Effects of short term treatment with pentagastrin, proglumide, tamoxifen given separately or together with 5-fluorouracil on the growth in the murine transplantable Colon 38 cancer.

It is well known that 5-fluorouracil (5-FU) is the most effective drug in the treatment of colon cancer, however the positive response is small, only about 20%. On the other hand, it has been postulated that the growth of colon cancer depends on many growth factors, such as gastrin and estrogens. The search for new substances increasing the antitumor effect of 5-FU has lasted for many years. The aim of the present study was to examine the effects of pentagastrin (PEN, syntetic gastrin analogue), proglumide (PRO, a blocker of gastrin receptor) and tamoxifen (TAM, a partial estrogen antagonist) given separately or together with 5-FU on proliferation, apoptosis, necrosis and proliferation/apoptosis (P/A) ratio in the murine transplantable Colon 38 cancer. The male mice were implanted with a suspension of Colon 38 cells. After 7 days, the animals were treated with PEN (250 microg/kg b.w., twice daily), PRO (100 mg/kg. b.w., twice daily), TAM (10 microg/animal) separately or together with 5-FU (60 mg/kg b.w., once) for 2 days. The incorporation of bromodeoxyuridine (BrdU) into cell nuclei was used as an index of cell proliferation (labeling index--LI). The in situ labeling of nuclear DNA fragmentation according to TUNEL method was considered as an apoptotic index (AI). It was found that 5-FU increased the apoptosis, unexpectedly increased the LI and decreased the P/A ratio when compared to control. Both PEN and PRO increased the apoptosis and in the case of PRO decreased P/A ratio when compared to control. TAM did not affect any of the examined parameters. All of the investigated substances modify the 5-FU action: PEN and PRO on AI and LI and TAM on AI and P/A ratio. Necrosis was observed in 3 tumors treated with PEN + 5-FU, in 2 tumors of PRO + 5-FU group and in 1 tumor of group with 5-FU and with PEN. Further studies are needed to elucidate if those modification of 5-FU action by the examined substances will be useful in the inhibition of the growth of Colon 38 cancer.

Pentagastrin gastroprotection against acid is related to H2 receptor activation but not acid secretion.

BACKGROUND: Pentagastrin enhances gastric mucosal defense mechanisms against acid and protects the gastric mucosa from experimental injury. AIMS: To investigate whether this gastroprotection is mediated by histamine receptors or occurs as a secondary effect of acid secretion stimulation. METHODS: The effects of omeprazole (100 mumol/kg), ranitidine (20 mg/kg), and pyrilamine (10 mg/kg) on pentagastrin (80 micrograms/kg/h) induced gastroprotection against acidified aspirin injury were examined in a luminal pH controlled model. The effects of these compounds on pentagastrin enhanced gastroprotective mechanisms were investigated using intravital microscopy, in which intracellular pH of gastric surface cells (pH1), mucus gel thickness, gastric mucosal blood flow, and acid output were measured simultaneously. RESULTS: Pentagastrin protected rat gastric mucosa from acidified aspirin injury. This gastroprotection was abolished by ranitidine, but not omeprazole or pyrilamine. Pentagastrin induced a hyperaemic response to luminal acid challenge, increased mucus gel thickness, and elevated pHi during acid challenge. Ranitidine reversed these enhanced defence mechanisms, whereas omeprazole and pyrilamine preserved these effects. CONCLUSIONS: These data indicate that pentagastrin associated gastroprotection and enhanced defence mechanisms against acid result mainly from activation of histamine H2 receptors, and not as an effect of the stimulation of acid secretion.

Pentagastrin has panic-inducing properties in obsessive compulsive disorder.

The effects of the CCKB-receptor agonist pentagastrin, a synthetic analogue of the cholecystokinin tetrapeptide (CCK-4), were studied in seven patients suffering from obsessive compulsive disorder (OCD) and seven healthy controls. All subjects were challenged with an IV dose of 0.6 micrograms/kg pentagastrin or placebo under double blind placebo controlled conditions, on two separate occasions, with a minimum interval of 1 week. Six (86%) out of seven OCD patients experienced a panic-like reaction after pentagastrin administration, against only two (29%) in the control group. These differences failed to reach statistical significance, probably due to the small sample size. No increases were observed in obsessions or compulsive behaviors as assessed with the Yale-Brown Obsessive Compulsive Challenge Scale, neither in the pentagastrin, nor in the placebo condition. These findings suggest that pentagastrin has panic-inducing properties in OCD patients, without affecting the core symptoms. The panic-inducing properties of pentagastrin are not specific for panic disorder patients, which might be indicative of a common neurobiological dysfunction in panic disorder and OCD at the level of CCK-B receptors.

[Effect of glutamate and combined with inosine monophosphate on gastric secretion]. / Deistvie glutamata i ego sochetaniia s inozinmonofosfatom na zheludochnuiu sekretsiiu.

Experiments on dogs with Pavlov pouch and gastric fistula demonstrate that monosodium glutamate (MSG) enriched with inosine monophosphate (IMP) potentiate pentagastrin-induced gastric secretion. The preparation (Chi-Mi) was introduced directly into the intestine through a fistula. When given alone in an equal quantity MSG produced the same effect. In per os administration Chi-Mi was more effective, probably due to a different response of the gustatory receptors to MSG and Chi-Mi. When the latter two were added to meat used as a food stimulus, Chi-Mi brought about more intensive gastric secretion in all its phases. In sham feeding Chi-Mi also intensified the secretion augmenting the reflex phase of gastric secretion when added to food substances. The findings may appear helpful in further search for medical application of glutamate and allied substances.

[Specifics of endocrine regulation of digestion in patients with esophageal neoplasms after esophagogastroplasty]. / Osobennosti éndokrinnoi reguliatsii pishchevareniia u bolnykh rakom pishchevoda posle ézofagogastroplastiki.

In 67 patients with esophageal cancer, the peculiarities of endocrine regulation of alimentation after resection and plasty of the esophagus, using an isoperistaltic gastric tube were studied. Of these patients, 15 underwent correction of the disorders revealed. Accelerated evacuation of the content from a gastric transplant is accompanied by atony of the pylorus and is due to relative incompetence of neuroendocrine elements in gastric and duodenal mucosa (presence of a small amount of EC- and P-cells). Use of pentagastrin at the early postoperative period permits to accelerate the process of formation of the compensatory-adjusting mechanisms in the system of alimentation due to increase in functional activity of EC- and I-cells.

[Effects of pentagastrin in patients with diabetes mellitus]. / Effekty pentagastrina u bol'nykh sakharnym diabetom.

Pentagastrin used in patients with diabetes mellitus at a dose necessary for a study of gastric secretion regularly enhances the blood flow in the gastric mucosa and liver raising absorptive and antitoxic liver function.

Pharmacological constriction of the lower oesophageal sphincter: a simple method of arresting variceal haemorrhage.

The effect of pharmacological constriction of the lower oesophageal sphincter (LOS) on oesophageal varices was investigated in an experimental study followed by a controlled clinical trial. In the experimental study intravariceal pressure was measured just above the LOS in 11 patients before and after constricting the LOS by intravenous pentagastrin. Intravariceal pressure fell from a mean of 23 (range 12-36) mmHg to 4 (range 0-7) mmHg (p less than 0.001). This marked pressure drop indicated the considerable compression of varices that occurred within the LOS. A prospective controlled clinical trial examined whether LOS constriction (effected by the longer acting metoclopramide) would compress varices sufficiently to arrest active variceal bleeding originating from the lowest 2 cm oesophagus--the area encircled by the LOS. Of 11 patients who received metoclopramide, 10 stopped bleeding compared with four of the 11 who received placebo (p less than 0.01). Pharmacological constriction of the LOS appears to offer a new and effective approach for arresting active bleeding from oesophageal varices.

Pentagastrin protects the proximal small intestine against indomethacin-induced ulcers in the rat.

The possible protective effects of pentagastrin on indomethacin-induced small intestinal ulceration were investigated in rats. Ulcers were induced by subcutaneous injection of 30 mg/kg indomethacin, 30 min after refeeding rats fasted for 24 h. Administration of pentagastrin at a dose of 250 or 400 micrograms/kg i.p., 3 h prior to refeeding, reduced total ulcer area from 27.6 +/- 6.5 to 7.2 +/- 1.97 mm2 (mean +/- SEM; p less than 0.02) in the proximal small intestine only. Cyclic adenosine monophasphate, but not prostaglandin E2 levels were significantly raised by 250 micrograms/kg pentagastrin (0.15 +/- 0.05 vs. 0.38 +/- 0.07 pmol/mg protein; mean +/- SEM; p less than 0.02) in the same intestinal segment.

Cytoprotective effect of pentagastrin and epidermal growth factor on stress ulcer formation. Possible role of somatostatin.

This study was designed to test the effects of pentagastrin and epidermal growth factor (EGF) on stress-induced ulceration and on the antral content of gastrin and somatostatin (SLI) in rats. Four groups of 14 to 15 rats had been prepared for 7 days by one of the following methods: saline injection (control); injection of pentagastrin (250 micrograms/kg, 3 times/day); injection of EGF (10 micrograms/kg, 3 times/day); or injection of EGF plus pentagastrin. At the end of the treatment period, half of each group of rats were sacrificed (nonstress group). There were no ulcers in the nonstress control groups of rats. Stress was applied by water immersion in the remaining half of the rats. The injections of pentagastrin and/or EGF resulted in substantial increase in antral content of SLI. After 20 hours of stress, the ulcer index was 40.5 +/- 3.3 in the controls, compared to 6.4 +/- 1.2 and 16.2 +/- 2.3 in rats that received pentagastrin or EGF, respectively. Injections of both pentagastrin and EGF resulted in an ulcer index of 26.2 +/- 2.0, which was significantly lower than that in controls, but higher than that in rats treated with either peptide alone. The stress resulted in significant decrease in antral SLI in all groups of rats, whereas SLI content in rats treated with pentagastrin and/or EGF remained significantly higher than that of controls. Antral content of gastrin did not differ significantly in the four groups tested. The ulcer index was inversely correlated with antral SLI content. We confirm and extend previous observations that pentagastrin and EGF prevent stress ulcer formation, and suggest that endogenous SLI may account, at least in part, for their antiulcer activity.

Pharmacologic manipulation of lower esophageal sphincter pressure. A possible means of treatment of variceal bleeding.

Ten patients with portal hypertension and esophageal varices had percutaneous transheptic portography with selective catheterization of the short gastric or left gastric vein. The effect was studied on variceal blood flow after injection of various drugs (vasopressin IV, pentagastrin IV, somatostatin IV, domperidone IV, and methylcholine SC). Vasopressin had no effect on variceal flow; pentagastrin gave a total occlusion of flow in five of nine patients; somatostatin interrupted the flow in one of four patients; domperidone obstructed flow completely in one patient, while another receiving the same dose was unaffected; methylcholine did not affect the flow in three patients examined.

[One hundred cases of highly selective vagotomy without pyloroplasty for duodenal ulcer, with a follow-up of 4 to 8 years (author's transl)]. / Cent cas de vagotomie supersélective sans pyloroplastie pour ulcère duodénal suivis pendant quatre à huit ans.

The authors relate about a pilot series of 100 controlled cases of duodenal ulcer, operated by means of a highly selective vagotomy without pyloroplasty. These patients, all followed during a mean period of 5 1/2 years, showed a recurrent ulcer rate of 5%. Literature studies indicate that, when one wants to improve the results of this operation, it is necessary to avoid a pyloroduodenal stenosis and to clear completely the esophagus over the distal 5 to 7 cm. The pH-measurements during operation seem to be of accessory importance. The duodenal ulcers with and without hypersecretion can be operated by means of a highly selective vagotomy with equal chances of healing.