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Prechronic inhalation toxicity studies of 2-mercaptobenzimidazole (2-MBI) in F344/N rats.

2-Mercaptobenzimidazole (2-MBI), used in rubber processing, is a suspect carcinogen structurally related to ethylene thiourea. The inhalation toxicity of 2-MBI was evaluated in male and female F344/N rats exposed 6 hr/day, 5 days/week to respirable aerosols generated by spray atomization of aqueous suspensions of the 2-MBI powder and subsequent drying of the resulting aerosols. Twelve exposures at target concentrations of 0, 6.3, 12.5, 25.0, 50.0, or 100 mg/m3 of 2-MBI produced a dose-related reduction in body weight gains, thyroid follicular cell hyperplasia, adrenal cortex fatty change, and pituitary atrophy. Sub-chronic exposures were conducted at target concentrations of 0, 3.1, 6.2, 12.5, 25.0, and 50.0 mg/m3 of 2-MBI. Rats at greater than or equal to 25 mg/m3 displayed hunched posture, hypoactivity, and reduced body weight gain, with compound related mortality at the highest exposure level. Anemia; increased SGPT, SGOT, alkaline phosphatase, sorbitol dehydrogenase, BUN, and cholesterol; and reduced free fatty acid were seen in rats at greater than or equal to 25 mg/m3. Increased thyroid weight and thyroid follicular cell hyperplasia were noted in both sexes at greater than or equal to 6.2 mg/m3, with reduced triiodothyronine and thyroxine levels in both sexes at greater than or equal to 12.5 mg/m3. Thyroid follicular cell hyperplasia was also seen in rats at 3.1 mg/m3. Thymus weights were significantly reduced in both sexes at all exposure levels with liver weight increases at greater than or equal to 6.2 mg/m3. Exposure-related histopathologic changes included pituitary cytoplasmic vacuolization, adrenal cortex necrosis, lymphoid depletion, thymic atrophy, liver cell hypertrophy, renal mineralization and tubular atrophy, and hypocellularity of the bone marrow.

Administration, Inhalation↗

Artificial composite bone as a model of human trabecular bone: the implant-bone interface.

The use of artificial bones in implant testing has become popular due to their low variability and ready availability. However, friction coefficients, which are critical to load transfer in uncemented implants, have rarely been compared between human and artificial bone, particularly for wet and dry conditions. In this study, the static and dynamic friction coefficients for four commercially used titanium surfaces (polished, Al(2)O(3) blasted, plasma sprayed, beaded) acting on the trabecular component of artificial bones (Sawbones) were compared to those for human trabecular bone. Artificial bones were tested in dry and wet conditions and normal interface stress was varied (0.25, 0.5, 1.0MPa). Friction coefficients were mostly lower for artificial bones than real bone. In particular, static friction coefficients for the dry polished surface were 20% of those for real bone and 42-61% for the dry beaded surface, with statistical significance (alpha<0.05). Less marked differences were observed for dynamic friction coefficients. Significant but non-systematic effects of normal stress or wet/dry condition on friction coefficients were observed within each surface type. These results indicate that the use of artificial bone models for pre-clinical implant testing that rely on interface load transfer with trabecular bone for mechanical integrity can be particularly sensitive to surface finish and lubrication conditions.

Biomechanical Phenomena↗

First LC-MS/MS electrospray ionization validated method for the quantification of perindopril and its metabolite perindoprilat in human plasma and its application to bioequivalence study.

A high throughput bioanalytical method based on solid phase extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS), has been developed for the estimation of perindopril and its metabolite perindoprilat, an angiotensin-converting enzyme inhibitor in human plasma. Ramipril was used as internal standard (IS). The extraction of perindopril, perindoprilat and ramipril from the plasma involved treatment with phosphoric acid followed by solid phase extraction (SPE) using hydrophilic lipophilic balance HLB cartridge. The SPE eluate without drying were analyzed by LC-MS/MS, equipped with turbo ion spray (TIS) source, operating in the negative ion and selective reaction monitoring (SRM) acquisition mode to quantify perindopril and perindoprilat in human plasma. The total chromatographic run time was 1.5 min with retention time for perindopril, perindoprilat and ramipril at 0.33, 0.35 and 0.30 min. The developed method was validated in human plasma matrix, with a sensitivity of 0.5 ng/ml (CV, 7.67%) for perindopril and 0.3 ng/ml (CV, 4.94%) for perindoprilat. This method was extensively validated for its accuracy, precision, recovery, stability studies and matrix effect especially because the pattern of elution of all the analytes appears as flow injection elution. Sample preparation by this method yielded extremely clean extracts with very good and consistent mean recoveries; 78.29% for perindopril, 76.32% for perindoprilat and 77.72% for IS. The response of the LC-MS/MS method for perindopril and perindoprilat was linear over the range 0.5-350.0 ng/ml for perindopril and 0.3-40 ng/ml for perindoprilat with correlation coefficient, r>/=0.9998 and 0.9996, respectively. The method was successfully applied for bioequivalence studies in human subjects samples with 4 mg immediate release (IR) formulations.

Angiotensin-Converting Enzyme Inhibitors↗

Antiviral activity of alcohol for surface disinfection.

Bacteria and viruses from the patient's mouth travel with dental splatter and spills. A surface disinfectant should possess antiviral activity as well as antibacterial action. Because of frequent and 'open' application in the dental office, such a disinfectant should be non-toxic, non-allergenic and safe for the hygienist. It now appears that high-concentration alcohol mixtures (i.e. 80% ethanol + 5% isopropanol) are not only excellent antibacterials, but quickly inactivate HIV as well as hepatitis B and hepatitis C viruses. Compared to alternative surface disinfectants, use of high-concentration alcohol for the spray-wipe-spray method of surface disinfection in dentistry appears safe and efficient. However, dried matter should be wiped and hydrated first.

Anti-Bacterial Agents↗

Prevention of surface mold growth on Italian dry sausage by natamycin and potassium sorbate.

Inhibition of uncontrolled mold growth on three types of raw cured Italian dry salami was studied under commercial production conditions. Salami were dipped or sprayed with natamycin (pimaricin) or were given a combined organic acid-plus-potassium sorbate treatment. Acetic and citric acids potentiated the inhibitory effects of potassium sorbate significantly, but lactic and succinic acids showed little or no effect. Treatment of salami by dipping in 2.5% (wt/vol) potassium sorbate or 2,000 ppm (mg/liter) of pimaricin did not successfully prevent the growth of surface molds. At 10% potassium sorbate on all types of salami and at 2.5% sorbate on Casalingo salami, visual inhibition of mold growth was observed, but numbers of viable fungi on all salami types treated with 2.5% sorbate were not significantly (95% confidence) different from numbers found in the untreated controls. Pimaricin spray (2 X 1,000 ppm) was as good as or slightly better than 2.5% potassium sorbate, but greater concentrations of each were required to satisfactorily inhibit surface mold growth during the 25- to 50-day ripening period.

Antifungal Agents↗

Ultrasonic cleaning in the hospital.

Ultrasonic cleaning can prolong the life of expensive instruments. In the past, many fine instruments were discarded due to stiffening hinges and box locks, or sticking plungers. Hand scrubbing and spray washing could not thoroughly clean these areas. Ultrasonic cleaners effectively remove dried and baked blood, serums and medications from these instruments. Also, hinged instruments and syringes operate more smoothly during use in surgery when cleaned using ultrasonics. In addition, the use of ultrasonics alleviates the necessity for hand scrubbing of contaminated surgical instruments and laboratory apparatus, a procedure which could lead to injury or infection. The superb cleaning powers of ultrasonic cleaners, their speed and simplicity of operation, and their ability to remove blood, tissue, bacteria and microorganisms within minutes, makes them a valuable addition to any operating room suite, central service department, or emergency room. Their cost-effectiveness is considerable for the small hospital, and compelling for the large hospital.

Central Supply, Hospital↗

[A case of pneumonitis possibly due to isocyanate associated with high levels of serum KL-6].

A 47-year-old automobile painter developed dry cough, chills and dyspnea after four months of painting work. The spray contained isocyanates (HDI). A chest radiograph showed bilateral ground-glass shadows. The serum KL-6 level was very high: 11,100 U/ml. Marked lymphocytosis and a striking decrease in the CD4/CD8 ratio were observed in the bronchoalveolar lavage fluid. Transbronchial lung biopsy specimens showed alveolitis and bronchiolitis. Cessation of exposure to isocyanates improved the symptoms and laboratory data. We suspected that the patient was suffering from hypersensitivity pneumonitis induced by isocyanates. Specific IgG antibodies for TDI, MDI, and HDI were not demonstrated by enzyme-linked immunosorbent assay. Because abnormal shadows in the chest radiograph did not improve quickly after admission, we administered glucocorticoids which improved the symptoms, the chest radiograph findings, and the serum KL-6 level.

Alveolitis, Extrinsic Allergic↗

Effect of direct-fed fibrolytic enzymes on the lactational performance of dairy cows.

In trial 1, 30 midlactation (213 d in milk) Holstein cows were randomly assigned to a control or enzyme treatment in a two-period crossover design and were fed a total mixed ration based on alfalfa hay and silage. Cows on the enzyme treatment received an enzyme solution containing cellulases and xylanases, which was sprayed on the forage component of the ration at a rate of 1.65 ml/kg of forage dry matter (DM) between 8 and 24 h prior to feeding. Cows consuming the forage treated with enzyme produced more milk (27.2 vs. 25.9 kg/d) and digested more DM per day than did cows fed the control forage. In trial 2, 40 early lactation Holstein cows were assigned to one of four treatments for 16 wk. Following a 2-wk covariate period, cows were assigned to 1) no enzyme treatment, 2) a low (1.25 ml/kg of forage DM) enzyme treatment, 3) a medium (2.5 ml/kg of forage DM) enzyme treatment, or 4) a high (5.0 ml/kg of forage DM) enzyme treatment. Enzymes were a 2:1 combination of cellulase and xylanase diluted in water and sprayed on a combination of alfalfa hay and silage and whole cottonseed immediately before mixing with a concentrate based on barley. Dry matter intakes were similar for cows on treatments 2, 3, and 4 and were greater than those for cows on treatment 1. Production of milk, 3.5% fat-corrected milk, and energy-corrected milk was greater for cows on treatment 3 than for cows on treatment 1. Fibrolytic enzymes applied to the forage portion of the rations prior to feeding improved lactational performance of early and midlactation cows.

Animals↗

Investigation of hygiene aspects during air chilling of poultry carcases using a model rig.

1. An experimental rig, designed and built to simulate conditions found in commercial poultry chilling systems, was used to investigate the effects of varying air temperature and chilling duration, and the effect of chlorinated water sprays, on the microbial load present on the skin and in the body cavity of freshly eviscerated poultry carcases; deep muscle and skin temperatures were monitored during chilling at three different temperatures. 2. During dry chilling for 2 h, total viable microbe counts (TVC) and counts of coliforms and pseudomonads from the body cavity fell by between half and one log unit; smaller reductions were observed in samples from the breast skin. 3. The situation changed when chlorinated water sprays (50, 100 or 250 ppm available chlorine) were applied for the first hour of chilling; spraying carcases enhanced the reduction in numbers on the skin; the effect was most pronounced with 250 ppm chlorine; conversely in the body cavity, the general effects of sprays was to increase contamination by up to one log unit. 4. There was no evidence that sprays increased the rate of chilling. 5. When carcases were held overnight in the rig at 11 degrees C after chilling, microbe counts on dry-chilled carcases remained stable, but increased on carcases that had been sprayed with chlorinated water.

Animals↗

A clinical trial of ipratropium bromide nasal spray in patients with perennial nonallergic rhinitis.

Intranasal ipratropium bromide has been shown to significantly reduce rhinorrhea. Use of a freon-propelled intranasal preparation has resulted in side effects associated with the drying properties of the propellant. The purpose of the present trial was to study the safety and efficacy of a new isotonic aqueous ipratropium bromide nasal spray pump, specifically in patients with perennial nonallergic rhinitis. Two hundred thirty-three patients participated in an 8-week double-blind parallel comparison of ipratropium bromide nasal spray with its vehicle, a saline solution. Treatment with the ipratropium spray resulted in a 30% reduction in rhinorrhea; this reduction was significantly greater than that seen with the saline vehicle. There was a modest reduction in postnasal drip, sneezing, and congestion with both treatments, which may be attributable to the salutary effects of the saline solution. Patients also perceived a significant reduction in the degree to which rhinorrhea interfered with their daily activities and moods. Treatment was well tolerated, with no drug-related systemic adverse events and no evidence of nasal rebound on discontinuation of treatment. Minor, infrequent episodes of nasal dryness and epistaxis were the only significant adverse events reported; these did not limit treatment.

Adult↗

A novel gel formation method, microstructure and mechanical properties of calcium polysaccharide gel films.

Hydrophilic gels, formed by the interaction of calcium ions with either sodium alginate or potassium pectinate, can be deposited as a wet coating on to the surface of drug loaded pellets. If the coated pellets are dried, they could be dispensed to a patient in a capsule for oral delivery of the active drug. In contact with the aqueous fluids of the gastrointestinal tract, the gel coat will rehydrate, swell and will sustain the release of active drug from the core. In order to facilitate the development and refinement of this novel coated system, it is beneficial to have a method that can produce free gel films in a manner that closely mimics the way the gel coat is formed and deposited on the pellet surface. Traditional film producing methods would involve the spraying or depositing (by evaporation) the gel forming polysaccharide on to an inert surface, drying it and then exposing the dry film to a solution containing calcium ions. Because the film is dry before it is gelled, it is fundamentally different to the wet gel coats that are deposited on to the pellets. We have developed a method to produce wet gel films and have evaluated different manufacturing conditions in order to optimize the quality of the completed gel film. Additionally, we have used these films to assess the effect that the type of polysaccharide and the environmental conditions experienced during rehydration (pH and ionic strength) has on the mechanical properties and the microscopic morphology of the gel. Irrespective of the rehydration medium, the calcium pectinate gel films were softer, weaker and more porous, than the calcium alginate films. Although calcium alginate gels that were rehydrated in 0.1M NaCl were porous, the same films rehydrated in either water, simulated gastric fluid USP (without pepsin) or 0.1M HCl were stronger and much more dense microscopically. Furthermore, of the four different alginates that were evaluated, those with a high content of guluronic acid saccharides were the strongest but most brittle when rehydrated in water.

Alginates↗

Dry aerosol vaccination against Newcastle disease: II. Serological response in chicks.

Day-old chickens with Newcastle disease maternal antibodies are separated in two batches. One batch (S) is vaccinated by liquid spray method with HB1 strain: the other one (NS) is not vaccinated. At 2, 3 or 4 weeks subgroups from S and NS batches are vaccinated with HB1 strain by dry aerosol method. Serological controls reveal an important increase of Newcastle antibodies within two weeks after dry aerosol vaccination. Then a drop of the antibody quantities is observed during weeks 2 to 4 post dry aerosol vaccination. In the following weeks, the antibody level increases very slowly.

Aerosols↗

Assessment of spray application of Saint GERVAIS water effects on skin wettability by contact angle measurement comparison with bidistilled water.

BACKGROUND: The skin is responsible for protecting the body from physical, chemical and microbial injuries. The stratum corneum is the top layer of the epidermis and it plays a key role in helping to contain moisture. When the skin becomes damaged, its ability to perform these functions is compromised. Dry skin is a common form of skin damage. Contact angle 0 between a surface and water is a good indicator of hydrophobic or hydrophilic tendency of surfaces. OBJECTIVE: To quantify the influence of spray application of an isotonic mineral water (Saint GERVAIS water) on the hydrophobic tendency of dry skin and to compare spreading of both types of water on the skin through 0 measurement of each water drop on the skin before and after mineral spray application. MATERIALS AND METHODS: Contact angles theta between skin surface and the two types of water (bidistilled and mineral water) were measured before and after application of mineral water by a system allowing the measurement of theta in vivo and in vitro. The cutaneous hydration, the temperature and pH were also measured before and after mineral water application. RESULTS: As for the application of mineral water, the cutaneous pH significantly increased so the strong skin acidity decreased. The cutaneous temperature was modified (a decrease of 2 degrees C was noted) and the cutaneous hydration was also increased (+47AU). The hydro-phobic tendency of the dry skin tested in this study was strongly decreased after mineral water application. This parameter was illustrated by a decrease of contact angle theta value. CONCLUSION: Saint GERVAIS water application allowed a regulation of skin pH, a fresh sensation on the skin and an increase in the cutaneous hydration. Moreover, the contact angle measurement with bidistilled water illustrated the increased wettability of the skin.

Administration, Topical↗

Liquid chromatography/electrospray ionization tandem mass spectrometry validated method for the simultaneous quantification of sibutramine and its primary and secondary amine metabolites in human plasma and its application to a bioequivalence study.

A high-throughput and sensitive bioanalytical method using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) has been developed for the estimation of sibutramine and its two metabolites (M1 and M2). The extraction of sibutramine, its metabolites and imipramine (internal standard (IS)) from the plasma involved treatment with phosphoric acid followed by solid-phase extraction (SPE) using a hydrophilic-lipophilic balanced HLB cartridge. The SPE eluate without drying and reconstitution was analyzed by LC/MS/MS, equipped with a with turbo ion spray (TIS) source, operating in the positive and multiple reaction monitoring (MRM) acquisition mode. Sample preparation by this method yielded extremely clean extracts with quantitative and consistent mean recoveries; 95.12% for sibutramine, 92.74% for M1, 95.97% for M2 and 96.60% for the IS. The total chromatographic run time was 3.0 min with retention times of 2.51, 2.13, 2.09 min for sibutramine, M1, M2 and imipramine, respectively. The developed method was validated in human plasma matrix, with a sensitivity of 0.1 ng/mL (coefficient of variance (CV), 2.07%) for sibutramine, 0.1 ng/mL (CV, 3.59%) for M1 and 0.2 ng/mL (CV, 4.93%) for M2. Validation of the method for its accuracy, precision, recovery, matrix effect and stability was carried out especially with regard to real subject sample analysis. The response was linear over the dynamic range 0.1 to 8.0 ng/mL for sibutramine and M1, and 0.2 to 16.0 ng/mL for M2 with correlation coefficients of r > or = 0.9959 (sibutramine), 0.9935 (M1) and 0.9943 (M2). The method was successfully applied for bioequivalence studies in 40 human subjects with 15 mg capsule formulations.

Amines↗

Antifungal activity of Bacillus subtilis 355 against wood-surface contaminant fungi.

A strain of Bacillus subtilis was examined for antifungal activity against phytopathogenic and wood-surface contaminant fungi. The bacterium was grown in five culture media with different incubation times in order to study cell development, sporulation, and the production of metabolites with antifungal activity. The anti-sapstain and anti-mould activity of the bacterium grown in yeast extract glucose broth (YGB) medium in wood was also evaluated. In YGB, the bacterium inhibited the growth of several fungi and displayed a broader spectrum of activity than in the other media tested. A relationship between bacterial spore production and the formation of metabolites with antifungal activity was detected. YGB medium displayed effective control in wood block tests. YGB medium was extracted with solvents of increasing polarity and the dry residues were applied to silicagel plates, resolved with the appropriate solvent and sprayed with different solutions, detecting the presence, of amines, and higher alcohols. The bioautographic method revealed the presence of at least two active compounds against the blue-stain fungus Cladosporium cucumerinum.

Antibiosis↗

Worker exposure to asbestos during removal of sprayed material and renovation activity in buildings containing sprayed material.

Contents and types of asbestos in fireproofing insulation materials sprayed on ceilings of 127 buildings throughout the U.S. were studied. Asbestos was found to be present in more than 50% of the buildings and chrysotile was the main component identified. Frequency distribution of airborne fiber concentrations was lognormal. During renovation activities by various workers, including sheet-metal workers, carpenters and electricians, average fiber concentrations at workers' breathing zones were less than 2 fibers/cc, but exceeded 0.1 fibers/cc. During removal of sprayed materials, workers were exposed to extremely high concentrations (average 16.4 fibers/cc) when dry methods were used. When wet methods were used during removal, the airborne fiber concentrations were sharply reduced to less than 2 fibers/cc.

Air Pollutants↗

Bioengineering of therapeutic aerosols.

The new field of therapeutic aerosol bioengineering (TAB), driven primarily by the medical need for inhaled insulin, is now expanding to address medical needs ranging from respiratory to systemic diseases, including asthma, growth deficiency, and pain. Bioengineering of therapeutic aerosols involves a level of aerosol particle design absent in traditional therapeutic aerosols, which are created by conventionally spraying a liquid solution or suspension of drug or milling and mixing a dry drug form into respirable particles. Bioengineered particles may be created in liquid form from devices specially designed to create an unusually fine size distribution, possibly with special purity properties, or solid particles that possess a mixture of drug and excipient, with designed shape, size, porosity, and drug release characteristics. Such aerosols have enabled several high-visibility clinical programs of inhaled insulin, as well as earlier-stage programs involving inhaled morphine, growth hormone, beta-interferon, alpha-1-antitrypsin, and several asthma drugs. The design of these aerosols, limited by partial knowledge of the lungs' physiological environment, and driven largely at this stage by market forces, relies on a mixture of new and old science, pharmaceutical science intuition, and a degree of biological-impact empiricism that speaks to the importance of an increased level of academic involvement.

Administration, Inhalation↗