Ranitidine Use and Risk of Upper Gastrointestinal Cancers.

BACKGROUND: The discovery that ranitidine is contaminated with N-nitrosodimethylamine, a suspected human carcinogen, raises the hypothesis of a gastrointestinal carcinogenic effect; however, evidence remains inconclusive. METHODS: We used the nationwide Danish Prescription Registry to identify a cohort of incident ranitidine users and two active comparator cohorts comprising users of other histamine-2 receptor blockers (H2RB) and users of proton pump inhibitors (PPI). All Danish adults with a first prescription of ranitidine, other H2RBs, or PPIs in 1996 through 2008 were followed virtually completely through 2018 for incidence of esophageal, stomach, liver, and pancreatic cancers. We used Cox regression with propensity-score weighting to calculate hazard ratios and 10-year cumulative risk with 95% confidence intervals. RESULTS: We ascertained 276 newly diagnosed esophageal, 342 stomach, 133 hepatocellular, and 517 pancreatic cancers among ranitidine users during follow-up (median 14 years). In comparison with use of other H2RBs or PPIs, we found no consistent evidence of increased HRs or excess 10-year cumulative risk of any upper gastrointestinal cancer following ranitidine use. We observed no association after restriction to subjects with at least 5 or 10 prescriptions or those with 10 prescriptions and at least 10 years of follow-up. CONCLUSIONS: Our large prospective study using high-quality prescription and cancer incidence data, with two active comparator groups, provides no compelling evidence that ranitidine increases the risk of upper gastrointestinal cancers. IMPACT: Our results, which do not support any carcinogenic effect on esophagus, stomach, liver or pancreas, should be reassuring for millions of concerned past users of ranitidine.

Hepatic extraction of chenodeoxycholic acid in dogs chronically intoxicated with dimethylnitrosamine.

The pharmacokinetics of chenodeoxycholic acid (CDCA) in hepatic dysfunction were evaluated by analyzing the plasma disappearance curves after simultaneous administration of [3H]- and [14C]-CDCA through the femoral and portal veins, respectively, in dogs chronically intoxicated with dimethylnitrosamine (DMN). The plasma concentration-time curve of intravenously administered [3H]-CDCA was best fitted to a three-exponential equation, while that of intraportally administered [14C]-CDCA was fitted to either a two- or a three-exponential equation. In the DMN-intoxicated dogs, significant decreases were observed in total body plasma clearance (CLp), hepatic extraction ratio (EH) and apparent intrinsic clearance (CLint) compared to those of the untreated (control) dogs. The hepatic blood flow (QH), calculated from CLp, CLint and blood-to-plasma concentration ratio (RB) according to the equation reported by Wilkinson and Shand [Clin. Pharmac. Ther. 18, 377 (1975)], was reduced to approximately 70% in the DMN-intoxicated dogs compared to the control dogs. The bindings of CDCA to plasma and liver cytosol fraction were determined by equilibrium dialysis; no significant difference was observed in the unbound fraction between the DMN-treated and control dogs. By comparing both pharmacokinetic parameters obtained from intravenous and intraportal administration, the usefulness of the oral bile acid tolerance test was examined. From these findings, it was suggested that the decrease in the CLp of the DMN-intoxicated dogs was due to both the decrease in QH and that in CLint, and that the decrease in CLint may be due not to an alteration of plasma or cytosol binding but to that of a carrier-mediated transport system. It is also suggested that the measurement of fasting plasma bile acid concentration or the oral bile acid tolerance test is more sensitive for the detection of hepatic dysfunction than the intravenous bile acid tolerance test.

Fatal nitrosamine poisoning.

A case is reported in which progressive liver symptoms with rise in bilirubin concentration, hemorrhagic diathesis, and signs of portal hypertension developed three years before death in liver coma. The pathologic and neuropathologic findings are described. The case was clarified after dimethylnitrosamine was demonstrated in food intended for the patient and after it was established that small amounts of nitrosamine could have been repeatedly ingested by the patient over a period of years. Comparable cases of human dimethylnitrosamine poisonings published in the literature are presented. The relatively typical morphologic alterations in the liver are described. Problems involved in the histological interpretation of such liver changes as well as the forensic conclusions to be drawn are discussed.

Acute dimethylnitrosamine poisoning outbreak.

In an 8-h period, five members of two kindred families suddenly became ill with nausea, vomiting, and malaise. This was followed by acute liver disease, a generalized bleeding tendency, and a low platelet count. Two of the patients died four and five days after onset of illness. It was established that dimethylnitrosamine had been intentionally added to lemonade and milk that were consumed by the victims.

Methylated purines in human liver DNA after probable dimethylnitrosamine poisoning.

DNA, isolated from two samples of human liver obtained from a suspected dimethylnitrosamine poisoning, contained 1363 to 1373 micromol of 7-methylguanine per mol of guanine and 273 to 317 micromol of O6-methylguanine per mol of guanine. Liver and kidney DNA obtained from unrelated cases contained no detectable methylated purines. From the DNA methylation levels, it is estimated that the dimethylnitrosamine-poisoning victim had been exposed to a dose of 20 mg or more of dimethylnitrosamine per kg of body weight. The results indicate for the first time that humans, like rodents, appear to activate dimethylnitrosamine metabolically to a strong methylating agent, resulting in methylation of liver DNA at both the 7- and O6 positions of guanine.

Lethal exitus of a patient with N-nitrosodimethylamine poisoning, 2.5 years following the first ingestion and signs of intoxication.

The report describes the lethal exitus of a 44-year-old woman after repeated criminal poisoning with N-nitrosodimethylamine. She died 32 months following the initial symptoms and developed a liver cirrhosis with multiple bleeding, a hemolytic syndrome and diabetes mellitus.

Early investigations on the effect of methyl mercuric chloride upon DMN-acute hepatotoxicity.

Acute toxicity induced by DMN was partially prevented by previously administering methyl mercuric chloride (MMC), a chemical inhibitor of the drug metabolizing enzyme system (DMES). We have studied the early changes occurring during the course of DMN-intoxication, namely disaggregation of polysomal profiles and necrosis, evaluated morphologically and by the release of S-GPT.

[Zonal distribution of haptoglobin and ceruloplasmin synthesis in the liver]. / Zonal'noe raspredelenie sinteza gaptoglobina i tseruloplazmina v pecheni

Effect of hepatotoxic agents (carbon tetrachloride and dimethyl nitrosamine) on the rate of the haptoglobin and ceruloplasmin synthesis in liver tissue was studied. In impairment of hepatocytes in the central zone of liver lobes, the distinct decrease in content of haptoglobin was shown to occur with a simultaneous increase in content of ceruloplasmin in blood serum. When parenchyma of the central zone of liver lobes regenerated, the haptoglobin content tended to normalization. The data obtained suggest that the synthesis of haptoglobin and ceruloplasmin is carried out in different zones of liver tissue lobes: haptoglobin is mainly found in the central zone and ceruloplasmin -- in the peripheral one.