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Biomedical subjects

R E Dobbs

Publications and source records attributed to R E Dobbs.

At least 19 recordsLinked to original sources
PubMed1988

Red blood cell sorbitol lowering effects and tolerance of single doses of AL 1576 (HOE 843) in diabetic patients.

The safety and biochemical effects of AL 1576 (HOE 483), a recently developed aldose reductase inhibitor, were evaluated. In a double-blind, placebo-controlled, clinical trial, AL 1576 (HOE 483) was administered to diabetic patients for the first time. Four single, orally administered dose levels were tested, (2, 5, 10, and 20 mg). No clinically important adverse effects were seen in any of the patients. AL 1576 (HOE 483) suppressed red blood cell (RBC) sorbitol concentrations in a dose-related fashion. Also found were statistically significant inverse correlations between the plasma drug concentration and both RBC sorbitol concentrations as well as RBC sorbitol/serum glucose ratios. In single doses up to 20 mg, AL 1576 (HOE 483) is well tolerated and decreases RBC sorbitol, a biochemical marker of pharmacologic activity, in diabetic patients.

Adolescent↗
PubMed1988

High-performance liquid chromatographic assay of the aldose reductase inhibitor spiro-(2-fluoro-9H-fluorene-9,4'-imidazolidine)-2',5'-dione (AL01567) in plasma and urine and its pharmacokinetics in humans.

Two selective high-performance liquid chromatographic (HPLC) methods have been developed for the quantitative determination of spiro-(2-fluoro-9H-fluorene-9,4'-imidazolidine)-2',5'-dione (AL01567; 1) in plasma and urine, with an assay sensitivity of 0.25 micrograms/mL for plasma and 0.13 micrograms/mL for urine. The plasma assay procedure involved precipitation of proteins with acetonitrile followed by dilution with water. The diluted supernatant was analyzed on an ODS column eluting with acetonitrile:0.5% phosphoric acid (30:70) adjusted to pH 7.2 with concentrated ammonium hydroxide. The urine assay procedure involved extraction of 1 with 10% n-butanol in hexane, followed by back extraction with 0.05 M sodium hydroxide. The basic extract was neutralized and analyzed on a phenyl column eluting with acetonitrile:10 mM potassium phosphate (30:70; monobasic, pH 5.6). The pharmacokinetics of 1 was investigated in humans following single and multiple oral doses. The elimination half-life from 12 normal subjects following single 100-400-mg oral doses was independent of dose, and the overall mean half-life was 66 +/- 9 h. The overall mean oral clearance (assuming a bioavailability of 100%) was 11 +/- 3 mL/min, and the mean apparent volume of distribution was 59 +/- 13 L. The mean urinary recovery of intact drug during the first 24 h after dosing was 1.2 +/- 0.4% of the administered dose. During once daily 100-mg oral dosing of 1 to five subjects for 21 d, plasma concentrations of 1 reached apparent steady-state by 7 d.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1979

Somatostatin analogs inhibit somatostatin release.

To determine if, like insulin, somatostatin inhibits its own secretion from the pancreas, nonimmunoreactive analogs of somatostatin were perfused in an isolated dog pancreaticoduodenal preparation using a nonrecirculating system. [D-Trp8-D-Cys14]somatostatin, at a concentration of 200 ng/ml, blocked the response of somatostatin-like immunoreactivity (SLI) to cholecystokinin and arginine. When perfusion of the analog was discontinued, SLI release increased. At a concentration of 0.1 ng/ml, des Asn5-[D-Trp8]somatostatin lowered SLI levels significantly without significantly reducing glucagon levels. At a concentration of 1 ng/ml, des Asn5-[D-Trp8]somatostatin significantly inhibited SLI as well as insulin and glucagon release. Perfusion of glucagon at a concentration of 10 ng/ml failed to overcome the blockade of SLI and insulin release caused by 50 ng/ml des Asn5-[D-Trp8]somatostatin. The results are compatible with a direct inhibitory effect of somatostatin analogs upon SLI release and raise the possibility of a self-inhibiting action of the native hormone.

Animals↗
PubMed1979

Glucagon-like polypeptides in canine brain.

Glucagon-like material has been detected by radioimmunoassay in several areas of the canine brain. High concentrations of glucagon-like immunoreactivity (GLI), measured with antibodies directed against the N-terminal region of glucagon, have been found in the hypothalamus, amygdala, and mesencephalon, but a high concentration of immunoreactive glucagon (IRG), measured with antibodies directed against the C-terminal region of glucagon, has been found only in the hypothalamus. The predominant molecular forms of GLI isolated from brain extracts by affinity chromatography are the same as those isolated from gut extracts. The predominant form of IRG in brain extracts is of the same (approximate) molecular weight as pancreatic glucagon.

Animals↗
PubMed1978

The role of glucagon deficiency in the Houssay phenomenon of dogs.

Plasma glucose, immunoreactive glucagon (IRG), and insulin were measured in hypophysectomized dogs receiving cortisol and thyroid replacement therapy. 4 wk after hypophysectomy mean fasting plasma glucose levels had declined from 90+/-2 mg/100 ml to 64+/-2; fasting and arginine-stimulated insulin and IRG levels were, respectively, approximately 50% lower and unchanged. 12 wk or more after hypophysectomy, despite lower plasma glucose levels, fasting and arginine-stimulated IRG levels were significantly below control dogs. Hypophysectomized and shamhypophysectomized dogs were subjected to total pancreatectomy. Postoperatively, in the sham-hypophysectomized, depancreatized dogs fasting glucose levels ranged from 300-500 mg/100 ml on 8-10 U/day of insulin; IRG levels averaged 215+/-29 pg/ml. The hypophysectomized, depancreatized dogs required 0-4 U/day and fasting glucose levels under 100 mg/100 ml were not uncommon, even without insulin; fasting IRG levels averaged 63+/-4 pg/ml (P < 0.001). During arginine infusion in sham-hypophysectomized, depancreatized dogs, IRG levels rose from 215+/-60 pg/ml to a peak of 404+/-112 pg/ml; in hypophysectomized, depancreatized dogs, the base line IRG averaged 44+/-8 and the peak 110+/-25 pg/ml (P < 0.05). IRG levels in the venous effluent of the gastric fundus, the major source of nonpancreatic glucagon, reached a peak of 4,898+/-959 pg/ml in the sham-hypophysectomized, depancreatized group during arginine infusion and only 219+/-128 pg/ml in the hypophysectomized, depancreatized group. In three hypophysectomized, depancreatized dogs, a replacement infusion with glucagon for 10 h promptly increased hyperglycemia by 80-180 mg/100 ml and worsened glycosuria, evidence of a hepatic response to glucagon replacement. It is concluded that hypophysectomy somehow decreased both the hypersecretion of gastric IRG and the severe hyperglycemia that otherwise follows pancreatectomy. The hypophysectomized, depancreatized animal, therefore, has combined insulin and glucagon deficiency, and the latter may contribute to reduced severity of its hyperglycemia.

Adrenalectomy↗
PubMed1977

Immunocytochemical evidence for glucagon-containing cells in the human stomach.

To determine if glucagon-containing cells could be identified in the human fundus, stomachs attained at autopsy within 4-hours of death from persons previously considered to be in good health were examined by the indirect immunoperoxidase technique using antiglucagon serum 30K. Glucagon-containing cells were demonstrated in one of eight gastric fundi examined. The glucagon content of acid alcohol extracts of the fundi examined. The glucagon content of acid alcohol extracts of the funci was low in all cases. Glucagon content was also low in canine stomach removed 4-hours after death. It is concluded that glucagon-containing cells, demonstrable by immunocytochemical techniques, may be present in the gastric fundus of humans.

3,3'-Diaminobenzidine↗
PubMed1977

Pancreatic immunoreactive somatostatin release.

The location of the somatostatin-containing D-cells of the pancreatic islets between the A- and B-cells suggests that their function might be to inhibit insulin and/or glucagon secretion by these neighboring cells. To determine if insulin and/or glucagon, in concentrations that might be present in the extracellular space surrounding the D-cells, stimulate immunoreactive somatostatin (IRS) release, we perfused 10 microng of glucagon or 10 milliunits of insulin per ml in 11 isolated dog pancreases, for 40 min in seven experiments and for 100 min in four experiments. In eight of the nine experiments in which glucagon was perfused, a prompt and significant rise in mean IRS release, ranging from 71 to 128% above the control level, was observed. In the eight experiments in which insulin was perfused. IRS did not increase during the first 40 min; in the two 100-min insulin experiments, it did rise during the final 50 min, however. To determine the effect of an A- and B-cell secretogogue on IRS release, we perfused 20 mM arginine for 60 min in six experiments. In all, IRS rose within 3 min and reached a level 71-465% above the control, remaining significantly elevated throughout the perfusion, while glucagon and insulin rose to peak levels at 2 min and then declined somewhat despite continuing arginine perfusion. The results indicate that perfusion of the normal dog pancreas with high doses of glucagon or arginine is accompanied by a prompt increase in IRS release and are compatible with a local feedback circuit involving A- and D-cells. Insulin appears not to augment IRS release, at least not promptly, but IRS stimulated by local endogenous glucagon could inhibit the B-cell response to locally secreted glucagon and thereby influence the composition of the insulin/glucagon secretion mixture.

Animals↗
PubMed1977

Release of immunoreactive somatostatin from the pancreas in response to glucose, amino acids, pancreozymin-cholecystokinin, and tolbutamide.

The effects of glucose, amino acids, pancreozymin-cholecystokinin, and tolbutamide upon the release of immunoreactive somatostatin (IRS) from the isolated perfused pancreas were studied. In seven experiments in which glucose was perfused either at a concentration of 100 or 350 mg/dl or at 25 mg/dl, IRS levels were significantly greater at the higher glucose concentrations. In three dose-response experiments in which the perfusing glucose concentration was increased at 30-min intervals from an initial concentration of 25 mg/dl to a final concentration of 300 mg/dl, progressive increases in IRS release were noted at glucose concentrations of 100 mg/dl and above. Perfusion of a 20 mM mixture of 10 amino acids also elicited a prompt and significant biphasic IRS rise in each of six experiments. In five experiments, 20 mM leucine evoked a similar response in mean IRS. Perfusion with 0.075 Ivy U/ml of pancreozymin-cholecystokinin, with or without the presence of a 1 mM 10-amino acid mixture, elicited a prompt rise in IRS with a pattern resembling that of insulin in a total of six experiments. Tolbutamide (0.75 mg/min) also stimulated IRS release in five of six challenges. The IRS responses to nutrients and to pancreozymin and their similarity to the insulin responses raise the possibility that, like insulin, pancreatic somatostatin may have an endocrine role related to nutrient homeostasis.

Amino Acids↗
PubMed1977

The effects of gastrin, gastric inhibitory polypeptide, secretin, and the octapeptide of cholecystokinin upon immunoreactive somatostatin release by the perfused canine pancreas.

The effects of gastrin, gastric inhibitory polypeptide, secretin, and the octapeptide of pancreozymin-cholecystokinin on immunoreactive somatostatin release were studied in the isolated perfused dog pancreas. Gastrin at a concentration of 65 ng/ml and the octapeptide of pancreozymin-cholecystokinin at a concentration of 25 ng/ml produced a prompt, but transient statistically significant, twofold rise in mean somatostatin concentration. Secretion at a concentration of 0.3 U/ml and gastric inhibitory polypeptide concentration of 58 ng/ml produced a prompt two- to threefold rise in mean somatostatin release, which persisted throughout the perfusion period. With all four polypeptides the pattern of the somatostatin response resembled that of insulin. It appears that pancreatic somatostatin release is stimulated by gastrointestinal hormones that influence the secretion of insulin and glucagon.

Animals↗
PubMed1977

Effects of hypothalamic factors on insulin and glucagon release from the islets of Langerhans.

Isolated pancreatic islets were used to determine whether substances of hypothalamic origin could directly influence the release of insulin and glucagon. Media in which various regions of the brain had been incubated were tested in the islet system, as were the synthetic peptides neurotensin and substance P, and the catecholamines, dopamine and norepinephrine. Substance(s) released from the ventromedial hypothalamic (VMH) segments in vitro inhibited insulin release and stimulated glucagon release from the islets. Incubates of ventrolateral hypothalamic (VLH) or cortex tissue failed to alter insulin or glucagon levels. The VMH medium retained these activities even after oxidation with K3Fe (CN)6, whereas the ability of the catecholamines to inhibit insulin release and stimulate glucagon release was eliminated by this treatment. Neurotensin and substance P (0.1 and 1.0 nmol/ml) inhibited insulin release while glucagon release was increased; however, radioimmunoassay indicated that these peptides were virtually absent from the VMH incubate. These results show that incubates of VMH contain substances which can inhibit insulin and stimulate glucagon release in vitro. They may influence the endocrine pancreas by way of the peripheral circulation although the possibility of their occurrence in or near the pancreas itself has not been excluded.

Animals↗
PubMed1977

Demonstration of gastric glucagon hypersecretion in insulin-deprived alloxan-diabetic dogs.

The contribution of the gastric fundus to the hyperglucagonemia of poorly controlled diabetes was studied in insulin-deprived alloxan-diabetic dogs by simultaneously measuring plasma glucagon in the venous effluents of the fundus and the pancreas, and the inferior vena cavae plasma. In the basal state, mean glucagon averaged 411 +/- 45 pg./ml. in the gastric vein and 941 +/-161 in the pancreaticoduodenal vein; both values were significantly above the vana caval level of 281 +/-35 (p less than 0.01). Intravenous arginine infusion to 1,180 +/- 432 after 1.5 minutes; this was significantly above the mean vena caval glucagon concentration which reached a peak of only 352 +/- 74 (p less than 0.01 to 0.05). Intragastric instillation of arginine was followed by a doubling of gastric vein glucagon within 10 minutes, and the increases in the gastric vein were significantly greater than in the peripheral plasms at several points. The infusion of insulin at a rate of 0.0015 u./kg./min. rapidly lowered glucagon in the gastric and pancreaticoduodenal veins, abolishing the gradient across the stomach and reducing the transpancreatic gradient. The studies raise the possibility that extrapancreatic glucagon may contribute to the hyperglucagonemia of insulin deficiency.

Animals↗
PubMed1976

Gastric A-cell function in normal dogs.

Glucagon release from the gastric fundus and pancreas were compared in normal dogs by measuring glucagon in plasma from a major gastroepiploic vein, the superior pancreaticoduodenal vein, and the inferior vena cava. In 32 dogs in the basal state, gastric vein glucagon averaged 97 +/- 40 pg/ml, not significantly different from the 93 +/- 41 pg/ml level in the vena cava. Pancreaticoduodenal vein glucagon averaged 250 +/- 32 pg/ml (P less than 0.001). Intravenous arginine infused in four dogs caused a rise in mean gastric vein glucagon to 210 +/- 33 pg/ml within 3 min, and glucagon remained between 53 and 98 pg/ml above the vena caval level thereafter. In the gastric vein, the rise in glucagon was significantly greater than in the vena cava at 3, 5, and 10 min (P less than 0.05), but was far less than in the pancreaticoduodenal vein where glucagon rose to 1,295 +/- 379 pg/ml at 1.5 min. Evidence of modest gastric glucagon release was observed after the intragastric instillation of arginine, but not during insulin or phloridzin-induced hypoglycemia. It was concluded that in normal dogs under the circumstances studied, the gastric fundus is not a major source of circulating glucagon.

Animals↗