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William B Smith

Publications and source records attributed to William B Smith.

16 recordsLinked to original sources
PubMed2006

Eosinophilic mucus chronic rhinosinusitis: clinical subgroups or a homogeneous pathogenic entity?

BACKGROUND: Eosinophilic mucus chronic rhinosinusitis (EMCRS) can be subclassified using the criteria of detection of fungi in eosinophilic mucus and systemic fungal allergy. Allergic fungal sinusitis (AFS), a subgroup of EMCRS characterized by the presence of fungal allergy, is proposed to be an immunoglobulin (Ig)E-driven disease, distinct from other EMCRS subgroups. However, our recent studies cast doubt on the central pathogenic role of allergy in AFS. The purpose of this study was to examine the clinical features of EMCRS patients from the different subcategories to determine the relevance of this classification system. METHOD: The demographic, clinical, and immunologic characteristics of the EMCRS subgroups were examined prospectively and compared with three control groups: healthy volunteers, allergic rhinitis with fungal allergy, and chronic rhinosinusitis without eosinophilic mucus. RESULTS: EMCRS patients with allergy were younger than those without. There was no significant difference in clinicopathologic parameters between EMCRS subgroups. As a single group, EMCRS had a more severe sinus disease compared with chronic rhinosinusitis patients. CONCLUSIONS: AFS was not clinically distinct from other subgroups of EMCRS. However, eosinophilic mucus may mark a more severe and distinct form of sinus disease.

Adult↗
PubMed2006

Pharmacokinetics of telbivudine in subjects with various degrees of hepatic impairment.

This study evaluated the effect of hepatic impairment on the pharmacokinetics of telbivudine, an investigational nucleoside antiviral for the treatment of chronic hepatitis B virus infection. Twenty-four subjects were assigned to four hepatic function groups (normal function and mild, moderate, and severe impairment, with six subjects in each group) on the basis of Child-Pugh scores. The subjects were administered a single oral dose of 600 mg telbivudine, and blood samples were collected over a 48-h interval for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. Telbivudine plasma concentration-time profiles were similar across the four hepatic function groups. The principal pharmacokinetic parameters of drug exposure, i.e., the maximum plasma concentration and area under the drug concentration-time curve, were comparable between subjects with various degrees of hepatic impairment and those with normal hepatic function. Results from this single-dose pharmacokinetic assessment therefore provide a pharmacologic rationale for further evaluation of the safety and efficacy of telbivudine in hepatitis B virus-infected patients with decompensated liver diseases.

Administration, Oral↗
PubMed2005

Efficacy and safety of fasudil in patients with stable angina: a double-blind, placebo-controlled, phase 2 trial.

OBJECTIVES: This study sought to evaluate the efficacy and safety of fasudil, an orally available rho kinase inhibitor, in patients with stable angina. BACKGROUND: Several small, non-placebo-controlled trials suggest that fasudil reduces myocardial ischemia in patients with stable or vasospastic angina. METHODS: In a multicenter, double-blind, placebo-controlled, randomized trial, the efficacy and safety of fasudil were evaluated in stable angina patients. Of the 206 patients screened, 84 patients with reproducible exercise times were randomized 1:1 to fasudil or placebo. Nitroglycerin as needed and a beta- or calcium-channel blocker were allowed. Fasudil or matching placebo was force-titrated from 20 mg three times daily to 80 mg twice daily with 20 mg twice-daily increments every two weeks. Symptom-limited exercise testing was performed after two, four, six, and eight weeks of treatment. RESULTS: At peak, exercise duration was significantly improved at all visits in both groups, although exercise duration was numerically greater in patients receiving fasudil versus those receiving placebo. Time to > or =1 mm ST-segment depression was increased with fasudil at both peak and trough compared with placebo (172.1 s vs. 44.0 s, p = 0.001, and 92.8 s vs. 26.4 s, p = 0.02, respectively). Fasudil improved Seattle Angina Questionnaire scores. No significant differences in Canadian Cardiovascular Society class, time to angina, or frequency of angina or nitroglycerin use were noted between groups. Fasudil did not affect heart rate or blood pressure, and was well tolerated. CONCLUSIONS: Fasudil up to 80 mg three times daily significantly increased the ischemic threshold of angina patients during exercise with a trend toward increased exercise duration. Further investigation of fasudil doses >80 mg three times daily is indicated.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2005

Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure.

Diuretics are frequently required to treat fluid retention in patients with congestive heart failure (CHF). Unfortunately, they can lead to a decline in renal function, electrolyte depletion, and neurohumoral activation. Arginine vasopressin (AVP) promotes renal water reabsorption via the V2 receptor, and its levels are increased in CHF. This study was designed to assess the effects of a single oral dose of tolvaptan, a selective V2-receptor blocker, in the absence of other medications, on renal function in human CHF and to compare this to the effects of a single oral dose of furosemide. We hypothesized that V2-receptor antagonism would yield a diuresis comparable to furosemide but would not adversely affect renal hemodynamics, plasma electrolyte concentration, or neurohumoral activation in stable human CHF. Renal and neurohumoral effects of tolvaptan and furosemide were assessed in an open-label, randomized, placebo-controlled crossover study in 14 patients with NYHA II-III CHF. Patients received placebo or 30 mg of tolvaptan on day 1 and were crossed over to the other medication on day 3. On day 5, all subjects received 80 mg of furosemide. Tolvaptan and furosemide induced similar diuretic responses. Unlike tolvaptan, furosemide increased urinary sodium and potassium excretion and decreased renal blood flow. Tolvaptan, furosemide, and placebo did not differ with respect to mean arterial pressure, glomerular filtration rate, or serum sodium and potassium. We conclude that tolvaptan is an effective aquaretic with no adverse effects on renal hemodynamics or serum electrolytes in patients with mild to moderate heart failure.

Antidiuretic Hormone Receptor Antagonists↗
PubMed2005

Photorearrangement of alpha-azoxy ketones and triplet sensitization of azoxy compounds.

[reaction: see text] Although some aspects of azoxy group radical chemistry have been investigated, unhindered alpha-azoxy radicals remain poorly understood. Here we report the generation of alpha-azoxy radicals under mild conditions by irradiation of alpha-azoxy ketones 4a,b. These compounds undergo alpha-cleavage to yield radicals 5a,b, whose oxygen atom then recombines with benzoyl radicals to produce presumed intermediate 15. Formal Claisen rearrangement gives alpha-benzoyloxyazo compounds 8a,b, which are themselves photolabile, leading to both radical and ionic decomposition. The ESR spectrum of 5a was simulated to extract the isotropic hyperfine splitting constants, which showed its resonance stabilization energy to be exceptionally large. Azoxy compounds have been found for the first time to be good quenchers of triplet excited acetophenone, the main sensitized photoreaction of 7Z in benzene being deoxygenation. While this reaction has been reported previously, it was always in hydrogen atom donating solvents, where chemical sensitization occurred. The principal direct irradiation product of 4bZ and model azoxyalkane 7Z is the E isomer, whose thermal reversion to Z is much faster than that of previously studied analogues.

Journal Article↗
PubMed2005

Fungal-specific humoral response in eosinophilic mucus chronic rhinosinusitis.

OBJECTIVES/HYPOTHESIS: An immunoglobulin (Ig)E-mediated allergic pathogenesis is presumed in allergic fungal sinusitis (AFS), yet extensive polyps and eosinophilic mucus (EM) in the paranasal sinuses may also occur in the absence of allergy. Although a noninvasive fungal pathogenesis is presumed in all chronic rhinosinusitis with EM (EMCRS), fungal-specific nonallergic immune responses have not been thoroughly investigated. We tested the hypothesis that there is a fungal-specific humoral response in EMCRS and that it is not confined to IgE. STUDY DESIGN: EMCRS patients were prospectively stratified into subgroups based on the presence or absence of fungi within EM and of fungal-specific systemic IgE. There were 12 AFS, 5 AFS-like, 8 nonallergic fungal eosinophilic sinusitis (NAFES), and 5 nonallergic, nonfungal eosinophilic sinusitis (NANFES) patients. METHODS: Alternaria alternata and Aspergillus fumigatus-specific serum IgE, IgG, IgM, and IgA was measured by enzyme-linked immunosorbent assay and compared with strictly defined healthy and disease-control groups. RESULTS: Fungal-specific IgG (Alternaria alternata P = .0002; Aspergillus fumigatus P = .004), and IgA levels (Alternaria alternata P = .0016; Aspergillus fumigatus P = .002) were higher in EMCRS compared with healthy volunteers but not with disease controls. Fungal-specific IgG3 levels were significantly elevated in all the EMCRS subgroups compared with controls for either fungal antigen (P < .0001). Importantly, fungal-specific IgE levels were not significantly different between fungal-allergic EMCRS and disease controls. CONCLUSIONS: Fungal-specific immunity characterized by serum IgG3 and not IgE, distinguished the EMCRS subgroups from control groups regardless of the presence of fungus within EM or of systemic fungal allergy. Fungal-specific IgE responses in fungal-allergic EMCRS were no different to those in fungal-allergic controls, thus challenging the presumption of a unique pathogenic role of fungal allergy in "allergic fungal sinusitis."

Adolescent↗
PubMed2005

Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction.

Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catechol-O-methyltransferase. The objectives of this study were to estimate the pharmacokinetic parameters and plasma protein binding of micafungin in volunteers with moderate hepatic dysfunction (n = 8), volunteers with creatinine clearance < 30 mL/min (n = 9), and matched controls (n = 8 and n = 9, respectively). Single-dose micafungin pharmacokinetics were estimated using noncompartmental techniques. There was a statistically lower area under the observed micafungin concentration-time curve (AUC) from time 0 to infinity for subjects with moderate hepatic dysfunction as compared to control subjects (97.5 +/- 19 microg.h/mL vs 125.9 +/- 26.4 microg.h/mL, P = .03), although there was no difference in micafungin weight-adjusted clearance (10.9 +/- 1.7 mL/h/kg vs 9.8 +/- 1.8 mL/h/kg, P = .2). The difference in area under the concentration-time curve may be explained by the differences in body weight between subjects and controls. Renal dysfunction did not alter micafungin pharmacokinetics.

Adult↗
PubMed2002

Multicenter evaluation of SonoVue for improved endocardial border delineation.

OBJECTIVES: Two multicenter studies were conducted to evaluate the safety and efficacy of SonoVue as a contrast agent for enhanced left ventricular endocardial border delineation (LVEBD), and to compare the efficacy of SonoVue and Albunex in adult patients with a suboptimal, nonenhanced echocardiogram. BACKGROUND: The use of contrast to enhance echocardiographic assessment of LVEBD is well-established. SonoVue is a new microbubble contrast agent that contains sulfur hexafluoride. METHODS: Patients were randomized to receive four injections of SonoVue (0.5, 1, 2, and 4 ml), or two injections of Albunex and two injections of hand-agitated saline (0.08 and 0.22 ml/kg). Echocardiographic images were evaluated at the study centers and by four blinded, offsite reviewers for degree of left ventricle opacification (LVO), duration of contrast enhancement, and LVEBD. RESULTS: LVO scores were significantly higher for all doses of SonoVue. Patients with complete LVO ranged from 34%-87% for SonoVue and from 0%-16% for Albunex. The mean duration of useful contrast effect ranged from 0.8-4.1 minutes for SonoVue and < 15 seconds for Albunex. Mean increases in LVEBD scores ranged from 3.8-18.2 for SonoVue and 0.1-4.3 for Albunex. SonoVue (cumulative 7.5 ml dose) was well-tolerated, with a safety profile similar to that observed in the control group. CONCLUSIONS: SonoVue is superior to Albunex for improving visualization of endocardial borders in patients with suboptimal noncontrast echocardiograms. Optimal increases in LVEBD, LVO, and duration of useful contrast effect were observed at the 2.0 ml dose of SonoVue.

Adult↗
PubMed1980

Right to treatment.

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Commitment of Persons with Psychiatric Disorders↗
PubMedDate not supplied

Pharmacokinetics and safety of binodenoson after intravenous dose escalation in healthy volunteers.

BACKGROUND: Binodenoson, a highly selective agonist of the adenosine A 2A receptor, is being developed as a short-acting coronary vasodilator as an adjunct to radiotracers for use in myocardial stress imaging. This study was designed to assess the single-dose pharmacokinetics, safety, and tolerability of intravenous binodenoson. METHODS AND RESULTS: This was a single-center, open-label, nonrandomized, dose-escalation study in 24 healthy volunteers. Each subject received 3 successive intravenous doses of binodenoson (0.1, 0.2, 0.4, 0.6, 1, 2, 3, 4, 5, and 6 microg/kg), each infused over a period of 10 minutes and separated by washout periods of at least 120 minutes. Generally, binodenoson was well tolerated. There were no serious adverse events. However, there was a dose-related increase in adverse events (e.g., headache, nausea, vasodilation, chest pain), consistent with the pharmacology of the drug. Binodenoson exhibited linear pharmacokinetics as indicated by a dose-proportional increase in peak concentration (C max ) and area under the concentration-time curve (AUC). Systemic clearance was independent of dose but was correlated with body weight. The mean terminal half-life of binodenoson across all doses was 10 +/- 4 minutes. CONCLUSIONS: Overall, binodenoson was well tolerated and exhibited linear pharmacokinetics when administered intravenously over a 60-fold dose range from 0.1 to 6 microg/kg.

Adenosine↗