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Biomedical subjects

R H Dowling

Publications and source records attributed to R H Dowling.

At least 91 records · Page 5Linked to original sources
PubMed1983

Effect of colonic perfusion with sulfated and nonsulfated bile acids on mucosal structure and function in the rat.

A single-pass perfusion system was used in conscious restrained rats to measure changes in water and electrolyte transport and in protein and deoxyribonucleic acid output after perfusing 5-15-mM solutions of sulfated or nonsulfated bile acids through the colon. Perfusion with 5 mM nonsulfated deoxycholic acid or chenodeoxycholic acid changed net water and sodium absorption to net secretion, provoked marked increases in protein and DNA output into the perfusion effluent, and caused microscopic mucosal damage. In contrast, perfusion with 5 and 15 mM sulfated deoxycholic acid or with 5 mM sulfated chenodeoxycholic acid had no effect on water and electrolyte transport and caused only modest changes in protein and DNA output. To see whether or not sulfated bile acid could prevent the effect of its nonsulfated parent compound on colonic structure and function, perfusion with a mixture of 5 mM nonsulfated and 10 mM sulfated deoxycholic acid was performed. This produced net secretion of water and sodium together with less marked increases of protein and deoxyribonucleic acid output and less pronounced microscopic mucosal damage than was seen after 5 mM nonsulfated deoxycholic acid alone. Finally, 5 mM nonsulfated cholic acid had no effect on water or sodium transport, but 5 mM sulfated cholic acid, with one alpha-hydroxyl group masked and two alpha-hydroxyl groups "exposed," reduced water transport. These results suggest that sulfation prevents the cathartic effect of alpha-dihydroxyl bile acids in the colon.

Animals↗
PubMed1982

Is recurrence inevitable after gallstone dissolution by bile-acid treatment?

Gallstone dissolution was observed on 60 occasions in 54 patients; in 6, recurrent stones were dissolved by a second course of medical treatment. When complete gallstone dissolution was confirmed (by two consecutive cholecystograms, 3 months apart) bile-acid treatment was stopped, and the patients were followed for up to 71/2 years with oral cholecystograms taken annually (or sooner if symptoms suggested early recurrence). Recurrence was detected 30 times after the 60 episode of gallstone dissolution (50%), in 25 of the 54 patients (46%), and in 25 of 46 patients who had had at least one post-dissolution X-ray before recurrence (54%). In 21 of these 25 patients (84%) the recurrence was observed within 2 years of treatment being stopped. There were no significant differences in clinical details and pre-treatment gallstone characteristics between the 25 gallstone-recurrent (at any time) and the 29 gallstone-free (at the time of study) patients, nor between a subgroup of patients in whom recurrent stones developed rapidly (less than or equal to 1 year) and a subgroup who remained gallstone-free for 3 years. It is concluded that long-term follow-up is advisable and that post-dissolution treatment will be necessary to prevent gallstone recurrence.

Adult↗
PubMed1982

Relationship between hepatic cholesterol synthesis and biliary cholesterol secretion in man: hepatic cholesterol synthesis is not a major regulator of biliary lipid secretion.

1. To examine the role of newly synthesized cholesterol as a determinant of bile lipid secretion, both hepatic cholesterol synthesis (as judged by the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, EC 1.1.1.34; HMGCoAR) and steady state biliary cholesterol output were measured in nine patients. 2. HMGCoAR levels varied four fold (9-40 pmol min-1 mg-1) and biliary cholesterol secretion 2.5-fold (0.60-1.15 mumol h-1 kg-1) but there was no correlation between these two variables (r = 0.18; P greater than 0.05) nor between biliary bile acid output and HMGCoAR activity (r = 0.34; P greater than 0.05). 3. There was, however, a linear relationship between bile acid and phospholipid secretion (r = 0.77; P less than 0.001) and between bile acid and cholesterol secretion (r = 0.69; P less than 0.05). 4. These results suggest that HMGCoAR activity is not a major determinant of cholesterol secretion nor at these secretion rates is HMGCoAR activity related to bile acid return to the liver.

Bile Acids and Salts↗
PubMed1982

Outcome of chenodeoxycholic acid (CDCA) treatment in 125 patients with radiolucent gallstones. Factors influencing efficacy, withdrawal, symptoms and side effects and post-dissolution recurrence.

Of 125 patients with radiolucent gallstones in functioning gallbladders treated with chenodeoxycholic acid (CDCA) between 1971 and 1977, 47 showed complete gallstone dissolution--an overall efficacy of 38%. However, a retrospective analysis of factors governing efficacy carried out in 1976 showed that in patients with stones less than 15 mm in diameter, treated with greater than 13 mg CDCA kg-1 day-1 for not less than one year who developed unsaturated bile (n = 27), efficacy rose to 78% complete and 93% partial plus complete gallstone dissolution. The usefulness of this selection/management approach was then confirmed prospectively in 42 comparable patients selected for treatment since 1977, efficacy (complete gallstone dissolution) reached 76%. The median duration of treatment for complete gallstone dissolution was 7.5 months for stones less than 5 mm in diameter, 12.0 for 5-10 mm stones; 22.0 for 10-15 mm stones and 28.5 for the only two patients (of 26) with large (greater than 15 mm) stones who ultimately showed complete gallstone dissolution. Seventy-eight patients withdrew from therapy, 21 within 6 months of starting CDCA (before their first follow-up cholecystogram): the remaining 57 withdrew because of: complications of gallstones (11 patients), inadequate treatment (dose and/or duration, 20 patients), inappropriate selection or unsuitable stones (19 patients) and resistance to CDCA (7 patients). Diarrhea, although common, was usually mild or transient. Biliary colic and non-specific dyspepsia tended to improve during therapy. To date, gallstone recurrence has been detected in 14 patients (30%), 3 months to 5 years after discontinuing treatment with CDCA.

Adolescent↗
PubMed1982

Retrospective comparison of 'Cheno' and 'Urso' in the medical treatment of gallstones.

In two groups of gallstone patients ideally suited for medical treatment, the effect of six to 18 months' therapy was compared retrospectively in 52 given chenodeoxycholic acid (CDCA) and 46 given ursodeoxycholic acid (UDCA). The minimum dose (mg kg-1 day-1) required to desaturate bile consistently was 10.1 for UDCA and 14.3 for CDCA. In patients completing six months' treatment, 23 of 35 (66%) taking a mean of 7.7 (+/- SEM 0.5) mg UDCA and 34 of 42 (81%) taking 14.7 +/- 0.2 mg CDCA showed partial or complete dissolution of gallstones. The mean dose in the UDCA-treated patients, however, was artefactually lowered by previous dose-response studies: in those who had not taken multiple doses, the mean UDCA intake in the 'responders' at six months was 9.1 +/- 0.3 mg kg-1 day-1. At six months, more UDCA (five of 35 or 14.3%) than CDCA (four of 42 or 9.5%)-treated patients showed complete dissolution of gallstones, but, by one year, the situation was reversed, 20 of 41 (49%) CDCA-treated and eight of 30 (27%) UDCA-treated patients showing complete dissolution of gallstones. Cumulative efficacy at one year had risen to 76% for UDCA and 89% for CDCA. Both treatments reduced the frequency of dyspepsia and biliary colic; 37% of CDCA and 2.6% of UDCA-treated patients showed hypertransaminasaemia; diarrhoea developed in 60% of the CDCA group but in none of the UDCA group.

Chenodeoxycholic Acid↗
PubMed1982

Small bowel adaptation and its regulation.

Since the subject of intestinal adaptation was last reviewed (16, 20, 97), there have been relatively few major advances but many useful minor additions and extensions which have helped to consolidate our knowledge of the field. The aim of this chapter is to summarise the results of a series of experiments which build up to our present state of knowledge. In doing so, the results of relatively old studies carried out some 15 years ago are briefly reviewed since they provide an essential background for, our current work. However, the article concentrates mainly on the new developments and in discussing these, areas of doubt and controversy are emphasised.

Adaptation, Physiological↗
PubMed1981

Prolactin and the small intestine. Effect of hyperprolactinaemia on mucosal structure in the rat.

To study the mechanism for the adaptive mucosal hyperplasia which occurs independent of luminal nutrition and pancreatico-biliary secretions in isolated Thiry-Vella segments of intestine from lactating rats, and to examine the effects of prolactin on small bowel mucosal structure in the rat, we used two models of experimental hyperprolactinaemia and compared quantitative histology and several markers of mucosal mass in jejunum and ileum from control rats and from test and lactating animals. Hyperprolactinaemia, induced by perphenazine injections (5 mg/kg/day for two or seven weeks) or transplantation of four pituitary glands from donor animals to beneath the renal capsule in the recipient, was confirmed by radioimmunoassay. Proof of its biological activity was obtained by weighing the mammary pads and by demonstrating true breast hyperplasia on histological section. Median serum prolactin levels increased from 50 ng/ml in the controls to 570 ng/ml in the perphenazine treated animals and to 600 ng/ml in the pituitary transplanted rats-levels comparable with those seen in lactation (870 ng/ml). In the lactating rats, there was striking mucosal hyperplasia of both jejunum and ileum but, despite the hyperprolactinaemia, there were no such changes in villus height, crypt depth, or in mucosal wet weight, protein, or DNA/unit length intestine in the perphenazine-injected or pituitary-transplanted animals. We conclude that prolactin is not atrophic to the intestine in rats and that hyperprolactinaemia cannot explain the intestinal adaptive changes of lactation.

Animals↗
PubMed1980

Measurement of faecal bile acid sulphates.

A method is described for the measurement, by difference, of the sulphate fractions of faecal bile acids. A solvolysis step (for the deliberate hydrolysis of the bile acid sulphates) was added to the procedure of sample homogenisation, extraction, enzymatic hydrolysis and thin-layer chromatography. The bile acids were quantitated by gas-liquid chromatography of their methyl ester and trifluoroacetate methyl ester derivatives on 3% QF-1 columns. The total bile acid excretion in 15 control subjects was 603 +/- 71 mg/24 h (mean +/- S.E.M.). The major bile acid peaks (mg/24 h) were: lithocholic acid, without solvolysis 118 +/- 26 and including solvolysis 175 +/- 30; deoxycholic acid 60 +/- 8 and 90 +/- 18 and chenodeoxycholic acid 13 +/- 7 and 15 +/- 7. It was concluded that bile acid sulphates may form a considerable proportion of the total bile acids excreted in man.

Adolescent↗
PubMed1980

Speed of onset of adaptive mucosal hypoplasia and hypofunction in the intestine of parenterally fed rats.

1. To establish the speed on onset of jejunal and ileal mucosal hypoplasia and hypofunction in parenterally fed rats, we measured three indices of mucosal mass, three mucosal enzymes and quantitative histology after 3, 6, 10 and 15 days of total parenteral nutrition and compared the results with those in two orally fed control groups, one with and one without intravenous catheters and metabolic cage restraint. The kinetics of galactose absorption in vivo were also measured after 10 days of total parenteral nutrition and in both control groups. 2. The most striking decrease in both jejunal and ileal mucosal wet weight and protein and DNA content per 10 cm length of intestine, occurred after only 3 days of total parenteral nutrition; thereafter the mean values showed only a slight further decrease. 3. The results of the morphometric studies showed that the hypoplasia affected the villi slightly more than the crypts. Within 3 days of starting total parenteral nutrition, mean jejunal mucosal thickness decreased by 16% and after 15 days it had fallen by 28%. The ileum showed similar, although less marked, changes. In the jejunum (not the ileum) modest cellular hypotrophy accompanied the mucosal hypoplasia; there were more epithelial cells/unit length of mid-villus and there was more DNA per g of mucosa in the total parenteral nutrition group than in the control group of rats. 4. Jejunal galactose absorption from the 16, 32 and 64 mmol/l solutions was significantly less in the 10-day total parenteral nutrition rats than in the controls, the apparent Vmax. being five times greater in the orally fed animals. The apparent Michaelis constant (Km) was also significantly less than normal in the jejunum of the parenterally fed rats, suggesting increased affinity of the hypothetical carrier for galactose, perhaps as a result of functionally hypermature cells. 5. Mucosal alkaline phosphatase and catalase activities per unit length of intestine decreased and alpha-D-glucosidase activity increased in the jejunum and ileum of the total parenteral nutrition rats. 6. These results show that during total parenteral nutrition, the ileum and particularly the jejunum show marked reductions in mucosal mass and function after only 3 days of total parenteral nutrition and that there is a more gradual and progressive loss of mucosal mass thereafter up to 15 days.

Animals↗
PubMed1980

Speed of change in pancreatic mass and in intestinal bacteriology of parenterally fed rats.

1. Indices of pancreatic mass and bacterial counts for jejunal and ileal mucosa were studied in rats after 3, 6, 10 and 15 days of total parenteral nutrition and compared with the results from orally fed and sham intravenously fed control rats. 2. Pancreatic wet weight corrected for body weight decreased significantly by 31--42% after 3, 6, 10 and 15 days of total parenteral nutrition. The most striking decrease occurred within 3 days. Other indices of pancreatic mass (protein and DNA) showed a similar pattern suggesting pancreatic hypoplasia. There was more DNA per g of pancreas, indicating that unless there were changes in tissue water cellular hypotrophy must have accompanied the hypoplasia. 3. Pancreatic RNA also decreased significantly after 3--10 days of total parenteral nutrition, suggesting reduced protein synthesis. 4. Bacterial counts (log number) whether expressed as number/unit length of intestine or number/g wet weight of mucosa were decreased for anaerobic bacteria in the jejunum after 3--15 days of total parenteral nutrition. In the ileum both aerobic and anaerobic bacteria increased after 6 days of parenteral nutrition and then decreased significantly. 5. The changes in bacterial flora are unlikely to account for the adaptive hypoplasia seen in the intestine of intravenously fed rats.

Animals↗
PubMed1980

Intestinal solubilization, absorption, pharmacokinetics and bioavailability of chenodeoxycholic acid.

Little is known about the physical state, intestinal solubilization, absorption and bioavailability of chenodeoxycholic acid used in the medical treatment of gallstones. Therefore the concentrations of unconjugated chenodeoxycholic acid were measured in the supernatant and precipitate phases of intestinal contents aspirated from stomach, duodenum and jejunum of nine control subjects who took 500 mg chenodeoxycholic acid (4 X 125 mg gelatin-coated capsules) either fasting or together with a standard liquid meal. Chenodeoxycholic acid solubility was markedly influenced by luminal pH but was little affected by endogenous conjugated bile acids when their concentrations were > 1-2 mmol/l. Systemic bioavailability of 250, 500 and 750 doses of chenodeoxycholic acid was measured in five subjects by comparing areas under 4 h serum concentration-time curves after giving the bile acid first as a bolus intraduodenal aqueous infusion of 3H-labelled chenodeoxycholic acid containing either 14C-polyethylene glycol or bromsulphthalein as non-absorbable markers, and then as gelatin-coated capsules by mouth. Absorption was assessed by measuring the ratio of marker: bile acid in intestinal contents aspirated for 2 h from sites 60 and 120 cm distal to the duodenal infusion port and in three subjects quantitative recovery of marker was measured proximal to an occluding intestinal balloon. Absorption of duodenally-infused chenodeoxycholic acid was 96-99% complete and bioavailability was complete with the 250 and 500 mg doses but fell to 81% with the 750 mg dose.

Adult↗
PubMed1980

Hepatic HMGCoA reductase in human cholelithiasis: effects of chenodeoxycholic and ursodeoxycholic acids.

To study further the role of hepatic cholesterol synthesis in patients with gallstones, the activity of the rate-limiting step in cholesterogenesis, hydroxymethyl glutaryl co-enzyme A reductase (HMGCoAR), was measured in operative wedge liver biopsies from ten patients with untreated cholesterol gallstones, six with pigment stones and ten controls. Hepatic HMGCoAR was also measured in six patients with cholesterol-rich gallstones treated for 1-24 months with 14.6-18.6 mg chenodeoxycholic acid (CDCA) kg-1 day-1, in two patients with radiolucent pigment stones treated with 17.3 and 17.7 mg CDCA kg-1 day-1 and in ten other patients with cholesterol-rich stones given 4.5-7.2 mg ursodeoxycholic acid kg-1 day-1 for 1-6 months. HMGCoAR activity was also related to the free and esterified cholesterol content of both hepatic homogenates and the microsomal fractions. Compared with the controls (HMGCoAR activity 14.6 +/- 1.6 (SEM) pmole mg microsomal protein-1 min-1), the mean activity in untreated cholesterol cholelithiasis was 32.2 +/- 2.0 (P < 0.001), but was near normal in patients with pigment stones (16.2 +/- 1.5). In cholesterol gallstone patients, chenodeoxycholic acid treatment reduced the mean enzyme activity by 51% compared with the untreated gallstone group (P < 0.001) and in smaller doses, ursodeoxycholic acid therapy lowered it by 40% (P < 0.001) but in the two patients with pigment stones, CDCA did not seem to affect HMGCoAR activity. Despite this four-fold variation in enzyme activity, there were no significant differences in mean free or esterified cholesterol concentrations in whole liver homogenates or in the microsomal fraction from any of the patient groups.

Adolescent↗