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R G Morris

Publications and source records attributed to R G Morris.

At least 145 records · Page 8Linked to original sources
PubMed1994

High-performance liquid chromatography determination of clonazepam in plasma using solid-phase extraction.

The use of high-performance liquid chromatography for therapeutic drug monitoring of clonazepam has previously been limited by low sensitivity and labor-intensive liquid-liquid extractions. The present method was developed employing a rapid solid-phase extraction, thus minimising sample workup and providing analytical sensitivity down to 2 micrograms/L using 1 ml of plasma. Plasma samples were loaded onto C18 solid-phase extraction columns, and clonazepam and its internal standard (methyl-clonazepam) were eluted with methanol, dried, and reconstituted in 130 microliters of mobile phase. Chromatographic separation was achieved using a 3-microns RP18 column at 40 degrees C and a mobile phase of 32% acetonitrile and 0.5% glacial acetic acid in distilled water at 0.5 ml/min. Detection was carried out using ultraviolet absorbance at 306 nm. Retention times for clonazepam and methyl-clonazepam were approximately 7 and 12 min respectively. Standard curves were linear over a range of 5-200 micrograms/L with intraassay coefficients of variation of 1.2 and 4.8% at 200 and 5 micrograms/L, respectively. Plasma concentrations measured in patient samples were not statistically different from those obtained using an established gas chromatographic method, and quality control specimens from the Heathcontrol EQA Scheme were consistently within +/- 1.2 SD of the group means. There was no chromatographic interference from other benzodiazepines or other drugs used for the treatment of epilepsy.

Chromatography, High Pressure Liquid↗
PubMed1994

Australian cyclosporin therapeutic monitoring method survey: 1993.

A detailed questionnaire was distributed to the 30 Australian laboratories known to provide cyclosporin-A (CsA) therapeutic drug monitoring (TDM) services with a view to evaluating the range of approaches to such monitoring. Replies were received from all 30 laboratories. The data suggested there was a wide discordance in approaches to CsA TDM due to the fact that laboratories appeared to have adopted individual approaches to this service, both in method selection(s) and proposed therapeutic range(s). In many cases, patients served were shown to travel to more distant centers for their graft, returning to their home city/town for longer term management. Hence, services of several laboratories were involved during their clinical care. A strong mandate was received from respondents for development of national guidelines for the monitoring of CsA and other immunosuppressant drugs in order to avoid such discrepancies in the future. The approaches to external analytical quality assurance (QA) and, to a lesser extent, internal quality control (QC) were generally inadequate.

Australia↗
PubMed1994

Cyclosporin A monitoring in Australia: consensus recommendations.

Cyclosporin-A (CsA) therapeutic drug monitoring plays an integral role in therapeutic management of immunosuppressed patients, including those with organ transplants. This communication, prepared by an Australian team, presents recommendations for the routine monitoring of CsA, including blood sampling methodological approaches and interpretation of results generated. The consensus approach described is intended to address the diversity of attitudes to CsA monitoring demonstrated in a recent national survey of Australian laboratories that provide CsA analyses.

Australia↗
PubMed1994

Analysing brain function and dysfunction in transgenic animals.

Many neuropsychiatric disorders have a genetic aetiology. In vivo gene modification offers a route to simulating such disorders in transgenic animals, allowing a systematic study of the underlying pathophysiology. However, attempts to mimic diseases such as Alzheimer's disease in transgenic animals have not yet been successful. This principally reflects our lack of knowledge concerning normal brain function, and an understanding of the biochemical mechanisms underlying cognitive processes is a primary objective. We and others have therefore focused on the hippocampus, a brain region involved in learning and memory and an early target for degeneration in Alzheimer's disease. Genetic intervention to date has yielded transgenic animals with apparent functional deficits in the hippocampus, leading the way to a greater understanding of brain function.

Animals↗
PubMed1994

Inhibition of nitric oxide synthase does not impair spatial learning.

Nitric oxide (NO), a putative intercellular messenger in the CNS, may be involved in certain forms of synaptic plasticity and learning. This article reports a series of experiments investigating the effects of N omega-nitro-L-arginine methyl ester (L-NAME) upon various forms of learning and memory in the watermaze. L-NAME (75 mg/kg, i.p., sufficient to bring about > 90% inhibition of NO synthesis in brain) produced an apparent impairment in spatial learning when given to naive rats during acquisition (3 d, six training trials per day). This impairment was dose related, stereoselective, and attenuated by coadministration of L-arginine. A second study showed that L-NAME did not affect the retention of a previously learned spatial task. In addition, in a visual discrimination task, the rate at which criterion levels of performance were reached was unaffected by L-NAME. Thus, inhibition of NO synthase may cause a selective impairment of spatial learning without effect upon retention. However, analysis of the early training trials of the visual discrimination task revealed significantly elevated escape latencies in the L-NAME-treated rats, suggesting that inhibition of NO synthase may have more general effects. As normal rats learn the spatial task very rapidly, the possibility arises that the apparent deficit in learning is due to a disruption of some process other than learning per se. A further series of experiments investigated this possibility. L-NAME was found not to impair the learning of a new platform position in the same spatial environment. Surprisingly, L-NAME also had no effect on spatial learning in a second watermaze located in a novel spatial environment by rats well practiced with all aspects of watermaze training. Finally, L-NAME had no effect on spatial learning in naive rats trained with just one trial per day. Thus, systemic injection of an NO synthase inhibitor impairs behavioral performance in two tasks during their initial acquisition, but the basis of this functional disruption is unlikely to be due to any direct effect upon the mechanisms of spatial learning.

Amino Acid Oxidoreductases↗
PubMed1994

Inhibition of nitric oxide synthase does not prevent the induction of long-term potentiation in vivo.

Nitric oxide (NO), a putative intercellular messenger in the CNS, may be involved in certain forms of synaptic plasticity and learning. This article reports a series of experiments investigating whether an inhibitor of NO synthase, N omega-nitro-L-arginine methyl ester (L-NAME), affects long-term potentiation (LTP) in vivo, as the results of recent in vitro experiments would predict. L-NAME, given as an acute injection at a dose sufficient to inhibit hippocampal NO synthase (> 90%), had no effect on perforant path-dentate gyrus LTP induced by a strongly suprathreshold tetanus, but appeared to impair LTP induced by a weak near-threshold tetanus that may be more physiologically relevant. However, subsequent studies revealed that chronic L-NAME treatment (> 95% inhibition of NO synthase) had no effect upon LTP induction, and that acute (but not chronic) treatment resulted in a gradual but significant reduction in nontetanized baseline field potentials. The baseline shift appeared to be of a magnitude sufficient to account for the apparent impairment of weak tetanus-induced LTP. This possibility was further examined in a two-hemisphere experiment in which the time course of changes in the field EPSP of the nontetanized pathway served as the within-subject control for the tetanized pathway. No impairment of LTP induction was observed; indeed, if anything, there was a trend for greater potentiation with L-NAME. Because NO has also been implicated in the control of vasodilation, the effect of L-NAME on cerebrovascular function was also investigated. Peripheral blood pressure was significantly increased by L-NAME at the same dose that affected the field EPSP. Local cerebral glucose utilization was unchanged, while local cerebral blood flow decreased significantly in various brain regions, including the hippocampus, indicating an uncoupling of cerebral metabolism and blood flow. Thus, while NO synthase inhibition does not appear to limit the induction of LTP in vivo, it does reduce the size of baseline field EPSPs and affect local cerebrovascular function.

Amino Acid Oxidoreductases↗
PubMed1993

Thymocyte apoptosis induced by p53-dependent and independent pathways.

Death by apoptosis is characteristic of cells undergoing deletion during embryonic development, T- and B-cell maturation and endocrine-induced atrophy. Apoptosis can be initiated by various agents and may be a result of expression of the oncosuppressor gene p53 (refs 6-8). Here we study the dependence of apoptosis on p53 expression in cells from the thymus cortex. Short-term thymocyte cultures were prepared from mice constitutively heterozygous or homozygous for a deletion in the p53 gene introduced into the germ line after gene targeting. Wild-type thymocytes readily undergo apoptosis after treatment with ionizing radiation, the glucocorticoid methylprednisolone, or etoposide (an inhibitor of topoisomerase II), or after Ca(2+)-dependent activation by phorbol ester and a calcium ionophore. In contrast, homozygous null p53 thymocytes are resistant to induction of apoptosis by radiation or etoposide, but retain normal sensitivity to glucocorticoid and calcium. The time-dependent apoptosis that occurs in untreated cultures is unaffected by p53 status. Cells heterozygous for p53 deletion are partially resistant to radiation and etoposide. Our results show that p53 exerts a significant and dose-dependent effect in the initiation of apoptosis, but only when it is induced by agents that cause DNA-strand breakage.

Animals↗
PubMed1993

Landmark stability is a prerequisite for spatial but not discrimination learning.

Neurons sensitive to both place and direction from distinct regions of the hippocampal formation, allometric relationships between spatial learning and hippocampal structure and pronounced impairments in spatial learning after lesions in this area, indicate that the hippocampal formation subserves allocentric spatial learning. To learn more about the process of spatial representation, we have developed a task that provides independent control of both landmark and directional cues. On the basis of physiological and behavioural work, this task also makes it possible to investigate the relevance of associative learning principles, such as predictability, to the spatial domain. We report here that although rats learn to discriminate between landmarks on the basis of their proximity to a reliably predicted food reward, they will only learn to use them to represent its location if they maintain stable locations within a geometric frame of reference.

Animals↗
PubMed1993

Cumulative long-term potentiation in the rat dentate gyrus correlates with, but does not modify, performance in the water maze.

The electrically induced increase in hippocampal synaptic strength known as long-term potentiation (LTP) is thought to involve some of the same mechanisms as those mediating information storage during spatial learning. Physiological saturation of synaptic weights might therefore be expected to occlude spatial learning. In support of this, Castro et al. (Castro CA, Silbert LH, McNaughton BL, Barnes CA, 1989, Nature 342:545-548) reported that repeated induction of LTP to asymptotic levels, over a 14-day period, blocked the ability of rats to learn the position of a hidden platform in a water maze shortly afterwards. The authors have attempted to replicate this finding in two experiments. In Experiment 1, rats were given either 400 Hz stimulation as 50 trains/day over a 5-day period, to induce LTP, or were given the same number of stimulus pulses at 1 Hz. Two hours after the last stimulation session they underwent eight spatial learning trials, occurring at 2-hour intervals. In Experiment 2, the procedure of Castro et al. was followed exactly, with LTP induced by 10 trains of 400 Hz stimulation daily for 14 days. Spatial learning trials began 10 minutes after the last stimulation session and consisted of 12 trials with alternating 30-second and 2-minute intervals. In neither experiment was a significant impairment of spatial learning observed. However, there was a strong positive correlation, in both experiments, between the final level of LTP and subsequent performance in the water maze.

Animals↗
PubMed1993

Neural correlates of planning ability: frontal lobe activation during the Tower of London test.

Single-photon emission computerised tomography (SPECT) was used to investigate whether pre-frontal cerebral blood flow in normal adults is increased during planning activity. A subtraction technique was used in which regional cerebral blood flow (rCBF) was measured in subjects during a computerised version of the Tower of London task. Both rCBF and performance on this task were compared to a motor control condition requiring the same responses and using the same visual display. The level of rCBF was significantly increased in the left pre-frontal cortex during the Tower of London task. In addition, subjects who took more time planning their moves, and less moves to complete a problem had a significantly higher level of rCBF in the left pre-frontal cortex. Subsequent execution latencies for the task were correlated negatively with both left and right rCBF.

Adult↗
PubMed1993

The enigma of olfactory learning.

It has been suggested, on the basis of neuroanatomical and behavioural data, that olfactory discrimination in the rat provides privileged access to higher cognitive processes, involves the acquisition of a learning-set and, importantly, can be used to model human hippocampal function and dysfunction. In this article, Ian C. Reid and Richard G. M. Morris question the assumptions upon which these claims have been based and criticize the application of odour discrimination learning in the rat to the study of human memory.

Animals↗
PubMed1993

Regional blood flow as a determinant of drug absorption description of an animal model.

Factors that influence recommended dosage guidelines for intramuscularly and subcutaneously injected drugs include a spectrum of variables, including therapeutic objective(s), the drug's therapeutic index, the inclusion of concomitant vasoconstrictors, and so on. However, little account is taken of the likely influence of regional blood flow at the injection site. This may vary according to the site of injection, the age and medical condition of the patient with the potential to markedly affect the rate of drug absorption and the resultant therapeutic and toxicity outcomes. An animal model is described for simultaneously quantifying the drug's pharmacokinetic profile and the regional blood flow (using technetium99 elution) at sites of differing vascularity so that the potential relationship can be ascertained. An application to lignocaine absorption is provided, however, the model would be applicable to a range of drug applications and could serve as a means of investigating differences both within a drug class (e.g., members with differing lipophilicity) as well as across drug classes (e.g., local anesthetics, opiates, insulin preparations, etc.).

Anesthesia, General↗
PubMed1993

Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer.

Thirty-four primary, untreated sporadic breast cancers were examined for loss of heterozygosity (LOH) at tumour suppressor loci involved in colorectal cancer: APC/MCC at 5q21 and DCC at 18q21. LOH was identified in 28% informative patients at 5q21 and 31% at 18q21. LOH at 5q21 and 18q21 was compared with allele loss at 17p13 and concurrent LOH at two or more of the loci was noted in 24% of tumours. Expression of a 12 kb DCC mRNA was demonstrated in 14/34 (42%) of the cancers and in all five tumours with LOH at the DCC locus there was an additional 11 kb DCC mRNA. Abnormalities of three loci involved in colorectal cancer (5q21, 17p13 and 18q21) therefore also occur in sporadic breast cancer. The accumulation of such genetic abnormalities may confer a growth advantage important in the development of breast cancer.

Alleles↗
PubMed1993

Experiences with the enzyme-multiplied immunoassay cyclosporine specific assay in a therapeutic drug monitoring laboratory.

Cyclosporin-A (CsA) monitoring is well established in the management of most organ transplant patients. The present communication reviews the performance of the recently introduced specific enzyme-multiplied immunoassay (EMIT) CsA method during the first 7 months of its operation and compares costs of providing this service with those of the specific 125I radioimmunoassay (RIA) method previously employed in this clinical laboratory. Results suggest that the EMIT method performed well, giving long calibration curve stability (up to 12 weeks), and only 4.4% of the 31 kits through this period were consumed in assaying calibration standards compared with 20.8% with RIA. However, more quality control assays were performed, with the net result that only a slight improvement in the percentage of kit consumed in patient assays was noted (74.0% compared with 70.3%) with the EMIT method. This method appears to have been well accepted clinically as the CsA assay request rate over this period increased by 23% and, since it is both specific and rapid, is, therefore, recommended as the best CsA method currently available.

Calibration↗
PubMed1993

The relationship between regional blood flow and absorption of lignocaine.

With the increasing application of certain surgical procedures to 'day surgery' cases, there has been greater utilization of local anaesthetic agents. Such procedures are undertaken using single infiltration dosage recommendations for lignocaine, both with and without adrenaline. The present paper describes results obtained from a sheep model that considers the role of the regional blood flow of the injected site as a determinant of lignocaine absorption and resultant pharmacokinetics. The peak concentration of lignocaine in plasma following administration to two selected sites of different vascularity (as determined by a technetium99 washout method), as well as the effect of concomitant adrenaline administration, was shown to correlate with the regional blood flow to the site (rs = 0.73, P = 0.008). Extrapolating these animal data to the clinical situation suggests that larger dosages of lignocaine could be used safely for infiltration anaesthesia in regions of poor regional blood flow without posing a threat of lignocaine-induced toxicity, and that the current dosage recommendations could be modified in respect of the regional blood flow of the particular site to be infiltrated.

Absorption↗
PubMed1993

Evaluation of the safety of inguinal hernia repair in the elderly using lignocaine infiltration anaesthesia.

Repair of inguinal hernia using local anaesthesia is becoming increasingly popular as it avoids many of the systemic side effects associated with general or spinal/epidural anaesthesia and provides excellent early postoperative pain relief. Dosages of local anaesthetic approaching the recommended maximum are frequently required for adequate anaesthesia of the inguinal region. The present study describes the disposition and safety of lignocaine with adrenaline in 14 elderly patients to ascertain its safety with a view to more widespread application of the technique in more complicated hernia repairs. Serial plasma lignocaine concentrations were determined for up to 24 h following doses approaching the recommended maximum for infiltration (7 mg/kg). Peak lignocaine concentrations (normalized to 7 mg/kg) ranged from 0.23 to 0.90 mg/L (mean of 0.54 mg/L); that is, the maximum recorded concentration was less than one-fifth the toxicity threshold for lignocaine of 5 mg/L. The study suggested that the majority of patients tolerated the local anaesthetic approach very well and that the wide safety margin allowed ample scope to develop the local anaesthetic approach for the repair of more complex hernia repairs (e.g. large, bilateral or strangulated herniae, or those in obese patients) without risk of exposing patients to lignocaine concentrations which may cause toxic side effects.

Age Factors↗
PubMed1993

Felodipine improves pulmonary hemodynamics in chronic obstructive pulmonary disease.

Pulmonary hypertension in chronic obstructive pulmonary disease (COPD) is associated with a poor prognosis. Reduction of pulmonary artery pressure in COPD by prolonged oxygen treatment has been shown to be associated with increased survival. In an attempt to find a suitable pharmacologic method of reducing pulmonary artery pressure and pulmonary vascular resistance in COPD, we enrolled 13 stable pulmonary-hypertensive, hypoxemic COPD patients in a study to test the effects of felodipine, a relatively new, vascular-selective calcium antagonist. Doppler echocardiography was used to estimate pulmonary artery pressure and cardiac output before treatment, 2, 7, and 12 weeks during felodipine treatment (10 to 20 mg/d), and after a 1-week placebo washout period. Measurements of lung function, arterial blood gases, and exercise capacity during an incremental bicycle ergometer test were also performed at intervals during the study period. Three patients withdrew from the study and of the remaining 10, 8 had some side effects of medication (peripheral edema or headache) that improved either spontaneously or following a reduction in drug dose. In the 10 patients who completed the study (8 male; mean age, 67 years), felodipine resulted in significant reductions in mean pulmonary artery pressure (22 percent) and total pulmonary (vascular) resistance (30 percent) and increases in cardiac output (15 percent) and stroke volume (13 percent) compared with baseline measurements and those taken after placebo washout. These effects were sustained over the 12 weeks of felodipine treatment. There was no adverse effect of felodipine treatment on pulmonary gas exchange at rest or during exercise and no change in lung function or exercise capacity. We conclude that in pulmonary hypertensive, hypoxemic COPD patients, felodipine substantially improves pulmonary hemodynamics.

Aged↗