Anti-colitic efficacy of SC-41930 in colitic cotton-top tamarins

To evaluate anti-colitic efficacy, eight cotton-top tamarins (CTTs) with histologically confirmed persistent active colitis were given the anti-inflammatory agent SC-41930 (10 mg/kg BW by gavage BID) for eight weeks. Colonic endoscopy and biopsy observations, CBCs and clinical chemistries, and stool consistency were evaluated pre-, mid-, and posttreatment. Colitic activity was graded histologically from A1 (mild) to A5 (severe); results varied among the seven animals that completed the study: five improved, one worsened, and one was unchanged. Serum enzyme levels were significantly reduced with treatment. Stool condition remained puddly throughout treatment and body weights did not vary from pretreatment levels. However, SC-41930 produced histological evidence (reduced numbers of polymorphonuclear cells) of anti-colitic efficacy over an eight-week treatment period in CTTs with persistent active colitis. These results support the use of the CTT colitis model to evaluate efficacy of therapeutic agents and provide useful predictive information to aid in the medical management of human IBD.     

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.     

Anti-inflammatory activity of the leukotriene B4 receptor antagonist,SC-41930, in colitic cotton-top tamarins

Cotton-top tamarins (CTTs) with histologically confirmed persistent and active colitis were given the leukotriene B₄ (LTB₄) receptor antagonist, SC-41930, (10 mg/kg BW, by gavage b.i.d.) for eight weeks. Anti-inflammatory activity was evaluated by colonic biopsy, stool consistency and the level of the lipid mediators LTB₄ and prostaglandin E₂ (PGE₂) in rectal dialysates. Stool consistency did not improve with treatment but did not worsen. Blood chemistry (ALT, AST, LDH) and hematological parameters neither showed any untoward effects of SC-41930 treatment nor was there any effect on body weight. In rectal dialysate LTB₄ levels were significantly reduced from pretreatment level of 4.87±1.46 ng/ml to 1.07±0.67 and 2.45±0.13 ng/ml at 4 and 8 weeks, respectively, and higher prostaglandin E₂ (PGE₂) over time. Histologically, 5/7 improved, 1/7 remained the same and 1/7 worsened.

Oral SC-41930 treatment was safe and associated with an anti-colitic effect. The reduced LTB₄ levels (affecting granulocyte degranulation and recruitment into tissues) and increased PGE₂ (perhaps exerting a mucosal protective effect) may, in part explain the observed efficacy of this compound in active tamarin colitis. Use of the CTT model could provide insight into the inflammatory mediator contribution to idiopathic colitis and serve as a useful bridge between preclinical pharmacology and the assessment of these compounds in the medical management of human inflammatory bowel disease.

     

Pathogenesis of spontaneous idiopathic colitis in cotton-top tamarins (Saguinus oedipus)

The pathogenesis of cotton-top tamarin (CTT) spontaneous idiopathic ulcerative colitis was investigated. A 6-yr examination (endoscopy and mucosal biopsy) of forty 4- to 7-yr-old CTTs at 2- to 3-month intervals has shown that CTT spontaneous colitis resembles the human disease in its time course, age dependence, varying periods of exacerbation and remission, and eventual susceptibility of the animal to colon cancer. Considerable animal-to-animal variation existed, as is seen in humans. Active colitis (increased PMNs) was superimposed upon chronic (inactive) colitis and occurred either asymptomatically or symptomatically. While age had little effect on body weight and stool condition, the severity of the colitis (mild vs. severe) and the duration of the disease dramatically affected both CTT body weight and stool condition. Spontaneous CTT colitis closely mimics pathogenesis of the human disease and further demonstrates its validity as an animal model; the model also offers promise of helping afflicted human patients through targeted therapeutics.

     

Effects of SC-41930 on leukocyte adherence and emigration in rat mesenteric venules

This study demonstrates that 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 LTB₄ receptor antagonist, reduces LTB₄-induced leukocyte adhesion and emigration in rat mesenteric venules. The mesentery of Sprague-Dawley rats was prepared for intravital microscopic examination and venules of 25–35 m were chosen for evaluation. In control animals, LTB₄ (20nM) was superfused over the mesentery for 30 min. In the treatment group SC-41930 (5 M) was superfused for 30 min, followed by a 30 min superfusion with SC-41930 and LTB₄. The LTB₄-induced increase in leukocyte adherence and emigration in postcapillary venules was significantly attenuated by pretreatment with SC-41930. Other experiments demonstrated that platelet-activating-factor-induced leukocyte adherence was not affected by SC-41930. These results indicate that SC-41930 is a potent inhibitor of LTB₄-induced leukocyte-endothelial cell adhesive interactions in postcapillary venules.     

The design and synthesis of second generation leukotriene B4 (LTB4) receptor antagonists related to SC-41930

SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, is a selective, orally active, LTB₄ receptor antagonist currently in clinical trials for psoriasis and ulcerative colitis. Exhaustive SAR studies found a potential backup compound, SC-50605, which was 7–16 times more potent than SC-41930 in LTB₄ receptor binding, chemotaxis and degranulation assays. SC-50605 also inhibited LTB₄-induced intradermal chemotaxis in cavine skin at an oral dose of 0.10 mg/kg and displayed good activity in animal models of colitis and epidermal inflammation both orally and topically.     

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.     

SC-41930, a leukotriene B4 receptor antagonist,inhibits 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) binding to epidermal cells

SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxyl]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, a potent leukotriene-B₄ (LTB₄) receptor antagonist, inhibitsin vivo 12-hydroxyei-cosatetraenoic acid (12-HETE)-induced neutrophil infiltration, suggesting a potential 12-HETE receptor antagonist effect, as well. Since 12-HETE is assumed to have a pathophysiological role in inflammatory skin diseases, and epidermal cells possess high affinity binding sites for 12(S)-HETE, we studied the effect of SC-41930 on 12(S)-HETE binding to the human epidermal cell line, SCL-II. SC-41930 antagonized the 12(S)-HETE binding to SCL-II cells with a Ki of 480 nM. This Ki value is similar to that obtained for the inhibition of LTB₄ binding to human neutrophils. Our results show that SC-41930, in addition to its LTB₄ receptor antagonist effect, exhibits 12-HETE receptor antagonist effect as well, and therefore may be of benefit in skin diseases with elevated 12-HETE levels.Dr. Kemény is on leave from the Department of Dermatology, Albert Szent-Györgyi Medical University, Szeged, Hungary, as a recipient of the Humboldt Fellowship, and his work was supported by the Alexander von Humboldt Foundation.     

Comparative immunogenicity studies on epstein-barr virus membrane antigen (MA) gp340 with novel adjuvants in mice,rabbits, and cotton-top tamarins

The effectiveness of immunisation of mice, rabbits, and cotton-top tamarins with small amounts of EB virus MA glycoprotein gp340, incorporated into artificial liposomes, has been compared using various routes of injection with or without additional adjuvants. Liposomes containing gp340 gave specific high titre antibodies after i.p. or i.v. administration, and the addition of lipid A to the liposomes resulted in a significant enhancement of the response. Antibodies generated by the above procedure were virus neutralising and bound gp340 specifically. These findings indicate an advantageous approach for use with a prototype vaccine for the prevention of EB virus infection.     

Inflammatory related changes in lung tissue mechanics after bleomycin-induced lung injury

The impact of lung remodelling in respiratory mechanics has been widely studied in bleomycin-induced lung injury. However, little is known regarding the relationship between the amount of lung inflammation and pulmonary tissue mechanics. For this purpose, rats were intratracheally instilled with bleomycin (n=29) or saline (n=8) and sacrificed at 3, 7, or 15 days. Forced oscillatory mechanics as well as indices of remodelling (elastic fibre content and hydroxyproline) and inflammation (myeloperoxidase content, total cell count, alveolar wall thickness, and lung water content) were studied in lung tissue strips. Tissue resistance increased significantly at day 15, while hysteresivity was significantly higher in bleomycin group compared to control at all time points. Elastic fibres, hydroxyproline and myeloperoxidase contents augmented after bleomycin at days 7 and 15. Tissue resistance and hysteresivity were significantly correlated with myeloperoxidase, elastic fibre and lung water content. In conclusion, inflammatory structural changes and elastogenesis are the main determinants for hysteretic changes in this 2-week bleomycin-induced lung injury model.     

Development of hepatic pathology in GBV-B-infected red-bellied tamarins (Saguinus labiatus)

GB virus B (GBV-B) is a new world monkey-associated flavivirus used to model acute hepatitis C virus (HCV) infection. Critical for evaluation of antiviral or vaccine approaches is an understanding of the effect of HCV on the liver at different stages of infection. In the absence of longitudinal human tissue samples at defined time points, we have characterized changes in tamarins. As early as 2 weeks post-infection histological changes were noticeable, and these were established in all animals by 6 weeks. Despite high levels of liver-associated viral RNA, there was reversal of hepatic damage on clearance of peripheral virus though fibrosis was demonstrated in four tamarins. Notably, viral RNA burden in the liver dropped to near undetectable or background levels in all animals which underwent a second viral challenge, highlighting the efficacy of the immune response in removing foci of replication in the liver. These data add to the knowledge of GBV-B infection in New World primates which can offer attractive systems for the testing of prophylactic and therapeutic treatments and the evaluation of their utility in preventing or reversing liver pathology.     

Morphofunctional changes in the placenta after ozone therapy

Macro- and microscopic aspects in the morphology of placenta after ozone therapy were studied in pregnant women with placental insufficiency and the results were compared with the control group. In the main group, the placentas were smaller and weighed less. After ozone therapy enlargement of terminal villi with true syncytiocapillary membranes was noted. A stimulating effect of ozone therapy on the growth and differentiation of terminal villi was established. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 130, No. 7, pp. 117–120, July, 2000     

Morphofunctional changes in the placenta after ozone therapy

Macro- and microscopic aspects in the morphology of placenta after ozone therapy were studied in pregnant women with placental insufficiency and the results were compared with the control group. In the main group, the placentas were smaller and weighed less. After ozone therapy enlargement of terminal villi with true syncytiocapillary membranes was noted. A stimulating effect of ozone therapy on the growth and differentiation of terminal villi was established. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 130, No. 7, pp. 117–120, July, 2000     

Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation

The atherogenic lipoprotein(a) (Lp(a)) is significantly increased in patients with kidney disease. Some studies in hemodialysis patients described this increase to be dependent on the genetic apolipoprotein(a) (apo(a)) isoforms. Only patients who express high molecular weight (HMW) apo(a) isoforms but not those with low molecular weight (LMW) isoforms show a relative increase of Lp(a) when compared to healthy controls matched for apo(a) isoforms. However, this was not confirmed by all studies. We therefore prospectively investigated the changes of Lp(a) deriving from each apo(a) isoform in heterozygotes following kidney transplantation. Lp(a) concentrations were measured by ELISA. To calculate the isoform-specific concentrations and the changes of Lp(a) deriving from each isoform, we densitometrically scanned the apo(a) bands from immunoblots before and after transplantation in 20 patients expressing two apo(a) isoforms. Of these, 10 patients expressed both an LMW and an HMW apo(a) isoform. The other 10 patients expressed only HMW isoforms. Densitometric scanning of apo(a) bands and calculation of isoform-derived Lp(a) concentrations clearly demonstrated that the decrease of Lp(a) following kidney transplantation is caused by changes in the expression of HMW apo(a) isoforms. In some patients, we observed an almost complete disappearance of the HMW apo(a) isoform after transplantation. This study clearly demonstrates that the changes of Lp(a) plasma concentrations in kidney disease depend on the genetically determined size of apo(a). This provides evidence for an interaction of apo(a) genetic variability and kidney function on Lp(a) concentrations.     

Hormone replacement therapy (HRT) in women after genital cancer

Women treated for genital cancer are not only suffering from the disease itself, but are in most cases confronted with the side effects of the loss of ovarian function. Therefore, it is of utmost importance for the gynecologist, who cares for these patients, to strongly consider the benefits and drawbacks of hormone replacement therapy (HRT) in these women. Overall, it appears, that in women with vulva, vaginal, cervical, ovarian and tubal cancer individually adjusted HRT can be employed for the benefit and well-being of these patients considering psychosomatic, functional and organic aspects. Patients after endometrial cancer should be differentiated according to the stage of the disease. In all cases the individual minimal effective dose of HRT should be searched for.     

Plastic changes of motor network after constraint-induced movement therapy

The effects of short-term constraint-induced movement (CIM) therapy on the activation of the motor network were investigated with functional magnetic resonance imaging (fMRI). Movement of the less-affected arms of five patients was restricted and intensive training of the affected upper limb was performed. Functional MRI was acquired before and after two-weeks of CIM therapy. All patients showed significant improvement of motor function in their paretic limbs after CIM therapy. For three patients, new activation in the contralateral motor/premotor cortices was observed after CIM therapy. Increased activation of the ipsilateral motor cortex and SMA was observed in the other patient. Our results demonstrated that plastic changes of the motor network occurred as a neural basis of the improvement subsequent to CIM therapy following brain injury.     

Inflammatory Manifestations in Chronic Granulomatous Disease (CGD)

Chronic granulomatous disease (CGD) is a genetically heterogeneous disease characterized by recurrent life-threatening infections with bacteria and fungi as well as dysregulated inflammatory mechanisms. CGD is caused by defects in the NADPH oxidase, the enzyme complex responsible for generation of superoxide and other reactive oxygen species (ROS) in phagocytic cells. In this review we will focus our attention on those particular inflammatory manifestations associated with CGD, their frequencies and the underlying immunologic mechanisms favoring it occurrence.     

Renal hemodynamic changes after beta-blocker-diuretic combination therapy in azotemic hypertensive patients

The effects of beta-blocker therapy with either nadolol or propranolol were compared during therapy with hydrochlorothiazide (HCTZ) 50 mg b.i.d. on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), effective renal blood flow (ERBF), blood pressure, and heart rate in 22 patients with essential hypertension and mild to moderate renal insufficiency. The clearances of inulin and para-aminohippurate (PAH) were used to estimate renal hemodynamic measurements. These parameters were determined after 2 weeks of HCTZ plus placebo and at 1, 3, and 6 months after the addition of beta-blocker to HCTZ. Significant reductions in blood pressure and heart rate were seen, but no significant reduction of renal hemodynamics were seen with either beta-blocker-HCTZ combination. Since 50% of the patients in each drug group were either Black or White, hemodynamic data were also analyzed by race. One month after beta-blocker addition there was a slight reduction of GFR in both Whites (47 +/- 6 vs. 40 +/- 5 ml/min, p greater than .05) and Blacks (44 +/- 5 vs. 40 +/- 6 ml/min, p less than .05). By month 6, GFR in Whites rose to 57 +/- 9 ml/min, whereas in Blacks it fell significantly to 36 +/- 6 ml/min (p less than .01). Similarly, at month 1, ERBF declined by 12% and 13% in Whites and Blacks, respectively. However, at month 6, ERBF rose by 28% in Whites and remained 11% lower in Blacks, p less than .05. In summary, in the group as a whole neither beta-blocker significantly altered renal hemodynamics when added to HCTZ therapy.(ABSTRACT TRUNCATED AT 250 WORDS)