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Biomedical subjects

A D Morris

Publications and source records attributed to A D Morris.

At least 109 records · Page 6Linked to original sources
PubMed1994

Insulin resistance and essential hypertension: mechanisms and clinical implications.

The epidemiologic links among essential hypertension, obesity, and noninsulin-dependent diabetes mellitus (NIDDM) are well recognized, and it has been proposed that these links may reflect an underlying common pathophysiologic link of resistance to the action of insulin (insulin resistance). In essential hypertension, data suggest the insulin resistance pertains predominantly to nonoxidative glucose disposal, especially in skeletal muscle and adipose tissue, which contrasts with a more generalized deficit in obesity and NIDDM. A number of animal studies of genetic hypertension have confirmed the presence of insulin resistance, whereas acquired models of animal hypertension have not. The clinical significance of insulin resistance on long-term morbidity in hypertension remains unclear; there is limited evidence that insulin resistance may be an independent risk factor for subsequent vascular events, but it is more likely that it clusters with other better defined risk factors for the vascular complications of hypertension. The potential clinical sequelae of insulin resistance and hyperinsulinemia and the effect of antihypertensive medication on insulin resistance in general are addressed.

Animals↗
PubMed1994

Estimation of blood levels of endothelin and neurokinin receptor antagonists at the rat portal and jugular veins after oral administration as a tool in peptide drug design.

The blood concentration of three representative endothelin and four neurokinin receptor antagonists were monitored both at the portal and jugular vein of rats 30, 60 and 90 min after oral administration. Peptide-derived structures, in the size range tetra-pentapeptides, were shown to be absorbed in the reverse order of their log P values, to be weakly metabolized in the first hepatic transit and to maintain high blood levels during the observation time. These interesting results obtained by a simple and convenient UV assay, stress once again the importance of monitoring oral absorption early in the process of peptide drug design.

Absorption↗
PubMed1993

Tetrapeptide tachykinin antagonists: synthesis and modulation of the physicochemical and pharmacological properties of a new series of partially cyclic analogs.

We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the pseudopeptide pharmacophore cyclo[-Abo-Asp(D-Trp-Phe-N(Me)Bzl)-] which contains the 2-azabicyclo[2.2.2]octane-3(S)-carboxylic acid (Abo) residue. Variation of the substituents on the tryptophan indole nitrogen was shown to modulate water solubility and transport properties of the analogs as well as potency in classical in vitro response and binding assays. One water-soluble compound, 16, in which the substituent was 3-carbonylpropionate, strongly prolonged the reaction time in the mouse hot-plate test both after iv or oral administration and was devoid of degranulating activity in rat peritoneal mast cells.

Analgesics↗
PubMed1993

Effects of angiotensin II on insulin sensitivity: a placebo-controlled study.

1. There is evidence that hyperinsulinaemia increases the aldosterone response to angiotensin II, and that angiotensin-converting enzyme inhibitor drugs enhance peripheral glucose utilization, but the direct effects of angiotensin II on insulin sensitivity have not been reported previously. 2. In a randomized, double-blind, placebo-controlled, cross-over study, 12 healthy male subjects attended on 3 study days for the evaluation of the effects of a subpressor (1 ng min-1kg-1) and pressor (5 ng min-1kg-1) infusion of angiotensin II on whole-body insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. Frequent measurements of blood pressure and heart rate were recorded and blood samples were collected for determination of serum insulin, C-peptide and K+ concentration, plasma renin activity and plasma angiotensin II concentration. 3. Plasma angiotensin II concentrations (means +/- SD) were 11 +/- 5 pg/ml after placebo, and 27 +/- 9 and 125 +/- 28 pg/ml after low and high dose angiotensin II, respectively. The higher dose of angiotensin II was associated with significant increases in blood pressure (e.g. 13 mmHg systolic blood pressure at 150 min) and serum aldosterone concentration. Whole-body insulin sensitivity was 10.5 +/- 2 mg of glucose min-1kg-1 after placebo, and 10.5 +/- 2.2 and 10.9 +/- 3.4 mg of glucose min-1kg-1 after low and high dose angiotensin II (not significant). 4. Angiotensin II had no effect on hyperinsulinaemia-induced reductions in serum potassium and triacylglycerol concentrations. 5. Thus, acute infusion of angiotensin II for 3 h, with or without an increase in blood pressure, has no effect on whole-body insulin sensitivity.

Adult↗
PubMed1993

Synthesis and in vitro activities of new tryptophan-modified and thiomethylene-containing pseudopeptide antagonists of the neurokinins.

A series of pseudopeptide analogs of the substance P-like hexapeptide Ava-Phe-Phe-Gly-Leu-Met-NH2 was produced by N alpha-protection, introduction of the thiomethylene bond, of D- and non-proteinogenic amino acids, and alteration of the side chain of tryptophan. Synthesis of the pseudopeptides on a solid phase was successfully improved by direct formation of the CH2-S bond on the resin. However, while thiomethylene formation between leucine and norleucine led to the expected SS diastereoisomer, the major product of the similar coupling between two phenylalanines was the SR isomer. An improved resistance of the analogs to proteolysis was observed, which could be related to the structural changes. Interestingly, these modifications led to three water-soluble and potent neurokinin antagonists on classical in vitro bioassays.

Amino Acid Sequence↗
PubMed1993

Modulation of the activity and assessment of the receptor selectivity in a series of new RGD-containing peptides.

We have investigated the structure-activity relationship of a series of new synthetic RGD analogs and their potential use as specific platelet aggregation inhibitors. Twelve short linear peptides showed high potency to inhibit aggregation in ADP-stimulated dog platelets. In order to assess the selectivity of these analogs towards platelet integrin GPIIb-IIIa, a new cell adhesion inhibition system was devised which was able to discriminate between the two closely related beta 3-integrins of the vasculature, GPIIb-IIIa (alpha IIb beta 3), present in platelets, and the vitronectin receptor (alpha v beta 3), expressed in endothelial cells and platelets. As reported for other peptides by Scarborough et al. (1993, J. Biol. Chem. 268, 1066), the analogs containing lysine instead of arginine in position 1 showed increased selectivity towards GPIIb-IIIa. One of them, in which the piperidine carboxylic group was attached to the N-terminus of KGDW, not only strongly inhibited platelet aggregation, but also selectively abolished cell adhesion mediated by GPIIb-IIIa without effect on the vitronectin receptor.

Amino Acid Sequence↗
PubMed1993

The experiences of an acute stroke unit--implications for multicentre acute stroke trials.

The suitability of 200 consecutive patients admitted to a newly established acute stroke unit was assessed for participation in two multicentre trials currently in their pilot phase: the International Stroke Trial of aspirin and heparin, and the Multicentre Acute Stroke Trial of streptokinase versus placebo. Of the 200 patients (74 men, 126 women, mean age 71 years), 96% had cerebral CT, and 94% had a final diagnosis of cerebrovascular disease. Overall, 50% of patients presented within 6 hours and 70% within 12 hours of the onset of ictus. A total of 113 patients (56.5%) were potentially eligible for trial treatment with aspirin/heparin. Only 9 patients (4.5%) were eligible for streptokinase treatment: 50% were excluded because they presented after 6 hours; 23% had a previous stroke with clinical sequelae and 23% had severe systemic illness. Forty eight per cent of patients had more than one exclusion criterion. The potentially high enrollment rates in trials of antithrombotic agents contrast with the restricted recruitment for trials of streptokinase, emphasising the need for multiple centres to achieve useful study enrollment.

Adult↗
PubMed1993

Metabolic effects of lacidipine: a placebo-controlled study using the euglycaemic hyperinsulinaemic clamp.

1. Twelve healthy male volunteers received lacidipine 4 mg and matching placebo, each for 2 weeks, in a randomised, double-blind crossover study, and attended on 4 study days to evaluate the effects of single and multiple dosing using the euglycaemic hyperinsulinaemic 'clamp'. 2. On each study day, a primed constant-rate infusion of soluble insulin (1.5 mu kg-1 min-1) was administered for 180 min with a variable-rate infusion of 20% dextrose to maintain euglycaemia (5.2 mmol l-1). Whole-body insulin sensitivity was calculated during the past 40 min of the 'clamp'. At frequent intervals, measurements of BP and HR were recorded and venous blood samples collected for serum insulin, C-peptide, potassium, triglyceride (TG) and plasma noradrenaline concentrations. 3. Lacidipine was generally well tolerated and there were no adverse biochemical events. Mean values for insulin sensitivity +/- s.d. were 8.9 +/- 1.6 and 9.1 +/- 2.0 mg kg-1 min-1 after single doses of lacidipine and placebo respectively (95% CI, -1.0, 1.3), and correspondingly 9.6 +/- 2.1 and 9.7 +/- 1.5 mg kg-1 min-1 after 2 weeks (95% CI, -1.0, 1.3). 4. There was a significant reduction in fasting serum TG concentrations after 2 weeks of lacidipine: 0.7 +/- 0.3 mmol l-1 vs 0.9 +/- 0.6 (P < 0.001). However, changes in serum TG and potassium concentrations during the 'clamp' were not significantly different between the 4 study days. 5. Thus, in 'insulin sensitive' volunteers, lacidipine reduces fasting serum TG concentrations but has no effect on insulin-stimulated uptake of glucose, potassium and TG under euglycaemic hyperinsulinaemic conditions.

Adolescent↗
PubMed1992

The influence of methotrexate on radiation-induced damage to different lengths of the rat spinal cord.

An experimental model in the rat has been used to assess the possible enhancement of damage to the spinal cord when radiation is given in the presence of methotrexate (MTX). The dose of MTX used, 4 mg/kg, was the maximum dose that could be given to the rat, when administered into the cerebral spinal fluid circulation, without risk of serious neurological effects. Lengths of 4, 8 and 16 mm of the cervical spine were irradiated with single doses of X rays. For animals that developed paralysis within 30 weeks, caused predominantly by the presence of white matter necrosis, there was no evidence to indicate that MTX enhanced the radiation response of the rat spinal cord, at least at a more clinically relevant level of effect i.e. a low incidence of paralysis. However, for the doses associated with the 50% level of effect (ED50) to an 8 mm long field a significant (p less than 0.005) enhancement of the response was seen, suggesting a dose modification factor of 1.19 +/- 0.07. This was interpreted in terms of an hypothesis to explain the well documented volume effect for very small fields in the rat spinal cord which is based on the migration of viable cells in the periphery of the irradiated site. The apparent smaller effect seen when only 4 mm of the spine was irradiated might be related to the nature of the lesion induced at doses required to produce paralysis in these small fields; the lesions were not restricted to white matter but were more severe and also involved the grey matter and nerve roots after a slightly shorter latent period.

Animals↗
PubMed1988

The disposition of carboplatin in the beagle dog.

Carboplatin was administered i.v. to four groups of three male beagle dogs at doses of 3, 6, 12, and 24 mg/kg (60-580 mg/m2). Plasma samples were obtained at appropriate times and protein-free plasma ultrafiltrates (PU) were generated with Amicon Centrifree micropartition systems. Urine was collected at 24-h intervals for 96 h. PU and urine samples were analyzed for carboplatin by HPLC and for total platinum by atomic absorption spectrophotometry. Carboplatin accounted for about 90% of the free platinum in plasma. The Cmax and AUCinf values for carboplatin and for free platinum increased linearly with dose. The terminal elimination half-life and mean residence times for carboplatin and free platinum were each about 1 h. Total-body clearances for carboplatin (5.6 l/h per m2) and free platinum (5.1 l/h per m2) were constant over the dose range studied, as were the respective volumes of distribution (5.7 and 5.0 l/m2). A mean of 46% of the dose was excreted as carboplatin in 24-h urine; and by 72 h, 70% of the platinum administered was excreted in the urine. Free platinum was cleared by both renal and non-renal processes. These results show that a dose of carboplatin is rapidly excreted in the urine and that carboplatin and plasma-free platinum exhibit linear pharmacokinetics in the beagle dog.

Animals↗
PubMed1988

The disposition of carboplatin in ovarian cancer patients.

Carboplatin was given as a 30-min infusion to 11 ovarian cancer patients at doses of 170-500 mg/m2. The ages, weights, and creatinine clearances (Clcr) ranged from 44 to 75 years, from 44 to 74 kg, and from 32 to 101 ml/min, respectively. Plasma, plasma ultrafiltrate (PU), and urine samples were obtained at appropriate times for 96 h and were analyzed for platinum. The PU and urine were also analyzed for the parent compound by HPLC. In patients with a Clcr of about 60 ml/min or greater, carboplatin decayed biexponentially with a mean t1/2 alpha of 1.6 h and a t1/2 beta of 3.0 h. The mean (+/- SD) residence time, total body clearance, and apparent volume of distribution were 3.5 +/- 0.4 h, 4.4 +/- 0.85 l/h, and 16 +/- 3 l, respectively. Cmax and AUCinf values increased linearly with dose, and the latter values correlated better with the dose in mg than in mg/m2. No significant quantities of free, ultrafilterable, platinum-containing species other than the parent compound were found in plasma, but platinum from carboplatin became protein-bound and was slowly eliminated with a minimal t1/2 of 5 days. The major route of elimination was excretion via the kidneys. Patients with a Clcr of 60 ml/min or greater excreted 70% of the dose as the parent compound in the urine, with most of this occurring within 12-16 h. All of the platinum in 24-h urine was carboplatin, and only 2%-3% of the dosed platinum was excreted from 48 to 96 h. Patients with a Clcr of less than about 60 ml/min exhibited dose-disproportional increases in AUCinf and MRT values. The latter were inversely related to Clcr (r = -0.98). Over a dose range of 300-500 mg/m2, carboplatin exhibited linear, dose-independent pharmacokinetics in patients with a Clcr of about 60 ml/min or greater, but dose reductions are necessary for patients with mild renal failure.

Adult↗
PubMed1988

Evaluation of the hypothalamic-hypophysial, thyroid, and gonadal axes before and after disulfiram administration in patients with chronic alcoholism.

We studied 14 alcoholic men without evidence of liver damage. After two weeks of alcohol abstinence, the patients were divided into two groups of seven patients each. Hypothalamic-hypophysial, thyroid, and gonadal axis tests were done on group 1 patients before disulfiram administration, and the tests were later repeated while the patients were taking disulfiram. Group 2 patients had initial testing done while taking disulfiram and repeat testing after the drug was stopped. The following abnormalities were found and were not affected by disulfiram: lack of suppression of both growth hormone and glucagon with oral glucose intake, and lack of response of follicle-stimulating hormone after administration of synthetic gonadotropin-releasing hormone. After disulfiram administration, we noticed a blunted response of thyrotropin to thyrotropin-releasing hormone.

Adult↗
PubMed1987

The influence of field size on the late tolerance of the rat spinal cord to single doses of X rays.

Varying lengths of the cervical spinal cord of rats were irradiated with single doses of X rays. Dose-related changes in the latency for the development of paralysis, or for the presence of histological lesions in the spinal cord, indicated a dependency on the length of spine irradiated. The dose associated with a specified latency increased as the field size was reduced from 16 mm to 4 mm. A more precise indication of the importance of field size came from a determination of the ED50 values for rats developing paralysis in less than 30 weeks of irradiation or from those that showed neurological signs, or histological evidence, of irradiation damage, occurring after latent periods of greater than 30 weeks. These end-points were primarily related to white-matter necrosis and gross vascular damage respectively. For paralysis in greater than 30 weeks the ED50 increased markedly from 21.5 +/- 0.3 Gy for a 16 mm field to 50.98 +/- 2.28 Gy when a 4 mm length of cord was irradiated. For vascular lesions only a small change in ED50 value was found, from 20.0 +/- 0.5 Gy to 25.58 +/- 2.78 Gy for 16 mm and 4 mm fields respectively. At less than or equal to ED25 no evidence for a field-size effect was seen for this late lesion. These results were examined in the light of some old and some more recently analysed clinical data for radiation myelopathy. It is hoped that this will initiate other investigations in this important area of radiotherapy practice.

Animals↗
PubMed1983

Combined effects of radiation and methotrexate on the cells of the rat subependymal plate.

The brains of 20-week-old rats were locally irradiated with single doses of X-rays (400-1400 cGy). A similar group of animals received an intraventricular injection of methotrexate (MTX) prior to irradiation with single doses of X-rays (600-1400 cGy). Animals were killed six weeks after irradiation. A group of unirradiated age-matched animals acted as controls. In irradiated animals, the most severe effect on the subependymal plate (SEP) of the brain was denoted by the fall in the mitotic count (MC) and the number of small dark (SD) nucleated cells. SD nucleated cells are believed to represent the proliferative compartment of the subependymal layer. Other cell types in the SEP, believed to arise from the SD nucleated population, were affected to a lesser degree. After combination treatment with MTX, the decline in the MC and the SD nuclear density was more severe. The data for the dose-related decline in SD nuclear density and the MC fitted equally well on log-linear and linear plots. From the log-linear plots of the data it was concluded that MTX was radiation dose modifying (DMF 1.25-1.44). However, on the basis of the linear plots the effect of radiation and MTX was apparently additive. While no firm conclusions could be drawn regarding the mechanism of action of MTX on the radiation response of SEP cells, the possible mechanisms are discussed.

Animals↗
PubMed1982

Pathogenic role of a monoclonal IgA (kappa ) anti-IgG paraprotein associated with hemorrhagic diathesis, rheumatoid arthritis, vascular purpura, and acute membranoproliferative glomerulonephritis.

Sixteen years earlier a 42-year-old woman with an IgA kappa plasma cell neoplasm presented with bleeding disorder. Her prolonged course was complicated by subsequent development of rheumatoid arthritis, vascular purpura, and an acute membranoproliferative glomerulonephritis (MPGN). The paraprotein and its (Fab')2 fragment showed affinity for a test myeloma IgG2 (lambda ) paraprotein. The patient's serum and the IgA-IgG complex separated by gel filtration did not exhibit cryoprecipitation. The complex also did not dissociate by ultracentrifugation. Electron microscopic and immunofluorescent studies of a renal biopsy sample taken during the episode of nephritis showed subendothelial deposits and a lacy fluorescent pattern strongly positive for IgA and IgG. The same immunoglobulins were eluted from the kidney at postmortem. A low concentration of monoclonal IgA kappa (antibody) and excess unbound polyclonal IgG (antigen) were demonstrated in the patient's serum at the time of MPGN, apparently analogous to the conditions necessary for the induction of experimental immune complex nephritis.

Acute Disease↗
PubMed1981

Effect of anti-inflammatory drug administration in patients with rheumatoid arthritis. An endoscopic assessment.

A prospective endoscopic study was carried out in 65 patients with rheumatoid arthritis to assess the prevalence of gastroduodenal lesions on aspirin alone or aspirin plus another anti-inflammatory drug (n = 26). All patients were taking greater than or equal to 8 tablets aspirin/day for greater than or equal to 3 months. Drug therapy consisted of regular, buffered or enteric-coated aspirin +/- one other non-steroidal anti-inflammatory drug or less than or equal to 10 mg prednisone/day. Endoscopic findings were graded as normal, or gastric and/or duodenal erythema, erosions, or ulcer; only the most serious lesion was tabulated. Fifty-three percent of patients on aspirin alone has a gastric ulcer or erosions, and 13% duodenal ulcer or erosions compared to 35% with gastric lesions and 4% with duodenal lesions on aspirin plus a second drug. Twenty-two percent of patients taking regular aspirin had gastric ulcers compared to only 6% taking enteric coated. Patients on enteric coated aspirin and prednisone had only a 10% prevalence of severe gastro-duodenal lesions. In conclusion, the combination of a second anti-inflammatory drug and aspirin therapy did not result in a higher prevalence of gastro-duodenal damage over that produced by aspirin therapy alone. Enteric coated aspirin produced significantly fewer serious lesions than regular or buffered aspirin. The combination of enteric-coated aspirin plus low dose prednisone caused a low prevalence of severe gastro-duodenal lesions.

Anti-Inflammatory Agents↗