(1/279) Lack of absorption of didanosine after rectal administration in human immunodeficiency virus-infected patients.
The feasibility of rectal administration of didanosine (DDI) was studied in six human immunodeficiency virus-infected patients. After oral intake of a DDI solution (100 mg/m2 of body surface area) combined with an antacid (Maalox), pharmacokinetic parametric values were in accordance with previously published data; the mean +/- standard deviation for terminal half-life was 59.5 +/- 15.0 min, that for peak concentration was 5.2 +/- 3.9 mumol/liter, and that for the area under the time-concentration curve (AUC) was 494 +/- 412 min.mumol/liter. After rectal administration of a similarly prepared DDI solution (100 mg/m2 of body surface area), plasma DDI levels were below the detection limit (0.1 mumol/liter) at all time points in five of the six patients, and in the remaining patient the AUC after rectal application was only 5% of that after oral administration. We conclude that oral administration of DDI cannot be easily replaced by rectal application. (+info)
(2/279) Mucosal vaccination strategies for women.
Women were immunized orally, rectally, or vaginally with a recombinant cholera toxin B-containing vaccine to determine which of these mucosal immunization routes generate the greatest levels of antibody in the female genital tract and rectum. ELISA was used to measure concentrations of cholera toxin B-specific IgA and IgG antibody in serum and secretions before and after three immunizations. Each immunization route similarly increased specific IgG in serum and specific IgA in saliva. Only the vaginal route increased IgA antibodies in genital tract secretions and could be shown to induce a local IgG response. However, vaginal immunization failed to produce antibody in the rectum. In a similar fashion, rectal immunization elicited highest concentrations of locally derived IgA and IgG antibody in the rectum but was ineffective for generating antibody in the genital tract. The data suggest that local immunization may induce the greatest immune responses in the female genital tract and rectum of humans. (+info)
(3/279) Trefoil peptide TFF2 (spasmolytic polypeptide) potently accelerates healing and reduces inflammation in a rat model of colitis.
BACKGROUND: The trefoil peptides are major secretory products of mucus cells of the gastrointestinal tract and show increased expression after inflammatory or ulcerative damage. Recombinant human TFF2 (spasmolytic polypeptide) has been shown to be cytoprotective, and enhances repair in models of gastric injury. AIMS: To test the healing effects of recombinant human (h)TFF2 in a rat model of chronic colitis. METHODS: Colitis was induced by intracolonic administration of dinitrobenzene sulphonic acid in ethanol. Mucosal repair was quantified macroscopically, microscopically by image analysis of tissue histology, and by measuring myeloperoxidase activity. RESULTS: Initial validation studies showed that maximal injury and inflammation occurred at the end of the first week after colitis induction (active phase), and that spontaneous healing was complete by eight weeks. Once daily intrarectal application of hTFF2 (2.5 mg/kg; approximately 0.5 mg/rat) for five days after maximal damage had been sustained, reduced both microscopic and macroscopic injury by 80% and inflammatory index by 50% compared with vehicle controls. In addition, endogenous concentrations of rat TFF2 and TFF3 (intestinal trefoil factor) were increased in the active phase of colitis and were reduced to basal levels by hTFF2 treatment. CONCLUSIONS: This study has shown that hTFF2 enhances the rate of colonic epithelial repair, and reduces local inflammation in a rat model of colitis, and suggests that luminal application of trefoil peptides may have therapeutic potential in the treatment of inflammatory bowel disease. (+info)
(4/279) Efficient gene delivery to the inflamed colon by local administration of recombinant adenoviruses with normal or modified fibre structure.
BACKGROUND/AIMS: Replication deficient recombinant adenoviruses represent an efficient means of transferring genes in vivo into a wide variety of dividing and quiescent cells from many different organs. Although the gastrointestinal tract is a potentially attractive target for gene therapy approaches, only a few studies on the use of viral gene transfer vehicles in the gut have been reported. The prospects of using recombinant adenoviruses for gene delivery into epithelial and subepithelial cells of the normal and inflamed colon are here analysed. METHODS: An E1/E3 deleted recombinant adenovirus (denoted AdCMVbetaGal) and an adenovirus with modified fibre structure (denoted AdZ.F(pk7)) both expressing the bacterial lacZ gene under the control of a human cytomegalovirus promoter were used for reporter gene expression in vitro and in vivo. beta-Galactosidase activity was determined by specific chemiluminescent reporter gene assay. RESULTS: Intravenous or intraperitoneal injection of AdCMVbetaGal into healthy Balb/c mice caused strong reporter gene expression in the liver and spleen but not in the colon. In contrast, local administration of AdCMVbetaGal resulted in high reporter gene expression in colonic epithelial cells and lamina propria mononuclear cells. A local route of adenovirus administration in mice with experimental colitis induced by the hapten reagent trinitrobenzenesulphonic acid was next evaluated. Interestingly, rectal administration of AdCMVbetaGal caused a higher beta-galactosidase activity in isolated lamina propria cells from infected mice with experimental colitis than in those from controls. Furthermore, isolated lamina propria cells from mice with colitis infected in vitro showed a significant increase in reporter gene activity compared with controls. Finally, AdZ.F(pk7) adenoviruses with modified fibre structure produced 10- to 40-fold higher reporter gene activity in spleen T cells and lamina propria mononuclear cells of colitic mice compared with standard AdCMVbetaGal vectors. CONCLUSIONS: Local administration of recombinant adenoviruses with normal or modified fibre structure could provide a new reliable method for targeted gene expression in the inflamed colon. Such gene delivery could be used to specifically express signal transduction proteins with therapeutic potential in inflamed colonic tissue. In particular, adenoviruses with modified fibre structure may be useful in T cell directed therapies in intestinal inflammation. (+info)
(5/279) Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates.
AIM: To investigate the pharmacokinetics, metabolism, and dose-response relation of a single rectal dose of paracetamol in preterm infants in two different age groups. METHODS: Preterm infants stratified by gestational age groups 28-32 weeks (group 1) and 32-36 weeks (group 2) undergoing painful procedures were included in this study. Pain was assessed using a modified facies pain score. RESULTS: Twenty one infants in group 1 and seven in group 2 were given a single rectal dose of 20 mg/kg body weight. Therapeutic concentrations were reached in 16/21 and 1/7 infants in groups 1 and 2, respectively. Peak serum concentrations were significantly higher in group 1. Median time to reach peak concentrations was similar in the two groups. As serum concentration was still in the therapeutic range for some infants in group 1, elimination half life (T1/2) could not be determined in all infants: T1/2 was 11.0 +/- 5.7 in 11 infants in group 1 and 4.8 +/- 1.2 hours in group 2. Urinary excretion was mainly as paracetamol sulphate. The glucuronide:sulphate ratio was 0.12 +/- 0.09 (group 1) and 0.28 +/- 0.35 (group 2). The pain score did not correlate with therapeutic concentrations. CONCLUSIONS: A 20 mg/kg single dose of paracetamol can be safely given to preterm infants in whom sulphation is the major pathway of excretion. Multiple doses in 28-32 week old neonates would require an interval of more than 8 hours to prevent progressively increasing serum concentrations. (+info)
(6/279) Anatomic segmentation of the intestinal immune response in nonhuman primates: differential distribution of B cells after oral and rectal immunizations to sites defined by their source of vascularization.
We show that the distribution of specific antibodies and antibody-secreting cells in the intestine after oral and rectal immunizations corresponds to the vascularization and lymph drainage patterns of the gut. Oral immunizations induce antibody responses along the parts of the intestine connected to the superior mesenteric vessels and lymph ducts, whereas rectal immunizations induce antibody responses along the parts of the intestine associated with the inferior mesenteric vessels and ducts. (+info)
(7/279) Rectally administered dimenhydrinate reduces postoperative vomiting in children after strabismus surgery.
We have investigated the effectiveness of rectally administered dimenhydrinate on postoperative vomiting in children undergoing strabismus surgery, in a double-blind, randomized, placebo-controlled study. In one group, dimenhydrinate 50 mg was administered rectally 30 min before starting anaesthesia, whereas in the control group, placebo suppositories were given. Children who received dimenhydrinate showed a significantly (P < 0.001) lower incidence of vomiting (15%) than those in the control group (75%). We conclude that rectal administration of dimenhydrinate is an effective means of reducing postoperative vomiting in children undergoing strabismus surgery. (+info)
(8/279) Investigation of diazepam lipospheres based on Witepsol and lecithin intended for oral or rectal delivery.
Diazepam was incorporated in lipospheres prepared by high pressure homogenization of melted Witepsol (10%) dispersed in aqueous lecithin (2.4%). Diazepam content was 0.4% and more than 98% of the dose was found to be encapsulated in the lipospheres. Although the initial mean particle size was 0.3 micron, the liposhperes agglomerated during storage and this phenomenon was not eliminated by increasing lecithin concentration to 4% or incorporation of oleic acid (0.1%) and co-surfactants, polysorbate 80 (0.5%) or poloxamer (up to 6%). The formulation was not able to mask effectively bitter taste of diazepam, even when lipids of higher melting temperature, namely glyceryl tripalmitate or stearic acid, were introduced. (+info)