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Biomedical subjects

R E Howell

Publications and source records attributed to R E Howell.

At least 19 recordsLinked to original sources
PubMed1999

University of Iowa Hospital and Clinics: outcomes management.

Delivery of quality patient care and management of patient outcomes is critical to the success of academic medical centers in the ever-changing health care market. The University of Iowa Hospitals and Clinics (UIHC) promotes quality care through the provision of organizational structures and processes that are described in this article. In addition, quality of care and outcomes management are described by members in various roles within the UIHC health care system. It is the authors' belief that understanding quality from these various perspectives helps UIHC work across departments to achieve excellence in patient care.

Attitude of Health Personnel↗
PubMed1999

Etiology of fibrous dysplasia and McCune-Albright syndrome.

In this paper, the etiology of monostotic fibrous dysplasia and McCune-Albright syndrome is explained. Both monostotic fibrous dysplasia and McCune-Albright syndrome are sporadically occurring disorders in which a mutation in the GNAS1 gene occurs postzygotically in a somatic cell. All cells descended from the mutated cell can manifest features of McCune-Albright syndrome or fibrous dysplasia. Cells descended from non-mutated cells develop into normal tissues. Thus, the clinical pattern is variable in distribution and appearance. More generalized vs more localized expression depend on (a) how small or how large the cell mass is during embryogenesis when the mutation occurs and (b) where in the cell mass the mutation occurs. Topics discussed include G proteins and their receptors, cycling of stimulatory G protein between active and inactive forms, and specific mutations in GNAS1. We also discuss four possibilities: (a) Are there masked mutations? (b) Are there effects of imprinting? (c) Are there non-classical mutations? and (d) Is fibrous dysplasia a neoplasm?

Fibrous Dysplasia, Monostotic↗
PubMed1995

Hypotensive effect of an M2-selective muscarinic antagonist in anaesthetized guinea-pigs.

1. In order to determine an involvement of muscarinic M2 receptors in the regulation of systemic arterial blood pressure, we investigated the cardiovascular effects of the M2-selective antagonist methoctramine and other agents in anaesthetized guinea-pigs. 2. Intravenous injection of methoctramine, atropine, pirenzepine (an M1-selective muscarinic antagonist) or 4-DAMP (an M3-selective muscarinic antagonist) each significantly increased heart rate in comparison to vehicle controls. 3. Methoctramine produced significant, dose-dependent decreases in mean arterial blood pressure, with an ED50 of 0.1 mg kg-1. Atropine decreased blood pressure only at high doses. Pirenzepine and 4-DAMP did not alter blood pressure, indicating that M1 or M3 receptor antagonism was not responsible for the cardiovascular effects of methoctramine. 4. The hypotensive effect of methoctramine was unaltered by indomethacin pretreatment, ruling out an alteration in arachidonic acid metabolism as the mechanism of action. 5. In contrast to methoctramine, mecamylamine (a nicotinic ganglionic receptor antagonist) greatly decreased heart rate and slightly decreased blood pressure, suggesting that ganglionic blockade was not the mechanism for the cardiovascular effects of methoctramine. 6. Methoctramine (0.3 mg kg-1) pretreatment did not alter the hypertensive effect of intravenous noradrenaline, demonstrating that methoctramine did not directly inhibit vascular reactivity and indicating an indirect hypotensive of action of methoctramine. 7. In summary, the results suggest that the hypotensive action of methoctramine resulted from selective M2 receptor antagonism. Therefore, muscarinic M2 receptors appear to play a role in the regulation of systemic arterial blood pressure in guinea-pigs. However, the anatomical site(s) of action of methoctramine remains to be determined.

Animals↗
PubMed1995

Inhibition of lipopolysaccharide-induced pulmonary edema by isozyme-selective phosphodiesterase inhibitors in guinea pigs.

There is a need for pharmacological agents for the treatment of pulmonary edema associated with the adult respiratory distress syndrome. Therefore, we examined the effects of isozyme-selective cyclic AMP phosphodiesterase (cAMP PDE) inhibitors, as well as aminophylline and dexamethasone, on the pulmonary edema, protein leakage into the airways and airway neutrophilia induced by aerosolized lipopolysaccharide (LPS) in intact guinea pigs. Twenty-four hours after LPS exposure lung wet/dry weight ratios increased from 4.9 +/- 0.004 to 5.8 +/- 0.02. Rolipram (PDE4 selective), CI-930 (PDE3 selective), aminophylline and dexamethasone (given p.o. 1 hr before and 4 hr after LPS exposure) inhibited pulmonary edema formation with ED50 values of 1.7, 0.5, 31 and 2.8 mg/kg, respectively. Maximum inhibition occurred with rolipram at 10 mg/kg (70 +/- 17%), CI-930 at 10 mg/kg (101 +/- 4%), aminophylline at 50 mg/kg (88 +/- 14%) and dexamethasone at 3 mg/kg (64 +/- 6%). Denbufylline and milrinone also inhibited pulmonary edema formation at 10 mg/kg i.p., supporting the inhibition of PDE4 and PDE3 as the mechanisms of action of rolipram and CI-930, respectively. Rolipram, CI-930, aminophylline and dexamethasone (at maximum doses for inhibiting pulmonary edema) inhibited the 3-fold increase in bronchoalveolar lavage albumin concentration 24 hr after LPS exposure (42 +/- 14%, 98 +/- 2%, 70 +/- 9% and 53 +/- 13%, respectively). However, none of these compounds (at maximum doses for inhibiting pulmonary edema) inhibited the corresponding 400-fold increase in lavage neutrophil counts.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1994

Methoctramine induces nonspecific airway hyperresponsiveness in vivo.

We investigated the effects of subtype-selective muscarinic receptor antagonists upon aerosol antigen-induced bronchoconstriction in anesthetized guinea pigs. Neither pirenzepine (muscarinic M1 receptor-selective), 4-methylpiperidine methiodide (4-DAMP, muscarinic M3 receptor-selective), [N-iminomethyl-N'-[(2-hydroxy-2-phenyl-2-cyclohexyl)-ethyl] piperazine HCl (DAC-5945, muscarinic M3 receptor-selective), ipratropium or atropine inhibited bronchoconstriction, but methoctramine (muscarinic M2 receptor-selective) produced a dose-dependent increase in bronchoconstriction (up to 46%). Methoctramine also produced increases in bronchoconstriction induced by aerosols of histamine (up to 45%) and platelet activating factor (up to 118%), demonstrating nonspecific airway hyperresponsiveness. This effect of methoctramine was not inhibited by atropine, DAC-5945 or vagotomy and could not be attributed to altered arachidonic acid metabolism or beta-adrenergic antagonism. However, propranolol prevented methoctramine-induced airway hyperresponsiveness, suggesting that this effect resulted from the reported ganglionic blocking activity of methoctramine. In conclusion, muscarinic receptors do not appear to play an important role in antigen-induced bronchoconstriction in anesthetized guinea pigs. Furthermore, caution should be exercised in using methoctramine to characterize the roles of muscarinic receptors in airway inflammatory responses in vivo.

Aerosols↗
PubMed1994

Pulmonary pharmacology of a novel, smooth muscle-selective muscarinic antagonist in vivo.

The need for a smooth muscle-selective muscarinic antagonist that could provide oral bronchodilator activity with minimal side effects has led to the discovery of 3-(4-benzyl-piperazinyl)-1-cyclobutyl-1-hydroxy-1-phenyl-2-propanone (NPC-14695). Orally administered NPC-14695 was as potent as albuterol in the prevention of aerosolized carbachol-induced collapse in conscious guinea pigs. After s.c. administration in conscious guinea pigs challenged with aerosolized carbachol, NPC-14695 was more potent in the inhibition of collapse than in the inhibition of salivation or the production of mydriasis. Moreover, NPC-14695 exhibited a greater selectivity for the inhibition of collapse over salivary or pupillary effects than either ipratropium or oxybutynin. NPC-14695 was more M3/M2 selective than diphenyl-acetoxy-4-methylpiperidine methiodide (4-DAMP) in vivo, which was determined from the reversal of bronchoconstriction and bradycardia after i.v. administration in anesthetized guinea pigs infused with methacholine, but was less potent than ipratropium or 4-DAMP. At increasing equieffective bronchodilator doses of aerosolized ipratropium and intraduodenally administered NPC-14695 in anesthetized guinea pigs infused with methacholine, ipratropium reversed the bradycardia and then produced tachycardia whereas NPC-14695 did not alter the heart rate. At doses that produced 50% of the maximum bronchodilation, neither aerosolized ipratropium or intraduodenally administered NPC-14695 affected the pupillary diameter or salivation. At doses that produced a maximum bronchodilation, the two drugs produced an equivalent inhibition of salivation and NPC-14695 produced mydriasis. NPC-14695 did not inhibit the bronchoconstriction induced by three other agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Leukotrienes mediate antigen-induced airway hyper-reactivity in guinea pigs.

The involvement of leukotrienes (LTs) in antigen-induced airway hyper-reactivity (AHR) was characterized pharmacologically by using several 5-lipoxygenase (5-LO) inhibitors and LTD4 antagonists in guinea pigs. AHR was evidenced by consistent and significant increases in sensitivity to bronchoconstriction induced by i.v. methacholine in anesthetized and ventilated animals 24 hr after a single ovalbumin aerosol challenge, but maximum methacholine-induced bronchoconstriction did not increase. Animals were pretreated with maximum doses of WY-50,295 tromethamine (WY-50,295), LY-171,883, MK-886 or zileuton, based upon inhibition of antigen-induced LT-dependent bronchoconstriction. WY-50,295, having a long duration of action, was the only compound that prevented AHR when given once before antigen challenge. However, LY-171,883 and MK-886 prevented AHR when a second dose was given 4 hr after challenge. Zileuton, having a short duration of action, failed to prevent AHR when given before and after challenge. The prevention of AHR did not result from functional antagonism (bronchodilation) by any compound. In bronchoalveolar lavage studies, neither WY-50,295 nor MK-886 inhibited the influx of eosinophils into the airways 24 hr after antigen challenge. The results provide pharmacological evidence that LTs play an important role in the pathogenesis of antigen-induced AHR in guinea pigs. Furthermore, the effectiveness of 5-LO inhibitors and LTD4 antagonists in this model depends upon a long duration of drug action and appears to result from inhibition of a direct airway effect of LTs rather than inhibition of eosinophil influx into the airways.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetophenones↗
PubMed1993

Potential species dependency for the pulmonary antiallergic effects of aerosolized heparin.

The inhibition of antigen aerosol-induced bronchoconstriction by heparin aerosol pretreatment has been demonstrated in conscious sheep. Therefore, we investigated the effect of heparin aerosol pretreatment on antigen aerosol-induced bronchoconstriction in anaesthetized and ventilated guinea-pigs. In one study all animals were pretreated with propranolol and indomethacin in order to produce a large bronchoconstriction, whereas in a second study this pretreatment was omitted in order to produce a smaller bronchoconstriction. In both studies aerosolized heparin failed to inhibit antigen aerosol-induced bronchoconstriction, whether delivered at 1, 10 and 100 mg/ml 10 min prior to antigen challenge or delivered at 50 mg/ml 60 min prior to antigen challenge. In contrast, salbutamol aerosol pretreatment (1 mg/ml, delivered 10 min prior to antigen challenge) produced a near-maximum inhibition of antigen aerosol-induced bronchoconstriction. These results suggest that the pulmonary antiallergic effects of aerosolized heparin are potentially species dependent.

Administration, Inhalation↗
PubMed1993

Pulmonary antiallergic and bronchodilator effects of isozyme-selective phosphodiesterase inhibitors in guinea pigs.

The effectiveness of theophylline (aminophylline) in treating asthma may result in part from nonselective inhibition of multiple isozymes of cyclic nucleotide phosphodiesterase (PDE). The roles for inhibition of different PDE isozymes in the pulmonary antiallergic and bronchodilator effects of theophylline were investigated in anesthetized and ventilated guinea pigs by using the PDE-III-selective inhibitor Cl-930, the PDE-IV-selective inhibitor rolipram and the PDE-V-selective inhibitor zaprinast. Aminophylline, Cl-930 and rolipram inhibited aerosol ovalbumin-induced full [leukotriene (LT) + histamine] and LT-dependent bronchoconstriction, but zaprinast was inactive. At doses producing an equieffective inhibition of antigen-induced full bronchoconstriction, aminophylline and Cl-930 produced a similar inhibition of aerosol histamine-induced bronchoconstriction, whereas rolipram produced much less inhibition of histamine-induced bronchoconstriction. At doses producing an equieffective inhibition of antigen-induced LT-dependent bronchoconstriction, aminophylline and Cl-930 produced a similar inhibition of i.v. LTD4-induced bronchoconstriction, whereas rolipram did not inhibit LTD4-induced bronchoconstriction. Acute airway hyperreactivity was evidenced by significant leftward shifts in dose-response curves to i.v. methacholine-induced bronchoconstriction 24 hr after aerosol ovalbumin challenge. Aminophylline and rolipram prevented airway hyperreactivity without causing residual bronchodilation 24 hr after antigen challenge. In contrast, Cl-930 failed to inhibit airway hyperreactivity, but produced substantial residual bronchodilation. The results indicate that PDE-IV inhibition produces pulmonary antiallergic effects in vivo, including the apparent inhibition of LT release, which may contribute to the antiasthmatic actions of theophylline. The results also support previous suggestions that PDE-III inhibition contributes to the bronchodilator effect of theophylline.

Aminophylline↗
PubMed1992

Comparison of the airway hyperreactivity produced by single and multiple antigen exposures in sensitized guinea pigs.

Chronic airway hyperreactivity is a hallmark feature of asthma, but animal models of airway hyperreactivity often utilize a single antigen challenge. Therefore, we compared the airway hyperreactivity produced by single and multiple antigen challenges in ovalbumin-sensitized guinea pigs. Significant (2-fold) leftward shifts in dose-response curves for i.v. methacholine- or LTD4-induced bronchoconstriction in anesthetized and ventilated animals occurred 24 h following a single ovalbumin challenge. This nonspecific airway hyperreactivity was prevented by pretreatment with ketotifen or dexamethasone. However, airway hyperreactivity was no greater 24 h following the last of 3 daily antigen challenges than after 1 challenge and was absent 72 h following one antigen challenge. These results raise concern over the similarity of antigen-induced airway hyperreactivity in guinea pigs to the chronic airway hyperreactivity in asthmatics.

Animals↗
PubMed1992

Human papillomavirus type 16 in an oral squamous carcinoma and its metastasis.

DNA was extracted from fresh frozen tissues of eight patients with primary oral squamous carcinoma. Samples of normal oral mucosa were available in seven cases and metastatic tumor in two cases. The samples were probed for human papillomavirus types 16 and 18 by Southern hybridization. In one case of squamous carcinoma of the floor of the mouth, human papillomavirus type 16 was identified in the primary tumor and a lymph node metastasis, but it was not detectable in normal oral mucosa from this patient. Human papillomavirus DNA was not detected in any other sample of primary tumor, metastasis, or normal oral mucosa. Restriction enzyme digests of the human papillomavirus positive primary tumor and its metastasis revealed that the viral DNA was identical to the prototype human papillomavirus type 16 and present at 50 to 100 copies per cell in an episomal state with no evidence of integration into the host DNA. Compared to the human papillomavirus DNA in the primary tumor, the viral DNA in the metastasis was of the same type, in the same physical state, and at the approximately the same copy number. The consistent maintenance of human papillomavirus DNA in metastases from human papillomavirus positive primary tumors supports the hypothesis that human papillomaviruses are cofactors in the pathogenesis of some carcinomas.

Aged↗
PubMed1992

Pulmonary accumulation of propranolol in vivo: sites and physiochemical mechanism.

Despite the therapeutic importance of propranolol and the potential usefulness of propranolol extraction measurements for the assessment of lung disorders, the pulmonary disposition of propranolol remains poorly understood. The extraction, accumulation and distribution of propranolol in lungs of conscious and anesthetized sheep were investigated by indicator-dilution methods, lung lymph fistula preparations and bronchoalveolar lavage. Pulmonary extraction of propranolol from plasma (0.81 +/- 0.03) was significantly less than that of imipramine (0.89 +/- 0.03), not significantly different from that of lidocaine (0.74 +/- 0.03) and much greater than that of water (0.44 +/- 0.02), whereas there were no differences in apparent red blood cell extraction of each indicator from plasma in vitro as determined under similar conditions (0.08-0.1). Pulmonary accumulation of imipramine (78 +/- 3%), lidocaine (52 +/- 4%), propranolol (37 +/- 4%) and water (7 +/- 2%), after a single pass through the pulmonary circulation, correlated positively with octanol/saline partition coefficients but not with pKa values. After bolus i.v. injection of [3H]propranolol, tritium concentrations in lung lymph increased rapidly to exceed plasma concentrations within 60 min and tritium concentrations in bronchoalveolar lavage equaled plasma concentrations 5 to 15 min after injection. It is concluded that by a mechanism not involving molecular charge, propranolol permeates capillary endothelium and alveolar epithelium to accumulate in hydrophobic regions of the lungs. This study in normal sheep suggests that reduced propranolol extraction by damaged lungs reflects pathological alterations other than endothelial cell dysfunction, such as pulmonary edema.

Animals↗
PubMed1992

Hospital efforts in smoking control: remaining barriers and challenges.

BACKGROUND: This study reports the barriers and challenges for hospital tobacco control efforts after the institution of smoke-free policies. METHODS: Surveys of employees and inpatients of five hospitals in Augusta, Georgia, were conducted and evaluated 4 months after joint hospital implementation of smoke-free policies. A random sample of 1997 employees and a convenience sample of 517 inpatients returned usable surveys. RESULTS: Although attitudes to the hospital bans on smoking reflected strong support for smoke-free policies, four out of five hospitals reported significant implementation problems. Despite the bans, 49% of patients who were smokers continued to smoke while hospitalized, and almost one half of all hospitalized smokers had received no advice to quit smoking from a physician or a nurse since admission. Employees and patients both agreed that the smoke-free policies had benefited employees more than patients. CONCLUSIONS: Despite achieving a smoke-free status, there are many challenges that remain for comprehensive hospital tobacco-control efforts. Hospitals and health care professionals must remain particularly alert and attentive to the needs of patients and employees still addicted to tobacco.

Hospitals↗
PubMed1991

Characterization of the airway smooth muscle muscarinic receptor in vivo.

We examined the bronchodilator activity of eight subtype-selective and non-selective muscarinic antagonists in anesthetized, ventilated guinea pigs bronchoconstricted by carbachol aerosols. Relative bronchodilator potencies were consistent with M3 receptor antagonism and correlated with inhibition of bladder smooth muscle contraction in vivo. We conclude that the airway smooth muscle muscarinic receptor can be functionally characterized in vivo as M3 and that it is of the same subtype as the muscarinic receptor in bladder smooth muscle.

Aerosols↗
PubMed1991

Airway smooth muscle selectivity of the muscarinic antagonist DAC 5945 in vivo.

We investigated the M3/M2 antagonist selectivity of [N-iminomethyl-N'-[(2-hydroxy-2-phenyl-2-cyclohexyl)-ethyl] piperazine HCI (DAC 5945) in vivo. ED50 values for reversal of methacholine-induced bronchoconstriction and bradycardia by muscarinic antagonists were determined in anesthetized and ventilated guinea pigs. Atropine, ipratopium, pirenzepine and diphenyl-acetoxy-4-methylpiperidine methiodide (4-DAMP) were non-selective, whereas methoctramine was cardioselective. In contrast, DAC 5945 was a more potent muscarinic antagonist in the airways than in the heart, demonstrating M3/M2 selectivity in vivo.

Animals↗