Introductory immunologic studies on human gastrointestinal tract tumors.
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Absorption↗
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Development of a rectal nicotine delivery system for the treatment of ulcerative colitis.
The aims of this investigation were: i. to develop a rectal nicotine delivery system with bioadhesives for the treatment of ulcerative colitis and ii. to evaluate nicotine transport and cytotoxicity of the delivery system using Caco-2 cell culture systems. Rectal nicotine suppository formulations were prepared in semi-synthetic glyceride bases (Suppocire AM and AI, Gattefosse Inc.) by fusion method. The in vitro release of nicotine was carried out in modified USP dissolution apparatus 1. Differential scanning calorimetry (DSC) and powder X-ray diffraction were used to study the polymorphic changes if any in the formulations. An LC method was used for the assay of nicotine. The effect of bioadhesives (glyceryl monooleate (GMO), and Carbopol) on the nicotine flux was evaluated using Caco-2 cell permeability studies and Caco-2 cell viability was determined using the MTT toxicity assay. In vitro release studies indicated that the low melting AI base was superior to that of the AM base. Presence of GMO in the formulation enhanced the release of nicotine whereas Carbopol showed an opposite effect. The enhanced release of nicotine in the presence of GMO was found to be partly due to the melting point lowering effect of this compound. Caco-2 cell absorption studies showed that there was a decrease in the flux of nicotine in the presence of both the bioadhesives. The flux of the fluorescein marker which is used to study the integrity of the cell monolayers was found to be slightly higher only in the presence of 10% (w/w) Carbopol. Nicotine, Carbopol, and GMO do not have any cytotoxic effect on these cell monolayers within the concentration range used in the formulations. Rectal nicotine formulations containing bioadhesives were developed and characterized. Both in vitro release and cell culture studies have indicated that one can manipulate the nicotine release from these rectal delivery systems by incorporation of various bioadhesives or the use of different bases in the formulation. Nicotine concentration below 2% (w/v) and bioadhesive concentration below 10% (w/w) do not have any cytotoxic effect on Caco-2 cells.
Acrylic Resins↗
Systemic availability of ergotamine tartrate after oral, rectal and intramuscular administration.
Plasma ergotamine levels were measured in 33 volunteers (subgroups 11, 12 and 10) after a single dose of ergotamine administered by various routes. Ergotamine tartrate was given in doses normally used in the treatment of acute migraine--2.0 mg orally, 2.0 mg combined with 100 mg caffeine rectally and 0.5 mg i.m. Plasma ergotamine concentrations were determined by radioimmunoassay. The highest and longest lasting levels were found after i.m. administration, the peak concentration being 1.94 +/- 0.34 (SEM) ng/ml at 1/2 h. The corresponding maximum concentrations after oral and rectal administration were 0.36 +/- 0.08 ng/ml at 2 h and 0.42 +/- 0.09 ng/ml at 1 h. In most of the subjects the plasma ergotamine level began to rise again at 24 to 48 h. The cause of the elevation is not known but it might favour possible accumulation of the drug. Absorption from suppositories was at least as good as after oral administration and the former route may therefore be advantageous for migraine patients in whom nausea and vomiting during an attack may prevent efficient oral medication.
Administration, Oral↗
Studies of the digestibility of pigs fed dietary sucrose, fructose or glucose.
Digestion of sucrose, fructose and glucose was studied in pigs with reentrant cannulas in the distal ileum or intact pigs fed diets formulated with sucrose, fructose and glucose as the major energy source and torula yeast. Sucrose and glucose were completely digested in the small intestine (apparent digestibility, 98.3 and 98.3%, respectively but a fraction of the dietary fructose escaped to the large intestine (adjusted value, 11.7%). There was no carbohydrate in rectal contents of the pigs. There was no carbohydrate influence on the pre-caecal or total digestibility of nitrogen.
Animals↗
Treatment of ulcerative colitis with hydrocortisone enemas. Comparison of absorption and clinical response with hydrocortisone alcohol and hydrocortisone acetate.
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17-Hydroxycorticosteroids↗
Dose-dependent resorption of quinine after intrarectal administration to children with moderate Plasmodium falciparum malaria.
The pharmacokinetics of increasing doses of an intrarectal Cinchona alkaloid combination containing 96.1% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine (Quinimax) was compared to that of parenteral regimens in 60 children with moderate malaria. Quinine exhibited a nonlinear pharmacokinetics, suggesting a saturation of rectal resorption. When early rejections appeared, blood quinine concentrations decreased by 30 to 50% and were restored by an immediate half-dose administration of the drug. Rectal administration of doses of 16 or 20 mg/kg of body weight led to concentration-time profiles in blood similar to those of parenteral regimens and could be an early treatment of childhood malaria.
Administration, Rectal↗
Effect of hyperthermia on cisplatin pharmacokinetics in normal dogs.
In vitro and in vivo cisplatin pharmacokinetic studies were conducted at 37 degrees C and 42-43 degrees C in dogs. Cisplatin at 1, 2, 3, 4 and 5 micrograms/ml was incubated with canine serum at 37 degrees and 43 degrees C. Aliquots were processed immediately for atomic absorption spectrophotometry to determine total as well as free, ultrafilterable cisplatin concentrations. Thirteen healthy, average-sized mongrel dogs received 1 mg/kg cisplatin as an intravenous bolus. Four were maintained unanaesthetized at 37 degrees C, two were anaesthetized and maintained at 37 degrees C and seven were anaesthetized and maintained at a rectal temperature of 42 degrees C for 60 min. Serum samples were obtained and processed for free and total cisplatin. There were no detectable concentration effects present in either in vitro group. The rate constant reflecting the decay of free cisplatin at 37 degrees C was 0.0035 +/- 0.0007 min-1 and increased significantly (P less than 0.0001) to 0.0053 +/- 0.001 min-1 at 43 degrees C. In vivo pharmacokinetic analysis consisted of model-independent parameters (total body clearance, volume of distribution, half-life and mean residence time). A significant increase (P less than or equal to 0.05) in all parameters was observed with free-cisplatin at 42 degrees C. This data would indicate that at the elevated temperatures encountered in whole body hyperthermia, the rate of formation of reactive metabolites from parent cisplatin is increased.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Experience with the rectal prednisone therapy in general practice with special reference to the prevention of spastic conditions of the respiratory tract].
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Adolescent↗
Effects on the prostate of environmental cadmium exposure--a cross-sectional population study in China.
To explore possible effects of environmental cadmium exposure on prostate in humans, and the possible relationship of serum sex hormones to occurrence of clinic signs of tissue changes in the prostate, a case-control study was undertaken in the southeast part of China in 1998. A total of 297 male volunteers from a control area and two cadmium-polluted areas were included as subjects in this study. All the subjects were required to answer a questionnaire and to undergo a complete physical examination including digital-rectal examination (DRE). Blood and urine samples were collected. Serum total prostate specific antigen (PSA), total serum testosterone (T), follicle stimulating hormone (FSH) and luteinizing hormone (LH) were measured by radioimmunoassay and enzymeimmunoassay method, respectively. The data of urinary cadmium (U-Cd) and blood cadmium (B-Cd) were obtained by atomic absorption spectrometry (AAS) as an indicator of cadmium body burden. Statistical analysis was applied to investigate a possible relation between cadmium exposure and prostate pathological changes. The results show that there is a clear dose-response relationship between cadmium exposure and the prevalence of cases with abnormal PSA. The blood cadmium content in cases with positive DRE was significantly higher than that of subjects with negative DRE (P < 0.05). Significant differences in the level of FSH between cases with positive DRE and the normal subjects were also noted (P < 0.05). These results indicate that chronic environmental cadmium exposure is associated with injuries to human prostate. A possible relationship to changes in circulating sex hormones needs further investigation.
Adult↗
Villous adenoma of the colon and rectum: an ultrastructural study.
The villous component of nine colonic polyps (three pure villous adenoma and six mixed adenomatous and villous adenomas) was studied by light and electron microscopy. Normal colonic mucosa was used for control. The predominant cell was an undifferentiated epithelial cell resembling those of the base of the crypts of normal colonic mucosa. A minority of these cells differentiated toward goblet cells and absorptive cells. Interdigitations of the plasma membrane with enlarged intercellular spaces were frequently observed, possibly related to the loss of water and electrolytes in some of these tumors, suggesting an analogy to renal tubular plasma membrane changes in kalliopenic nephropathy. Numerous membrane-bound, inter and intracellular "inclusion bodies" representing degenerated lymphocytes and epithelial cell organelles were commonly found. Viral inclusions were not detected in this material. The possibility that the inclusion bodies observed in villous adenoma may represent lysosome-modified vesicles, secondary to absorption of protein and surface mucosubstances appears unlikely.
Adenoma↗
An ultrastructural study of enteropathogenic Escherichia coli infection in human infants.
Over the past 2 years, we have studied and treated 18 infants with protracted diarrhea due to an enteropathogenic Escherichia coli serogroup 0119. All patients had persistent stool escretion and jejunal over-growth with this pathogenic E. coli. Jejunal biopsy revealed atrophy of villi with a chronic inflammatory cell infiltrate in the lamina propria. E. coli 0119 adhered to the luminal surface of enterocytes. Electron microscopy showed disappearance of glycocalyx and microvilli at the areas of bacterial adherence. Intracellular damage was indicated by dilatation of rough endoplasmic reticulum, mitochondrial changes, and cytoplasmic pallor. Similar changes in histology and ultrastructure occurred in ileal epithelial cells. Glandular crypt epithelium showed prominent subnuclear vacuolation and separation of lateral intercellular junctions throughout the small intestine. Rectal mucosal biopsy showed mucus depletion and irregular atrophy of the epithelium, with E. coli 0119 adherent to the luminal surface. Ultrastructural damage paralleled that in the small intestine. E. coli 0119 causes damage to epithelial cells throughout the infant intestinal tract. This damage leads to atrophy of villi and a marked reduction in absorptive surface area, resulting in protracted diarrhea.
Colon↗
Chemoprevention of colorectal cancer in inflammatory bowel disease? A potential role for folate.
Patients with ulcerative colitis have an increased risk for developing colon cancer compared to the general population. The risk is related to the extension of the disease and its duration. This risk is the same for Crohn's colitis patients of equal extension and duration. By chemoprevention we mean the use of specific natural or synthetic chemical agents to reverse, suppress or prevent progression to invasive cancer. The chemopreventive agents for colon cancer are either of natural origin (vitamins, minerals, food constituents) or synthetic chemicals (difluoromethyl ornithine) and pharmaceutical agents (aspirin, oltipraz). Apart from folate, no other agent has so far been used in vivo for the prevention of colon cancer in long-standing inflammatory bowel disease. The use of folate was, however, not primarily intended to prevent cancer but to enhance folate absorption in ulcerative colitis. From retrospective studies, within the framework of cancer surveillance programmes, it became evident that folate supplementation may play a positive role as a chemopreventive agent against colorectal cancer in patients with long-standing, extensive ulcerative colitis. There is also evidence suggesting that folate supplementation may contribute to regulation of rectal cell proliferation in ulcerative colitis patients. There is a real need for multicentre, randomized, prospective clinical studies in order to evaluate the promising role of folate in preventing colorectal cancer in patients with long-standing inflammatory bowel disease.
Colitis, Ulcerative↗
Intestinal bicarbonate secretion by marine teleost fish--why and how?
Intestinal fluids of most marine teleosts are alkaline (pH 8.4-9.0) and contain high levels of HCO(3)(-) equivalents (40-130 mM) which are excreted at a significant rate (>100 microEq kg(-1) h(-1)). Recent research reveals the following about this substantial HCO(3)(-) secretion: (1) It is not involved in acid-base regulation or neutralisation of stomach acid, but increases in parallel with drinking rate at elevated ambient salinities suggesting a role in osmoregulation; (2) In species examined so far, all sections of the intestine can secrete bicarbonate; (3) The secretion is dependent on mucosal Cl(-), sensitive to mucosal DIDS, and immuno-histochemistry indicates involvement of an apical Cl(-)/HCO(3)(-) exchanger. In addition, hydration of CO(2) via carbonic anhydrase in combination with proton extrusion appears to be essential for bicarbonate secretion. The mode of proton extrusion is currently unknown but potential mechanisms are discussed. One consequence of the luminal alkalinity and high bicarbonate concentrations is precipitation of calcium and magnesium as carbonate complexes. This precipitation is hypothesised to reduce the osmolality of intestinal fluids and thus play a potential role in water absorption and osmoregulation. The present studies on European flounder reveal that elevated luminal calcium (but not magnesium) concentrations stimulate intestinal bicarbonate secretion both acutely and chronically, in vitro and in vivo. At the whole animal level, the result of this elevated bicarbonate secretion was increased calcium precipitation with an associated reduction in the osmolality of rectal fluids and plasma. These observations suggest direct functional links between intestinal bicarbonate secretion, divalent cation precipitation and osmoregulation in marine teleost fish.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children.
AIMS: The aims of this study were to describe paracetamol pharmacokinetics in neonates and infants. METHODS: Infants in their first 3 months of life (n = 30) were randomised to sequentially receive one of three paracetamol formulations (dose 30-40 mg kg-1) over a 2 day period. The formulations were (a) elixir, (b) glycogelatin capsule suppository and (c) triglyceride base suppository. Approximately six blood samples were taken after each dose over the subsequent 10-16 h. Data were analysed using a nonlinear mixed effect model. These neonatal and infant data were then included with data from four published studies of paracetamol pharmacokinetics (n = 221) and age-related pharmacokinetic changes investigated. RESULTS: Population pharmacokinetic parameter estimates and their coefficients of variation (CV%) for a one compartment model with first order input, lag time and first order elimination were volume of distribution 69.9 (18%) l and clearance 13.0 (41%) l h-1 (standardized to a 70 kg person). The volume of distribution decreased exponentially with a half-life of 1.9 days from 120 l 70 kg-1 at birth to 69.9 l 70 kg-1 by 14 days. Clearance increased from birth (4.9 l h-1 70 kg-1) with a half-life of 3.25 months to reach 12.4 l h-1 70 kg-1 by 12 months. The absorption half-life (tabs) for the oral preparation was 0.13 (154%) h with a lag time (tlag) of 0.39 h (31%). Absorption parameters for the triglyceride base and capsule suppositories were tabs 1.34 (90%) h, tlag 0.14 h (31%) and tabs 0.65 (63%) h, tlag 0.54 h (31%), respectively. The tabs for elixir and capsule suppository in children under 3 months were 3.68 and 1.51 times greater than children over 3 months. The relative bioavailability of rectal formulations compared with elixir were 0.67 (30%) and 0.61 (23%) for the triglyceride base and capsule suppositories, respectively. CONCLUSIONS: Total body clearance of paracetamol at birth is 62% and volume of distribution 174% that of older children. A target concentration above 10 mg l-1 in approximately 50% subjects can be achieved by a dose from 45 mg kg-1 day-1 at birth and up to 90 mg kg-1 day-1 in 5-year-old children. A reduced dose of 75 mg kg-1 day-1 in an 8-year-old child is sufficient because clearance is a nonlinear function of weight.
Acetaminophen↗
17 beta-Hydroxysteroid dehydrogenase type 2 expression and enzyme activity in the human gastrointestinal tract.
The 17 beta-hydroxysteroid dehydrogenases (17 beta HSDs) play an important role in the regulation of intracellular levels of biologically active sex steroid hormones in various human tissues. To date, eight distinctive 17 beta HSD enzymes have been cloned and characterized in humans. Among these isoenzymes, 17 beta HSD type 2 (17 beta HSD2) catalyses the conversion of testosterone into androstenedione and/or oestradiol into oestrone in various tissues, and it has thus been suggested to be involved in the biological inactivation of these sex steroids. The human gastrointestinal tract and liver are considered as the principle sites of inactivation and metabolism of various forms of orally administered sex steroids. We therefore examined 17 beta HSD2 expression and activity in human adult non-pathological gastrointestinal tract in order to clarify further the biological significance of this enzyme. A total of 80 specimens (40 from males and 40 from females) of normal oesophageal, stomach, duodenal, ileal, colonic and rectal tissues were examined for immunohistochemistry. Altogether, 17 tissue specimens were used for enzyme assay, and eight for RNA analysis. 17 beta HSD2 activity was detected in the stomach, duodenum, ileum, colon and rectum. 17 beta HSD2 mRNA was most abundant in the small intestine. 17 beta HSD2 immunoreactivity was localized almost exclusively to the absorptive epithelium, which may be involved in the inactivation of excessive endogenous and exogenous active sex steroids. Results from the present study thus suggest that the human gastrointestinal tract is an important sex steroid metabolizing organ in humans.
17-Hydroxysteroid Dehydrogenases↗
Neurotransmitters and stimulation of fluid reabsorption in migratory locust rectal cells.
Several biogenic amines enhance fluid reabsorption and the accumulation of cyclic adenosine-monophosphate (cAMP) in the rectum of the migratory locust but only 5-hydroxytryptamine (5-HT) acts in a dose-dependent manner at low concentrations (between 10(-8) and 5.10(-7) M). Cyclic AMP is a second messenger of 5-HT, and its actions on fluid reabsorption are calcium-dependent. Polymyxin B (a protein kinase C inhibitor) mimics the actions of 5-HT on fluid reabsorption and on calcium-dependent cAMP accumulation. This suggests the presence of other sources of calcium and a possible relationship between several transduction systems within different rectal cells. The second messenger system mediating the 5-HT antidiuretic message differs from those involved in the transduction of the known locust antidiuretic hormones.
1-Methyl-3-isobutylxanthine↗
Effects of experimentally induced Streptococcus suis infection on the pharmacokinetics of penicillin G in pigs.
The pharmacokinetics of potassium penicillin G were studied in both healthy (n = 8) and experimentally Streptococcus-suis-infected (n = 6) pigs following intramuscular administration (15,000 iu/kg). Streptococcus-suis infection was induced artificially in young cross-bred pigs by subcutaneous inoculation with 9 x 10(8) to 10(9) colony-forming units of S. suis. The rectal temperature of infected pigs was significantly increased (P less than 0.01) before penicillin G injection and this was maintained for 8 h after the drug was given. Other clinical symptoms were also present. The serum concentration-time data for penicillin were found to fit a one-compartment open model with first-order absorption in the two groups of pigs. Significant changes were not observed between healthy and diseased pigs in following parameters: A, Ka, Ke and Tmax. However, in diseased pigs, significant increases (P less than 0.01) were found in Vd and ClB, and significant decreases (P less than 0.01) in Cmax and AUC occurred. The increased body clearance (ClB) and greater apparent volume of distribution (Vd) of penicillin G could partly explain why the serum values of the drug were much lower in diseased pigs than in healthy pigs.
Animals↗
Migraine-associated symptoms: clinical significance and management.
Nausea is common in patients with migraine. A number of antiemetic drugs can be useful in migraine treatment, and those with a prokinetic action (metoclopramide and domperidone) may also improve gastrointestinal absorption of analgesics and triptans during a migraine attack. In addition to providing headache relief, the triptans are very effective in relieving migraine-associated nausea. For migraine patients with nausea and/or vomiting severe enough to interfere with the use of oral medications, alternative drug delivery methods can be used. These include the injectable, intranasal and rectal suppository routes, and specialized oral medications such as sublingual tablets and oral wafers that dissolve in the mouth. Fortunately, effective medications that use some of these alternative delivery routes have become more available over the past several years.
Humans↗