The effect of the converting enzyme inhibitor HOE 498 on the renin angiotensin system of normal volunteers.

The converting enzyme inhibitor HOE 498 was evaluated in 12 normotensive male volunteers aged 21 to 26. The efficacy of single 5, 10 or 20 mg oral doses in blocking the pressor response to exogenous angiotensin I was tested in 3 of the subjects. All 3 doses of HOE 498 reduced the pressor response to exogenous angiotensin I to below 50% of control within 1,5 h following administration of the drug. Plasma renin and converting enzyme activity, blood angiotensin I, as well as plasma angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of a single dose of 2.5, 5, 10 or 20 mg of HOE 498 to groups of 5 volunteers each. As expected, blood angiotensin I levels and plasma renin activity rose while plasma converting enzyme activity, plasma angiotensin II and aldosterone concentration fell after administration of the drug. While the dose of 2.5 mg did not reduce plasma converting enzyme activity below 20% of control, the higher doses all resulted in plasma converting enzyme inhibition exceeding 90%. No side-effects were observed. It is concluded that in normal volunteers HOE 498 is an effective potent and long-acting converting enzyme inhibitor. Based on these preliminary findings it is expected that 5 mg HOE 948 will turn out to be adequate for therapeutic use.

[Use of high frequency ventilation in patients with respiratory insufficiency]. / Anwendung der Hochfrequenz-Beatmung bei Patienten mit respiratorischer Insuffizienz.

High frequency ventilation is very common today for treatment of patients with respiratory insufficiency in the ICU as well as intraoperatively. This special kind of artificial ventilation is suitable for patients with decreased lung volume and reduced thoracic and lung compliance. Favourable results in the treatment of ARDS are described. During high frequency ventilation the same degree of oxygenation and CO2-elimination can be reached as with conventional mechanical ventilation. The resulting lower peak and mean airway pressure is advantageous. Therefore the barotrauma of the lung is reduced during high frequency ventilation. For these reasons high frequency ventilation is an alternative method for ventilation of patients with so called "stiff lungs" with reduced thoracic and lung compliance.

[Experiences with the use of oscillating high frequency ventilation]. / Erfahrungen bei der Anwendung der oszillatorischen Hochfrequenzbeatmung.

Our investigations have demonstrated that the effect of oscillatory high-frequency ventilation (HFO) on gas exchange in dogs is directly proportional to the oscillatory flow amplitude VM. Because of the equation: VM = PM/Z, gas exchange is increasing with rising oscillatory amplitude of the ventilation pressure PM and decreasing with rising impedance Z of the respiratory system. This system consists of endotracheal tube and the lungs of the dog investigated. The impedance Z = square root of R2 + X2 (resistance R and reactance X) achieves a minimal value near at the resonant frequency (reactance X = 0, in healthy intubated dogs near at 5 Hz) and increases with rising oscillatory frequency. Thus the oscillatory high-frequency ventilation is most effective near to the resonant frequency of the respiratory system. The results presented allow the conclusion that the application of high-frequency ventilation can be optimized by monitoring the respiratory mechanics parameters.

[Equipment combination for the use of normal frequency and high frequency jet ventilation]. / Gerätekombination zur Anwendung der normofrequenten und hochfrequenten Jetventilation.

Over the last eight years high-frequency ventilation has been extensively evaluated both in the clinical and laboratory settings. Two types of jet ventilators for application of normofrequency and high-frequency jet ventilation have been developed. A combined equipment is described with gas mixer, heater-humidifier, monitoring, membrane solenoid valve and a special injection system.

Determination of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) and its hydrolysis product in serum and urine.

A highly sensitive and specific enzymatic assay for the quantitative determination of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) and its hydrolysis product Hoe 498-diacid in serum and a GLC method for the simultaneous determination of both compounds in urine are described. Both methods involve extraction from the respective biological fluid using disposable C 18 columns. In serum, the enzyme-inhibiting properties of Hoe 498-diacid (Hoe 498 can readily be converted to its hydrolysis product) are utilized for the determination of both compounds concurrently. The serum extract is dissolved in buffer solution and incubated with human serum as angiotensin converting enzyme (peptidyl-dipeptide-hydrolase, EC 3.4.15.1) source and hip-his-leu substrate. The hippuric acid liberated is quantitated by HPLC. The urine extract is treated with diazomethane followed by trifluoroacetic anhydride to convert Hoe 498 and Hoe 498-diacid to their methylester, trifluoroacetyl derivatives, which are then determined simultaneously by GLC using a nitrogen specific detector.

[Animal experiment studies of morphologic changes in the trachea and lung in high frequency ventilation]. / Tierexperimentelle Untersuchungen zu morphologischen Veränderungen an Trachea und Lunge bei Hochfrequenzbeatmung.

Prolonged high frequency ventilation (24 hrs) in dogs leads to morphological changes in the trachea as well as in the bronchi. Erosive changes of tracheal epithelium were observed whereas small bronchi and bronchioli exhibited luminal obstructions by mucus plugs, caused by hypersecretion of goblet cells. Using histochemical methods degenerative changes of bronchiolar epithelium were observed.