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Biomedical subjects

M R Littner

Publications and source records attributed to M R Littner.

At least 19 recordsLinked to original sources
PubMed2000

Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease.

Tiotropium (Spiriva; Ba679BR) is a new-generation, long-acting anticholinergic bronchodilator that has muscarinic M(1) and M(3) receptor subtype selectivity. A multicenter, randomized, double-blind, parallel group, placebo-controlled study was conducted to evaluate the dose-response characteristics of tiotropium inhalation powder given once daily to stable patients with chronic obstructive pulmonary disease (COPD). Patients (mean FEV(1) = 1.08 L [42% predicted]) were randomized to receive 0, 4.5, 9, 18, or 36 microg tiotropium once daily at noon for 4 wk, with spirometry done before and hourly for 6 h after dosing. Patients measured and recorded their peak expiratory flow rates (PEFRs) three times each day. Significant dose-related improvement in FEV(1) and significant improvement in FVC occurred within 1 h after the first dose of tiotropium as compared with placebo. Over the 29 d of the study, all doses of tiotropium produced significant increases over placebo in trough (i.e., as measured spirometrically at 20 to 24 h after the previous dose and just before the next dose of tiotropium), peak, and 6-h postdose average FEV(1) and FVC, and in PEFR, without a significant difference among the different doses investigated. PEFR gradually returned to pretreatment baseline levels over a 3-wk evaluation period following the discontinuation of tiotropium. The overall safety profile for the tiotropium doses was similar to that for placebo. In summary, tiotropium was shown to be safe and effective in doses ranging from 4.5 to 36 microg delivered once daily. The improvements in spirometry with once-daily dosing confirm the long duration of action of tiotropium reported in single-dose studies, and its sustained improvement of spirometric measures over the 1 mo of testing in the study points to utility of tiotropium as a maintenance bronchodilator for patients with COPD. On the basis of the comparable bronchodilator response at doses from 9 to 36 microg, and advantages suggested by the safety profile at doses below 36 microg in this study, a dose of 18 microg once daily was selected for use in long-term studies of the safety and efficacy of tiotropium.

Administration, Inhalation↗
PubMed1999

The prevalence of carotid atheromas seen on panoramic radiographs of patients with obstructive sleep apnea and their relation to risk factors for atherosclerosis.

PURPOSE: Persons with obstructive sleep apnea syndrome (OSAS) suffer inordinately high rates of stroke, but the cause remains in doubt. Atherosclerosis (atheroma formation) of the extracranial carotid artery has been suggested as a possible cause. Because atheromas can be recognized on panoramic radiographs, this study compared their prevalence in subjects with OSAS and normal controls and analyzed their relation to atherogenic risk factors. PATIENTS AND METHODS: Panoramic radiographs and medical records of 54 male subjects (mean age, 60.4 years) with OSAS (apnea/hypopnea index [AHI] of 15 or greater and a history of snoring and excessive daytime sleepiness) were assessed for atheromas and risk factors. Age-matched controls were likewise assessed. RESULTS: Twelve individuals (22%) with OSAS showed atheromas on their radiographs. The radiographs of the controls showed that 3.7% had atheromas. This finding was statistically significant (P = .0079). The prevalence of type 2 diabetes mellitus among individuals with OSAS and atheroma formation (7 of 12 persons, 58%) was far greater than the prevalence of diabetes (10 of 42 persons, 24%) experienced by individuals with OSAS but free of atheroma formation. This finding was also statistically significant (P = .035). The lesions seen in both the subject and control populations were similar and were located in the neck, 1.5 to 2.5 cm inferior-posterior to the angle of the mandible. CONCLUSIONS: Persons with OSAS are more likely to manifest calcified atheromas on their panoramic radiographs than age-matched controls. Type 2 diabetes is significantly more prevalent in individuals with both OSAS and calcified atheromas.

Aged↗
PubMed1998

The prevalence of calcified carotid artery atheromas in patients with obstructive sleep apnea syndrome.

PURPOSE: Persons with obstructive sleep apnea syndrome (OSAS) suffer cerebrovascular accidents at three to six times the rate of other Americans. Atherosclerosis of the cervical portion of the carotid artery has been suggested as a possible cause of these strokes. Lateral cephalometric radiographs used to determine the site of upper airway obstruction in sleep apnea patients can also image calcified cervical carotid artery atheromas. However, their prevalence in this group of patients has not been previously reported. PATIENTS AND METHODS: The radiographs of 47 male subjects (mean age 59.2 years, range 45 to 77 years) diagnosed as having OSAS (apnea/hypopnea index [AHI] of > or = 15 and a history of snoring and excessive daytime sleepiness) were assessed for calcified carotid atheromas. Healthy, age-matched (+/-18 months) controls were likewise assessed. RESULTS: The radiographs of the subjects with OSAS showed that 21.3% had calcified atheromas. The radiographs of the controls showed that only 2.5% had calcified atheromas. This finding was statistically significant (P = < .000001). The lesions seen in both populations were similar, and located within the soft tissues of the neck at the level of C3 and C4. The lesions were superimposed over these tissues, the prevertebral fascia, and the pharyngeal airspace. CONCLUSIONS: The results of this study seem to indicate that persons with OSAS have a greater prevalence of calcified carotid artery atheromas than healthy, age-matched persons. These lesions, a possible cause of future stroke, can be detected on lateral cephalometric radiographs.

Aged↗
PubMed1994

Inhibition of eicosanoids does not prevent neutrophil injury from phorbol in isolated rabbit lung.

Studies suggest that pulmonary and neutrophil cyclooxygenase and lipoxygenase products (i.e., eicosanoids) play a role in oxidant lung injury. We tested the hypothesis that such eicosanoids contribute to lung injury from activation of rabbit neutrophils by phorbol myristate acetate (PMA) in the pulmonary circulation of salt-perfused isolated rabbit lung preparations. We measured lung injury from PMA-activated neutrophils under zone 2 pulmonary vascular conditions with transvascular albumin flux by 125I-labeled albumin. We found that this flux was increased; catalase prevented the increase, confirming that the increase was from oxidant injury. However, results were inconsistent: about one-half of the preparations showed a marked increase and about one-half were not elevated. In preparations with a > 40-mmHg increase in pulmonary arterial pressure (Ppa), albumin flux increased, and in those with Ppa < 40 mmHg it did not. In those with Ppa > 40 mmHg, vascular volume, and presumably vascular surface area, was markedly reduced. We next studied PMA-activated neutrophils under zone 3 pulmonary vascular conditions in preparations with Ppa that increased < 40 mmHg. Albumin flux or filtration coefficient (Kf,c) was used to measure injury. Both were elevated. As with albumin flux, catalase prevented increases in Kf,c. BW-755C (a dual lipoxygenase and cyclooxygenase inhibitor) prevented increases in cyclooxygenase products and leukotriene B4 (a lipoxygenase product) but did not prevent increases in Kf,c. We conclude that a marked decrease in vascular volume can occur in zone 2 preparations and may mask the presence of injury as measured by transvascular albumin flux. A zone 3 vascular condition overcomes the vasoconstrictor-induced decrease in surface area and unmasks injury. Finally, oxidant injury from PMA-stimulated rabbit neutrophils in isolated rabbit lungs cannot be readily attributed to formation of eicosanoids.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1994

Increase in filtration coefficient from actions of melittin on neutrophils in isolated rabbit lungs.

Activation of neutrophils may contribute to lung injury in the adult respiratory distress syndrome. We added rabbit neutrophils to the pulmonary circulation of salt-perfused and ventilated isolated rabbit lungs. These neutrophils were activated by adding synthetically pure melittin to the perfusate. This led to lung injury as measured by filtration coefficient under no-flow conditions. We also activated neutrophils in vitro before addition to the pulmonary circulation. These preactivated neutrophils also produced lung injury, indicating a primary action of melittin on neutrophils rather than on lung. The injury was prevented by aristolochic acid, which is an inhibitor of phospholipase A2 (PLA2), and independently by catalase, which is scavenger of hydrogen peroxide (H2O2). Aristolochic acid also appeared to act primarily on neutrophils since addition to neutrophils in vitro prevented injury from in vitro activation by melittin. Aristolochic acid did not appear to act as a free radical scavenger since it did not prevent injury from neutrophils activated by phorbol myristate acetate (PMA). PMA is a direct activator of protein kinase C in neutrophils and leads to formation of H2O2 with consequent lung injury. We conclude that activation of neutrophils by melittin leads to oxidant lung injury possibly from activation of PLA2. Since PLA2 does not directly produce a second messenger, such as diacylglycerol or inositol triphosphate, it is likely that other actions of PLA2 produce an intermediary mediator. We previously showed that an inhibitor of eicosanoid synthesis prevents lung injury from exogenous PLA2. This suggests that the formation of leukotriene B4 (LTB4), a 5-lipoxygenase product of arachidonic acid, may contribute to the oxidant lung injury from melittin.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1990

The effects of neutrophils and phospholipase A2 on transvascular albumin flux in isolated rabbit lungs.

In this study, addition of phospholipase A2 (PLA2) to salt-perfused isolated rabbit lungs containing rabbit polymorphonuclear leukocytes leads to an increase in pulmonary capillary permeability. We add 1.5 X 10(8) polymorphonuclear leukocytes to the perfusate. Next, indomethacin is added to the perfusate and 40 units of PLA2 are infused into the pulmonary arterial inflow of the lungs. At the end of the study, a lung sample is removed for measurement of transvascular albumin flux using I125-albumin as a measure of the permeability-surface area product. Control studies demonstrate no increase in transvascular albumin flux. Addition of a dual cyclooxygenase and lipoxygenase inhibitor, BW755C, to the perfusate prevents the increase in transvascular albumin flux. We conclude that PLA2 interacts with polymorphonuclear leukocytes to increase protein permeability. Since PLA2 can release endogenous arachidonic acid and platelet-activating factor from cells, this suggests that release of such products may contribute to an increase in pulmonary capillary permeability from polymorphonuclear leukocytes. The ability of BW755C to prevent the increase suggests the possibility that lipoxygenase products contribute.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1989

Edema from cyclooxygenase products of endogenous arachidonic acid in isolated lung.

We infused A23187, a calcium ionophore, into the pulmonary circulation of dextran-salt-perfused isolated rabbit lungs to release endogenous arachidonic acid. This led to elevations in pulmonary arterial pressure and to pulmonary edema as measured by extravascular wet-to-dry weight ratios. The increase in pressure and edema was prevented by indomethacin, a cyclooxygenase enzyme inhibitor, and by 1-benzylimidazole, a selective inhibitor of thromboxane (Tx) A2 synthesis. Transvascular flux of 125I-albumin from vascular to extravascular spaces of the lung was not elevated by A23187 but was elevated by infusion of oleic acid, an agent known to produce permeability pulmonary edema. We confirmed that A23187 leads to elevations in cyclooxygenase products and that indomethacin and 1-benzylimidazole inhibit synthesis of all cyclooxygenase products and TxA2, respectively, by measuring perfusate levels of prostaglandin (PG) I2 as 6-ketoprostaglandin F1 alpha, PGE2, and PGF2 alpha and TxA2 as TxB2. We conclude that release of endogenous pulmonary arachidonic acid can lead to pulmonary edema from conversion of such arachidonic acid to cyclooxygenase products, most notably TxA2. This edema was most likely from a net hydrostatic accumulation of extravascular lung water with an unchanged permeability of the vascular space, since an index of permeability-surface area product (i.e., transvascular albumin flux) was not increased.

Animals↗
PubMed1988

Cyclooxygenase products from endogenous arachidonic acid in isolated dog and rabbit lungs.

We infused various doses of A23187, a calcium ionophore, into the pulmonary circulation to release endogenous arachidonic acid (AA) in salt-perfused isolated dog and rabbit lungs. Levels of prostaglandin (PG) I2 (as 6-keto-PGF1 alpha), thromboxane A2 (TXA2) as TXB2, and PGF2 alpha but not levels of PGE2 were elevated. Levels of TXA2 were similar between dog and rabbit lungs but levels of PGI2 and PGF2 alpha were higher in dog than in rabbit lungs. However, this difference was not the same at all levels of TXA2. At lower levels of TXA2, the differences were greater and narrowed at higher levels of TXA2. This led to an overlap in the ratios of PGI2/TXA2 and PGF2 alpha/TXA2 between dog and rabbit lungs. We conclude that species differences exist in formation of cyclooxygenase products between dog and rabbit lungs. With respect to products, differences may be dependent on the level of products in response to an AA-releasing agent. This suggests that rabbit lungs can be more sensitive than dog lungs to formation of relatively greater amounts of TXA2. However, the ratios of PGI2/TXA2 and PGF2 alpha/TXA2 can be similar between these species as follows: (1) if there is a sufficient dose of AA-releasing stimulus, or (2) if there is a sufficient difference in doses of the stimulus, with the lower dose being applied to rabbit lungs. Speculatively, physiologic effects of cyclooxygenase products may be similar under these conditions despite the species differences.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

cAMP levels from endogenous and exogenous arachidonic acid in isolated dog lung.

We infused exogenous arachidonic acid (AA) into salt-perfused isolated dog lungs. This led to elevations in adenosine 3',5'-cyclic monophosphate (cAMP) which were from conversion of the AA to cyclooxygenase products. The maximal levels of cAMP occurred at far less than maximal levels of cyclooxygenase products. Next, we infused A 23187 to release endogenous pulmonary AA. This led to elevations in cAMP that were from conversion of this endogenous AA to cyclooxygenase products. The level of these products was far less than maximal levels from exogenous AA. However, maximal levels of cAMP from conversion of endogenous AA were similar to maximal levels of cAMP from conversion of exogenous AA. We conclude that maximal levels of pulmonary cAMP from endogenous or exogenous AA are from conversion of the AA to far less than maximal levels of pulmonary cyclooxygenase products. This indicates that levels of cAMP rather than levels of cyclooxygenase products are a potential rate-limiting step in cAMP-linked pulmonary actions of such products from pulmonary conversion of endogenous or exogenous AA.

Animals↗
PubMed1987

Effects of A23187, exogenous phospholipase A2 and exogenous arachidonic acid on pulmonary vascular resistance in isolated rabbit lung.

The authors gave infusions of exogenous arachidonic acid (AA), exogenous phospholipase A2 (PLA2) or A23187 into the pulmonary circulation of isolated salt-perfused rabbit lungs. Exogenous PLA2 and A23187 are agents that release the AA that is usually in the lung (i.e., endogenous pulmonary AA). The exogenous AA or A23187 led to pulmonary cyclooxygenase enzyme conversion of exogenous and endogenous AA to thromboxane A2 (TXA2), as TXB2, and prostacyclin, as 6-keto-prostaglandin-F1 alpha, as well as to elevations in pulmonary vascular resistance (PVR). The elevations in PVR as well as the elevations in TXB2 and 6-keto-prostaglandin-F1 alpha were prevented by indomethacin, a cyclooxygenase enzyme inhibitor, and the elevations in TXB2 and PVR but not the elevations in 6-keto-prostaglandin-F1 alpha were prevented by 1-benzylimidazole, a selective inhibitor of thromboxane synthesis. Maximum elevations in PVR occurred from conversion of AA to less than maximum levels of TXA2. Exogenous PLA2 led to release of endogenous AA with conversion to prostacyclin. However, such release of endogenous AA by exogenous PLA2 did not lead to conversion to TXA2 or to elevations in PVR. The authors conclude that elevations in PVR that depend on conversion of AA to TXA2 are limited by factors other than the amount of TXA2 or the amount of AA that is potentially available for such conversion.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Distribution of cyclooxygenase products with cyclooxygenase inhibition in isolated dog lung.

Arachidonic acid metabolism can lead to synthesis of cyclooxygenase products in the lung as indicated by measurement of such products in the perfusate of isolated lungs perfused with a salt solution. However, a reduction in levels of cyclooxygenase products in the perfusate may not accurately reflect the inhibition of levels of such products as measured in lung parenchyma. We infused sodium arachidonate into the pulmonary circulation of isolated dog lungs perfused with a salt solution and measured parenchymal, as well as perfusate, levels of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), prostaglandin F2 alpha (PGF2 alpha), prostaglandin E2 (PGE2), and thromboxane B2 (TxB2). These studies were repeated with indomethacin (a cyclooxygenase enzyme inhibitor) in the perfusate. We found that indomethacin leads to a marked reduction in perfusate levels of PGF2 alpha, PGE2, 6-keto-PGF1 alpha, and TxB2, as well as a marked reduction in parenchymal levels of 6-keto-PGF1 alpha and TxB2 when parenchymal levels of PGF2 alpha and PGE2 are not reduced. We conclude that, with some cyclooxygenase products, a reduction in levels of these products in the perfusate of isolated lungs may not indicate inhibition of levels of these products in the lung parenchyma and that a reduction in one parenchymal product may not predict the reduction of other parenchymal products. It can be speculated that some of the physiological actions of indomethacin in isolated lungs may result from incomplete or selective inhibition of synthesis of pulmonary cyclooxygenase products.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Effect of oral administration of arachidonic acid on prostaglandin and zinc metabolism in plasma and small intestine of the rat.

The effect of different doses of arachidonic acid (AA) on the intestinal zinc transport rate and on the plasma and intestinal PGE2, PGF2 alpha and 6-keto-PGF1 alpha levels in rats were measured to determine whether the metabolism of AA is involved in the zinc transport mechanism. Twenty-four rats were divided into 4 groups of 6 rats. Each rat received either 1.0 ml of distilled water, 0.5 mg, 1.0 mg or 1.5 mg/ml of AA intraduodenally at 24 and 4 hours before sacrifice. One hour before sacrifice, each rat also received 10 micrograms of 65Zn intraduodenally. The zinc transport rate decreased in comparison to controls when 0.5 mg of AA was given to the rats, but increased when 1.0 mg or 1.5 mg of AA was given. The levels of PGE2, PGF2 alpha and 6-keto-PGF1 alpha (PGI2 metabolite) in the intestinal mucosa all decreased in proportion to the amount of AA given. However, in the plasma, only PGF2 alpha levels decreased while PGE2 and 6-keto-PGF1 alpha levels showed no change compared to controls. When rats were given 1.5 mg of AA without oral administration of 65Zn, plasma PGE2 levels increased while PGF2 alpha levels decreased. The results suggest that AA metabolism influences the zinc transport mechanism by modulating the relative levels of PGE2, PGF2 alpha and PGI2 in plasma and small intestine.

Animals↗
PubMed1984

Inhibition of cyclooxygenase production does not prevent arachidonate from increasing extravascular lung water and albumin in an isolated dog lung.

We examined the hypothesis that arachidonic acid can lead to pulmonary edema, increased pulmonary vascular permeability, and increased pulmonary vascular resistance (PVR) in an isolated dog lung. The lung was perfused with a dextran-salt solution to remove blood elements. Compared to controls, 20 mg/min sodium arachidonate into the pulmonary circulation led to edema and to an increase in a permeability and surface area index (PSI%), PVR, and cyclooxygenase (i.e. prostaglandin) production as measured by 6-keto-PGF1 alpha, TXB2 and PGF2 alpha. With 20 mg/min arachidonate, indomethacin inhibited the increase in cyclooxygenase production, reduced the increase in PVR and increased the edema and PSI%. Indomethacin, alone, did not produce edema or an increase in PSI% or PVR. Lower doses of arachidonate (0.1 to 5 mg/min) led to increasing cyclooxygenase production without obvious edema or an increase in PSI% or PVR. We conclude: 1) arachidonate can lead to pulmonary edema and an increase in PVR, and may lead to an increase in pulmonary vascular permeability; these effects of arachidonate do not require normal numbers of circulating blood elements; 2) arachidonate appears to contribute to pulmonary edema and increased PSI% by a noncyclooxygenase effect since inhibition of cyclooxygenase production did not prevent, and lower doses of cyclooxygenase production did not produce edema or an increase in PSI%; 3) the increase in PVR appeared to have a cyclooxygenase component since inhibition of cyclooxygenase production reduced the increase, and 4) indomethacin can increase the magnitude of edema and PSI% from arachidonate by an undefined mechanism.

Animals↗
PubMed1983

Restoration of hypoxic pulmonary vasoconstriction following normoxia in isolated dog lungs occurs in the presence but not in the absence of prostaglandin synthesis inhibitors.

We examined the possibility that eucapnic (6% CO2) alveolar hypoxia (3% O2) in isolated dog lungs not only produces an increase in pulmonary vascular resistance but also initiates the subsequent prostaglandin (PG) dependent reduction in this hypoxic pulmonary vasoconstriction (HPV). We determined that a reduction in HPV occurred after 45 min including a 35-min period of hypoxia (prolonged hypoxia), after 45 min of intermittent hypoxia, and after 45 min of normoxia (14% O2). These reductions were PG dependent, since they were reversed or prevented by PG synthesis inhibitors in the autologous blood perfusate. In addition to the PG-dependent reduction that required 45 min to develop, a separate reduction in HPV also occurred. This reduction occurred during prolonged hypoxia, was not prevented by PG synthesis inhibitors, was reversed after 6 min of normoxia, and was reproduced in a second period of prolonged hypoxia. We conclude that alveolar hypoxia did not initiate the PG-dependent reduction in HPV, since it occurred after normoxia as well as after hypoxia. However, hypoxia appeared to contribute to a separate PG-independent reduction in HPV, since this reduction was initiated and maintained exclusively during prolonged hypoxia and was unaffected by PG synthesis inhibitors.

Animals↗
PubMed1983

Double-blind comparison of acute effects of inhaled albuterol, isoproterenol and placebo on cardiopulmonary function and gas exchange in asthmatic children.

Although albuterol aerosol is an effective bronchodilator in adult asthmatics its efficacy and safety are not fully established in asthmatic children. Albuterol (100 and 200 micrograms), isoproterenol (70 and 140 micrograms) and placebo were administered from metered dose aerosol cannisters to 11 asthmatic children (9 to 16 years of age). Our findings indicate that in asthmatic children albuterol aerosol causes bronchodilation for up to six hours and greater bronchodilation than comparable doses of inhaled isoproterenol and does not produce overt effects on the cardiovascular system, significant changes in arterial partial pressure of oxygen or excessive tremor.

Adolescent↗