias following myocardial ischaemia in the conscious rat is largely due to the calcium antagonist effects of the drug.

Improved peribulbar anaesthesia with alkalinization and hyaluronidase

A prospective double-blind randomized study was carried out to determine the effect ofpH and the addition of hyaluronidase to a mixture of lidocaine and bupivacaine on the efficacy of peribulbar anaesthesia. One hundred patients were assigned to one of five groups. All groups received a solution of two parts bupivacaine (0.75%) and one part lidocaine (2%) (with 1:100,000 adrenaline) as the base components of their anaesthesia. Group 1 received only the bupivacaine-lidocaine mixture, pH 3.9. Group 2 received a solution supplemented with hyaluronidase (ten units · ml−1), pH of 5.1. Group 3 received the bupivacaine-lidocaine mixture alkalinized with sodium bicarbonate to a pH of 5.1, the same as solution 2. Group 4 received the mixture with hyaluronidase alkalinized to pH of 6.7. Group 5 received the bupivacaine-lidocaine mixture alkalinized to a pH of 6.7. Efficacy of each block was graded according to the degree of residual movement 30 min following injection, as described by House et al1. The solution containing hyaluronidase and pH adjusted to 6.7 was found to be the most effective (P < 0.025). The presence of hyaluronidase without alkalinization did not improve the efficacy of the mixture; and similarly, alkalinization in the absence of hyaluronidase was ineffective. These results reflected the pH- and temperaturedependent thermodynamic properties of local anaesthetics, and the pH-dependent activity of hyaluronidase.RésuméUne étude randomisée et à double insu est réalisée dans le but de déterminer l’effet du pH et de l’ajout d’hyaluronidase à un mélange de lidocaine et de bupivacaïne sur l’efficacité de l’anesthésie péribulbaire. Cent patients sont répartis en cinq groupes. Tous les groupes recoivent une solution de deux parties de bupivacaïne (0,75%) et d’une partie de lidocaïne (2%) adrénalinées à 1:100,000 comme agent de base. Le groupe 1 ne reçoit que le mélange bupivacaïne-lidocaïne à pH 3,9. Le groupe 2 reçoit la solution supplémentée d’hyaluronidase (10 u · ml−1) à pH 5,1. Le groupe 3 reçoit le mélange bupivacaïne-lidocaïne alcalinisé au bicarbonate de soude pour porter le pH à 5,1 comme la solution 2. Le groupe 4 reçoit le mélange supplémenté d’hyaluronidase alcalinisé au pH de 6,7. Le groupe 5 reçoit le mélange bupivacaïne-lidocaïne alcalinisé au pH 6,7. L’efficacité de chaque bloc est cotée selon le degré des mouvements résiduels 30 min après l’injection, selon la méthode de House et al1. La solution contenant de l’hyaluronidase avec un pH ajusté à 6,7 a été trouvée la plus efficace (P < 0,025). La présence d’hyaluronidase sans alcalinisation n’améliore pas l’efficacité du mélange et de la même façon, l’alcalinisation sans hyaluronidase n’améliore pas l’efficacité du mélange. L’alcalinisation en absence d’hyaluronidase n’est pas efficace. Ces résultats reflètent les propriétés thermodynamiques dépendantes du pH et de la températures des anesthésiques locaux, et l’activité de l’hyaluronidase elle-même dependante du pH.

The effect of modification of sympathetic activity on responses to ligation of a coronary artery in the conscious rat

1 Ligation of a coronary artery was performed in conscious rats whose sympathetic system activity had been altered by various treatments. 2 β‐Adrenoceptor blockade with acute (0.2 mg kg−1 plus 0.1 μg kg−1 min−1) or chronic (50–60 mg kg−1 daily for 12 days) propranolol treatment had little effect on arrhythmias, or other responses to ligation. 3 Abrupt withdrawal of chronic propranolol two days before ligation was also without effect. 4 Reduction of sympathetic activity acutely with labetalol (5 mg kg−1), or chronically with adrenomedullectomy and 6‐hydroxydopamine treatment, accentuated the adverse effects of ligation. 5 The results of this study suggest that, while activity of the sympathetic system is not detrimental during ligation in the conscious rat, it may be important for survival.

A prospective, double‐blind, randomized cross‐over study evaluating changes in urinary pH for relieving the symptoms of interstitial cystitis

To provide evidence for the clinical efficacy of changes in urinary pH on the pain associated with interstitial cystitis (IC).

Propofol reduces cognitive impairment after electroconvulsive therapy

Background: Cognitive impairments are the main complication after electroconvulsive therapy (ECT). Modification of treatment parameters has been shown to affect the magnitude of these impairments, but the role of anesthetic type remains unclear. This study tested whether there is a difference in cognitive impairments immediately after ECT with propofol compared to thiopental anesthesia. Methods: This randomized, double-blind, crossover study included 15 patients receiving right unilateral ECT for depression. Patients received propofol or thiopental on alternating ECTs up to 6 treatments. Immediate and delayed verbal memory, motor speed, reaction speed, visuospatial, and executive functions were assessed 45 minutes after each ECT. Differences were assessed with repeated measures analysis of variance. Results: Cognitive impairments were reduced after ECT with propofol compared to thiopental. Time to emergence was quicker and EEG seizure duration was shorter after propofol treatments. There was no significant correlation between seizure duration and neuropsychological test performance. Conclusions: Our results indicate that cognitive impairments in the early recovery period after ECT are reduced with propofol compared to thiopental anesthesia. We suggest that, in addition to ECT parameters, the type of anesthetic agent should be considered to reduce cognitive impairments after ECT.