Induction of DNA damage by risk factors of colon cancer in human colon cells derived from biopsies.

In order to increase the understanding of the factors responsible for causing human colon cancer, a technique was developed to detect genotoxic effects of chemicals in human colon cells. Risk factors suspected to be associated with the aetiology of human colon cancer were subsequently investigated: the method is based on the measurement of DNA damage in primary cells freshly isolated from human colon biopsies with the single cell microgel ectrophoresis technique ('Comet Assay'). 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3-methyl-3H-imidazo[4,5f]quinoline (IQ), N-methyl-N-nitro-N-nitrosoguanidine (MNNG), dinitrosocaffeidine (DNC) lithocholic acid (LCA), hydrogen peroxide (H2O2) and benzo[a]pyrene (B[a]P) were investigated for their genotoxic and cytotoxic effects following 30 min incubation with colon cells of human, and for comparative purposes also of the rat colon. The nitrosamides (MNNG, DNC) were very genotoxic in human colon cells. MNNG was more genotoxic in human than in rat colon cells. In contrast, the rat colon carcinogens PhIP and IQ were not genotoxic in human colon cells. PhIP did induce DNA damage in rat colon cells, which correlates to its capacity of inducing tumors in this animal tissue. LCA was toxic (rat > human) and concomitantly caused DNA damage in higher concentrations. The widespread contaminant B[a]P was not genotoxic in colon cells of either species using this system. H2O2 was found to be a potent genotoxic agent to both rat and human colon cells (human > rat). In summary, those compounds chosen as representatives of endogenously formed risk factors (MNNG, H2O2, LCA) have a higher toxic and/or genotoxic potency in human colon tissue than in rat colon. They are also more effective in this system than the contaminants tested so far (B[a]P, PhIP, IQ). The newly developed technique is rapid and yields relevant results. It is a novel and useful approach to assess different chemical compounds for genotoxic activities in tumour target tissues of the human.

Detection of genotoxic effects in human gastric and nasal mucosa cells isolated from biopsy samples.

To assess genotoxic burdens from chemicals, it is necessary to relate observations in experimental animals to humans. The success of this extrapolation would be increased by including data on chemical activities in human tissues. Therefore, we have developed techniques to assess DNA damage in human gastric and nasal mucosa (GM, NM) cells. Biopsy samples were obtained during gastroscopy from macroscopically healthy tissue of the stomach or from healthy nasal epithelia during surgery. The specimens were incubated for 30-45 min at 37 degrees C with a digestive solution. We obtained 1.5-8 x 10(6) GM cells and 5-10 x 10(5) NM cells per donor, both with viabilities of 80-95%. The cells were incubated in vitro for 1 hr at 37 degrees C with the test compounds added in their appropriate solvents. In GM cells, we studied N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), sodium dichromate (Na2Cr2O7), nickel sulphate (NiSO4), cadmium sulphate (CdSO4), and lindane. In NM cells, lindane was investigated. Each compound was assessed for DNA damaging activity in cells of at least three different human donor samples using the microgel single cell assay. Similar studies were performed with GM and NM cells obtained from Sprague-Dawley rats. We have found human GM cells to be more sensitive to the genotoxic activity of MNNG than rat GM cells (low effective concentration [LEC] = 0.16 and 0.625 micrograms/ml for human and rat, respectively). Human cells were also more sensitive to the cytotoxic/genotoxic activity of NiSO4 (LEC = 5 and 19 mumoles/ml for human and rat, respectively). CdSO4 was genotoxic in human GM cells (LEC = 0.03-0.125 mumoles/ml), whereas no dose-related genotoxicity was observed in rat GM at concentrations up to 0.5 mumoles/ml. In contrast, approximately equal responses regarding genotoxicity and cytotoxicity were observed in rat and human GM for Na2Cr2O7 (0.25-1 mumoles/ml). Lindane, however, was genotoxic in three out of four rat GM but not in human GM cells (0.5-1 mumoles/ml), whereas it was active in both rat and human NM cells. Together with other recently published in vivo findings, our results with lindane can be interpreted according to a parallelogram approach. In view of possible human exposure situations and the sensitivities of the two target tissues from both species, the data imply that lindane will pose a health risk to humans by inhalation but not by ingestion.

[Nizatidine in therapy and prevention of non-steroidal anti-rheumatic drug-induced ulcers in rheumatic patients]. / Nizatidin in Therapie und Prophylaxe NSAR-induzierter gastroduodenaler Ulzera bei Rheumapatienten.

269 patients with various rheumatic disorders who had been treated with non-steroidal anti-inflammatory drugs (NSAID) for at least three weeks, were enrolled in this randomised double-blind multicenter trial. Entry criteria were both the presence of an ulcer in gastric and/or duodenal mucosa (> 3 mm and < 20 mm in diameter) as well as dyspeptic symptoms. The patients had been treated with 150 mg nizatidine nocte (n = 86), 2 x 150 mg/d (n = 93) and 2 x 300 mg/d (n = 90) nizatidine. All patients continued to take their original NSAID-medication. The three nizatidine-groups had been well matched with respect to important patient characteristics. After 8 weeks of treatment more than 90% of gastric and duodenal ulcers had been healed under all three nizatidine-dosages. There was a tendency for higher healing rates in case of gastric ulcers after 4 weeks following the higher dose of nizatidine. Erosions in stomach and duodenum as well as esophagitis had been improved to a similar degree with all nizatidine doses. The same holds with respect to improvement of clinical symptoms such as epigastric pain, heartburn etc. Consumption of additional antacids was similar in all three groups. In the subsequent prophylactic trial 237/221 patients had been followed for 3/6 months. 116/107 received in addition to their continued antirheumatic medication nizatidine 150 mg nocte and 121/114 patients 2 x 150 mg nizatidine daily. The cumulative relapse rates within 6 months averaged 5.5% in the low and 1.8% in the high dose group (n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)

[High-dose ranitidine protects stomach and duodenum completely against piroxicam. An endoscopic double-blind pilot study]. / Hochdosiertes Ranitidin schützt Magen und Duodenum vollständig gegenüber Piroxicam. Eine endoskopische Doppelblind-Pilotstudie.

In a randomized placebo-controlled parallel and double-blind study the gastroduodenal effects of 20 mg piroxicam daily was evaluated endoscopically in the presence of ranitidine 150 mg bid or 300 mg bid in 31 healthy volunteers. Drugs were taken over a period of 14 days. Endoscopies were performed at entry and repeated after 14 days of treatment. A damage-score according to Lanza was used. At entry, all groups showed comparable mucosal damages in the stomach and in the duodenum. After 14 days the mean lesion score increased in the piroxicam/placebo group (group A) to 4.5 +/- 1.6 (+/- SEM) in the stomach and to 2.7 +/- 0.8 (+/- SEM) in the duodenum. The corresponding values in the piroxicam/ranitidine 150 mg bid group (group B) were 3.3 +/- 1.2 (stomach) (p > 0.05 vs. group A) and 1.4 +/- 0.7 (duodenum) (p < 0.05 vs. group A). The values in the piroxicam/ranitidine 300 mg bid group (group C) averaged 1.0 +/- 0.0 (stomach) and 0.3 +/- 0.1 (duodenum) (for both p < 0.05 vs. group A). Our data suggest that profound acid inhibition--achieved by doubling the usual dose--afforded complete protection of human stomach and duodenum against piroxicam.

Dose-range finding study with the proton pump inhibitor pantoprazole in acute duodenal ulcer patients.

Pantoprazole is a newly developed benzimidazole derivative with strong inhibitory actions on gastric acid secretion by blocking H(+)-K(+)-ATPase. This randomized double-blind multicenter trial investigated the efficacy of 20 mg, 40 mg and 80 mg pantoprazole o.m. on ulcer healing and symptomatic relief in 219 out-patients with endoscopically assessed acute duodenal ulcer. After 2 weeks complete ulcer healing was achieved in 58%, 89% and 82% of the patients with 20 mg, 40 mg and 80 mg pantoprazole o.m., respectively. After 4 weeks, corresponding figures were 93%, 99% and 100%; the difference of the healing rates between the 20 mg and 40 mg groups at 2 weeks was statistically significant (p < 0.0001). A rapid pain relief was achieved in all treatment groups: 72% of the 20 mg group, 89% of the 40 mg group, and 84% of the 80 mg group were pain-free after 2 weeks. The difference between 20 mg and 40 mg was statistically significant (p < 0.05). Pantoprazole was well tolerated. Adverse events occurred in 13 patients; headache, skin alterations, and diarrhea were reported most frequently. Severity and frequency of adverse events did not reveal any dose-dependence. In conclusion, pantoprazole provides fast healing of acute duodenal ulcer as well as rapid improvement of ulcer symptoms. For further clinical trials in peptic ulcer disease a daily dose of pantoprazole 40 mg o.m. is recommended.

An alprostadil analogue and human gastric secretion. A double-blind placebo-controlled study of the effects of a capsule and tablet formulation.

The effects of single oral doses of 800 and 1200 micrograms of the new alprostadil analogue mexiprostil (prostaglandin E1 16-methyl-16-methoxy derivative, MDL 646), presented as tablet and capsule formulation, on basal and pentagastrin-stimulated acid secretion, were studied in 10 healthy volunteers, using a randomized, double-blind, placebo-controlled, 5-way crossover design. Compared to placebo, administration of mexiprostil resulted in a significant inhibition of basal gastric acid secretion, at both doses and formulations. Pentagastrin-stimulated gastric secretion was reduced to a lesser degree and the differences compared to placebo did not achieve statistical significance when adjustments were made for basal effects present before starting stimulation. Total volume of gastric secretion, under basal conditions, was decreased by both doses and formulations, though the changes were significant only at 1200 micrograms for both formulation. The decrease in volume of gastric secretion during pentagastrin infusion did not reach statistical significance. Basal intragastric pH was increased by both doses and formulation, but the changes were significant only for the capsule formulation, at either dose. Neither dose of mexiprostil prevented the decrease in intragastric pH produced by pentagastrin infusion. Tolerability of mexiprostil was excellent with no unwanted effects reported either during or after the study. No changes in heart rate and systemic blood pressure were observed. Laboratory safety parameters were not altered by mexiprostil. There was no significant difference between the effects of both formulations of mexiprostil on any pharmacodynamic parameter.

Human gastric acid secretion following repeated doses of AG-1749.

The effect of increasing doses (15 mg, 30 mg and 60 mg) of the substituted benzimidazole, AG-1749, on gastric acid secretion and fasting serum gastrin concentration has been studied after repeated administration to healthy volunteers. AG-1749 produced a dose-dependent and profound decrease in basal and stimulated gastric acid secretion in all volunteers, with almost total suppression at the highest dose. The extent of inhibition increased between Day 2 and Day 8 with the 15 and 30 mg doses of AG-1749. The inhibitory effect of AG-1749 appears to be fully reversible as control levels of acid output were reached 7 days after drug withdrawal. Seven days' dosing with 60 mg AG-1749 induced a more than threefold increment of fasting serum gastrin concentration, but this increase was still within the normal range. Seven days after cessation of dosing, fasting serum gastrin concentration returned to a pre-dose level.

[Ranitidine ameliorates acemetacin and indomethacin-induced changes of the gastroduodenal mucosa, without modifying the pharmacokinetic behavior of both antirheumatic drugs]. / Ranitidin vermindert die durch Acemetacin und Indometacin induzierten gastroduodenalen Schleimhautveränderungen, ohne das pharmakokinetische Verhalten beider Antirheumatika zu beeinflussen.

12 healthy volunteers participated in this double-blind, randomized, cross-over study. All subjects were given indomethacin (50 mg tid) or acemetacin (60 mg tid) for 6 days in the presence and absence of ranitidine 300 mg at night. At day 6 120 minutes after the last morning dose an endoscopy was performed and the appearance of the gastric and duodenal mucosa was noted. In the indomethacin experiments mean lesion score averaged 2.2 +/- 0.2 (+/- SEM) when placebo was coadministered. In the corresponding acemetacin-series the lesions score was 1.6 +/- 0.1 (+/- SEM). A reduction in mucosal damage occurred in both NSAID-groups when ranitidine 300 mg at night was given concurrently: The mucosal lesions score was reduced to 1.7 +/- 0.2 and to 1.0 +/- 0.1 (+/- SEM), respectively. This protection afforded by ranitidine was significant when compared with placebo (p less than 0.05). In 8 subjects plasma concentrations of acemetacin and indomethacin were determined on day 1 and day 5. The AUC-values of indomethacin and acemetacin in the presence and absence of ranitidine were almost identical when analysed by the paired T-test. The mean plasma concentrations of both antirheumatic agents did not show any difference when coadministered with placebo or ranitidine. Our data suggest that 300 mg ranitidine at night improves the gastroduodenal tolerability of both indomethacin and acemetacin without affecting main pharmacokinetic parameters of both antirheumatics.

Comparison of the gastroduodenal tolerance of tenoxicam and diclofenac Na. A double-blind, endoscopically controlled study in healthy volunteers.

The gastroduodenal tolerance of Tenoxicam and Diclofenac Na has been evaluated in a double-blind, parallel group study in 36 healthy male volunteers. The doses used were 20 mg Tenoxicam and 100 mg Diclofenac Na daily in a retard formulation for 14 days. Gastric tolerance was assessed by endoscopy, which was performed at base-line, after the 14 day dosing period and after a 14 day follow-up period without treatment. The mucosal lesions were scored using modified Lanza criteria. Tenoxicam was significantly better tolerated at the end of the 14 day dosing period (mean gastric score: Tenoxicam 1.3; Diclofenac Na 2.2). The two treatment groups had comparable scores at the base-line and post study assessments. Tenoxicam and Diclofenac Na were generally well tolerated. Only two volunteers reported intermittant lack of appetite, heartburn and a feeling of pressure in the stomach.