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Biomedical subjects

L D Lewis

Publications and source records attributed to L D Lewis.

At least 55 records · Page 3Linked to original sources
PubMed1990

Fractionated ifosfamide therapy produces a time-dependent increase in ifosfamide metabolism.

1. Fifteen patients received 1.5 g m-2 of ifosfamide intravenously over 0.5 h every day for 5 days. Twenty-one courses of treatment were studied. Plasma was assayed for ifosfamide by gas liquid chromatography and plasma alkylating activity was measured using the nitrobenzylpyridine (NBP) reaction. 2. A pharmacokinetic analysis revealed a significant decrease in the median (range) elimination half-life of ifosfamide from 7.2 (2.8-14.2) h on day 1 to 4.6 (2.3-7.7) h on day 5 (P less than 0.001, Wilcoxon's test) with a concomitant significant increase in the median (range) clearance from 66 (31-148) ml min-1 on day 1 to 115 (52-381) ml min-1 on day 5 (P less than 0.001). There was no significant change in the volume of distribution on day 5 compared with day 1. 3. There was a highly significant 223% increase in the median (range) plasma nitrobenzylpyridine alkylating activity area under the curve on day 1 from 16 (0.6-105) nmol nor nitrogen mustard equivalents ml-1 h to 52 (13-238) nmol nor nitrogen mustard equivalents ml-1 h on day 5. 4. During five courses of treatment (in five patients in the group) 24 h urine samples were collected on days 1 and 5. The median (range) renal clearance of ifosfamide on day 1 was 6.8 (1.3-16.2) ml min-1 compared with 5.7 (1.3-15.3) ml min-1 on day 5. This difference was not significant. The median (range) metabolic clearance of ifosfamide in these five patients on day 1 was 78.6 (39.9-141.2) ml min-1 and 132.6 (54.6-149.5) ml min-1 on day 5.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗
PubMed1990

Plasma concentrations of salbutamol in acute severe asthmatics.

We studied prospectively 11 asthmatic patients presenting to the Accident and Emergency department with acute asthma. (Four patients reported historically that they were taking some form of oral salbutamol as part of their maintenance therapy.) Standard cardiovascular and respiratory parameters and plasma salbutamol concentrations were measured before and one hour after treatment with five milligrams of nebulised salbutamol. The median plasma salbutamol concentration before treatment was below the level of detection of the assay (less than 3 micrograms.l-1) with a range from less than 3 micrograms.l-1 to 34.6 micrograms.l-1. One hour post treatment the median plasma salbutamol concentration was 7.4 micrograms.l-1 (range less than 3.0 micrograms.l-1 to 56.0 micrograms.l-1) p less than 0.05. (Wilcoxons test). Correlations were investigated between the measured pretreatment physiological variables and pre-treatment plasma salbutamol concentrations. None were found to be significant. Similar analysis of the measured post-treatment physiological variables and post-treatment plasma salbutamol concentrations again revealed no significant correlations. However, a significant negative correlation was noted between the change in plasma salbutamol concentration with treatment and the change in respiratory rate (Rs = -0.56, p = 0.04). If asthmatics do indeed use high doses of inhaled beta-2-agonists (salbutamol) in an attempt to abort an acute attack (as many clinicians suspect), little, if any, of the drug appears to reach the systemic circulation. In this study the administration of five milligrams of nebulised salbutamol to acute asthmatics did not produce excessive increases in plasma salbutamol concentration, even in those patients taking oral salbutamol as part of their maintenance therapy.

Acute Disease↗
PubMed1990

Regulation of cholecystokinin secretion by food, hormones, and neural pathways in the rat.

Regulation of cholecystokinin (CCK) secretion was studied in conscious unrestrained rats by simultaneous duodenal perfusion with foodstuffs, intravenous infusion of hormones or neural agents, and arterial blood sampling for CCK bioassay. Duodenal infusion of casein resulted in elevation of plasma CCK from fasting level of 0.5 +/- 0.1 to 3.8 +/- 0.4 pM. Casein hydrolysate, calcium, and glucose did not elevate plasma CCK. Infusion of intact fat had a small, but nonsignificant, effect (1.4 +/- 0.4 pM), whereas infusion of oleate increased plasma CCK to 3.7 +/- 0.6 pM. Thus intact protein and fatty acids are the major dietary intestinal stimuli for CCK release in the rat. The CCK response to protein could be inhibited by somatostatin but not by peptide YY (0.2, 2, or 20 micrograms.kg-1.h-1); intravenous infusion of 1 or 10 micrograms.kg-1.h-1 somatostatin decreased casein-stimulated CCK levels to 1.5 +/- 0.2 and 0.9 +/- 0.3 pM, respectively. Stimulation of vagal discharge with 2-deoxy-D-glucose had no effect on basal or protein-stimulated plasma CCK levels; thus CCK release in the rat does not appear to be modulated by central vagal pathways. Gastrin-releasing peptide increased fasting plasma CCK levels to 1.6 +/- 0.1 pM. Administration of the cholinergic agonist bethanechol, while having no effect on fasting CCK level, inhibited protein-stimulated plasma CCK from 3.9 +/- 0.6 to 1.3 +/- 0.3 pM. Cholinergic blockade with atropine, in contrast, had no effect on basal or protein-stimulated plasma CCK. Thus CCK release is stimulated by dietary protein or fatty acid and by gastrin-releasing peptide and inhibited by somatostatin and bethanechol.

Animals↗
PubMed1989

Pancreatic digestive enzyme gene expression: effects of CCK and soybean trypsin inhibitor.

Regulation of pancreatic gene expression by cholecystokinin (CCK) was examined in the rat using cloned cDNA probes to quantify changes in specific mRNAs (amylase, trypsinogen I, chymotrypsinogen B, and ribonuclease). Rats were administered intraduodenally an elemental liquid diet. Plasma CCK levels were raised to levels comparable to physiological postprandial levels either by intraduodenal perfusion with soybean trypsin inhibitor (SBTI) (6.9 +/- 1.0 pM, n = 8) or by continuous intravenous infusion with cholecystokinin octapeptide (CCK-8, 6.0 +/- 0.9 pM, n = 6). SBTI infusion resulted in fivefold increases in trypsinogen I and chymotrypsinogen B mRNA levels after 48 h. In contrast SBTI infusion had no effect on amylase mRNA levels and led to a decrease in ribonuclease mRNA levels to approximately 50% of control after 48 h. Intravenous infusion with CCK-8 for 24 h resulted in plasma levels of CCK comparable to those obtained with SBTI and had similar effects on digestive enzyme mRNA levels. These data suggested that SBTI acted via its ability to raise plasma CCK levels. To further test the specificity of these effects, animals were infused intraduodenally with the specific CCK receptor antagonist L364,718. Although the antagonist itself had no effect on digestive enzyme mRNA levels, antagonist treatment totally abolished the effects of both CCK infusion and SBTI treatment. These data therefore indicate that CCK regulates digestive enzyme gene expression at plasma concentrations comparable to physiological postprandial levels. Furthermore, the ability of SBTI infusion to increase plasma CCK accounts for its effects on pancreatic digestive enzyme mRNA levels.

Amylases↗
PubMed1988

Ifosfamide plasma clearance in relation to polymorphic debrisoquine oxidation.

Ifosfamide (IF) pharmacokinetics and the plasma (NBP)-alkylating activity were determined in 33 patients with different tumours after the administration of IF as single-agent chemotherapy. All subjects had been phenotyped for debrisoquine oxidation. There is a lack of correlation between the debrisoquine metabolic ratio (DMR) and either the total plasma clearance of IF (CLIF) or the AUC of the plasma NBP-alkylating activity.

Adult↗
PubMed1988

Effects of cholecystokinin on pancreatic ornithine decarboxylase gene expression.

The effects of cholecystokinin (CCK) on pancreatic ornithine decarboxylase (ODC) gene expression were studied in the rat. Plasma CCK concentrations were raised to levels comparable to postprandial values either by intravenous infusion of CCK octapeptide (CCK-8) or by intraduodenal perfusion of soybean trypsin inhibitor (SBTI). ODC mRNA levels were quantified using a cloned cDNA probe. ODC mRNA increased to 166 +/- 34% (n = 4) of control after 1 h, peaked at 254 +/- 39% (n = 4) of control after 24 h, and remained significantly elevated for up to 48 h of SBTI infusion. Intravenous infusion of CCK-8 for 24 h increased ODC mRNA levels to the same extent observed with SBTI infusion. The CCK receptor antagonist L364,718 by itself had no effect on ODC mRNA levels but totally abolished the induction of ODC mRNA by both intravenous CCK infusion and intraduodenal infusion of SBTI. These data therefore indicate that CCK plasma concentrations comparable to postprandial values regulate pancreatic ODC at a pretranslational level and that SBTI exerts its effects on pancreatic ODC via an increase in plasma CCK.

Animals↗
PubMed1987

An unusual local reaction to continuous subcutaneous infused terbutaline in unstable asthmatics.

Three out of nine unstable asthmatics whose asthma is subjectively and objectively better controlled on continuous subcutaneous terbutaline infusions (6-12 mg/24 hours) developed tender indurated subcutaneous swellings at the infusion site. In the two cases reported here in detail, histologically the lesions were areas of panniculitis and deep dermal collagen necrosis. Further investigation of the possible causative mechanism for these lesions--drug solution pH, osmolality, or impurities--suggests that impurities in the solution are the most likely cause.

Adult↗
PubMed1987

Structural characterization of the somatostatin receptor in rat anterior pituitary membranes.

To structurally characterize the somatostatin receptor in the anterior pituitary, the chemical cross-linking reagent N-5-azido-nitrobenzoyloxysuccinimide was used to attach covalently [125I-Tyr11]somatostatin-14 to its receptor in pituitary membranes. Rat anterior pituitary membranes were incubated with [125I-Tyr11]somatostatin-14, washed, and then treated with 100 microM cross-linker, which was activated by exposure to UV light. Gel electrophoresis followed by autoradiography revealed a broad band centered at 88,000 mol wt. The appearance of this band was unaffected by dithiothreitol. Competitive inhibition of binding by unlabeled somatostatin resulted in a parallel inhibition of labeling of the 88,000 mol wt protein. The addition of guanine nucleotides in concentrations that inhibit binding similarly inhibited cross-linking. The cross-linked membranes were solubilized in Zwittergent 3-12, a nondenaturing detergent, and the glycosylation pattern of the labeled protein was investigated by incubation with various lectins coupled to agarose. The cross-linked protein was selectively adsorbed by wheat germ agglutinin, and this interaction was blocked by the addition of N,N',N"-triacetylchitotriose, indicating that the rat anterior pituitary somatostatin receptor is a glycoprotein containing polymeric beta-1-4 linked N-acetylglucosamine groups. The results of this study show that the rat anterior pituitary somatostatin receptor is a glycoprotein of 88,000 mol wt containing no disulfide-linked subunits.

Adsorption↗
PubMed1986

Human gastrointestinal absorption of acyclovir from tablet duodenal infusion and sipped solution.

On two occasions at least 1 week apart, nine healthy male volunteers were administered in random order either 2 X 200 mg (1.8 mmol) acyclovir tablets or 400 mg of acyclovir in 500 ml of 5% dextrose solution which was infused at constant rate into the duodenum over 4 h. Six of the subjects subsequently sipped the same solution at the rate of 10.4 ml in each 5 min period for 4 h. Blood and urine were sampled over 24 h for each mode of administration. Acyclovir was assayed by radioimmunoassay. Mean areas under the plasma concentration-time curves (AUCs) +/- s.d. for tablet (T), intraduodenal infusion (I) and sipping (S) were, respectively: T = 14.7 +/- 5.1; I = 24.6 +/- 5.1; S = 28.4 +/- 9.5 (n = 6) mumol l-1 h. AUCs for I and S were significantly greater than that for T (2P less than 0.05). Mean apparent maximum plasma concentrations (Cmax) +/- s.d. were T = 3.8 +/- 1.5; I = 4.8 +/- 0.9; S = 5.1 +/- 1.5 mumol l-1. This trend to higher values for I and S was not significant. Mean apparent plasma disappearance half-lives (t1/2) +/- s.d. were respectively T = 2.3 +/- 0.4; I = 2.7 +/- 0.5; S = 3.0 +/- 0.2 h, I being significantly greater than T (2P less than 0.05), as was S greater than T (2P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Acyclovir↗
PubMed1986

Ergotamine-induced peripheral ischaemia reversed by oral thymoxamine hydrochloride.

Although there is no generally accepted therapy for ergotamine-induced vasoconstriction, infusion of directly acting vasodilators is regarded presently as the treatment of choice. We present a case of peripheral arterial ischaemia secondary to excessive use of ergotamine suppositories, which was reversed with oral thymoxamine hydrochloride (an alpha 1-adrenoceptor antagonist) and ergotamine withdrawal. We suggest that in patients with ergotamine-induced peripheral arterial vasoconstriction with no evidence of gangrene, oral thymoxamine may be considered as a useful adjunct or possible alternative to infused vasodilator treatment.

Adult↗
PubMed1986

The third phase of in vitro insulin secretion. Evidence for glucose insensitivity.

In this study, in vitro B-cell models are described, which may be applicable for studying the reported B-cell desensitization produced by hyperglycemia in IDDM and NIDDM. Using a programmable perifusion/perfusion system, insulin secretion from perifused islets was measured at 10-30-min intervals for 24-50 h. After 3-4 h continuous glucose (11 mM), a new phase of insulin release occurs in which secretion declines to, and remains at, approximately 25% maximal release. Results were similar when using: perifused islets embedded in Cytodex 3, or Bio-Gel P-2, 100-200 mesh; batchincubated islets with hourly changes of medium; and the isolated pancreas perfused for 8 h. Three different media, Hana HB 104 (fortified, fully defined medium), RPMI-1640 + 10% FBS, and perfusion bufferalbumin, were used. Despite reduced secretion to continuous glucose, each system responded vigorously to an acute stimulation with glucose-forskolin. Decreased secretion was primarily caused by decreased secretagogue efficiency (reduced fractional secretion). Prolonged stimulation with glucose or glucose-IBMX produced a similar waning of secretion regardless of the amount of insulin released. It is concluded that the third phase of insulin secretion may represent a secret-agogue-induced, signal desensitization of the B-cell, rather than exhaustion of a B-cell compartment of stored insulin.

Animals↗
PubMed1984

Evaluation of ammonium chloride as a urinary acidifier in the cat.

Twenty-four cats were fed a dry commercial cat food once daily for 2 weeks and then ad libitum for 2 weeks. Urine pH was measured 4 times daily the last 3 days of each feeding period. Subsequently, the cats were allotted to 2 equal groups and fed ad libitum an experimental, dry ration with or without 1.5% ammonium chloride for 11 months. During this period, urine pH was measured at 1, 3, 6, and 9 weeks, then monthly through 29 weeks, and then every 6 weeks for the duration of the study. When the cats were fed ad libitum, urine pH remained constant throughout the day, regardless of ration. In cats fed once daily, urine pH increased to 7.6 by 2 hours after feeding and remained between 6.6 and 7.6 for 9 hours. Urine pH remained constant throughout the study when cats were fed the experimental ration with or without 1.5% ammonium chloride, but was significantly different (P less than 0.01) between the 2 groups, 5.9 +/- 0.3 (n = 1,035) and 7.0 +/- 0.5 (n = 616), respectively. Ammonium chloride consumption had no effect on food and water consumption or body weight. It was concluded that ammonium chloride was an effective urinary acidifier for a prolonged time, maintained urine pH below 6.6, and did not decrease food intake when given at a concentration of 1.5% of the diet.

Ammonium Chloride↗