Reduced door-to-balloon times in acute ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention.

BACKGROUND: Primary percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI) significantly reduces mortality and morbidity, particularly when door-to-balloon (D2B) time is < 90 min. We sought to minimize preventable delays by instituting an on-site cardiology team-based approach in the emergency department (ED). METHODS: The on-site group comprised 146 consecutive patients with STEMI undergoing primary PCI after implementation of the on-site strategy. This new patient care model was compared with the conventional care administered before instituting the on-site cardiology team-based strategy in ED, which included 90 patients (interim group) receiving primary PCI at a catheterization room in the same building as the ED, and 147 patients (pre-on-site group) undergoing primary PCI at a catheterization room two blocks away from the ED. RESULTS: Median D2B time decreased from 107 min in the pre-on-site group to 72 min in the interim group, and to 47 min in the on-site group, respectively (p < 0.001). The percentage of D2B times < 90 min increased from 34% to 78% and 96%, respectively among the three groups (p < 0.001). Hospitalization costs were significantly reduced in the on-site and interim vs. pre-on-site groups ($5944, $5999, and $6581, respectively; p = 0.008). In-hospital mortality did not differ significantly among the three groups (4.8%, 2.2%, and 6.1%, respectively; p = 0.387). CONCLUSIONS: Institution of an on-site cardiology team-based approach in the ED significantly reduces D2B time in STEMI patients eligible for primary PCI.

Rubella seroepidemiology and estimations of the catch-up immunisation rate and persistence of antibody titers in pregnant women in Taiwan.

OBJECTIVE: To examine rubella seroepidemiology, and estimate rates of catch-up immunisation and persistence of antibody titers in pregnant women in Taiwan after mass immunisation. DESIGN: A retrospective study. SETTING: Two medical centres and four regional hospitals specialising in obstetric care. SAMPLE: A total of 43,640 prenatal rubella test results for pregnant women from 2001 to 2008. METHODS: Rubella immunoglobulin G (IgG) antibody assay. MAIN OUTCOME MEASURES: Seronegativity, rate of catch-up immunization, and antibody decline. RESULTS: The seronegativity was 10.9% in all pregnant women. Immigrant women had higher seronegativity than indigenous women (OR 2.86; 95% CI 2.65, 3.01). Indigenous women born prior to implementation of the vaccination programmes were more susceptible (20.1%) to rubella infection than were women born thereafter (6.7%). Rates of seropositive conversion were low in both Taiwanese-born and foreign-born women (11.5 and 30.7%, respectively). The rubella antibody titers for vaccinated Taiwanese women in the 1971-1976 and after-1976 birth cohorts declined by 0.6 and 2.3% per year, respectively. CONCLUSIONS: This study demonstrates high seronegativity of older indigenous and immigrant women, a low catch-up immunisation rate, and the persistence of rubella antibodies in Taiwan after mass vaccination. Our study suggests that a single dose of rubella vaccine in teenagers effectively increased rubella seropositivity during their childbearing years. This finding is useful for countries that lack the resources necessary for a two-dose regimen. We recommend free rubella antibody tests to women of childbearing age and free vaccination as required. All postpartum women testing negative for rubella antibodies should be vaccinated before they leave hospital.

Controlling chemical reactivity with antibodies.

The remarkable specificity of an antibody molecule has been used to accomplish highly selective functional group transformations not attainable by current chemical methods. An antibody raised against an amine-oxide hapten catalyzes the reduction of a diketone to a hydroxyketone with greater than 75:1 regioselectivity for one of two nearly equivalent ketone moieties. The antibody-catalyzed reaction is highly stereoselective, affording the hydroxyketone in high enantiomeric excess. Similarly, the reduction of ketones containing branched and aryl substituents, including the highly symmetrical 1-nitrophenyl-3-phenyl-2-propanone, was enantioselective. The simple strategy presented herein may find general applicability to the regio- and stereoselective reduction of a broad range of compounds.

Urinary calcium, sodium, and bone mass of young females.

Calcium is an important determinant of peak bone mass in young adults because of its influence on skeletal development during growth. Attainment of maximum peak bone mass requires optimal positive balance between calcium intake and obligatory losses of calcium, primarily in urine and feces. Urinary excretion is an important determinant of calcium retention in the body. Accordingly, the purpose of this study was to evaluate the influence of various nutrients on urinary calcium excretion, and to assess their impact on bone mass of young females, aged 8-13 y, during early puberty. The study was conducted in 381 healthy white females in pubertal stage 2. From each participant we collected basic anthropometric measurements, a 3-d food record, blood, a 24-h urine sample, and bone mass measurements of the total body and forearm by dual X-ray absorptiometry. Urinary sodium was found to be one of the most important determinants of urinary calcium excretion: [urinary calcium (mmol/d) = 0.01154 x urinary sodium (mmol/d) + 0.823], whereas calcium intake had relatively little impact: [urinary calcium (mmol/d) = 0.02252 x calcium intake (mmol/d) + 1.5261]. Urinary calcium was much higher at a calcium intake of approximately 37.5 mmol/d (1500 mg/d), supporting the notion that calcium is a threshold nutrient. Calcium intake had a significant positive influence on the bone mineral content and density of the whole body and radius shaft whereas urinary calcium had a negative influence, presumably by reducing calcium accretion into the skeleton.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of single photon and dual X-ray absorptiometry of the forearm in children and adults.

We compared single photon absorptiometry (SPA) to dual x-ray absorptiometry (DXA) for determination of bone mineral content (BMC), bone mineral density (BMD), and bone width (BW) of the forearm. The SPA and DXA measurements were done on the same subjects, using Lunar densitometers. The measurements were performed over the proximal radius (1/3 shaft) of the nondominant arm in 285 healthy, Caucasian females and males, ages 9-53. Correlation, linear, and split regression analyses for all subjects, and for subgroups (adults and children), were performed to compare SPA and DXA measurements. Corresponding measurements performed on two densitometers were highly correlated: r = 0.987, 0.975, and 0.943 for BMC, BMD, and BW, respectively. The corresponding measurements were also very similar in value, ranging from 0.9% to 4.1% difference, although they were different statistically. Correlations dropped slightly when subjects were separated into adult and children subgroups, and therefore, split regression analysis was performed resulting in R2 (adjusted) values of 97.6%, 95.5%, and 89.0% for BMC, BMD, and BW, respectively. Because the group indicator was statistically significant (p < 0.001) only for the BMC measurements but not for BMD and BW, linear regression of the whole sample was done as well. The difference in fitted values between the two regression methods was insignificant; therefore, we concluded that linear regression was sufficient for description of the relationship between SPA and DXA measurements. The precision study showed that the DXA had better reproducibility than SPA. The DXA precision in vivo (CV%) for BMC, BMD, and BW was 1.06, 0.83, and 0.95, respectively; and the SPA precision for same variables was 2.08, 2.12, and 0.95, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold.

The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.

Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines.

A series of hydroxamates was prepared from an aminoproline scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors, such as compound 47, display broad-spectrum activity with sub-nanomolar potency for some enzymes. Modifications of the P1' portion of the molecule played a key role in affecting both potency and selectivity within the MMP family. Longer-chain aliphatic substituents in this region of the molecule tended to increase potency for MMP-3 and decrease potency for MMP-1, as exemplified by compounds 48-50, while aromatic substituents, as in compound 52, generated broad-spectrum inhibition. The data is rationalized based upon X-ray crystal data which is also presented. While the in vitro peroral absorption seemed to be less predictable, it tended to decrease with longer and more hydrophilic substituents. Finally, a rat model of osteoarthritis was used to evaluate the efficacy of these compounds, and a direct link was established between their pharmacokinetics and their in vivo efficacy.

Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines.

A series of carboxylic acids were prepared from a propargylglycine scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for four enzymes within the MMP family. The inhibitors were typically potent against collagenase-3 (MMP-13) and gelatinase A (MMP-2), while they spared collagenase-1 (MMP-1) and only moderately inhibited stromelysin (MMP-3). Compound 40 represents a typical inhibition profile of a compound with reasonable potency. Introduction of polar groups was required in order to generate inhibitors with acceptable water solubility, and this often resulted in a loss of potency as in compound 63. High serum protein binding proved to be a difficult hurdle with many compounds such as 48 showing >99% binding. Some compounds such as 64 displayed approximately 90% binding, but no reliable method was discovered for designing molecules with low protein binding. Finally, selected data regarding the pharmacokinetic behavior of these compounds is presented.

Disposition of fenbendazole in the rabbit.

The disposition of fenbendazole was studied in rabbits following either oral or intravenous administration. The major metabolites appearing in plasma were fenbendazole sulphoxide (oxfendazole) and fenbendazole sulphone. Calculation of the total urinary and faecal elimination of the drug and of its known metabolites showed that only 40 per cent of the dose was recovered after oral dosing; 29.7 per cent after an intravenous dose. The sulphoxide and sulphone were minor elimination products. The major excretory metabolite was p-hydroxyfenbendazole.

Elimination of salicylic acid in goats and cattle.

Sodium salicylate was administered to cattle and goats IV and PO according to a crossover design. Total urinary excretion of SA and its metabolites was measured for 3 days after dosing. Salicyluric acid (SUA) was the only metabolite detected in urine of either species. Recovery of sodium salicylate and SUA in goats amounted to 67.9 and 34.6% of the dose, respectively, after IV administration. After oral dosing, total recoveries were 30.2% (sodium salicylate) and 71.7% (SUA) of dose. By comparison, cattle excreted significantly (P less than 0.05) less sodium salicylate (54.0%) and more SUA (49.9%) after IV dosing. The same pattern was observed after oral administration, wherein cattle excreted less than 12% as sodium salicylate and more than 99% as SUA. In both species, almost 90% of the drug excreted as sodium salicylate was found in urine within the first 12 hours after an IV dose and within 24 hours after oral dosing. The excretion of SUA was somewhat slower in both species, especially after oral administration. The data suggested that there were only quantitative differences in the metabolism and elimination of sodium salicylate between the 2 species, with cattle excreting a higher proportion of the drug as the glycine conjugate SUA.

Disposition of fenbendazole in the goat.

The disposition of fenbendazole was studied in goats after oral or IV administration. Plasma concentration vs time profiles were determined for fenbendazole and all of its metabolites. The total excretion of the drug and its metabolites in urine and feces was also measured for 6 days. A biliary cannula was inserted in 1 goat to study the excretion of fenbendazole and its metabolites into the bile. Fenbendazole was converted to its sulfoxide (oxfendazole), and the sulfone, primary amine, and p-hydroxylated metabolites. The active metabolite, oxfendazole, appeared in plasma, but only trace amounts were found in feces or urine. The major excretory metabolite was p-hydroxyfenbendazole.

Disposition of fenbendazole in cattle.

Fenbendazole (FBZ) was administered to cattle IV and orally in a crossover design. Plasma concentration vs time profiles were reported for FBZ and its major metabolites, the sulfoxide (oxfendazole) and the sulfone. The total excretion of FBZ and its metabolites in urine and feces was also measured for 6 days after administration. All known metabolites were identified in urine and feces except for fenbendazole amine. Neither this minor metabolite nor p-hydroxyfenbendazole (FBZ-OH) appeared in plasma. The major excretory product was FBZ-OH. After oral administration, only 44.6% of the dose was eliminated after 6 days, indicating a fairly high degree of sequestration, probably within the gastrointestinal tract.

Pharmacokinetics and metabolism of fenbendazole in channel catfish.

Fenbendazole (FBZ) was administered intravenously (1 mg/kg) and orally (5 mg/kg) to catheterized, confined channel catfish. Blood samples were collected for 72 h, and resulting FBZ plasma concentrations were pharmacokinetically modelled. Following intravenous administration t 1/2 alpha was 0.51 h, t 1/2 beta was 16.8 h, body clearance (C1B) was 0.0598 L/kg/h, and Vd (area) was 1.45 L/kg. After oral administration the t 1/2 (abs) was 1.47 h, the t 1/2 beta was 20.1 h, and the tlag was 0.1 h. Following oral administration of 5 mg FBZ/kg body weight, the following tissues and body fluids were sampled for concentrations of FBZ, oxfendazole (FBZ-SO), sulphone metabolite (FBZ-SO2) and hydroxy metabolite (FBZ-OH): liver, posterior kidney, fat, muscle, bowel contents and urine. Fenbendazole was detected in the highest concentrations in abdominal fat, whereas oxfendazole was found primarily in the kidney, liver and abdominal fat. The sulphone metabolite was detected only in urine and bowel contents, while the hydroxy metabolite was found most often in the liver and abdominal fat samples.

A versatile method for treating intracranial wide-neck aneurysms: catheter-assisted technique of three variations.

Successful management of aneurysms of complex morphology depends primarily on adjunct use of balloons or stents. However, these two methods are technically demanding and have higher complication rates. As an alternative to these two techniques, we have used a catheter-assisted technique with a number of cases. It is simple, versatile, and less demanding technically. This technique should be considered as an alternative strategy in cases of wide-necked aneurysms.

Comparison of the pharmacology of hydroxamate- and carboxylate-based matrix metalloproteinase inhibitors (MMPIs) for the treatment of osteoarthritis.

OBJECTIVE AND DESIGN: Hydroxamic-and carboxylic-acid based matrix metalloproteinase inhibitors (MMPIs) were compared for their potency against various MMPs, pharmacodynamic properties and in vivo efficacy in a model of cartilage degeneration. MATERIALS AND METHODS: The MMPIs were evaluated for their ability to inhibit human MMPs using the quenched fluorescence assay. The ability of the MMPIs to inhibit the degeneration of the knee joint was evaluated in rats injected intraarticularly with iodoacetate. The amount of MMPI in the plasma and cartilage was determined using liquid chromatography/mass spectrometry/mass spectrometry (LC/ MS/MS). Plasma protein binding was measured by ultrafiltration and unbound MMPI was quantitated using HPLC. RESULTS: The hydroxamic acid based inhibitor PGE-3321996 and the carboxylic acids PGE-2909492 and PGE-6292544 were potent MMP-13 inhibitors, but only the hydroxamic acid PGE 3321996 demonstrated significant inhibition of knee degeneration in the rat iodoacetate model. Both of the carboxylic acids demonstrated superior pharmacokinetic properties and established much higher plasma concentrations than the hydroxamic acid. However, neither of the carboxylic acids was detectable in the cartilage, whereas, the hydroxamic acid was present in both the cartilage and the plasma. The carboxylic acid based MMPIs also demonstrated higher plasma protein binding (>99%) than the hydroxamic acid (79%). CONCLUSIONS: Carboxylic acid-based MMPIs were identified that had superior in vivo plasma exposure compared to a hydroxamic acid inhibitor but lacked in vivo efficacy in the rat iodoacetate model of cartilage degeneration. The lack of in vivo efficacy of the carboxylic acid based MMPIs were probably due to their lack of cartilage penetration which was related to their physicochemical properties.

Competitive inhibition of [3H]dexamethasone binding to mammary glucocorticoid receptor by leupeptin.

The inhibitory effect of leupeptin on [3H]dexamethasone binding to the glucocorticoid receptor from lactating goat mammary cytosol has been studied. Leupeptin (10 mM) caused a significant (about 35%) inhibition of [3H]dexamethasone binding to glucocorticoid receptor. Binding inhibition is further increased following filtration of unlabeled cytosolic receptor through a Bio-Gel A 0.5-m column. Binding inhibition was partially reversed by monothioglycerol at 10 mM concentration. A double reciprocal plot revealed that leupeptin appears to be a competitive inhibitor of [3H]dexamethasone binding to the glucocorticoid receptor. Low salt sucrose density gradient centrifugation revealed that the leupeptin-treated sample formed a slightly larger (approximately 9 S) receptor complex (leupeptin-free complex sediments at 8 S).

Methodology for the analysis of fenbendazole and its metabolites in plasma, urine, feces, and tissue homogenates.

New methodology for the extraction and analysis of the anthelmintic fenbendazole and its metabolites from plasma, urine, liver homogenates, and feces from several animal species is presented. Quantitation of fenbendazole and its metabolites was conducted by high-pressure liquid chromatography using ultraviolet detection at 290 nm. The combined extraction and analysis procedures give excellent recoveries in all of the different biological matrices examined. High specificity, low limits of detection, and excellent linearity, accuracy, and inter- and intrasample variability were also obtained. The study of fenbendazole pharmacokinetics in vitro and in vivo should be greatly enhanced through the utilization of these methods.

The oxidative metabolism of fenbendazole: a comparative study.

The oxidative metabolism of fenbendazole (FBZ) was studied in hepatic fractions prepared from livers of cattle, sheep, goats, chickens, ducks, turkeys, rats, rabbits and catfish. All species produced the sulfoxide metabolite (oxfendazole; FBZ-SO), and p-hydroxyfenbendazole (FBZ-OH) was produced by all species except sheep. The product of demethoxycarbonylation, fenbendazole amine (FBZ-NH2), was not produced by liver preparations of any species. A fourth metabolite, resulting from the further oxidation of oxfendazole, fenbendazole sulfone (FBZ-SO2), was formed in all species but at highly varying rates. The chicken exhibited the highest overall rate of FBZ metabolism, followed by the duck, goat, sheep, steer, catfish, rat, rabbit, and turkey. Considerable variation was evident among avian species, the duck and turkey produced substantially less of the FBZ-OH and FBZ-SO2 metabolites than the chicken. Catfish liver preparations formed equivalent amounts of metabolite at 25 degrees C and 37 degrees C incubation temperatures. The formation of the sulfone metabolite (FBZ-SO2), however, was practically nonexistent in catfish.

Qualitative and quantitative analysis of the anthelmintic fenbendazole and its metabolites in biological matrices by direct exposure probe mass spectrometry.

Methodology for the qualitative and quantitative analysis of the anthelmintic fenbendazole and its metabolites in goat feces using electron impact (EI)/direct exposure probe (DEP)/mass spectrometric (MS) and tandem mass spectrometric (MS/MS) techniques is presented. Analyses were conducted on extracts from spiked feces and feces from animals treated per os with 5 mg fenbendazole/kg, with samples being collected at zero time and at twelve hour intervals for 144 h. The results of the EI/DEP/MS quantitation of these samples are compared to those for the same samples analysed by high pressure liquid chromatography (HPLC). Mass spectral data for fenbendazole and its metabolites are presented and the advantages of the use of EI/DEP/MS and/or DEP/MS/MS over HPLC are discussed. This methodology may be used as a confirmatory method for the HPLC analysis of fenbendazole and its metabolites or may be used as a method in its own right for the rapid qualitative and quantitative analysis of these compounds.