Comparative effects of cimetidine on biliary lipid secretion in fasted and fed rats.

The effect of cimetidine on biliary lipid secretion has been investigated in fasted and fed rats with biliary drainage for 4 h after a single intraperitoneal administration at a dose of 120 mg/kg body weight. Bile flow, bile acids, cholesterol and phospholipids in bile have been determined. In intact rats similarly treated, serum bile acids, cholesterol and phospholipids have been determined. Biochemical and morphological studies have been conducted on the liver tissue in both experiments. Bile flow and bile acid secretion were not affected by cimetidine in fasted rats, but, 15 min after administration of the drug, fed rats showed an increase of the molar percentage of cholic acid together with a decrease of deoxycholic acid, a decreased secretion of cholesterol and an increased secretion of phospholipids. The values of these biliary lipids were in the range observed in fasted animals, so that the drug appeared to ''mimic'' the effect of fasting. These findings could be related to altered vascular properties of the gastro-intestinal wall induced by cimetidine, leading to interference with intestinal postprandial hyperaemia and capillary permeability, so that there appears to be a conversion of bile composition from a digestive to an interdigestive pattern.     

Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules.

To assess the fate and efficacy of orally ingested enzymes in pancreatic insufficiency, we administered pancreatin to six patients by two schedules--eight tablets with a standard meal or two tablets hourly--and in six normal controls, quantified duodenal enzyme activity and related inactiviation of ingested enzymes to gastric and duodenal pH; in the six patients we measured malabsorption by fecal balance studies. Postprandially, gastric pH was similar in health and pancreatic insufficiency, and below 4 after 40 minutes. Duodenal pH in pancreatic insufficiency declined to approximately 4 beyond 100 minutes--lower than in health (P less than 0.05). Approximately 22 per cent and 8 per cent of trypsin and lipase activity ingested with either schedule was delivered to the ligament of Treitz. Prandial was as effective as hourly administration in decreasing steatorrhea and perhaps more effective in abolishing azotorrhea, and since it is also more convenient, we recommend it.     

Ranitidine, cimetidine and antacids in the prevention of recurrence after healed duodenal ulcer: one-year experience

A total of 110 subjects with duodenal ulcer healed with cimetidine (C) (50 patients), ranitidine (R) (40 patients) or pirenzepine (20 patients) was randomly divided in 3 groups. The first group (40 patients) was treated with R (150 mg nightly); the second group (40 patients) with C (400 mg nightly) and the third group with antacids as needed for symptomatic relief. The presence of the ulcer and its healing were established by endoscopy, which was repeated after 6 and 12 months of treatment, or previously if symptoms suggested recurrence. At the end of the year's follow-up, no recurrence of ulcers was observed in 75% of the R group, in 77.5% of the C group and in 40% of the antacids group. Some erosive duodenitis developed in the first and second groups (17.5% and 20% respectively), but none in the antacids group. Most of the ulcers that recurred did so in the first 6 months of treatment. No relevant side-effects were observed with the treatments described. Although no significant difference was detected between C and R treatments, both appeared to be clearly more effective than antacids. The usefulness of adequate prophylactic treatment against the tendency of duodenal ulcer to recur is stressed.     

The effect of cimetidine on the immediate cutaneous response to allergens.

The effects of an H2 antagonist cimetidine on the immediate cutaneous response to timothy or ragweed extract were evaluated. Cimetidine had no effect on the immediate cutaneous response to either allergen. These findings suggest that cimetidine need not be discontinued prior to allergy skin testing.     

Comparative effects of cimetidine on biliary lipid secretion in fasted and fed rats

The effect of cimetidine on biliary lipid secretion has been investigated in fasted and fed rats with biliary drainage for 4 h after a single intraperitoneal administration at a dose of 120 mg/kg body weight. Bile flow, bile acids, cholesterol and phospholipids in bile have been determined. In intact rats similarly treated, serum bile acids, cholesterol and phospholipids have been determined. Biochemical and morphological studies have been conducted on the liver tissue in both experiments. Bile flow and bile acid secretion were not affected by cimetidine in fasted rats, but, 15 min after administration of the drug, fed rats showed an increase of the molar percentage of cholic acid together with a decrease of deoxycholic acid, a decreased secretion of cholesterol and an increased secretion of phospholipids. The values of these biliary lipids were in the range observed in fasted animals, so that the drug appeared to 'mimic' the effect of fasting. These findings could be related to altered vascular properties of the gastro-intestinal wall induced by cimetidine, leading to interference with intestinal postprandial hyperaemia and capillary permeability, so that there appears to be a conversion of bile composition from a digestive to an interdigestive pattern.     

Influence of enteric parasitism on hormone-regulated pancreatic secretion in dogs.

The objective of this study was to test the hypothesis that enteric parasites affect pancreatic secretion in their host. Pancreatic bicarbonate and protein outputs were studied in dogs with gastric and pancreatic fistulas to determine the secretory response to exogenously administered secretin and cholecystokinin and to intraduodenal stimulation with hydrochloric acid and sodium oleate to release endogenous hormones. Bicarbonate and protein concentrations in pancreatic juice were measured prior to infection with Trichinella spiralis and at various periods during primary and secondary infections. Dose-related increases in secretory activity were observed in uninfected hosts in response to all stimuli. Infected dogs responded like controls to exogenous hormones, but showed reduced secretion under duodenal stimulation during the 1st wk of primary infection. This altered response returned to normal 3 wk after primary infection and did not occur following secondary infection. Results support the conclusion that reduced pancreatic secretion is associated with enteric parasitism and is due to a defect in hormone release or in the supply of hormone available for release.     

Comparison of inhibitory effects of atropine, cimetidine, and atropine plus cimetidine on the indomethacin-provoked gastric mucosal erosions in rats

20 mg/kg-1 indomethacin suspended in 1% carboxymethyl-cellulose solution was given subcutaneously into rats to provoke gastric mucosal erosions during 5 h. Dose-dependent inhibitions of indomethacin erosions were observed following different doses of atropine (0.025; 0.2; 1.0 mg/kg-1) and cimetidine (2.5; 10; 50 mg/kg-1) administered intraperitoneally (25%; 38%; 81% and 0%; 42%; 89% respectively). More pronounced inhibitory effects have been obtained with the combinations of both drugs (51%; 68%; 92%). In particular there was a remarkable potentiated synergism in the lowest doses of atropine and cimetidine (51%, against 0% and 25%). These results provide further evidence of synergism of histamine H2-receptor blockers and anticholinergics, which combinations would be useful, for example, in peptic ulcer therapy.     

Comparative effects of mammalian pancreastatins on the pancreatic exocrine secretion

We have reported that porcine pancreastatin inhibits cholecystokinin (CCK)-stimulated pancreatic exocrine secretion in conscious rats. In the present study, the effects of mammalian pancreastatins on exocrine pancreatic functions in rats were compared using synthetic pancreastatins (porcine, bovine, human, and rat). Rats were prepared with cannulae draining pure pancreatic juice and bile separately and a duodenal cannula to return bile-pancreatic juice to the intestine and with a jugular vein cannula. After 90-min basal collection of pancreatic juice, CCK-8 (100 pmol/(kg.h] was infused for 3 h with or without pancreastatins (100 pmol/(kg.h]. All pancreastatins significantly inhibited protein output at an equivalent molar potency. These results suggest that mammalian pancreastatins have the same biological activity of a comparable magnitude and exert a similar biological action on the exocrine pancreas.     

Gastric acid and serum gastrin response to sham feeding, and the effect of cimetidine on the response to sham feeding in duodenal ulcer patients

Sham feeding resulted in a significant increase of gastric acid secretion in 12 male patients with duodenal ulcer. No significant change in serum gastrin concentration was produced by sham feeding. Reproducibility of gastric acid response to sham feeding was very good (r = 0.74). The mean peak 30 min acid output amounted to 9.5 +/- 1.0 mmol/30 min following sham feeding. That was 46.5% of the 30 min peak acid output elicited by pentagastrin infusion administered in a dose of 1.5 micrograms/kg/h. Cimetidine in a dose of 2 mg/kg/h almost completely reduced (by 85%) the gastric acid secretion induced by sham feeding. Cimetidine did not cause any change in serum gastrin concentration during and after sham feeding.     

Immunomodulation and therapeutic effects of the oral use of interferon-alpha: mechanism of action.

It is now well accepted that type 1 interferons (IFNs), IFN-alpha and IFN-beta, in addition to being molecules with powerful antiviral activity, play a critical role in modulating immune responses to foreign and self-antigens. This review of the literature documents the immunomodulatory effects of IFN-alpha and discusses its position and importance in the cytokine cascade. In addition, this review attempts to organize the literature describing local and systemic immunomodulatory effects of orally administered low doses of IFN-alpha, and provide a physiological explanation for the mechanism of action. Evidence suggests that, early in the process of antigen presentation to T helper (Th) cells, IFN-alpha derived principally from the antigen-presenting cells (APC) provides an important signal for Th precursor differentiation in favor of a Th1 immune response. IFN-alpha, perhaps via upregulation of the high-alphaffinity interleukin-12beta1/beta2 (IL-12beta1/beta2) receptor, renders Th1 cells responsive to IL-12 resulting in production of high levels of IFN-gamma crucial to the development of Th1 immune responses. In addition to being instrumental in the development of Th1 immune responses, IFN-alpha appears to be the major cytokine responsible for the amplification of the CD8+ T cell response and resistance to viral infections. Orally administered IFN-alpha induces similar Th1 cytokine responses in buccal mucosal lymph nodes (LN), including upregulation of IFN-gamma expression and downregulation of IL-4. Moreover, reports of systemic immune effects such as decreased autoimmune responses, increased antiviral and antibacterial responses, and generalized immune function changes after oral IFN-alpha administration are consistent with the known immunomodulatory role of IFN-alpha in a physiological setting. Responses to orally administered low doses of IFN-alpha also adhere to the principle of low-dose priming and high-dose anergy that dictates the cellular and cytokine responses to exogenously added cytokines both in vivo and in vitro. These observations collectively suggest that IFN-alpha administered to mucosal-associated immune tissue replicates the known physiological role of IFN-alpha, including regulation of CD4+ Th1 immunomodulatory cells and activation of CD8+ effector cells, which are both crucial to development of protective immune responses. What remains to be determined is how local mucosal immune responses to IFN-alpha given orally are translated into systemic immune responses and resistance to disease. This important question, the answer to which will have profound implications for new immunotherapies for immune-based diseases, is the focus of current research.     

Comparative study of cyclophosphamide, 6-mercaptopurine, azathiopurine and methotrexate. Relative effects on the humoral and the cellular immune response in the mouse.

The effects of cyclophosphamide, methotrexate, azathioprine and 6-mercaptopurine on the concomitant development of the humoral and the cellular immune responses of mice to a single antigen, the El4 tumour cell, were investigated. The measurements of cellular and humoral immunity were carried out in the same animal using lymphocyte and antibody mediated lysis of the El4 cell, a measurement system independent of underlying anti-inflammatory effects. A regimen of daily cyclophosphamide had a more pronounced suppressive effect on the humoral response than on the cellular response, in agreement with other investigators. A single low dose of cyclophosphamide stimulated the cellular response and suppressed the humoral response. Single or multiple high doses of cyclophosphamide maximally suppressed both the cellular and humoral response. Azathioprine and 6-mercaptopurine, in contrast to the results of other investigations, caused equivalent inhibition of both the humoral and cellular responses and thus lacked selectivity. Methotrexate also provided equivalent inhibition of both the humoral and cellular responses at all dose levels investigated.     

The effects of oral D-penicillamine treatment on experimental arthritis and the associated immune response in rabbits. II. The effects on cellular parameters.

Prolonged oral treatment (up to 410 days) of rabbits with D-penicillamine at a dose of 15 mg/kg body weight commencing either before or after immunization and the onset of arthritis, diminished and eventually abolished the delayed hypersensitivity response to intradermally administered tuberculin PPD. The 48 h cutaneous hypersensitivity response to the immunizing antigen (ovalbumin) was also significantly reduced, as was the inhibition of leucotye migration by ovalbumin. Cutaneous Arthus reactivity to ovalbumin was unaffected by D-penicillamine treatment. D-penicillamine treatment of normal rabbits was also found to increase the phagocytic index of the reticuloendothelial system as measured by carbon clearance.     

椎基底动脉供血不足ENG、BAEP、TCD的对照研究

目的：探讨眼震电图（ＥＮＧ）、脑干听觉诱发电位（ＢＡＥＰ）及脑超声波（ＴＣＤ）三项检查联合用于椎基底动脉供血不足（ＶＢＩ）的诊断价值。方法：５２例临床诊断为ＶＢＩ的病人均在发病一周内行ＥＮＧ、ＢＡＥＰ及ＴＣＤ检查。结果：ＥＮＧ异常率为８８％，ＢＡＥＰ异常率为５３％，ＴＣＤ异常率为７６％。结论：三项检查联合应用，可以反映小脑及脑干的功能，为评估小脑及脑干的供血情况提供有益的信息     

Comparative effects of indomethacin on hepatic enzymes and histology and on serum indices of liver and kidney function in the rat.

The effects of high-dose indomethacin (three daily dose, 8.5 mg/kg ip) on pathology and histology, on serum and urine biochemistry, and on various hepatic enzyme activities were studied in rats. Hepatic cytochrome P-450 and aminopyrine N-demethylase were decreased by 52-62%, but glucuronyl transferase fell by only 22%. Hepatic glucose-6-phosphatase, aryl esterase, 6-phosphogluconate dehydrogenase and sulphotransferase remained unchanged, while glucose-6-phosphate dehydrogenase increased by 29%. There were no widespread changes in hepatic and renal pathology or histology, but noteworthy was a mild, focal, centrilobular hepatic response. By contrast, there were severe intestinal lesions: the effects on hepatic enzymes might have been partly a consequence of the intestinal damage. There was a reversible uraemia and significant decreases (20-40% below normal) in both serum albumin and protein, while serum levels of creatinine and aspartate-amino-transferase activity remained constant. A reversible N-acetyl-beta-D-glucoseaminidase (NAG) enzymuria occurred (300% above normal), but no significant proteinuria (less than 300 mg/l). Administration of 16, 16-dimethylprostaglandin F2 alpha(0.5 mg/kg iv) concomitantly with the indomethacin greatly ameliorated the intestinal lesions and prevented the decreases in hepatic drug-metabolizing enzymes. Concomitant 16,16-dimethylprostaglandin F2 alpha did not, however, influence the indomethacin-induced decreases in serum protein, albumin or NAG-enzymuria. It was concluded that indomethacin had a highly selective effect causing a decrease in hepatic cytochrome P-450, which was not accompanied by severe damage to hepatocyte structure.     

VBI性眩晕患者的BAEP，TCD，CDFI的对照研究

目的：探讨脑干听觉诱发电位（BAEP）,经颅多普勒超声（TCD）,彩色多普勒超声（CDFI）对椎基底动脉供血不足（VBI）的诊断价值。方法：对66例临床确诊的VBI性眩晕患者进行BAEP,TCD,CDFI检测。结果：VBI患者上述三项检查的异常率分别为70％,79％,82％。BAEP提示：内耳型8例,脑干型31例,混合型7例。TCD提示：单血管流速异常30例,多血管流速异常22例;低流速38例,高流速14例;伴有阻力指数（RI）异常22例。CDFI提示：单侧异常33例,双侧异常21例,既有椎动脉形态学异常又伴有血流参数异常的36例,单纯血流参数异常的18例。结论：此三项检查均是较理想的非创伤性检查,有助于VBI早期定位和定性诊断。     

Occurrence and distribution of sucrose-metabolizing enzymes in oral streptococci.

Specific growth rates, growth yields, and the level and cellular distribution of three sucrose-metabolizing enzyme activities were determined for seven oral streptococci (Streptococcus mutans strains E49, BHT, 10449, SL-1, and LM-7, S. sanguis 10558, and S. salivarius 25975). Cultures were grown in a fermentor at pH 6 with either 20 mM glucose or 10 mM sucrose.Generation times varied between 21 and 70 min. Whereas some strains grew 10 to 50% more slowly with sucrose than with glucose, others did not. Growth was always logarithmic, and the growth yields were similar. Glcosyl transferase (EC 2.4.1.5) was largely extracellular; in sucrose cultures it was appreciably lower, but no major shift to a cell-associated form was found. In glucose cultures, the activity varied between 4 and 140 IU per 6-liter culture. The glucan formed was mostly or exclusively water insoluble. Glcosyl transferase was stimulated weakly (60% or less) by various dextrans. Fructosyl transferase (EC 2.4.1.10) was primarily extracellular (except in glucose cultures of S. salivarius) and varied between 0 and 337 IU/culture. In S. salivarius, the extracellular fructosyl transferase was induced by sucrose. In all S. Mutans cultures, the total fructosyl transferase activity was lower after growth with sucrose. All strains had extra- and intracellular invertase (EC 3.2.1.26) activity. Total levels varied between 210 and 3,500 IU/culture. Less extracellular activity was present in sucrose cultures. Only S. salivarius had appreciable activity in the cellular particulate fraction. Invertase activity was significantly higher than the combined glucosyl and fructosyl transferase activities in all cultures.     

Preventive and therapeutic effects of oral tolerance in a murine model of asthma

Allergic asthma is an inflammatory disease of the airways, and Th2 cells secreting IL-4 and IL-5 play a pivotal role in its pathogenesis. We have previously demonstrated that oral tolerance can be induced and maintained more profoundly in a Th2-related immune response, and that an ongoing immune response can be suppressed by the oral administration of antigen combined with an appropriate feeding regimen. In the present study, we examined the preventive and therapeutic effects of the oral administration of allergen on a Th2-mediated immune disorder using a murine model of asthma. Our results show that the development of asthma can be blocked completely by orally administering allergen. Airway hyperreactivity, allergen-specific IgE production, Th2-derived cytokines, allergen-induced T cell proliferation and the infiltration of inflammatory effector cells into the lung were prevented by such oral administration. To assess the therapeutic effects of oral administration on the progression of asthma, we tested the effects of oral tolerance in an established asthma model, and found that a multiple high dose-feeding regimen was effective at suppressing the progression of mild asthma. In the high dose-feeding group, the number of eosinophils in bronchoalveolar lavage fluid was reduced and airway reactivity also decreased. However, this was insufficient to reduce airway reactivity and eosinophilia in bronchoalveolar lavage fluid in cases of severe asthma. These results demonstrate that allergic asthma may be ameliorated by feeding allergen; there is hope that these results will provide a new immunotherapeutic strategy for allergic asthma.     

An open, controlled, crossover study on the effects of cimetidine on the steady-state pharmacokinetics of trovafloxacin

Twelve healthy male volunteers participated in this open, randomized, placebo-controlled, two-way crossover study to investigate the effects of cimetidine on the steady-state pharmacokinetics of oral trovafloxacin. Volunteers were randomized to receive either 400 mg cimetidine twice daily or placebo for 5 days. From day 3–5, volunteers received 200 mg trovafloxacin once daily in addition to either cimetidine or placebo. After a minimum 7-day washout period, the study was repeated; those volunteers who received placebo during the first study period were administered cimetidine, and vice versa. The maximum observed serum trovafloxacin concentration, the area under the concentration-time curve of trovafloxacin within the dosing interval of 24 h and the earliest time to the maximum serum concentration for trovafloxacin in volunteers receiving concomitant cimetidine were 2.4 (g/ml, 27.8 g·h/ml and 1.4 h, respectively, compared with 2.5 g/ml, 27.1 g·h/ml and 1.5 h, respectively, in volunteers receiving concomitant placebo. Thus, multiple dosing with cimetidine had no significant effect on the absorption or disposition of trovafloxacin at steady state. Co-administration of cimetidine and trovafloxacin was also well tolerated and without serious adverse effects.