Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: comparison of RESPIMAT with conventional metered-dose inhalers with and without spacer devices

STUDY OBJECTIVES: To compare lung deposition of fenoterol or flunisolide administered from a novel, multidose inhalation device delivering liquid droplets (RESPIMAT; Boehringer Ingelheim Ltd; Bracknell, UK) or from conventional metered-dose inhalers (MDIs) with and without spacers. DESIGN: Two randomized, three-way crossover studies. SETTING: Clinical research laboratory. PARTICIPANTS: Healthy, nonsmoking volunteers. INTERVENTIONS: In one study, radiolabeled aerosols of fenoterol from the RESPIMAT device and from a conventional MDI with or without an Aerochamber spacer (Trudell Medical; London, Ontario Canada). In the second study, radiolabeled aerosols of flunisolide from a RESPIMAT device, from a RESPIMAT device modified by inclusion of a baffle/impactor in the mouthpiece, and from a conventional MDI with an Inhacort spacer (Boehringer Ingelheim; Ingelheim, Germany). MEASUREMENTS AND RESULTS: Assessment of the deposition of fenoterol or flunisolide in the lung and oropharynx using gamma scintigraphy. Safety was assessed based on reported adverse effects and spirometry (FEV1, FVC, and peak expiratory flow rate) to detect any paradoxical bronchoconstriction. The RESPIMAT device delivered significantly more fenoterol to the lungs than either an MDI alone or an MDI with Aerochamber (39.2% vs 11.0% and 9.9% of metered dose, respectively; p<0.01). Oropharyngeal deposition of fenoterol from the new device was lower than that from the MDI (37.1% vs 71.7%, respectively; p<0.01). The RESPIMAT device deposited significantly more flunisolide in the lungs compared with MDI plus spacer (44.6% vs 26.4%, respectively; p<0.01), while resulting in similar oropharyngeal deposition (26.2% vs 31.2%, respectively). Introduction of a baffle into the RESPIMAT system reduced lung deposition of flunisolide to 29.5%, and oropharyngeal deposition to 7.8% (p<0.01). CONCLUSION: The RESPIMAT device may prove to be an effective alternative to MDIs for the administration of inhaled bronchodilators and corticosteroids. The high lung deposition and low oropharyngeal deposition may lead to improved efficacy and tolerability of inhaled medications, especially corticosteroids.     

Circulating plasma prekallikrein and tissue kallikrein in normotensive and hypertensive humans: effects of angiotensin II infusion

Kinins lower blood pressure but the stimuli leading to kinin generation and their origin are less well known. We administered angiotensin II in graded infusion doses to patients with primary hypertension and normotensive controls to study the effects of on circulating kallikreins. Angiotensin II infusion did not significantly alter plasma prekallikrein or tissue kallikrein levels and the plasma levels and their changes did not correlate with blood pressure levels or changes. In the normotensive group prekallikrein levels and renin activity correlated negatively with urinary sodium and chloride excretion during basal conditions and partially during the infusion. U-tissue kallikrein concentration increased in the normotensive group. Thus, acute elevation of blood pressure induced by angiotensin II does not activate the circulating kallikrein-kinin systems. Data rather indicate that the circulating kallikrein-kinin systems may be related to alterations in volume and sodium balance and that these mechanisms may be altered in primary hypertension.     

Intracellular localisation of urea-cycle enzymes in liver (author's transl)

Enzymes of the Krebs-Henseleit urea-cycle were localized by means of differential centrifugation and fractional tissue extraction in rat liver and in human liver. Argininosuccinatlyase (ASAL) and Argininosuccinatsynthetase (ASAS) represent enzymes of the soluble cytoplasmic fraction. Ornithine-ketoacid-transaminase(OKT), carbamyl-phosphate-synthetase (CPS) and ornithine-carbamyl-transferase (OCT) are localized in the mitochondrial and nuclei fractions of the liver cell. Most of the arginase activity is bound to subcellular structures (probably to nuclei). A small portion of arginase-activity was found in the soluble cytoplasmatic fraction. The enzymes of the Krebs-Henseleit urea-cycle are equally distributed in rat liver and in human liver. Differences in the subcellular localisation of (mitochondrial) enzymes in human liver could be attributed to mitochondrial breakage during tissue preparation and do not represent in-vivo conditions.     

Calciphylaxis in man. A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure

Eleven patients with chronic renal failure and presumed secondary hyperparathyroidism developed a syndrome of medial calcinosis of the arteries and painful ischemic ulcers of the fingers, legs, or thighs, or any combination of the three. Five patients required maintenance hemodialysis; six had functioning renal homografts. Severe hyperphosphatemia had existed in each; seven showed roentgenographic evidence of subperiosteal resorption. Similarities are evident between the lesions and experimentally produced calciphylaxix. The lesions demonstrated a relentless, progressive course, with serious morbidity and mortality. Hyperplastic or adenomatours parathyroid tissue was removed from ten of 11 patients unergoing surgical procedures; healing followed in seven patients. Treatment with phosphate-binding antacids to lower serum phosphorus levels may prevent this syndrome. Total or subtotal parathyroidectomy should be considered when ischemic skin lesions appear in uremic patients or in renal transplant recipients.     

Long posterior flap amputation in geriatric patients with ischaemic disease

A series of 165 primary amputations performed on 148 patients at Queen Mary's Hospital, Roehampton, from 1967 to 1975 is reported. The average age of these patients was 70 years, the oldest being 95. Those aged 70 years and over are considered in special detail. The problems of management of these elderly patients are complex, involving medical, surgical, and social problems. The object of treatment is to restore these patients to their previous way of life with the shortest possible time in hospital. Every patient is assessed with a view to arterial surgery, and amputation is avoided where possible by a lumbar sympathetic block or direct arterial surgery. When amputation cannot be avoided a below-knee level is selected if possible. A long posterior flap technique is used which forms a myoplasty of the gastrocnemius muscle; thus the ischaemic anterior tibial skin is avoided. Before the operation the patient is assessed by a specialist team and the management is discussed in detail. Every patient is kept in hospital until rehabilitation is achieved to the point of independence inside the home. Of the 90 patients in the group aged 70 years and over, 22% had above-knee amputations and 75% had below-knee amputations, with the result that 69% of the latter were discharged home walking. This result is contrasted with the smaller number who had an above-knee amputation. Below-knee amputation gives the elderly patient a better chance of walking because of the use of the patellar tendon bearing prosthesis. When followed up 36% of those patients with below-knee amputation were fully independent for periods exceeding six months. The price of a below-knee level of amputation is a longer hospital stay, but the quality of function and mobility obtained by the patient makes this worth while.