Lawrence D. Jewell

A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease☆☆☆

BACKGROUND & AIMS Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the trafficking and activation of leukocytes and is up-regulated in inflamed mucosa in Crohns disease. ISIS 2302 is an antisense phosphorothioate oligodeoxynucleotide that inhibits ICAM-1 expression. The aim of this study was to obtain preliminary assessment of tolerability, pharmacology, and efficacy of ISIS 2302 in Crohns disease. METHODS Twenty patients with active, steroid-treated Crohns disease were randomized (3:1, ISIS 2302 to placebo) to receive over 26 days 13 intravenous infusions of ISIS 2302 (0.5, 1, or 2 mg/kg) or saline placebo in a double-blinded study. The patients were followed up for 6 months. RESULTS At the end of treatment. 47% (7 of 15) of ISIS 2302-treated and 20% (1 of 5) of the placebo-treated patients were in remission (Crohns Disease Activity Index [CDAI] < 150). At the end of month 6, 5 of these 7 ISIS 2302-treated remitters were still in remission, and a 6th patient had a CDAI of 156. Corticosteroid usage was significantly lower (P = 0.0001) in the ISIS 2302-treated patients. These findings were corroborated by significant increases in beta7 and alpha d bearing CD3+ peripheral blood lymphocytes and by decreases in intestinal mucosal ICAM-1 expression during the treatment period. CONCLUSIONS ISIS 2302 seems to be a well-tolerated and promising therapy for steroid-treated Crohns disease.

Antibiotic therapy attenuates colitis in interleukin 10 gene–deficient mice☆☆☆

BACKGROUND & AIMS Interleukin (IL)-10 gene-deficient mice, raised under germfree conditions, do not develop colitis, implying a role for bacteria. This study mapped the appearance of luminal colonic bacteria and, using antibiotic treatment, determined their association with colitis in IL-10 gene-deficient mice. METHODS Mice were treated with ciprofloxacin or with neomycin and metronidazole. The intestine was harvested for histological scoring and bacterial assessment. RESULTS At 2 weeks of age, before the development of colitis, IL-10 gene-deficient mice demonstrated an earlier appearance of Streptococcus and Clostridium sp., and had a greater proportion (P < 0.01) of bacteria adherent to the colonic mucosa. This pattern of increased adherent bacteria persisted for the 12 weeks of study. Treatment of mice before the onset of colonic inflammation, with either antibiotic regime, reduced mucosal adherent bacteria and prevented colitis (P < 0.01). In contrast, treatment of established colitis with neomycin and metronidazole did not reduce adherent bacterial levels, yet was more efficacious (P < 0.05) in treating established colitis than ciprofloxacin, which did reduce adherent colonic bacteria. CONCLUSIONS In the IL-10 gene-deficient mouse model, the appearance and number of mucosal adherent colonic bacteria are altered before the onset of colitis. Antibiotics both prevent and treat the colitis through correction of this primary bacterial alteration.

Half-Life of the Duck Hepatitis B Virus Covalently Closed Circular DNA Pool In Vivo following Inhibition of Viral Replication

ABSTRACT Covalently closed circular DNA (cccDNA) is a crucial intermediate in the replication of hepadnaviruses. We inhibited the replication of duck hepatitis B virus in congenitally infected ducks with a combination of lamivudine and a dideoxyguanosine prodrug. Inhibition of viral replication should prevent renewal of the cccDNA pool, and its decay was measured in liver biopsy samples collected over a 5-month period. In three ducks, the cccDNA pools declined exponentially, with half-lives ranging from 35 to 57 days. In two others, the pools declined exponentially for about 70 days but then stabilized at about 6 copies/diploid genome. The selection of drug-resistant virus mutants is an unlikely explanation for this unexpected stabilization of cccDNA levels. Liver sections stained for the cell division marker PCNA showed that animals in which cccDNA loss was continuous had significantly greater numbers of PCNA-positive nuclei than did those animals in which cccDNA levels had plateaued.

Mucosal protective effects of vitamin E and misoprostol during acute radiation-induced enteritis in rats

Cytotoxic effects of ionizing radiation on gastrointestinal epithelium may be mediated by oxygen free radicals. Therapeutic intervention directed toward oxidant scavenging and increasing tissue oxygen tension may provide a novel approach to management. We investigated the effects of a nonenzymatic oxygen radical scavenger (vitamin E) and an exogenous PGE1 analog known to increase mucosal blood flow (misoprostol) on acute radiation enteritis. Rats were pretreated with: (1) vitamin E, (2) misoprostol, or (3) a combination of both agents prior to 10 Gy abdominal radiation. Three days following irradiation, net fluid absorption usingin vivo isolated loops, mucosal histology, and mucosal morphometry using a computerized videoplan were determined in jejunum, ileum, and colon. Nonirradiated control intestine demonstrated net fluid absorption in all segments, which was not altered by vitamin E and/or misoprostol treatment. Irradiation significantly reduced net fluid absorption in jejunum, ileum, and colon. Vitamin E administered prior to irradiation maintained jejunal, ileal, and colonic fluid absorption near control levels. In contrast misoprostol or a combination of vitamin E and misoprostol did not provide protection against the injury caused by abdominal irradiation. Alterations in intestinal fluid absorption occurred without significant changes in histologic or morphometric appearance. In conclusion, ionizing radiation reducesin vivo intestinal fluid absorption without significant changes in histologic or morphometric appearance. Treatment with vitamin E, but not misoprostol, protects gastrointestinal mucosa against radiation-induced absorptive injury.

Lack of interleukin‐10 leads to intestinal inflammation, independent of the time at which luminal microbial colonization occurs

Previous studies have demonstrated that the resident bacteria harbored by interleukin (IL)-10 gene-deficient mice initiate an enterocolitis in the neonatal period. The associated intestinal injury is characterized by an increase in the secretion of interferon (IFN)-&ggr; and tumor necrosis factor (TNF)-&agr;, and by a systemic response to endogenous bacterial antigens, supporting the hypothesis that a lack of tolerance may be the initiating cause. Whether bacterial initiation of this enterocolitis would occur in the adult intestine or whether it is only seen in the developing neonatal intestine was not known. Adult (9 weeks of age), axenic, luminally sterile IL-10 gene-deficient mice, which do not spontaneously develop enterocolitis, were inoculated with intestinal microbial flora. These mice rapidly developed intestinal injury and demonstrated elevated levels of IFN-&ggr; in cecal and colonic tissue. This response precedes a systemic spleen cell response to stimulation by bacterial antigens. Similarly, axenic, IL-10 gene-deficient mice exposed to microflora as neonates experience a comparable intestinal injury and IFN-&ggr; release before the appearance of IFN-&ggr;–producing cells in the spleen. Microbial colonization in control mice leads to systemic IL-10 production, but not systemic IFN-&ggr; production, suggesting that an IL-10–mediated suppression regulates the response in normal control mice but is absent in IL-10 gene-deficient mice. Our results suggest that the point at which intestinal microbial colonization occurs does not significantly influence the severity or specificity of the inflammatory response in IL-10 gene-deficient mice. The lack of tolerance to bacterial antigens appears to result from the absence of IL-10 during bacterial exposure.

Effects of intravenous lipid as a source of energy in parenteral nutrition associated hepatic dysfunction and lidocaine elimination: a study using isolated rat liver perfusion.

The effects on liver function and hepatic lidocaine elimination using 20% Intralipid® as a source of non‐protein calories (30%) in parenteral nutrition were studied using an isolated rat liver perfusion procedure. Rats were randomly assigned to one of the three treatment groups: PNL group (n =6), consisting of 16·94% dextrose, 2·46% Intralipid®, and 5·2% amino acids; PN group (n =5), consisting of 24·2% dextrose and 5·2% amino acids; and CF group (n =6), chow fed (rat chow and water). The rate of lidocaine metabolism was significantly reduced after 7 d in the two PN treated groups when compared to CF. Steatosis was observed in five out of six PNL treated animals and two out of five PN treated animals. Intrinsic clearance was reduced by 80% in the PNL group and by 60% in the PN animals (p <0·05). Molar metabolite to drug ratios revealed significant reductions in N‐dealkylation, m ‐hydroxylation, and aryl methyl hydroxylation in groups PNL and PN; these values amounted to 67–92% (p <0·05). These findings suggest that a dextrose–amino acid solution induced steatosis and reduced the rate of lidocaine metabolism. The incorporation of Intralipid® caused further deterioration.

Effects of Light-Exposed Parenteral Nutrition on Hepatic Function and Lidocaine Metabolism: A Study Using Isolated Rat Liver Perfusion

Effects of light-exposed parenteral solutions on hepatic function and lidocaine metabolism were studied. Male rats (190-220 g) were randomly assigned to one of the three isocaloric treatment groups: parenteral nutrition(PN)(+L) group (n = 6), animals received a solution of 24.2% dextrose and 5.2% amino acids with light exposure; PN(-L) group (n = 5), animals received the same solution without light exposure; and CF group, chow-fed animals (n = 6) that received rat chow and water. Average energy intake in these animals was ≈33 kcal/100 g/d. Lidocaine metabolism was studied in livers isolated from animals 7 d after treatment. Liver morphology indicated that five livers from PN(+L) animals developed steatosis. The lidocaine metabolism rate was the slowest in PN(+L) animals; this is marked by changes in the steady state levels (% dose) of lidocaine [PN(+L), 47.9 ± 17.6; PN(-L), 25.9 ± 2.1; versus CF, 11.3± 5.3; p < 0.05]. The extraction ratio and intrinsic clearance values were reduced by 41 and 86% in PN(+L) group and 16 and 70% in PN(-L) group, respectively, when compared with CF (p < 0.05). Metabolite to drug ratios indicated that N-dealkylation,ring-hydroxylation, and aryl methyl hydroxylation of lidocaine were severely impaired, particularly in the PN(+L) animals. The extents of reduction in metabolic pathways were in the ranges 79-95% in the PN(+L) group and 44-90% in the PN(-L) (p < 0.05). These findings suggest that parenteral nutrition infusion induces steatosis and reduces the rate of lidocaine metabolism and exposure of parenteral nutrition solutions to light exacerbates this change.

Idiopathic colitis associated with scrotal cellulitis.

by The Rehabilitation Center of the New York University Medical Center. ~ They point out that the rate of loss of vital capacity slows once it has fallen below one liter. We saw dramatic restoration of activity in our patients after an initial period of aggressive treatment. Although bound to wheelchairs, Patients 1 and 5 have been able to resume their daily activities. They were not ready to die, and they and their families are grateful that they were given the option not to do so. Our patient with centronuclear myopathy is able to walk between classes without a wheelchair. All three of these young adults use their respirators only at night. We urge that any physician caring for children with neuromuscular disease include pulmonary function testing as part of the periodic examination. The option of ventilatory support should be thoroughly understood by patient, parent, and physician. Patients may wish to consider elective fitting of a cuirass prior to the onset of respiratory failure. Frequently, nighttime use may be all that is necessary. A cuirass seems to fit the unique needs of the patient with neuromuscular diseaseS: mobility, preservation of voice, and independence.