Cyclopentane. CAS#287-92-3.
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Administration, Inhalation↗
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Neopentane (2,2-dimethylpropane). CAS# 463-82-1.
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Administration, Inhalation↗
Combining histology and biochemical measurements of connective tissue components in small samples of lung: application to bleomycin-induced fibrosis in the mouse.
Bleomycin-induced lung injury in mice was used to illustrate the plausibility of quantitating changes in elastin or protein concentration in histologically defined regions of mouse lungs. Mice were instilled by either the intranasal or intratracheal route with varying levels of bleomycin and the lungs were removed and fixed under pressure for histology and analysis. Histological sections that bracketed a defined volume of tissue was used for biochemical analysis and was limited to the alveolar region of the lung. Our studies showed that the intranasal method of instillation was as effective as the intratracheal method for inducing fibrosis. Even though distribution to the 4 major lobes of the lung was fairly uniform, there was no consistency in the degree of fibrosis between the various lobes of the same animal. The most dramatic change in biochemical parameters was protein concentration, which increased over 10-fold in some fibrotic lungs compared to normal lungs, whereas desmosine concentration increased up to 5-fold. Fibrosis scores agreed well with desmosine concentration, except with moderate desmosine increases where histologically defined fibrosis was not observed. The experiments illustrate the feasibility and desirability of comparing histology and biochemical analysis on the same fixed lung sample.
Administration, Inhalation↗
Differential in vivo effects of whole cigarette smoke exposure versus cigarette smoke extract on mouse ciliated tracheal epithelium.
In this study the authors compared the affect of vapor phase cigarette smoke (CS) versus cigarette smoke extract (CSE) on the lungs and upper airway of C57BL/6 mice. The authors found that CSE treatment significantly increased neutrophil influx (P < .001), baseline ciliary beat frequency (CBF) (P < .05), and protein kinase C activity compared to CS and controls. Isoproterenol increased CBF with CS exposure, but decreased CBF with CSE (P < .01). Isoproterenol increased protein kinase A (PKA) activity in all groups except CSE. CSE exposure induced inflammatory cell bronchiolitis. These data indicate that CSE exposure has differential effects on the lungs and tracheal epithelium compared to CS exposure.
Administration, Inhalation↗
The impact of spirometry on pediatric asthma diagnosis and treatment.
Research has shown that spirometry is underutilized in the clinical setting. This study profiles the use of spirometry in an asthma management program at an inner-city community health clinic. Eligible subjects included 56 children who presented with an acute asthma exacerbation. Physicians recorded patient diagnosis before and after viewing spirometry. Bivariate and multivariate analysis was used to determine associations between symptoms and forced expiratory volume in 1 second (FEV1). Physicians changed 30.4% of patients' treatment plans after viewing spirometry results. Wheezing was significantly associated with FEV1 in bivariate analysis; however, multivariate modeling failed to identify significant relationships. The use of spirometry influenced patient diagnosis and treatment.
Acute Disease↗
Nebulized budesonide versus oral steroid in severe exacerbations of childhood asthma.
The aim of this study was to assess whether nebulized budesonide may substitute for oral prednisolone in the management of children whose asthma is severe enough to warrant hospital admission, but who have no life threatening features. In a prospective, double-blind, randomized study nebulized budesonide (2 mg 8 hourly) was compared with oral prednisolone (2 mg/kg at entry and again at 24 h) in 46 children admitted to hospital with severe asthma exacerbations. Efficacy variables (including lung function measurements such as the primary outcome variable, Forced Expiratory Volume in 1 second (FEV1) and symptoms) were measured 24 h after treatment initiation. FEV1 improved significantly compared to baseline in patients who received nebulized budesonide compared to the prednislone group. The data show nebulized budesonide to be at least as effective as oral steroid in improving lung function and symptom severity in severe exacerbations of childhood asthma.
Administration, Inhalation↗
Pharmacotherapies to enhance smoking cessation during pregnancy.
Smoking during pregnancy is a significant public health concern. Maternal smoking increases the risk of spontaneous abortion, low birth weight, premature delivery, sudden infant death syndrome and learning and behavioral problems in the offspring. Unfortunately, the majority of pregnant women do not quit smoking during pregnancy. Although pharmacotherapy may improve smoking cessation rates in pregnancy, very few studies exist that have studied the safety and efficacy of medications to treat pregnant smokers. This article reviews the available safety and efficacy data for the use in pregnancy of the five first-line therapies and two second-line therapies that are recommended for smoking cessation in non-pregnant smokers. Other promising nicotine replacement therapies are also reviewed. Ultimately, the choice whether to use pharmacotherapy for smoking cessation should be made jointly by the pregnant smoker and her health care provider. This article reviews factors that may be considered when prescribing pharmacotherapy to pregnant smokers (i.e. the role of behavioral counseling, identification of appropriate patients, potential advantages and disadvantages of each of the pharmacotherapies, proposed monitoring strategies, dose and duration and goals of treatment). More research regarding the safety and efficacy of pharmacotherapy during pregnancy is needed to define the risk/benefit profile of each medication for use in smoking cessation in pregnant women.
Administration, Cutaneous↗
Amended final report of the safety assessment of t-Butyl Alcohol as used in cosmetics.
t-Butyl Alcohol (t-BuOH) is a tertiary aliphatic alcohol that is used as a solvent or an alcohol denaturant and as a perfume carrier in cosmetics. t-BuOH was reported as an ingredient in 32 formulations of eye makeup, fragrance, and shaving preparations, at concentrations ranging from 0.00001% and 0.3%. There is little acute oral toxicity in animals; e.g., the acute oral LD(50) in rats was 3.0 to 3.7 g/kg. In short-term oral studies in rats, t-BuOH at 2% (w/v) or less in drinking water did not cause gross organ or tissue damage in mice, although weight loss was reported and microscopic damage to livers and kidney and alterations such as centrilobular necrosis, vacuolation in hepatocytes, and loss of hepatic architecture were noted. Subchronic oral dosing with t-BuOH increased the mineralization of the kidney, nephropathy, and urinary bladder transitional cell epithelial hyperplasia in rats; and liver damage, chronic inflammation, hyperplasia of transitional cell epithelium urinary, and proliferative changes including hyperplasia and neoplasia in the thyroid in mice. Male rats exposed to t-BuOH were susceptible to alpha 2mu-globulin nephropathy. t-BuOH (99.9%) was a moderate to severe ocular irritant to rabbits and caused mild to moderate dermal irritation to rabbits. It was not considered to be a primary dermal irritant to rabbits. In animal studies, fetotoxicity generally increased with concentration, and fetal weights were slightly depressed at concentrations of 0.5% to 1% t-BuOH. t-BuOH produced a significant increase in the number of resorptions per litter. There was also a significant decrease in the number of live fetuses per litter. t-BuOH reduced maternal weight gain, litter sizes, birth weights, and weights at weaning, and increased perinatal and postnatal mortality. t-BuOH was not mutagenic in several bacterial and mammalian test systems. The principal effects from 2 years of exposure to t-BuOH in drinking water (up to 10 mg/ml for rats and 20 mg/ml for mice) were proliferative lesions (hyperplasia, adenoma, and carcinoma) in the kidneys of exposed male rats, and nephropathy in all exposed groups of female rats. There was some evidence of carcinogenic activity, but it was not consistent between species, sexes, or doses. A repeat-insult patch test (RIPT) test showed no potential for eliciting either dermal irritation or sensitization by 100% t-BuOH. Dermatitis can result from dermal exposure of humans to t-BuOH. In consideration of these data, it was concluded that t-BuOH was (at most) a weak carcinogen and unlikely to have significant carcinogenic potential as currently used in cosmetic formulations. In addition, the renal tubule effects found in male rats were likely an effect of alpha 2mu-globulin. In consideration of the reproductive and developmental toxicity data, the increased incidence of still births occurred at high exposure levels and was likely secondary to maternal toxicity. Based on the available animal and clinical data in this report, it was concluded that t-BuOH is safe as used in cosmetic products.
Administration, Inhalation↗
Development of a physiologically based pharmacokinetic model for chlorobenzene in F-344 rats.
A physiologically based pharmacokinetic (PBPK) model to describe the absorption, distribution, metabolism, and elimination of chlorobenzene in rats was developed. Partition coefficients were experimentally determined in rat tissues and blood samples using an in vitro vial equilibration technique. These solubility ratios were in agreement with previous reports. The in vivo metabolism of chlorobenzene was evaluated using groups of three F344 male rats exposed to initial chlorobenzene concentrations ranging from 82 to 6750 ppm in a closed, recirculating gas uptake system. An optimal fit of the family of uptake curves was obtained by adjusting Michaelis-Menten metabolic constants, K(m) (affinity) and Vmax (capacity), using the PBPK model. At the highest chamber concentration, the uptake curve could not be modeled without the addition of a first-order (Kfo) metabolic pathway. Pretreatment with pyrazole, an inhibitor of oxidative microsomal metabolism, had no impact on the slope of the uptake curve. The completed PBPK model was evaluated against real-time exhaled breath data collected from rats receiving either an intraperitoneal (i.p.) injection or oral gavage dose of chlorobenzene in corn oil. Exhaled breath profiles were evaluated and absorption rates were determined. Development of the chlorobenzene PBPK model in rats is the first step toward future extrapolations to apply to humans.
Absorption↗
Bronchial asthma: diagnostic and treatment issues.
The increasing morbidity and mortality associated with asthma may, in part, be due to inadequate treatment. Step-care management aims to improve control by addressing both the bronchospastic and inflammatory components of the disease. beta-Adrenergic agonists are central to alleviating symptoms, whereas corticosteroids may reduce inflammation and associated airway hyperresponsiveness.
Administration, Inhalation↗
Characteristics of acute adult poisoning in Gaziantep, Turkey.
BACKGROUND: The objective of this prospective hospital-based study was to evaluate the rate and characteristics of acute human poisoning in our province (Gaziantep City, Turkey). METHODS: All cases of acute human poisonings admitted to the emergency department of the Gaziantep University Hospital, Gaziantep, Turkey, between January 2000 and December 2001, were included in the study. The rate and causes of mortality from poisoning as well as demographic data of the patients were investigated. RESULTS: There were 179 (0.7%) poisoning cases among 25,605 patients who admitted to the emergency department. Of the poisoning cases, 64.3% were female and 35.6% were male patients. The poisoning made a peak between the ages of 16 and 25. The majority of poisonings resulted from oral ingestion with deliberate intake accounting for 78.7% of the cases. Most of the suicide attempt cases were also females. Analgesics were the most common agents (42.4%) among the drugs incriminated in poisoning. Twenty-four patients (13.7%) were admitted to intensive care unit, of whom 42% were female and 58% were male patients. Drugs for suicide attempts were the main cause of poisoning in the patients who admitted to intensive care unit. Five patients (2.8% of all cases) died in the intensive care unit. CONCLUSIONS: These data provide important preliminary information on the pattern of symptomatic poisonings in this south-east part of our country.
Acute Disease↗
Characterization of nasal spray pumps and deposition pattern in a replica of the human nasal airway.
Deposition patterns are described of a nasal spray formulation for a novel rhinovirus protease inhibitor. These patterns, which were generated from different nasal spray pumps, were characterized using a multisectional nasal airway model. A human nasal replica was made from an in vivo magnetic resonance imaging (MRI) scan of an adult male human. The nasal replica consisted of 77 acrylic plastic sections, 1.5-mm thick. Our data showed that the aerosols were deposited mainly in the anterior and turbinate regions with little passing beyond the nasopharyngeal region. Detailed deposition information from the turbinate region indicated that deposition was high toward the anterior portion where most deposition was concentrated on the inferior meatus. Spray droplets were also deposited in spots of the middle and posterior portions of the turbinate region, and this nonuniform deposition pattern may be correlated with the flow pattern. The spray angle and droplet size of the nasal spray were found to be important in influencing the deposition pattern in the nasal airway. The droplet size was determined by a laser-diffraction technique and the spray angle by high-speed photography. Larger droplets and a wider spray angle increased deposition in the anterior region of the nasal airway, which prevented more material from depositing in the turbinate region.
Administration, Inhalation↗
A concentrated and stable aerosol formulation of cationic lipid:DNA complexes giving high-level gene expression in mouse lung.
Advances in gene therapy vectors and techniques hold promise for treatment of many inherited and acquired diseases. For lung indications, especially those involving the epithelium, delivery of the gene therapy vehicle ideally will involve the use of an aerosol. Aerosol delivery of transgenes using cationic lipids is currently limited by the ability to generate highly concentrated formulations of lipid:DNA complexes that are stable and retain their activity following aerosolization. We have examined many of the variables inherent in aerosolizing cationic lipid gene delivery vehicles and have devised a new formulation that incorporates small amounts of a polyethylene glycol-containing lipid. This formulation has allowed the preparation of concentrated dispersions of cationic lipid:plasmid DNA (pDNA) complexes (> 20 mM pDNA) at approximately 10-fold higher concentrations than previously reported. Most of the pDNA in these formulations was bound to the lipid component and thereby protected from nebulizer-induced shearing; the pDNA also maintained full biological activity both in vitro and in vivo. This new formulation thus represents a significant improvement over current methods to prepare concentrated, active cationic lipid gene delivery vectors, and provides a new tool with which to test gene transfer to the lung.
Administration, Inhalation↗
Safety of pulmonary administration of gemcitabine in rats.
The purpose of this research was to evaluate the safety of pulmonary administration of gemcitabine and to determine the maximum tolerated dose by weekly pulmonary administrations in an animal model. Five groups of eight Wistar rats received gemcitabine at doses of 2, 4, 6, or 8 mg/kg or the vehicle solution by endotracheal spray with scintigraphic imaging of lung deposition. In order to document the safety of digestive exposure, five groups of eight rats received gemcitabine at the same dosages or the vehicle solution by gavage. Nine weekly sessions were planned, and blood cell counts and histological examinations were performed in live animals at day 64. Scintigraphic imaging confirmed pulmonary deposition in 310 of 316 spray administrations (98%) with homogeneous pattern of deposition. The maximum tolerated dose of gemcitabine by pulmonary administration was 4 mg/kg. At this dosage, administered once a week for 9 consecutive weeks, there were no chemotherapy-related deaths and no clinical, histological, or hematological signs of toxicity except for a decrease in platelet and red blood cell counts, with no clinical significance. The toxicity of gemcitabine was higher via oral than lung delivery in terms of weight loss and white blood cell toxicity at dosages of 2, 4, and 6 mg/kg. Pulmonary administration of gemcitabine is safe in rats at a maximum tolerated dose of 4 mg/kg once a week for 9 weeks. At an equivalent dosage, the toxicity of gemcitabine is lower by lung than oral administration.
Administration, Inhalation↗
Novel routes of opioid administration.
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Administration, Inhalation↗
Threshold mechanisms and site specificity in chromium(VI) carcinogenesis.
Ten years have elapsed since the International Agency for Research on Cancer (IARC) evaluated the carcinogenicity of chromium and chromium compounds. Further studies performed during the last decade have provided further epidemiological, experimental and mechanistic data which support the IARC conclusions. A wealth of results indicate that, at variance with chromium(0) and chromium(III), chromium(VI) can induce a variety of genetic and related effects in vitro. The lack of carcinogenicity of chromium(0) and chromium(III) compounds in experimental animals is well established, and only a minority of animal carcinogenicity data with chromium(VI) compounds were positive (30 out of 70, i.e. 42.9%). Moreover, most positive studies used administration routes which do not mimic any human exposure and by-pass physiological defense mechanisms. Typically, positive results were only obtained at implantation sites and at the highest dose tested. Exposure to chromium(VI) has been known for more than a century to be associated with induction of cancer in humans. Carcinogenicity requires massive exposures, as is only encountered in well defined occupational settings, and is site specific, being specifically targeted to the lung and, in some cases, to the sinonasal cavity. Increased death rates for cancers at other sites, which were occasionally reported in some epidemiological studies, were almost invariably not statistically significant, and inconsistent (being counterbalanced by other studies which apparently showed decreased rates for the same cancers). As we recently quantified in human body compartments, chromium(VI) can be reduced in body fluids and non-target cells, which results in its detoxification, due to the poor ability of chromium(III) to cross cell membranes. In target cells, chromium(VI) tends to be metabolized by a network of mechanisms leading to generation of reduced chromium species and reactive oxygen species, which will result either in activation or in detoxification depending on the site of the intracellular reduction and its proximity to DNA. When introduced by the oral route, chromium(VI) is efficiently detoxified upon reduction by saliva and gastric juice, and sequestration by intestinal bacteria. If some chromium(VI) is absorbed by the intestine, it is massively reduced in the blood of the portal system and then in the liver. These mechanisms explain the lack of genotoxicity, carcinogenicity, and induction of other long-term health effects of chromium (VI) by the oral route. Within the respiratory tract, chromium(VI) is reduced in the epithelial-lining fluid, pulmonary alveolar macrophages, bronchial tree and peripheral lung parenchyma cells. Hence, lung cancer can only be induced when chromium(VI) doses overwhelm these defense mechanisms. The efficient uptake and reduction of chromium(VI) in red blood cells explains its lack of carcinogenicity at a distance from the portal of entry into the body. All experimental and epidemiological data, and the underlying mechanisms, point to the occurrence of thresholds in chromium(VI) carcinogenesis.
Administration, Inhalation↗
Combined oral benzo[a]pyrene and inhalatory ozone exposure have no effect on lung tumor development in DNA repair-deficient Xpa mice.
There is considerable concern about an enhanced risk of lung tumor development upon exposure of humans to polycyclic aromatic hydrocarbons (PAHs), like benzo[a] pyrene (B[a]P), in combination with induced lung cell proliferation by toxic agents like ozone. We studied this issue in wild-type (WT) C57BL/6 mice, the cancer prone nucleotide excision repair-deficient Xeroderma pigmentosum complementation group A mice (Xpa-/-) and the even more sensitive Xpa-/-/p53+/- mice. The mice were treated with B[a]P through the diet at a dose of 75 p.p.m., in combination with intermittent ozone exposures (0.8 p.p.m.). First, a dose-range finding study with WT and Xpa-/- mice was conducted to determine the optimal ozone concentration giving high cell proliferation and low toxic side effects. We show by BrdU incorporation that cell proliferation in the lung was induced by ozone, with an optimal concentration of 0.8 p.p.m., which was subsequently used in the (sub)chronic studies. In the subchronic study, in which lacZ mutant frequency and BPDE-DNA adduct formation were measured, the mice were treated for 13 weeks with B[a]P and/or ozone, whereas in the chronic study this treatment protocol was followed by a 6 month period on control feed and filtered air. As expected, oral B[a]P exposure appeared to be highly carcinogenic to Xpa-/- and Xpa-/-/p53+/- mice and to a lesser extent to WT mice. A high incidence of forestomach tumors and some tumors of the esophagus were found. In the lung, a clear genotoxic effect of B[a]P was found as shown by the presence of BPDE-DNA adducts. However, these DNA adducts in combination with induction of cell proliferation did not result in increased lacZ mutations, nor in lung tumor formation not even in the highly sensitive Xpa-/- and Xpa-/-/p53+/- mice. The implication of these findings for tumor risk assessment will be discussed.
Administration, Inhalation↗
Effects of cannabinoids (marijuana) on taste intensity and hedonic ratings and salivary flow of adults.
Cannabinoids purportedly improve taste responsiveness and enhance the sensory appeal of foods. These properties and a commonly cited oral drying effect were evaluated in a series of studies with 'light' marijuana users. The first was a double-blind, placebo-controlled, acute oral dosing trial, involving an age and gender stratified sample of 57 adults. An influence of route of drug delivery was explored in another 11 individuals who were administered a single dose orally, sublingually and via cigarette. To explore effects following chronic administration, six additional individuals were dosed twice per day for 3 days orally and by rectal suppository. Taste intensity and hedonic responses for sweet, sour, salty and bitter food stimuli were monitored at baseline, 2, 4 and 6 hours post-dosing in the acute studies, and daily in the chronic study. Stimulated saliva samples were collected at these same times. Salivary flow rate was significantly negatively correlated with plasma drug levels, and reported 'high' 2 and 4 h post-dosing. No effects of the drug were observed on taste responses. Self-reported shifts in taste responsiveness and hedonics may be related to alterations of memory and cognition, rather than gustatory function.
Administration, Inhalation↗