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Biomedical subjects

J T Smith

Publications and source records attributed to J T Smith.

At least 109 records · Page 6Linked to original sources
PubMed1990

Sufotidine 600 mg bd virtually eliminates 24 hour intragastric acidity in duodenal ulcer subjects.

In a double blind study, 24 hour intragastric acidity and 24 hour plasma gastrin concentrations were measured simultaneously in seven duodenal ulcer subjects on the fifth day of receiving either sufotidine 600 mg bd or placebo. Compared with placebo, during treatment with sufotidine 600 mg bd the median integrated 24 hour intragastric acidity was decreased by 95% (range 74% to 99%) from 1000 to 51 mmol/h/l, whilst the median integrated 24 hour plasma gastrin concentration increased from 416 to 927 pmol/h/l.

Adult↗
PubMed1990

Inappropriate hypergastrinaemia in asymptomatic healthy subjects infected with Helicobacter pylori.

An ELISA test determined serologically that eight of 95 apparently healthy men (aged 19-26 years) had an asymptomatic infection with Helicobacter pylori at the time of simultaneous measurement of 24 hour intragastric acidity and 24 hour plasma gastrin concentration. There was no significant difference in the median integrated 24 hour intragastric acidity between the H. pylori positive and H. pylori negative subjects (688 and 842 mmol/h/l; p = 0.271, respectively), whereas the median integrated 24 hour plasma gastrin concentration was significantly higher in the H pylori positive than in the H pylori negative subjects (389 and 198 pmol/h/l; p less than 0.001). Longterm hypergastrinaemia, associated with persistent H pylori infection, could be a cause of the increased parietal cell mass that is considered characteristic of duodenal ulcer patients.

Adult↗
PubMed1990

Absence of a gastrin inhibitory factor in the IgG fraction of serum from patients with pernicious anaemia.

Patients with Addisonian pernicious anaemia are alleged to generate antibodies directed against the gastrin receptor. We purified IgG from 15 patients with pernicious anaemia and 15 healthy controls in an effort to show attenuation of gastrin specific binding in vitro and inhibition of gastrin stimulated acid secretion in vivo. Binding of the IgG fraction was determined in a radioreceptor assay utilising the rat pancreatic carcinoma cell line AR42J which expresses high affinity gastrin binding sites (Kd = 5 x 10(-10)). In comparison with control serum, there was no significant displacement (p = 0.10) of human gastrin-17 binding by pernicious anemia samples at either 0.3 mg protein/ml (control (mean (SEM)) 1489 (131) cpm; patients 1858 (174) cpm) or 3 mg protein/ml (control 1930 (110); patients 2195 (107) cpm). The effect of intravenous and intragastric IgG on acid secretion in the anaesthetised rat was determined over a 60 minute period after stimulation with 1 microgram/kg human gastrin-17. A bolus injection of IgG (60-200 mg/kg) had no significant effect (p = 0.50) on gastrin stimulated acid output (29.21 (1.28) mumol H+/h) compared with control (27.48 (4.70) mumol H+/h). Similarly, instillation of 800 mg/kg IgG directly into the stomach for 90 minutes also failed to influence gastrin stimulated acid output (29.69 (3.22) mumol H+/h). Thus, we have been unable to confirm previous reports of an IgG from patients with pernicious anaemia capable of blocking gastrin receptor binding or gastrin stimulated acid secretion.

Adult↗
PubMed1990

Royal Free Hospital protocol for 24-hour intragastric acidity and plasma gastrin concentration.

The Royal Free Hospital protocol for simultaneous measurement of 24-hour intragastric acidity and plasma gastrin concentration is described in detail. The methods of analysing such data are discussed, with recommendations for a standard four-way analysis: median hourly 24-hour intragastric acidity or pH, or plasma gastrin concentration; integrated 24-hour intragastric acidity, or plasma gastrin concentration; analysis of integrated values according to meal-related intervals; and quantification of the percentage of time in a 24-hour period that intragastric pH is greater than 3.

Anti-Ulcer Agents↗
PubMed1990

Tolerance during 29 days of conventional dosing with cimetidine, nizatidine, famotidine or ranitidine.

Twenty-four-hour intragastric acidity and 24-h plasma gastrin concentration were measured on four occasions in six groups of eight healthy male subjects. Each group was studied before dosing, and on days 1, 15 and 29 of dosing with a standard regimen of an H2-receptor antagonist (cimetidine 800 mg nocte, nizatidine 300 mg nocte, famotidine 40 mg nocte, ranitidine 150 mg nocte, ranitidine 150 mg b.d., or ranitidine 300 mg nocte). On the first day of dosing, each regimen using an H2-antagonist caused a significant decrease of intragastric acidity and a significant rise of plasma gastrin concentration. Continued dosing with each H2-antagonist resulted in a significant attenuation of the effect on intragastric acidity, which was most noticeable overnight, but no significant change of plasma gastrin concentration. When grouped together, median integrated nocturnal acidity for the 48 subjects was 485, 35, 67 and 117 mmol.h/L for days 0, 1, 15 and 29, respectively, associated with a median nocturnal integrated plasma gastrin concentration of 46, 72, 79 and 73 pmol.h/L. The study demonstrates that a degree of tolerance develops during continued dosing with all available H2-receptor antagonists, and that this phenomenon occurs during sustained elevation of plasma gastrin concentration.

Adult↗
PubMed1990

Tolerance during 8 days of high-dose H2-blockade: placebo-controlled studies of 24-hour acidity and gastrin.

Simultaneous 24-h intragastric and plasma gastrin concentrations were measured in 36 healthy subjects, when receiving placebo (day 0) and on days 1 and 8 of dosing with either placebo (n = 8), or high-dose H2-blockade with either ranitidine 300 mg q.d.s. (n = 8), ranitidine 1200 mg o.m. (n = 8), or sufotidine 600 mg b.d. (n = 12). Triplicate placebo studies demonstrated good reproducibility for this technique, with no significant differences of acidity or plasma gastrin concentration between the studies. There was a decrease in the anti-secretory activity of all three high-dose H2-antagonist regimens on day 8, when compared with that observed on day 1. This occurred in the presence of sustained or increasing hypergastrinaemia. It is concluded that a degree of tolerance develops during continued H2-blockade, and that this could be due to increasing gastrin drive to the parietal cells.

Adult↗
PubMed1990

Intravenous pentagastrin can induce the illusion of 'tolerance' to a single dose of an H2-blocker in man.

In a double-blind study of Latin square design, twelve healthy male subjects were dosed with combinations of ranitidine 300 mg or placebo (at 08.50 hours) and intravenous pentagastrin (0.6 microgram.kg/h) or 0.9% saline (07.00-18.00 hours). Breakfast and lunch were served at 08.15 and 13.15 hours, respectively; hourly intragastric acidity and plasma gastrin concentration were measured from 08.00-18.00 hours. During oral dosing with placebo, intravenous pentagastrin raised median 10-h integrated intragastric acidity (315 to 615 pmol.h/L; P less than 0.001) and lowered gastrin (86 to 55 mmol.h/L; P less than 0.001). During oral dosing with ranitidine 300 mg, compared with intravenous saline, the pentagastrin infusion returned acidity towards normal (67 to 293 pmol.h/L; P less than 0.001) and lowered gastrin (209 to 135 pmol.h/L; P less than 0.001). This study demonstrates that a continuous pentagastrin infusion can overcome H2-blockade and return intragastric acidity towards normal. Hypergastrinaemia observed during continued dosing with an H2-blocker may be the mechanism for the development of tolerance.

Adult↗
PubMed1990

Mutation rates to 4-quinolone resistance.

The sensitivity of Staph. aureus, Staph. warneri, Pseudomonas aeruginosa, Strep. pneumoneae and Strep. faecalis to eleven 4-quinolone antibacterials was compared by determining their minimum inhibitory concentrations on nutrient agar. In all cases where the minimum inhibitory concentration was less than 10 micrograms/ml then the frequency at which 4-quinolone-resistant mutants arose was estimated using each drug at 5, 10 and 20 times its minimum inhibitory concentration. It was found with all five bacterial species tested that ciprofloxacin and ofloxacin were the most potent antibacterial and that no mutants could be detected in 10(12) bacteria for either drug with Staph. warneri, Strep. pneumoneae and Strep. faecalis. On the other hand, mutants of Pseudomonas aeruginosa resistant to both 5 and 10 times (but not 20 times) the minimum inhibitory concentrations of ofloxacin and ciprofloxacin were detected at similar frequencies in the 10(12) bacteria tested. With Staph. aureus, mutants resisting 5 times (but not 10 or 20 times) the minimum inhibitory concentrations of ofloxacin and ciprofloxacin were detected in the 10(12) bacteria tested at similar frequencies. However, all mutants resistant to ciprofloxacin retained the ability to produce coagulase while the majority of ofloxacin-resistant mutants had lost their ability to produce coagulase. Hence clear evidence for pathogenicity loss was observed with ofloxacin but not with ciprofloxacin.

Anti-Infective Agents↗
PubMed1989

Bactericidal activity of enoxacin and lomefloxacin against Escherichia coli KL16.

Enoxacin and lomefloxacin were found to display a biphasic response when their bactericidal activities were investigated against Escherichia coli KL16 in nutrient broth. Although enoxacin required bacterial protein and RNA synthesis to exert bactericidal activity, it was able to kill non-dividing bacteria. On the other hand, the protein synthesis inhibitor chloramphenicol and the RNA synthesis inhibitor rifampicin did not abolish enoxacin's killing activity against Escherichia coli KL16 in nutrient broth. Lomefloxacin was also shown to be active against non-dividing Escherichia coli KL16.

Anti-Infective Agents↗
PubMed1989

In vitro effects of fibrous and nonfibrous silicon nitride on bovine pulmonary macrophages.

Bovine pulmonary macrophages were exposed in vitro to 0.3, 0.1, 0.03, or 0.01 mg/ml of a fibrous silicon nitride, nonfibrous (milled) silicon nitride comminuted from the fibrous powder, alpha-quartz (an active control), or glass beads (an inert control). Functional evaluation of the exposed cells indicated that the fibrous silicon nitride was as cytotoxic as quartz, while the nonfibrous silicon nitride was relatively inert. To further evaluate the mechanisms of cytotoxicity, the cells were exposed to 1 mg/ml of the control and test materials and biochemical studies were performed. Quartz increased release of both the cytoplasmic enzyme, lactate dehydrogenase (LDH), and the lysosomal enzyme, acid phosphatase (AP), consistent with both cell membrane and lysosome lysis. In addition, total protein levels were significantly depressed, suggesting significant impairment of cellular synthetic processes. LDH, but not AP, values were increased with fibrous silicon nitride treatment, but not with the nonfibrous silicon nitride. In contrast to quartz, which increased LDH levels by 65%, the fibrous silicon nitride only increased LDH levels by 11%. Scanning electron micrographs further indicated that the fibrous silicon is cytotoxic and poorly tolerated by macrophages. These studies provide further evidence of morphology as a primary determinant of cytotoxicity since the milled powder test article was comminuted from the fibrous material.

Acid Phosphatase↗
PubMed1989

4-quinolones and the SOS response.

The SOS DNA repair system is induced in bacteria treated with 4-quinolones. However, whether the response exacerbates or repairs the damage caused by these drugs is still unclear. The recA13 and the recB21 mutations impair recombination repair and render bacteria unable to induce the SOS response when treated with nalidixic acid or other agents that affect DNA synthesis. However, UV treatment induces the SOS response in recB21 mutants but not in recA13 mutants. Both these mutants are hypersensitive to nalidixic acid and, therefore, either recombination repair or SOS repair would appear to repair DNA damage caused by the drug. However, since the lexA3 mutation (which also renders bacteria incapable of inducing the SOS response without affecting recombination repair) had no effect on the susceptibility of bacteria to nalidixic acid, the SOS response neither contributes to nor repairs DNA damage caused by the drug. Consequently, it would seem that the hypersensitivity of the recA13 and recB21 mutants to nalidixic acid is due to their deficiency in recombination repair. This view was confirmed by testing a recA430 mutant that is recombination-repair proficient but SOS repair-deficient and finding it to be no more sensitive to nalidixic acid than its parent. Thus it would appear that, although induced by nalidixic acid treatment, the SOS DNA repair system does not play any role in bacterial responses to the damage caused by the drug. In contrast, the recombination repair system does repair damage caused by nalidixic acid.

Anti-Infective Agents↗
PubMed1989

Interactions of the 4-quinolones with other antibacterials.

The effect of sub-inhibitory concentrations of 16 antibacterials on the bactericidal activity of the 4-quinolones nalidixic acid, ciprofloxacin and ofloxacin against Escherichia coli KL16 in nutrient broth was investigated. Sub-inhibitory concentrations of rifampicin, clindamycin, chloramphenicol, erythromycin or tetracycline antagonised the bactericidal activity of the 4-quinolones. Conversely, all seven aminoglycosides tested enhanced the bactericidal activity of the 4-quinolones whereas the cell wall antagonists, azlocillin, mezlocillin, ceftazidime and vancomycin had no effect on the bactericidal activity of the 4-quinolones.

Anti-Bacterial Agents↗
PubMed1989

The absorption of bismuth from oral doses of tripotassium dicitrato bismuthate.

Two studies measured plasma concentrations of bismuth during dosing with tripotassium dicitrato bismuthate (De-Noltab). The first study compared 24 h plasma bismuth concentration and urinary bismuth excretion in six patients who had already received 29-131 days (median 47 days) of treatment with De-Noltab 2 b.d., and six healthy subjects who only received De-Noltab 2 b.d. on the day of study. There was a prompt rise in plasma bismuth concentration after each dose of De-Noltabs. The median 24 h integrated plasma bismuth concentration was similar in both groups, but the median 24 h urinary bismuth excretion was 5.4-fold higher in the patients. The second study compared the plasma bismuth concentrations after the first and third doses of De-Noltab 2 b.d. in 16 healthy subjects. The median peak bismuth concentration occurred 30 min (range 15-105 min) post-dosing. The peak plasma bismuth concentration was greater than 50 ng/ml in 14 of the 16 subjects, and greater than 100 ng/ml in nine of the subjects. There was no significant difference in the median integrated 10-h plasma bismuth concentration after the first or third dose of De-Noltabs. The results of these studies confirm that bismuth is absorbed and sequestrated during dosing with De-Noltabs. Bismuth is absorbed rapidly after oral dosing with De-Noltabs, to produce peak plasma bismuth concentrations hitherto considered to be in the range associated with bismuth neurotoxicity.

Administration, Oral↗
PubMed1989

The effect of SK&F 94482 (BMY-25368) on 24-hour intragastric acidity and plasma gastrin concentration in healthy subjects.

In a double-blind, placebo-controlled study of SK&F 94482 (BMY-25368) (400-mg, post-evening meal, for 7 days in 11 healthy subjects), there was a significant 75% decrease in median integrated 24-h intragastric acidity during dosing with the drug (218 mmol h/L) compared with placebo (883 mmol h/L; P = 0.003). The single daily dose of 400 mg SK&F 94482 decreased median hourly intragastric acidity until the time of the next dose 24 h later. There was also a sustained and significant 80% rise in median 24-h integrated plasma-gastrin concentration during dosing with SK&F 94482 (364 pmol h/L) when compared with placebo (202 pmol h/L; P = 0.003). The study demonstrates a significant inverse correlation between 24-h integrated intragastric acidity and 24-h plasma gastrin concentration (rs = -0.484; P less than 0.001). The study shows that a single oral daily dose of an H2-antagonist can provide control of intragastric acidity throughout the day and night, decreased acidity being associated with statistically significantly, but modestly elevated plasma-gastrin levels.

Adult↗