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PubMed2002

Antigen delivery to mucosa-associated lymphoid tissues using liposomes as a carrier.

Oral vaccination requires an antigen delivery vehicle to protect the antigen and to enhance translocation of the antigen to the mucosa-associated lymphoid tissue. A variety of antigen delivery vehicles including liposomes have been studied for mucosal immunization. The advantages of liposome formulations are their particulate form and the ability to accommodate immunomodulators and targeting molecules in the same package. Many conventional liposomes are variably unstable in acids, pancreatic juice and bile. Nevertheless, carefully designed liposomes have demonstrated an impressive efficacy in inducing mucosal IgA responses, compared to free antigens and other delivery vehicles. However, liposomes as an oral vaccine vehicle are not yet optimized. To design liposomes that are stable in the harsh intestinal environment and are efficiently taken up by the M cells remains a challenge. This review summarizes recent research efforts using liposomes as an antigen carrier for oral vaccines with practical attention to liposome designs and interaction with the M cells.

Adjuvants, Immunologic↗
PubMed2000

Alosetron.

Alosetron is a potent and highly selective serotonin 5-HT3 receptor antagonist which has been evaluated for the management of irritable bowel syndrome (IBS). It blocked the fast 5HT3-mediated depolarisation of guinea-pig myenteric and submucosal neurons in vitro, with half-maximal inhibition at approximately 55 nmol/L. Alosetron attenuated the visceral nociceptive effect of rectal distension in conscious or anaesthetised dogs. It increased the compliance of the colon to distension in patients with IBS and delayed colonic transit in patients with IBS or carcinoid diarrhoea and in healthy volunteers. A single dose of alosetron 4 mg increased in vivo fluid absorption in normal human small intestine. In clinical trials in patients with IBS, alosetron 1 mg twice daily was effective in relieving abdominal pain and discomfort. Alosetron was most effective in female patients and particularly in those with diarrhoea-predominant IBS. In patients with IBS and healthy volunteers who received alosetron, the most common adverse event was constipation.

Adult↗
PubMed2000

Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects.

The pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories at three dosage strengths and oral syrup were studied. The study had an open-label, randomized, crossover design. At intervals of five to nine days, healthy volunteers were given two 12.5-mg promethazine rectal suppositories, one 25-mg suppository, one 50-mg suppository, or 50 mg (10 mL) of promethazine oral syrup. Blood samples were collected before each dose and at intervals from 0.5 to 48 hours afterward. Promethazine concentration was determined by high-performance liquid chromatography, and pharmacokinetic values were calculated with noncompartmental methods. Thirty-six subjects (18 men and 18 women) completed the study. Absorption was highly variable for all the formulations. On average, absorption was more rapid and the maximum plasma concentration (Cmax) higher for the syrup than for the suppositories. Cmax was significantly lower for the 50-mg suppository (mean, 9.04 ng/mL) than for the syrup (19.3 ng/mL). The time to Cmax (tmax) was significantly shorter for the syrup (mean, 4.4 hours) than for the suppositories (6.7-8.6 hours). There were no significant differences in dose-normalized Cmax among the three suppository treatments. Area under the concentration-versus-time curve (AUC) was comparable between the syrup and the 50-mg suppository and between the treatments with two 12.5-mg suppositories and the 25-mg suppository. Elimination profiles were similar among all treatments (mean half-life [t1/2], 16-19 hours). There were no significant differences in pharmacokinetics on the basis of sex or race. The mean relative bioavailability for the three suppository treatments ranged from 70% to 97%. Individual relative bioavailabilities ranged from 4% to 343%. The pharmacokinetics of promethazine administered in oral syrup and rectal suppositories were highly variable, but, in general, the suppositories produced a lower Cmax and later tmax than the syrup. All formulations were comparable in terms of dose-normalized AUC and t1/2, and the three suppository treatments were comparable in terms of dose-normalized Cmax.

Administration, Oral↗
PubMed1993

Transmucosal delivery of leucine enkephalin: stabilization in rabbit enzyme extracts and enhancement of permeation through mucosae.

Leucine enkephalin (Tyr-Gly-Gly-Phe-Leu; Leu-Enk) is a naturally occurring peptide that has been shown to have pain modulating properties. To evaluate the feasibility of using various absorptive mucosae as a route of systemic delivery, the stability of Leu-Enk and the effect of enzyme inhibitors (e.g., amastatin, EDTA, and thimerosal) on stabilization and permeation of Leu-Enk through rabbit mucosae in the presence of dihydrofusidates were investigated. Enzymes in the nasal, rectal, and vaginal mucosae were extracted and Leu-Enk (50 micrograms/mL) was added to each of the enzyme extracts and incubated to determine the kinetics and mechanism of degradation. The rate of degradation in the extracts in the absence of inhibitors followed the order: rectal > vaginal > nasal. Whereas EDTA had the best stabilizing effect on Leu-Enk, thimerosal was the best stabilizer for the degradation intermediates. A combination of amastatin (50 microM), EDTA (5 mM), and thimerosal (50 microM) had the greatest stabilizing effect on Leu-Enk and its degradation intermediates. For permeation studies, each mucosa was mounted onto a Valia-Chien permeation cell with Leu-Enk (200 micrograms/mL) in isotonic phosphate buffer (as donor solution). The enhancers used for the study were sodium tauro-dihydrofusidate (STDHF), sodium glycodihydrofusidate (SGDHF), and phosphato-dihydrofusidate (PHDHF). The greatest effect was achieved by PHDHF for all the mucosae. STDHF had a significant effect only on the rectal permeation, whereas SGDHF had significant effects on rectal and vaginal mucosae. Mechanisms by which the dihydrofusidates enhance permeating may involve micelle formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1986

Increased permeability to polyethylene glycol 4000 in rabbits with experimental colitis.

Little information is available regarding colonic permeability to macromolecules in health or disease states. In vivo permeability of rabbit colon to [14C]polyethylene glycol 4000 (14C-PEG) was examined in the presence of immune complex-mediated experimental colitis and compared with that of partially treated (control) and normal rabbits. Permeability was assessed by urinary 14C-PEG excretion after intrarectal administration of 0.1 mM solution of 14C-PEG (1 ml/kg, 7.5 X 10(6) cpm/ml). Experimental colitis greatly increased colonic permeability (p less than 0.001 in two-way analysis of variance) compared with control and normal groups (2.06% +/- 0.19%, 0.14% +/- 0.04%, and 0.01% +/- 0.004%, respectively, of rectally administered counts). Gel diffusion chromatography showed that absorbed 14C-PEG was excreted into urine unchanged, demonstrating its applicability as an inert, nonmetabolizable macromolecular probe. Urinary clearance after mesenteric vein administration of 14C-PEG was similar in normal animals and animals with colitis, implicating colonic absorption as the source of the group differences. Postmortem histology confirmed the acute colitis lesions in the experimental group. These findings support the hypothesis that nonspecific colonic inflammation is associated with significant alterations of mucosal permeability.

Animals↗
PubMed1988

Bacterial lipopolysaccharide-induced intestinal microvascular lesions leading to acute diarrhea.

Subcutaneous challenge of mice with lipopolysaccharide (LPS) from gram negative bacteria, produced an intestinal microvascular lesion causing fluid exudation into the lumen of the intestine and diarrhea. The microvascular lesion was characterized by endothelial cell damage and microthrombi in the venules and capillaries of the intestinal lamina propria. Marker organisms, given orally to challenged mice, grew in the exuded fluid and could invade the mucosa. Intravenous transfer of postchallenge plasma produced the lesion in normal mice and absorption of such plasma by Sepharose coupled to LPS-antibody abolished this effect. Instillation of large quantities of LPS into the lumen of the intestine produced scattered microvascular lesions, although none of these animals developed diarrhea. Since a similar microvascular lesion has been described in the rectal mucosal lamina propria of adults with acute diarrhea, it is suggested that LPS-induced vascular damage may be a novel mechanism in the pathogenesis of acute diarrhea.

Acute Disease↗
PubMed2004

Pathogenesis of slow transit and pelvic floor dysfunction: from bench to bedside.

The colon and anorectum function together to provide intraluminal mixing, absorption of water, electrolytes, and short chain fatty acids, dehydration of fecal material, storage, and ultimately, elimination in a socially appropriate manner. Normal function and continence require accommodation of the colon and rectum to the entry of fecal materials, which includes receptive relaxation, perception, and discrimination of rectal contents, and voluntary and reflex motor function of the anorectum. Defecation, on the other hand, requires the reflex relaxation of the internal anal sphincter, voluntary and reflexive relaxation of the external anal sphincters and pelvic floor structures, and adequate rectosigmoid tone to allow funneling of contents through the anal canal. The sensation of urgency with rectal filling, and the motivation and prior learning of the appropriate responses are also required. Continence and defecation, therefore, involve complex sensory, structural, and motor mechanisms that involve both the colon and pelvic floor. These mechanisms and their relative importance to the pathogenesis of slow-transit constipation and pelvic floor dysfunction will be reviewed.

Chronic Disease↗
PubMed1983

[Experimental and clinical evaluation of an ampicillin suppository (KS-R1)].

The basic and clinical studies of ampicillin suppository (KS-R1) in pediatric infections were carried out, and the following results were obtained: For study of absorption and excretion of KS-R1, a single dose of 250 mg of KS-R1 was administered to 3 cases. The mean serum levels were obtained 4.10 +/- 1.55 micrograms/ml at 30 minutes, and 1.52 +/- 0.25 micrograms/ml, 0.38 +/- 0.04 micrograms/ml at 1 and 2 hours after rectal administration, respectively. The serum levels were not detectable after 4 hours in all cases. The half lives were 0.39, 0.54 hour and 0.44 hour, respectively. The mean urinary excretion rate to 6 hours was 14.8%. Clinical efficacy was evaluated in 17 cases with tonsillitis (15 cases), bronchitis (1 case) and scarlet fever (1 case). Good responses were obtained in 15 of 17 cases (88.2%). Bacteriological response in the form of eradication was noted in 4 of 5 cases. Side effects were examined with all of the 19 cases, and eosinophilia was observed in 1 case.

Age Factors↗
PubMed1998

Regional brain heating during microwave exposure (2.06 GHz), warm-water immersion, environmental heating and exercise.

Nonuniform heating may result from microwave (MW) irradiation of tissues and is therefore important to investigate in terms of health and safety issues. Hypothalamic (Thyp), cortical (Tctx), tympanic (Tty), and rectal (Tre) temperatures were measured in rats exposed in the far field, k-polarization (i.e., head pointed toward the transmitter horn and E-field in vertical direction) to two power densities of 2.06 GHz irradiation. The high-power density (HPM) was 1700 mW/cm2 [specific absorption rate (SAR): hypothalamus 1224 W/kg; cortex 493 W/kg]; the low-power density (LPM) was 170 mW/cm2 (SAR: hypothalamus 122.4 W/kg; cortex 49.3 W/kg). The increase (rate-of-rise, in degrees C/s) in Thyp was significantly greater than those in Tctx or Tre when rats were exposed to HPM. LPM produced more homogeneous heating. Quantitatively similar results were observed whether rats were implanted with probes in two brain sites or a single probe in one or the other of the two sites. The qualitative difference between regional brain heating was maintained during unrestrained exposure to HPM in the h-polarization (i.e., body parallel to magnetic field). To compare the temperature changes during MW irradiation with those produced by other modalities of heating, rats were immersed in warm water (44 degrees C, WWI); exposed to a warm ambient environment (50 degrees C, WSED); or exercised on a treadmill (17 m/min 8% grade) in a warm ambient environment (35 degrees C, WEX). WWI produced uniform heating in the regions measured. Similar rates-of-rise occurred among regions following WSED or WEX, thus maintaining the pre-existing gradient between Thyp and Tctx These data indicate that HPM produced a 2-2.5-fold difference in the rate-of-heating within brain regions that were separated by only a few millimeters. In contrast, more homogeneous heating was recorded during LPM or nonmicrowave modalities of heating.

Animals↗
PubMed1994

Biopharmaceutical aspects of tolfenamic acid.

The pharmacokinetics of tolfenamic acid is well described by a two-compartment model with relatively short half-lives (T/2 beta 1-2 hours) and tolfenamic acid is highly protein-bound with small volumes of distribution. It is cleared relatively fast (150-200 ml/min), mainly by hepatic metabolism and the metabolites are renally cleared as glucuronic acid conjugates. The peroral absorption is good and the peroral bioavailability is about 75%, as first pass metabolism accounts for about 20%. Tolfenamic acid shows linear pharmacokinetics and during multiple dosage regimen, i.e. thrice daily, no accumulation beyond the second dose is observed. The bioavailability in dependence of age and disease has been studied and only in the case of severe liver or kidney impairment, a change in dosage regimen seems warranted. The development of different formulations will be outlined, mainly on rectal delivery, on sustained release and rapid release oral formulations, on topical ointment, and on parenteral delivery. The problems with tolfenamic acid in pharmaceutical formulation caused mainly by poor solubility will be discussed. Formulations ready for the market now or very soon are Clotam capsules (tablets). Clotam retard tablets, Clotam suppositories, and Clotam oral suspension, whereas rapid tablets, topical ointments, and parenteral formulations need further development to be ready for marketing in the years to come.

Absorption↗
PubMed1995

Thermally gelling poloxamine Synperonic T908 solution as a vehicle for rectal drug delivery.

Thermally reversible gels of the block copolymer, Synperonic T908, have been evaluated as vehicles for the rectal administration of indomethacin. Prolonged plasma levels of indomethacin following rectal administration in such gels was observed with the 40% w/w Synperonic T908 gels when compared with commercial suppositories. The release rate decreased with an increase in gel concentration over the range 30% to 40% w/w. Histological observation showed no damage to the rectal mucosal membrane in animals at 6 h after the administration of a 40% w/w gel.

Animals↗
PubMed1984

The rabbit as an experimental model for biopharmaceutical studies following rectal administration of theophylline.

In order to find a suitable animal model for biopharmaceutical studies after rectal application of theophylline, the pharmacokinetics of theophylline following the administration in rabbits of three different rectal preparations were examined and compared with those of the oral and i. v. route. No significant formulation related impact from the studied rectal dosage forms on the bioavailability of the drug was found. However, the unexpected rapid achievement of peak serum concentration after insertion of the suppository lacked any correlation with human experiments. It was concluded that the evaluation of rectal theophylline medication for man cannot directly be based on the data obtained from rabbits.

Administration, Oral↗
PubMed2006

Bioavailability and therapeutic activity of alicaforsen (ISIS 2302) administered as a rectal retention enema to subjects with active ulcerative colitis.

BACKGROUND: Alicaforsen is a phosphorothioate-modified antisense oligodeoxynucleotide designed to sequence-specifically reduce intercellular adhesion molecule 1 messenger RNA levels. AIMS: To determine the systemic and local bioavailability of alicaforsen, and its activity when administered as a once daily enema in subjects with active ulcerative colitis. METHODS An open-label study was conducted to assess the relative absorption (local and systemic pharmacokinetics) and pharmacologic activity of alicaforsen enema in subjects with active ulcerative colitis. Fifteen subjects received nightly enemas of alicaforsen (240 mg) for a treatment period of 6 weeks. Alicaforsen concentrations in plasma and colonic tissue biopsies were determined. Disease activity index and multiple measurements including endoscopy were used to assess alicaforsen activity in these subjects. RESULTS: Plasma concentrations of parent alicaforsen represented < 0.6% mean bioavailability when compared with historical intravenous area under the plasma concentration-time curves. Concentrations of the intact oligonucleotide in mucosal colonic tissue biopsies were orders of magnitude higher than those observed in plasma. A 46% reduction in mean Disease Activity Index and 33% rate of remission as defined by complete mucosal healing were observed at the end of treatment. Conclusion These data confirm that alicaforsen enema provides local treatment for a local disease with little meaningful systemic exposure.

Absorption↗
PubMed1995

Comparative effectiveness of hypothermia rewarming techniques: radio frequency energy vs. warm water.

The purpose of this study was to compare the rewarming effectiveness of a radio frequency coil (13.56 MHz) at a specific absorption rate (SAR) of 2.5 W/kg (RF) with warm water immersion (40 degrees C) (WW) and an insulated mummy-type insulating sack (IS) under simulated field conditions. Four male subjects, ages 24-35, were immersed in 10 degrees C water for up to 90 min or until their rectal temperatures (Tre) decreased to 35 degrees C. Each subject had 3 trials in which they were immersed. After each immersion, rewarming was accomplished with either RF, WW, or IS, so that each subject was rewarmed once with each method. Comparisons of the 3 rewarming methods were based on the rate of increase of Tre during rewarming (Tre/t), Tre 60 min after the start of rewarming (Tre60), the time-interval measured from extraction from the water to the end of afterdrop (tad), and the magnitude of any observed Tre afterdrop (Tad). WW had significantly greater Tre/t and Tre60 than either RF or IS (P < 0.03) and a smaller tad than IS (P < 0.05). IS had significantly greater Tad than either WW or RF (P < 0.05). No significant differences in Tre/t, Tre60, or tad were observed between IS and RF. The results of this study indicate that for mildly hypothermic individuals, active rewarming with RF at a SAR of 2.5 W/kg is less effective than WW and roughly equivalent to passive rewarming with IS.

Adult↗
PubMed1981

Ileal mucosal morphology after total colectomy in man.

The structure of human terminal ileum mucosa was studied both after total colectomy and conventional ileostomy and after total colectomy and ileo-rectal anastomosis. Villous height, gland depth, number of mitoses, relative density of goblet cells and types of mucins secreted were microscopically evaluated in ileal biopsy specimens from 24 patients a minimum 6 months after surgery. Subtotal villous atrophy with glandular hypertrophy was demonstrated after both surgical procedures. The degree of villous atrophy and glandular hypertrophy was not dependent either on the disease for which surgery was performed, nor on the duration of the post-surgical period. Villous atrophy and glandular hypertrophy appeared greater in ileo-rectal anastomosis specimens than in those from ileostomy. Goblet cell density did not seem to be affected by total colectomy. After surgery no changes in the types of mucins secreted were shown by the histochemical techniques employed. This light microscopical study did not provide any evidence of increase ileal absorptive surface after total colectomy.

Adolescent↗
PubMed1999

Light and electron microscopic study of the hindgut of the ant (Formica nigricans, hymenoptera): I. Structure of the ileum.

The study of the ileum of the ant Formica nigricans by light and electron microscopy revealed the existence of three differentiated regions: proximal, middle, and distal ileum. The middle region constitutes most of the length of the organ. Its wall is made up by a folded simple epithelium lined by a cuticle, which is surrounded by an inner circular muscle layer and various external longitudinal muscle fibers adjacent to the hemolymph. A subepithelial space is present between the epithelium and the circular muscle layer. Epithelial cells show extensive infoldings of the apical, and to a lesser extent the basolateral plasma membrane. Apical infoldings are characterized by the presence of 10-nm particles (portasomes) covering the cytoplasmic side of the membrane. Mitochondria are abundant throughout the cytoplasm, although they mainly are present underneath the apical infoldings. Lateral borders of epithelial cells display an apical junctional complex, mainly constituted by a long and convoluted pleated septate junction. These features support the view that epithelial cells in the middle ileum are specialized in ion solutes and water transport. The proximal ileum connects with the ampulla into which the Malpighian tubules drain. As opposed to the middle ileum, epithelial cells of the proximal ileum show less developed basolateral infoldings, and the apical plasma membrane is devoid of portasomes and only occasionally invaginates. These features suggest that the proximal ileum plays no relevant role in ion and water transport. The distal ileum penetrates into the rectal sac, forming a valve-like structure; this region presumably controls the amount of urine reaching the rectum.

Animals↗
PubMed1995

Effects of moisture absorption by clothing on thermal responses during intermittent exercise at 24 degrees C.

The effects of two kinds of clothing with different properties with respect to moisture absorption on thermophysiological responses and pulse rate were studied during intermittent exercise at an ambient temperature (Ta) of 24 degrees C. The two kinds of clothing ensemble tested were cotton T-shirt with short sleeves and cotton long-sleeved working dress with full-length trousers (C), and polyester T-shirt with short sleeves and polyester long-sleeved working dress with full-length trousers (P), the thermal resistances of which were nearly equal. Five women aged 21-32 years, served as subjects. The environmental conditions were 24 degrees C Ta, 50% relative humidity and 0.14 m.s-1 air velocity. The subjects, wearing either C or P, exercised for 10-min on a cycle ergometer at an intensity of 30% maximal oxygen uptake and then 10-min rest. This sequence was repeated four times. Rectal and skin temperatures at several sites, local sweating rate, pulse rate and clothing microclimates were continuously compared between C and P throughout the experiment. The major findings were firstly, rectal temperature rose significantly higher in P; secondly, pulse rate was higher in P both during exercise and rest; thirdly, clothing surface temperature on the back rose highly significantly during the fourth exercise period and then fell significantly during the fourth rest period in C; and fourthly, four out of five subjects felt wetter in P during the latter half of the experiment. These results are discussed from the viewpoint that the reduced thermal insulation due to the absorption of moisture in C accelerated dry heat loss, resulting in an inhibition of the increases in core temperature and pulse rate.

Absorption↗
PubMed1987

Mechanism of enhanced transcellular potassium-secretion in man with chronic renal failure.

Previous studies from our laboratory demonstrated that net K secretion in human rectum was 2.5-fold higher in patients with chronic renal failure than in controls. The present study was performed to determine whether K secretion in human large intestine involves an active process and whether an active transport process accounts, at least in part, for the rise in net K secretion in patients with renal insufficiency. Studies were performed under conditions when net water and electrolyte transport approached zero, and the observed distribution of K and Na across the rectal mucosa was compared to expected equilibrium values. In control subjects an active transport of 27.6 +/- 2.6 mV was observed for K and 63 +/- 4.2 mV for Na. Similar values were demonstrated in patients with chronic renal failure. The results of these studies demonstrated that net secretion of K and absorption of Na are governed, at least in part, by active transport processes, and suggest that, since active K secretion is not impaired, the rise in net K secretion in patients with renal insufficiency is caused by active secretion as well as by passive driving forces.

Biological Transport, Active↗