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PubMed1977

Effect of amiloride on electrical activity and electrolyte transport in human colon.

It is not known whether factors other than Na transport are involved in generating the electrical potential difference (PD) across the human colonic wall. Therefore, experiments were performed in which the effect of amiloride on PD and ion transport was evaluated in the in vitro short-circuited human colon. In control periods the short-circuit current (Isc) was 2.9 +/- 0.3 (mean +/- S.E.M.) muEq per hr per cem2, while the corresponding net transfer of Na and Cl was 4.6 +/- 0.4 and 1.4 +/- 0.1 respectively. The residual flux was insignificantly different from zero. Amiloride caused a prompt, but reversible, decrease in Isc, PD, and conductance when added to the mucosal sie,dbut only a relatively small reduction of the mucosa to serosa fluxes of Na occurred. Bidirectional Cl fluxes were unchanged while the residual flux increased significantly. It is proposed, therefore, that some ions other than Cl (presumably mucosa to serosa fluxes of H and/or serosa to mucosa fluxes of HCO3) are the main counter ions for actively transported Na in the large bowel. Experiments performed in vivo showed that the rectal PD decreased exponentially from -46 mV +/- 0.8 TO -27 MV +/- 0.3 (mean +/- S.E.M.) following rectal instillation of 10-3 M amiloride. The half-time required for this effect was less than 13 seconds.

Adult↗
PubMed1977

[1st studies on the problem of rectal resorption of MPS in the treatment of arthroses].

Ten patients suffering from degenerative arthropathies were treated to demonstrate a significant influence of suppositoroes containing 500 mg mucopolysaccharide polysulfuric acid ester on certain clotting parameters such as plasma recalcification time, partial thromboplastin time and thrombin time. These investigations had been preceeded by blank determinations and tests with suppositories containing 250 and 400 mg resp. of active substance. It could be shown that the active substance is absorbed even if the substance is applied rectally in form of suppositories if these contain sufficient doses of MPS. Consequently, suppositories containing MPS could be used for a therapy of degenerative arthropathies whenever intraarticular and periarticular or intramuscular administration are not possible.

Aged↗
PubMed1984

Clinical pharmacokinetic comparison of two indometacin containing suppositories with different vehicula.

A single dose each of two brands of indometacin (INN; in some pharmacopoeias called indomethacin) containing suppositories, made with different vehicula , was administered rectally - in a cross over design - to ten healthy volunteers. Product A ( Dolcidium ) was made of a new waxy excipient which emulsifies at body temperature; product B was a leading brand of indometacin containing suppository, made of a hydrophilic polyethyleneglycol basis, which dissolves in body fluid. Plasma indometacin concentrations were measured frequently during a period of 9 h after dosing. Both products showed rather consistent absorption profiles. The maximum plasma indometacin concentration after administration of the product A 50 mg suppository was found after 62 +/- 18 min (mean +/- S.D.), and measured 2.0 +/- 0.5 mg X l-1. After dosing with the reference product those values were 66 +/- 21 min and 1.8 +/- 0.4 mg X l-1, respectively. The area under the plasma indometacin concentration-time curve was found to be 384 +/- 130 mg X l-1 X min for product A 50 mg suppositories and 372 +/- 62 mg X l-1 X min for the reference product. This results in a relative bioavailability of the product A 50 mg suppositories of 1.02, after correction for actual amount of indometacin in each dosage form. None of the above mentioned pharmacokinetic parameters were statistically significantly different (p greater than 0.05), indicating bioequivalence of the two products.

Adult↗
PubMed2002

[Successful use of mild hypothermia therapy in a patient with severe clinical Reye syndrome].

This report describes a case of two-yr-old female with severe clinical Reye syndrome (Stage III and over), who was treated with not only conventional therapies but also mild hypothermia therapy. She presented acute episodes of tonic convulsion, hepatic dysfunction and intracranial hypertension. The first treatment consisted of the administration of anticonvulsant and mannitol, which were not effective to control intracranial pressure. Therefore, we induced mild hypothermia to rectal temperature of 33-34 degrees C for ten days to control intracranial hypertension as well as barbiturate therapy and hyperventilation under mechanical ventilation. Although she had hypokalemia, atelectasis of the right upper lung lobe and thrombocytopenia as the side effects during this therapy, we effectively controlled ICP. Glucose fluid therapy is recommended for Reye syndrome. We especially should pay attention to hypokalemia because of hyperventilation, absorption of potassium with insulin and transudation of potassium from the intestine. We determined the initiation and weaning of mild hypothermia therapy by findings of MRI as well as intracranial pressure. MRI findings will contribute to the determination of initiation and weaning of mild hypothermia therapy. Mild hypothermia therapy should be considered in patients with severe clinical Reye syndrome if conventional supportive therapies are not effective.

Child, Preschool↗
PubMed1976

A galactosidase immunosorbent test for carcinoembryonic antigen.

A galactosidase immunosorbent test for carcinoembryonic antigen (CEA) is described in which the amount of galactosidase adsorbed to a cellulose disc is a hyperbolic function of CEA concentration. Thus, molecules with CEA-like activity can be characterized by mathematical analysis of data obtained from the galactosidase immunosorbent test. By such analysis, CEA-reactive molecules in normal human plasma were distinguished from normal cross-reacting antigen and from authentic CEA. Variation of the amount of antibody-enzyme conjugate used in the galactosidase immunosorbent test permitted CEA-reactive material in plasma of a patient with rectal carcinoma to be antigenically distinguished from the CEA-reactive material in urine of a patient with bladder carcinoma. The galactosidase immunosorbent test is a useful tool for analysis of CEA-reactive molecules.

Absorption↗
PubMed1984

Rectal bioavailability of bacampicillin hydrochloride in man as determined by reversed-phase liquid chromatography.

The relative bioavailability of bacampicillin hydrochloride, a pro-drug of ampicillin, was compared after rectal and oral administration. Bacampicillin was administered rectally as a microenema . The oral formulation was an aqueous microcapsule suspension. They were given as single doses of 400 mg to 12 healthy volunteers after overnight fasting using a randomized cross-over design. Ampicillin and bacampicillin were determined in plasma and blood, respectively, using HPLC. Bacampicillin was rapidly absorbed from the rectum but to a much smaller degree compared to the oral dose. The median t-max was 0.5 and 0.75 h after the rectal and oral doses, respectively. The mean (SD) Cp-max was 1.2 (0.33) mg/l after rectal and 4.8 (0.98) mg/l after oral administration, respectively. Blood concentrations of bacampicillin were extremely low or undetectable with no indication of differences between the two modes of administration. The 95% confidence limits for the relative bioavailability of the microenema were 22.4-39.2 and 22.5-40.4% based on area under the plasma concentration time curve and urinary recovery, respectively. The rectal dose was followed by distress, diarrhea or pain, in 7 subjects. There were no adverse reactions after the oral dose. Bacampicillin was unaffected by beta-lactamases produced by intestinal bacteria.

Absorption↗
PubMed1980

[Multiple-dose pharmacokinetics of paracetamol and salicylamide in man after combined rectal application (author's transl)].

The pharmacokinetic behaviour of paracetamol (300 mg) and salicylamide (200 mg) in the course of combined repetitive (three times tau = 4 h) administration of suppositories was investigated in 10 healthy, male volunteers. The estimation of the pharmacokinetic constants was performed by a simultaneous curve fitting from all single values with a direct search procedure, based on an open two-compartment model and the multiple-dose equation. Both drugs showed a pharmacokinetic behaviour which was conformable to the literature data for single dose and mono substance applications. The dynamics of the absorption kinetics was decreased, as is generally seen after the application of suppositories. In spite of this both substances reached a steady state after the 3rd application. A calculation of collapse coefficients showed for paracetamol as well as for salicylamide a pharmacokinetic distribution behaviour deviating from an open one-compartment model. Due to the good conformity of the parameters, which causes the synchronism of the time-concentration curves after multiple dose application, paracetamol and salicylamide are suited combination partners as seen from a pharmacokinetic point of view.

Acetaminophen↗
PubMed2004

Nerve growth factor mediates alterations of colonic sensitivity and mucosal barrier induced by neonatal stress in rats.

BACKGROUND & AIMS: Maternal deprivation (MD) increases nerve growth factor (NGF) expression and colonic mast cell density and alters visceral sensitivity. This study aimed to establish whether NGF overexpression induced by neonatal stress is involved in altered visceral sensitivity and gut mucosal integrity in adult rats. METHODS: Male Wistar rat pups were either submitted to MD and treated with anti-NGF antibodies or left with their dam and treated daily with NGF. All rats were tested 10 weeks later for visceral sensitivity and 12 weeks later for gut permeability, myeloperoxidase activity, and mast cell numbers. Colonic NGF and NGF receptor expression were determined at 14 days and 12 weeks of age. To determine the involvement of colonic NGF overexpression and mast cell hyperplasia in visceral hyperalgesia induced by MD, neonatally deprived adult rats received anti-NGF antibodies or doxantrazole. RESULTS: MD increased visceral sensitivity to rectal distention, gut permeability, colonic myeloperoxidase activity, and mast cell density, and anti-NGF antibodies abolished these effects. Neonatal daily treatment with NGF mimicked the alterations induced by MD on both rectal sensitivity and mucosal barrier. In deprived compared with nondeprived rats, colonic NGF immunostaining and NGF messenger RNA were increased at 14 days and 12 weeks. Overexpression of NGF receptor messenger RNA, present at 14 days, was not observed later. Moreover, adult deprived rats treated with doxantrazole or anti-NGF antibodies exhibited normal gut permeability and visceral sensitivity to rectal distention. CONCLUSIONS: These data indicate that NGF triggers and maintains long-term alterations of visceral sensitivity and gut mucosal integrity induced by MD.

Animals↗
PubMed1978

Rectal mucosa in cystic fibrosis. Morphological features before and after short term organ culture.

Histological changes observed in the large intestinal mucosa of cystic fibrosis (CF) patients, including crypt enlargement as well as intracellular and extracellular accumulation of mucus, have been considered by some to be useful diagnostic signs of this disease. The extent of these changes, however, has not been evaluated quantitatively. In this study, quantitative stereological methods were applied to biopsies of rectal mucosa from 5 CF patients, 5 sibling controls, and 2 normal adults, to measure goblet cell numbers, crypt luminal volume, and volume of intracellular mucus. It was found that CF crypt lumina were variably dilated, but that the average relative volume of intracellular mucus and the numbers of goblet cells in CF mucosae were comparable to those of sibling and adult controls. In CF biopsies, however, surface columnar absorptive cells consistently contained putative lipid droplets and rapidly accumulated additional large lipid droplets during short term organ culture. Lipid droplets were not observed in the same cell types of control biopsies before or after short term organ culture.

Adolescent↗
PubMed2004

Diclofenac and metabolite pharmacokinetics in children.

BACKGROUND: Data concerning metabolism of diclofenac in children are limited to intravenous and enteric coated oral formulations. There are no data examining diclofenac or its hydroxyl metabolite pharmacokinetics after rectal administration in children. METHODS: Infants (n = 26) undergoing tonsillectomy were given diclofenac 2 mg.kg(-1) followed by 1 mg.kg(-1) 8 h as suppository formulation for postoperative analgesia. Serum was assayed for diclofenac, 4'-hydroxydiclofenac and 5'-hydroxydiclofenac concentrations during the procedure and 1, 2 and 4 h postoperatively. The formation clearances of diclofenac to hydroxyl metabolites were estimated using nonlinear mixed effects models. A single compartment, first order absorption and first order elimination model was used to describe diclofenac pharmacokinetics. Published data from 11 children given enteric-coated diclofenac tablets were used to assess relative bioavailability. RESULTS: Mean (sd) age and weight of the patients were 4.5 (1.5) years and 20.5 (4.1) kg. The formation clearance to 4'-hydroxydiclofenac (% CV) and to 5'-hydroxydiclofenac were 8.41 (8.1) and 3.41 (113) l.h(-1) respectively, standardized to a 70 kg person using allometric '1/4 power' models. Clearance by other routes contributed 33.0 (64) l.h(-1) 70 kg(-1). Elimination clearance of hydroxyl metabolites was fixed at 27.5 l.h(-1) 70 kg(-1). The volumes of distribution of parent diclofenac and its hydroxyl metabolite were 22.8 (19.0) and 45.3 (l.70) kg(-1). The suppository formulation had an absorption half-life of 0.613 (33.2) h with a lag time of 0.188 (24.9) h. Interoccasion variability of formation clearance to 4'-hydroxydiclofenac, diclofenac volume of distribution, absorption half-time and lag time for the suppository was 36%, 55%, 14% and 119%, respectively. The relative bioavailability of the suppository compared with an enteric-coated tablet was 1.26. CONCLUSION: The formation clearance of the active metabolite 4'-hydroxydiclofenac contributed 19% of total clearance (44.82 l.h(-1) 70 kg(-1)). The rectum is a suitable route for administration of diclofenac in children 2-8 year of age and was associated with a higher relative bioavailabilty than enteric-coated tablets and an earlier maximum concentration (50 vs. 108 min). This pharmacokinetic profile renders diclofenac suppository a suitable formulation for short duration surgery.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

In vitro and in vivo evaluation of the transdermal iontophoretic delivery of sumatriptan succinate.

The objective was to evaluate the transdermal delivery of the 5-HT(1B/1D) agonist, sumatriptan from an iontophoretic patch system, in vivo. Initial in vitro experiments were conducted to optimize formulation parameters prior to iontophoretic delivery in Yorkshire swine. It was found in vitro that increasing drug load in the patch from 9.7 to 39 mg had no statistically significant effect on cumulative delivery (cf. 305.6+/-172.4 vs. 389.4+/-80.4 microg cm(-2), respectively). However, for a given drug load (39 mg) increasing formulation pH from pH 4.7 to 6.8 significantly increased the cumulative amount of sumatriptan delivered across the skin (389.4+/-80.4 vs. 652.4+/-94.2 microg cm(-2)). A biphasic current profile comprising intensities of 1.8 mA from t=0 to t=180 min and 0.8 mA from t=181 min to t=360 min was used for the in vivo experiments. Drug levels in the blood were 13.7+/-4.5 and 53.6+/-10.2 ng ml(-1) at the 30 and 60 min time-points, rising to 90-100 ng ml(-1) during the 90-180 min time-period. The in vivo results show that the pharmacokinetics following transdermal iontophoretic delivery are comparable to those after oral, nasal or rectal administration, but do not match those upon subcutaneous injection.

Administration, Cutaneous↗
PubMed1981

[Absorption of the antibody formation to anticartilage-antiparathyroid antibodies administered into the rectum (author's transl)].

The absorption of and specific antibody formation to Artroglobina (:AG, beta and gamma-globulin fractions of anticartilage-antiparathyroid immune serum from the horse) administered into the rectum were studied in rats and guinea-pigs, an immunological tests in the "Phase I Study" were carried out using serum from volunteers. 1) When the radio-labelled AG (125I-AG) was administered into the rat rectum, the plasma level of 125I reached the maximum (3.1% of the total dosage) at 2 hour later and 0.3 per cent of the total dosage retained the reactivity with the anti-Fab antibody. 2) Gel diffusion and PCA tests gave positive reactions in the sera after the second administration of AG in a dose of 20 mg/kg, corresponding to 40 times the clinical dose, with a certain interval after the first treatment. From the results, it was confirmed that rectally-administered AG induces mainly IgG or IgE antibody formation, in the rat. 3) The administration of AG through the rectum did not induce the systemic anaphylaxic reaction in the guinea-pigs which had been administered AG into the rectum. The intravenous challenge, however, resulted in a positive anaphylaxic reaction in animals treated with AG rectally. This indicates the sensitization of the animal with AG by the rectal administration. 4) The specific antibody responses, immune complexes and complement values did not change in the sera of volunteers given AG which consisted of alternating cycles of twelve days of treatment with one suppository daily, and twelve days without treatment, in a clinical dose of 25 mg. Nevertheless, AG must be carefully prescribed as higher doses given to experimental animals induced adverse immunological effects.

Anaphylaxis↗
PubMed1973

Electrical potential difference and sodium and potassium fluxes across rectal mucosa in ulcerative colitis.

The transmucosal electrical potential difference (pd) and the sodium and potassium flux rates (using a dialysis method) have been measured in the rectum and distal sigmoid colon of patients with ulcerative colitis and compared with measurements made in individuals having normal bowel function. In active colitis, a very low transmucosal pd was found and was associated with loss of the characteristic ability of the mucosa to absorb sodium against considerable electrochemical gradients; a marked increase in the plasma-to-lumen sodium flux rate, suggesting increased leakiness of the mucosa; and loss of the active sodium absorption mechanism. In resolving colitis, the pd was higher and all these changes of sodium transport tended to return towards normal. With full recovery, epithelial function was normal to the present tests. Potassium secretion rate showed little difference at various stages of the disease, but the nearly normal secretion of potassium in ulcerative colitis when the pd was low suggested that potassium loss to the lumen was excessive. Mucus collected from patients with ulcerative colitis had a relatively high sodium and potassium content. Measurement of pd and absorption by using a dialysis tube offers a simple means of rapid assessment of mucosal functional integrity.

Adult↗
PubMed1986

Effect of purgatives on antidotal efficacy of oral activated charcoal.

The effects of purgatives on the antidotal efficacy of oral activated charcoal were studied in seven volunteer subjects. The volunteer subjects were given 1000 mg of aspirin, 100 mg of atenolol and 50 mg of phenylpropanolamine with 100 ml of water on an empty stomach and were assigned randomly to the following treatment groups: after 5 min 150 ml of water, after 5 min 25 g of charcoal, after 5 min charcoal orally with 20 mg of metoclopramide rectally, followed by 10 mg of bisacodyl rectally 3 h afterwards, after 5 min charcoal with 250 ml of magnesium citrate USP and after 60 min charcoal with metoclopramide followed by bisacodyl 3 h thereafter. The plasma concentrations (0-24 h) and the cumulative urinary excretion (0-72 h) of salicylates, atenolol and phenylpropanolamine were measured. Both magnesium citrate and metoclopramide combined with bisacodyl hastened the gastrointestinal transit but magnesium citrate was more effective. Charcoal alone reduced the absorption of aspirin and phenylpropanolamine by about 50% and that of atenolol by about 95%. The purgatives did not modify significantly the efficacy of charcoal. When the antidotal treatment was delayed by 60 min its efficacy was reduced to some extent, possibly depending on the pharmaceutical formulation of the test drugs. The present results do not support the routine use of purgatives in combination with activated charcoal. In some instances, however, their use may promote the evacuation of, for example, depot formulations from the gastrointestinal tract and thus have a beneficial effect together with activated charcoal in reducing absorption.

Administration, Oral↗
PubMed1984

Treatment of acute asthma in children with rectal administration of aminophylline solution.

In a double-blind cross-over study, 20 children suffering from acute bronchoconstriction were treated with an interval of 90 min with placebo and 9.0 mg theophylline per kg given rectally in aqueous solution. Each child took part on 2 occasions. Fifteen min after both administrations of theophylline there was a significant increase in peak flow (PEF) as compared with placebo treatment (p less than 0.05). The increase in PEF was related to the serum level of theophylline, a significant bronchodilating effect was observed at about 7 mg/l. Substantial inter- and intrapatient variations were found in the improvement of PEF. The absorption of theophylline was rapid. The measured peak serum levels varied from 7.3 to 16.0 mg/l and occurred within 60 min in most patients. The intra-subject variations in the dose-to-dose absorption profiles were generally small and within a range acceptable for clinical use. The solutions allowed an accurate dosage calculation, did not initiate the urge to defecate, and were retained well.

Acute Disease↗
PubMed1982

Changes in [3H]galactose uptake in human colonic mucosa with carcinoma: an ultrastructural study.

As part of our investigation on glycoprotein synthesis in pre-malignant colonic epithelium, changes in the uptake of [3H]galactose were studied at the ultrastructural level. Normal control mucosa from rectal biopsies of patients with no known gastro-intestinal disease and mucosa adjacent to carcinoma ('transitional' mucosa) from specimens resected for colo-rectal cancel were compared. These tissues were incubated in TC 199 medium containing [3H]galactose for various intervals of time and for pulse labelling. Silver grain distribution was statistically analysed. The results showed a reduction in the incorporation of the galactose by 'transitional' mucosa. The uptake by this mucosa was less uniform than normal and showed considerable peaking in the endoplasmic reticulum of the goblet cells and in the Golgi of the absorptive cells, suggesting a blockage or alteration in glycoprotein synthesis. The differences were most marked in the middle crypt (the region of differentiation) and in the upper crypt (the region of maturation).

Colon↗
PubMed1996

Olsalazine is contraindicated during pelvic radiation therapy: results of a double-blind, randomized clinical trial.

PURPOSE: A randomized clinical trial from Great Britain suggested a possible beneficial effect of acetylsalicylate in the prevention of radiation-induced bowel toxicity. Olsalazine is an orally administered drug designed to deliver 5-aminosalicylate to the large bowel with minimal systemic absorption. A randomized clinical trial was undertaken to assess the effectiveness of olsalazine in preventing acute diarrhea in patients receiving pelvic radiation therapy. METHODS AND MATERIALS: Patients receiving pelvic radiation therapy were randomized, in double-blind fashion, to olsalazine 250 mg, two capsules twice daily, or an identical appearing placebo, two capsules twice daily. Patients were then evaluated weekly during radiation therapy for the primary study endpoint, diarrhea, as well as rectal bleeding, abdominal cramping, and tenesmus. RESULTS: The study was closed early, after entry of 58 evaluable patients, when a preliminary analysis showed excessive diarrhea in patients randomized to olsalazine. The incidence and severity of diarrhea were worse in patients randomized to olsalazine (p = 0.0036). Sixty percent of the patients randomized to olsalazine experienced Grade 3 or 4 diarrhea compared to only 14% randomized to placebo. There was also a trend toward higher incidence and greater severity of abdominal cramping in patients who were randomized to olsalazine (p = 0.084). CONCLUSION: Administration of olsalazine during pelvic radiation therapy resulted in an increased incidence and severity of diarrhea. Olsalazine is contraindicated in patients receiving pelvic radiation therapy.

Aged↗
PubMed1992

An Eudragit-coated prednisolone preparation for ulcerative colitis: pharmacokinetics and preliminary therapeutic use.

Prednisolone metasulphabenzoate, a steroid with poor colonic absorption, was coated with the pH-dependent acrylic resin Eudragit S, as a means of delivering an orally administered preparation to the proximal colon. The therapeutic potential of delivering this steroid with potentially less systemic side-effects to the proximal colon was assessed in extensive ulcerative colitis. Plasma and urine prednisolone profiles in 6 healthy volunteers confirmed minimal absorption from Eudragit S-coated prednisolone metasulphabenzoate compared to prednisolone acetate: peak plasma prednisolone concentrations 29 +/- 21 ng/ml vs. 570 +/- 185 ng/ml (P less than 0.01), area under curve measurements 204 +/- 214 vs. 2724 +/- 1236 ng.h/ml (P less than 0.01). Prednisolone metasulphabenzoate coated with Eudragit S (30-60 mg daily) was then administered for 12 weeks to 12 patients with colonoscopically proven extensive ulcerative colitis in relapse. Symptoms, sigmoidoscopic appearances and rectal histological abnormalities all improved during therapy. Complete clinical remission occurred in 7 patients, a partial response in 2 patients and no response in 3 patients. Cortisol responses to tetracosactrin demonstrated no significant adrenal suppression following treatment. Eudragit S-coated prednisolone metasulphabenzoate may be a useful treatment for extensive ulcerative colitis, without risk of systemic steroid side-effects.

Acrylic Resins↗