The need for tuberculosis education in the homeless male population.
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Ill-Housed Persons↗
Biomedical subjects
D A Smith
Publications and source records attributed to D A Smith.
Continence nurses: a survey of who they are and what they do.
This survey is the first report on the characteristics, functions, and barriers to practice reported by continence care nurses in the United States. The data obtained provide valuable information regarding a new subspecialization in nursing.
Adolescent↗
Zolmitriptan (311C90) does not interact with fluoxetine in healthy volunteers.
Zolmitriptan (Zomig, formerly 311C90) is a selective 5-hydroxytryptamine (5-HT)1B/1D-receptor agonist with central and peripheral activity for the acute treatment of migraine. This randomized, placebo-controlled, crossover study investigated the effects of fluoxetine administration on the pharmacokinetics and pharmacodynamics of zolmitriptan. Twenty volunteers were given single doses of fluoxetine 20 mg or an identical placebo daily for 28 days prior to receiving a single 10 mg oral dose of zolmitriptan. Sixteen volunteers completed the two treatment phases. The pharmacokinetic parameters of zolmitriptan and its metabolites were not significantly affected by fluoxetine pretreatment. The pharmacodynamic effects of zolmitriptan were also unaffected by fluoxetine pretreatment. There were small, clinically insignificant increases in blood pressure following zolmitriptan which were unaltered by fluoxetine. Zolmitriptan was well tolerated when given alone or concomitantly with fluoxetine. These results indicate that there is no contraindication to the use of zolmitriptan in patients treated concurrently with selective serotonin reuptake inhibitors and that no adjustment of the zolmitriptan dose is required in these circumstances.
Adolescent↗
Interaction of terfenadine and its primary metabolites with cytochrome P450 2D6.
The substrate structure-activity relationships described for the major human drug-metabolizing cytochrome P450 (P450 or CYP) enzymes suggest that the H1 receptor antagonist terfenadine could interact with CYP2D6 either as a substrate or as an inhibitor, in addition to its known ability to act as a substrate for CYP3A4. Based on this substrate structure-activity relationship, computer modeling studies were undertaken to explore the likely interactions of terfenadine with CYP2D6. An overlay of terfenadine and dextromethorphan, a known substrate of CYP2D6, showed that it was possible to superimpose the site of hydroxylation (t-butyl group) and the nitrogen atom of terfenadine with similar regions in dextromethorphan. These observations were substantiated by the ease of docking of terfenadine into a protein model of CYP2D6. Experimentally, terfenadine inhibited CYP2D6 activity in human liver microsomes with an IC50 of 14-27 microM, depending on the CYP2D6 substrate used. The inhibition of CYP2D6 was further defined by determining the Ki for terfenadine against bufuralol 1'-hydroxylase activity in four human livers. Terfenadine inhibited bufuralol 1'-hydroxylase activity with a Ki of approximately 3.6 microM. The formation of the hydroxylated metabolite (hydroxyterfenadine) in microsomes prepared from human liver and specific P450 cDNA-transfected B lymphoblastoid cells indicated that only CYP2D6 and CYP3A4 were involved in this transformation. As expected, the rate of formation was greatest with CYP3A4 (Vmax = 1257 pmol/min/nmol of P450), with CYP2D6 forming the metabolite at a 6-fold lower rate (Vmax = 206 pmol/min/nmol of P450). The two enzymes had similar KM values (9 and 13 microM, respectively). These data indicate that, as predicted from modeling studies, terfenadine has the structural features necessary for interaction with CYP2D6.
Chromatography, High Pressure Liquid↗
Hazards of nitrous oxide exposure in healthcare personnel.
Nitrous oxide, a commonly used agent in the dental and anesthesia practice, carries serious risks to healthcare providers. Complications from its exposure can range from hematological abnormalities and neurological deficits to increased risk of spontaneous abortions in women. A concentrated effort by all anesthesia personnel is necessary to prevent the adverse effects associated with the use of this agent.
Adult↗
Current status of computed radiography in emergency departments.
This study reports the findings of a computed radiography (CR) imaging experience questionnaire sent to 35 emergency departments (ED) in North America. A total of 25 responses to the questionnaire were received corresponding to a return rate of 71%. The median daily workload was 71 patient examinations and the average number of films per patient examination for the 21 facilities was 3.0 +/- 0.8. A total of 91% of respondents printed to film all ED trauma images obtained with CR with only one ED claiming to be filmless. CR in the ED was easy to use and had significant benefits of reducing examination repeat rates, permitting a prompt availability of radiographic images, improving image quality, providing improved operational efficiency, and eliminating lost films. Major limitations of CR were deemed to be limited viewing stations, CR costs, and inefficient patient ID entry. Radiology departments were very happy with the introduction of CR into the ED setting with approximately half being highly satisfied and half somewhat satisfied. The degree of satisfaction by ED personnel was similar with about half being highly satisfied, 40% somewhat satisfied, and the remainder neutral. The fact that not a single respondent was in any way dissatisfied shows that CR can play a useful role in the ED setting.
Emergency Service, Hospital↗
Identification of the cytochrome P450 isoforms involved in the O-demethylation of 4-nitroanisole in human liver microsomes.
1. 4-Nitroanisole is O-demethylated to 4-nitrophenol by human liver microsomes. Kinetic studies indicate that this metabolic route is mediated by two cytochrome P450 isoforms, one with a K(m) = 2.1 microM and the other with a K(m) = 220 microM. 2. Chemical inhibition and correlation studies in human liver microsomes indicate that the low K(m) enzyme is CYP2A6 and the high K(m) enzyme is CYP2E1 suggesting that44-nitroanisole is not a general cytochrome P450 substrate. 3. Studies using expressed recombinant cytochrome P450s indicated that all the cytochrome P450s investigated metabolized 4-nitroanisole but CYP2A6 and CYP2E1 produced the highest rates. Kinetic studies with these two isoforms produced a K(m) for CYP2A6 of 9 microM and 54 microM for CYP2E1. 4. The involvement of these two isoforms in the O-demethylation of 4-nitroanisole can be rationalized in terms of a hydrogen bond interaction with the nitro group and the active site of CYP2A6 and a hydrophobic interaction with the active site of CYP2E1.
Adult↗
Pharmacokinetics and pharmacodynamics in toxicology.
1. Pharmacokinetics aids interpretation of the dose-response relationship in individual toxicology studies. 2. When used to compare across studies, even in a single species other factors, including variation in pharmacodynamic response, must be taken into account. Variation in pharmacodynamic response becomes more profound when one compares across species. 3. Examples do occur where plasma concentration-response relationships are constant across species, particularly when corrected for unbound drug. These examples should not be taken as support, however, of a general universal principle. 4. Owing to multiple factors such as species differences in receptors, enzymes and ion channels, dose or plasma concentration-response relationships can vary enormously across species. In the light of this, the results of toxicology studies should be viewed as qualitative rather than quantitative. Once sufficient clinical experience is gained the human database is the overriding measure of drug safety.
Animals↗
Granulocyte-macrophage colony stimulating factor exacerbates collagen induced arthritis in mice.
OBJECTIVE: To examine the effect of granulocyte-macrophage colony stimulating factor (GM-CSF) on disease progression in the collagen induced arthritis (CIA) model in mice. METHODS: DBA/1 mice were primed for a suboptimal CIA response by intradermal injection of chick type II collagen without a secondary immunisation. Three weeks after immunisation the mice were given four to five consecutive daily intraperitoneal injections of recombinant murine GM-CSF (15 micrograms; 5 x 10(5) U), or vehicle, and arthritis development was monitored by clinical scoring of paws and calliper measurements of footpad swelling. At approximately six to eight weeks after immunisation mice were killed, their limbs removed and processed for histological analyses of joint pathology. RESULTS: Control animals receiving a single immunisation with collagen exhibited a varied CIA response both in terms of incidence and severity. Mice treated with GM-CSF at 20 to 25 days after immunisation with collagen had a consistently greater incidence and more rapid onset of disease than the vehicle treated control mice, based on clinical assessment. GM-CSF treated mice showed higher average clinical scores and greater paw swelling than controls. Histological analyses of joints reflected the clinical scores with GM-CSF treated mice displaying more pronounced pathology (synovitis, pannus formation, cartilage and bone damage) than control mice. CONCLUSION: GM-CSF is a potent accelerator of the pathological events leading to chronic inflammatory polyarthritis in murine CIA supporting the notion that GM-CSF may play a part in inflammatory polyarthritis, such as rheumatoid arthritis.
Animals↗
Relationship between maximum aerobic power and resting metabolic rate in young adult women.
The literature is inconclusive as to the chronic effect of aerobic exercise on resting metabolic rate (RMR), and furthermore there is a scarcity of data on young women. Thirty-four young women exhibiting a wide range of aerobic fitness [maximum aerobic power (VO2max) = 32.3-64.8 ml.kg-1.min-1] were accordingly measured for RMR by the Douglas bag method, treadmill VO2max, and fat-free mass (FFM) by using Siri's three-compartment model. The interclass correlation (n = 34) between RMR (kJ/h) and VO2max (ml.kg-1.min-1) was significant (r = 0.39, P < 0.05). However, this relationship lost statistical significance when RMR was indexed to FFM and when partial correlation analysis was used to control for FFM differences. Furthermore, multiple linear-regression analysis indicated that only FFM emerged as a significant predictor of RMR (kJ/h). When high- (n = 12) and low-fitness (n = 12) groups were extracted from the cohort on the basis of VO2max scores, independent t-tests revealed significant between-group differences (P < 0.05) for RMR (kJ.kg-1.h-1) and VO2max (ml.kg-1.min-1) but not for RMR (kJ/h), RMR (kJ.kg FFM-1.h-1), and FFM. Analysis of covariance of RMR (kJ/h) with FFM as the covariate also showed no significant difference (P = 0.56) between high- and low-fitness groups. Thus the results suggest that 1) FFM accounts for most of the differences in RMR between subjects of varying VO2max values and 2) the RMR per unit of FFM in young healthy women is unrelated to VO2max.
Adult↗
Norepinephrine-induced contraction of isolated rabbit bronchial artery: role of alpha 1- and alpha 2-adrenoceptor activation.
The contractile effect of norepinephrine (NE) on isolated rabbit bronchial artery rings (150-300 microns in diameter) and the role of alpha 1- and alpha 2-adrenoceptors (AR) on smooth muscle and endothelium were studied. In intact arteries, NE increased tension in a dose-dependent manner, and the sensitivity for NE was further increased in the absence of endothelium. In intact but not in endothelium-denuded arteries, the response to NE was increased in the presence of both indomethacin (Indo; cyclooxygenase inhibitor) and NG-nitro-L-arginine methyl ester [L-NAME; nitric oxide (NO) synthase inhibitor], indicating that two endothelium-derived factors, NO and a prostanoid, modulate the NE-induced contraction. The alpha 1-AR antagonist prazosin shifted the NE dose-response curve to the right, and phenylephrine (alpha 1-AR agonist) induced a dose-dependent contraction that was potentiated by L-NAME or removal of the endothelium. The sensitivity to NE was increased slightly by the alpha 2-AR antagonists yohimbine and idazoxan, and this effect was abolished by Indo or removal of the endothelium. Similarly, contractions induced by UK-14304 (alpha 2-AR agonist) were potentiated by Indo or removal of the endothelium. These results suggest that NE-induced contraction is mediated through activation of alpha 1- and alpha 2-ARs on both smooth muscle and endothelium. Activation of the alpha 1- and alpha 2-ARs on the smooth muscle causes contraction, whereas activation of the endothelial alpha 1- and alpha 2-ARs induces relaxation through release of NO (alpha 1-ARs) and a prostanoid (alpha 2-ARs).
Adrenergic alpha-Agonists↗
Past is prologue: moving forward from psychiatric training.
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Cost Control↗
Cutaneous mycoses in chameleons caused by the Chrysosporium anamorph of Nannizziopsis vriesii (Apinis) Currah.
A dermatophyte-like fungus was isolated from skin biopsies of three different species of captive chameleon in which fungal elements had been observed by histologic examination. An adult Parson's chameleon (Chamaeleo parsonii) presented with vesicles that became crusty brown lesions on the limbs and body. Skin biopsies revealed fungal hyphae in the affected epidermis and underlying dermis. The lesions regressed fully after oral administration of itraconazole. An adult jewel chameleon (Chamaeleo lateralis) from the same private collection presented with localized black skin lesions and died while being treated with itraconazole. A pulmonary granuloma was also present in this chameleon at autopsy. Cultures obtained from skin and lung lesions yielded the same fungus. A third isolate was obtained from a skin biopsy of a Jackson's chameleon (Chamaeleo jacksoni) with deep ulcerative cutaneous lesions located at the base of the tail. The fungus, in all three cases, has been identified as the Chrysosporium anamorph of Nannizziopsis vriesii, a poorly known ascomycetous species recorded previously from the skin of a lizard and from soil, on the basis of its keratinolytic activity, resistance to cycloheximide, strongly restricted growth at 37 degrees C, formation of clavate or pyriform single-celled or two-celled aleurioconidia, and alternate and fission arthroconidia.
Administration, Oral↗
Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics.
Drug metabolism input to the discovery process had historically been on an empirical case-by-case basis, since, detailed descriptors of the effect on pharmacokinetics of a change in structure or physicochemical property were not available. Considerable advances have been made in recent years, such that basic rules can be applied to predict the behavior of a compound in man based on physicochemistry and structure. This is particularly true in the areas of absorption, distribution, and clearance. In particular, knowledge of the reactions catalyzed by the enzymes of drug metabolism, including the cytochrome P450 super family, can be used in the design of new chemical entities, together with the usual pharmacological-derived SAR. The combination of both pharmacokinetics and pharmacodynamics at the discovery stage leads to drugs with optimum performance characteristics. Such drugs are easier to develop, representing a huge saving in resources. Moreover, the marketed compound is much more likely to find high clinical utilization. This review uses dofetilide, fluconazole, and amlodipine to highlight the multifaceted consequences of changing chemical structure, in terms of drug disposition, and reinforces these principles with examples from the literature.
Absorption↗
Complete amino acid sequences of two trypsin inhibitors from buckwheat seed.
The major trypsin isoinhibitors from seed extracts of buckwheat (Fagopyrum esculentum Mönch) were purified by affinity chromatography, anion exchange chromatography, anion exchange HPLC and reversed-phase HPLC, and the complete amino acid sequences of two isoinhibitors, BTI-1 and BTI-2, were established by automated Edman degradation. Each isoinhibitor consists of a single polypeptide chain of 69 amino acids, including two Cys residues. The N-terminal sequence of a third isoform, BTI-3, was also determined. The buckwheat trypsin isoinhibitors exhibit clear sequence similarities with the potato chymotrypsin inhibitor I family of serine proteinase inhibitors.
Amino Acid Sequence↗
OBRA regulations and the use of psychotropic drugs in long-term care facilities: impact and implications for geropsychiatric care.
This article reviews governmental guidelines regulating the use of psychotropic drugs in long-term care facilities as established by the Omnibus Budget Reconciliation Act (OBRA) of 1987 and their impact on the use of psychotropic agents in these settings. A major component of these guidelines is to regulate the clinical indications for psychoactive drugs (neuroleptics, benzodiazepines, and sedative hypnotics) in residents of long-term care facilities. Responsibilities of the prescribing physician, facility medical director, and consulting pharmacist--as well as quality assurance procedures-in complying with OBRA regulations are examined. Evidence that OBRA regulations have reduced the use of psychotropic drugs and physical restraints in long-term nursing facilities is reviewed. Implications of the OBRA regulations for the training and clinical practice of psychiatrists and primary care clinicians are discussed as well as recommendations for increasing the availability of mental health services for this patient population via multidisciplinary geropsychiatric consultation-liaison teams.
Aged↗
Enhanced antiopiate activity and enzyme resistance in a peptidomimetic of FMRFamide containing E-2,3-methanomethionine and E-2,3-methanophenylalanine.
FMRFamide is a molluscan peptide that has shown antiopiate activity in a number of mammalian test systems. Peptidomimetics of FMRFamide substituted with conformationally constrained stereoisomers of Z-2,3-methanomethionine or E-2,3-methanomethionine precipitated abstinence syndrome far more potently than FMRFamide itself. The current study determined the effect on antiopiate potency of an additional rigid substitution. A peptidomimetic containing a stereoisomer of E-2,3-methanomethionine was compared with a peptidomimetic additionally substituted at the C-terminal with E-2,3-methanophenylalanine. Morphine abstinence signs were observed after varying doses (0.125-25.0 micrograms) of these two peptidomimetics were injected into the third ventricle of morphine-dependent rats. The peptidomimetic containing both rigid substitutions was far more potent than the peptidomimetic of FMRFamide containing methanomethionine alone. The increased potency appears to be related to enzyme resistance rather than receptor affinity.
Amino Acid Sequence↗
Nitric oxide synthesis inhibition attenuates behavioral actions of neuropeptide FF.
Neuropeptide FF (NPFF) has certain antiopiate actions and may play a role in opiate tolerance and dependence. Third ventricle injection of 10 micrograms NPFF induces a quasimorphine abstinence syndrome in opiate-naive rats. Nitric oxide synthesis may also contribute to opiate tolerance and dependence. The present study tests the hypothesis that NPFF acts through stimulation of nitric oxide synthase (NOS). Third ventricular injection of 10 micrograms NPFF precipitated an average of 46 abstinence-like signs during a 20-min observation. Pretreatment (30 min earlier) with 7.5 or 15 mg/kg s.c. of the NOS inhibitor nitro-L-arginine (L-NNA) resulted in a significant and dose-dependent alleviation of NPFF-induced abstinence-like signs. The anti-NPFF activity of 15 mg/kg L-NNA was blocked by 750 mg/kg L-arginine, but not by the same amount of D-arginine, indicating that L-NNA attenuates NPFF activity through a stereospecific inhibition of NOS.
Animals↗