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PubMed1996

Five days of whole-bowel irrigation in a case of pediatric iron ingestion.

The maximum duration and volume of polyethylene glycol electrolyte solution (PEG-ELS) that can be safely administered during whole-bowel irrigation of the poisoned patient are poorly defined. We present a case of a 33-month-old boy who ingested at least 160 mg/kg elemental iron and received 44.3 L of PEG-ELS (2,953 ml/kg) over 5 days because of the persistence of iron tablets in teh gastrointestinal tract. The child remained clinically well after initiation of PEG-ELS therapy, and further significant iron absorption did not appear to occur. The rectal effluent cleared within 2 days of the start of PEG-ELS therapy despite the persistence of iron in the gastrointestinal tract as shown on radiography. No adverse effects resulted from teh large volume or duration of the PEG-ELS therapy. This is the greatest reported volume of PEG-ELS to be used for whole-bowel irrigation in the treatment of a toxic ingestion.

Child, Preschool↗
PubMed1997

Nicotine tartrate liquid enemas for mildly to moderately active left-sided ulcerative colitis unresponsive to first-line therapy: a pilot study.

BACKGROUND: Ulcerative colitis is predominantly a disease of non-smokers, and transdermal nicotine is therapeutic but often results in side-effects. Administration of nicotine as a liquid rectal enema results in less systemic nicotine absorption. AIM: To determine the safety and clinical response of nicotine tartrate liquid enemas for active left-side ulcerative colitis in a pilot study. METHODS: Ten non-smoking patients with mildly to moderately active left-sided ulcerative colitis unresponsive to first-line therapy were treated in an open protocol with nightly nicotine tartrate liquid enemas at a dose of 3 mg nicotine base for 1 week then 6 mg for 3 weeks. Clinical assessments were determined at baseline and 4 weeks by endoscopy, physician assessment and a patient diary of daily symptoms. Peak and trough serum nicotine and trough plasma cotinine were determined by gas chromatography/mass spectrometry and high performance liquid chromatography, respectively. RESULTS: After 4 weeks of treatment, 5/7 patients (71%) showed clinical and sigmoidoscopic improvement (per protocol analysis). The other three patients discontinued therapy within 7 days because of inability to retain the liquid enemas. No patients showed histologic improvement. Six of the patients who completed the 4-week study had peak and trough serum nicotine concentration determined, only 1 of 6 patients had a detectable peak nicotine concentration (value 2.3 ng/mL), and all six patients had undetectable trough nicotine concentrations. The mean trough plasma cotinine concentration was 13 +/- 10 ng/mL. Transient and mild adverse events occurred in 4/10 patients (nausea, lightheadedness, tremor, sleep disturbance). Given the low or undetectable serum nicotine concentrations, these adverse events are not likely to be related to the nicotine enemas. CONCLUSIONS: Nicotine tartrate liquid enemas administrated at a dose of 3 mg nicotine base/day for 1 week and then 6 mg/day for 3 weeks are safe and appear to result in clinical improvement in some patients with mildly to moderately active, left-sided ulcerative colitis unresponsive to first-line therapy. Placebo-controlled trials are warranted to confirm these preliminary findings.

Adult↗
PubMed1998

[Preparation and utility of glibenclamide suppository for hospital use].

Glibenclamide (GC) is widely used as an oral hypoglycemic drug in the treatment of non-insulin dependent diabetes mellitus (NIDDM). Since GC is usually taken for a long period, side effects and noncompliance are among the problems. In order to solve those problems, we prepared GC suppositories and examined their usefulness. Suppositories containing 4, 20, and 40 mg of GC were prepared and examined for drug release, drug absorption and blood glucose levels after the rectal administration of suppositories in rabbits. In the release test, GC suppositories released the drug continuously for 6 hours. The areas under the drug release time curve (ADT) of 20 and 40 mg GC suppositories were 3.5 and 6.2 times of 4 mg GC suppositories respectively. The plasma concentrations after administration of 4 and 20 mg GC suppositories showed about the same profiles for 6 hours. After administration of 40 mg GC suppositories, the maximum plasma concentration (Cmax) was observed at 2 hours. All the GC suppositories showed lower blood glucose levels compared with the control. The remainder of the area under the blood glucose concentration time curve between the control (RAUC) in the case of 40 mg GC suppository was 1.3 times larger than that of the 4 mg GC suppository. The GC suppositories sufficiently lowered the blood glucose levels. These results suggest that the GC suppositories should be useful in the hospital preparation for the treatment of NIDDM patients.

Animals↗
PubMed1988

Pharmacokinetics of midazolam and alpha-hydroxy-midazolam following rectal and intravenous administration.

1. In an open cross-over trial, plasma concentrations of midazolam were measured in eight healthy male volunteers following administration of 0.3 mg kg-1 body weight given by the rectal and intravenous routes. 2. Maximum plasma concentrations of 92-156 ng ml-1 (mean 118 ng ml-1) were recorded from 20 to 50 min (mean 31 min) after rectal application. The rectal bioavailability was 40-65% (mean 52%) and the terminal half-life was 114-305 min (mean 161 min). 3. A substantial first-pass hepatic effect was observed following rectal administration. 4. No systemic or local intolerance was noted. 5. In conclusion, the rectal route of administration provides a rapid and reliable absorption of midazolam.

Administration, Rectal↗
PubMed1976

Congenital chloridorrhoea. A question of reversed brush border transport processes and varying junctional tightness.

The surprising results of intestinal perfusion studies in an 8-month-old child with congenital chloridorrhoea offered a unique opportunity not only to elucidate the underlying defect, but also to test the adequacy of proposed models for normal intestinal transport. In ileum Na, K and Cl as well as water were secreted and HCO3 absorbed. Lumen was 91 mV negative to blood. Only Cl was transported against both electrical and chemical gradients, but discrepancies between observed and predicted Na flux ratios suggested the presence of a Na-absorbing mechanism as well. Mucosa was impermeable to Cl from the lumen side. 2.5 mM glycochenodeoxycholic acid (GCDC) mediated Na and water absorption and abolished any transport of Cl. PD was -95 mV. In colon a similar pattern was observed and mucosa to serosa fluxes of Cl were abnormally low. Rectal PD was -116 mV. GCDC made the epithelium more absorptive in function, but contrary to ileum the effect was due to an increase of Na and Cl fluxes from mucosa to serosa. The patient was at that time in severe electrolyte imbalance. He was reinvestigated three months later when he was in a good clinical condition with normal serum electrolytes. Net transfer of electrolytes and water and bidirectional fluxes of Cl and K were unchanged while bidirectional Na fluxes had increased considerably and PD decreased to -18 mV. Rectal PD was -45 mV. In jejunum water and electrolyte transport were normal and PD -3 mV. It is tentatively concluded that the abnormal transport in ileum is due to an inversion of the brush border transport processes, which also satisfies the paradoxical effects of GCDC. Furthermore, Na and Cl seem to migrate through separate pathways. A varying degree of junctional tightness, which is almost completely cationic, may be responsible for the functional differences observed in resonse to improvement of the general electrolyte status.

Biological Transport, Active↗
PubMed1991

Microemulsions for improved peptide absorption from the gastrointestinal tract.

Results on gastrointestinal absorption of three peptides, insulin, cyclosporin from microemulsions, obtained from studies in our laboratories during the past years have been summarized. The routes of administration were period, intralumenal or rectal. The experiments were carried out in dogs, rabbits and rats. An absorption model for peptides using microemulsions as delivery systems is presented.

Administration, Oral↗
PubMed1985

Suppositories containing cyclodextrin complexes. Part 2: Dissolution and absorption studies.

The dissolution and absorption of poorly water-soluble drugs from rectal suppositories can be enhanced by complexing these substances (e.g., essential oils, indomethacin) with beta-cyclodextrin. Preliminary in vivo studies showed, that the application of cyclodextrin complexes to suppositories, the same as to oral applications, resulted in an increased blood level.

Absorption↗
PubMed1978

Rectal administration of sodium valproate in status epilepticus.

Six patients suffering from status epilepticus were refractory to parenteral treatment with either diazepam, amobarbital or both, and were given sodium valproate 200 to 800 mg every 6 hours. The drug was administered rectally as 200 mg lipid-based suppositories, thereby avoiding impaired absorption, which occurs in the presence of paralytic ileus. Plasma levels of sodium valproate in all patients reached the therapeutic range within 36 hours of starting therapy. Seizures were totally controlled in five patients and a 75 percent reduction was noted in the sixth. In two patients, the route of administration was changed from rectal to an equivalent oral dose with continuing control of seizures and minimal change in plasma levels, suggesting that bioavailability is similar for the two forms of the drug. The rectal route of administration was effective in achieving systemic absorption of sodium valproate in the treatment of status epilepticus.

Adolescent↗
PubMed2002

Antiasthmatic drug delivery in children.

Asthma therapy can be administered to children via a number of routes, including oral, inhaled (via a multiplicity of devices), rectal, intravenous, subcutaneous, and intramuscular. The inhaled route is used most often. This can reduce, but never eliminate, systemic absorption. Swallowed aerosolized medication is subject to hepatic first-pass metabolism, but this metabolic route is bypassed by the drug impacting on the airway, including the pharynx. Although there are a large number of studies from a laboratory setting about drug deposition characteristics, there is very little evidence from community-based studies about what families think actually works well in the everyday treatment of the child. However, it is clear that altering the inhaler device can result in marked changes in the dose administered, and any such change should be part of a review of the dose of prescribed medication. Nebulizers are being used much less frequently, and in particular, all but the most severe exacerbations can be treated at least as effectively with equivalent dosages of beta(2)-adrenoceptor agonists from a large volume spacer.

Absorption↗
PubMed1992

Pharmacokinetics and absolute rectal bioavailability of hydrocortisone acetate in distal colitis.

The hydrocortisone pharmacokinetic profiles of hydrocortisone acetate foam (Proctocort) administered rectally was assessed in healthy volunteers and patients with ulcerative colitis or X-irradiation colitis. Endogenous production of hydrocortisone was suppressed by dexamethasone. Comparison of these data with those obtained after intravenous administration enabled assessment of absolute bioavailability, which was 30.0 +/- 15.1% in healthy volunteers vs. 16.4 +/- 14.8% in patients (P = 0.09). Maximal concentrations of hydrocortisone were also decreased in patients, 277 +/- 215 nmol/L vs. 610 +/- 334 nmol/L (P = 0.03). There was a nonsignificant tendency to faster absorption of hydrocortisone in patients vs. healthy volunteers, as the times to peak concentration were, respectively, 2.5 +/- 1.2 h vs. 2.8 +/- 0.8 h (P = 0.64), and the mean absorption times were 1.96 +/- 1.45 h vs. 2.54 +/- 1.62 h (P = 0.46). Thus, rectal inflammation resulted in a lower absorption of hydrocortisone. In addition systemic plasma levels remained in the physiological range, so that only minor side effects are to be expected.

Administration, Rectal↗
PubMed1992

Recurrent rectal cancer and scar: differentiation with PET and MR imaging.

The value of positron emission tomography (PET) and magnetic resonance (MR) imaging in differentiating recurrent rectal cancer and scar was investigated. PET with fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) and MR imaging were performed in 15 patients with suspected recurrence. FDG accumulation in the mass was measured by means of the differential absorption ratio (DAR). All 11 patients with confirmed recurrent rectal cancer had increased accumulation of FDG in the mass (DAR = 4.73 +/- 2.28). Low FDG accumulation in the mass (DAR = 0.97 +/- 0.15) was noted in the remaining four patients, in whom the presence of a scar was proved by means of follow-up observation with or without biopsy. On the MR images, the recurrent tumor could be differentiated from scar in all but one case. The lesion-muscle signal intensity ratios on the T2-weighted images for the recurrent tumor and scar were 2.18 +/- 0.55 and 0.89 +/- 0.30, respectively. PET and MR imaging complement each other in the differential diagnosis between recurrent rectal cancer and scar. PET may also permit the evaluation of the effect of therapy.

Adult↗
PubMed2003

Fecal acetate is inversely related to acetate absorption from the human rectum and distal colon.

In humans, colonic bacteria ferment unabsorbed carbohydrates, producing the SCFA acetic, propionic and n-butyric acids. To test for interactions among the SCFA that may affect their absorption, healthy subjects (n = 10) were given 300-mL rectal infusions containing acetate (60 mmol/L), propionate (20 mmol/L) and butyrate (20 mmol/L), alone or in combinations of two or three. The solutions were retained for 30 min, and then subjects voided a sample for SCFA measurement. To examine the relationship between absorption and fecal SCFA concentrations, a fecal sample was collected at the end of the study. The mean percentage of butyrate absorption (30.2 +/- 4.6%) exceeded that of acetate (24.1 +/- 3.7%) (P < 0.05). Absorption tended to be less (P = 0.12) when a SCFA was infused alone (26.7 +/- 4.0%) than when all three were infused (32.0 +/- 5.7%). Bicarbonate concentration was higher after butyrate-containing infusions than after saline. The fecal molar acetate percentage was inversely correlated with the percentage of acetate absorption from the infusion of three SCFA (r = -0.834, P < 0.005). We conclude that there was no combination effect on SCFA absorption, and the chain-length effect suggests passive diffusion as a likely mechanism of absorption. Furthermore, fecal acetate may reflect absorption, rather than production of colonic acetate.

Acetic Acid↗
PubMed2000

Pharmacokinetics of metronidazole in horses after intravenous, rectal and oral administration.

Metronidazole pharmacokinetics in horses was studied after intravenous (i.v.), rectal (p.r.) and oral (p.o.) administration at 20 mg/kg using a triple crossover study design. Metronidazole mean+/-SD half-life was 196+/-39, 212+/-30 and 240+/-65 min after i.v., p.r. and p.o. administration, respectively. The metronidazole clearance was 2.8 (mL/min/kg) and the volume of distribution at steady state was 0.68 L/kg. The pharmacokinetic parameters calculated for metronidazole after administration of the drug by the various routes showed that bioavailability (74+/-18 vs. 30+/-9%) and maximum serum concentration (22+/-8 vs. 9+/-2 microg /mL) were significantly higher after p.o. administration compared with p.r. administration. There were no significant differences in mean absorption time (45+/-69 vs. 66+/-18 min) and the time to reach maximum serum concentration (65+/-36 vs. 58+/-18 min). The results indicated that p.r. administration of metronidazole to horses, although inferior to p.o. administration in terms of bioavailability, provides an alternative route of administration when p.o. administration cannot be used.

Absorption↗
PubMed1997

Experiences with the rectal use of trimethoprim.

The possibility of rectal use of trimethoprim was studied. The in-vitro liberation of the drug from 24 different suppository bases was examined and the results used to select bases for in-vivo examination. The in-vitro liberation from the suppositories containing 50-200 mg trimethoprim was studied by the method of dynamic diffusion, and the released drug content was measured spectrophotometrically. The in-vivo examinations were performed in anaesthetized rats. The concentration of trimethoprim in blood was determined by bioassay. The absorption of the drug in the form of oral suspension, rectal solution and suppository was also studied. The pharmacokinetic parameters obtained after blood-level curve fitting were compared by use of the MedUSA 1.6 program. The best in-vivo results were achieved with the lipohydrophilic Witepsol W 35 vehicle containing 10% polysorbate 20 and 10% polysorbate 61 (bioavailability = 63.8%) and with Witepsol W 35 containing 10% polysorbate 60 (bioavailability = 63.8%). The results for hydrophilic Macrogol 1540 vehicle containing 5% of Macrogol 400 were only slightly worse (bioavailability = 52.9%). In the case of the lipohydrophilic Witepsol W 35 vehicle with 10% polysorbate 20 and 10% polysorbate 61 content a significant negative exponential relationship was found between the administered doses and their respective bioavailability values; this tendency was also observed during in-vitro examinations. When incorporated in the appropriate vehicle trimethoprim was absorbed well. With three vehicles the extent of absorption exceeded that for oral administration on the same model (bioavailability = 38.8%). Trimethoprim rectal suppositories, which are formulated with the vehicles having the best in-vitro and in-vivo results, are suitable for clinical pharmacological investigation.

Administration, Oral↗
PubMed2000

The innervation of human bowel mucosa and its alterations in Hirschsprung's disease using a whole-mount preparation technique.

The innervation of the human bowel wall and its structural and functional changes in Hirschsprung's disease (HD) are well-recognised. The luminal surface of the bowel acts as a multifunctional barrier, and modifications in its physiochemical properties can result in serious complications such as enterocolitis (EC). The whole-mount preparation (WMP) technique produces a three-dimensional (3D) picture to better demonstrate the neuronal networks and the relationship of branching and interconnecting nerve fibres to each other. The aim of this study was to investigate the innervation of the mucosal layer in normal and HD bowel using a WMP immunohistochemistry technique in order to better understand the pathophysiology of HD. Full-thickness bowel specimens were collected from 9 HD patients at pull-through operation. Normal control small- and large-bowel specimens were collected from 10 patients at the time of bladder augmentation. Suction rectal biopsies from 8 patients with chronic constipation and 2 patients with HD were also included in this study. A WMP of the mucosal layer was made and stained with various neuronal markers (S100, PGP 9.5, and LICAM) using fluorescein immunohistochemistry. PGP 9.5, S100, and L1CAM immunofluorescence staining of the normal mucosa demonstrated a characteristic 3D meshlike neuronal network of uniform thickness surrounding the crypts. In the aganglionic bowel S100, PGP 9.5, and L1CAM-positive meshlike networks were replaced by thick nerve trunks in the muscosa without any interconnecting network. The present study demonstrates for the first time the 3D morphology of mucosal innervation in normal and aganglionic bowel. The WMP technique clearly demonstrated that the mucosal innervation in HD is morphologically abnormal, and this may adversely influence secretory and absorptive functions of the bowel. WMPs using suction rectal biopsy specimens may be a useful additional technique to diagnose HD.

Antigens, Differentiation↗
PubMed1996

Comparative bioavailability of oral, rectal, and intramuscular artemether in healthy subjects: use of simultaneous measurement by high performance liquid chromatography and bioassay.

1. The pharmacokinetic and effect kinetic properties of oral (p.o.), intramuscular (i.m.), and intrarectal (i.r.) artemether (5 mg kg-1) were compared in a crossover study in eight healthy adult volunteers. Plasma concentrations of artemether (AM) and its active metabolite dihydroartemisinin (DHA) were measured by high performance liquid chromatography with reductive mode electrochemical detection (h.p.l.c.-ECD), and plasma antimalarial activity in vitro (effect) was assessed on the same samples by a sensitive bioassay (BA). 2. Artemether was absorbed rapidly after oral administration with a mean (95% CI) Cmax for the parent compound of 406 (249 to 561) nmol l-1 and for DHA of 1009 (639 to 1379) nmol l-1 with tmax values of 1.7 (1.2 to 2.2) and 1.8 (1.4 to 2.2) h respectively. The mean (95% CI) elimination half-life of AM was 2.6 (1.8 to 3.4) h and for DHA was 1.9 (1.4 to 2.4) h. Plasma concentration and effect profiles with h.p.l.c.-ECD and BA were similar suggesting that other unidentified bioactive metabolites contributed little to antimalarial activity in vivo. 3. Absorption was slower, more variable, and DHA concentrations were lower following the i.m. and i.r. routes of administration. The mean (95% CI) relative bioavailability compared with oral artemether in the 6 h following administration AUC (0.6h) was 25 (9 to 41)% following i.m. and 35 (10 to 60)% following i.r. artemether. 4. These data demonstrate that oral artemether undergoes extensive first pass metabolism to the more active metabolite DHA. Plasma antimalarial activity following oral administration is significantly greater than following i.m. administration. The i.r. route of administration provided similar bioavailability to i.m. injection but there was considerable variability in absorption following both routes. Further studies are needed to determine whether i.r. artemether would be an effective treatment of severe malaria in the rural tropics in situations where oral or parenteral administration is not possible.

Absorption↗
PubMed1992

Indomethacin worsens and a leukotriene biosynthesis inhibitor accelerates mucosal healing in rat colitis.

The implication of leukotrienes as mediators of inflammation and recent evidence that prostaglandin analogues provide a beneficial effect during experimental colitis led to the speculation that (i) leukotrienes may be injurious and (ii) prostaglandins may be protective to colonic mucosa. Using a 2% acetic acid induced rat colitis model, we administered specific cyclooxygenase (indomethacin) and leukotriene biosynthesis inhibitors (MK-886) to examine the effect of endogenous prostaglandins and leukotrienes on colonic macroscopic injury, mucosal inflammation as measured by myeloperoxidase activity, net in vivo intestinal fluid absorption, and colonic PGE2 and LTB4 levels as measured by in vivo rectal dialysis. Indomethacin treatment prior to induction of colitis reduced endogenous mucosal PGE2 levels and exacerbated macroscopic ulceration and net fluid absorption. Addition of the exogenous PGE1 analogue misoprostol to the indomethacin-exacerbated colitis completely healed colonic macroscopic ulceration and inflammation but only partially improved fluid absorptive injury. The specific leukotriene biosynthesis inhibitor MK-886 administered prior to induction of colitis healed macroscopic ulceration and inflammation but not fluid absorptive injury. This mucosal reparative effect of MK-886 occurred at a dose that reduced colonic LTB4 synthesis while concomitantly enhancing PGE2 levels. Combining MK-886 with misoprostol treatment improved not only macroscopic ulceration and inflammation but also provided a synergistic effect that maintained net colonic fluid absorption at noncolitic control levels. These studies suggest that, during the induction of experimental colitis, endogenous prostaglandins play a pivotal role in providing a mucosal healing effect, and that leukotriene biosynthesis inhibitor may manifest part of its beneficial effect by shifting arachidonic acid metabolism towards production of prostaglandins.

Acetates↗
PubMed1985

[13C]Acetate oxidation in infants after oral versus rectal administration: a kinetic model.

To study the fate of volatile fatty acids (VFA) in the large bowel, we compared the rate of oxidation of 13C-labeled VFA administered rectally with that of the orally administered substrate. On two different days, 1-[13C]acetate was administered rectally or orally to five infants recovering from diarrhea. Breath samples were collected over 4 h and analyzed for 13C enrichment of breath CO2 by gas isotope ratio mass spectrometry. The percent dose recoveries of 13C in breath were fitted to multicompartmental models using the SAAM-27 program. Following model development procedures, the oral acetate breath test curves could be accounted for only by a compartmental model in which labeled acetate underwent absorption into and mixed with a systemic pool before oxidation took place. The rectal acetate breath test curves could be accounted for by a simpler model in which oxidation occurred directly in the compartment in which the rectal acetate was administered, and required no rate-limiting absorptive process. Our results indicate that the labeled acetate was oxidized more rapidly when the substrate was administered rectally than orally. This observation points to the direct utilization of volatile fatty acids within the colon.

Acetates↗