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.

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.

The development of new carboxylic acid-based MMP inhibitors derived from a cyclohexylglycine scaffold.

A series of carboxylic acids was prepared based on cyclohexylglycine scaffolds and tested for potency 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 18 display low nanomolar potency for MMP-2 and MMP-13, while selectively sparing MMP-1 and MMP-7.

Heterocycle-based MMP inhibitors with P2' substituents.

Potent and selective inhibition of matrix metalloproteinases was demonstrated for a series of sulfonamide-based hydroxamic acids. The design of the heterocyclic sulfonamides incorporates a six- or seven-member central ring with a P2' substituent that can be modified. Binding interactions of this substituent at the S2' site are believed to contribute to high inhibitory potency against stromelysin, collagenase-3 and gelatinases A and B, and to provide selectivity against collagenase-1 and matrilysin. An X-ray structure of a stromelysin inhibitor complex was obtained to provide insights into the SAR and selectivity trends observed for the series.

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.

Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors.

OBJECTIVE: To determine the effect of matrix metalloproteinase (MMP) inhibitors in mono-iodoacetate-induced arthritis in rats. DESIGN: The ability of compounds to inhibit MMPs in vitro was assessed kinetically using a quenched fluorescent substrate. Rats were injected with iodoacetate intraarticularly in one knee joint and damage to the tibial plateau was evaluated from digitized images captured using an image analyser and by histology. Collagenase and gelatinase activity in cartilage from iodoacetate injected knees were evaluated using(3)H-rat type I collagen and gelatin zymography, respectively. RESULTS: Collagenase and gelatinase activity significantly increased in the knee cartilage of rats injected with iodoacetate with peak activity by day 7. Three MMP inhibitors were examined for their efficacy in the rat iodoacetate-induced arthritis model. Significant (P< 0.05) inhibition of cartilage damage was observed in animals treated orally with 35 mg/kg b.i.d. of the three different MMP inhibitors. Inhibition of cartilage damage by the MMP inhibitors ranged from 36-42%. CONCLUSION: MMP inhibitors are partially protective against cartilage and subchondral bone damage induced by iodoacetate. These results support an important role for MMPs in mediating the joint damage in this model of arthritis.

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.

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.

AF12198, a novel low molecular weight antagonist, selectively binds the human type I interleukin (IL)-1 receptor and blocks in vivo responses to IL-1.

Interleukin-1 (IL-1) -alpha and -beta are potent regulators of inflammatory responses. The naturally occurring interleukin-1 receptor antagonist (IL-1ra) is effective in vitro and in vivo in modulating biological responses to IL-1. We have previously reported the discovery of IL-1 antagonist peptides from the search of phage display libraries. Further characterization of this group of peptides has led to a 15-mer, AF12198, Ac-FEWTPGWYQJYALPL-NH2 (J represents the unnatural amino acid, 2-azetidine-1-carboxylic acid), with both in vitro and in vivo IL-1 antagonist activity. AF12198 selectively binds the human type I IL-1 receptor but not the human type II receptor or the murine type I receptor. In vitro, AF12198 inhibits IL-1-induced IL-8 production by human dermal fibroblasts with a half-maximal inhibition concentration or IC50 of 25 nM and IL-1-induced intercellular adhesion molecule-1 (ICAM-1) expression by endothelial cells with an IC50 of 9 nM. When given as an intravenous infusion to cynomolgus monkeys, AF12198 blocks ex vivo IL-1 induction of IL-6 and down modulates in vivo induction of IL-6. This is the first small molecule to show IL-1 receptor antagonist activity in vivo.

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)

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.

Matrix solid phase dispersion (MSPD) isolation and liquid chromatographic determination of furazolidone in pork muscle tissue.

A method for the isolation and liquid chromatographic (LC) determination of furazolidone in pork muscle tissue is presented. Blank or furazolidone-fortified pork muscle tissue samples (0.5 g) were blended with octadecylsilyl (C18, 18% load, endcapped, 2 g) derivatized silica. A column made from C18/pork matrix was first washed with hexane (8 mL), followed by elution of furazolidone with ethyl acetate. The ethyl acetate extract was then passed through an activated alumina column. The eluate contained furazolidone that was free from interfering compounds when analyzed by LC with UV detection (photodiode array, 365 nm). Detector response with increasing concentrations of furazolidone isolated from fortified samples was linear (r = 0.998 +/- 0.002) with an average percentage recovery of 89.5 +/- 8.1% for the concentration range (7.8-250 ng/g) examined and resulted in a minimum detectable limit of 390 pg on column, and a detector response of more than 5 times baseline noise. The inter-assay variability was 9.9 +/- 5.4% with an intra-assay variability of 1.5%.

Pharmacokinetics and elimination of salicylic acid in rabbits.

Sodium salicylate was administered to rabbits in order to compare its disposition with that in other major and minor agricultural species. A dose of 44 mg/kg was given orally (p.o.) or intravenously (i.v.), and plasma and urine samples were collected for 36 h and 96 h, respectively. The majority of the drug was excreted as salicylic acid (SA) within 12 h. The major metabolites following an oral dose were salicyluric acid (SUA) and the glucuronide conjugates of SA and SUA. Following i.v. dosing, sulfate conjugates of both SA and SUA were also evident. Both SA and SUA were detected in plasma. Following i.v. administration, SA was distributed with a Vss of 0.249 +/- 0.082 l/kg and cleared at a rate of 0.0432 +/- 0.006 l/h/kg. The biological half-life, calculated from the terminal disposition-rate constant, was 4.3 h (i.v.) or 9.7 h (p.o.). The urinary elimination pattern of SA and metabolites in the rabbit was similar to that previously reported by our laboratories for cattle and goats, although total recovery of the administered dose was not as high as for the latter two species. However, the volume of distribution was larger than for cattle and goats, and rabbits cleared the drug more slowly than those species. As a consequence, the biological half-life was eight to ten times longer than in the ruminants studied previously.

Matrix solid phase dispersion isolation and liquid chromatographic determination of oxytetracycline in catfish (Ictalurus punctatus) muscle tissue.

A method for isolation and liquid chromatographic determination of oxytetracycline in catfish (Ictalurus punctatus) muscle tissue is presented. Blank control and oxytetracycline-fortified fish muscle tissue samples (0.5 g) were blended with octadecylsllyl (C18, 40 microns, 18% load, endcapped) derivatized silica packing material (2 g) containing 0.05 g each of oxalic acid and disodium ethylenediaminetetraacetate. A column made from the C18/fish tissue matrix was first washed with hexane (8 mL), following which the oxytetracycline was eluted with acetonitrile-methanol (1 + 1, v/v) containing 0.06% w/v each of butylated hydroxyanisole and butylated hydroxytoluene. The eluate contained oxytetracycline analyte that was free from interfering compounds when analyzed by liquid chromatography with UV detection (photodiode array set at 365 nm). Standard curves for oxytetracycline isolated from fortified samples were linear (0.998 +/- 0.002) with an average absolute percentage recovery of 80.9 +/- 6.6% for the concentration range (50, 100, 200, 400, 800, 1600, and 3200 ng/g) examined. The interassay variability was 11.3 +/- 5.2% with an intra-assay variability of 1.1%.

Matrix solid phase dispersion isolation and liquid chromatographic determination of sulfadimethoxine in catfish (Ictalurus punctatus) muscle tissue.

A method for the isolation and liquid chromatographic determination of sulfadimethoxine in catfish (Ictalurus punctatus) muscle tissue is presented. Blank control and sulfadimethoxine-fortified fish muscle tissue samples (0.5 g) were blended with octadecyisilyl (C18, 40 micrograms, 18% load, endcapped) derivatized silica packing material. A column made from the C18/fish tissue blend was first washed with hexane (8 mL), following which the sulfadimethoxine was eluted with dichloromethane (8 mL). The eluant contained sulfadimethoxine analyte that was free from interfering compounds when analyzed by liquid chromatography with UV detection (photodiode array, 270 nm). Standard curves for sulfadimethoxine isolated from fortified samples were linear (0.999 +/- 0.001) with an average relative percentage recovery of 101.1 +/- 4.2% for the concentration range (50, 100, 200, 400, 800, and 1600 ng/g) examined using sulfamethoxazole as the internal standard. The interassay variability was 10.7 +/- 8.2% with an intra-assay variability of 2.2%.

Matrix solid phase dispersion isolation and liquid chromatographic determination of five benzimidazole anthelmintics in fortified beef liver.

A multiresidue method for isolation and liquid chromatographic determination of 5 benzimidazole anthelmintics (thiabendazole, oxfendazole, mebendazole, albendazole, and fenbendazole) in beef liver tissue is presented. Blank or benzimidazole-fortified liver samples (0.5 g) were blended with octadecylsilyl derivatized silica packing material (C18, 18% load, endcapped, 2 g). A column made from the C18/liver matrix was first washed with hexane (8 mL), following which the benzimidazoles were eluted with acetonitrile. The acetonitrile extract was then passed through an activated alumina column. The eluate contained benzimidazole analytes that were free from interfering compounds as determined by UV detection (photodiode array, 290 nm). Correlation coefficients of standard curves for individual benzimidazoles isolated from fortified samples, using internal standardization, were linear (0.996 +/- 0.002 to 0.999 +/- 0.001) with average relative percentage recoveries from 62.0 +/- 6.7 to 86.8 +/- 8.6% for the concentration range (100-3200 ng/g) examined. The interassay variability was 7.0 +/- 4.1 to 12.9 +/- 10.2% with an intra-assay variability from 2.2 to 4.0%.