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PubMed2003

Ketamine/xylazine attenuates LPS-induced iNOS expression in various rat tissues.

Ketamine and xylazine (K/X) are commonly used in combination as an anesthetic agent in experimental animal models. We previously noted that K/X attenuated lipopolysaccharide (LPS)-induced liver injury, gastric stasis, and reduced symptoms of endotoxemia. Because ketamine attenuates expression of several proinflammatory genes, we examined the effects of K/X on inducible nitric oxide synthase (iNOS), which has been implicated in endotoxin-induced tissue injury. We hypothesized that K/X would attenuate LPS-induced expression of iNOS in various organs in the rat. Rats were given either intraperitoneal saline or ketamine (70 mg/kg) and xylazine (6 mg/kg) 1 h before saline or LPS (20 mg/kg). Rats were sacrificed 5 h later and stomach, duodenum, jejunum, ileum, colon, liver, lung, kidney, and spleen were collected for determination of iNOS protein immunoreactivity by Western immunoblot. Data reported in densitometric units (DU) as mean +/- SEM (n >/= 5; ANOVA). LPS significantly increased iNOS protein immunoreactivity in all tissues examined versus saline controls (P </= 0.05, all groups). K/X significantly attenuated LPS-induced iNOS protein immunoreactivity in all of the aforementioned organs (P </= 0.05, all groups). Furthermore, K/X almost completely blunted LPS-induced expression of iNOS in stomach, duodenum, jejunum, and colon. These data indicate that K/X attenuates LPS-induced upregulation of iNOS in a variety of tissues. Furthermore, in rat models studying the in vivo effects of endotoxin, especially those evaluating the gastrointestinal system, careful consideration needs to be given if the anesthetic combination of K/X is used, as it alters LPS-induced expression of iNOS, an important pathophysiologic mediator in endotoxemia.

Adrenergic alpha-Agonists↗
PubMed1993

Infantile hypertrophic pyloric stenosis and hydronephrosis: is there an association?

Infantile hypertrophic pyloric stenosis is a common condition requiring surgical intervention during the first few weeks of life. The incidence of infantile hypertrophic pyloric stenosis ranges from 0.13 to 0.4% of live births in the United States, Britain and Scandinavia. Associated anomalies have been described in 6 to 33% of the cases in the central nervous system, gastrointestinal tract and heart. An association of infantile hypertrophic pyloric stenosis with urinary tract anomalies has not been previously documented. A review of 422 patients with infantile hypertrophic pyloric stenosis revealed urinary tract anomalies in 6 (10 renal units), including 4 renal units with vesicoureteral reflux and 9 with hydronephrosis. This incidence of 1.4% is greater than the 0.2% incidence expected in the general population. This 7-fold increase in urinary tract anomalies in patients with infantile hypertrophic pyloric stenosis suggests an association between the two and warrants further investigation. Serious consideration should be given to obtaining renal ultrasound examinations in patients with infantile hypertrophic pyloric stenosis.

Abnormalities, Multiple↗
PubMed2000

Receptors for NPY in peripheral tissues bioassays.

Neuropeptide Y (NPY) and its congeners, peptide YY (PYY) and the pancreatic polypeptide (PP), have a large spectrum of peripheral actions. NPY is found in peripheral neurons, co-localized or not with noradrenaline; PYY and PP are expressed in endocrine cells of the pancreas and in the intestine of vertebrates. NPY is the most abundant peptide in the brain and is involved in the regulation of food intake and of circadian rhythm. It intervenes also in the process of anxiety and memory. NPY is a potent vasoconstrictor, a cardiac stimulant, and may affect the gut through enteric neurons. PYY and PP act mainly on the gastrointestinal system; however, when in blood, they can cross-react with functional sites elsewhere and replace NPY in some parts of the brain (e.g. regions involved in feeding behavior). These peptides act through G protein coupled receptors (GPCR) of which five different types are known and have been cloned (1,2); functional sites (receptors) for NPY have been found in vessels, the gut, and in vasa deferentia (3-6).

Animals↗
PubMed2001

Inhibition of peristaltic activity by cannabinoids in the isolated distal colon of mouse.

The effects of the cannabinoid receptor agonist Win 55,212-2 and of the competitive cannabinoid receptor antagonist SR 141716A on the electrically-evoked peristalsis of isolated distal colon of mouse were studied. Intraluminal pressure, longitudinal displacement, ejected fluid volume and changes in morphology of external intestinal wall were simultaneously recorded in the pre-drug period and in presence of Win 55,212-2 alone or in combination with SR 141716A. In the pre-drug period (control), peristaltic activity was characterised by regular, monophasic waves and the intraluminal content propelled towards anterograde (oro-aboral) direction with a propulsion velocity of 1.25 +/- 0.1 mm x s(-1). Pressure and shortening waves showed a peak amplitude of 2.44 +/- 0.32 kPa and 1.8 +/- 0.72 mm, respectively. The mean amount of fluid volume ejected during each contraction was 80 +/- 12.6 microl. The addition of Win 55,212-2 [10(-7)-10(-4) M] to the organ bath determined a dose-related attenuation of peristaltic activity consequent to the decrease of circular and longitudinal muscle strength. The decrease of contractile activity was followed by dose-dependent decrease of the amount of fluid ejected during peristalsis. The effects of Win 55,212-2 [10(-7)-10(-5) M] were prevented by SR 141716A, indicating the presence of cannabinoid CB1 receptors in the mouse distal colon. SR 141716A alone enhanced both tonic and phasic motor activities in the colonic longitudinal smooth muscle, suggesting that CB1 receptor antagonists could act either through antagonising the effect of endogenous CB1 receptor agonist or by an agonist effect on these receptors. The present results further support the hypothesis that cannabinoids perform a neuromodulatory role in various tracts of gastrointestinal system and first demonstrate their action also in the distal colon of rodents.

Animals↗
PubMed2003

Chronic pelvic pain.

Chronic pelvic pain is a common and significant disorder of women. It is estimated to have a prevalence of 3.8% in women. Often the etiology of chronic pelvic pain is not clear, as there are many disorders of the reproductive tract, gastrointestinal system, urological organs, musculoskeletal system, and psychoneurological system that may be associated with chronic pelvic pain. The history and physical examination are crucial in evaluating a woman with chronic pelvic pain and must address all of the possible systems potentially involved in chronic pelvic pain, not just the reproductive system. Laboratory and imaging studies should be selectively utilized, as should laparoscopy. Conscious laparoscopic pain mapping has been proposed as a way to improve information derived from laparoscopic evaluations. Treatment of chronic pelvic pain may consist of two approaches. One is to treat chronic pain itself as a diagnosis, and the other is to treat diseases or disorders that might be a cause of or a contributor to chronic pelvic pain. These two approaches are not mutually exclusive, and in many patients effective therapy is best achieved by using both approaches. Treatment of chronic pain as well as treatment of four of the more common disorders associated with chronic pelvic pain (endometriosis, adhesions, irritable bowel syndrome, and interstitial cystitis) are discussed in this review.

Chronic Disease↗
PubMed1996

Crohn's disease in children.

Crohn's disease is a chronic inflammatory condition that may affect any part of the gastrointestinal system and multiple extraintestinal organs. Although its exact pathogenesis remains unknown, increasing evidence suggests an abnormality in the control of "physiologic" inflammation caused by bacterial and other antigens. Diagnosis starts with a careful history and physical examination, and confirmation rests with radiologic and histologic studies. Newer treatments are more specifically targeting the cascade of cytokine-mediated events that perpetuate inflammation.

Adolescent↗
PubMed1997

Olfactory sensory-specific satiety in humans.

It is shown that olfactory sensory-specific satiety, measured by ratings of the pleasantness of the odour of a food eaten relative to the change in pleasantness of other foods, can be produced by eating a food to satiety. It is also shown that olfactory and taste sensory-specific satiety can be produced by chewing samples of a food for approximately as long as the food would normally be eaten in a meal. It is further shown that partial olfactory sensory-specific satiety can be produced by smelling the food for approximately as long as it would be in the mouth during a meal. These sensory-specific changes in the pleasantness of a food do not appear to reflect changes in the intensity of the foods, which were small and not highly correlated with the changes in pleasantness. The results show that at least partial olfactory, as well as taste, sensory-specific satiety does not require food to enter the gastrointestinal system, and does not depend on the ingestion of calories. The implications for the control of food intake, and the way in which the brain computes sensory-specific satiety, are considered.

Adult↗
PubMed1999

Murine mast cells exposed to mercuric chloride release granule-associated N-acetyl-beta-D-hexosaminidase and secrete IL-4 and TNF-alpha.

BACKGROUND: Mast cells, by virtue of their location within the skin, respiratory tract, and gastrointestinal system, are considered as potential targets for environmental agents with immunotoxic effects. Mercuric chloride (HgCl2), is a xenobiotic, which induces autoimmune glomerulonephritis and stimulates polyclonal IgE production. OBJECTIVE: We sought to determine the ability of HgCl2 to degranulate murine mast cells and promote cytokine secretion and whether this was an active biologic process. METHODS: Bone marrow-derived murine mast cells were exposed to HgCl2, and the release of N-acetyl-beta-D-hexosaminidase and secretion of IL-4 and TNF-alpha were measured. RESULTS: HgCl2 was found to directly activate murine mast cells to release the granule-associated enzyme N-acetyl-beta-D-hexosaminidase and to secrete the proinflammatory cytokines IL-4 and TNF-alpha. Cytokine secretion occurred hours after exposure to HgCl2 and required transcription and protein synthesis. The secretion of cytokines mediated by HgCl2 was additive to that which followed FcepsilonRI-induced mast cell activation. The IL-4 secretion by mast cells occurred at concentrations of HgCl2 (10(-6) mol/L to 10(-5) mol/L) comparable with those required to induce upregulation of IgE production in experimental animals. CONCLUSION: These findings demonstrate that HgCl2 will directly activate mast cells, which is followed by degranulation and IL-4 and TNF-alpha synthesis and secretion. These findings are consistent with recognition of HgCl2 as a biologically important environmentally derived immunotoxic agent for mast cells.

Animals↗
PubMed2006

Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials.

BACKGROUND: Treatment options for HIV-1 infected individuals who have received extensive previous antiretroviral therapy are limited. We compared efficacy and safety of the novel non-peptidic protease inhibitor tipranavir co-administered with ritonavir plus an optimised background regimen with that of an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI-ritonavir) in such patients. METHODS: We did a combined analysis of 48-week data from two ongoing, randomised, open-label, multinational, phase III, RESIST studies. HIV-1-infected adults with 3 months or longer previous triple antiretroviral class experience, two or more previous protease inhibitor regimens, HIV-1 RNA 1000 copies per mL or greater, and genotypically demonstrated primary resistance to protease inhibitor, were eligible. Primary endpoints were proportion of treatment responders (with reduction in viral load of 1 log(10) copies per mL or greater below baseline without treatment change) at 48 weeks and time to treatment failure through 48 weeks (intention-to-treat analysis). The RESIST studies are registered with ClinicalTrials.gov, numbers NCT00054717 (RESIST-1) and NCT00144170 (RESIST-2). FINDINGS: 3324 patients were screened; 746 received tipranavir-ritonavir and 737 CPI-ritonavir. 486 (65.1%) patients on tipranavir-ritonavir and 192 (26.1%) on CPI-ritonavir remained on assigned treatment until week 48. At week 48, more patients achieved and maintained treatment response in the tipranavir-ritonavir group than in the CPI-ritonavir group (251 [33.6%] vs 113 [15.3%]; p<0.0001). Median time to treatment failure was significantly longer in the tipranavir-ritonavir group than in the CPI-ritonavir group (113 days vs 0 days; p<0.0001). Gastrointestinal system disorders and raised transaminase, cholesterol, and triglycerides were more frequent in the tipranavir-ritonavir group than in the CPI-ritonavir group. INTERPRETATION: Compared with CPI-ritonavir, tipranavir-ritonavir with an optimised background regimen provides better virological and immunological responses over 48 weeks in patients who have received extensive previous antiretroviral treatment.

Adult↗
PubMed2000

COX-1, COX-2, and COX-3 and the future treatment of chronic inflammatory disease.

A new generation of non-steroidal anti-inflammatory drugs has been described that selectively targets the inducible isoform of cyclo-oxygenase, cyclo-oxygenase 2 (COX-2). This isoform is expressed at sites of inflammation, which has led to the speculation that its inhibition could provide all the benefits of current nonsteroidal anti-inflammatory drugs, but without their major side-effects on the gastrointestinal system (which are due to inhibition of COX-1). We have shown that COX-2 (identified by use of specific antibodies) is induced during the resolution of an inflammatory response, inhibition of COX-2 resulting in persistence of the inflammation due to the prevention of the synthesis of a range of anti-inflammatory prostanoids. We propose that there is a third isoform of this enzyme family, COX-3, a proposal that will have implication for the prescription of both existing and new generation anti-inflammatory drugs, and might represent a new therapeutic target.

Animals↗
PubMed2002

Bioadhesive properties of polygalacturonides against colonic epithelial membranes.

Diseases of the gastrointestinal system are often related with irritations or pathological changes of mucous membranes. In an ex vivo system based on porcine colonic tissue various neutral and acidic polysaccharides were tested concerning their bioadhesive potential in order to form artificial mucin layers on colon epithelial membranes. Rhamnogalacturonans with a low degree of esterification and linear oligogalacturonids derived from pectin showed significant bioadhesion against colonic mucous membranes. In contrast highly esterified pectins and neutral polysaccharides were ineffective. Within a structure-activity relationship linear, strongly acidic homogalacturonides were shown to be most adhesive agents. Esterification, branching or non-linear backbone structures will reduce the adhesive properties. The bioadhesive effects were concentration-dependent. Polysaccharide layers, located exclusively on the apical membrane surface of colonic tissue, were visualized by fluorescent microscopy. The adhesion of the exogenous galacturonides on the tissue surface was mediated by interaction with the endogenous mucin, for the release of the endogenous mucines with a mucolytic agent resulted in a decreased bioadhesion of exogenous galacturonides. Additionally, mucin-galacturonide synergism was shown by rheological methods. The artificial mucin layers provide protective effects on colonic mucous membranes against toxic agents as shown by incubation of the tissue with TritonX-100.

Animals↗
PubMedDate not supplied

Piroxicam fast-dissolving dosage form in the treatment of patients with acute low back pain.

An open-label, noncomparative study of the efficacy and tolerability of a once-daily piroxicam fast-dissolving dosage form (FDDF) comprised 157 patients aged 15 to 76 years (56.7% men) with acute low back pain of not more than 48 hours' duration. Patients received 40-mg piroxicam FDDF once daily for the first 2 days and 20 mg once daily for up to a total of 14 days of treatment. Fifteen investigators in three countries examined patients at baseline and at follow-up visits on days 4, 8, and 15. All efficacy assessments-including general low back pain; pain on sitting, standing, and walking; overall severity of night pain; duration of morning stiffness; lumbosacral tenderness on moderate pressure; modified Schober test of ability to bend forward; restriction of passive motion; length of time to resumption of an activity impaired by back pain; and overall restriction of back motion-demonstrated statistically significant improvements from baseline at each follow-up visit. Relief of pain, noted 30 minutes after the first dose, was maintained for the 24-hour dosing interval during the first 3 days. At visit 4, after piroxicam FDDF treatment had been completed, the number of patients being assessed had declined by half, principally because the resolution of symptoms had prompted discontinuation of the study drug. At the end of the treatment, 82.9% of patients evaluated the efficacy of piroxicam FDDF as good or excellent and investigators rated efficacy as good or excellent in 85.6% of patients. Tolerability was also rated highly, with 91% of patients characterizing piroxicam FDDF treatment as good or excellent, and investigators rating the treatment as good or excellent in 92% of patients. In all, 12.7% of the patients experienced drug-related adverse events, most frequently involving the gastrointestinal system. Drug-related adverse experiences prompted discontinuation of the study medication in five (3.2%) patients. These results suggest that the newly developed dosage form, piroxicam FDDF, administered in a dosage of 40 mg/d for the first 2 days and 20 mg/d thereafter (for up to 14 days), is effective and well tolerated in the treatment of patients with acute low back pain.

Adolescent↗
PubMedDate not supplied

Itraconazole oral solution versus clotrimazole troches for the treatment of oropharyngeal candidiasis in immunocompromised patients.

This multicenter, open-label, third-party-masked trial compared the efficacy and safety of itraconazole oral solution (200 mg once daily) and clotrimazole troches (10 mg five times daily) in a population of immunocompromised subjects composed primarily of patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Patients were treated for 14 days; patients who exhibited a clinical response were followed up for an additional month to document the occurrence of relapse. Efficacy was judged by changes from baseline in symptoms of oropharyngeal candidiasis (erythema, soreness/burning), extent of oral lesions, and the presence/absence of Candida species on fungal culture. A total of 162 patients were randomized, and 149 were evaluated for efficacy. The percentage of patients with negative cultures at the end of treatment was significantly greater in the itraconazole group than in the clotrimazole group (60% vs 32%, respectively). Negative culture plus clinical response was achieved in significantly more itraconazole-treated patients (53%) than clotrimazole-treated patients (30%); results were similar in the subgroup of patients with HIV/AIDS. Both drugs were well tolerated, with the most frequently reported adverse events for both agents involving the gastrointestinal system. In conclusion, systemic therapy with intraconazole oral solution is efficacious and well tolerated in immunocompromised patients, including those with HIV/AIDS, when administered once daily for 14 days for the treatment of oral candidiasis.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Developmental gene expression of gastrin receptor in rat stomach.

Gastrin, which is present in fetal plasma, may have important roles in the development of gastric mucosa, since it is not only a potent stimulator of gastric acid secretion but also a growth promoting factor. Gastrin regulates various cellular functions via its receptors on cell membrane. Therefore, in order to elucidate a role for gastrin in the development of gastrointestinal system during gestation, Northern blot analysis was performed. The results of the study suggested that gastrin receptor is mainly present on parietal cells. Furthermore, proton pump and gastrin receptor gene expressions in parietal cells were strongly stimulated by the administration of exogenous gastrin. In conclusion, gastrin may be involved in the developmental change of parietal cells through its receptors.

Animals↗
PubMed1999

Biological relevance of pituitary adenylate cyclase-activating polypeptide (PACAP) in the gastrointestinal tract.

Since its initial discovery in 1989, pituitary adenylate cyclase activating peptide (PACAP) has been noted to distribute widely in the brain, the respiratory and the gastrointestinal system. It occurs in two bioactive molecules, PACAP-27 and the C-terminally extended PACAP-38, which evoke activity by binding to three distinct types of high-affinity, G-protein coupled membrane receptors. It is present throughout the entirety of the gut but is rare in certain areas such as the intestinal mucosa and islets of Langerhans. PACAP-induced biological effects are protean and include alterations of motility in the bowel and the gallbladder, stimulation of gastric acid and intestinal secretion, hormone/enzyme release from the exocrine and endocrine pancreas, and the induction as well as inhibition of proliferation in neuroendocrine cells and tumors. Its hepatic activity has to date not been elucidated in detail. One of the interesting features of PACAP is the species and organ dependent variation of its biological effects. Of particular note is its superior potency when compared with other neuropeptides identified in the gut, and the involvement of a number of different second messenger systems upon PACAP receptor activation.

Animals↗
PubMed1996

Presentation of Ehlers-Danlos syndrome: iliac artery pseudoaneurysm rupture.

We present a case of acute flank and groin pain resulting from a ruptured left iliac artery with pseudoaneurysm in a patient with previously undiagnosed Ehlers-Danlos syndrome (EDS). EDS is an uncommon, heterogeneous disease of abnormal collagen production with potentially fatal sequelae. The nine major types of EDS have varying clinical manifestations and degrees of severity. Type IV EDS is of special concern in that it is frequently associated with life-threatening vascular complications such as arterial aneurysm formation with rupture and dissection. EDS should be suspected in young people with vascular complications, recurrent joint dislocations, or fragile skin. In patients with known EDS, abdominal, flank, or pelvic pain should be investigated promptly to rule out life-threatening complications involving the vascular system, gastrointestinal tract, or gravid uterus.

Acute Disease↗
PubMedDate not supplied

Non-pigmenting cutaneous-mucosal fixed drug eruption due to piroxicam.

BACKGROUND: Piroxicam is a widely used anti-inflammatory drug. Most adverse reactions affect gastrointestinal system, liver and skin. Fixed drug eruption although very unusual, has also been described, but with cutaneous involvement exclusively. We present the case of a 49-year-old man who suffered three episodes of fixed drug eruption with cutaneous-mucosal involvement, even simulating an autoimmune disease, whenever he was treated with oral piroxicam. METHODS AND RESULTS: He was patch tested on normal skin with the GEIDC standard series and an NSAIDs series. He was patch tested on normal skin and on fixed eruption with piroxicam, meloxicam and tenoxicam (all of them 1 % pet). Oral challenge test was not performed due to the severity and reproducibility in previous reactions. Results showed a positive patch test to piroxicam (1 % pet) on fixed eruption, with negative results to the rest. CONCLUSIONS: Adverse drug reactions may present a wide variability of clinical symptoms. In these situations an accurate clinical history is necessary. To our knowledge this is the 1st report of non-pigmenting fixed drug eruption with cutaneous-mucosal involvement due to piroxicam. Cross-reactivity between oxicams could not be demonstrated by patch test on fixed eruption.

Anti-Inflammatory Agents, Non-Steroidal↗