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Biomedical subjects

D Rachmilewitz

Publications and source records attributed to D Rachmilewitz.

At least 19 recordsLinked to original sources
PubMed1997

[Cyclosporin for severe ulcerative colitis].

In recent years there have been numerous reports of successful treatment of resistant ulcerative colitis with cyclosporin. A series of 9 patients with moderate to severe active ulcerative colitis was treated with cyclosporin between September 1993 and October 1994. All 9 had failed to respond to conventional therapy, including salazopyrine and intravenous corticosteroids. They underwent colonoscopy and after contraindications to therapy were ruled out, received intravenous cyclosporin, 4 mg/kg/day for 7-10 days. They were discharged on oral cyclosporin with average serum levels maintained at 200 ng/ml. Response was assessed using the clinical score system of Schroeder et al. 2 out of 9 patients (22%) responded with full clinical remissions lasting more than 6 months. 6 patients had partial responses to the intravenous therapy, but symptoms resumed shortly after its cessation. Factors predicting favorable response to cyclosporin therapy were a shorter duration of disease with a fulminant clinical course. The success rate was less than that reported in the literature, possibly because of comparatively low serum cyclosporin levels. Potential complications of therapy and high cost preclude the routine use of cyclosporin in ulcerative colitis. Larger controlled studies are required to assess its efficacy and safety. Until such studies are available, cyclosporin may be tried in poor surgical risks or those not yet ready psychologically for total colectomy.

Administration, Oral↗
PubMed1997

A more liberal approach to the surgical treatment of Crohn's disease.

BACKGROUND: Surgery for Crohn's disease is not intended for cure, but rather to relieve symptoms and treat complications. Perioperative morbidity, the fear of creating short bowel syndrome, and the tendency of the disease to recur convinced many physicians to refer their Crohn's patients for surgery only when life-threatening complications occur. METHODS: This is a retrospective analysis of 47 patients operated on for Crohn's disease between 1989 and 1994. Twenty-six patients were operated on for "classic" indications ("classic" group) and the other 21 were operated on to improve their quality of life ("quality" group). RESULTS: There was no operative or postoperative mortality during a mean follow-up period of 50 (27 to 84) months. All major postoperative complications occurred only in patients operated on for the classic indications (four abscesses, two fistulas, one wound dehiscence, and two small bowel obstructions). During the follow-up period, a total of 13 patients (50%) in the classic group and only 5 patients (24%) in the quality group required reintroduction of medical therapy or additional operations for exacerbations and complications of Crohn's disease. CONCLUSIONS: Our data suggest that surgical intervention intended to improve the quality of life for Crohn's disease patients is safe and effective for carefully selected patients. It does improve quality of life, may prevent life-threatening complications, and offers a lower recurrence rate following surgery.

Adolescent↗
PubMed1997

The effect of ketotifen on nitric oxide synthase activity.

1. We studied the effect of ketotifen, a second generation H1-receptor antagonist on nitric oxide synthase (NOS) activity in colonic mucosa and in renal tissues, and on rat renal haemodynamics in vivo. 2. Ketotifen (100 micrograms ml-1) increased human colonic NOS activity from 3.7 +/- 0.6 to 14.5 +/- 1.3 nmol g-1 min-1 (P < 0.005, ANOVA). In rat renal cortical and medullary tissues ketotifen increased NOS activity by 55% and 86%, respectively (P < 0.001). The stimulation of NOS activity was attenuated by NADPH deletion and by the addition of N omega nitro-L-arginine methyl ester (L-NAME) or aminoguanidine, but not by [Ca2+] deprivation. NOS activity was unaffected by two other H1-antagonists, diphenhydramine and astemizole, or by the structurally related cyproheptadine. Renal cortical NOS activity was also significantly stimulated 90 min after intravenous administration of ketotifen to anaesthetized rats. 3. Ketotifen administration to anaesthetized rats induced modest declines in blood pressure and reduced total renal, cortical and outer medullary vascular resistance. This is in contrast to diphenhydramine, which did not induce renal vasodilatation. 4. We conclude that ketotifen stimulates NOS activity by mechanisms other than H1-receptor antagonism. The association of this effect with therapeutic characteristics of ketotifen and the clinical implications of these findings are yet to be defined.

Animals↗
PubMed1997

Assessing disease activity in Crohn's disease--are we there yet?

Many attempts have been made over recent years to assess accurately disease activity in Crohn's disease. We review some of these attempts, giving particular emphasis to the combination of serum levels of proinflammatory cytokines (interleukin-6, tumour necrosis factor alpha, recombinant interleukin-2 and acid alpha-1-glycoprotein).

Biomarkers↗
PubMed1997

Sulphydryl blocker induced small intestinal inflammation in rats: a new model mimicking Crohn's disease.

BACKGROUND: Sulphydryl compounds are essential for maintaining mucosal integrity in the gastrointestinal tract. AIM: To characterise a model of experimental inflammation in the small intestine induced by a sulphydryl blocker. METHODS: Inflammation in the small intestine was induced in rats by intrajejunal administration of 0.1 ml 2% iodoacetamide. The possible amelioration of the damage induced was modulated by intragastric administration of TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; 50 mg/100 g body weight), ketotifen (200 micrograms/100 g body weight), or by addition of L-NAME (NG-nitro-L-arginine methyl ester; 0.1 mg/ml) or apocynin (120 micrograms/ml) to the drinking water. Rats were sacrificed at various time intervals, the small intestine resected, weighed, macroscopic lesions were assessed, and mucosal generation of inflammatory mediators and nitric oxide synthase activity were determined. RESULTS: Intrajejunal administration of iodoacetamide induced, after one week, multifocal mucosal erosions, ulcerations with granulomas and giant Langhans cells. At two weeks, the mucosa was almost macroscopically intact but histologically epithelial granuloma and giant cells were present. Myeloperoxidase activity was increased in the first 24 hours, one week later mucosal nitric oxide synthase activity and generation of leukotriene B4, leukotriene C4 and thromboxane B2 were increased, whereas prostaglandin E2 generation was decreased notably. Ketotifen and apocynin significantly decreased the extent of injury which was not affected by TEMPOL or L-NAME. CONCLUSIONS: Jejunal inflammation induced by the sulphydryl blocker, iodoacetamide, resembles the pathological changes in Crohn's disease. The protective effect of ketotifen and apocynin indicates the contribution of O2- and pro-inflammatory mediators to the pathogenesis of the damage, and may be a novel approach to the treatment of inflammatory bowel disease.

Acetophenones↗
PubMed1997

Effect of colchicine and bisacodyl on rat intestinal transit and nitric oxide synthase activity.

BACKGROUND: Bisacodyl and colchicine affect smooth-muscle contractility, intestinal water, and electrolyte transport. Nitric oxide (NO) stimulates intestinal electrolyte secretion and has an important role as a mediator of intestinal motility. We therefore studied, in rats, the effects of these agents on nitric oxide synthase (NOS) activity and gastrointestinal transit. METHODS: Rats were treated with bisacodyl (10 mg/kg intragastrically) or colchicine (5 mg/kg intraperitoneally) with or without pretreatment with ketotifen (1 mg/kg intragastrically). Rats were killed after 1, 2, and 4 h. The intestine was isolated and rinsed, the mucosa scraped, and NOS activity determined. In all rats small-intestinal transit was measured 15 min after intragastric administration of charcoal. RESULTS: Bisacodyl (10 mg/kg) and colchicine (5 mg/kg) induced a significant decrease in jejunal NOS activity. Pretreatment with the mast cell stabilizer ketotifen, which has been shown to attenuate the increased permeability induced by NO inhibition, prevented the decrease in colonic and jejunal NOS activity induced by bisacodyl and colchicine. Bisacodyl and colchicine significantly decreased intestinal transit time. Their effect on transit time was similar to that induced by intravenous administration of NG-nitro-L-arginine methyl ester (10 mg/kg). CONCLUSIONS: It is suggested that the effect of bisacodyl and colchicine on intestinal transport is, at least partly, mediated through NO inhibition.

Animals↗
PubMed1996

Renal vasoactive mediator generation in portal hypertensive and bile duct ligated rats.

BACKGROUND/METHODS: Vasoactive substances may have a role in the pathogenesis of functional renal abnormalities in patients with cirrhosis. We determined renal vasoactive mediators in rats with portal hypertension since the balance in each part of the kidney between the vasodilator activity of prostaglandin E2 and the vasospastic activity of thromboxane A2, leukotriene B4, leukotriene C4, endothelin-1 and platelet activating factor may determine renal function. Rats with partial portal vein ligation (n = 7), complete bile duct ligation (n = 6) and sham operated (n = 10) were studied. Three weeks following surgery renal function tests, including fractional excretion of sodium [Fe(Na)] were measured. Rats were anesthetized, splenic pulp pressure was measured, kidneys were removed, and cortex, medulla and papilla were separated and homogenized for determination of prostaglandin E2, thromboxane B2, leukotriene B4, leukotriene C4 and endothelin-1 by radioimmunoassay (ng/g) and platelet activating factor activity (pg/10 mg) by platelet aggregation. RESULTS: Pulp pressure was > 13 mmHg in portal vein ligated and bile duct ligated and 6 mmHg in sham operated rats. In bile duct ligated rats there was a 70% decrease in Fe(Na) and a significant decrease in cortical and papillary prostaglandin E2, whereas cortical thromboxane B2 and platelet activating factor activity in the cortex, medulla and papilla were double that of sham operated rats. A similar but insignificant trend of changes was found in portal vein ligated rats. Medullary leukotriene B4 was significantly decreased in bile duct ligated rats. Papillary leukotriene B4 was not detected in bile duct ligated and portal vein ligated rats. Renal leukotriene C4 generation in the three groups was either unchanged (papilla) or beyond detection (cortex and medulla). Medullary and papillary endothelin-1 in portal vein ligated and bile duct ligated rats were 178%-130% higher than in sham operated rats. A significant negative correlation was found between Fe(Na) and cortical and medullary thromboxane B2 generation and medullary platelet activating factor activity. CONCLUSIONS: 1) In bile duct ligated rats enhanced intrarenal generation of thromboxane A2 and platelet activating factor may contribute to decreased renal sodium excretion. 2) The role of decreased intrarenal prostaglandin E2 and increased intrarenal endothelin-1 content in bile duct ligated rats is not yet understood. 3) Renal leukotriene generation is either decreased or undetected in portal vein ligated and bile duct ligated rats.

Animals↗
PubMed1996

Antiphospholipid syndrome manifested by ischemic stroke in a patient with Crohn's disease.

Cerebrovascular accidents are rare but well documented in patients with Crohn's disease. Up to 10% of hypercoagulable state manifestations reported in association with inflammatory bowel disease are ischemic strokes. However, no clear mediating factor has thus far been suggested. A 44-year-old woman with Crohn's disease for 25 years developed a left temporal stroke associated with anticardiolipin antibody and lupus anticoagulant suggesting antiphospholipid syndrome. A thorough evaluation did not reveal any other risk factor for ischemic stroke. No possible sources of emboli were found in the carotids and heart, and no deficiencies of protein C and activated protein C, protein S, and anti-thrombin III leading to hypercoagulable state were present. There may be a possible association between antiphospholipid syndrome and hypercoagulable state in Crohn's disease.

Adult↗
PubMed1996

Gastric and colonic inflammatory and vasoactive mediators in experimental portal hypertension.

Rats with portal hypertension and experimental liver disease may exhibit increased susceptibility of the gastric mucosa to damage by noxious agents, and increased bacterial translocation through the bowel wall. The aim of this study was to determine mucosal gastric and colonic generation of vasoactive substances, because they may contribute to the altered mucosal function. Rats with partial vein ligation (n = 7), complete bile duct ligation (n = 6) and sham-operated rats (n = 10) were studied. Three weeks following surgery rats were anesthetized, splenic pulp pressure was measured, stomachs and colons were removed and mucosa was extracted for determination of prostaglandin E2, thromboxane B2, leukotriene B4, leukotriene C4 and endothelin-1 by radioimmunoassay (ng/g) and platelet activating factor activity (pg/10 mg) by platelet aggregation. Pulp pressure was > 13 mmHg in partial vein ligated rats and bile duct ligated rats and 6 mmHg in sham-operated rats. No macroscopic or microscopic lesions were seen any of the removed tissues. Gastric mucosal prostaglandin E2 and thromboxane B2 generation were decreased by 35% and 7%, respectively, in bile duct ligated rats (bile duct ligated versus sham-operated, p < 0.05 for prostaglandin E2 and thromboxane B2). Gastric leukotriene B4 and C4 generation, platelet activating factor activity and endothelin-1 content did not differ significantly among the three groups. A different pattern of changes was observed in the colon. Colonic leukotriene B4 generation and endothelin-1 content were increased in bile duct ligated rats by 105% and 210%, respectively (bile duct ligated versus sham-operated, p < 0.05 for leukotriene B4 and endothelin-1). The decreased gastric mucosal prostaglandin E2 generation of bile duct ligated rats may render the gut mucosa of these animals relatively ischemic and vulnerable to damage by noxious agents. The increased colonic leukotriene B4 generation and the increased endothelin-1 content of the colonic mucosa of bile duct ligated rats may promote inflammatory and ischemic changes in the colonic mucosa and may enable bacterial translocation.

Animals↗
PubMed1996

Sulphydryl blocker induced gastric damage is ameliorated by scavenging of free radicals.

BACKGROUND: Sulphydryl compounds and nitric oxide are essential in maintaining gastric mucosal integrity. AIMS: To characterise the gastric damage induced by a sulphydryl blocker, to evaluate the role of nitric oxide in its pathogenesis, and to reveal its possible prevention by scavenging of free radicals. METHODS: Gastritis was induced in rats by addition of iodoacetamide (0.1%) to the drinking water, with and without daily intragastric administration of TEMPOL. After death, the stomach was resected, washed, lesion area assessed, and mucosal inflammatory mediators, myeloperoxidase and nitric oxide synthase activities were determined. RESULTS: Administration of iodoacetamide induced gastric mucosal erosions present for up to two weeks. Myeloperoxidase activity was increased for up to seven days and nitric oxide synthase activity was significantly decreased for up to 14 days. Treatment for seven days with the free radical scavenger, TEMPOL, decreased by 68% the damage induced by iodoacetamide. CONCLUSIONS: Gastric damage induced by iodoacetamide, a sulphydryl alkylator, accompanied by inhibition of nitric oxide synthase activity shows the important contribution of sulphydryl compounds and nitric oxide to the maintenance of gastric mucosal integrity. Nitric oxide donation and scavenging of free radicals may be a novel approach to prevent gastric damage.

Animals↗
PubMed1996

Role of small bowel biopsy in the endoscopic evaluation of adults with iron deficiency anemia.

OBJECTIVES: The recommended evaluation of adult patients presenting with iron deficiency anemia (IDA) includes the performance of colonoscopy and esophagogastroduodenoscopy. IDA is a common feature in patients with celiac disease and, in several, may be the only presenting sign. The performance of small bowel biopsy (SBB) for the evaluation of celiac disease as the cause of IDA is not routinely recommended. The aim of the present study was to determine the yield of SBB performed during routine endoscopy of adults with IDA. METHODS: We prospectively studied 93 patients with IDA. Three control groups were included: 23 patients with steatorrhea, 37 patients with idiopathic diarrhea, and 9 patients in whom SBB was performed for miscellaneous indications. RESULTS: Eleven patients with IDA and two patients with steatorrhea had SBB findings compatible with celiac disease. None of the patients from the other two groups had similar findings. Two patients with IDA, who were later diagnosed to suffer from celiac disease, presented: one with occult blood in the stool and the other with rectal bleeding. Subgroup analysis of patients with IDA revealed that patients with celiac disease were younger, had significantly more episodes of diarrhea, lower mean hemoglobin level, and longer duration of anemia than those without celiac disease. Other mucosal abnormalities were found in a substantial number of patients with celiac disease: esophagitis, gastritis, duodenitis, hemorrhoids, and colitis. CONCLUSIONS: A substantial number of adult Israeli patients who present with IDA are found, on SBB, to have mucosal abnormalities compatible with the diagnosis of celiac disease. The presence of esophagitis, gastritis, or duodenitis on esophagogastroduodenoscopy, or other abnormalities on colonoscopy, do not exclude the coexistence of celiac disease. Celiac disease should be included and routinely looked for in the differential diagnosis of adult patients with IDA.

Adult↗
PubMed1995

Ketotifen and nitroxides decrease capsaicin-augmented ethanol-induced gastric damage in rats.

Systemic administration of capsaicin aggravates ethanol-induced injury of rat gastric mucosa. We evaluated the effect of subcutaneous administration of capsaicin on the gastric mucosa and on inflammatory mediators in saline- and ethanol-treated rats. Functional ablation of primary afferent C-fibers by capsaicin (total 100 mg/kg subcutaneous) tripled ethanol-induced damage. Pretreatment with ketotifen, a mast cell stabilizer (1 mg/kg) protected rat gastric mucosa from the amplified injury induced by capsaicin and ethanol. Tempol, a selective nontoxic cell-permeable nitroxide, completely prevented the amplified gastric ulceration induced by capsaicin and ethanol. This was accompanied by a significant decrease in leukotriene B4 and C4 generation. It is therefore suggested that mast cells and free radicals contribute to the amplified injury observed in rats pretreated with capsaicin and ethanol and that the pharmacological modulation of mast cell release and scavenging of free radicals may be of therapeutic efficacy in the prevention of gastric injury.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Ketotifen ameliorates capsaicin-augmented acetic acid-induced colitis.

Capsaicin-sensitive afferent neurons are involved in maintaining the integrity of the gastrointestinal mucosa. These neurons are closely apposed to mast cells and could, therefore, lead to their activation. In the present study, the role of capsaicin-sensitive neurons in the pathogenesis of experimental colitis and the possible involvement of mast cells and nitric oxide were evaluated. Rats were treated with capsaicin subcutaneously, 20, 30, and 50 mg/kg, on three consecutive days, a regimen shown to ablate primary afferent neurons. Colitis was induced two weeks later by flushing 2 ml 5% acetic acid into the proximal colon. Control rats received saline, acetic acid, or capsaicin alone. Another group of rats received ketotifen (100 micrograms/100 g body wt x 2/day) intragastrically 48 hr prior to damage induction and thereafter. Rats were sacrificed 24 hr after damage induction, the colon isolated, damage assessed, explants were organ-cultured for 24 hr for determination of nitric oxide generation, and mucosa extracted for determination of leukotriene B4 generation and nitric oxide synthase activity. Significant increases in colonic weight, nitric oxide synthase activity, and nitric oxide and leukotriene B4 generation accompanied the near tripling of acetic acid-induced damage in capsaicin-pretreated rats. Ketotifen pretreatment significantly decreased the macroscopic damage and the increase in colonic weight. The protection provided by ketotifen was accompanied by a significant decrease in leukotriene B4 generation and nitric oxide synthase activity (80%).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1995

NO chi generation by cultured small intestinal epithelial cells.

The effect of cytokines, growth factors, mitogens, and bacterial products on nitric oxide (NO) generation by monolayers of small intestinal epithelial cells-6 (IEC-6) cells was evaluated. Subconfluent IEC-6 cells were maintained in DMEM containing 5% fetal calf serum and after 16-24 hr of incubation, the medium was replaced with fresh medium in the presence or absence of calcium ionophore (CaI), L-NAME, L-NNA, individual growth factors, cytokines, or mitogens. After 72 hr of culture, the media supernatant was collected and NO chi generation was determined. NO synthase activity was determined in sonicated supernatants of IEC-6 cells by [14C] arginine conversion to citrulline. NO chi generation in subconfluent cultures was greater than in fully confluent cultures, suggesting contact inhibition. NO chi generation by IEC-6 cells was significantly increased by CaI and inhibited by L-NAME and L-NNA. LPS, IL-1 beta, IL-2, IL-8, IFN-8, TFN-alpha, EGF, TGF-alpha, bFGF, and PHA significantly increased NO chi generation. NO synthase activity in IEC-6 cells (4.2 +/- 1.7 pmol/min/10(6) cells) was NADPH dependent. These results suggest that stimulation of NO chi generation by intestinal epithelial cells through cytokine bacterial products and mitogens may be one of the mechanisms responsible for their effects in the intestinal tract.

Animals↗
PubMed1995

Sulfhydryl blocker-induced rat colonic inflammation is ameliorated by inhibition of nitric oxide synthase.

BACKGROUND & AIMS: Sulfhydryl compounds are essential in maintaining mucosal integrity, and nitric oxide may contribute to tissue injury. The aim of this study was to characterize experimental colitis induced by a sulfhydryl blocker. METHODS: Colitis was induced in rats by intracolonic administration of 0.1 mL 3% iodoacetamide with and without addition of 0.1 mg/mL NG-nitro-L-arginine methyl ester (L-NAME) to the drinking water. After death, the distal colonic segment was resected and weighed, and mucosal inflammatory mediator, myeloperoxidase, and NO synthase activities were determined. RESULTS: Iodoacetamide induced multifocal mucosal erosions and ulceration that were present for up to 1 week. At 3 weeks, the mucosa was almost intact. Colonic wet weight was maximal at 7 days. Myeloperoxidase activity and NO generation were increased in the first 72 hours, and NO synthase activity and prostaglandin E2 generation were increased up to 21 days. Leukotriene B4 and leukotriene C4 generation were increased up to 14 days. One week after iodoacetamide plus L-NAME treatment, lesion area was reduced by 85% and NO synthase activity by 52%. CONCLUSIONS: Inflammatory mediators have an important contribution to the pathogenesis of colonic injury induced by a sulfhydryl alkylator. The protective effect of L-NAME indicates that NO contributes to tissue injury and that its modulation may be a novel approach to treat inflammatory bowel disease.

Amino Acid Oxidoreductases↗