Pantoprazole provides rapid and sustained symptomatic relief in patients treated for erosive oesophagitis.

BACKGROUND: Effective symptom control is a primary concern of most heartburn suffers. AIM: To compare the safety and efficacy of pantoprazole, placebo and the H2 antagonist nizatidine in relieving symptoms in patients with erosive oesophagitis. METHODS: Data from two randomized, double-blind studies were pooled. Patients received pantoprazole 10, 20 or 40 mg, or placebo daily (study 1, n = 603), or pantoprazole 20 or 40 mg daily or 150-mg nizatidine b.d. (study 2, n = 243) for either 4 or 8 weeks. Endoscopy was performed at baseline, week 4 and week 8. Persistent absence of symptoms was defined as the first day that no symptoms were reported by the patient on that day or any subsequent study day. RESULTS: A significantly higher percentage (P < 0.05) of pantoprazole patients reported elimination of all symptoms by week 8. Daytime heartburn, night-time heartburn and regurgitation were significantly better controlled with pantoprazole (with a dose-response at most time-points). Absence of symptoms was a powerful predictor of healing; presence of symptoms correlated poorly. CONCLUSION: Pantoprazole is more effective than placebo or nizatidine for controlling heartburn and acid regurgitation in patients with erosive oesophagitis. Relief of GERD symptoms is highly predictive of healing of erosive oesophagitis at 4 and 8 weeks.

Pantoprazole maintenance therapy prevents relapse of erosive oesophagitis.

OBJECTIVES: To compare the safety and efficacy of pantoprazole with ranitidine for the maintenance of endoscopically documented healed (grade 0 or 1) erosive oesophagitis. METHODS: Patients (371) were randomly assigned to receive pantoprazole 10, 20 or 40 mg or ranitidine 150 mg. Endoscopies were performed after 1, 3, 6 and 12 months or when symptoms suggesting relapse (grade = 2) developed. Gastric biopsies were obtained at baseline and on at least one postbaseline visit. Symptom-free days and Gelusil use were assessed. RESULTS: Pantoprazole was significantly (P < 0.001) more effective in maintaining erosive oesophagitis healing. After 12 months, 33%, 40%, 68% and 82% of patients remained healed for the ranitidine and pantoprazole 10, 20 and 40 mg groups, respectively. Daytime and night-time heartburn were eliminated in > 90% of days for the pantoprazole 40 mg group. Gelusil use was significantly lower with pantoprazole 20 and 40 mg than with ranitidine (P < 0.02) during the first 9 months. CONCLUSIONS: Twelve months of maintenance therapy with pantoprazole (10-40 mg once daily) was superior to ranitidine (150 mg twice daily) in maintaining erosive oesophagitis healing. Pantoprazole 40 mg provided the most consistent efficacy and was well tolerated.

Comparative efficacy of new investigational agents against Helicobacter pylori.

BACKGROUND: Emergence of antibiotic resistant Helicobacter pylori has necessitated the identification of alternate therapies for the treatment of this infection. AIM: To assess the in vitro efficacy of two investigational agents: DMG-MINO CL 344 (a N,N-dimethylglycylamido derivative of minocycline), and davercin, a cyclic carbonate of erythromycin A as compared to older antibiotics (clarithromcyin, azithromycin, minocycline, tetracycline, ofloxacin, ciprofloxacin, cefixime) against clinical isolates of H. pylori. METHODS: Testing was performed using the agar dilution method approved by the NCCLS subcommittee on antimicrobial susceptibility testing, Helicobacter pylori working group. Under these guidelines, Mueller-Hinton agar containing 5% aged sheep blood was used. All incubations were done under CampyPak Plus conditions for 72 h at 37 degrees C. The drug concentrations in the agar ranged from 0.016 to 16 microg/mL. Twenty-one clarithromycin-resistant and 16 clarithromycin-susceptible clinical isolates of H. pylori obtained from patients with duodenal ulcer were used. H. pylori ATCC 43504 was used as the control in all determinations. RESULTS: Against clarithromycin susceptible isolates, all antimicrobial agents except the fluoroquinolones were highly effective. Against clarithromycin-resistant H. pylori, the MIC50/MIC90 values showed that the tetracyclines and cefixime were the most efficacious agents. The fluoroquinolones and macrolides were ineffective. Macrolide cross-resistance was detected. CONCLUSION: Macrolide cross-resistance prevents the use of this entire class of antimicrobials when clarithromycin resistance is present. Tetracyclines and cefixime are possible alternative agents for the treatment of H. pylori infection in these patients.

Secretin, cholecystokinin and the biliary canalicular secretion in the rat.

An attempt has been made to further assess which fraction of bile can be stimulated by the main gastrointestinal hormones in rats. In the cannulated conscious animals the i.v. infusions of glucagon, impure Boots secretin, impure Boots cholecystokinin (CCK) and OP-CCK resulted in 8.9% (N.S.), 68.5% (P < 0.001), 88.7% (P < 0.001) and 19.0% (P < 0.05) increase in the estimated bile acid-dependent bile flow (BAF) and in 25.4% (P < 0.01), 49.2% (P < 0.001), 44.5% (P < 0.001) and 1.6% (N.S.) increase in the estimated bile acid-independent bile flow (BAIF), respectively as compared to the control values. When the calculated BAF values corresponding to the bile acid impurities in Boots secretin and Boots CCK were subtracted from BAF and BAIF values obtained during hormone infusions (the corrected values), the increase in both BAF and BAIF was equal to 38.9% (P < 0.02) and 29.4% (P < 0.02) during Boots secretin infusion and to 61.1% (P < 0.01) and 29.4% (P < 0.02) during Boots CCK infusion, respectively as compared to the control values. It can be suggested that the hormonal impurities in the Boots preparations interacting with the principal hormonal component are able to stimulate BAF in the rat. Further extensive study embracing the interactions of the purified gut hormones may confirm their role in the control of canalicular bile secretion in the rat.

Effect of hyperglycemia and the aldose reductase inhibitor tolrestat on sural nerve biochemistry and morphometry in advanced diabetic peripheral polyneuropathy. The Tolrestat Study Group.

Tolrestat is a well tolerated nonhydantoin aldose reductase inhibitor that has been reported to improve nerve conduction in diabetic animals and humans. Its effects on nerve biochemistry and structure have not been studied in patients with diabetic neuropathy. Patients with advanced diabetic neuropathy treated with long-term open-label tolrestat were randomly assigned to continuation on drug treatment or to placebo-controlled drug withdrawal for 12 months. At the end of this period, sural nerve biopsies were obtained for measurement of glucose, sorbitol, and fructose content, and for detailed morphometric analysis. Tolrestat ameliorated the glucose-mediated increase in sorbitol and fructose in sural nerve tissue. No statistically significant differences in nerve morphometry emerged between the two groups; however, both treatment groups exhibited increased nerve-fiber regeneration and normalization of axo-glial dysfunction and segmental demyelination following long-term tolrestat treatment. These findings are similar to those previously reported in a placebo-controlled sequential nerve biopsy study with the aldose reductase inhibitor sorbinil. Thus tolrestat is a biochemically effective aldose reductase inhibitor in human diabetic nerve with potential therapeutic efficacy for diabetic neuropathy.

Carbohydrate content of apolipoprotein B-48 from rat chylomicrons of varying density.

Monosaccharide composition was determined in apolipoprotein B-48 (apoB) of chylomicrons of rat mesenteric lymph. Chylomicrons were separated into three fractions based on density. Triglyceride and apolipoprotein content were determined in each. ApoB was isolated and quantified using precipitation with isopropanol. Chylomicrons were collected in lymph under normal conditions, and with Poloxalene 2930 when chylomicron secretion was inhibited. Most of the triglyceride was carried in the least dense fraction, while the highest apoB content was in the most dense fraction under normal conditions. Mannose and galactosamine contents of apoB were similar in all fractions while contents of both glucosamine and galactose were highest in the least dense fraction. When chylomicron secretion was inhibited by Poloxalene, the amount of triglyceride recovered in the least dense fraction was significantly reduced. Despite the inhibition of lipid transport in the least dense fraction of chylomicrons by Poloxalene, there was little change in apoB recoveries and in the relative content of various monosaccharides in the apoB from each of the three fractions as compared to results obtained during lipid absorption under normal conditions. In conclusion, carbohydrate composition of apoB of chylomicrons is heterogeneous and varies with chylomicron density.

Hydrophobic surfactant inhibits hypercholesterolemia in pair-fed rabbits on a cholesterol-free, low-fat diet.

Poloxalene, a hydrophobic surfactant, is known to prevent hypercholesterolemia in animals fed a high-fat, high-cholesterol diet. It has not been demonstrated, however, whether this agent is of benefit when hypercholesterolemia is induced in animals by means other than the feeding of a high-fat diet. In this study, hypercholesterolemia was produced in rabbits by feeding a low-fat, cholesterol-free diet with dietary protein supplied by casein for a period of 8 weeks. Controls were given this diet without poloxalene and experimentals were given the diet with poloxalene. Total serum cholesterol levels increased in both groups, but the rise was greater for the control group. Lipoprotein analysis performed at the conclusion of the study showed significantly greater low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels in the control group as compared to the experimental group. Total protein and apolipoprotein B (apo B) were also greater in control LDL. It was concluded that poloxalene favorably affects this model of hypercholesterolemia as total serum cholesterol, LDL cholesterol, and LDL apo B were all less and the HDL cholesterol to LDL cholesterol ratio was higher in surfactant-treated rabbits.

Alterations of secretory pattern of intestinal lipoproteins by the benzoyl ester derivative of poloxalene surfactant (BEP).

Hydrophobic surfactant BEP was administered intraduodenally as part of lipid emulsion to rats with cannulated mesenteric lymphatic duct. The effect on the size and composition of intestinal triglyceride-rich lipoproteins (TRLp) was assessed by comparing the results with those obtained during infusion of the lipid emulsion alone. Administration of BEP decreased intestinal capacity to transport triglyceride and cholesterol in large TRLp, SF greater than 2000, and resulted in a significant reduction of total triglyceride in lymph. Non-apoB apolipoproteins decreased significantly in large and increased in small TRLp without appreciable change in total content. Contrary to these findings total apoB protein content increased significantly, primarily due to an increase in small TRLp. Changes in lipid and protein content of apolipoproteins produced by BEP resulted in increased ratios of apolipoproteins to lipids in TRLp. It was therefore concluded that inhibition of lipid transport by BEP was not a result of apolipoprotein deficiency. Discontinuation of BEP administration resulted in a prompt recovery of the intestinal lipid transport system.

Hydrophobic surfactant effects on aortic cholesterol accumulation and atherosclerosis in hypercholesterolemic rabbits.

Studies were performed in hypercholesterolemic rabbits to determine whether the hydrophobic surfactant, Poloxalene 2930 (Pol), is of benefit under these conditions. Lipoprotein analyses plus chemical and morphologic studies of the aorta were performed to evaluate the results. In one study, rabbits were made hypercholesterolemic by dietary means and then divided into two groups and given a cholesterol-free diet with one group additionally given Pol with treatment continued for 10 weeks. Pol treatment resulted in less atherosclerosis but the mechanism for this effect was not apparent from lipoprotein analysis. In the other study 3 groups of rabbits were given a cholesterol-rich diet for 16 weeks. Two groups received Pol supplement with one of these groups receiving a dose that was too small to prevent hypercholesterolemia. In this group plus the group on diet alone comparable degrees of hypercholesterolemia were maintained throughout the study. Lipoprotein abnormalities were similar in these two groups except that those on Pol had a more normal cholesterol to apolipoprotein B ratio. The amount of atherosclerosis in both groups was mild but aortic cholesterol content was much less for the Pol group. It is concluded that Pol limits cholesterol accumulation in the aortic wall of hypercholesterolemic rabbits and can retard the development of atherosclerosis.

Poloxalene 2930, a hydrophobic surfactant that prevents atherosclerosis, alters composition of rabbit lipoproteins.

Poloxalene 2930, a hydrophobic surfactant, was incorporated into an atherogenic diet at dose levels, 0.5% and 1% of the diet, and fed to rabbits for 10 weeks. Another group received plain atherogenic diet alone and a control group was fed chow. After this period, serum lipoproteins were separated by centrifugation and analyzed. The composition of lipoproteins from rabbits on atherogenic diet was abnormal. The cholesterol: triglyceride ratio of every lipoprotein fraction was significantly increased as was the cholesterol: protein ratio of very low density lipoproteins. Supplementing the diet with Poloxalene 2930 prevented these alterations. In all groups on the atherogenic diet the percentage of apolipoprotein E in VLDL and HDL increased. In the case of Poloxalene-treated rabbits this developed even though serum cholesterol levels were normal or slightly increased. It is concluded that Poloxalene 2930 has a systemic effect on lipoproteins which may contribute to its antiatherogenic action.

Inhibition of lipid absorption by non-ionic hydrophobic surfactant Pluronic L-81, and its benzoyl esters.

The benzoyl ester of Pluronic L-81 (BEP) has been purified on an aluminium oxide column and fractionated on the basis of its mobility characteristics into three fractions, BEP I, II and III. Absorption studies were made with rats fed by gavage a lipid preparation containing [14C]triolein and [3H]cholesterol (control animals) and one of the fractions or Pluronic L-81, or crude BEP. After 4 h the amount of lipid absorbed and transported was calculated as the difference between the dose fed and the amount of lipid recovered from the gastric and intestinal luminal contents and intestinal mucosa. Pluronic L-81 was the most effective in inhibiting absorption of triolein but it did not inhibit absorption of cholesterol. BEP-II was almost as effective in inhibiting the absorption of triolein and also inhibited absorption of cholesterol. Crude BEP was less effective and BEP-I and III had only limited activity. Inhibition of triolein absorption by Pluronic L-81 may be partly related to its delaying action on gastric emptying. As purified BEP preparations had practically no effect on gastric emptying, their inhibiting activity involved intestinal mechanisms of lipid absorption.

Absorption and excretion of the hydrophobic surfactant, 14C-poloxalene 2930, in the rat.

Absorption and excretion of 14C-Poloxalene 2930 (PX), a nonionic hydrophobic surfactant of large molecular weight, were studied using bile fistula rats. Approximately half of the dose infused intraduodenally was absorbed and some of the absorbed surfactant was excreted in bile. The remainder was excreted in urine. Only trace quantities of the 14C-PX were recovered in liver and carcass at termination of the study. Two studies were also performed with 14C-PX incorporated into the diet. In the first feeding study of 7 days duration, most of the agent was excreted via the gastrointestinal tract within 72 hr of discontinuing treatment. In the second study, rats were fed dietary 14C-PX for 7, 14, or 23 days to determine whether the surfactant continued to accumulate in the body as the test period was extended. Further accumulation did occur between the 7th and 14th days but not when feeding was continued for a total of 23 days. Of the amount of 14C-PX ingested after 23 days of feeding, essentially all was excreted by the end of 7 days after discontinuing treatment. These studies indicate that despite its large molecular weight of about 3,000 some 14C-PX is absorbed. Furthermore, absorbed material is promptly excreted in bile and urine with little retained in body tissues.

Effect of surfactant poloxalene 2930 on food intake, lipid absorption, and serum cholesterol in rats.

Effect of hydrophobic surfactant, poloxalene 2930, on lipid absorption was studied in rats. Under acute conditions with surfactant infused intraduodenally with a lipid meal absorbed lipid accumulated abnormally in the enterocytes. This effect was quickly reversed after terminating treatment. Long-term administration of poloxalene given in semipurified diets resulted in changes in food intake, weight gain, fecal fat output, and serum cholesterol concentrations. The composition of the diet used as the vehicle for administration had a considerable effect on these results. When semipurified diets were used, food intake and weight gain were greatest when the dietary fat content was at the highest level. When the surfactant was given in ground chow, food intake was not affected and weight gain was only slightly, but significantly, less than the controls as a result of mild fat malabsorption. It is concluded that poloxalene 2930 affects lipid absorption, food intake, and serum cholesterol concentration but that results of this treatment are considerably affected by dietary factors.

Effect of secretin, pancreozymin OP-CCK, and glucagon on bile flow and bile lipid secretion in rats.

Rats equipped with biliary, duodenal, and vena cava cannulae and supplemented with Na taurocholate received 4 hour infusions of gastrointestinal hormones. Boots secretin increased bile flow by 63% and bile acid, cholesterol, and phospholipid output by 75, 96, and 73% respectively. This stimulatory effect on bile flow and bile acid secretion was observed also in the four hour postinfusion period. Kabi secretin had practically no effect on bile secretion. Boots pancreozymin stimulated bile flow by 45% and to some extent also stimulated bile acid output. OP-CCK and glucagon stimulated mainly bile flow rate.

Hydrophobic surfactant treatment prevents atherosclerosis in the rabbit.

The hypocholesterolemic effect of the hydrophobic surfactant, poloxalene 2930, was studied in the rabbit to determine whether this agent prevents experimentally produced atherosclerosis. Male rabbits were divided into four groups and fed a control diet (group A) or an atherogenic diet (groups B, C, and D) for 10 wk. Diets of groups C and D were supplemented with 0.5 and 1% poloxalene 2930, respectively. Animals in group B developed significantly greater levels of cholesterol in the serum and aorta compared with group A. Addition of poloxalene 2930 to the diets of groups C and D prevented significant elevations in cholesterol concentrations of both serum and aorta compared with group B with values for group D being essentially similar to those observed in group A. Groups C and D also had significant increases of fecal excretion of both neutral fat and neutral steroids as compared with either groups A or B. There were no atherosclerotic lesions of the aortas from group D. Aortas from rabbits in group B had numerous atheromatous plaques while one rabbit each from groups A and C had several very small atheromatous lesions. These results demonstrate that poloxalene 2930 reduces the rise of serum cholesterol in rabbits in response to an atherogenic diet and prevents the development of atherosclerosis. This hypocholesterolemic effect is likely mediated by the effect of this surfactant on the small intestine.

Hypolipemic activity of benzoyl ester of polyoxypropylene-polyoxyethylene block copolymer (BEP) in rabbits.

BEP mixed with food was administered to rabbits fed an atherogenic diet at concentrations of 0.5% and 1.5% (w/w) and the results were compared with control animals. After 8 weeks plasma cholesterol in the animals receiving 0.5% BEP was almost 4 times lower and in the rabbits taking 1.5% BEP 8 times lower than in the controls. Plasma triglycerides were practically unaffected by BEP. Hepatic total lipid and cholesterol were significantly decreased in the treated animals but there was little difference between the two experimental groups. The same applies to aortic and heart muscle cholesterol content. At autopsy control rabbits showed fatty changes in their livers and atherosclerosis of the aorta, while in the experimental animals no such lesions were found.