Disposition and hypoglycaemic action of glipizide in diabetic patients given a single dose of nifedipine

Summary Adrenaline, when administered in dental local anaesthetic solutions, significantly reduces the plasma potassium concentration in young healthy adults. This effect occurs within 10 min of extravascular injections into the maxillary buccal sulcus and may influence the choice of local anaesthetic solution for patients receiving kaliuretic diuretics.     

Neurotoxicity after spinal anaesthesia induced by serial intrathecal injections of magnesium sulphate An experimental study in a rat model

We have previously demonstrated in a rat model that the lumbar intrathecal injection of 0.02 ml 6.3% magnesium sulphate, a concentration iso-osmolar with rat plasma, produces a state of spinal anaesthesia and general sedation which reversed completely after 6 h, without evidence of neurotoxicity, immediately or during the week thereafter. Using the same model and five groups of six animals in each, we administered the same volume and concentration of magnesium sulphate and compared its clinical effects with those of 0.02 ml 12.6% magnesium sulphate, 0.02 ml 2% lignocaine and 0.02 ml 0.9% sodium chloride solution, given as a series of 15 injections on alternate days for a period of 1 month. The animals were then killed and their spinal cords and meninges examined histologically. No significant differences were noted in the times of onset, durations of sensory and motor blockade and the times to full recovery throughout the entire period of 1 month's observation in the animals receiving intrathecal 6.3% magnesium sulphate. In the group receiving 12.6% magnesium sulphate, the time of onset of sensory and motor blockade was shorter and the duration of both parameters was significantly longer than in the former group. Full clinical recovery and resumption of normal eating and drinking took place in both groups throughout the entire series of 15 successive intrathecal injections. Identical, mild, uniform histopathological changes in the spinal cord were seen in all the five groups, including the group in which only the intrathecal catheter was implanted. The complete recovery and benign consequences of repeated intrathecal injections of iso-osmolar magnesium sulphate in a rat model indicate a lack of neurotoxicity and provide an impetus for further trials in larger animal species, before initial clinical trials of this substance, given intrathecally, in humans.     

Lignocaine–induced convulsion does not induce c–fos protein (c–Fos) in rat hippocampus

Recent studies have shown that proto–oncogene c–fos mRNA is induced in the central nervous system by a variety of stimuli including generalised convulsions. In this study, the expression of c–fos protein (c–Fos) following lignocaine–induced convulsions was examined and compared with that following convulsions induced by non–anesthetic convulsants, such as pentylenetetrazol, kainic acid and electroconvulsive shocks, in rat brain.
Administration of 120 mg kg^-1 lignocaine by the intraperitoneal route induced generalised convulsions in all rats examined within 10 min. C–Fos was markedly induced in the piriform cortex and amygdala, and slightly induced in the neocortex and thalamus, while no c–Fos expression was observed in the hippocampus. In contrast, c–Fos expression following generalised convulsions induced by non–anaesthetic convulsants was very marked in the hippocampal region, piriform cortex and amygdala, and extended to the thalamus and neocortex.
These results contradict those of previously reported local cerebral metabolic studies using 2–deoxyglucose as a metabolic marker, and suggest that lignocaine–induced convulsions, unlike those induced by non–anaesthetic convulsants, may not cause severe sequelae (plastic changes) in the hippocampus.     

Continuous extradural infusion of lignocaine 0.75% vs bupivacaine 0.125% in primiparae: quality of analgesia and influence on labour

We studied 86 primiparous women with uncomplicated pregnancy and labour requesting extradural analgesia in labour. All the women were over 36 weeks of gestation with a cephalic-presenting singleton fetus. The women were allocated randomly to two groups: group A, who received an extradural infusion of lignocaine 0.75%, after an initial dose of 10 ml of lignocaine 1.5%, and group B, who received an infusion of bupivacaine 0.125% after an initial dose of 10 ml of bupivacaine 0.25%. All the women had their labour actively managed. Assessment of analgesia during labour and delivery, and the requirements for additional top-ups were noted, as were mode of delivery, requirement for oxytocic augmentation and incidence of fetal distress. Maternal and umbilical cord plasma concentrations of lignocaine were measured at delivery in 12 women receiving extradural lignocaine. There were no statistically significant differences between the two groups in terms of the mode of delivery, incidence of fetal distress, fetal heart rate abnormalities, or Apgar scores of the babies. Women in the bupivacaine group had a significantly better quality of analgesia during both the first and second stages of labour (p = 0.0005) and required fewer top-ups than those in the lignocaine group. However, the requirement for oxytocin augmentation during the first and second stages of labour was significantly less in the lignocaine group (p = 0.004). Similarly, the duration of the second stage was shorter compared with the bupivacaine group. In spite of high plasma concentrations of lignocaine, no side effects were noted in either mothers or babies.     

Is local anaesthesia actually beneficial in flexible fibreoptic nasendoscopy?

Although the application of a topical local anaesthetic before fibreoptic nasendoscopy is routine practice in many otolaryngological outpatients, the actual benefit to the patient of this procedure remains in doubt. Eighty-two patients were recruited in this double-blind randomized control trial which compared the patients’ experiences of fibreoptic nasendoscopy with nasal preparations of Xylocaine^® (lidocaine), normal saline, and no spray to the nose and throat. A visual analogue scoring system was used to determine scores for the overall unpleasantness of procedure, receiving a spray, and taste of the spray, and pain. This study has shown significantly worse overall experience (P = 0.001) and pain (P = 0.048) scores for Xylocaine^® spray versus no spray. It is concluded that the routine use of topical local anaesthetics within the nose before routine fibreoptic nasendoscopy is not only of no value, but actually makes the experience worse for the patient.     

A clinical evaluation of three topical anaesthetic agents

This study compared the efficacy of EMLA 5% Cream, Xylocaine 5% (lignocaine 5 per cent) and NUM (benzocaine 15 per cent, amethocaine 1.7 per cent) to a placebo in reducing the pain experience during needle insertion. In a random, double blind study three groups of twenty volunteers each had a paired topical anaesthetic/placebo placed bilaterally in the buccal sulcus of the upper premolar regions for two minutes, followed by the insertion of a standard 27 gauge needle to a depth of 5 mm. Pain experience was measured with visual analogue scales. Results showed that all three agents significantly reduced pain when compared with the placebo--EMLA (p less than 0.002); Xylocaine (p less than 0.05); NUM (p less than 0.005).     

Parenteral lignocaine in cancer neuropathic pain: A series of case reports

Abstract

Neuropathic cancer pain is a clinical challenge and significantly more difficult to treat. The treatment approach differs from nociceptive pain. Use of parenteral lignocaine has been studied extensively in postoperative and neuropathic chronic pain syndromes, and its use in cancer pain is extrapolated from this research. We report on our experience in using parenteral lignocaine in four patients admitted to an inpatient hospice unit. All four patients suffered neuropathic pain from tumour involvement. Delirium with confusion and drowsiness was present in all four patients, precluding the use of adjuvants such as ketamine which could potentially aggravate confusion. In all four patients, there was a positive response to a parenteral lignocaine bolus of 50 mg. With an objective reduction in pain after the bolus, a continuous lignocaine infusion was initiated. The duration of infusions ranged from 2 to 13 days, and the infusion dosages were between 800 and 1500 mg per day. There were no documented adverse effects at these doses. The mean equivalent daily dose of morphine remained stable during the duration of treatment with lignocaine. In our experience, parenteral lignocaine can be used safely in an inpatient hospice care setting and should be considered as part of the analgesic armamentarium to manage cancer neuropathic pain, even at the terminal phase.     

Correlation between midazolam and lignocaine pharmacokinetics and MEGX formation in healthy volunteers

AIMS: The objectives of the present investigation were: (a) to determine the correlation between lignocaine and midazolam pharmacokinetics following intravenous administration in healthy volunteers, (b) to determine the effects of treatment with an inhibitor of CYP3A4 (erythromycin) on this correlation and (c) to assess the precision of the MEGX-test as a sole predictor of lignocaine and midazolam pharmacokinetics. METHODS: The study was conducted in four male and four female healthy volunteers, aged between 21 and 26 years, who received 1 mg kg-1 lignocaine HCl i.v. on days 1, 3, 5, 9 and 10 of the investigation. On days 5 and 10 they also received midazolam, 0.075 mg kg-1 i.v. and from days 6-10 they took erythromycin 500 mg orally, four times daily. Following administration of lignocaine and midazolam, frequent venous blood samples were obtained for determination of the concentrations of lignocaine, MEGX and midazolam. RESULTS: In the absence of erythromycin a statistically significant linear correlation was observed between the clearance of lignocaine and midazolam (CL(midazolam)= 0.41 x CL(lignocaine)+ 1.2; r(2) = 0.857; P < 0.001). Erythromycin cotreatment resulted in a loss of the correlation between the two clearances (r(2) = 0.39; P = 0.1). Erythromycin caused a statistically significant reduction in midazolam clearance from the original value of 3.8 to 2.5 (95% CI for the difference -2.27, -0.35) ml kg-1 min-1. Interestingly there was no significant change in the clearance of lignocaine (6.4 vs 5.8 (95% CI for the difference -2.74, -1.51) ml kg-1 min-1). Furthermore no correlation at all was observed between the MEGX-test and lignocaine or midazolam clearances. Considering the data on day 1, 3 and 5 the intra-individual coefficient of variation in the MEGX-test was 45.3% at 15 min and 23.5% at 30 min, respectively. CONCLUSIONS: It is concluded that there is a significant correlation between lignocaine and midazolam clearances but this correlation is lost after CYP3A4 inhibition by erythromycin. The MEGX-test is of no value in assessing intra- and inter-individual variability in midazolam clearance.     

Inclusion of lignocaine base into a polar lipid formulation--in vitro release, duration of peripheral nerve block and arterial blood concentrations in the rat

BACKGROUND: Slow-release formulations of local anaesthetics may produce nerve blocks of long duration. The present study aimed at investigating the in vitro and in vivo properties of a polar lipid formulation for slow release of lignocaine and the effects on nerve block duration by inclusion of dexamethasone into the system. METHODS: In vitro release of lignocaine from the lipid formulation was studied in a US Pharmacopoeia rotating apparatus. Sciatic nerve blocks were induced in rats by 0.1 ml of test formulations containing lignocaine HCl 20 mg. ml-1 in aqueous solution, lignocaine base 20, 100 or 200 mg. ml-1 in lipid formulation or the last formulation with dexamethasone 0.05, 0.5 or 5 mg. ml-1. The durations of sensory and motor block and the arterial blood concentrations of lignocaine were investigated. RESULTS: In vitro there was a sustained release of lignocaine from the lipid formulation, with 50% release at around 48 h. In vivo lignocaine base 20 mg. ml-1 in lipid formulation produced sciatic nerve blocks of significantly shorter duration than lignocaine HCl 20 mg. ml-1 in aqueous solution, while lignocaine base 100 and 200 mg. ml-1 in lipid formulation produced blocks lasting two and three times longer, respectively, than the lignocaine HCl solution. Addition of dexamethasone did not affect the duration of nerve block. Following administration of lignocaine base 200 mg. ml-1 in lipid formulation, as compared to lignocaine HCl 20 mg. ml-1 in aqueous solution, the maximal blood concentration of lignocaine was only three times higher in spite of the ten-fold difference in dose, and the mean terminal half-life was three times longer, reflecting the slow release from the formulation. CONCLUSIONS: Our findings indicate that lignocaine base in polar lipids acts as a slow-release preparation of local anaesthetic both in vitro and in vivo.