386
11. Tindall VR, Reid GD. The management of intrauterine death. Prog Obstet Gynaecol 1989; 7: 199-215. 12. Gordon H, Pipe NGJ. Induction of labor after intrauterine fetal death: a
comparison between prostaglandin E2 and oxytocin. Obstet Gynecol 1975; 45: 44-46.
Liggins GC. The treatment of missed abortion by high dosage syntocinon intravenous infusion. J Obstet Gynaecol Br Cmwlth 1962; 69: 277-81. 14. Morgan DB, Kirwan NA, Hancock KW, Robinson D, Ahmad S. Water intoxication and oxytocin infusion. Br J Obstet Gynaecol 1977; 84: 6-12. 15. Hendricks and Brenner cited by Theobald GW. The induction of labour. In: Hawkins DF, ed. Obstetric therapeutics. London: 1974: 352. 16. Toppozada MK. Prostaglandin in mid-trimester abortion. Prostagland Perspect 1986; 2: 1-3. 17. Eton B. Prostaglandin termination of pregnancy. Br Med J 1981; 282: 13.
72-73. 18. Scher J,
Jeng D, Moshipur J, Kerenyi TD. A comparison between vaginal prostaglandin E2 suppositories and intrauterine extra-amniotic prostaglandins in the management of fetal death in utero. Am J Obstet Gynecol 1980; 137: 769-72. 19. Cameron IT, Baird DT. Use of 16, 16-dimethyl-trans &Dgr;2 prostaglandin E2 methyl ester (gemeprost) vaginal pessaries for the termination of pregnancy in the early second trimester. A comparison with extraamniotic prostaglandin E2. Br J Obstet Gynaecol 1984; 91: 1136-40. 20. Consumers’ Association. Gemeprost for second-trimester termination of pregnancy. Drug Therapeut Bull 1989; 27: 101. 21. Schulman H. Saldana L, Lin CC, Randolph G. Mechanism of failed labor after fetal death and its management with prostaglandin E2. Am J Obstet Gynecol 1979; 133: 742-48. 22. Karim SMM, Ng SC, Ratnam SS. Termination of abnormal intrauterine pregnancy with prostaglandins. In: Karim SMM, ed. Practical applications of prostaglandins and their synthesis inhibitors. Lancaster: MTP, 1979: 319-74. 23. Kanhai HHH, Keirse MJNC. Induction of labour after fetal death: a randomized controlled trial of two prostaglandin regimens. Br J Obstet Gynaecol 1989; 96: 1400-04.
OMEPRAZOLE AND GENOTOXICITY
Long-term studies in rats have shown that complete block of gastric-acid secretion, whether drug-induced or surgical, leads to development of carcinoid tumours of the stomach. Associated features include a massive increase of gastrin drive and proliferation of mucosa and endocrine cells. These conditions of total block of acid secretion and massive hypergastrinaemia do not seem to prevail with the clinical use of inhibitors of gastric-acid secretion, so the gastrin mechanism is unlikely to pose a danger to patients. However, if there were a genotoxic, mutagenic type of carcinogen that also blocked acid secretion the two actions might be difficult to disentangle in animal tests of carcinogenicity and patients might be at risk. It is therefore important to ascertain whether drugs used as inhibitors of gastric acid secretion are genotoxic as part of the overall risk assessment.
-
The genetic toxicology group at Glaxo have developed a testl to show whether a chemical damages DNA in the gastric mucosa. This test has been applied to about a dozen substances so far. It has given a false-negative with one gastric carcinogen of three tested (aristocholic acid), a negative with some Hz receptor blockers such as Glaxo’s ranitidine, and a positive with Astra’s omeprazole, a drug that irreversibly binds to the hydrogen ion pump and so blocks acid secretion. The basis of the test is that rats are given the compound under investigation and 16 hours later radioactive thymidine is injected. The thymidine is massively incorporated into any cell where DNA synthesis is taking place before cell division, and to a lesser extent, by a factor of a thousand or so, in cells where DNA has been damaged and is undergoing repair by rebuilding the damaged section of DNA. The treated rats are killed, and a proteinase solution is injected
into the stomach lumen. In control conditions the proteinase digests off only the superficial layer of gastric mucosal cells, leaving behind the actively dividing cell layer. The DNA is isolated from the digest and very little radioactivity is found, because there is no cell division, nor much in the way of DNA damage and repair in the superficial layer. If the rat has been treated with a powerful gastric carcinogen like the nitrosoguanidine MNNG, the radioactivity in the digest goes up by a factor of perhaps 10. In principle, this result could mean that DNA damage and repair have taken place or that the treatment has altered the distribution of dividing cells, their adhesiveness, or their resistance to proteinase digestion. It would only need a few dividing cells to match the counts produced by large amounts of DNA damage and repair. With a new uncertain and untried test it is difficult to draw firm conclusions, but the Glaxo group (p 419) seem confident that omeprazole presents a risk. Perhaps it does, but Astra (p 419) are not convinced. Meanwhile, Glaxo have unilaterally called a halt to comparative clinical studies of ranitidine and omeprazole; this action is bound to have an effect on prescribers and seems premature. One would like to see further controls of the experiment. The use of hydroxyurea, which blocks DNA synthesis but not repair, the study of covalent binding of omeprazole to DNA, and alkaline elution to detect DNA damage are all fairly standard
procedures. Moreover,
an agent that causes extensive damage to the stable DNA molecule would be expected to cause cell death in high doses, as do the reactive N-nitroso compounds. One can argue that in this case the pharmacokinetics of omeprazole activation and binding conceal such an effect, but clearly there are many issues to be settled before the Glaxo results can be incorporated into a sensible risk assessment. Work to validate the new method of measuring DNA damage in the stomach should be carried out with all speed, and further investigation into the action of omeprazole on acid-secreting cells should be done. These events bear some resemblance to the fright caused by the introduction of cimetidine. Not surprisingly, some patients with gastric symptoms proved to have gastric cancers. The amazing view was put forward that a few weeks of treatment might have caused these tumours and a hypothesis was built up that cimetidine might be nitrosated to form a genotoxic carcinogen. All the evidence that has subsequently accumulated suggests that there was no substance in these assertions. But it shows clearly that the development and research programme and especially the post-marketing surveillance for a drug is never safely finished as long as the drug remains in use. It is regrettable that research on basic mechanisms of toxicity is conducted by a few groups in universities who are struggling for funds, and by groups in industry who cannot be expected to expend the same effort on clearing up the mechanisms of action of their competitors’ drugs as they would put into the investigation of their own compounds. The question of omeprazole’s safety should have been evaluated independently by national licensing bodies. The present 8 weeks’ limited duration of treatment with omeprazole that is suggested for general prescribing purposes seems a sensible part of the step-by-step procedure of learning to use a new class of drug.
1. Burlinson B. An in vivo unscheduled DNA rat
synthesis (UDS) assay in the gastric mucosa: preliminary development. Carcinogenesis 1989; 10:
1425-28.
11. Tindall VR, Reid GD. The management of intrauterine death. Prog Obstet Gynaecol 1989; 7: 199-215. 12. Gordon H, Pipe NGJ. Induction of labor after intrauterine fetal death: a
comparison between prostaglandin E2 and oxytocin. Obstet Gynecol 1975; 45: 44-46.
Liggins GC. The treatment of missed abortion by high dosage syntocinon intravenous infusion. J Obstet Gynaecol Br Cmwlth 1962; 69: 277-81. 14. Morgan DB, Kirwan NA, Hancock KW, Robinson D, Ahmad S. Water intoxication and oxytocin infusion. Br J Obstet Gynaecol 1977; 84: 6-12. 15. Hendricks and Brenner cited by Theobald GW. The induction of labour. In: Hawkins DF, ed. Obstetric therapeutics. London: 1974: 352. 16. Toppozada MK. Prostaglandin in mid-trimester abortion. Prostagland Perspect 1986; 2: 1-3. 17. Eton B. Prostaglandin termination of pregnancy. Br Med J 1981; 282: 13.
72-73. 18. Scher J,
Jeng D, Moshipur J, Kerenyi TD. A comparison between vaginal prostaglandin E2 suppositories and intrauterine extra-amniotic prostaglandins in the management of fetal death in utero. Am J Obstet Gynecol 1980; 137: 769-72. 19. Cameron IT, Baird DT. Use of 16, 16-dimethyl-trans &Dgr;2 prostaglandin E2 methyl ester (gemeprost) vaginal pessaries for the termination of pregnancy in the early second trimester. A comparison with extraamniotic prostaglandin E2. Br J Obstet Gynaecol 1984; 91: 1136-40. 20. Consumers’ Association. Gemeprost for second-trimester termination of pregnancy. Drug Therapeut Bull 1989; 27: 101. 21. Schulman H. Saldana L, Lin CC, Randolph G. Mechanism of failed labor after fetal death and its management with prostaglandin E2. Am J Obstet Gynecol 1979; 133: 742-48. 22. Karim SMM, Ng SC, Ratnam SS. Termination of abnormal intrauterine pregnancy with prostaglandins. In: Karim SMM, ed. Practical applications of prostaglandins and their synthesis inhibitors. Lancaster: MTP, 1979: 319-74. 23. Kanhai HHH, Keirse MJNC. Induction of labour after fetal death: a randomized controlled trial of two prostaglandin regimens. Br J Obstet Gynaecol 1989; 96: 1400-04.
OMEPRAZOLE AND GENOTOXICITY
Long-term studies in rats have shown that complete block of gastric-acid secretion, whether drug-induced or surgical, leads to development of carcinoid tumours of the stomach. Associated features include a massive increase of gastrin drive and proliferation of mucosa and endocrine cells. These conditions of total block of acid secretion and massive hypergastrinaemia do not seem to prevail with the clinical use of inhibitors of gastric-acid secretion, so the gastrin mechanism is unlikely to pose a danger to patients. However, if there were a genotoxic, mutagenic type of carcinogen that also blocked acid secretion the two actions might be difficult to disentangle in animal tests of carcinogenicity and patients might be at risk. It is therefore important to ascertain whether drugs used as inhibitors of gastric acid secretion are genotoxic as part of the overall risk assessment.
-
The genetic toxicology group at Glaxo have developed a testl to show whether a chemical damages DNA in the gastric mucosa. This test has been applied to about a dozen substances so far. It has given a false-negative with one gastric carcinogen of three tested (aristocholic acid), a negative with some Hz receptor blockers such as Glaxo’s ranitidine, and a positive with Astra’s omeprazole, a drug that irreversibly binds to the hydrogen ion pump and so blocks acid secretion. The basis of the test is that rats are given the compound under investigation and 16 hours later radioactive thymidine is injected. The thymidine is massively incorporated into any cell where DNA synthesis is taking place before cell division, and to a lesser extent, by a factor of a thousand or so, in cells where DNA has been damaged and is undergoing repair by rebuilding the damaged section of DNA. The treated rats are killed, and a proteinase solution is injected
into the stomach lumen. In control conditions the proteinase digests off only the superficial layer of gastric mucosal cells, leaving behind the actively dividing cell layer. The DNA is isolated from the digest and very little radioactivity is found, because there is no cell division, nor much in the way of DNA damage and repair in the superficial layer. If the rat has been treated with a powerful gastric carcinogen like the nitrosoguanidine MNNG, the radioactivity in the digest goes up by a factor of perhaps 10. In principle, this result could mean that DNA damage and repair have taken place or that the treatment has altered the distribution of dividing cells, their adhesiveness, or their resistance to proteinase digestion. It would only need a few dividing cells to match the counts produced by large amounts of DNA damage and repair. With a new uncertain and untried test it is difficult to draw firm conclusions, but the Glaxo group (p 419) seem confident that omeprazole presents a risk. Perhaps it does, but Astra (p 419) are not convinced. Meanwhile, Glaxo have unilaterally called a halt to comparative clinical studies of ranitidine and omeprazole; this action is bound to have an effect on prescribers and seems premature. One would like to see further controls of the experiment. The use of hydroxyurea, which blocks DNA synthesis but not repair, the study of covalent binding of omeprazole to DNA, and alkaline elution to detect DNA damage are all fairly standard
procedures. Moreover,
an agent that causes extensive damage to the stable DNA molecule would be expected to cause cell death in high doses, as do the reactive N-nitroso compounds. One can argue that in this case the pharmacokinetics of omeprazole activation and binding conceal such an effect, but clearly there are many issues to be settled before the Glaxo results can be incorporated into a sensible risk assessment. Work to validate the new method of measuring DNA damage in the stomach should be carried out with all speed, and further investigation into the action of omeprazole on acid-secreting cells should be done. These events bear some resemblance to the fright caused by the introduction of cimetidine. Not surprisingly, some patients with gastric symptoms proved to have gastric cancers. The amazing view was put forward that a few weeks of treatment might have caused these tumours and a hypothesis was built up that cimetidine might be nitrosated to form a genotoxic carcinogen. All the evidence that has subsequently accumulated suggests that there was no substance in these assertions. But it shows clearly that the development and research programme and especially the post-marketing surveillance for a drug is never safely finished as long as the drug remains in use. It is regrettable that research on basic mechanisms of toxicity is conducted by a few groups in universities who are struggling for funds, and by groups in industry who cannot be expected to expend the same effort on clearing up the mechanisms of action of their competitors’ drugs as they would put into the investigation of their own compounds. The question of omeprazole’s safety should have been evaluated independently by national licensing bodies. The present 8 weeks’ limited duration of treatment with omeprazole that is suggested for general prescribing purposes seems a sensible part of the step-by-step procedure of learning to use a new class of drug.
1. Burlinson B. An in vivo unscheduled DNA rat
synthesis (UDS) assay in the gastric mucosa: preliminary development. Carcinogenesis 1989; 10:
1425-28.
