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At least 55 records · Page 3Linked to original sources

PubMed1990

Optimized inhalation aerosols. II. Inertial testing methods for particle size analysis of pressurized inhalers.

Pressurized metered dose inhaler (MDI) output from three different albuterol formulations was characterized using three inertial separation devices. Results were compared for the Delron six-stage cascade impactor (DC16), the Andersen Mark II eight-stage impactor (AC18), and Copley's twin-stage liquid impinger (LI). None of the devices tested in this study was ideal in all respects. All devices could differentiate between formulations in terms of respirable doses (albuterol amount with aerodynamic diameters less than 5.5 through 6.4 microns). Only the high-flow rate LI could differentiate among all three formulations when data were presented in terms of respirable percentage (RP) of drug collected. Values for RP were in excellent agreement for the independently calibrated impactors when the same evaporation chamber was used atop the impactors. The LI appeared to overestimate values for RP in vivo. Results are discussed in light of the debate surrounding the revision of USP aerosol testing requirements. Rigorous specifications for evaporation chambers and methodologies are necessary for meaningful inter- and intra-laboratory comparison of results when any of these devices are used.

Aerosols↗

PubMed1978

Demonstration of a platelet bypass mechanism in the clotting system using an acquired anticoagulant.

A lupus-type anticoagulant which causes strong inhibition of the partial thromboplastin time with kaolin (PTTK), the stypven time, and the thrombin generation tests has been investigated. All tests for platelet function were normal, as were all specific coagulation factor assays with the exception of a slightly reduced factor XI in this patient. A diethylaminoethyl-cellulose-immunoglobulin (DEAE-cellulose-IgG) fractionation of the patient's plasma produced two peaks containing inhibitory activity in the PTTK test. The first of these peaks had a cloudy appearance, suggesting the presence of immunoglobulin aggregates. Studies with IgG aggregates prepared from normal IgG and from the patient's IgG demonstrated that such aggregates were not the cause of inhibition. It was possible to neutralize the inhibitory activity of the purified IgG but not platelet-poor plasma (PPP) with a rabbit anti-IgG. The inhibition of the patient's PPP in the thrombin generation, the contact product, and the stypven time tests were corrected by the inclusion in the test system of platelets activated either by aggregation due to adenosine diphosphate (ADP) or formalin fixation and washing. These studies lend support to earlier findings that platelets interact at several sites in the coagulation cascade.

Antibodies↗

PubMed1992

Different beta-subunits determine G-protein interaction with transmembrane receptors.

Regulatory GTP-binding proteins (G proteins) are membrane-attached heterotrimers (alpha, beta, gamma) that mediate cellular responses to a wide variety of extracellular stimuli. They undergo a cycle of guanine-nucleotide exchange and GTP hydrolysis, during which they dissociate into alpha-subunit and beta gamma complex. The roles of G-protein alpha-subunits in these processes and for the specificity of signal transduction are largely established; the beta- and gamma-subunits are essential for receptor-induced G-protein activation and seem to be less diverse and less specific. Although the complementary DNAs for several beta-subunits have been cloned, isolated subunits have only been studied as beta gamma complexes. Functional differences have been ascribed to the gamma-subunit on the basis of extensive sequence similarity among beta-subunits and apparent heterogeneity in gamma-subunit sequences. Beta gamma complexes can interact directly or indirectly with different effectors. They seem to be interchangeable in their interaction with pertussis toxin-sensitive alpha-subunits, so we tested this by microinjecting antisense oligonucleotides into nuclei of a rat pituitary cell line to suppress the synthesis of individual beta-subunits selectively. Here we show that two out of four subtypes of beta-subunits tested (beta 1 and beta 3) are selectively involved in the signal transduction cascades from muscarinic M4 (ref. 4) and somatostatin receptors, respectively, to voltage-dependent Ca2+ channels.

Animals↗

PubMed1991

In vitro inhalation behaviour and therapeutical response of salbutamol particles administered from two metered dose aerosols.

In this study the particle size, as well as the in vitro deposition and the immediate bronchodilating effect on asthmatic patients, of two salbutamol inhalation aerosol preparations (Ventoline, Glaxo, UK, and salbutamol inhalation aerosol, Orion Pharmaceutica, Finland) were compared. The in vitro deposition study was performed using the modified Sierra Andersen cascade impactor. The bronchodilating effect of inhaled aerosol doses were monitored by measuring peak expiratory flow (PEF) values. In the clinical study, the pulse and blood pressure of the patients, as well as the side effects, were also recorded. Due to the anatomy and physiology of human lungs, the accepted optimum size for inhaled drug particles is under 5 microns, and preferably under 2 microns. Over 95% of the drug particles in both aerosol preparations were under 5 microns. 30% of the salbutamol particles in the Ventoline inhalation aerosol were under 2 microns, whereas in Orion salbutamol aerosol 14% of the drug particles were under 2 microns. Respectively 23% of Ventoline and 19% of the Orion salbutamol preparation penetrated into the therapeutically most significant imitated alveolar stages of the modified cascade impactor. Both salbutamol aerosols showed a clear clinical efficacy in the bronchodilating test. In addition, no significant differences existed in the bronchodilating effect of these inhalation aerosols. In conclusion, although there seemed to be a slight difference in the particle size distribution and in the in vitro inhalation behaviour, this variation did not have any effect on the clinical response.

Adult↗

PubMed1990

Evidence of grass-pollen allergenic activity in the smaller micronic atmospheric aerosol fraction.

In June 1988, during the grass-pollen season in Leiden, The Netherlands, outdoor airborne particulate matter was collected and separated into fractions according to aerodynamic sizes (greater than or equal to 10 microns, 4.9-10 microns, 2.7-4.9 microns, 1.3-2.7 microns, 0.6-1.3 microns, less than or equal to 0.6 microns), with a cascade impactor mounted on top of a high volume sampler. The different fractions were tested for the presence of grass-pollen allergenic activity using a RAST-inhibition assay: specific IgE-antibody-containing patient serum was applied on the particle-loaded impaction strips, and the serum was recovered by descending elution for further analysis in the RAST. Simultaneously, continuous measurements were made of the airborne grass-pollen concentration using a volumetric pollen trap. Sampling observations lasting 7-9 hr during a period with relatively high airborne grass-pollen concentrations showed reliably detectable amounts of grass-pollen allergen, not only in the first impaction stage where intact pollen were collected, but also in the lower stages collecting the smaller, paucimicronic and submicron atmospheric aerosol fraction. It is evident that this result has serious implications for the understanding of the bronchial symptoms frequently seen in hay fever patients on days with high pollen concentrations in the air.

Air↗

PubMed1990

Exertional intensities and energy requirements of technical mountaineering at moderate altitude.

The purpose of this study was to determine the exertional energy requirements of technical mountaineering at moderate altitude. Six subjects completed maximum graded exercise tests (MGXT) prior to a 7-day ice climbing seminar conducted in the North Cascade Range of the United States. Mean weight, percent body fat, and maximum oxygen uptake (VO2max) were 71.3 (+/- 15.1) kg, 11.7 (+/- 4.2) %, and 53.7 (+/- 5.4) ml.kg-1.min-1 respectively. Heartrates (HR) were recorded and averaged over 5-second to 1-minute intervals during selected mountaineering activities of the ice climbing seminar. Average and peak estimated VO2 (EstVO2) and estimated energy expenditure (EstEE) were calculated from HR utilizing regression equations generated from the MGXT results. Trail hiking with loads averaging 45% of individual body weight required an average EstVO2 of 21.8 (+/- 3.0) ml.kg-1.min-1 and average EstEE of 7.5 (+/- 1.9) kcal.min-1 over a 2.2 hr period. Mean peak EstVO2 was 37.4 (+/- 3.4) ml.kg-1.min-1 and mean peak EstEE was 13.4 (+/- 3.0) kcal.min-1 during this period. Technical ice climbing involving movement up and down a 12 m vertical height for a mean time of 14.3 (+/- 2.6) min required an average EstVO2 and EstEE of 25.7 (+/- 7.6) ml.kg-1.min-1 and 9.5 (+/- 3.4) kcal.min-1 respectively. Peak EstVO2 and EstEE means were 38.4 (+/- 7.7) ml.kg-1.min-1 and 14.6 (+/- 3.5) kcal.min-1. Two subjects were monitored during a 6-hour summit ascent on snow and ice from 1636 m to 3266 m. Means for average EstVO2 and EstEE were 21.6 (+/- 3.3) ml.kg-1.min-1 and 7.2 (+/- 0.8) kcal.min-1 respectively while peak EstVO2 and EstEE means were 38.0 (+/- 6.1) ml.kg-1.min-1 and 13.3 (+/- 1.6) kcal.min-1. The total EstEE was 3096.8 and 2485.4 kcal for these two subjects over the 6-hour ascent. The most experienced climber averaged 0.078 kcal.kg-1.min-1 and the least experienced subject averaged 0.105 kcal.kg-1.min-1 while climbing at identical paces over the same terrain. This indicates a possible experience factor which may increase climbing efficiency.

Adult↗

PubMed1989

Inositol trisphosphate production in squid photoreceptors. Activation by light, aluminum fluoride, and guanine nucleotides.

The light-stimulated production of inositol triphosphate (IP3), via hydrolysis of phosphatidylinositol bisphosphate (PIP2), can be demonstrated in an in vitro preparation of isolated distal segments of squid photoreceptors. The retina is labeled with [3H]inositol (Szuts, E. Z., Wood, S. F., Reid, M. S., and Fein, A. (1986) Biochem. J. 240, 929-932), and the rhodopsin-containing distal segments are isolated in artificial cytosol. Within 2 s after a flash, IP3 levels increase 200% (corresponding to an intracellular increase of approximately 5 microM), and the lipid precursor PIP2 decreases by 50%. Inositol bisphosphate (IP2) levels increase later, as a breakdown product of IP3. IP3 response is light-dependent, saturating when 0.5% of the rhodopsin is photoactivated. Guanosine-5'-O-(3-thiotriphosphate (GTP gamma S) binding demonstrates that the plasma membrane of most of the photoreceptor distal segments is intact or only transiently permeable. Membrane permeabilization enhances light-activated GTP gamma S binding but abolishes the light-activated IP3 production. Receptor-mediated production of IP3 is believed to be the result of a receptor-G-protein-phospholipase C cascade (i.e. Cockcroft, S., and Gomperts, B. D. (1985) Nature 314, 534-536). To test for G-proteins, we incubated the photoreceptors in AlF4- (an activator of G-proteins) in the dark. IP3 and IP2 were produced with a corresponding decrease in PIP2. Incubation with GTP or GTP gamma S, in hypotonic buffer, which causes transient leakiness, increased dark levels by IP3 by 50%. Addition of GTP in isotonic buffer enhanced the light-induced increase of IP3. These results localize the light-stimulated phospholipase C activity to the distal segments and suggest that a G-protein couples rhodopsin to phospholipase C.

Aluminum↗

PubMed1989

Neural networks--an artificial intelligence approach to the analysis of clinical data.

This paper describes an approach to the pattern recognition problem of categorizing evoked response waveforms, using that branch of artificial intelligence known as neural networking. A total of 19 subjects (38 eyes) were exposed to a reversing chequerboard pattern, and the resulting Pattern electroretinogram (PERG) recorded. This was repeated for each of the subjects at contrast levels of 75%,50% and 25%, with the resulting response becoming less pronounced as the contrast level was decreased. The subjects were also given an Arden contrast sensitivity test, and the resulting scores recorded for each eye. The averaged responses from each of the 3 contrast levels for each of the 38 eyes tested were used as the input to a computer simulated 3-input per neuron cascaded neural network. The output and weighting parameters for the individual neurons were then varied until the network was able to optimally classify the PERG results on the basis of the Arden contrast sensitivity scores. The neural network was thus taught to recognize patterns in the PERG responses in much the same way that an experienced clinician might. A second neural network was similarly taught to classify the PERG responses on the basis of a clinician's subjective rating of each of the responses.

Adult↗

PubMedDate not supplied

The effect of heparin on three whole blood activated clotting tests and thrombin time.

Whole blood activated clotting time (ACT) can be determined by many different methods that use a variety of clotting cascade activators and end-points. This study compared the results of three whole blood ACT instruments at equivalent concentrations of heparin. Whole blood (9.8 ml) from 10 healthy adult volunteers without coagulation abnormalities was added to 0.2 ml of heparin solution producing heparin concentrations of 0, 0.1, 0.2, 0.4, 0.6, 0.8, and 1.0 U/ml. Coagulation status was determined in duplicate with the Hemochron 400 System (HC), the HemoTec Automated Coagulation Timer (HT), and the TriMed ACTivator (TM). Thrombin times or dilutions (TT) were also determined for each sample. Baseline values did not differ (p greater than 0.05); however, the HT and TM ACT values were significantly longer (p less than 0.05) than the HC ACT values at predicted heparin concentrations greater than 0.2 U/ml. Results from the HT and TM instruments were not significantly different. The HT and TM instruments both provided a greater ACT range over the heparin concentrations tested. Of the tests studied to monitor heparin therapy, mean scaled TTs showed the best correlation with predicted heparin concentrations.

Adult↗

PubMed1992

Human 55-kDa receptor for tumor necrosis factor coupled to signal transduction cascades.

The numerous biological activities of tumor necrosis factor (TNF) appear mediated by two types of receptors of 55 kDa (TR55) and 75 kDa (TR75) molecular mass. To test TR55 for its individual role in signaling across the membrane, a cDNA coding for the human TR55 was stably expressed in murine 70Z/3 pre-B cells, which lack binding sites for, and proved nonresponsive to human TNF. The transfected TR55 showed high affinity ligand binding and active internalization. It is demonstrated that the TNF signaling cascade, i.e. stimulation of protein kinase C, sphingomyelinase, and phospholipase A2, production of the second messengers diacylglycerol and ceramide, can occur completely through exclusive binding of TNF to TR55. The p55 TNF-binding site functions as an autonomous TNF receptor that mediates key signal transduction pathways, which may control the majority of TNF actions.

Animals↗

PubMed1988

Characterization of a monoclonal antibody MoAb bH6 reacting with a neoepitope of human C3 expressed on C3b, iC3b, and C3c.

Activation products of the complement cascade contain neoepitopes that are not present in the individual native components. Monoclonal antibodies detecting neoepitopes have been used for direct quantification of activation at different steps in the cascade. These methods are suggested to be more sensitive and reliable than conventional complement activation tests, which are hampered by precipitation or fractionation procedures. The present study describes production screening and characterization of a monoclonal antibody (MoAb) bH6. MoAb bH6 exhibited a significantly higher binding capacity to ELISA plates coated with zymosan-activated human serum than to plates coated with EDTA plasma. When fixed to the enzyme-linked immunosorbent assay (ELISA) plates, MoAb bH6 retained material from zymosan-activated serum that only reacted with anti-C3 antibodies. Crossed immunoelectrophoresis performed on zymosan-activated serum demonstrated that MoAb bH6 co-precipitated with anti-C3c antibodies. In experiments using highly purified cell-bound fragments MoAb bH6 showed reactivity with C3b and iC3b, but not with C3d. MoAb bH6 reacted in ELISA with purified C3c, but not with C3dg, both as capture antibody and in tests with the fragments absorbed to the solid phase. Thus, MoAb bH6 is highly specific for a neoepitope of human C3 expressed on the cleavage fragments of C3b, iC3b, and C3c.

Antibodies, Monoclonal↗

PubMed1989

Morphogen gradients and the control of body pattern in insect embryos.

The basic body plan of insects is set up in response to determinants initially localized at the anterior and posterior poles of the egg. Early in development, these determinants give rise to a series of morphogen gradients which in turn trigger a cascade of molecular signals determining the body pattern. This signalling process is outlined and recent experiments testing the roles of these gradient systems in determining anterior and posterior pattern are described. The results of these experiments suggest that anterior pattern is controlled by a single instructive gradient, whereas posterior pattern depends on the overlap of several gradients, each providing only one or a few distinct responses.

Animals↗

PubMed1992

cAMP modulates multiple K+ currents, increasing spike duration and excitability in Aplysia sensory neurons.

Enhancement of the defensive withdrawal reflex of Aplysia involves a prolongation of the action potentials of mechanosensory neurons, which contributes to facilitation of transmitter release from these cells. Recent reports have suggested that whereas cAMP-dependent modulation of K+ current increases sensory neuron excitability, a cAMP-independent decrease in K+ current may increase the action potential duration and, thus, facilitate transmitter release. We have tested this proposal using Walsh cAMP-dependent protein kinase inhibitor or activators of the cAMP cascade and found that cAMP plays a major role in the spike-broadening effects of facilitatory transmitter; however, broadening requires higher levels of activation of the cAMP-dependent kinase than does increasing excitability. A steeply voltage-dependent transient K+ current, termed IKV,early, and the slowly activating S-type K+ (S-K+) current are both reduced by activation of the cAMP cascade, although with different sensitivities to the second messenger, enabling excitability and spike duration to be regulated independently. Differences in cAMP sensitivity also suggested that the originally described S-K+ current actually consists of two independent components, a slowly activating component and a time-independent, "steady-state" current that is activated at rest.

Action Potentials↗

PubMed1989

Leukocyte stimulation of intimal lesion formation is inhibited by treatment with diclofenac sodium and dexamethasone.

This investigation tested the effect of anti-inflammatory agents acting at different levels of the arachidonic acid cascade on leukocyte migration into the vessel wall. An animal model of vasculitis was used in which leukocytes stimulate migration of smooth muscle cells from the media into the intima resulting in formation of intimal lesions. In this model, an endotoxin-soaked thread is implanted in the adventitia along the ventral side of the rat femoral artery. At 2 days, subendothelial and medial leukocyte accumulation occurs exclusively in the ventral half of the vessel. At 14 days, intimal lesions composed primarily of smooth muscle cells are localized to the ventral half of the vessel. Treatment with neither the lipoxygenase inhibitor L-651,392 nor the dual cyclooxygenase and lipoxygenase inhibitor BW755C affected leukocyte migration into the vessel wall or subsequent lesion formation. Treatment with the cyclooxygenase inhibitor diclofenac sodium greatly reduced both leukocyte accumulation and lesion formation, whereas leukocyte migration and lesion formation were nearly totally inhibited by treatment with dexamethasone. Thus, it has been demonstrated that although leukocyte accumulation in the vessel wall stimulates intimal lesion formation, pharmacologic inhibition of leukocyte accumulation prevents lesion formation.

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

PubMedDate not supplied

The effects of drugs on the arachidonate cascade in experimentally burned rabbits.

Platelet reduction and renal dysfunction may occur after major thermal injury and be causally related to changes in the arachidonate cascade. In this article two new drugs, prostaglandin I2 analog OP-41483 (Venopirin) and thromboxane synthetase inhibitor OKY-046 (Cataclot), were tested in addition to aspirin in animal experiments with rabbits. The rabbits were divided into five groups and measurements made before and 8 and 24 hours after burn injury. The results indicate that platelet reduction and renal dysfunction occur within 8 hours after thermal injury in the no-therapy group and renal dysfunction could not be prevented completely even by adequate infusion therapy, but treatment with OP-41483 proved to suppress platelet reduction and improve renal function. Improvement in renal function was also noted in animals treated with aspirin or OKY-046, but platelet reduction could not be prevented by these drugs. Analysis of the time course of changes in thromboxane B2 level and 6-keto prostaglandin F1 alpha level disclosed that animals treated by infusion showed an elevation in thromboxane B2 and a significant elevation in the thromboxane B2/6-keto prostaglandin F1 alpha ratio, whereas animals treated with these three drugs showed a reduction in the thromboxane B2/6-keto prostglandin F1 alpha ratio. These results indicate that an effective measure for prevention of dysfunction of the organs after thermal injury is treatment with drugs that can modify the arachidonate cascade and cause an absolute or relative reduction in TXA2.

6-Ketoprostaglandin F1 alpha↗

PubMed1990

The first EGF-like domain from human factor IX contains a high-affinity calcium binding site.

It has been suggested that epidermal growth factor-like (EGF-like) domains, containing conserved carboxylate residues, are responsible for the high-affinity calcium binding exhibited by a number of vitamin K-dependent plasma proteins involved in the control of the blood coagulation cascade. These include the procoagulant factors IX and X, and the anticoagulants protein C and protein S. To test this hypothesis we have expressed the first EGF-like domain from human factor IX (residues 46-84) using a yeast secretion system, and examined calcium binding to the domain. Using 1H-NMR to measure a calcium-dependent shift assigned to Tyr69 we have detected a high-affinity calcium binding site (Kd = 200-300 microM). We suggest that other EGF-like domains of this type may have similar calcium binding properties. In addition, we have completely assigned the aromatic region of the NMR spectrum by NOESY and COSY analysis, and have used these data to discuss the effect of calcium and pH on the conformation of the domain with reference to a model based on the structure of human EGF.

Amino Acid Sequence↗

PubMed1991

The prophenoloxidase system and in vitro interaction of Trypanosoma rangeli with Rhodnius prolixus and Triatoma infestans haemolymph.

The presence of the prophenoloxidase (proPO) system in the haemolymph of Rhodnius prolixus and Triatoma infestans and the role played by Trypanosoma rangeli in the in vitro activation of proPO were tested. Both R. prolixus and T. infestans whole blood preparations showed a very active ProPO system. The proPO cascade of the two insect species were differentially activated by microbial-derived extracts: laminarin was a better activator of T. infestans haemolymph than of R. prolixus blood, and lipopolysaccharides from Shigella flexneri or Pseudomonas aeroginosa caused significant proPO activation of T. infestans haemolymph but not of R. prolixus preparations. For the two insect species, neither T. rangeli from culture nor parasite lysates were able to trigger proPO activation. The presence of the parasite in R. prolixus haemolymph/laminarin assays, however, significantly reduced the level of proPO activation to that of spontaneous activating controls. The immobilization of T. rangeli in vitro in haemolymph preparations occurred in both insect species and was dependent on the proPO activation intensity. Our results suggest that the susceptibility of R. prolixus to T. rangeli haemocoel infection may be explained, at least in part, by the suppression of the insect immune defence system i.e., inhibition of proPO in the presence of this protozoan parasite.

Animals↗

PubMed1991

Physical properties and clinical efficacy of two sodium cromoglycate inhalation aerosol preparations.

In this study, the particle size distribution and the droplet characteristics of the delivered aerosol cloud were first determined for two disodium cromoglycate inhalation aerosol preparations obtained from different manufacturers. In addition, the in vitro deposition properties and the clinical efficacy of these preparations were compared. The evaluation of the in vitro deposition was performed using a cascade impactor. The clinical efficacy was monitored by measuring the peak expiratory flow (PEF) values after the exercise test in fifteen asthmatic patients. The particle size and the spray characteristics of these two inhalation aerosol preparations were similar; the results of the in vitro test confirmed their similar physical properties. Both disodium cromoglycate preparations clearly alleviated the bronchoconstriction after the exercise test. According to the results of the clinical trial, supported by the laboratory scale studies, both disodium cromoglycate aerosols are of equal value in asthma inhalation therapy.

Administration, Inhalation↗