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PubMed2005

Molecular properties and pharmacogenetics of a polymorphism of adenylyl cyclase type 9 in asthma: interaction between beta-agonist and corticosteroid pathways.

In asthma, the response to beta-agonists acting at beta2-adrenergic receptors (beta2AR) displays extensive interindividual variation. One effector for airway beta2AR, adenylyl cyclase type 9 (AC9), was considered a candidate locus for predicting beta-agonist efficacy in the absence and presence of corticosteroid treatment. One non-synonymous AC9 polymorphism has been identified, which results in substitution of Met for Ile at amino acid 772. Under standard culture conditions in stably transfected cells, we found decreased catalytic activity of Met772. However, cells cultured in the presence of glucocorticoid expressing Met772 had a significantly increased albuterol-stimulated adenylyl cyclase response (approximately 80%) when compared with those expressing Ile772 (approximately 20%, P=0.02). An equivalent increase in beta2AR expression was observed in both lines due to glucocorticoid, but AC9 expression was unaffected. The hypothesis that Met772-AC9 is associated with an improved albuterol bronchodilator response in asthmatics was investigated in 436 asthmatic children who were followed for 4 years and randomized to receive placebo or the inhaled corticosteroid budesonide. Met772 carriers on budesonide showed a significant improvement in forced expiratory volume in 1 s (P=0.005). Moreover, a highly significant interaction (P=0.002) was found for budesonide treatment and the AC9 polymorphism. These in vitro and human association studies are consistent with this AC9 polymorphism altering albuterol responsiveness in the context of concomitant inhaled corticosteroid administration, which is a common asthma regimen. The Met772-AC9 polymorphism represents one of most likely several multi-gene polymorphisms along the receptor-relaxation axis, which together may provide for a composite pharmacogenetic index for asthma therapy.

Adenylyl Cyclases↗
PubMed1993

A comparison of the efficacy of azithromycin and clarithromycin in oral therapy of experimental airborne Legionnaires' disease.

The activities of two new macrolides, azithromycin and clarithromycin, were compared in an aerosol-infected guinea-pig model of legionnaires' disease. The results of this study indicate that a low oral dose of azithromycin (3.6 mg/kg) administered once daily gives 100% survival in Legionella pneumophila-infected animals. An eight-fold higher dose of clarithromycin (28.8 mg/kg) given twice-daily was required to achieve the same effect. Similarly, azithromycin was more effective than clarithromycin in preventing pyrexia and in reducing numbers of bacteria and lesions in the lung.

Administration, Inhalation↗
PubMedDate not supplied

A reverse isotope dilution method for determining benzene and metabolites in tissues.

A method utilizing reverse isotope dilution for the analysis of benzene and its organic soluble metabolites in tissues of rats and mice is presented. Tissues from rats and mice that had been exposed to radiolabeled benzene were extracted with ethyl acetate containing known, excess quantities of unlabeled benzene and metabolites. Butylated hydroxytoluene was added as an antioxidant. The ethyl acetate extracts were analyzed with semipreparative reversed-phase HPLC. Isolated peaks were collected and analyzed for radioactivity (by liquid scintillation spectrometry) and for mass (by UV absorption). The total amount of each compound present was calculated from the mass dilution of the radiolabeled isotope. This method has the advantages of high sensitivity, because of the high specific activity of benzene, and relative stability of the analyses, because of the addition of large amounts of unlabeled carrier analogue.

Administration, Inhalation↗
PubMedDate not supplied

Human urinary excretion profile after smoking and oral administration of [14C]delta 1-tetrahydrocannabinol.

The urinary excretion profiles of delta 1-tetrahydrocannabinol (delta 1-THC) metabolites have been evaluated in two chronic and two naive marijuana users after smoking and oral administration of [14C]delta 1-THC. Urine was collected for five days after each administration route and analyzed for total delta 1-THC metabolites by radioactivity determination, for delta 1-THC-7-oic acid by high-performance liquid chromatography, and for cross-reacting cannabinoids by the EMIT d.a.u. cannabinoid assay. The average urinary excretion half-life of 14C-labeled delta 1-THC metabolites was calculated to be 18.2 +/- 4.9 h (+/- SD). The excretion profiles of delta 1-THC-7-oic acid and EMIT readings were similar to the excretion profile of 14C-labeled metabolites in the naive users. However, in the chronic users the excretion profiles of delta 1-THC-7-oic acid and EMIT readings did not resemble the radioactive excretion due to the heavy influence from previous Cannabis use. Between 8-14% of the radioactive dose was recovered in the urine in both user groups after oral administration. Lower urinary recovery was obtained both in the chronic and naive users after smoking--5 and 2%, respectively.

Administration, Inhalation↗
PubMed1994

Sweat testing for heroin, cocaine, and metabolites.

Although a variety of drugs have been detected in sweat, little information is available on the characteristics of drug excretion in sweat under controlled-dosing conditions. A series of clinical studies were designed to determine the identity, concentration, time course, dose dependency, and variability of drug and metabolite excretion in sweat following administration of single doses of cocaine and heroin to human subjects. Sweat was collected by means of a sweat patch that could be worn for a period of several days to several weeks at a time, resulting in accumulation of drug in the patch. Sweat patches were removed at specified times and frozen until analyzed by gas chromatography--mass spectrometry. Cocaine and heroin were the major analytes excreted in sweat following their administration. Smaller amounts of cocaine metabolites were also detected following cocaine administration. 6-Acetylmorphine appeared rapidly after heroin administration and continued to increase while heroin content decreased, suggesting that heroin was undergoing hydrolysis in the sweat patch. Cocaine appeared in sweat within 1-2 hours and peaked within 24 hours in an apparent dose-dependent manner. Analysis of duplicate adjacent patches from individual subjects who had been administered cocaine provided similar quantitative results, suggesting that intrasubject variability was relatively low, whereas intersubject variability was high. These observations regarding the excretion of cocaine and heroin analytes in sweat have important forensic implications to other fields such as hair analysis. Sweat excretion could be an important mechanism by which drugs enter hair. These data also suggest that the sweat patch could serve as a useful monitoring device in surveillance of individuals in treatment and probation programs.

Administration, Inhalation↗
PubMed1995

Pharmacokinetics and pharmacodynamics of cocaine.

A dramatic shift has occurred over the last decade in the route of cocaine administration by drug abusers in the United States. The favored route has changed from intranasal and intravenous use to administration of cocaine ("crack") by the smoking route. The reasons for this shift are not well understood but may include social and environmental factors such as the ease and convenience of the smoking route, avoidance of needle-transmitted disease, and possible pharmacological differences produced by the different routes of administration. This study examined the influences exerted by changes in the route of administration on pharmacokinetic parameters and drug-induced behavioral and physiological effects of cocaine. Six male subjects who provided informed consent and had a recent history of cocaine use by the intravenous and smoked routes participated in a blind, double-dummy, crossover study conducted on a clinical research ward. On different occasions, subjects received single doses of cocaine by the intravenous (25 mg, cocaine HCl), intranasal (32 mg, cocaine HCl), and smoked (42 mg, cocaine base) routes. Physiological and behavioral measures were collected prior to and periodically after drug administration. Concurrent blood samples were collected and analyzed for cocaine and metabolites by gas chromatography-mass spectrometry, Plasma concentrations of cocaine and benzoylecgonine were fitted to pharmacokinetic models by nonlinear regression analysis. Behavioral measures of "good" drug effects and "liking" were higher by the smoked route than the intravenous route, but physiological changes were approximately equal at equivalent plasma concentrations of cocaine. Intranasal cocaine administration was characterized by lower cocaine plasma concentrations and a slower onset of pharmacological effects that were generally of lesser magnitude than those observed by other routes of administration. Overall, this study demonstrated that cocaine administration by the smoked route produced substantially higher behavioral responses than an equivalent dose of cocaine administered by the intravenous route. This finding suggests that smoked cocaine (crack) has a higher abuse liability and greater dependence-producing properties than equivalent doses of cocaine administered by the intravenous or intranasal route.

Administration, Inhalation↗
PubMed1997

Cocaine disposition in saliva following intravenous, intranasal, and smoked administration.

Saliva concentrations of cocaine, benzoylecgonine, ecgonine methyl ester, and anhydroecgonine methyl ester were measured by gas chromatography-mass spectrometry in six healthy male subjects following cocaine administration by the intravenous, intranasal, and smoked routes of administration. Cocaine appeared in saliva rapidly following all routes of administration. Saliva/plasma (S/P) ratios were generally greater than 1, and there was evidence of moderate to extreme contamination of saliva by cocaine immediately following intranasal and smoked routes of administration. Contamination of the oral cavity and saliva cleared rapidly. Saliva obtained 2 h after dosing appeared to be free of contamination and demonstrated S/P ratios comparable with intravenous administration. Benzoylecgonine and ecgonine methyl ester concentrations were consistently low and were only comparable with cocaine concentrations at times when cocaine concentrations had declined to below 100 ng/mL. Anhydroecgonine methyl ester was detectable in saliva following smoked drug administration, but it was quickly cleared. Terminal half-life estimates for cocaine administered by the intranasal and smoked routes were significantly shorter in saliva compared with those measured in plasma. Half-life estimates following intravenous administration tended to be lower for saliva than plasma, but the differences were not significant. The duration of pharmacologic effects was generally the same as or shorter than detection times of cocaine in plasma and saliva. Overall, the study demonstrated the usefulness of saliva as a test matrix for the detection and measurement of cocaine following administration by different routes of administration.

Administration, Inhalation↗
PubMed2003

Dose coefficients for the embryo and fetus following intakes of radionuclides by the mother.

The International Commission on Radiological Protection has recently issued Publication 88, giving dose coefficients for the embryo, fetus and newborn child from intakes of selected radionuclides of 31 elements by the mother, either before or during pregnancy. The biokinetic models used for calculating these doses were based upon the available human data and the results of animal experiments. This paper summarises the approach used for the development of biokinetic and dosimetric models. It also compares the estimates of dose received by the offspring with those received by the reference adult. The main findings are that, in general, doses to the offspring are similar to or lower than those to the reference adult. For a few radionuclides, however, the dose to the offspring can exceed that to the adult. The reasons for these variations in comparative doses are examined.

Administration, Inhalation↗
PubMed2003

A new model for the human alimentary tract: the work of a Committee 2 task group.

The absorbed doses received from ingested radionuclides are currently calculated using the method outlined in ICRP Publication 30. It has been recognised by the ICRP that some of the assumptions used to calculate absorbed doses should be reviewed. A new physiologically based model has been developed, applicable to intakes of radionuclides in food and liquids by children and adults. All parts of the alimentary tract are included, additional sites for absorption and retention are considered and the morphometric and transit parameter values are reviewed in coordination with the ICRP Reference Man revision. Features of the new model are explained and preliminary dose estimates are presented.

Administration, Inhalation↗
PubMed2003

An analysis of a puncture wound case with medical intervention.

A worker noted a small wound to his thumb when leaving a work site that was undergoing decontamination because of past operations with plutonium (Pu) and americium (Am). Direct surveys of the wound site confirmed the presence of contamination. The chelating agent Ca-DTPA was administered via a nebuliser within an hour after discovery of the wound. External measurements were made of the wound site and wound dressings; 24-h urinary excretion data were collected periodically and the Pu and Am urine content was determined. Zn-DTPA was administered on three occasions. The ICRP Pu systemic model was modified to consider the enhanced urinary excretion following administration of the chelating agents. The analysis indicated that the wound resulted in an initial deposition of 400 Bq 238Pu, 2240 Bq (239/240)Pu and 1060 Bq 241Am. About 70% of the initial wound activity was removed by surgical procedures and less than 1% of the wound activity was removed by chelation therapy. This paper compares the observed urinary excretion data with that indicated by a simulation of the kinetics of the transfer from the wound site and the kinetics of the chelating agent and Pu.

Administration, Inhalation↗
PubMed2003

Prolonged ethanol ingestion enhances benzene myelotoxicity and lowers urinary concentrations of benzene metabolite levels in CD-1 male mice.

Benzene toxicity is attributed to its metabolism, which is primarily mediated by the ethanol-inducible cytochrome P450 2E1 isoform (CYP2E1). The present study investigated the myelotoxicity and urinary concentrations of major benzene metabolites in adult CD-1 male mice treated with low levels of benzene vapors, ethanol, or a combination of the two. Groups of ethanol-treated (5% in a Lieber-DeCarli liquid diet, 3 weeks) or pair-fed control mice were exposed to 10 ppm benzene, 6 h per day, 5 days per week for 2 weeks, starting from the second week of ethanol administration. On the last day of treatment, the number of early and late erythroid progenitors (BFU-E and CFU-E) was reduced by 55%, while the number of granulocyte/macrophage progenitors (CFU-GM) was reduced by 36% in benzene-treated mice. Ethanol lowered the CFU-E, BFU-E, and CFU-GM colony formation by 33, 28, and 12%, respectively. In animals coexposed to benzene and ethanol, the CFU-E colony counts were decreased by 70%, the BFU-E by 80%, and the CFU-GM by 45%. Phenol (Ph), hydroquinone (HQ), catechol (Cat), and trans,trans-muconic acid (MA) were measured by HPLC-UV in urine samples collected weekly during the last 6-h benzene/air exposure session. In benzene-exposed mice urinary metabolite levels peaked at the end of the first week of treatment (microg/kg body weight (bw): Ph: 4931 +/- 1055; Cat: 109 +/- 17; HQ: 784 +/- 137; MA: 534 +/- 92) and significantly decreased at the end of the second week (microg/kg bw: Ph: 3909 +/- 984; Cat: 82 +/- 24; HQ: 337 +/- 72; MA: 235 +/- 55). In mice given benzene and ethanol, the urinary levels of Ph, Cat, HQ, and MA were significantly lower than those measured in the group given benzene alone. The urinary levels of Ph and Cat showed a decreasing trend, again, from the first to the second week of benzene exposure. These data indicate that chronic ethanol ingestion exacerbates benzene myelotoxicity and, in addition, reduces the urinary excretion of benzene metabolites in mice, suggesting that the influence of ethanol intake should be considered carefully in biomonitoring benzene exposure.

Administration, Inhalation↗
PubMed1989

Choice of dose measure for extrapolating carcinogenic risk from animals to humans: an empirical investigation of 23 chemicals.

When estimating carcinogenic risk in humans from animal data, animal to human extrapolation is often accomplished by assuming that humans and animals are equally sensitive when dose is measured appropriately in common units in both species. This paper reports on an empirical investigation of several dose units, based on data from 23 chemicals for which both animal and human data were available. The dose units were evaluated using a measure called "bias," which represents roughly the factor by which the TD25 calculated from animal data must be multiplied to correspond, on average, to the TD25 calculated from human data. (A TD25 is the average human dose rate per unit of body weight in mg kg-1 d-1, administered between ages 20 and 65, that would cause an extra lifetime cancer risk of 25%.) Biases of greater than one mean that estimates of human risk from animal data exceeded estimates made from human data. Five dose measures are evaluated in this paper; they are based on several risk assessment methods. The resulting ranges of biases are: dose rate per surface area in mg m-2 d-1, 2.1 to 12; dose rate per unit of body weight in mg kg-1 d-1, 0.36 to 1.6; parts per million in diet, 1.1 to 6.2; cumulative dose per unit of body weight in mg kg-1 per lifetime, 13 to 84; parts per million in air, 1.1 to 4.5. These findings suggest that all of these measures of dose except dose rate per unit of body weight tend to result in overestimation of human risk.

Administration, Inhalation↗
PubMed2001

Impact on internal doses of photon SAFs derived with the GSF adult male voxel phantom.

This paper describes the effect on over 3,000 sets of internal dose estimates of using photon Specific Absorbed Fractions (SAFs) calculated using two different types of phantoms, specifically the MIRD-type anthropomorphic phantom originally developed by Snyder and the new adult male voxel phantom, GOLEM, developed at GSF. The SAFs based on the MIRD-type phantom are currently used by the International Commission on Radiological Protection (ICRP) in internal dose calculations, but there are suggestions of moving towards SAFs generated from voxel phantoms, thus there is an interest in the potential differences in internal doses. Overall, it is found that some tissue doses calculated using the voxel phantoms can differ significantly from those of the MIRD-type phantom; however, the effective dose appears to be quite robust to changes in photon SAFs.

Administration, Inhalation↗
PubMed2004

Medicinal use of cocaine: a shifting paradigm over 25 years.

OBJECTIVES/HYPOTHESIS: Human cocaine research is predicated on data from the clinical practice of otolaryngology that are more than 25 years old and predate both the cocaine epidemic and the first reported association between cocaine use and myocardial infarction. The authors' objective was to reassess the epidemiology and toxicity of medicinal cocaine use among otolaryngologists and to compare current trends in usage and safety data with previously reported data. STUDY DESIGN: An anonymous closed-question survey replicating the methodology of a previous study was used. METHODS: The survey was mailed to active members of the American Academy of Otolaryngology-Head and Neck Surgery. The survey used a closed-question format asking about the use of cocaine, safety measures taken, and adverse outcomes and included information about practice type and location. Results were compared with previously published data using a chi test with P < .05 considered significant. RESULTS: In all, 7815 surveys were mailed. Four thousand seventeen otolaryngologists returned the survey, representing a 54% response rate. Of the respondents, only 50% had used cocaine in their practice during the previous year. Physicians who had been in practice for less than 10 years were less likely to have used cocaine than those who had been in practice for more than 10 years (78% vs. 93% [P < .001]). Compared with the data reported in 1977, fewer physicians reported ever using cocaine in their practice (88% vs. 92% [P < .001]), fewer physicians had used cocaine in their practice at any time in the previous 10 years (68% vs. 92% [P < .001]), and a greater number of adverse reactions were reported by current respondents (26% vs. 22% [P < .001]). Tachycardia and hypertension were the most commonly reported adverse effects. Other important adverse events included 14 deaths, survivable cardiac arrest, ventricular tachycardia, and seizures. CONCLUSION: The clinical use of cocaine in otolaryngology has decreased significantly in the past 25 years as a result of discontinuation of use by physicians who had previously used cocaine and an increasing number of otolaryngologists who have never used it. This decline may reflect a better understanding of its potential toxicities, problems associated with storing and dispensing of a tightly controlled substance, increased availability of safer alternative medications, or a combination of these.

Administration, Inhalation↗
PubMed2001

Drug treatments and topics: the year in review.

In 2000, more than 100 new drugs and devices were approved for use in the United States. Many drugs were reformulated to provide new uses, more effective dosing, or improved costs. In an effort to ensure safe prescribing practices, the Food and Drug Administration has increased drug and device monitoring and services available to clinicians.

Administration, Inhalation↗
PubMed2003

Are nasal steroids safe?

Nasal steroids have emerged as an integral part of rhinitis management. Most studies have shown no evidence of significant hypothalamic-pituitary-adrenal axis suppression from nasal steroid use, at least based on dynamic testing. Bone mineral density loss, glaucoma, and cataract formation are risks associated with systemic steroids, but reports with nasal steroid use are few. Growth retardation has been seen with some nasal steroids, but not others, based on stadiometric growth studies. Further studies are certainly needed to resolve this issue. Nasal steroids, in general, have an excellent safety record.

Administration, Inhalation↗