3(S)-hydroxy-leukotriene B4 is a potent granulocyte chemotaxin in the guinea pig dermis

Inflammation Research -     

Antiinflammatory effects of second-generation leukotriene B4 receptor antagonist,SC-53228: Impact upon Leukotriene B4- and 12(R)-HETE- mediated events

Leukotriene B₄ (LTB₄) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] are proinflammatory products of arachidonic acid metabolism that have been implicated as mediators in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB₄ and 12(R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 {7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxyl]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid}, a first-generation LTB₄ receptor antagonist, inhibited the chemotactic actions of LTB₄ when given orally with an ED₅₀ value of 1.7 mg/kg. The second-generation LTB₄ receptor antagonist, SC-53228 [(+)-(S)-7-(3-{2-(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy} propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid], inhibited LTB₄-induced chemotaxis when given intragastrically with an ED₅₀ value of 0.07 mg/kg. Furthermore, SC-53228 inhibited 12(R)-HETE-induced granulocyte chemotaxis with an oral ED₅₀ value of 5.8 mg/kg. When dosed orally over a range of 0.03–100 mg/kg, SC-53228 gaveC _max plasma concentrations of 0.015–41.1g/ml. SC-53228 inhibited LTB₄-primed membrane depolarization of human neutrophils with an IC₅₀ value of 34 nM. As a potent LTB₄ receptor antagonist, SC-53228 may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, in which LTB₄ and/or 12(R)-HETE are implicated as inflammatory mediators.     

Temporal relationships of cytokine production in mouse non-lethal sepsis: Effect of nitric oxide synthase inhibitors

Inflammation Research -     

Modulation of the chemotactic properties of complement fragments C5a and C3 by the anti-inflammatory agent,SC-41930

Cleavage of the fifth component of complement yields C5a, a potent neutrophil (PMN) and eosinophil chemoattractant, and modulator of microvascular permeability. Similarly, but to a lesser degree, C3 increases vascular permeability and histamine release. SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid), an orally-active antiinflammatory agent was tested in anin vivo model of dermal PMN chemotaxis induced by r-hu-C5a and hu-C3. Intradermal injection of C5a in the guinea pig resulted in a significant dose-dependent influx of PMNs at 4 hours as assessed by the dermal levels of myeloperoxidase (MPO). SC-41930 (20 mg/kg) given orally to guinea pigs with intradermal injections of 1 μg C5a significantly (p<0.001) reduced dermal MPO content. SC-41930 was less potent against C3, requiring 40 mg/kg to significantly reduce dermal MPO levels. Agents such as SC-41930, which nullify complement's proinflammatory properties, may well have therapeutic potential.     

Effect of the leukotriene B4 receptor antagonist,SC-41930, on experimental allergic encephalomyelitis (EAE) in the guinea pig

The accepted model for the human demyelinating disease, multiple sclerosis (MS), is experimental allergic encephalomyelitis (EAE). We assessed the ability of SC-41930(7-[3(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxyl acid), to modulate the symptoms of acute EAE generated in guinea pigs. Animals were pretreated with SC-41930 (20 mg/kg, i.p.) for two days followed by thrice-weekly maintenance. At day 52, a significant number of the SC-41930-treated animals were alive as compared to EAE alone. Control animals had an increase in body weight while EAE animals lost over 20% (p<0.5) of their body weight by day 18. SC-41930-treatment significantly reduced, but did not completely inhibit the cachectic response. The results indirectly implicate LTB₄ in the pathogenesis of EAE. Agents that modify this model be useful in the treatment of human MS.     

Inflammatory mediators in cotton-top tamarins (CTT) with acute and chronic colitis

Spontaneous colitis in CTT's presents cytological characteristics similar to chronic ulcerative colitis in humans, e.g. inflammatory cell infiltrate and crypt abscesses. To better characterize CTT colitis as a potential model for human inflammatory bowel disease (IBD), inflammatory mediators identified in colonic tissue of human IBD patients and/or experimental colitis models were assayed. Inflammatory mediator changes in plasma and colon from tamarins with acute (n=10) and chronic (n=10) colitis (by mucosal biopsy) were assayed by RIAs. Similar inflammatory mediators were found in the CTT's with acute colitis. In the plasma, PAF and PGE₂ levels were lower in acute colitis CTT's, no LTB₄ was detected, and histamine levels were not different from chronic colitic animals. In the colon, myeloperoxidase and interleukin-1 were significantly higher in acute colitis, PGE₂ and LTB₄ were higher but not significantly, and PAF was not different from chronic CTT's. These data suggest that a combination of events are occurring in the pathogenesis of tamarin colitis that involves some of the same mediators that are found in the human disease and in other experimental models. The importance of these findings to human IBD remains for further investigation; however, the spontaneous primate model offers an exciting approximation of the disease development and merits further investigation for understanding the pathogenesis of human IBD as well as to aid in development of targeted therapeutics.     

Laparoscopic Surgery for Solid Pseudopapillary Tumor of the Pancreas

Background and Objectives:

Solid pseudopapillary tumors of the pancreas are rare and occur most frequently in young women. They have an uncertain pathogenesis and unclear clinical behavior. Our aim was to evaluate the clinical presentation of solid pseudopapillary tumors and assess the efficacy of treatment with minimally invasive surgery.

Methods:

From March 1997 to February 2011, 13 of 273 patients who underwent laparoscopic procedures on the pancreas were found to have solid pseudopapillary tumors. There were 12 female patients and 1 male patient. The median age was 21 years (range, 15–77 years). Abdominal pain was the most common presenting symptom (n = 9). Tumors were incidentally found in 3 patients on computed tomography scans obtained for other reasons.

Results:

Enucleation of the tumor was performed in 4 patients, including 3 in whom the tumor was located in the head of the pancreas. Eight patients underwent distal pancreatectomy with splenectomy, whereas spleen-preserving distal pancreatectomy was performed in one case. The median tumor size was 6 cm (range, 1.5–11 cm), the median operative time was 197 minutes (range, 68–320 minutes), and the median blood loss was 50 mL (range, <50–750 mL). Distal resections were performed with a linear stapler. Four patients had postoperative complications. The median length of hospital stay was 5 days (range, 2–12 days). During a median follow-up period of 11 months (range, 3–121 months), no local recurrences or distant metastases were found.

Conclusion:

Laparoscopic resections and enucleations of solid pseudopapillary tumors of the pancreas can be performed safely and with adequate resection margins even if the tumors are located in the head of the organ.     

Acetylator phenotype and genotype in HIV-infected patients with and without sulfonamide hypersensitivity

Adverse reactions to sulfonamides occur at a higher frequency in patients infected with the human immunodeficiency virus (HIV) than noninfected patients. Some studies have suggested that patients with the slow acetylator phenotype are predisposed to these reactions, whereas other studies suggest that the slow acetylator genotype is not a predisposing factor. To rationalize these seemingly contradictory observations, the authors determined the N-acetyltransferase 2 (NAT2) genotype and phenotype in patients with and without a history of hypersensitivity reactions to sulfonamides. HIV-infected patients with a history of a delayed-type hypersensitivity reaction to trimethoprim-sulfamethoxazole were enrolled, along with a group of AIDS patients with no history of hypersensitivity (delayed or immediate). NAT2 phenotype was determined in both groups using dapsone, while the genotype was determined using a polymerase chain reaction-restriction fragment length polymorphism assay. Ten of 14 patients (71%) with a history of hypersensitivity exhibited the slow acetylator phenotype, while 8 of 14 patients (57%) without such a history exhibited this same phenotype (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 0.4-9.0; p = 0.69, Fisher's Exact Test). While 9 of 14 patients (64%) with a history of hypersensitivity exhibited a slow acetylator genotype, only 4 of 14 patients (29%) without such a history exhibited this genotype (ns). There were more instances of discordance between deduced and actual phenotype in the nonhypersensitive patients (n = 4) than in the hypersensitive patients (n = 1). The reported higher frequency of the slow acetylator phenotype among patients with a history of hypersensitivity to sulfonamides does not appear to be explained by metabolic changes that would cause discordance between acetylator genotype and phenotype.     

Acetylator phenotype and genotype in patients infected with HIV: discordance between methods for phenotype determination and genotype

The acetylator phenotype and genotype of AIDS patients, with and without an acute illness, was compared with that of healthy control subjects (30 per group). Two probe drugs, caffeine and dapsone, were used to determine the phenotype in the acutely ill cohort. Polymerase chain reaction amplification and restriction fragment length polymorphism analysis served to distinguish between the 26 known NAT2 alleles and the 21 most common NAT1 alleles. The distribution (%) of slow:rapid acetylator phenotype seen among acutely ill AIDS patients differed with the probe substrate used: 70:30 with caffeine versus 53:47 with dapsone. Phenotype assignment differed considerably between the two methods and there were numerous discrepancies between phenotype and genotype. The NAT2 genotype distribution was 45:55 slow:rapid. Control subjects, phenotyped only with caffeine, were 67:33 slow:rapid versus 60:40 genotypically. Stable AIDS patients, phenotyped only with dapsone, were 55:45 slow:rapid versus 46:54 genotypically. Following resolution of their acute infections, 12 of the acutely ill subjects were rephenotyped with dapsone. Phenotype assignment remained unchanged in all cases. The distribution of NAT1 alleles was similar in all three groups. It is evident from the amount of discordance between caffeine phenotype and dapsone phenotype or genotype that caution should be exercised in the use of caffeine as a probe for NAT2 in acutely ill patients. It is also clear that meaningful study of the acetylation polymorphism requires both phenotypic and genotypic data.     

Association between acetylator genotype and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) DNA adduct formation in colon and prostate of inbred Fischer 344 and Wistar Kyoto rats

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine (HCA) found in cooked meats, causes colon and prostate tumors in male rats. Polymorphic N-acetyltransferase metabolizes N-hydroxy-PhIP to a DNA-reactive form. Liver, colon, and prostate PhIP-DNA adduct levels were compared in male rapid-acetylator Fischer 344 (F344) and slow-acetylator Wistar-Kyoto (WKY) rats fed 0.01 or 0.04% PhIP. Liver PhIP-DNA adduct levels at both PhIP doses, and colon PhIP-DNA adduct levels at the 0.01% PhIP dose were unaffected by acetylator genotype. However, in rats fed 0.04% PhIP, colon PhIP-DNA adduct levels were higher in rapid acetylator F344 rats (P < 0.05). Similarly, prostate PhIP-DNA adduct levels were higher in rapid acetylator F344 rats at both PhIP doses (P < 0.05). The combination of the high-PhIP dose and rapid-acetylator genotype resulted in the highest level of PhIP-DNA adducts in rat colon and prostate.