Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis.
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BACKGROUND: Soluble iron salts are toxic for parenteral administration because free iron catalyzes free radical generation. Pyrophosphate strongly complexes iron and enhances iron transport between transferrin, ferritin, and tissues. Hemodialysis patients need iron to replenish ongoing losses. We evaluated the short-term safety and efficacy of infusing soluble ferric pyrophosphate by dialysate. METHODS: Maintenance hemodialysis patients receiving erythropoietin were stabilized on regular doses of intravenous (i.v.) iron dextran after oral iron supplements were discontinued. During the treatment phase, 10 patients received ferric pyrophosphate via hemodialysis as monthly dialysate iron concentrations were progressively increased from 2, 4, 8, to 12 micrograms/dl and were then sustained for two additional months at 12 micrograms/dl (dialysate iron group); 11 control patients were continued on i.v. iron dextran (i.v. iron group). RESULTS: Hemoglobin, serum iron parameters, and the erythropoietin dose did not change significantly from month 0 to month 6, both within and between the two groups. The weekly dose of i.v. iron (mean +/- SD) needed to maintain iron balance during month 6 was 56 +/- 37 mg in the i.v. iron group compared with 10 +/- 23 mg in the dialysate iron group (P = 0.001). Intravenous iron was required by all 11 patients in the i.v. iron group compared with only 2 of the 10 patients receiving 12 micrograms/dl dialysate iron. The incidence of adverse effects was similar in both groups. CONCLUSIONS: Slow infusion of soluble iron pyrophosphate by hemodialysis may be a safe and effective alternative to the i.v. administration of colloidal iron dextran in maintenance hemodialysis patients. (+info)
A macrolactam inhibitor of T helper type 1 and T helper type 2 cytokine biosynthesis for topical treatment of inflammatory skin diseases.
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T lymphocytes play a critical part in inflammatory skin diseases but are targeted by available therapies that have only partial efficacy, significant side-effects, or both. Because psoriasis, atopic dermatitis, and allergic contact hypersensitivity are associated with T helper type 1 (Th1), T helper type 2 (Th2), or mixed Th1-Th2 cell subsets and cytokine types, respectively, there is a need for a better broad-based inhibitor. The macrolactam ascomycin analog, ABT-281, was found to inhibit potently T cell function across species and to inhibit expression of multiple cytokines in human peripheral blood leukocytes which have been found in human skin disease cells and tissues. These included immunoregulatory Th1 (interleukin-2 and interferon-gamma) and Th2 (interleukin-4 and interleukin-5) cytokines. ABT-281 was shown to have potent topical activity (ED50 = 0.6% in acetone/olive oil) in a stringent swine model of allergic contact hypersensitivity, but its potency was markedly reduced compared with ascomycin when administered systemically due to more rapid clearance. Topical application of 3% ABT-281 in acetone/olive oil over 25% of the body surface in swine resulted in undetectable blood levels. Compared with a wide potency range of topical corticosteroids in clinical formulations, 0.3% and 1% ABT-281 ointments profoundly inhibited dinitrochlorobenzene-induced contact hypersensitivity in the pig by 78% and 90%, respectively, whereas super-potent steroids such as clobetasol propionate only inhibited in the 50% range and mild to moderate potency steroids such as fluocinolone acetonide were inactive. The potent topical activity of ABT-281 in swine, its superior efficacy, its rapid systemic clearance following uptake into the bloodstream, and its ability to inhibit cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value in inflammatory skin diseases, including psoriasis, atopic dermatitis, and allergic contact dermatitis. (+info)
Glucocorticosteroids in the management of rheumatoid arthritis.
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Glucocorticosteroids are used frequently in the management of patients with rheumatoid arthritis. Data supporting their efficacy and safety are still meagre. Glucocorticosteroids may be used systemically with different routes of administration (oral, i.m. and i.v.), in different doses and for different periods of time. The effectiveness of glucocorticosteroids in reducing inflammation in the short term has been shown for oral treatment in a dose of 7.5 mg prednisolone daily or more, for i.m. pulses (120 mg methylprednisolone every 4 weeks) and for i.v. methylprednisolone pulses. For longer periods of treatment, the evidence suggesting effectiveness of low-dose oral glucocorticosteroids is more limited. Some data suggest that different regimens of glucocorticosteroids may retard the development of erosions in patients with rheumatoid arthritis. The toxicity of short-term treatment is relatively low. For long-term treatment, the development of osteoporosis is a serious problem. Concomitant therapy with either calcitriol or bisphosphonates may reduce this risk. (+info)
Nasal immunization induces Haemophilus influenzae-specific Th1 and Th2 responses with mucosal IgA and systemic IgG antibodies for protective immunity.
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To determine the efficacy of a mucosal vaccine against nontypeable Haemophilus influenzae (NTHi), mice were immunized nasally, orally, intratracheally, or intraperitoneally with NTHi antigen together with cholera toxin. Antigen-specific IgA antibody titers in nasal washes and the numbers of antigen-specific IgA-producing cells in nasal passages showed the greatest increases in mice immunized nasally. Cytokine analysis showed that interferon-gamma, interleukin (IL)-2, IL-5, IL-6, and IL-10 were induced by nasal immunization, suggesting that Th2- and Th1-type cells were generated. Furthermore, bacterial clearance of a homologous strain of NTHi from the nasal tract was significantly enhanced in the nasal immunization group. These findings suggest that nasal immunization is an effective vaccination regimen for the induction of antigen-specific mucosal immune responses, which reduce the colonization of NTHi in the nasal tract. (+info)
Neonatal exposure to the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine via breast milk or directly induces intestinal tumors in multiple intestinal neoplasia mice.
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We examined whether the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) could increase intestinal tumorigenesis in neonatal C57BL/6J-Min/+ mice, a murine model for familial adenomatous polyposis. Min/+ mice are heterozygous for a nonsense mutation in the adenomatous polyposis coli gene and spontaneously develop multiple intestinal adenomas, primarily in the small intestine. Neonatal Min/+ mice (3-6 days old) were exposed to PhIP via breast milk from lactating dams given 8 s.c. injections of 50 mg/kg PhIP three times a week or to 8 s.c. injections of 25 or 50 mg/kg PhIP directly, over the same period. At the age of 11 weeks, the number, diameter and location of the intestinal tumors were scored. Remarkably, a 2- to 4-fold increase in the number of small intestinal tumors was seen in Min/+ mice exposed to PhIP via breast milk (P < 0.001). To our knowledge, this is the first time PhIP has been reported to induce tumors following exposure via breast milk from PhIP-exposed dams. Upon direct exposure to 50 mg/kg PhIP, a 6- to 9-fold increase in the number of small intestinal tumors was observed (P < 0.001). The diameter of the PhIP-induced small intestinal tumors was slightly increased (P < 0.001). In the colon, a 3- to 4-fold increase in the number of tumors was seen in Min/+ mice exposed to PhIP via breast milk (P = 0. 004). Direct exposure to 50 mg/kg PhIP caused a 2- to 6-fold increase in the number of colonic tumors (P = 0.014). The PhIP-induced colonic tumors were located more distally and displayed a smaller diameter than the tumors from the controls (P < 0.05). In contrast to a previous study, where PhIP showed only a moderate tumorigenic effect in adult Min/+ mice, the present study demonstrates a strong tumorigenic effect of PhIP in neonatally exposed Min/+ mice, even after exposure via breast milk from PhIP-exposed dams. (+info)
Intracoronary and intravenous administration of basic fibroblast growth factor: myocardial and tissue distribution.
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Therapeutic angiogenesis using various heparin-binding growth factors is a promising treatment for ischemic heart disease. Single dose intracoronary (IC) or i.v. delivery are most practical for clinical use. This study was designed to investigate the myocardial and tissue deposition of basic fibroblast growth factor (bFGF) after IC and i.v. administration in normal and chronically ischemic animals. Twenty-four Yorkshire pigs were used (12 normal and 12 ischemic animals) with IC and i.v. administration of 125I-bFGF (25 microCi) combined with cold bFGF (30 microg) and heparin (3 mg). Tissue and myocardial distribution was determined at 1 and 24 h by measuring 125I-bFGF specific activity and by organ and light level autoradiography. The liver accounted for the majority of 125I-bFGF activity at 1 h (37.6 +/- 17.1% for IC and 42.1 +/- 17.7% for i.v. delivery), with a reduction to 2.8 +/- 1.5% for IC and 1.5 +/- 0.9% for i.v. delivery by 24 h. Total cardiac specific activity at 1 h was 0.88 +/- 0.89% for IC and 0.26 +/- 0.08% for i.v. administration (p =.12) and decreased to 0.05 +/- 0.04% (p =.05, versus 1 h) and 0. 04 +/- 0.01% (p <.001, versus 1 h) at 24 h, respectively. IC but not i.v. delivery resulted in higher deposition in ischemic than normal myocardium. IC delivery resulted in enhanced bFGF deposition only in myocardial territories subtended by the infused artery. Intravenous delivery compares favorably with IC delivery with a 3- to 4-fold reduction in myocardial deposition at 1 h and with similar solid organ deposition. The less invasive nature of i.v. delivery, its potential for repeat administration, and its applicability to a larger population may offset its resultant reduced myocardial deposition. Efficacy studies are ongoing. (+info)
Inhibition of calcium/calmodulin-dependent protein kinase II in rat hippocampus attenuates morphine tolerance and dependence.
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Learning and memory have been suggested to be important in the development of opiate addiction. Based on the recent findings that calcium/calmodulin-dependent protein kinase II (CaMKII) is essential in learning and memory processes, and morphine treatment increases CaMKII activity in hippocampus, the present study was undertaken to examine whether inhibition of hippocampal CaMKII prevents morphine tolerance and dependence. Here, we report that inhibition of CaMKII by intrahippocampal dentate gyrus administration of the specific inhibitors KN-62 and KN-93 to rats significantly attenuated the tolerance to the analgesic effect of morphine and the abstinence syndrome precipitated by opiate antagonist naloxone. In contrast, both KN-04 and KN-92, the inactive structural analogs of KN-62 and KN-93, failed to attenuate morphine tolerance and dependence, indicating that the observed effects of KN-62 and KN-93 are mediated through inhibition of CaMKII. Furthermore, administration of CaMKII antisense oligonucleotide into rat hippocampal dentate gyrus, which decreased the expression of CaMKII specifically, also attenuated morphine tolerance and dependence, while the corresponding sense oligonucleotide of CaMKII did not exhibit such inhibitory effect. Moreover, the KN-62 treatment abolished the rewarding properties of morphine as measured by the conditioned place preference. These results suggest that hippocampal CaMKII is critically involved in the development of morphine tolerance and dependence, and inhibition of this kinase may have some therapeutic benefit in the treatment of opiate tolerance and dependence. (+info)
Respiratory mucosal immunization with reovirus serotype 1/L stimulates virus-specific humoral and cellular immune responses, including double-positive (CD4(+)/CD8(+)) T cells.
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Respiratory virus infections are a serious health challenge. A number of models that examine the nature of the respiratory immune response to particular pathogens exist. However, many pathogens that stimulate specific immunity in the lung are frequently not effective immunogens at other mucosal sites. A pathogen that is an effective respiratory as well as gastrointestinal immunogen would allow studies of the interaction between the mucosal sites. Reovirus (respiratory enteric orphan virus) serotype 1 is known to be an effective gut mucosal immunogen and provides a potential model for the relationship between the respiratory and the gut mucosal immune systems. In this study, we demonstrate that intratracheal immunization with reovirus 1/Lang (1/L) in C3H mice resulted in high titers of virus in the respiratory tract-associated lymphoid tissue (RALT). High levels of reovirus-specific immunoglobulin A were determined in the RALT fragment cultures. The major responding components of the bronchus-associated lymphoid tissue were the CD8(+) T lymphocytes. Cells from draining lymph nodes also exhibited lysis of reovirus-infected target cells after an in vitro culture. The present study also describes the distribution of transiently present CD4(+)/CD8(+) double-positive (DP) T cells in the mediastinal and tracheobronchial lymph nodes of RALT. CD4(+)/CD8(+) DP lymphocytes were able to proliferate in response to stimulation with viral antigen in culture. Furthermore, these cells exhibited lysis of reovirus-infected target cells after in vitro culture. These results establish reovirus 1/L as a viable model for future investigation of the mucosal immune response in the RALT and its relationship to the common mucosal immune system. (+info)