Andrew Garner

Age-related changes in morphology and secretory responses of male rat lacrimal gland

This study investigates the differences in the outward appearance and morphology of lacrimal glands, the morphology within the lacrimal acinar cells and the secretion of protein from acinar cells of young (3-5 months) and aged (20 and 24 months) male rats. The appearance of the glands, as seen by the naked eye, differed between the three age-groups. The lacrimal gland of young animals was a smooth pink tissue, while the tissue from aged animals appeared lobular and white in colour, thought to result from infiltration of fatty/connective tissue. Glands from 24 month old animals had a more pronounced lobular appearance than the glands from 20 month old animals. Light microscopy studies revealed that as the animals aged there was evidence of progressive morphological changes. These changes included thickening of the connective tissue sheath, chronic inflammation with increased infiltration by mast cells, patchy destruction of ductal and vascular tissues, enlargement of lacrimal ducts, luminal swelling of the acini, and changes in acinar type. Electron microscopy (EM) studies revealed the presence of 3 types of acini in the rat lacrimal gland: acini which contained only protein secretory granules (serous acini), acini which contained protein and mucous secretory granules (seromucous acini), and acini which contained only mucous secretory granules (mucous acini). In young glands the majority of acini were serous with a few seromucous acini and even fewer mucous acini. In aged glands there were significant reductions in serous acini (ANOVA; P < 0.01) when compared to the young glands. In 20-month-old glands, there were marked increases in the percentage occurrence of seromucous acini, while in 24 month old glands, there were large increases in the relative number of mucous acini. Qualitative EM studies demonstrated that the typical acini from young glands contained numerous protein secretory granules. Ageing was associated with a progressive loss of protein (serous) secretory granules. Furthermore, marked changes and patchy destruction of the endoplasmic reticulum and Golgi apparatus were observed in acini of glands from aged rats when compared to acini of glands from young rats. Measurement of total protein output from acini revealed a significant (Students t-test, P < 0.05) decrease in protein secretion from aged glands compared to glands from young animals. These results suggest that not only is there considerable structural damage, chronic inflammation and mast cell infiltration to the lacrimal gland with ageing, but also possible redifferentiation of acini from serous to seromucous and then to mucous acini. Furthermore, the results also suggest a reduction or an inability of the acini to synthesise and to secrete protein from glands of aged animals compared to glands of young rats. All of these changes appear to occur more rapidly as the rats mature between 20 and 24 months. These findings provide a morphological basis to explain the phenomenon of reduced tear/protein secretion with ageing.

Comparative morphology of the alimentary tract and its glandular derivatives of captive bustards

This study describes the gross anatomy of the alimentary tract of Houbara Bustards (Chlamydotis undulata macqueenii), Kori Bustards (Ardeotis kori), Rufous‐crested Bustards (Eupodotis ruficrista) and White‐bellied Bustards (Eupodotis senegalensis) maintained in captivity by the National Avian Research Center in the United Arab Emirates. The morphology of the alimentary tract and the proportions of each region were similar in all 4 species. The length of the oesophagus, combined proventriculus and ventriculus, small intestine, and large intestine formed 24.2–28.4%, 7.3–9.7%, 40.5–55.1% and 9.1–14.7% of the total alimentary tract length respectively. Neither crop nor oesophageal enlargement was observed in the birds examined in this study, although male Kori Bustards possessed a saccus oralis in the oropharyngeal cavity. Oesophagi, proventriculi, ventriculi, caeca and large intestine were well developed in all species. The small intestine was shorter than that of other avian herbivores and granivores when compared on a bodyweight basis. The well differentiated stomachs and well developed caeca of the bustards examined in this study are characteristic of omnivores. Analysis of the mean lengths of the alimentary tract components and weight of the liver and pancreas showed sexual dimorphism in cases where male and female data were available for direct comparison.

Comparison of five antisecretory agents acting via gastric H+/K+-ATPase.

Lansoprazole(L), pantoprazole (P), rabeprazole and RO-18-5364 (RO) are new benzimidazole derivatives which rival omeprazole (O) as proton pump inhibitors (PPIs) for treatment of ulcer disease. In this study, we compared the effects of these compounds on acid secretion and determined their relative potencies in relation to their effect on [14C]-aminopyrine (AP) accumulation in isolated gastric glands. Inhibition of AP (1.2 microCi x mL(-1)) accumulation was measured in rabbit isolated gastric glands. dbcAMP (1 mmol; stimulant of acid secretion) and Ro 20-1724 (0.1 mmol; a phosphodiasterase inhibitor) were added to the Eppendorf tubes containing the PPIs and AP and dose-response curves were done for each drug after incubating for 5, 10 and 20 min at 37 degrees C and AP accumulation was determined using a scintillation counter. All the PPIs significantly (P < 0.001) inhibited acid secretion as demonstrated by the inhibition of AP accumulation in the isolated gastric glands. Minimum inhibition occurred at a concentration of 0.001 micromol for lansoprazole and omeprazole, 0.01 micromol for rabeprazole and RO 18-5364 and 0.02 micromol for pantoprazole. No differences were observed between PPIs with regards to the maximum inhibition they produce. When expressed as a percentage inhibition of control at 10-min incubation and at concentrations of 1 micromol, L showed 85.6 +/- 0.5, O 87 +/- 0.5, P 83.2 +/- 1.1, R 86.4 +/- 1.1 and RO 87.8 +/- 1.9 inhibition respectively. When comparing the IC50 values, their relative potencies were different. Maximum potency was shown by L (0.007 micromol) > O (0.012 micromol) > R (0.018 micromol) > RO (0.034 micromol) > P (0.050 micromol). All the new PPIs showed different potencies as inhibitors of acid secretion as evident from their IC50s. Extensive ulcer healing trials demonstrated comparable efficacy with a number of studies indicating that symptoms relief are more rapid with P and L, while in this study L appeared to be the most potent in inhibiting AP accumulation in the isolated gastric glands.

Pantoprazole: a new and more specific proton pump inhibitor

Pantoprazole is the third proton pump inhibitor (PPI) to be launched for the treatment of acid-peptic diseases. Like other drugs in this class, pantoprazole causes long-lasting inhibition of acid secretion by inactivating the parietal cell H+/K+-ATPase. Compared with H2 antagonists, pantoprazole results in faster pain relief, more rapid ulcer healing, healing of resistant ulcers and far greater efficacy in oesophageal reflux disease. The three PPIs currently available display almost identical efficacy in the treatment of acid-peptic diseases and when included as part of Helicobacter pylori eradication regimes. However, pantoprazole shows improvements in selectivity and pharmacokinetic properties compared with omeprazole and lansoprazole. The bioavailability of pantoprazole is considerably higher than omeprazole, remains constant upon repeated dosing, and is unaffected by food. Significantly, pantoprazole does not influence hepatic cytochrome P450 activity and does not therefore interact with co-administered drugs. This is in contrast to omeprazole, which inhibits P450, and lansoprazole, which appears to weakly induce multiple metabolic pathways. Although pantoprazole is entering an antisecretory market dominated by omeprazole and ranitidine, it has a number of potential advantages. In this respect it is worth recalling that enhanced specificity and the absence of drug interactions were decisive factors in determining market share in the H2 antagonist era. Pantoprazole may therefore achieve significant market penetration, particularly at the expense of lansoprazole and the H2 blockers.

Effects of anaesthetic agents on basal and histamine-stimulated acid secretion in the fistula rat

Objectives: Anaesthetized rats or surgically modified preparations such as the Shay rat are widely used to study upper gastrointestinal function in the laboratory. Despite the existence of reports demonstrating that agents such as barbiturates can influence acid output, a systematic study of the effects of anaesthetics on gastric secretion has not been undertaken. Methods: Basal and histamine-stimulated acid output were measured in chronic fistula rats after administration of injectable and volatile anaesthetics frequently used in studies of gastric secretion in anaesthetized animals. With the exception of ether, for which recovery is very rapid, sedating rather than full anaesthetic doses were used. Results: Chloralose (40mg/kg) had no significant effect on gastric secretion. Pentobarbitone (25 mg/kg) inhibited basal and histamine-stimulated acid output, but the effect was relatively short-lived and secretion returned to control levels after 2h. Urethane (750 mg/kg) markedly inhibited basal acid output and abolished the secretory response to histamine given 15 to 60 min later. The effects of urethane on acid secretion persisted for the entire 3h duration of experiments, during which time basal acid output declined to levels observed in fully anaesthetized rats given 1.5 g/kg. Full anaesthesia with ether for 60 min also caused profound inhibition of basal secretion and, like urethane, abolished the effect of histamine despite the fact that the animals recovered consciousness within 5 min. Conclusions: The differential activity of anaesthetics and profound antisecretory activity of ether and urethane should be taken into account when studying gastrointestinal function and mucosal ulceration in anaesthetized animals. European Journal of Gastroenterology & Hepatology 1995, 7:1199–1202

Drug metabolizing enzyme systems in the houbara bustard (Chlamydotis undulata).

This study compared catalytic and immunochemical properties of drug metabolizing phase I and II enzyme systems in houbara bustard (Chlamydotis undulata) liver and kidney and rat liver. P450 content in bustard liver (0.34 +/- 0.03 nmol mg-1 protein) was 50% lower than that of rat liver (0.70 +/- 0.02 nmol mg-1 protein). With the exception of aniline hydroxylase activity, monooxygenase activities using aminopyrine, ethoxyresorufin and ethoxycoumarin as substrates were all significantly lower than corresponding rat liver enzymes. As found in mammalian systems the P450 activities in the bird liver were higher than in the kidney. Immunohistochemical analysis of microsomes using antibodies to rat hepatic P450 demonstrated that bustard liver and kidney express P4502C11 homologous protein; no appreciable cross-reactivity was observed in bustards using antibodies to P4502E1, 1A1 or 1A2 isoenzymes. Glutathione content and glutathione S-transferase (GST) activity in bustard liver were comparable with those of rat liver. GST activity in the kidney was 65% lower than the liver. Western blotting of liver and kidney cytosol with human GST isoenzyme-specific antibodies revealed that the expression of alpha-class of antibodies exceeds mu in the bustard. In contrast, the pi-class of GST was not detected in the bustard liver. This data demonstrates that hepatic and renal microsomes from the bustard have multiple forms of phase I and phase II enzymes. The multiplicity and tissue specific expression of xenobiotic metabolizing enzymes in bustards may play a significant role in determining the pharmacokinetics of drugs and susceptibility of the birds to various environmental pollutants and toxic insults.

Drug Evaluation: Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis: Lansoprazole: A new proton pump inhibitor for the treatment of peptic ulceration and reflux oesophagitis

Lansoprazole is the second inhibitor of the gastric H+/K+-ATPase to be marketed for the treatment of peptic ulcer disease and reflux oesophagitis. Like omeprazole, lansoprazole is an acid-activated, non-competitive and highly specific inhibitor of the proton pump which causes profound and long-lasting inhibition of acid secretion. In controlled clinical trials, lansoprazole results in more rapid healing of duodenal and gastric ulcers than histamine H2 receptor antagonists. The drug is extremely effective in treating oesophagitis, resistant ulcers and Zollinger-Ellison syndrome when compared with H2 blockers and can be used in combination with amoxycillin or clarithromycin to achieve eradication of Helicobacter pylori. In a number of trials in which proton pump inhibitors (PPIs) have been directly compared, lansoprazole has produced slightly faster rates of healing and pain relief than omeprazole. These marginal advantages may reflect the improved bioavailability of lansoprazole and/or the fact that it has...

Resistance of gastric mucosa to self-digestion

In recent years, the view of the gastric mucosal barrier as a static entity has given way to a dynamic system, the components of which have recently been reviewed in detail. These complex anatomical and physiological properties are conveniently divided into three categories. The major extrinsic factor is the pre-epithelial mucus-bicarbonate barrier, which provides a first line of defence. Intrinsic protection residing with the mucosal cells per se, involves cytoplasmic pH homeostasis together with epithelial restitution and regeneration. Finally, postepithelial factors within the submucosa and interstitium include the microvasculature and maintenance of acid-base balance.<<ETX>>