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Biomedical subjects

A M Gray

Publications and source records attributed to A M Gray.

At least 37 records · Page 2Linked to original sources
PubMed1998

ALS/MND and the perspective of health economics.

In health care, choices are constantly being made about alternative uses of scarce resources, and health economics offers a framework for analysing these choices and for improving resource allocation. In cost-effectiveness analysis, the costs and consequences of alternatives are systematically measured and compared, with the objective of achieving maximum health gain with the available resources. Treatment options for patients with ALS/MND are severely limited, but riluzole has been shown to offer modest improvements in survival. However, decision-makers are likely to want convincing evidence on the cost-effectiveness of this therapy before recommending widespread adoption. Here, some initial estimates of cost-effectiveness are provided, using published effectiveness data and considering only the costs of therapy and of tracheostomy. Compared with placebo, the incremental cost per life year gained of 50 mg/day of riluzole is pound sterling 45630, and of 100 mg/day is pound sterling 44890. Increasing the estimated costs of tracheostomy reduces the cost per life year gained of 50 mg/day to pound sterling 34940. However, if quality of life during the increased period of survival is 80% of full health, the cost per quality adjusted life year gained of 50 mg/day becomes pound sterling 57040. These cost-effectiveness ratios are well in excess of the range that is normally considered to be acceptable in UK health technology assessment. However, the comparatively small number of ALS/MND patients and the lack of treatment alternatives should also be considered. Meanwhile, better information on costs is required in order to produce more precise estimates of cost-effectiveness.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Actions of the traditional anti-diabetic plant, Agrimony eupatoria (agrimony): effects on hyperglycaemia, cellular glucose metabolism and insulin secretion.

Agrimony eupatoria (agrimony) has been documented as a traditional treatment of diabetes. Here, the effects of dietary administration of agrimony on streptozotocin (STZ)-diabetic mice and on in vitro glucose uptake and glucose metabolism, and on insulin secretion by BRIN-BD11 cells were investigated. Agrimony incorporated into the diet (62.5 g/kg) and drinking water (2.5 g/l) countered the weight loss, polydipsia, hyperphagia and hyperglycaemia of STZ-diabetic mice. Aqueous extract of agrimony (1 mg/ml) stimulated 2-deoxy-glucose transport (1.4-fold), glucose oxidation (1.4-fold) and incorporation of glucose into glycogen (2.0-fold) in mouse abdominal muscle comparable with 0.1 microM-insulin. In acute 20 min tests, 0.25-1 mg/ml aqueous extract of agrimony evoked a stepwise 1.9-3.8-fold stimulation of insulin secretion from the BRIN-BD11 pancreatic B-cell line. This effect was abolished by 0.5 mM-diazoxide and previous exposure to extract did not adversely affect subsequent stimulation of insulin secretion by 10 mM-L-alanine, thereby indicating that there was no detrimental effect of the extract on cell viability. The effect of extract was glucose-independent and was not evident in BRIN-BD11 cells exposed to a depolarizing concentration of KCl. The ability of agrimony extract to enhance insulin secretion was dependent on use of heat during extract preparation. These results demonstrate the presence of antihyperglycaemic, insulin-releasing and insulin-like activity in Agrimony eupatoria.

Analysis of Variance↗
PubMed1998

The involvement of the opioidergic system in the antinociceptive mechanism of action of antidepressant compounds.

1. Debate exists as to the nature of antidepressant-induced antinociception. It is unclear whether antidepressants are inherently antinociceptive, are able to potentiate opioid antinociception or both. We have used the acetic acid induced abdominal constriction assay in mice to investigate antidepressant-induced antinociception. 2. All the antidepressants tested (s.c.) produced dose-dependent protection against acetic acid-induced abdominal constriction. Similarly, morphine and aspirin were also effective antinociceptive agents in this nociceptive assay. 3. Opioid antagonists, naloxone (0.5 mg kg(-1), s.c.) and naltrindole (1 mg kg(-1), s.c.), shifted the dose-response relationships to the right for each of the antidepressant agents (dothiepin, amitriptyline, sibutramine, (+)-oxaprotiline and paroxetine). In this context the naloxone dose-ratios were 1.95, 3.90, 2.32, 4.50 and 2.65, with naltrindole dose-ratios of 4.36, 17.00, 4.28, 11.48 and 2.65 were obtained, respectively. Naloxone also shifted the morphine dose-response relationship to the right, by a factor of 2.62, whilst naltrindole had no effect upon morphine antinociception. Aspirin antinociception remained unaffected by both opioid antagonists. 4. The enkephalin catabolism inhibitor acetorphan, by itself, produced no activity in this test at a dose of 10 mg kg(-1) (s.c.). However, at higher doses, acetorphan produced a linear dose-response relationship against acetic acid-induced abdominal constriction. 5. When acetorphan was administered before either the antidepressants or morphine, there was a clear potentiation of the antidepressant- or morphine-induced antinociception. However, acetorphan had no effect on aspirin antinociception. 6. Since neither of the opioid antagonists were able to attenuate, nor was acetorphan able to potentiate, aspirin antinociception, we concluded that the mechanism of antidepressant-induced antinociception is different from that of the non-steroidal anti-inflammatory drugs. 7. These data are consistent with the view that antidepressants may induce endogenous opioid peptide release, as shown by the acetorphan study. In this context, the ability of naltrindole to displace the antidepressant dose-response relationship to the right without affecting morphine antinociception, implicates the delta-opioid receptor and endogenous opioid peptides in antidepressant-induced antinociception.

Abdominal Muscles↗
PubMed1998

Antihyperglycemic actions of Eucalyptus globulus (Eucalyptus) are associated with pancreatic and extra-pancreatic effects in mice.

Eucalyptus globulus (eucalyptus) is used as a traditional treatment for diabetes. In this study, incorporation of eucalyptus in the diet (62.5 g/kg) and drinking water (2.5 g/L) reduced the hyperglycemia and associated weight loss of streptozotocin-treated mice. An aqueous extract of eucalyptus (AEE) (0.5 g/L) enhanced 2-deoxy-glucose transport by 50%, glucose oxidation by 60% and incorporation of glucose into glycogen by 90% in mouse abdominal muscle. In acute, 20 min incubations, 0.25-0.5 g AEE/L evoked a stepwise 70-160% enhancement of insulin secretion from the clonal pancreatic beta-cell line (BRIN-BD11). The stimulatory effect of 0.5 g/L AEE was unaltered by the presence of 400 micromol diazoxide/L and prior exposure to AEE did not alter subsequent insulin secretory response to L-alanine, thereby negating adetrimental effect on cell viability. The effect of AEE was not potentiated by glucose or demonstrable in cells exposed to a depolarizing concentration of KCl. Further study of the insulin-releasing effects of AEE revealed the activity to be heat stable, acetone insoluble, stable to acid, but abolished by exposure to alkali. Sequential extraction with solvents revealed activity in both methanol and water fractions, indicating the presence of more than one biologically active extract constituent. These data indicate that Eucalyptus globulus represents an effective antihyperglycemic dietary adjunct for the treatment of diabetes and a potential source for discovery of new orally active agent(s) for future therapy.

Animals↗
PubMed1998

Gastric inhibitory polypeptide and effects of glycation on glucose transport and metabolism in isolated mouse abdominal muscle.

This study investigates the effects of gastric inhibitory polypeptide (GIP) and glycated GIP (glucitol adduct of GIP) on glucose uptake and metabolism in muscle. Glycated GIP (molecular mass 5147.2 Da) was purified by HPLC following in vitro incubation under hyperglycaemic reducing conditions (24 h at pH 7.4). GIP (10(-10)-10(-8) mol/l) significantly stimulated (1.4- to 1.5-fold, P < 0.001) 2-deoxy-D-[1-3H]glucose uptake in abdominal muscle pieces from 3- to 5-week-old lean mice compared with control incubations (without GIP). This stimulatory effect on glucose uptake at 10(-10)-10(-9) mol/l was decreased by 13-20% following glycation of the peptide (P < 0.05). GIP (10(-9) and 10(-8) mol/l) induced a stepwise 1.4- to 1.7-fold increase (P < 0.01, P < 0.001 respectively) in [14C]glucose oxidation compared with controls. This effect on glucose oxidation was diminished by 32% with 10(-8) mol/l glycated GIP (P < 0.05). GIP (10(-9) and 10(-8) mol/l) induced a 1.4- to 1.8-fold increase in [14C]glucose incorporation into muscle glycogen (glycogenesis) compared with controls. Glycated GIP (10(-8) mol/l) exhibited a 41% decrease in glycogenic activity (P < 0.01). GIP (10(-10)-10(-8) mol/l) stimulated lactate production in isolated abdominal muscle (1.2- to 1.3-fold, P < 0.05); however glycated GIP did not exert a significant effect. This study demonstrates for the first time that GIP promotes glucose uptake, glucose oxidation and glycogenesis in muscle tissue. Furthermore, modification of GIP through glycation diminishes its biological effectiveness.

Animals↗
PubMed1998

Insulin-releasing and insulin-like activity of Agaricus campestris (mushroom).

Agaricus campestris (mushroom) has been documented as a traditional treatment for diabetes. Here the administration of mushroom in the diet (62.5 g/kg) and drinking water (2.5 g/l) countered the hyperglycaemia of streptozotocin-diabetic mice. An aqueous extract of mushroom (1 mg/ml) stimulated 2-deoxyglucose transport (2.0-fold), glucose oxidation (1.5-fold) and incorporation of glucose into glycogen (1.8-fold) in mouse abdominal muscle. In acute 20 min tests, 0.25-1 mg/ml aqueous extract of mushroom evoked a stepwise 3.5- to 4.6-fold stimulation of insulin secretion from the BRIN-BD11 pancreatic B-cell line. This effect was abolished by 0.5 mM diazoxide and prior exposure to extract did not affect subsequent stimulation of insulin secretion by 10 mM L-alanine, thereby negating a detrimental effect on cell viability. The effect of extract was potentiated by 16.7 mM glucose, L-alanine (10 mM) and IBMX (1 mM), and a depolarising concentration of KCl (25 mM) did not augment the insulin-releasing activity of mushroom. Activity of the extract was found to be heat stable, acetone soluble and unaltered by exposure to alkali, but decreased with exposure to acid. Dialysis to remove components with molecular mass < 2000 Da caused a 40% reduction in activity. Sequential extraction with solvents revealed insulin-releasing activity to be greatest in polar fractions. Lack of haemagglutinin activity with extract activity indicated that activity was unlikely to be due to a lectin-mediated event. These results demonstrate the presence of antihyperglycaemic, insulin-releasing and insulin-like activity in A. campestris.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Intrastriatal adenosine A1 receptor antisense oligodeoxynucleotide blocks ethanol-induced motor incoordination.

Intrastriatal administration of a 21-mer phosphorothioate antisense oligodeoxynucleotide targeting the adenosine A1 receptor blocked ethanol-induced motor incoordination in the rat and reduced striatal adenosine A1 receptor content, as judged by specific binding of the A1-specific ligand 8-cyclopentyl-1,3-dipropylxanthine (Bmax = 0.350 +/- 0.07, Kd = 1.87 +/- 0.50 nM). No effect upon striatal adenosine A2 receptor content was observed (Bmax = 0.415 +/- 0.04, Kd = 13.13 +/- 1.25 nM) with the A2-specific ligand 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine. A mismatched control oligodeoxynucleotide of identical G-C base composition and general sequence structure was without effect on adenosine A1 receptor (Bmax = 0.666 +/- 0.11, Kd = 1.32 +/- 0.27 nM) or adenosine A2 receptor content (Bmax = 0.501 +/- 0.08; Kd = 14.65 +/- 1.82 nM) or ethanol-induced motor incoordination. These results confirm an important role of the striatal adenosine A1 receptor in mediating certain motor-related physiological effects of ethanol.

Animals↗
PubMed1997

Effects of non-glycated and glycated glucagon-like peptide-1(7-36) amide on glucose metabolism in isolated mouse abdominal muscle.

This study investigated the actions of non-glycated and glycated glucagon-like peptide-1(7-36)amide (tGLP-1) on glucose uptake and metabolism in isolated mouse abdominal muscle. Monoglycated tGLP-1 (Mr 3463.8) was prepared under hyperglycemic reducing conditions and purified by HPLC. Non-glycated tGLP-1 (10(-10)-10(-8) mol/l) stimulated both 2-deoxy-D-[1-3H]glucose uptake (1.3-1.5 fold) and 14C-glucose oxidation (1.4-1.7 fold) in muscle compared to controls without tGLP-1. Glycation reduced these stimulatory effects by 27-33% and 25% (at 10(-9) mol/l), respectively. tGLP-1 (10(-10)-10(-8) mol/l) promoted muscle glycogenesis and lactate production, whereas glycated peptide was ineffective below 10(-9) mol/l. This study demonstrates that tGLP-1 has potent glycogenic effects in mouse abdominal muscle in vitro and that glycation impairs its action.

Abdominal Muscles↗
PubMed1997

An economic analysis of varicella vaccination for health care workers.

A simulation model was constructed to assess the relative costs and cost-effectiveness of different screening and vaccination strategies for dealing with hospital incidents of varicella exposure, compared with current policies, using data from published sources and a hospital survey. The mean number of incidents per hospital year was 3.9, and the mean annual cost of managing these incidents was pounds 5170. Vaccination of all staff would reduce annual incidents to 2.2 at a net cost of pounds 48,900 per incident averted. Screening all staff for previous varicella, testing those who are uncertain or report no previous varicella, and vaccinating those who test negative for VZV antibodies, reduces annual incidents to 2.3 and gives net savings of pounds 440 per incident averted. Sensitivity analyses do not greatly alter the ranking of the options. Some form of VZV vaccination strategy for health care workers may well prove a cost-effective use of health care resources.

Chickenpox↗
PubMed1997

Pancreatic and extra-pancreatic effects of the traditional anti-diabetic plant, Medicago sativa (lucerne).

Medicago sativa (lucerne) is used as a traditional plant treatment of diabetes. In the present study, administration of lucerne in the diet (62.5 g/kg) and drinking water (2.5 g/l) reduced the hyperglycaemia of streptozotocin-diabetic mice. An aqueous extract of lucerne (1 mg/ml) stimulated 2-deoxy-glucose transport (1.8-fold), glucose oxidation (1.7-fold) and incorporation of glucose into glycogen (1.6-fold) in mouse abdominal muscle. In acute 20 min tests, 0.25-1 mg/ml aqueous extract of lucerne evoked a stepwise 2.5-6.3-fold stimulation of insulin secretion from the BRIN-BD11 pancreatic B-cell line. This effect was abolished by 0.5 mM-diazoxide, and prior exposure to extract did not affect subsequent stimulation of insulin secretion by 10 mM-L-alanine, thereby negating a detrimental effect on cell viability. The effect of extract was potentiated by 16.7 mM-glucose and by 1 mM-3-isobutyl-1-methylxanthine. L-Alanine (10 mM) and a depolarizing concentration of KCl (25 mM) did not augment the insulin-releasing activity of lucerne. Activity of the extract was found to be heat stable and largely acetone insoluble, and was enhanced by exposure to acid and alkali (0.1 M-HCl and NaOH) but decreased 25% with dialysis to remove components with molecular mass < 2000 Da. Sequential extraction with solvents revealed insulin-releasing activity in both methanol and water fractions indicating a cumulative effect of more than one extract constituent. The results demonstrate the presence of antihyperglycaemic, insulin-releasing and insulin-like activity in the traditional antidiabetic plant, Medicago sativa.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Genetic and immunologic characterization of viruses infecting MN-rgp120-vaccinated volunteers.

Proviral sequences were determined and immunologic characterization was carried out for envelope glycoproteins from 7 vaccinees who became infected with human immunodeficiency virus type 1 (HIV-1), through high-risk behavior, while participating in clinical trials of MN-rgp120, a candidate HIV-1 vaccine. All 7 infections resulted from subtype B viruses; however, only 3 of the viruses possessed the MN serotype-defining V3 domain sequence, IGPGRAF, prevalent in 60%-70% of US infections. Six of the 7 viruses differed from MN-rgp120 at a neutralizing epitope in the C4 domain, and all 7 differed from MN-rgp120 at a neutralizing epitope in the V2 domain. Recombinant gp120 was prepared from each breakthrough specimen and tested for binding to a panel of neutralizing monoclonal antibodies. The results suggest that 6 of 7 breakthrough infections may be related to incomplete immunization or to infection with viruses that differed from the vaccine immunogen at important virus-neutralizing epitopes.

AIDS Vaccines↗
PubMed1997

Problems in conducting economic evaluations alongside clinical trials. Lessons from a study of case management for people with mental disorders.

BACKGROUND: Case management has become the statutory basis of community care in the UK for people with long-term mental disorders, although a randomised controlled trial found no important improvements over standard care. Here we compare the costs and cost consequences of this intervention with standard care. METHOD: Resource-use data were collected over a six-month baseline period and for 14 months after randomisation on all patients in the trial. RESULTS: At 14 months the ratio of control group to treatment group weekly costs was 1.09 (95% CI 0.86-1.38) for total costs; 1.12 (0.76-1.65) for state benefits, and 1.21 (0.61-2.42) for health care costs. Costs were thus lower in the treatment group, but these differences were not significant. CONCLUSIONS: Retrospective power calculations indicated that the trial could have detected differences of 30% in total cost, but would have required 700 patients per arm to detect a 20% difference in health care costs. Hence this study, which had adequate power to detect clinically meaningful differences, was found to be far too small to detect large differences in costs. Funding agencies increasingly request that clinical trials include economic alongside clinical end-points: these findings may have important lessons for that policy.

Case Management↗
PubMed1996

Effect of alprazolam on opiate withdrawal: a combined behavioural and microdialysis study.

Benzodiazepines are commonly abused concurrently with opioids. The pharmacological rationale for this remains unknown. The present study has addressed behaviourally and neurochemically the action of alprazolam on the naloxone-precipitated morphine withdrawal syndrome in male rats. In naloxone (1 mg kg-1 i.p.)-precipitated morphine withdrawn rats, alprazolam (2.5 mg kg-1 s.c.) reduced the severity of the affective component, as measured by squeal on touch hostility, and the physical sequelae of opioid withdrawal. The microdialysis study in anaesthetized rats identified an increase in noradrenaline levels in hippocampal dialysates in rats undergoing naloxone-precipitated opioid withdrawal. Acute treatment with alprazolam (2.5 mg kg-1 s.c.) 20 min before administration of naloxone prevented the previously identified increase in noradrenaline in hippocampal dialysates. The only observable effect alprazolam induced in non-morphine-dependent rats was a 15% reduction in spontaneous locomotor activity. In conclusion, one interpretation of the data suggests that alprazolam decreases the withdrawal syndrome in rats through dampening down the previously identified hyperactivity of the locus coeruleus.

Alprazolam↗
PubMed1996

Hexose recognition by insulin-secreting BRIN-BD11 cells.

Clonal BRIN-BD11 cells were produced by electrofusion of NEDH rat islet B-cells with immortal RINm5F cells. Western blotting analysis revealed that unlike RINm5F, novel BRIN-BD11 cells expressed high levels of the glucose transport protein GLUT-2, coupled with a rapid and sustained uptake of D-glucose, significantly greater than RINm5F after only 5 min (p < 0.05). Whereas BRIN-BD11 cells expressed a high glucokinase:hexokinase ratio with 1.4-2.0 fold and 1.4-1.7 fold stepwise stimulation of insulin secretion with 4.2-16.7 mM D-glucose and D-mannose respectively, RINm5F had a lower glucokinase:hexokinase ratio (p < 0.001) and were notably unresponsive to D-glucose and D-mannose. Unlike RINm5F cells, BRIN-BD11 were unresponsive to other hexoses, with RINm5F only responding to D-galactose (p < 0.05). BRIN-BD11 cells should be useful for studies of nutrient-induced insulin secretion.

Animals↗
PubMed1996

Labour turnover in the British National Health Service: a local labour market analysis.

This study uses regression analyses to examine the relationship between staff turnover in the British National Health Service (NHS) and a range of labour market, job and worker characteristics. Data relating to nine staff groups in up to 103 District Health Authority areas, and covering over 300,000 employees, form the basis for the analysis. In the regression analysis, two variables consistently emerge as significantly related to turnover across a range of staff groups: the size of the private nursing homes, and the pay of the staff group relative to the local average for comparable workers. The results suggest that staff groups of different skill levels each have distinct labour markets, and this needs to be recognised in the future design of human resources management policies.

Employment↗
PubMed1996

The costs of nursing turnover: evidence from the British National Health Service.

This article reports empirical evidence on the costs of nursing and other staff turnover in the National Health Service. It begins by considering the possible costs and benefits associated with turnover. It then examines current turnover rates in the NHS and existing estimates of the direct administrative costs and the short-term productivity losses associated with turnover. Using these estimates, it compares the cost-effectiveness of a policy which uses across-the-board pay increases to reduce turnover with one which targets pay rises to certain groups only. Next, possible indirect costs of turnover are evaluated using data collected from a large cross-section of providers and other sources. No relationship is found between turnover rates and crude measures of patient service or staff morale measures. The paper concludes with a brief discussion of the main findings and some suggestions for future research.

Cost-Benefit Analysis↗