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The serum and urine levels obtained form administration of Erythromycin are generally good and the antibiotic is absorbed in a similar way; this happens also for the other ways of administration. We have noticed a variability in the absorption of antibiotic as the different components present in the suppositories administered.
PURPOSE: This study was conducted to develop and validate a dog colon model that predicts colon permeability in humans. METHODS: The following compounds were studied: Class 1 highly soluble (HS)/highly permeable (HP): aminophylline, propranolol, CP-409092; Class 2 LS/HP: nifedipine; trovafloxacin, sertraline; Class 3 HS/LP: azithromycin, atenolol, CP-331684, CP-424391; Class 4 LS/LP: CJ-13610. Administration to dogs was made 30 cm cranial to the anal sphincter with a lubricated Schott Model VFS-5 flexible endoscope. The bioavailability of the compound following the colon administration in dogs, relative to the same formulation administered orally (relative bioavailability), was determined. RESULTS: Except for atenolol, a small hydrophillic molecule, the relative bioavailability from administration to the colon of the dog correlated well with the following compound properties: high solubility and high, passive permeability > high solubility, low permeability > low solubility, high, passive permeability approximately low solubility, low permeability. CONCLUSION: The dog colon model is proposed as a surrogate for human intubation studies when the controlled release candidate falls in BCS Classes 2 (LS/HP), 3 (HS/LP), and 4 (LS/LP). However, no human intubation or dog colon studies are required for Class 1 (HS/HP), as these compounds are likely to be well absorbed from the colon.
BACKGROUND: Corticosteroid enemas represent effective treatment for ulcerative proctitis, but absorption into the systemic circulation may have undesirable metabolic consequences. Prednisolone metasulphobenzoate, a lipophobic corticosteroid derivative, is designed to be absorbed poorly through the recto-sigmoid mucosa, but the effects of foam enema preparations upon the hypothalamo-pituitary-adrenal axis have not been examined. METHODS: Nine patients suffering from active ulcerative proctitis underwent four weeks of therapy with prednisolone metasulphobenzoate foam enemas. The hypothalamo-pituitary-adrenal axis, defined using the modified single-dose metyrapone test, glucose homeostasis and lipid profiles were studied before and after treatment. RESULTS: The hypothalamo-pituitary-adrenal axis was significantly depressed after the treatment period; mean stimulated plasma cortisol concentration fell from 384 +/- 244 (s.d.) to 288 +/- 252 nmol/L, P < 0.02; stimulated mean plasma 11-deoxycortisol concentration fell from 677 +/- 333 to 407 +/- 326 nmol/L, P < 0.01. Mean fasting plasma glucose, insulin, C-peptide, fructosamine and triglyceride concentration were unchanged, whilst the mean serum cholesterol concentrations rose from 5.6 +/- 1.1 to 6.0 +/- 1.2 mmol/L (not significant). CONCLUSION: Prednisolone metasulphobenzoate foam enemas have significant systemic and endocrine metabolic effects, which could assume importance with long-term therapy.
The causal factors and the physiopathology of motor diarrhea are still unclear. This case report describes a 60-year-old white man with severe diarrhea for more than 10 years and minor signs of autonomic dysfunction. Extensive investigation showed that small intestinal motility and absorption were normal but that accelerated colon transit precluded water and solute absorption from the large bowel. Orthostatic hypotension, sexual dysfunction, and loss of sweating suggested dysfunction of the autonomous nervous system, which was confirmed by reduced plasma concentrations of norepinephrine and dopamine. Rectal biopsy specimens showed enlarged enteric ganglion cells filled with lipidic material. Levels of total hexosaminidase and hexosaminidase B in plasma, white blood cells, and fibroblasts were decreased, as found in Sandhoff disease. The pedigree of the proband's family showed several affected and heterozygous individuals, detected by examination of total hexosaminidase and hexosaminidase B levels in plasma. Among the five homozygous subjects, three had a clinical picture of diarrhea and orthostatic hypotension since the age of 50. Therefore, hexosaminidase B deficiency should probably be regarded as a cause for dysautonomia; dysfunction of the gastrointestinal tract, manifested by motor diarrhea or esophageal dysmotility, could be the initial and prevalent presentation of dysautonomia.
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The objective of this study was to determine (a) the rate of hydrolysis of insulin and proinsulin in homogenates of various non-oral absorptive mucosae relative to the ileal mucosa, and (b) the inhibitory effect of various protease inhibitors on the degradation of these peptides. Overall, insulin was somewhat more susceptible to hydrolysis than proinsulin in all mucosal homogenates. Proteolytic activity was highest in the nasal and rectal homogenates, followed by the ileal, vaginal, conjunctival and buccal homogenates in that order. The rate of insulin and proinsulin proteolysis differed by a factor of about 6 to 7 between the least and the most proteolytically active mucosa. A 5-fold maximum reduction in proteolytic rate was seen in the presence of Na glycocholate, aprotinin and p-chloromercuriphenyl-sulfonic acid (PCMPS). The rank order of effectiveness was Na glycocholate (1%) greater than aprotinin greater than PCMPS in all but the conjunctival and vaginal homogenates. Extrapolating the above in vitro findings to in vivo, both insulin and proinsulin are expected to be degraded to varying degrees during absorption across the various mucosae. Absorption may therefore be enhanced in the presence of protease inhibitors such as aprotinin, PCMPS, or Na glycocholate.
The molecular integrity of rectally absorbed antigens was studied in rats and mice. ABout 2% in the radioactivity of 125I-labelled horse gamma-globulin administered rectally reached the blood circulation. One fifth of this absorbed radioactivity (0.4%) reacted with anti-Fab antibody and about one eight (0.25%) of the original antigen-binding activity was maintained. The results indicated that a small but significant portion of the rectally administered proteins remained intact and retained the immunological function. Rectally-administered proteins induced IgE antibody responses in the rat and the mouse.
The local and systemic bioavailability of a mesalazine enema (Pentasa, Ferring A/S, Denmark) and a mesalazine suppository (Pentasa, Ferring) was assessed during steady-state conditions. Eleven healthy subjects took 1 g of the enema or the suppository twice daily for 1 week, with a drug-free period of at least 1 week in between. At the end of each treatment period the urine and faeces were collected for 48 h, and the concentrations of mesalazine and the metabolite acetyl-mesalazine were measured. Plasma concentrations of drug and metabolite were measured hourly during a 12-h dose interval. The faecal water concentration of mesalazine was significantly higher after suppository treatment (55.7 mmol/l) compared with enema treatment (31.7 mmol/l) (p less than 0.01). The systemic absorption was low; 15% of daily mesalazine dose was recovered in urine after enema treatment and 10% after suppositores (p less than 0.01). Plasma concentrations were low, and no accumulation of either mesalazine or acetyl-mesalazine occurred. In conclusion, the enema and the suppository can be continuously administered as 1 g of mesalazine twice daily, respectively, giving high faecal water concentrations of mesalazine and a low systemic absorption.
Microanatomical changes attributable to cadmium poisoning have been observed in the various regions of the alimentary tract of Notopterus notopterus after exposure to sublethal concentrations (75.54 mg CdCl2 liter-1) of the metal. In the buccopharynx, the major changes following treatment with cadmium were shrinkage of the stratified epithelial cells with shriveling of the microridges and loss of lateral contacts between neighboring epithelial cells. But the most pronounced effect was the aggravated secretion of mucin. The damage to the round or oval stratified epithelial cells in the esophagus was manifested by formation of an even sheet of microridges. In the stomach, the most conspicuous changes were the patchy necrosis of the columnar epithelial cells, fragmentation of microridges, and vigorous secretion of mucus from the apical portion of epithelial cells. Owing to cadmium treatment intestinal ceca exhibited disrupted mucosal folds with loss of the normal rectangular box-shaped arrangement. The columnar epithelial cells were found to lose their regular arrangement with an irregular positioning of the microridges within the cells after cadmium exposure. The mucosal folds of the anterior intestine became intensively disrupted with appreciable damage to the columnar epithelial cells. In the middle intestine the surface epithelial cells were adversely torn and the microvilli of the epithelial cells facing the lumen were heavily damaged. After cadmium exposure accelerated mucous cell activity in the intestine was distinct. No conspicuous changes were observed in the rectal portion after cadmium exposure, except for the disintegration of columnar epithelial cells and a concomitant release of large amounts of mucus into the lumen. All these findings suggest impaired digestion and absorption through the alimentary tract of the aforementioned fish.
In the healthy colon, sodium nitrite stimulates mucosal metabolism of short-chain fatty acids and absorption of ions, both functions that are impaired in the mucosa of patients with ulcerative colitis (UC). To assess the role of nitrite in colonic inflammatory disease, sodium nitrite was measured in rectal dialysate of 49 subjects (18 controls, 23 UC and 8 other colitis). None of the control or quiescent UC patients had measurable levels of nitrite while 78% of patients with acute UC and 38% of patients with other colitis had measurable nitrite levels (acute UC vs. other colitis chi 2 = 5.555, p less than 0.02). Functional activity of the colonic mucosa, judged by bicarbonate output, was impaired in all subjects with measurable nitrite levels in UC. Detection of nitrite in acute colitis suggests impaired oxidation of nitrite to nitrate in the colonic mucosa or impaired luminal reduction of nitrite to NH4 by bacteria.
The influence of different pH values in nutrient media on the drug-initiated contractility of rectal smooth muscle was isometrically investigated. The following results were obtained: (1) The response to drugs is potentiated in alkali media and is reduced in acidic media. (2) Facilitated responses in alkali media were lost with the removal of CaCl2 and the reduction of responses was markedly enhanced with the increase in H+ or in the absence of CaCl2. (3) Analysis with an atomic absorption spectrophotometer, shows that H+ may compete with Ca2+ in transmembrane transport. (4) Removal of NaCl can elicit the release of Ca2+ and this action was diminished in acidic conditions. (5) The contractile system of muscle cells was also inhibited by lowering pH values in nutrient media. Thus, interference with mobilization of Ca2+ by H+ is considered to be responsible for modifying the contractions of rectal smooth muscle in mice.
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AIMS AND OBJECTIVES: This paper considers the correct method for inserting a rectal suppository, both as a medication and also to achieve bowel evacuation. The aim is to find out whether the correct method is blunt end or pointed end foremost. BACKGROUND: It follows from a question raised by a third year student nurse. In the classroom, she had been taught that the correct method for the administration of a suppository for systemic absorption was to insert it blunt end foremost into the rectum. However, if the suppository was to be used for evacuant purposes, it should be given pointed end foremost. In clinical practice, however, she was told the suppository should always be inserted pointed end foremost in all cases, whatever the purpose. DESIGN: This article seeks to clarify the dilemma by examining the sources of evidence underpinning different methods for inserting a rectal suppository. Hence, the literature on the insertion of rectal suppositories was gathered as systematically as possible from medical journals and textbooks, nursing journals and textbooks and manufacturers' information to patients. METHOD: Having gathered the literature, this was examined, appraised and critically analysed for rigour, coherence and reliability. RESULTS: The review of the literature appears to show that evidence adduced for inserting the suppository blunt end foremost derives from one study published in the Lancet in 1991, which challenged 'commonsense'. There did not appear to be other, more recent research. On the other hand, manufacturers' information to patients states generally that the suppository should be inserted pointed end foremost. This has direct relevance for the administration of suppositories and also raises questions as to how research may become integrated into healthcare practice without adequate justification. CONCLUSIONS: An article published in the Lancet in 1991 has had a fundamental effect on nursing practice, but has not been subject to scrutiny. The advice given in this Lancet article differs from that currently given by most manufacturers of suppositories, which involves the terms of their product licence. Hence, there is a potential for problems with legal liability should an untoward event arise. RELEVANCE TO CLINICAL PRACTICE: Inserting rectal suppositories, whether as a medication or to achieve bowel evacuation, is a very common healthcare practice. Currently, there is inconsistency and discrepancy in the correct method for this procedure in both nursing education and practice. This paper examines the reliability of existing evidence and shows the need for further work in order to provide a reliable evidence base for this commonplace clinical procedure.
The in situ rat gut technique was used to study the effects of hypothermia on the intestinal absorption of a 1 mg/ml solution of sodium pentobarbital in 0.01 M phosphate buffer (pH 6.0). Male Sprague-Dawley rats weighing between 300 and 370 g were exposed to an atmosphere of helox (helium:oxygen, 80:20) at 0-4 degrees C for 5 hr. This procedure lowers the rectal temperature of the rats from 38 to 20 degrees C. The animals were prepared for surgery using ether as anesthetic after their rectal temperature reached 20 degrees C. Water flux in and out of the intestinal lumen was estimated from tritiated polyethylene glycol 4000 concentrations in the perfusate. The disappearance rate constant of pentobarbital from the intestinal lumen was 0.0638 +/- 0.007 min-1 for hypothermic rats, in comparison to 0.114 +/- 0.0123 min-1 for normothermic rats.
Clonidine, an alpha 2-adrenergic agonist, has been reported to stimulate the rate of electrolyte absorption in vitro, to alter intestinal motility in vivo, and to have antidiarrheal effects in animals. Experiments were performed in 8 healthy volunteers in order to evaluate the antidiarrheal effect of clonidine in humans. When diarrhea was induced by intragastric infusion of 2700 ml of balanced electrolyte solution over 90 min, oral administration of 0.3 mg of clonidine reduced the volume of rectal effluent by 48% (from 1233 +/- 62 to 640 +/- 77 ml, p less than 0.001), a clear-cut antidiarrheal effect. Clonidine increased total gut volume significantly (from 987 +/- 91 to 1830 +/- 142 ml, p less than 0.001), suggesting that clonidine exerted its antidiarrheal effect by altering gut motility, i.e., increasing the capacity of the gut and slowing the transit of fluid through the intestine. In other experiments, the net absorption rate of the whole gut during steady state total gut perfusion was measured. The rate of absorption of fluid was transiently stimulated by clonidine by 15% (from 696 +/- 77 to 799 +/- 55 ml/h, p less than 0.02), indicating an additional effect on mucosal cell function. These studies indicate that in this experimental diarrhea model, clonidine has antidiarrheal properties that are due largely to effects on motility of the gut but that clonidine also modestly stimulates the net rate of absorption by intestinal mucosa.
BACKGROUND: Ibuprofen is a nonsteroidal anti-inflammatory drug which has both peripheral and central analgesic effects. Ibuprofen has been shown to be an effective antipyretic and postoperative analgesic drug both in adults and children with few side effects. Pharmacokinetics of rectal ibuprofen has not been studied, although suppositories are frequently used for perioperative pain control in children. METHODS: There were four study groups: full-term infants aged 1-7 weeks (n = 9), infants aged 8-25 weeks (n = 8), and infants aged 26-52 weeks (n = 7). Adult patients were 20-40 years old (n = 7). Ibuprofen suppository 20 mg.kg(-1) was administered after induction of anesthesia. Blood samples were collected from 20 min to 10 h after dosing and pharmacokinetic analysis of ibuprofen enantiomers were done. RESULTS: Both ibuprofen enantiomers were detectable in blood in 20 min. Total ibuprofen plasma concentrations >10 mg.l(-1) were seen from 40 min to 8 h. Values for T(max) of ibuprofen enantiomers and total ibuprofen were higher in the adult group than any of the infant groups (P < 0.05). In addition, values for physiological (standardized) t(1/2) of (R)-(-)- and (S)-(+)-ibuprofen were higher in infants aged 1-7 weeks than the adults (P < 0.05). None of the other pharmacokinetic variables, C(max), AUC, chronological t(1/2) or AUC ratio differed between the groups. CONCLUSIONS: A single dose of ibuprofen suppository 20 mg.kg(-1) after induction of anesthesia guarantees analgesic plasma concentrations during the early postoperative period. Except for the delayed absorption of ibuprofen in adults and higher physiological t(1/2) in infants aged 1-7 weeks, no major pharmacokinetic differences were observed between study groups.