Small airway deposition of dornase alfa during exacerbations in cystic fibrosis; a randomized controlled clinical trial.

INTRODUCTION: Small airway obstruction is important in the pathophysiology of cystic fibrosis (CF) lung disease. Additionally, many CF patients lose lung function in the long term as a result of respiratory tract exacerbations (RTEs). No trials have been performed to optimize mucolytic therapy during a RTE. We investigated whether specifically targeting dornase alfa to the small airways improves small airway obstruction during RTEs. METHODS: In a multi-center, double-blind, randomized controlled trial CF patients hospitalized for a RTE and on maintenance treatment with dornase alfa were switched to a smart nebulizer. Patients were randomized to small airway deposition (n = 19) or large airway deposition (n = 19) of dornase alfa for at least 7 days. Primary endpoint was forced expiratory flow at 75% of forced vital capacity (FEF75 ). MAIN RESULTS: Spirometry parameters improved significantly during admission, but the difference in mean change in FEF75 between treatment groups was not significant: 0.7 SD, P = 0.30. FEF25-75 , FEV1 , nocturnal oxygen saturation and diary symptom scores also did not differ between groups. CONCLUSIONS: This study did not detect a difference if inhaled dornase alfa was targeted to small versus large airways during a RTE. However, the 95% confidence interval for the change in FEF75 was wide. Further studies are needed to improve the effectiveness of RTE treatment in CF.

Inhalation of tobramycin in patients with cystic fibrosis: comparison of two methods.

Inhalant tobramycin is established in the treatment of cystic fibrosis patients. Conventional nebulizers require a large amount of the expensive compound, because only a small fraction is deposited in the targeted lung region. In contrast, techniques based on controlled inhalation allow a high and reproducible deposition of the drug in specific lung regions. In our study we compared the efficiency of two techniques based on conventional and controlled inhalation in 16 cystic fibrosis patients aged 13-39 years. Inhalations with the doses of tobramycin of 300 mg and 150 mg were performed twice daily for three days. The efficiency of the drug deposition was measured by the determination of its serum concentration 1 h after the end of the inhalation. The mean FEV1 value in our patients was 61% of predicted, range 36%-116%. There were no differences in tobramycin serum concentrations among the three study days in both methods (controlled inhalation: 0.983 +/-0.381(+/-SD) mg/l, 1.119+/-0.448 mg/l, 1.194+/-0.568 mg/l; conventional inhalation: 1.075+/-0.798 mg/l, 1.294 0.839 mg/l and 1.269+/-0.767 mg/l, on Day 1, Day 2, and Day 3, respectively). Even though the drug amount was double in the conventional technique, there was no significant difference in its overall serum concentration from the three study days (conventional inhalation: 1.210+/-0.783 mg/l, controlled inhalation: 1.092+/-0.461 mg/l). In addition, the coefficient of variation and the required inhalation time were shorter in controlled inhalation than in conventional inhalation (42% vs. 65% and 7-8 min vs. 20 min, respectively). Our data suggest that controlled inhalation can significantly reduce the amount of a drug required for therapy, the inhalation time required for drug deposition, and the variability of pulmonary dosage. It seems probable that controlled inhalation can improve the antibiotic prevention of pulmonary infection.

Anticoagulative effects of the inhaled low molecular weight heparin certoparin in healthy subjects.

Inhalation of heparin results in local antiinflammatory and antifibrotic effects and an inhibition of blood coagulation. A number of experimental and clinical studies demonstrated that inhalant administration of heparin or low molecular weight heparin (LMWH) is a feasible and save tool for anticoagulative treatment. However, heparin and LMWH differ in respect to their molecular weight, pulmonary absorption, and principle of their anticoagulative pattern. In our study we investigated the anticoagulative effect of different doses of the LMWH certoparin after inhalation (3000 IU-9000 IU) and subcutaneous injection (3000 IU) in healthy individuals in a cross-over design. Inhalations were performed using a new device allowing inhalations with optimized and standardized breathing patterns. The anticoagulative effect was determined by measurement of the anti-factor-Xa (anti-FXa) activity. Lung function parameters were measured before and after drug inhalation. Analysis of the anti-FXa activity as a function of the time after administration revealed values of the area under the curve (AUC) of 5.70+/-1.58 U.hour/ml and 8.43+/-1.31 U.hour/ml (mean+/-SD) with interindividual coefficients of variation of 28% and 13% after injection of 3000 IU and inhalation of 9000 IU, respectively. The AUC after inhalation of 9000 IU was significantly higher (P=0.0007) compared with subcutaneous injection of 3000 IU. In consequence, in order to obtain plasma anti-FXa activities of above 0.2 U/ml, which is considered sufficient for prophylaxis of venous thrombosis, 9000 IU LMWH have to be inhaled. Compared with the subcutaneous administration, the action of certoparin is longer after inhalation than after injection. Apparently, the drug is released rapidly according to a two-compartment kinetics, and its anticoagulant activity lasts over a long time without a marked plasma peak after administration. In detail, an elevation of plasma anti-FXa activity is achieved for 12 hours to 24 hours without a distinct peak shortly after inhalation. Inhalation of LMWH does not result in any changes in lung function or other side effects. The administration of LMWH by inhalation bears the following: the non-invasive route of drug application, the low interindividual variability of the anticoagulative effect, and a long-time pharmacological effect. These properties suggest that controlled inhalation of heparin is an attractive alternative to subcutaneous administration.

[Comparison of unspecific bronchial provocation during controlled and spontaneous inhalation]. / Vergleich der unspezifischen bronchialen Provokation mit Methacholin unter kontrollierter und freier Inhalation.

Using controlled breathing patterns during inhalation of drugs is characterized by a high dose reproducibility which may be of advantage for bronchial provocation testing. In this study 30 healthy subjects with an anamnesis of atopy underwent in a randomized cross-over design bronchial provocation testing with methacholine either with the Viasys-Jäger-APS system or with controlled inhalations (AKITA-System) (controlled inhalation volume and flow). Measured was the frequency of positive test results. Positive test results were defined by a 20 % decline of FEV (1) or a 100 % increase of specific airway resistance (sRaw). There were no significant differences in the prevalence of positive test results obtained with both techniques: APS-FEV (1) : 8, AKITA-FEV (1) : 9; APS-sRaw: 18, AKITA-sRaw: 17. More subjects showed a 100 % increase of sRaw as compared to a 20 % decrease of FEV (1), which may be interesting in order to understand differences in the diagnostic information given by both parameters. However, there were some discrepancies: only in 25 of 30 cases (sRaw: 21 of 30 cases) the results (positive or negative) agreed between both techniques. Although the two techniques for bronchial provocation test showed some discrepancies, these data suggest that controlled inhalations may be an alternative to the APS-system.

Peripheral deposition of alpha1-protease inhibitor using commercial inhalation devices.

Patients with hereditary alpha1-proteinase inhibitor (alpha1-PI) deficiency are at risk of developing lung emphysema. To prevent the development of this disease, alpha1-PI replacement therapy via inhalation may be a more convenient and effective therapy than the intravenous administration of the drug. In order to optimise this treatment approach, lung deposition of inhaled radiolabelled alpha1-PI (Prolastin) was studied using four different commercial inhalation devices (PARI-LC Star, HaloLite, and AKITA system in combination with LC Star and Sidestream) in six patients with alpha1-PI deficiency and mild-to-severe chronic obstructive pulmonary disease. The time required to deposit 50 mg of the Prolastin (5% solution) in the lung periphery was used as a measure for the efficiency of delivery. The time was calculated from measurements of total and peripheral lung deposition of the radiolabelled alpha1-PI. This time was shortest for the AKITA system (18-24 min) and significantly higher for the PARI-LC Star (44 min) and the HaloLite (100 min). The higher efficiency of drug delivery using the AKITA system is due to the fact that this device controls breathing patterns, which are optimised for each patient individually.

Pulmonary deposition of monodisperse aerosols in patients with chronic obstructive pulmonary disease.

In order to improve patient convenience and drug availability for patients with alpha 1-protease inhibitor deficiency, the administration via the inhalation route has been considered. This study investigated if it is possible to obtain high values of peripheral aerosol deposition by using optimized and controlled inhalation conditions. Therefore, peripheral deposition was studied in 10 patients with alpha 1-protease inhibitor deficiency (phenotype PiZ) and moderate to severe chronic obstructive pulmonary disease by measuring the 24-hour Clearance of radiolabeled inert iron oxide particles with diameters of 2 microns, 3 microns, and 4 microns. Patients inhaled a large volume of aerosol (1000 to 2000 cm3), which was normalized to the individual lung function, with a flow rate of 200 cm3/S. Due to this breathing pattern, peripheral deposition was for all particle sizes above 50% of the inhaled aerosol. The highest peripheral deposition (68%) was found for 3-microns particles.

In vitro testing of two formoterol dry powder inhalers at different flow rates.

The efficiency of two different dry powder inhaler systems for the application of the beta2-sympathomimetic drug Formoterol in the lungs has been tested in vitro. Particle size distributions for each device have been measured at four different flow rates (28.3, 40, 60, and 80 L/min) using an Andersen-Impactor. Mass median aerodynamic diameters (MMAD) of the dispersed powder and deposition of the drug in the respiratory tract was determined using a semiempirical lung deposition model. The optimum output for both devices determined by in vitro measurements is supposed to be achieved with flow rates of 40-60 L/min. The Oxis Turbuhaler delivers the smaller particles as the Foradil P Aerolizer and, thus, the Formoterol deeper into the lungs, but the high specific airflow resistance will influence the ability of patients with severe asthma and children to use the system.

Increased sputum IL-8 and IL-5 in asymptomatic nonspecific airway hyperresponsiveness.

Since asymptomatic, nonspecific airway hyperresponsiveness (BHR) may be due to an enhanced local inflammatory response, we studied molecular markers of inflammation in induced sputum from subjects with asymptomatic BHR (n = 14) compared with control subjects (n = 13) and patients with chronic obstructive pulmonary disease (COPD) (n = 10). Pulmonary lung function parameters were measured by spirometry and body plethysmography. Hyperresponsiveness was defined based on histamine challenge. Induced sputum samples were collected and the solid phase was isolated and analyzed for leukocyte numbers and differential and for cytokines (ELISA). IL-8 was 2.4-fold increased (p = 0.036) in the sputum of subjects with asymptomatic BHR (24.8 +/- 22.0 ng/mL; +/- SD) and 11.2-fold enhanced in patients with COPD (117.8 +/- 106.3 ng/mL) as compared with control subjects (10.5 +/- 7.7 ng/mL). In control subjects, no IL-5 was measured, however, sputum of those with asymptomatic BHR contained IL-5 at 0.044 +/- 0.090 ng/mL fluid and COPD patients at 1.00 +/- 2.01 ng/mL. GM-CSF could not be detected in sputum samples of any subjects investigated. Number of total leukocytes was higher in those with asymptomatic BHR and COPD (with BHR: 9.4 +/- 10.8 x 10(5); COPD: 83.5 +/- 182.5 x 10(5)) compared with persons without BHR (2.9 +/- 3.4 x 10(5)). PMN were increased in patients with asymptomatic BHR (4.1 +/- 5.3 x 10(5)) (38.8 +/- 24.7%) and COPD (32.9 +/- 71.0 x 10(5)) (75.4 +/- 18.6%) compared with controls (0.7 +/- 0.9 x 10(5)) (25.8 +/- 25.7%). In contrast to PMN counts in those with asymptomatic BHR (0.06 +/- 0.11 x 10(5)) (1.5 +/- 3.7%), eosinophil counts were only slightly increased compared with control subjects (0.01 +/- 0.02 x 10(5)) (0.6 +/- 0.9%). This study supports the hypothesis that BHR in asymptomatic people is associated with airway inflammation that may predispose to development of chronic diseases such as COPD.

Antenatal administration of betamethasone to prevent respiratory distress syndrome in preterm infants: report of a UK multicentre trial.

In a prospective, randomized, double-blind, multicentre trial the effect of antenatal treatment with betamethasone phosphate was compared with placebo in the prevention of the respiratory distress syndrome (RDS) in preterm infants. The dose of betamethasone was 4 mg every 8 h for six doses, unless delivery occurred. The 251 women who were enrolled gave birth to 262 liveborn infants, 130 in the beta-methasone and 132 in the placebo group; the two groups were evenly matched in most respects. The diagnosis of RDS in the newborn was confirmed by two independent assessors. Seven of the 130 infants in the betamethasone group and 16 of the 132 in the placebo group developed RDS. In infants whose mothers had received at least three injections, RDS was also less frequent in the steroid group than in the placebo group (3/104 and 10/104 respectively; P less than 0.05). There was a significant reduction of RDS in those born between 24 h and 6 days after entry into the trial (0/30 and 8/45 respectively; P less than 0.05). The largest difference in frequency of RDS occurred in the subgroup of infants born before 34 weeks gestation, within 8 days of trial entry, and whose mothers had received at least three injections (0/27 steroid group and 7/32 placebo group; P = 0.03), and there were also significantly fewer neonatal deaths (2/27 and 13/32, respectively; P less than 0.01) in this subgroup. Betamethasone did not provoke earlier delivery. Premature rupture of the membranes and maternal hypertension did not seem to contraindicate the use of steroids: there was no increase in maternal or neonatal sepsis nor in stillbirth in hypertensive pregnancies in the steroid group. Neonatal jaundice was significantly less frequent in the steroid (55/129) than in the placebo group (81/127; P less than 0.01) but not in the subgroups born before 34 completed weeks gestation.

Acrivastine in allergic rhinitis: a review of clinical experience.

Acrivastine is an antihistamine with reduced sedating potential. This comprehensive review of clinical experience with acrivastine in allergic rhinitis considers all currently available data both published and, as yet, unpublished. Unequivocal evidence of the efficacy of 8 mg acrivastine three times daily for the control of symptoms of seasonal allergic rhinitis has been provided by 11 placebo-controlled studies involving almost 1000 patients. Additional trials have generated further supportive data as well as evidence for the use of acrivastine in the treatment of perennial allergic rhinitis. In common with most antihistamines, acrivastine alone has limited effect on the symptom of blocked nose. In a further series of 11 studies, mainly conducted in the USA, the combination of 8 mg acrivastine plus 60 mg pseudoephedrine was found to control not only the histamine-mediated symptoms of allergic rhinitis but also blocked nose. There were few adverse events associated with the use of acrivastine and the small increase in incidence of drowsiness over that found with placebo was similar to that observed for terfenadine. The marked absence of other signs of significant depression of the central nervous system (or anticholinergic activity) suggests that acrivastine will be an important addition for the antihistaminic control of symptoms of allergic rhinitis.

Responses of human peripheral arteries to agonists: similarities and differences.

A review of the literature indicates that the effects of many vasoactive substances, and particularly alpha agonists, have been investigated in a variety of human peripheral arterial models, including isolated digital, umbilical, uterine, and mesenteric arteries. The limited comparative data on different human arteries, or on animal vs. human arteries, make definition of inter- and intraspecies differences incomplete at this stage. Examination of recent data from our laboratory using the cystic artery indicates that observed differences in responsiveness of the same artery from different subjects may result from a variety of factors not usually considered in animal models. Hence, age of subjects must be controlled, because factors such as vessel wall thickness, optimal resting tension, and blood pressure vary with age. Even when age is controlled, mildly hypertensive or normotensive females with a family history of hypertension are found to have increased vascular responsiveness to some agonists, which implies the need also to control for sex of the subject. The use of appropriate controls and fastidious laboratory techniques are essential to clearly define inter- and intraspecies similarities and differences.

Treatment of cytotoxic drug-related infections.

Twenty-six patients with a malignancy who were receiving intermittent cytotoxic chemotherapy acquired putative bacterial infections while neutropenic. Fourteen patients with neutrophil counts less than 100 X 10(6)/L received cefuroxime plus amikacin. Twelve patients with neutrophil counts between 100 and 500 X 10(6)/L were given cefuroxime alone. The dosages were amikacin, 500 mg BID, and cefuroxime, 1.5 gm TID, although the dose of cefuroxime was halved in three patients because of low body weight and in one patient because of impaired renal function. Bacteriological proof of infection was obtained in 14 patients. In all but two, the bacteria were eradicated by therapy; those two had strains resistant to cefuroxime. Clinical cure was obtained in 15 patients (58%); marked improvement, in seven (27%). One of the patients not cured was probably not infected. In another, the organism was eradicated but the patient did not recover from preexisting shock and renal failure. There were minimal side effects. One patient had diarrhea, one complained of pain on injection, and two had slight increases in transaminase levels. Of particular note is the lack of renal toxicity, particularly in the five patients previously treated with cisplatin.

Placental transfer of cefuroxime.

The transfer of cefuroxime across the placenta was studied in 10 women in labour and 12 women being delivered by Caesarean section. Following a single intramuscular injection of 750 mg cefuroxime, high antibiotic concentrations were found in the amniotic fluid in women in labour; the peak concentration of 18 mg/l was achieved after five hours. Therapeutic concentrations of cefuroxime were present in umbilical vein serum for up to eight hours after injection. A similar pharmacokinetic picture was observed in the women undergoing Caesarean section although in the limited time interval (up to four hours) between injection and delivery the amniotic fluid levels of cefuroxime achieved were lower. Cefuroxime appears to cross the placenta well to produce effective concentrations in fetal blood and amniotic fluid.

Cefuroxime: potential use in pregnant women at term.

The placental transfer of cefuroxime was studied in 20 women after one or more 1.5 g intravenous injections. Ten women had labour induced at term and ten were delivered by elective Caesarean section. High concentrations of cefuroxime were found in the cord blood and amniotic fluid and therapeutically active antibiotic levels were found in the infants for up to six hours after delivery.

Cefuroxime and ampicillin compared in a double-blind study in the treatment of lower respiratory tract infections.

Cefuroxime and ampicillin were compared in a randomized double-blind trial in the treatment of severe lower respiratory tract infections. 750 mg of cefuroxime were given to 57 patients and 500 mg of ampicillin to 54 patients by intramuscular injection three times daily for 7-10 days. The patients had acute exacerbations of chronic bronchitis with or without pneumonia, a few had bronchiectasis and an underlying bronchial carcinoma was present in nearly a quarter. By the end of treatment the sputum, initially always mucopurulent, had become mucoid in 87.7% of patients receiving cefuroxime in comparison to 48.1% of those receiving ampicillin. A satisfactory clinical response was observed in 94.7 and 68.5%, respectively. Both these differences between cefuroxime and ampicillin are statistically significant (p less than 0.001).

Cefuroxime compared with penicillin for the treatment of gonorrhea.

One hundred seventy-eight men and women with acute gonorrhea were treated by intramuscular administration of cefuroxime. Use of 1 g of cefuroxime plus 1 g of probenecid gave a cure rate of 95.5%, which compared well with that of a standard treatment of 5 x 10(6) units of intramuscularly administered benzyl penicillin plus 1 g of probenecid. The latter gave a cure rate of 97.2% in a concurrent series of 178 patients. A subsequent comparison of 163 patients who received 750 mg of cefuroxime plus 1 g of probenecid with 145 patients who received 1.5 g of cefuroxime alone showed cure rates of 95.1% and 97.2%, respectively. Only two cases of possible hypersensitivity to cefuroxime were found. It is concluded that cefuroxime is a valuable drug for single-session treatment of acute gonorrhea in both men and women.

Experience with cefuroxime in 190 patients with severe respiratory infections.

Cefuroxime is a very effective agent for the treatment of severe purulent respiratory infections. 190 patients with purulent exacerbations of bronchitis or bronchiectasis, pneumonia or secondarily infected lung cancer received 2.25--3.0 g cefuroxime daily for an average of 9 days. A good clinical response was seen in 91% of 184 assessable patients. A remarkable improvement in sputum purulence was observed and side-effects to cefuroxime were minimal.

Single-dose cefuroxime in the prophylaxis of abdominal wound sepsis.

A double-blind study was carried out to investigate the prophylactic use of single-dose cefuroxime in elective abdominal surgery. Twenty-three patients received 1.5 g cefuroxime by intravenous injection immediately prior to induction of anaesthesia; 24 patients received no antibiotics. In the cefuroxime group, there were no cases of post-operative wound sepsis or septicaemia; in the control group, the incidence of these infections was 12.5% and 8.3% respectively.