The disposition of lorazepam after intravenous administration (2 mg) was investigated in patients with alcoholic cirrhosis and acute viral hepatitis, and compared to that in normal subjects ranging in age from 15 to 73 yr. No statistically significant age-dependent relationships in the drug's pharmacokinetic parameters were observed. Cirrhosis was associated with a doubling of the mean elimination half-life (21.7 ± 7.6 to 41.2 ± 24.5 hr). This was due to a similar increase in the volume of distribution of lorazepam, caused by a reduction in the extent of the drug's plasma binding (88.6 ± 2.5 from 93.2 ± 1.8). No changes in systemic plasma clearance of either the unbound (about II mllminlkg) or bound plus unbound (about 0.75 mllminlkg) lorazepam, or urinary recovery of conjugated drug (about 50%) were detected. In contrast, there were no significant changes in the kinetics of lorazepam in the patients with acute viral hepatitis.
Comparison of lorazepam' s systemic plasma clearance in the liver disease patients in whom studies with antipyrine and chlordiazepoxide had also been performed indicated impairment in their values but this was not the case for lorazepam. It is concluded that the degree of impairment, if any, in the metabolism of lorazepam in patients with liver disease is considerably less than that of certain other drugs including related benzodiazepines.Aging also does not lead to alterations either in distribution or metabolism as have been observed with other benzodiazepines. It is speculated that these observations may reflect characteristics of the drugs associated with their metabolic fate, i.e., glucuronidation or oxidative biotransformation.The central role of the liver in drug metabolism has stimulated many investigations into the possible impairment of this process in the presence of hepatic dysfunction typically associated
The clinical differentiation between hereditary nonpolyposis colorectal cancer (HNPCC) and attenuated familial adenomatous polyposis (AFAP) is very difficult. The 62-yr-old proband presented with duodenal adenocarcinoma. His history of subtotal colectomy for colon cancer, the rarity of duodenal adenocarcinoma in the general population, and his family history of colon cancer made us suspect that he might have FAP. We investigated this family by obtaining medical records and performing gene analysis. The proband had only 10 adenomatous colon polyps when he underwent subtotal colectomy for the cancer, so classic FAP was excluded. His family history included rectal cancer in his brother at 69 yr of age, colon cancer in his mother at 75 yr, and colon cancer in one maternal cousin at 42 yr. Three months after we started to study this family, the proband's 32-yr-old son presented with rectal cancer. His family fulfilled the Amsterdam criteria for HNPCC, but AFAP could not be excluded. Upon gene testing, the proband was negative for APC gene germline mutation, which made AFAP highly unlikely. Moreover, high microsatellite instability (MSI) was detected in his adenomas and cancer tissues. The fulfillment of Amsterdam criteria, the exclusion of FAP and AFAP, and the high MSI established the diagnosis of HNPCC in this family. We also summarize the differences between FAP, AFAP, and HNPCC; extend the graphic description of the MSI mechanism; and propose a diagnostic strategy for HNPCC.
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