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Biomedical subjects

M Küng

Publications and source records attributed to M Küng.

At least 19 recordsLinked to original sources
PubMed1998

Inhibition of matrix metalloproteinases attenuates anti-Thy1.1 nephritis.

There is accumulating evidence that matrix metallo-proteinases (MMP) play a prominent role in glomerular inflammatory diseases. The aim of the present study was to determine the anti-inflammatory effects of the synthetic MMP inhibitor BB-1101 in acute anti-Thy1.1 nephritis. Sixty-three male Wistar rats were studied: healthy rats (n = 9), treated healthy rats (n = 9), nephritic rats (n = 18), and treated nephritic rats (n = 27). BB-1101 therapy (30 mg/kg body wt per d) of nephritic animals was initiated either 2 d before (n = 18) or 2 d after (n = 9) disease induction. Renal histology was analyzed 11 d after induction of the nephritis, at the peak of MMP-2 production and total glomerular cellularity. Pretreatment of nephritic rats by BB-1101 resulted in a significant amelioration of glomerular histology, assessed by glomerular cellularity, extracellular matrix deposition, and size of glomerular cross-sections. These beneficial effects were less pronounced, but in part still significant, in animals treated by BB-1101 after induction of anti-Thy1.1 nephritis. Proteinuria, expressed as area under the curve of the protein:creatinine ratio versus time, was clearly decreased in both groups of treated nephritic rats. Healthy control rats were not affected by MMP inhibitor treatment. In summary, the present study demonstrates for the first time in vivo that mesangial cell proliferation can be effectively suppressed by MMP inhibition. Thus, MMP inhibition by synthetic compounds may represent a new approach to the therapy of mesangial cell-mediated forms of glomerulonephritis.

Animals↗
PubMed1997

Expression of intracellular and GPI-anchored forms of GPI-specific phospholipase D in COS-1 cells.

Glycosylphosphatidylinositol (GPI)-specific phospholipase D (GPI-PLD) is a secretory protein present in high amounts in mammalian body fluids. Its cDNA has been isolated and encodes a signal peptide of 23 amino acids and the mature protein of 816 amino acids. We generated cDNAs encoding a signal peptide-deficient and a GPI-anchored form of GPI-PLD and transiently transfected these constructs into COS-1 cells. The signal peptide-deficient form of GPI-PLD was expressed as a 90-kDa protein that was catalytically active and was localized intracellularly. Cells transfected with cDNA encoding the GPI-anchored form of GPI-PLD expressed a catalytically active enzyme of 100 kDa that could be labelled with [3H]ethanolamine demonstrating its modification by a GPI structure. Expression of the GPI-anchored form of GPI-PLD resulted in the release of endogenous GPI-anchored alkaline phosphatase from COS-1 cells, whereas expression of the intracellular form of GPI-PLD had no effect on membrane attachment of endogenous alkaline phosphatase. Similarly, in cells cotransfected with GPI-anchored placental alkaline phosphatase (PLAP) and the GPI-anchored form of GPI-PLD, PLAP was released into the cell culture supernatant while expression of the signal peptide-deficient form of GPI-PLD did not affect the amount of cell-associated PLAP.

Alkaline Phosphatase↗
PubMed1997

Addition of G418 and other aminoglycoside antibiotics to mammalian cells results in the release of GPI-anchored proteins.

Resistance to the neomycin analogue G418 forms the basis of a dominant marker selection system for mammalian cells transfected with the bacterial neomycin gene. We found that COS-1 cells stably transfected with the neomycin resistance gene had a greater than 50% reduction in cell-associated glycosylphosphatidylinositol (GPI)-anchored alkaline phosphatase (AP). A similarly reduced amount of AP was also observed in wild-type COS-1 cells incubated in the presence of G418 or other aminoglycoside antibiotics. The AP was released from cells into the culture supernatant in its GPI-anchored form. Our data suggest that the G418-induced reduction of AP involves a vesiculation process of COS-1 cells.

Alkaline Phosphatase↗
PubMed1990

Adenosine-induced bronchoconstriction in human asthmatics: effects of pretreatment with indomethacin or atropine sulfate.

The present investigation was designed to evaluate the effects of pre-treatment with the cholinergic muscarinic receptor antagonist, atropine sulfate, or with the cyclooxygenase inhibitor, indomethacin, on adenosine-induced bronchoconstriction in human asthmatics. Eight male subjects with a FEV1 of greater than 70% of the predicted normal value underwent bronchial provocation challenges with adenosine and with the cholinergic agonist, methacholine, in a double-blind, randomized, cross-over fashion. The log10 of the agonist dose provoking a 20% decrease in FEV1 (log PD20FEV1) was used to assess airways responsiveness. Challenges were performed in the untreated state and 30 min after inhalation of atropine sulfate (0.05 mg/kg). Pre-challenge FEV1 values after atropine inhalation were higher than in the untreated state (p less than 0.01). Without atropine, the log PD20FEV1 values for adenosine were higher than those for methacholine (p less than 0.01). Atropine prevented a decrease in the FEV1 of 20% or more in seven of the eight subjects following inhalation of methacholine up to a concentration of 25 mg/ml, but did not significantly change the log PD20FEV1 for adenosine. The effects of a 75 mg oral dose of indomethacin or placebo, administered in a double-blind, randomized, cross-over fashion two hours before adenosine or methacholine challenge, were assessed in 12 asthmatics. In four subjects (two after placebo and two after indomethacin pretreatment), aerosols of the highest adenosine concentration (10 mg/ml) failed to decrease the FEV1 by 20% or more. In the remaining eight subjects, log PD20FEV1 values for adenosine or methacholine after indomethacin were not significantly different from those after placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1989

Airways responsiveness determined by consecutive histamine challenges in asymptomatic asthmatics.

The effect of two consecutive histamine inhalation challenges on airways responsiveness was assessed in a group of eight nonsmoking nonmedicated asthmatics aged 19-27 yr. All subjects had a base-line forced expiratory volume in 1 s (FEV1) of greater than 80% of their predicted normal value before the initial challenge and were allowed to recover to greater than 95% of the initial base-line FEV1 value before the second challenge was initiated. The average airways recovery time after the first challenge was 44 min but ranged between 30 and 90 min. The mean +/- SD values of cumulative histamine dose units provoking a 20% decrease of the FEV1 from the buffer control value (PD20FEV1) were 10.79 +/- 5.95 determined with the first and 30.50 +/- 46.36 with the second challenge (P greater than 0.05). We conclude that sequential histamine challenges performed in mild asthmatics with closely controlled prechallenge airways function are well tolerated. Although some variance does exist in intersubject airways recovery time and in intra-subject histamine airways responsiveness determined by sequential challenges, our data do not support recent observations (J. Appl. Physiol. 63: 1572-1577, 1987) that histamine tolerance is a characteristic finding associated with bronchial asthma.

Adult↗
PubMed1989

Pulmonary gas exchange during histamine-induced bronchoconstriction in asthmatic subjects.

Bronchial provocation for testing airway hyperreactivity is now well-established. However, the effects of histamine-induced bronchoconstriction on pulmonary gas exchange in man have not been systematically studied. We empirically noted marked decreases in PaO2 in some asthmatic subjects following induced bronchoconstriction. Nine subjects with mild, stable asthma were studied, each on two separate days. The first determined the dose of inhaled histamine necessary to decrease FEV1 by 20 percent and the relationship to lung volume and to pulmonary resistance by the interrupter technique (Rint). On the second day arterial blood gases, ventilation, Rint, and the anatomic (VDan) and physiologic (VDphys) dead spaces were measured simultaneously. There was a significant (p less than 0.05), profound fall in PaO2 (mean, -21.8 mm Hg) and in P(A-a)O2 (mean +14.7 mm Hg) within 5 min after bronchoconstriction, associated with a significant (p less than 0.05) increase in respiratory frequency (mean +5.1 min-1); and decrease in tidal volume (mean, -0.3 L). The ratio VDphys/VT increased significantly (p less than 0.05; mean change, +0.08) even though VDan and VDphys did not. Bronchoconstriction induced the broadening of ventilation (V)/perfusion (Q) ratios, with, most likely, an increase in areas of high V/Q. Histamine-induced bronchoconstriction in mild asthma results in a marked fall in PaO2 due to induced V/Q inequality. Therefore, histamine airway challenge should be used with caution in patients with any preexisting hypoxemia.

Adult↗
PubMed1987

Systemic cardiovascular and metabolic effects associated with the inhalation of an increased dose of albuterol. Influence of mouth rinsing and gargling.

We designed this investigation to assess the occurrence of systemic beta adrenergic side effects associated with the inhalation of an increased dose of the beta2 receptor agonist albuterol. Since therapeutic aerosols delivered by metered dose inhaler (MDI) are preferentially deposited in the mouth and pharynx, we wished to determine whether mouth rinsing and gargling with water might reduce the magnitude of such side effects by partially removing oral and pharyngeal drug residues. Serum glucose, insulin and potassium concentrations, forced expiratory volume in one second (FEV1), heart rate (HR), and blood pressure (BP) were measured as parameters of beta-adrenergic stimulation. Each of eight nonmedicated mild asthmatic patients was studied on two separate days after an overnight fast. Measurements were obtained twice before and then repeatedly at various times up to three hours after inhalation of ten albuterol doses (total dose approximately 1 mg) delivered by MDI. On either day the patient did, or did not, rinse the mouth and gargle after drug inhalation. Aerosol-administered albuterol significantly increased HR, FEV1, systolic BP and serum concentrations of glucose and insulin and lowered diastolic BP as early as five min after inhalation, indicating early systemic drug absorption. Peak changes in all measured parameters were observed within 30 min after treatment. Mouth rinsing and gargling removed 24 +/- 11 percent of the total albuterol dose delivered, but did not lower the magnitude or shift the time course of these side effects or bronchodilation. Our data suggest that cardiovascular and metabolic side effects are associated with the inhalation of an increased dose of albuterol and that mouth rinsing and gargling are not effective in reducing the magnitude of these systemic effects.

Adult↗
PubMed1987

The effect of oral zindotrine (MDL-257), a bronchial smooth muscle relaxant, on histamine airways responsiveness in asymptomatic asthmatics.

We evaluated the efficacy of an oral dosage form of the investigational smooth muscle relaxant, zindotrine, a novel pyridazine derivative, in counteracting histamine-induced bronchospasm in a group of 12 non-medicated asymptomatic asthmatics. Histamine inhalation challenges were performed before (control) and 45, 150, and 300 minutes after zindotrine (200 and 300 mg), or the corresponding dose of placebo was administered orally in a randomized, double-blind crossover fashion. When compared to the control state, the 300-mg zindotrine dose markedly lowered histamine airway responsiveness as indicated by a significant (P less than .01) increase in the inhaled histamine dose necessary to provoke a 20% decrease in the forced expired volume in one second (PD20FEV1) 45 minutes after drug administration. The PD20FEV1 then decreased linearly over time but remained higher than the control PD20FEV1 value (P less than .05) during the entire observation period. The 200-mg zindotrine dose failed to affect the PD20FEV1. Our data indicate that orally administered zindotrine lowers airways responsiveness to inhaled histamine in asymptomatic asthmatics in a dose-dependent and time-dependent fashion.

Administration, Oral↗
PubMed1985

"Experimentation" with chloroform.

A young patient presented with unconsciousness, cardiac arrhythmias, arterial hypotension, and mild intravascular hemolysis after intentional inhalation of chloroform. After the initial complications had resolved, nausea, loss of appetite, and mild transitory jaundice developed. Chloroform-associated hepatotoxicity was biochemically and histologically documented. Facilitating factors included long-term moderate alcohol consumption and an initial episode of arterial hypoxemia. Chloroform inhalation for recreational purposes is probably uncommon. Yet, because of its delayed onset, chloroform poisoning should be considered in acute liver disease without a clear antecedent cause.

Adult↗
PubMed1985

How many spirograms for a histamine challenge?

Several reports have shown that a prior deep inspiration exerts a blunting effect on pharmacologically induced bronchoconstriction. Inspiration to total lung capacity is a mandatory requirement for valid determination of the FEV1, and thus, the FEV1 may underestimate the magnitude of induced airway obstruction. The present study was designed to assess the effect that the performance and separate analysis of 2 consecutive FEV1 maneuvers (FEV(1)1, FEV(1)2), obtained at different levels of histamine-induced bronchoconstriction, may have on the final interpretation of a histamine challenge. Eight asymptomatic nonsmoking asthmatics (mean age, 24 yr; range, 19 to 27 yr) underwent a total of 16 histamine challenges. Paired FEV1 measurements (FEV(1)1, FEV(1)2) were obtained after inhalation of buffer solution (control) and 3 min after inhalation of aerosolized, serially diluted, histamine diphosphate solutions. A significant airways response (FEV1 decreasing by 20% or more from the control value) was observed in all subjects after inhalation of 5 mg/ml of histamine or less, indicating histamine airway hypersensitivity. At lower doses of histamine the mean values for FEV(1)1 and FEV(1)2 were similar to the control value. At higher histamine doses FEV(1)2 was consistently higher than FEV(1)1 (p = 0.007) and exceeded FEV1 1 by a mean of 9% after inhalation of the provocational histamine concentration; delta FEV1(FEV(1)2-FEV(1)1) was correlated with the log10 of cumulative inhaled histamine dose units (p = 0.040). Assuming that the difference between corresponding FEV1 determinations at a given level of induced bronchoconstriction is a direct consequence of changes in lung mechanics induced by deep inspiration, we are led to conclude that during histamine inhalation challenges, only 1 spirogram should be performed at each level of induced bronchoconstriction.

Adult↗
PubMed1984

Benign clear cell tumor ("sugar tumor") of the trachea.

A benign clear cell tumor occurring in the trachea of a 48-year-old woman is described. This is the first such case to be reported with location outside of the lung parenchyma. Symptoms consisted of dyspnea on exertion, nonproductive cough, and finally fairly brisk hemoptysis. Histology and electron microscopy confirmed the diagnosis.

Cytoplasmic Granules↗
PubMed1984

The effect of subcutaneously administered terbutaline on serum potassium in asymptomatic adult asthmatics.

Several recent reports have linked the administration of beta-adrenergic agents to the development of hypokalemia. This led us to study, under controlled conditions, the effects of a subcutaneous injection of 0.25 mg terbutaline sulfate on serum potassium (K+), sodium (Na+), glucose, and insulin in a group of asymptomatic asthmatics. Heart rate (HR), blood pressure (BP), and forced expiratory volume in one second (FEV) were measured as parameters of beta-adrenergic stimulation. Each of 7 subjects was studied on 2 separate mornings after an overnight fast. Measurements were obtained before and at various time intervals after 0.25 mg) of terbutaline sulfate or 0.25 ml of a normal saline solution (placebo) were injected subcutaneously in a double-blind randomized crossover fashion. Terbutaline injection significantly increased HR and FEV and lowered diastolic BP for a period in excess of 3 h, indicating a prolonged beta stimulatory action of the drug. Significant effects on glucose, K+, and insulin were observed as early as 15 min after terbutaline injection; serum glucose and insulin increased and remained elevated for at least 2 h. Serum K+ fell significantly, reached a peak decline of 14% from the control value at 30 min after the injection and remained decreased for a period in excess of after subcutaneous terbutaline injection should be interpreted in the light of these effects of the drug and that terbutaline should be used with caution in patients prone to hypokalemia.

Adult↗
PubMed1984

Effect of inhaled diphemanil methylsulfate, a parasympatholytic agent, on histamine induced bronchoconstriction in asymptomatic asthmatics.

Parenterally administered diphemanil methylsulfate, a quarternary ammonium compound with both parasympatholytic and direct bronchial smooth muscle relaxing properties, has been found effective in the treatment of bronchial asthma. The present study was undertaken to test the effectiveness of inhaled diphemanil in preventing histamine induced bronchoconstriction in asymptomatic adult asthmatics. Twenty subjects, aged 19-40 years (average 25) were studied, each on three different days, observing an interval of at least 70 hours between testing. On day one, airway sensitivity to inhaled histamine was determined. On days two and three, histamine challenge was repeated 20 minutes after inhalation of either diphemanil (2 mg) or its vehicle in a double-blind crossover design. Airway sensitivity was assessed by determining cumulative log dose units of inhaled histamine required to provoke a 20% decline in FEV1 (log PD20 - FEV1). Diphemanil did not prevent histamine induced bronchoconstriction nor did it significantly affect log PD20 - FEV1 (p = 0.59). We conclude that a 2 mg dose of diphemanil, administered by oral inhalation 20 minutes before histamine challenge, is ineffective in protecting against induced bronchospasm in asymptomatic adult asthmatics.

Administration, Intranasal↗