Olsalazine in maintenance of clinical remission in patients with ulcerative colitis

Frequent minor side effects are associated with sulfasalazine. The realization that it is the 5-aminosalicylic acid moiety that is the active component of sulfasalazine and that the side effects are probably due to the sulfapyridine has prompted the search for a similar but safer compound. Olsalazine, consisting of two molecules of 5-ASA without sulfasalazine may avoid the problems due to sulfasalazine. One hundred one patients were entered into a double-blind placebo-controlled study of the use of olsalazine 92 g daily) in preventing relapse in patients who had recently recovered from an acute attack of ulcerative colitis. Patients were treated for 12 months. Forty-nine were randomized to olsalazine (39 with limited and 10 with extensive disease) and 52 to placebo (42 with limited and 10 with extensive disease). Life-table analysis showed that the median time to relapse in patients on olsalazine was 342 days, which was significantly longer than the 100 days in the placebo group (P=0.024). The most important side effect experienced with olsalazine that necessitated withdrawal from the study was drug-induced diarrhea in 16% (8/49). There was a similar incidence of minor side effects reported in the two groups, and in no patients were major or dangerous side effects reported. In patients who did not develop diarrhea, olsalazine was well tolerated and successfully prevented rapid relapse in the recently ill patients entered into this study.     

Risk factors for hepatitis C virus infection among blood donors in southern Brazil: a case-control study

Background  

In Brazil, it is estimated that between 2.5 and 4.9% of the general population present anti-hepatitis C virus (HCV) antibodies, which corresponds to as many as 3.9 to 7.6 million chronic carriers. Chronic liver disease is associated with HCV infection in 20% to 58% of the Brazilian patients. The objective of this case-control study was to investigate the risk factors for presence of anti-HCV antibody in blood donors in southern Brazil.     

Serum IgA anti-gliadin antibodies in an adult population sample

IgA-class anti-gliadin antibodies (AGA) and IgA-, IgG-, IgM-class anti-reticulin antibodies (ARA) were determined in 1461 persons, representing 84% of a population from the village of Karksi-Nuia. AGA were detected by enzyme-linked immunosorbent assay (ELISA) and ARA by indirect immunofluorescence. Fifty-two (3.5%) persons had IgA-class AGA, of whom 48 and an additional three of four persons with diarrhea were biopsied. All biopsies showed normal small intestinal mucosal architecture. All 1461 persons were negative for ARA. Our results demonstrate that AGA are frequently detected in an adult Estonian population and positivity increases with age in persons with normal small intestinal mucosa. Positivity for AGA does not predict silent undetected celiac disease but rather represents a normal response to dietary antigens in the elderly. Inability to detect ARA suggests that celiac disease does not exist in this population. As none of the AGA-positive but ARA-negative biopsied persons had celiac disease, ARA might be a more specific serologic marker for celiac disease than AGA.Supported by a grant from the Ministry of Health, Estonia. Dr. Oivi Uibo was also supported by a grant from the Emil Aaltonen Foundation.     

The Role of Late INa and Antiarrhythmic Drugs in EAD Formation and Termination in Purkinje Fibers

Multiple components of cardiac Na current play a role in determining electrical excitation in the heart. Recently, the role of nonequilibrium components in controlling cardiac action potential plateau duration, and their importance in regulating the occurrence of afterdepolarizations and arrhythmias have garnered more attention. In particular, late Na current (late I _Na) has been shown to be important in LQT2 and LQT3 arrhythmias. Class III agents like dofetilide, clofilium, and sotalol, which can all cause a drug-induced form of LQT2, significantly lengthen action potential duration at 50% and 90% repolarization in isolated rabbit Purkinje fibers, and can initiate the formation of early afterdepolarizations, and extra beats. These actions can lead to the development of a serious ventricular tachycardia, torsades de pointes, in animal models and patients. However, pretreatment with agents that block late I _Na, like lidocaine, mexiletine, and RSD1235, a novel mixed ion channel blocker for the rapid pharmacologic conversion of atrial fibrillation, significantly attenuates the prolonging effects of Class III agents or those induced by ATX-II, a specific toxin that delays Na channel inactivation and amplifies late I _Na greatly, mimicking LQT3. The Na channel block caused by lidocaine and RSD1235 can be through the open or inactivated states of the channel, but both equivalently inhibit a late component of Na current ( I _Na), recorded at 22°C using whole-cell patch clamp of Nav1.5 expressed in HEK cells. These protective actions of lidocaine, mexiletine, and RSD1235 may result, at least in part, from their ability to inhibit late I _Na during action potential repolarization, and inhibition of the inward currents contributing to EAD and arrhythmia formation.     

Urinary 6 beta-hydroxycortisol excretion in rheumatoid arthritis

The objective was to analyse whether the activity of the cytochrome P450 isoenzyme CYP3A4 is altered by disease activity of rheumatoid arthritis (RA). Urinary 6 beta-hydroxycortisol excretion, expressed as a fraction of the urinary creatinine output, was measured in 21 patients with RA treated with three different disease-modifying anti- rheumatic drugs (DMARDs) over 24 weeks. There were no correlations between urinary 6 beta-hydroxycortisol/creatinine (6 beta-OHC/Creat) ratio and measurements of disease activity such as plasma viscosity, Ritchie articular index and early morning stiffness. In addition, the three DMARDs sulphasalazine, sodium aurothiomalate and D-penicillamine, smoking and the intake of various CYP3A4 substrates had no consistent detectable effect on the 6 beta-OHC/Creat ratio. There is no evidence that the dosage of drugs metabolized by the CYP3A4 isoenzyme needs to be adjusted for disease activity in RA.      

Allogenic transplant of canine peripheral blood stem cells mobilized by recombinant canine hematopoietic growth factors

We have studied graft-versus-host disease (GVHD) after transplantation of allogeneic peripheral blood stem cells (PBSC) mobilized by either recombinant canine granulocyte colony-stimulating factor (rcG-CSF) alone or combined with stem cell factor (rcSCF). These studies were prompted by the observation of extremely rapid and sustained engraftment of growth factor-mobilized PBSC in the autologous setting using genetically marked cells and changes in function of T lymphocytes from donors that had undergone mobilization. Specifically, lymphocytes from growth factor-treated donors were hyporesponsive in mixed leukocyte culture and in response to Con A, raising hopes that GVHD in dogs given growth factor mobilized allogenic PBSC might be altered in a beneficial way. Eighteen dogs were given a median of 17.1 x 10(8) PBSC/kg from littermate donors after 920 cGy of total body irradiation without postgrafting immunosuppression. Donors were either genotypically DLA-identical (n = 9) or DLA-haploidentical (n = 9). The median number of colony-forming unit-granulocyte macrophage (CFU-GM) infused was 27 x 10(4)/kg, and the number of CD34+ cells in the transplant was on the order of 4.6 x 10(6)/kg. The dogs received a median of 52.8 x 10(7) CD4 cells/kg and 13.7 X 10(7) CD8 cells/kg. All 18 dogs had prompt hematopoietic engraftment of donor cells as assessed by chimerism studies using variable number tandem repeat, as well as cytogenetic markers. Three of the nine dogs given grafts from DLA- identical littermates had fatal GVHD, five had transient GVHD, and one had no GVHD. All nine DLA-haploidentical recipients of PBSC developed fatal hyperacute GVHD. In conclusion, the expectation about rapid engraftment was fulfilled. However, incidence and severity of acute GVHD after transplantation of mobilized PBSC were not different than previously reported for nonmobilized PBSC or marrow. This model will allow for further studies, including T-cell depletion to minimize GVHD without increasing graft rejection.     

In Vivo Ethanol Experience Increases D2 Autoinhibition in the Ventral Tegmental Area

Alcoholism is characterized by compulsive alcohol intake after a history of chronic consumption. A reduction in mesolimbic dopaminergic transmission observed during abstinence may contribute to the negative affective state that drives compulsive intake. Although previous in vivo recording studies in rodents have demonstrated profound decreases in the firing activity of ventral tegmental area (VTA) dopamine neurons after withdrawal from long-term ethanol exposure, the cellular mechanisms underlying this reduced activity are not well understood. Somatodendritic dopamine release within the VTA exerts powerful feedback inhibition of dopamine neuron activity via stimulation of D₂ autoreceptors and subsequent activation of G protein-gated inwardly rectifying K⁺ (GIRK) channels. Here, by performing patch-clamp recordings from putative dopamine neurons in the VTA of mouse brain slices, we show that D₂ receptor/GIRK-mediated inhibition becomes more potent and exhibits less desensitization after withdrawal from repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 days). In contrast, GABA_B receptor/GIRK-mediated inhibition and its desensitization are not affected. Chelating cytosolic Ca²⁺ with BAPTA augments D₂ inhibition and suppresses its desensitization in control mice, while these effects of BAPTA are occluded in ethanol-treated mice. Furthermore, inositol 1,4,5-trisphosphate (IP₃)-induced intracellular Ca²⁺ release and Ca²⁺/calmodulin-dependent protein kinase II are selectively involved in the desensitization of D₂, but not GABA_B, receptor signaling. Consistent with this, activation of metabotropic glutamate receptors that are coupled to IP₃ generation leads to cross-desensitization of D₂/GIRK-mediated responses. We propose that enhancement of D₂ receptor-mediated autoinhibition via attenuation of a Ca²⁺-dependent desensitization mechanism may contribute to the hypodopaminergic state during ethanol withdrawal.