Citations

We analysed the adverse events of placebo in acute and preventive randomized, double-blind, placebo-controlled studies for migraine treatment. Fifty-seven trials (oral triptans, non-steroidal anti-inflammatory drugs, nasal ergot alkaloids and preventive agents) were included. From 10 to 30% of subjects reported adverse events after placebo. Most common were features associated with a migraine attack, such as nausea, phono- and photophobia. Other frequent complaints resembled those of the active drug (e.g. chest pressure in triptan trials). A third group of adverse events appeared to be coincidental (e.g. sleep disturbance). Adverse events following placebo are probably related to the drug under study and the symptomatology of migraine; some have no obvious explanation.

ABSTRACT Fluorescein isothiocyanate-labeled monoclonal antibodies specific for fungal melanin were used in this study to visualize melanin-like components of the Pneumocystis carinii cell wall. A colorimetric enzyme assay confirmed these findings. This is the first report of melanin-like pigments in Pneumocystis .

Renal artery stenosis (RAS) may lead to renal injury, partly mediated through increased oxidative stress. However, the potential effects of chronic oral antioxidant intervention on the stenotic kidney remain unknown. This study was designed to test the hypothesis that chronic antioxidant vitamin supplementation in RAS would preserve renal function and structure. Single-kidney hemodynamics and function were quantified in vivo in pigs using electron-beam CT after 12 weeks of unilateral RAS (n=7), a similar degree of RAS orally supplemented with vitamins C (1 g) and E (100 IU/kg) (RAS+Vitamins, n=7), or controls (normal, n=7). Renal tissue was studied ex vivo using Western blotting and immunohistochemistry. Mean arterial pressure was similarly elevated in both RAS groups, while ischemic renal volume and glomerular filtration rate were similarly reduced. Renal blood flow was decreased in RAS compared with normal (326.5±99.9 versus 553.4±48.7 mL/min, respectively, P =0.01), but preserved in RAS+Vitamins (485.2±104.1 mL/min, P =0.3 versus normal). The marked increase in the expression of the NADPH-oxidase subunits p47phox and p67phox, nitrotyrosine, endothelial and inducible nitric oxide synthase, and nuclear factor-κB observed in RAS ( P <0.05 versus normal) was normalized in RAS+Vitamins ( P >0.1). Furthermore, trichrome staining and the expression of transforming growth factor-β and tissue inhibitor of matrix-metalloproteinase-1 were also decreased in RAS+Vitamins. In conclusion, chronic blockade of the oxidative stress pathway in RAS using antioxidant vitamins improved renal hemodynamics and decreased oxidative stress, inflammation, and fibrosis in the ischemic kidney. These observations underscore the involvement of oxidative stress in renal injury in RAS and support a role for antioxidant vitamins in preserving the ischemic kidney.

We examined whether interactions between angiotensin II (Ang II), endothelin (ET), nitric oxide (NO), and prostaglandins (PGs) differentially regulate perfusion to distinct vascular beds. For this, we blocked either angiotensin AT 1 or ET receptors or both and then sequentially inhibited NO and PG synthesis in anesthetized dogs. Blocking Ang II or ET had similar effects on systemic hemodynamics: Mean arterial pressure fell slightly without altering cardiac output. Blocking both caused a synergistic fall in mean arterial pressure and increased cardiac output. Pulmonary vascular resistance was not altered by blocking Ang II, ET, or both but progressively increased during NO and PG blockade in group 2 (which had unblocked ET receptors), suggesting that endogenous ET exerts pulmonary vasoconstriction that is tempered by NO and PGs. In the kidney, blocking Ang II increased regional blood flow (RBF), glomerular filtration rate (GFR), and fractional excretion of sodium (FENa). In contrast, blocking ET did not alter RBF, and it decreased GFR and FENa. Combined Ang II and ET blockade markedly increased RBF without altering GFR, and FENa was maintained at the levels as when only ET was blocked. Sequentially inhibiting NO and PGs decreased RBF when Ang II or ET were blocked but had little effect when both were blocked. Finally, Ang II or ET blockade did not alter iliac blood flow. Inhibiting NO and PGs decreased iliac blood flow when Ang II or ET but not both were blocked. These results suggest that regional differences in the interactions between endogenous Ang II, ET, NO, and PGs are important determinants in systemic, pulmonary, and regional hemodynamics.

Albuminuria increases the risk of cardiovascular events in patients with essential hypertension and diabetic subjects. The heritability (h 2 ) of albuminuria in multiplex hypertensive families is unknown. We calculated the familial aggregation of urine albumin:creatinine ratio (ACR) and performed a genome-wide scan to assess for loci contributing to ACR in participants enrolled in the Hyper tension G enetic E pidemiology N etwork (HyperGEN). To perform the genome scan, we analyzed genotype results from 2589 individuals from 805 families in the Family Blood Pressure Program. ACR and covariates were available in 1727 individuals (mean age, 57.1 years). Estimates of h 2 were obtained by using variance component methodology as implemented in the SOLAR software package. Linkage was tested between 387 markers spanning the genome at an average interval of 9.32 cM, using SOLAR multipoint analysis. The h 2 of log urine ACR was 0.49 ( P <1×10 −7 ) after controlling for significant main and interactive effects of age, gender, race, body mass index, blood pressure, and use of ACE inhibitors or angiotensin-2 receptor blockers. The genome-wide scan revealed a maximum LOD score of 2.73 on chromosome 19 (robust corrected LOD, 2.40; P =0.0009) at marker D19S591 and a LOD score of 2.0 on chromosome 12 (robust corrected LOD, 1.75; P =0.005) at marker PAH. These analyses demonstrate the marked heritability of urine ACR in families enriched for the presence of members with essential hypertension. They suggest that a gene(s) associated with urinary ACR may be present on human chromosomes 19 and 12.

Abstract Adaphostin (NSC 680410), an analog of the tyrphostin AG957, was previously shown to induce Bcr/abl down-regulation followed by loss of clonogenic survival in chronic myelogenous leukemia (CML) cell lines and clinical samples. Adaphostin demonstrated selectivity for CML myeloid progenitors in vitro and remained active in K562 cells selected for imatinib mesylate resistance. In the present study, the mechanism of action of adaphostin was investigated in greater detail in vitro. Initial studies demonstrated that adaphostin induced apoptosis in a variety of Bcr/abl- cells, including acute myelogenous leukemia (AML) blasts and cell lines as well as chronic lymphocytic leukemia (CLL) samples. Further study demonstrated that adaphostin caused intracellular peroxide production followed by DNA strand breaks and, in cells containing wild-type p53, a typical DNA damage response consisting of p53 phosphorylation and up-regulation. Importantly, the antioxidant N-acetylcysteine (NAC) blunted these events, whereas glutathione depletion with buthionine sulfoximine (BSO) augmented them. Collectively, these results not only outline a mechanism by which adaphostin can damage both myeloid and lymphoid leukemia cells, but also indicate that this novel agent might have a broader spectrum of activity than originally envisioned. (Blood. 2003;102:4512-4519)

Background— Statins primarily metabolized by cytochrome P450 3A4 (CYP3A4) reportedly reduce clopidogrel’s metabolism to active metabolite, thus attenuating its inhibition of platelet aggregation ex vivo. However, the clinical impact of this interaction has not been evaluated. Methods and Results— Clopidogrel for the Reduction of Events During Observation (CREDO) was a double-blind, placebo-controlled, randomized trial comparing pretreatment (300 mg) and 1-year (75 mg/d) clopidogrel therapy (clopidogrel) with no pretreatment and 1-month clopidogrel therapy (75 mg/d) (control) after a planned percutaneous coronary intervention. All patients received aspirin. The 1-year primary end point was a composite of death, myocardial infarction, and stroke. We performed a post hoc analysis to evaluate the clinical efficacy of concomitant clopidogrel and statin administration, categorizing baseline statin use to those predominantly CYP3A4-metabolized (atorvastatin, lovastatin, simvastatin, and cerivastatin) (CYP3A4-MET) or others (pravastatin and fluvastatin) (non-CYP3A4-MET). Of the 2116 patients enrolled, 1001 received a CYP3A4-MET and 158 a non-CYP3A4-MET statin. For the overall study population, the primary end point was significantly reduced in the clopidogrel group (8.5% versus 11.5%, RRR 26.9%; P =0.025). This clopidogrel benefit was similar with statin use, irrespective of treatment with a CYP3A4-MET (7.6% clopidogrel, 11.8% control, RRR 36.4%, 95% CI 3.9 to 57.9; P =0.03) or non-CYP3A4-MET statin (5.4% clopidogrel, 13.6% control, RRR 60.6%, 95% CI −23.9 to 87.4; P =0.11). Patients given atorvastatin or pravastatin had similar 1-year event rates. Additionally, concomitant therapy with statins had no impact on major or minor bleeding rates. Conclusions— Although ex vivo testing has suggested a potential negative interaction when coadministering a CYP3A4-metabolized statin with clopidogrel, this was not clinically observed statistically in a post hoc analysis of a placebo-controlled study.

B7‐H1 is a novel B7 family protein attributed to costimulatory and immune regulatory functions. Here we report that human myoblasts cultured from control subjects and patients with inflammatory myopathies as well as TE671 muscle rhabdomyosarcoma cells express high levels of B7‐H1 after stimulation with the inflammatory cytokine IFN‐γ. Coculture experiments of MHC class I/II‐positive myoblasts with CD4 and CD8 T cells in the presence of antigen demonstrated the functional consequences of muscle‐related B7‐H1 expression: production of inflammatory cytokines, IFN‐γ and IL‐2, by CD4 as well CD8 T cells was markedly enhanced in the presence of a neutralizing anti‐B7‐H1 antibody. This observation was paralleled by an augmented expression of the T cell activation markers CD25, ICOS, and CD69, thus showing B7‐H1‐mediated inhibition of T cell activation. Further, we investigated 23 muscle biopsy specimens from patients with polymyositis (PM), inclusion body myositis (IBM), dermatomyositis (DM), and nonmyopathic controls for B7‐H1 expression by immunohistochemistry: B7‐H1 was expressed in PM, IBM, and DM specimens but not in noninflammatory and nonmyopathic controls. Staining was predominantly localized to areas of strong inflammation and to muscle cells as well as mononuclear cells. These data highlight the immune regulatory properties of muscle cells and suggest that B7‐H1 expression represents an inhibitory mechanism induced upon inflammatory stimuli and aimed at protecting muscle fibers from immune aggression.