Chemistry of the diazeniumdiolates. 3. Photoreactivity.

We have found O(2)-substituted diazeniumdiolates, compounds of structure R(2)N-N(O)=NOR' that are under development for various possible pharmaceutical uses, to be rather photosensitive. With R = ethyl and R' = methyl, benzyl, or 2-nitrobenzyl, the observed product distributions suggest that two primary pathways are operative. A minor pathway involves the extrusion of nitrous oxide (N(2)O) with simultaneous generation of R(2)N(*) and R'O(*), which may then form amines, aldehydes, and alcohols. The major reaction pathway is an interesting photochemical cleavage of the N=N bond to form a nitrosamine (R(2)NN=O) and an oxygen-substituted nitrene (R'ON). The intermediacy of the O-nitrene was inferred from the production of abundant oxime, via rearrangement of the O-nitrene to a C-nitroso compound (R'ON --> O=NR'), and subsequent tautomerization to the more stable oxime. Involvement of the O-nitrene was confirmed by trapping with 2,3-dimethyl-2-butene to form the aziridine and with oxygen to generate the nitrate ester. 2-Nitro substitution on the benzyl derivative had surprisingly little effect on the reaction course. For each compound examined, minor amounts of nitric oxide (NO), presumably produced by secondary photolysis of the nitrosamine, were observed. Time-resolved infrared experiments provided additional support for the above reaction pathways and confirmed that the nitrosamine is a primary photoproduct. We have also found that the relative contributions of the reaction pathways can be altered in certain derivatives. For example, when R' = 2,4-dinitrophenyl, the contribution of the nitrosamine/O-nitrene-forming pathway was diminished. Pharmacological implications of these results are discussed.

Gastric acidity in older adults.

CONTEXT: Early studies suggested that gastric acidity declines as people age. However, sequelae of achlorhydria are uncommon in older people, making this conventional wisdom unlikely. OBJECTIVE: To ascertain the prevalence of basal gastric acidity and atrophic gastritis (indicated by serum pepsinogen ratio) in older adults. DESIGN: Cross-sectional study in a volunteer sample. SETTING: Retirement communities in suburbs of Kansas City, Mo. SUBJECTS: A total of 248 white male and female volunteers aged 65 years or older living independently. MAIN OUTCOME MEASURES: Presence of basal unstimulated gastric acid was evaluated noninvasively by having subjects swallow quininium resin. Gastric acid with a pH lower than 3.5 releases quinine, which is then absorbed and excreted into urine. Atrophic gastritis was defined as a ratio of serum pepsinogen I/pepsinogen II of less than 2.9. RESULTS: Basal unstimulated gastric content was acidic (pH <3.5) in 208 (84%) of 248 elderly subjects. On retesting 66 subjects (35 normals and 31 hyposecretors), 28 (80%) of 35 had pH less than 3.5 both times, and 22 (71%) of 31 had pH of 3.5 or higher twice; in the remaining 16 subjects, low vs high gastric pH changed between tests. Weighted population prevalence estimates in this sample were 67% for consistent acid secretion, 22% for intermittent secretion, and 11% for consistent gastric pH higher than 3.5. Whereas 14 (67%) of 21 consistent hyposecretors had serum pepsinogen ratios of less than 2.9, indicating atrophic gastritis, only 2 (5%) of 44 consistent or intermittent secretors of acid had ratios in this range (P<.001). CONCLUSIONS: In contrast to what is commonly stated, nearly 90% of elderly people in this study were able to acidify gastric contents, even in the basal, unstimulated state. Of those who were consistent hyposecretors of acid, most had serum markers of atrophic gastritis.

Reduction of serum cholesterol in Watanabe rabbits by xenogeneic hepatocellular transplantation.

Transplantation of xenogeneic hepatocytes would provide a novel therapy for liver disease and would help to solve the problem of an insufficient supply of donor organs. We have tested whether xenogeneic cells infused into the liver could correct the metabolic defect in the Watanable heritable hyperlipidemic (WHHL) rabbit, an animal model for homozygous familial hypercholesterolemia, and we have investigated whether the infused cells traverse the lining of the portal vasculature. We find that porcine hepatocytes are localized in the hepatic sinusoids after surgery and subsequently migrate out of the vessels and integrate into the hepatic parenchyma. The integrated porcine hepatocytes provide functional LDL receptors that lower serum cholesterol in the WHHL rabbit by 30-60% for at least 100 days.