Drug Marker Absorption in Relation to Pellet Size,Gastric Motility and Viscous Meals in Humans

Purpose. The objective of this study was to evaluate drug marker absorption in relation to the gastric emptying (GE) of 0.7 mm and 3.6 mm enteric coated pellets as a function of viscosity and the underlying gastric motility. Methods. Twelve subjects were evaluated in a 3-way crossover study. 0.7 mm caffeine and 3.6 mm acetaminophen enteric coated pellets were concurrently administered with a viscous caloric meal at the levels of 4000, 6000 and 8000 cP. Gastric motility was simultaneously measured with antral manometry and compared to time events in the plasma profiles of the drug markers. Results. Caffeine, from the 0.7 mm pellets, was observed significantly earlier in the plasma than acetaminophen, from the 3.6 mm pellets, at all levels of viscosity. Motility related size differentiated GE was consistently observed at all viscosity levels, however, less variability was observed with the 4000 cP meal. Specifically, the onset of absorption from the of 3.6 mm pellets correlated with the onset of Phase II fasted state contractions (r = 0.929, p < 0.01). Conclusions. The timeframe of drug marker absorption and the onset of motility events were not altered within the range of viscosities evaluated. Rather, the differences in drug marker profiles from the non-digestible solids were most likely the result of the interaction between viscosity and motility influencing antral flow dynamics. The administration of the two sizes of pellets and a viscous caloric meal with subsequent monitoring of drug marker profiles is useful as a reference to assess the influence of motility patterns on the absorption profile of orally administered agents.     

Lipid-rich keratin spherules containing cholesterol crystals in an epidermal cyst

Numerous, small spherical inclusions with laminated horn-like material were observed in an epidermal cyst from the left earlobe of a 52-year-old Japanese man. They were examined by light and electron microscopy. Positive reactions obtained by staining with both oil red-O and anti-pankeratin antibody led to the conclusion that the inclusions consisted of lipid-rich keratin spherules. These were thought to have been formed in the hydrophobic regions of keratin proteins and non-polar lipids in the hydrophilic milieu of the cyst. Electron microscopy revealed cholesterol crystals within the spherules, suggesting that cholesterol had been slowly isolated from the lipoproteins and the membrane components of the cornified cells included in the lipid-rich keratin spherules, and had gradually become concentrated, finally appearing in the spherules as cholesterol crystals. With further study, a more detailed understanding of this process may throw some light on the development of gallstones and atheroembolism.     

Moisture and mineral content of human feces--high fecal moisture is associated with increased sodium and decreased potassium content--

BACKGROUND: The origin of moisture in diarrhea feces is unknown but may represent the unabsorbed part of intestinal contents or alternatively, body fluid excreted into the digestive canal. If the latter mechanism contributes to moisture in the feces, active transport of water (H2O) associated with ion exchange channels may be involved. OBJECTIVE: To investigate this possibility we measured the content of moisture and minerals (sodium [Na], potassium [K], calcium [Ca], magnesium [Mg], phosphorus [P], zinc [Zn], iron [Fe], copper [Cu] and manganese [Mn]) in feces collected during a 12-d metabolic study on 11 young Japanese female students. DESIGN: The study was carried out as part of a human mineral balance study. The same quantity of food was supplied to each of the subjects throughout the study without consideration of body weight. Fecal specimens were collected throughout the study and were separated into those originating from the diet during the balance period based on the appearance of the ingested colored marker in the feces. RESULTS: The moisture content of the feces ranged between 53 and 92%. Na content in the feces was low and stable when the moisture content was below 80%, whereas it increased up to serum levels when the moisture content increased above 80%. On the other hand, K content increased when compared to dry matter base. However, when comparing concentration/g moisture, K content increased when moisture was below 70%, but decreased when this rose above 70%.     

Three dimensional analysis of retinal neuropeptides and amine in the chick

Three dimensional analysis of retinal neuropeptides and monoamine-containing amacrine cells were performed on flat-mount preparations of the chick retina by using indirect immunofluorescence method. somatostatin (SOM), neurotensin (NT), leu-enkephalin (ENK), vasoactive intestinal polypeptide (VIP), substance P (SP), corticotropin releasing factor (CRF), avian pancreatic polypeptide (APP), glucagon (GLC), 5-hydroxytryptamine (5HT) and tyrosine hydroxylase (TH) were examined with specific antisera. To localize these substances in the amacrine cells, and to see in which layers their processes arborize, frozen sections were examined. There were four patterns of distribution. (1) Substances with more immunoreactive cells in the central than in the peripheral portions (SOM, NT, VIP, SP, GLC, 5HT), (2) Substances with more immunoreactive cells in the peripheral portion than in the central portion (APP), (3) Substances for which such cells were evenly distributed (TH), and (4) Substances with more immunoreactive cells in the inferior than in the superior portion (CRF). Subtypes were identified among the amacrine cells containing single peptides or monoamine.     

Mandibular and Parotid Salivary Levels of Indomethacin Following Intravenous Administration to Rabbits

Indomethacin was measured in mandibular and parotid saliva, obtained from separate cannulas in the salivary ducts, after bolus intravenous administration (15 mg/kg) to male white rabbits that were stimulated for salivation with pilocarpine given subcutaneously. There was a significant correlation between each salivary drug concentration and plasma drug concentration. Saliva to plasma drug concentration ratio (S/P ratio) and pH were higher in mandibular saliva than in parotid saliva. These gland specific differences were in contrast with the previously reported differences in dogs. Matin's equation was found to predict approximately the mean observed S/P ratio of indomethacin for each saliva sample.     

Obesity and risk of cancer in Japan

We conducted a population-based prospective cohort study in Japan to examine the relationship between body mass index (BMI) and the risk of incidence of any cancer and of cancer at individual sites. Body mass index was calculated from self-administered body weight and height at baseline. Relative risks (RR) and 95% confidence intervals (CI) were calculated in multivariate proportional-hazards models. Among 27,539 persons (15,054 women and 12,485 men) aged 40 years or older who were free of cancer at enrollment in 1984, 1,672 (668 women and 1,004 men) developed cancer during 9 years of follow-up. In women, after adjustment for potential confounders, the RR of all cancers associated with different BMI, relative to a BMI of 18.5-24.9, were 1.04 (95% CI = 0.85-1.27) for BMI = 25.0-27.4, 1.29 (1.00-1.68) for BMI = 27.5-29.9 and 1.47 (1.06-2.05) for BMI >/=30.0 (p for trend = 0.007). Higher BMI was also significantly associated with higher risk of cancers of the colorectum, breast (postmenopausal), endometrium and gallbladder in women. In men, we observed significantly increased all-cancer risk among only never-smokers. Overweight and obesity could account for 4.5% (all subjects) or 6.2% (never-smokers) of the risk of any cancer in women and -0.2% (all subjects) or 3.7% (never-smokers) in men. The value for women was within the range among women reported from Western populations (3.2%-8.8%). Our data demonstrate that excess weight is a major cancer risk among Japanese women.     

Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan

Although case-control studies suggested that coffee consumption is associated with a decreased risk of liver cancer, no prospective cohort study has been carried out. To examine the association between coffee consumption and the risk of liver cancer, we conducted a pooled analysis of data available from 2 cohort studies in Japan. A self-administered questionnaire about the frequency of coffee consumption and other health habits was distributed to 22,404 subjects (10,588 men and 11,816 women) in Cohort 1 and 38,703 subjects (18,869 men and 19,834 women) in Cohort 2, aged 40 years or more, with no previous history of cancer. We identified 70 and 47 cases of liver cancer among the subjects in Cohort 1 (9 years of follow-up with 170,640 person-years) and Cohort 2 (7 years of follow-up with 284,948 person-years), respectively. We used Cox proportional hazards regression analysis to estimate the relative risk (RR) and 95% confidence interval (CI) of liver cancer incidence. After adjustment for potential confounders, the pooled RR (95% CI) of drinking coffee never, occasionally and 1 or more cups/day were 1.00 (Reference), 0.71 (0.46-1.09) and 0.58 (0.36-0.96), respectively (p for trend = 0.024). In the subgroup of subjects with a history of liver disease, we found a significant inverse association between coffee consumption and the risk of liver cancer. Our findings support the hypothesis that coffee consumption decreases the risk of liver cancer. Further studies to investigate the role of coffee in prevention of liver cancer among the high-risk population are needed.     

Stability of arsenic metabolites, arsenic triglutathione [As(GS)3] and methylarsenic diglutathione [CH3As(GS)2], in rat bile

Inorganic arsenicals such as arsenite (iAs(III)) and arsenate (iAs(V)) are well-known human carcinogens. Arsenic is metabolized by repetitive reduction and oxidative methylation, and is excreted mainly in urine as monomethylated arsenicals (MMAs) and dimethylated arsenicals (DMAs). Recently, it has been shown that iAs(III) administered intravenously or orally is excreted into bile as arsenic-glutathione (As-GSH) complexes such as arsenic triglutathione [As(GS)(3)] and methylarsenic diglutathione [CH(3)As(GS)(2)]. In order to carry out the speciation of As-GSH complexes, it is important to understand their stability. The present study was designed to clarify the stability of As-GSH complexes in rat bile, and the role of GSH in stabilizing these complexes. Arsenic species were separated on an anion-exchange column and were analyzed by high-performance liquid chromatography-inductively coupled argon plasma mass spectrometry (HPLC-ICP MS). As(GS)(3) and CH(3)As(GS)(2) were unstable in bile and were hydrolyzed to iAs(III) and monomethylarsonous acid (MMA(III)) in the absence of GSH. As(GS)(3) appeared to be stable in the presence of 10mM GSH. Exogenously added GSH also stabilized CH(3)As(GS)(2) in bile at the concentrations of 5mM or higher. It has been suggested that trivalent arsenicals, especially MMA(III), are more toxic than corresponding pentavalent ones. These results suggest that GSH plays an important role in preventing hydrolysis of As-GSH complexes and the generation of well-known toxic trivalent arsenicals.