Pulmonary drug delivery from the Taifun dry powder inhaler is relatively independent of the patient's inspiratory effort.

The Taifun dry powder inhaler (Leiras OY, Turku, Finland) is a breath-actuated, multidose device, each metered dose containing 200 micrograms of budesonide. A two-way randomized crossover gamma scintigraphic study was performed in 10 asthmatic patients to determine the in vivo deposition pattern of budesonide inhaled from the Taifun. In vitro radiolabelling validation studies demonstrated that the radiolabel could be used as an accurate marker to assess in vivo drug deposition. Patients used either maximal inspiratory effort (targeted peak inhalation flow 30 L/min) or submaximal inspiratory effort (targeted peak inhalation flow 15 L/min) on each study day. Mean (S.D.) whole lung deposition (% of metered dose) was 34.3 (5.8)% and 29.6 (5.9)% for the two inhalation flows. The intersubject coefficient of variation in lung deposition was less than 20% on both study days. Drug was deposited uniformly across the central, intermediate, and peripheral lung regions for maximal and submaximal inspiratory efforts. The study suggests that the Taifun is a superior drug delivery device compared with many other inhalers, in terms of the amount of drug deposited in the lungs, the reproducibility of the lung dose, and the relative flow--independence of lung deposition.

Protein C substitution in sepsis-associated purpura fulminans.

OBJECTIVE: To assess the effect of protein C (PC) substitution on imminent peripheral necroses and overall outcome in patients with sepsis-associated purpura fulminans. DESIGN: Case series. SETTING: Intensive care units of two university hospitals. PATIENTS: A total of 12 patients with purpura fulminans, disseminated intravascular coagulation and imminent peripheral necroses in association with sepsis caused by Neisseria meningitidis (n = 5), Streptococcus pneumoniae (n = 2), Capnocytophaga canimorsus (n = 2), and Staphylococcus aureus (n = 1). In two patients, no pathogens were identified. INTERVENTIONS: Intravenous administration of PC concentrate (100 IU/kg every 6 hrs). In addition, antithrombin III substitution, antimicrobial therapy, hemodynamic support, and mechanical ventilation in all patients and hemodiafiltration in 10 patients. MAIN RESULTS: After the onset of PC, progressive peripheral ischemia was reversed irrespective of the etiology of infection. Laboratory variables reflecting disseminated intravascular coagulation improved rapidly, although the recovery of the platelet count was retarded in the patients who subsequently died. No drug-related adverse events were noted. Amputations were necessary in two patients, and necrotic tips of fingers and toes were macerated in a third. The hospital mortality was 42%. Of the five lethal cases, two were caused by S. pneumoniae, one by N. meningitidis, one by C. canimorsus, and one by an unknown pathogen. CONCLUSIONS: This article provides encouraging results on the use of PC substitution in meningococcal purpura and presents new data on the administration of this drug to patients with septic purpura caused by other bacterial species. By clinical judgment, PC limited the extent of tissue necrosis. The small number of patients does not allow for any conclusions on the potential effect of PC on mortality. A controlled and randomized study with a larger number of patients is needed before any recommendations can be given on the use of PC in sepsis-related purpura fulminans and shock.

Comparison of the bronchodilating efficacies of a novel salbutamol metered dose powder inhaler and a pressurised metered dose aerosol with a spacer.

In a two-day, randomised, double-blind, double-dummy, cross-over multicenter study, the bronchodilating effect of 100 micrograms of salbutamol (CAS 18559-94-9) inhaled from a new metered dose powder inhaler (MDPI; Taifun) was compared with that of an identical dose of salbutamol inhaled from a conventional pressurised metered dose inhaler connected to a spacer (pMDI + S). Thirty-six non-smoking, adult asthmatic outpatients with a baseline forced expiratory volume in 1 s (FEV1) between 35 and 70% of the predicted value participated in the study. After inhalation of the study medication pulmonary function, FEV1 and airway resistance (R(aw)), blood pressure (BP), and heart rate (HR) were measured up to 6 h. Area under the FEV1 vs. time curve (AUCFEV1) was used as the primary efficacy parameter, and the 90% confidence intervals (CI) were used to judge clinical equivalence. Other efficacy parameters were used in supportive analyses as secondary parameters. Both treatments produced a clear improvement in pulmonary function. The mean +/- SD AUCFEV1 were 893 +/- 281 and 889 +/- 2761.min after MDPI and pMDI + S, respectively. The 90% CI for the relative efficacy of the MDPI is from 98 to 103% of that of the pMDI + S. Also the other efficacy parameters gave similar results without significant differences: the mean +/- SD values of percent increase in FEV1 were 47.2 +/- 19.3 and 44.7 +/- 20.8, the maximum absolute value of FEV1 were 2.87 +/- 0.77 and 2.86 +/- 0.77, the maximum percent decrease in R(aw) 53.2 +/- 20.5 and 55.0 +/- 19.1, and the minimum absolute value of R(aw) 0.27 +/- 0.11 and 0.30 +/- 0.12 kPa.s.l-1 for the MDPI and pMDI + S, respectively. The salbutamol doses had no significant effect on BP or HR, and were equally well tolerated. Furthermore, 57.5% of the patients preferred the MDPI, 35% the pMDI + S, and 7.5% considered that there was no difference between the devices. In conclusion, this study demonstrates that the new MDPI is as effective and safe a device as a conventional pMDI connected to a spacer in administering inhaled salbutamol for asthmatic patients. Further, most patients considered the MDPI easier to handle, and preferred it over the pMDI + S.

The bronchoprotective efficacy of salbutamol inhaled from a new metered-dose powder inhaler compared with a conventional pressurized metered-dose inhaler connected to a spacer.

The aim of this study was to compare the efficacy of 100 micrograms of salbutamol inhaled from a new metered-dose powder inhaler (MDPI, Leiras Taifun, Finland) with that of a same dose of salbutamol inhaled from a conventional pressurized metered-dose inhaler with a large volume spacer (pMDI + S) in protecting against methacholine (Mch) induced bronchoconstriction. This was a 3 day, randomized, cross-over, partly blinded, placebo-controlled multicentre study where the pMDI + S was used as an open control. Twenty-six asthmatic outpatients with a baseline FEV1 > or = 60% of predicted and with bronchial hyperreactivity (PD20 FEV1 < or = 890 micrograms of Mch) were studied. On each study day the patients underwent an Mch provocation 30 min after inhaling placebo from the MDPI or a dose of 100 micrograms of salbutamol from the MDPI and from the pMDI + S. PD20 FEV1 and dose-response slope [DRS; maximal change in FEV1 (%)/dose of Mch (mumol)] were used to evaluate efficacy. The median values of PD20 FEV1 were 250, 622 and 1737 micrograms after placebo MDPI, salbutamol pMDI + S and salbutamol MDPI, respectively. The corresponding DRS values were -11.0%, -4.5% and -2.0% mumol-1. With both parameters, all differences were statistically significant (P < 0.05). In conclusion, 100 micrograms of salbutamol inhaled from Leiras Taifun MDPI offers better protection against Mch-induced bronchoconstriction than 100 micrograms of salbutamol from a pMDI connected to a large volume spacer device.

Diagnosis of meningococcal meningitis by broad-range bacterial PCR with cerebrospinal fluid.

We used broad-range bacterial PCR combined with DNA sequencing to examine prospectively cerebrospinal fluid (CSF) samples from patients with suspected meningitis. Fifty-six CSF samples from 46 patients were studied during the year 1995. Genes coding for bacterial 16S and/or 23S rRNA genes could be amplified from the CSF samples from five patients with a clinical picture consistent with acute bacterial meningitis. For these patients, the sequenced PCR product shared 98.3 to 100% homology with the Neisseria meningitidis sequence. For one patient, the diagnosis was initially made by PCR alone. Of the remaining 51 CSF samples, for 50 (98.0%) samples the negative PCR findings were in accordance with the negative findings by bacterial culture and Gram staining, as well as with the eventual clinical diagnosis for the patient. However, the PCR test failed to detect the bacterial rRNA gene in one CSF sample, the culture of which yielded Listeria monocytogenes. These results invite new research efforts to be focused on the application of PCR with broad-range bacterial primers to improve the etiologic diagnosis of bacterial meningitis. In a clinical setting, Gram staining and bacterial culture still remain the cornerstones of diagnosis.

Protein C in the treatment of coagulopathy in meningococcal disease.

OBJECTIVE: To evaluate the clinical and laboratory effects of the substitution of protein C (PC) as an adjunct to conventional therapy in the treatment of purpura fulminans associated with meningococcal sepsis. DESIGN: case series. SETTING: Medical and medical-surgical intensive care units of two university hospitals. PATIENTS: Three patients with purpura fulminans and multiple organ failure caused by Neisseria meningitidis. INTERVENTION: Intravenous administration of PC concentrate (100 IU/kg every 6 to 8 hrs). MEASUREMENTS AND MAIN RESULTS: The administration of PC resulted in normal or above normal levels of the plasma PC activity in all patients. The laboratory and clinical parameters reflecting the severity of coagulopathy improved during the treatment, as did peripheral ischemia and the clinical manifestations of multiple organ failure. No adverse events were noted. One patient died of cerebral edema. CONCLUSION: The administration of PC had a beneficial effect on coagulopathy and peripheral gangrene formation associated with meningococcal disease and showed no adverse effects.

A method for measuring the effects of anticholinergics on histamine-induced bronchoconstriction in normal subjects. Oxitropium bromide provides dose-dependent protection.

To study whether it would be possible to assess anticholinergic drugs in normal subjects with histamine-(HIST) induced bronchoconstriction, three doses of oxitropium bromide (100, 200 and 400 micrograms) was inhaled in random order by twelve normal volunteers in a single-blind, placebo-controlled study. Dose response slope [DRS = maximal percentual fall in pulmonary function/maximal noncumulative histamine dose (mumol)] was used as an index of bronchial reactivity, and was calculated for FEV1 (DRSFEV1) and area under the flow-volume curve (DRSAEFV). The bronchial reactivity and its reproducibility was first tested with a standard provocation method. An abbreviated, single-dose, method was used in the measurement of the effects of oxitropium. The reproducibility of HIST-provocations were good with intraclass correlations of 0.97 and 0.99 for logDRSFEV1 and logDRSAEFV, respectively. However, DRSAEFV seemed to be better in this respect as DRSFEV1. Also, the single-dose method gave results that were comparable to the standard one. The largest dose of oxitropium diminished the median DRS from 2.6 to 0.01 and from 5.2 to -0.2 for FEV1 and AEFV, respectively. All oxitropium doses differed significantly from placebo (P < 0.01) and from each other (P < 0.05) with DRSAEFV-values, but when DRSFEV1 was used, a significant difference was detected only between placebo and active treatment (P < 0.01). In conclusion, since the vagal mechanisms seem to be the predominant system mediating HIST-induced bronchoconstriction in normal subjects, it is possible with DRSAEFV to evaluate the efficacy of anticholinergics against HIST-induced bronchoconstriction in these subjects.

The dose-response slope: a useful method for expressing the results of methacholine provocation tests in healthy subjects?

In order to study the reproducibility of different indices of airway responsiveness, two bronchial provocations with increasing methacholine concentrations up to 256 mg ml-1 were performed within 2 weeks on 30 healthy volunteers. The dose-response slope [DRS = maximal fall (%) in pulmonary function/maximal non-cumulative methacholine dose (mumol)] was calculated from forced expiratory volume in 1 s (FEV1) and from area under the expiratory flow-volume curve (AEFV). DRS reproducibility within 2 weeks in responsive (decline in FEV1 greater than 20%) and non-responsive subjects (decline in FEV1 less than 20%) was assessed. After log-transformation of the data the reproducibility was assessed with intraclass correlations (ICC) [with 95% confidence intervals (CIicc)], mean difference with limits of agreement (delta +/- SD), 95% confidence intervals for a single measurement (CIsm), and the absolute difference of the observations of the two days from each other (zero = ideal reproducibility). Provocative doses (PD20FEV1) could be calculated for 14 subjects on both occasions. In this responsive group the reproducibility of all the parameters used (PD20FEV1, DRSFEV1 and DRSAEFV) was high. In the non-responsive group, DRSFEV1 demonstrated a slightly, but not clearly, lower ICC than DRSAEFV. However, DRSFEV1 had clearly wider limits of agreement and CIsm than DRSAEFV. Also, with DRSFEV1 the observations of the two days differed significantly more from each other than with DRSAEFV (P less than 0.05).

Reproducibility of methacholine induced bronchoconstriction in healthy subjects: the use of area under the expiratory flow-volume curve to express results.

The usefulness of the pulmonary function variable, area under the expiratory flow-volume curve (AEFV), in methacholine provocation (MP) studies in normal subjects was evaluated. The baseline coefficients of variation (CV), maximal fall from post-saline values (MAX) and dose-response slope [DRS = maximal percentage fall in pulmonary function/maximal noncumulative methacholine dose (mumol)] were calculated for AEFV, and were compared to those of forced expiratory volume in one second (FEV1), maximum expiratory flow at 50% (MEF50%) and at 25% (MEF25%). Also the repeatability after 2 and 8 weeks was assessed. The rank order of CVs was FEV1 less than AEFV less than MEF50% approximately MEF25% all differences, except MEF50% vs. MEF25%, being significant (P less than 0.05). The order of sensitivities (estimated with MAX and DRS) was FEV1 less than AEFV less than MEF50% less than MEF25%. Again, all differences were significant (AEFV vs. MEF50% P less than 0.01, others P less than 0.001). After two weeks the correlation coefficients for MAX- and DRS-values of AEFV were 0.84 and 0.94 (P less than 0.001), respectively. After an eight week period the correlations were still high, 0.86 and 0.92 (P less than 0.001), respectively, but the actual MAX- and DRS-values tended to be smaller than eight weeks before. The repeatability of MAX of AEFV was not quite as high as that of FEV1. On the other hand, the correlations of DRS-value derived from AEFV were markedly better than those derived from FEV1. In conclusion, MP in normal subjects is well repeatable at least within two weeks, but after an eight week period disturbing factors may intervene reducing repeatability. AEFV can be considered at least as good a pulmonary function variable as FEV1 in demonstrating bronchoconstriction during MPs in normal subjects, and it might even be a better variable to obtain DRS-values than other variables tested.

Measuring the bronchial effects of bronchodilating drugs in healthy subjects with methacholine provocations: theophylline protects against induced bronchoconstriction in a dose-dependent manner.

To assess whether it would be possible to use methacholine (MCH) provocation tests with healthy subjects in the evaluation of bronchodilatory drugs, an intravenous infusion of theophylline ethylenediamine in increasing doses of 2.5, 5.0 and 7.5 mg/kg was given in random order to nine healthy non-smoking volunteers in a single-blind, placebo-controlled study. Dose response slope (DRS = maximal decline [%] in pulmonary function/the maximum dose of MCH [mumol]) was used to estimate airway reactivity. DRS was calculated to FEV1 (DRSFEV1) and to area under the flow-volume curve (AEFV, DRSAEFV). The bronchial reactivity was first tested with a standard MCH provocation method. An abbreviated, single-dose, method was used in the measurement of the effects of theophylline. The DRS-values obtained from the short method did not differ from those obtained from the standard one (p = 0.86, for DRSFEV1 and DRSAEFV), and correlation between these two methods was good (r = 0.93 and 0.98 for DRSFEV1 and DRSAEFV, respectively [p less than 0.001]). Serum theophylline concentrations achieved were (mean +/- SEM) 32.4 +/- 0.9, 63.7 +/- 3.3 and 93.4 +/- 3.3 mumol/l, which differed significantly from each other (p much less than 0.001). An inverse linear relationship between the serum theophylline concentration and the airway reactivity was observed with both indexes (r = -0.54, p less than 0.01 for DRSFEV1 and r = -0.65, p less than 0.001 for DRSAEFV). Even the lowest dose, which produced serum concentrations well under the therapeutic range, protected significantly (p less than 0.05) against MCH induced bronchoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Measuring the bronchial effect of bronchodilating drugs in healthy subjects after methacholine provocation. Salbutamol as a model drug.

To study whether it would be possible to assess bronchodilating drugs in healthy subjects with methacholine - induced bronchoconstriction, salbutamol 100, 200 and 300 micrograms was inhaled in random order by 12 healthy volunteers in a double-blind, placebo-controlled study. Dose response "slope" (DRS = maximum percentage fall in pulmonary function/maximal noncumulative methacholine dose (mumols] was used as an index of bronchial reactivity, and was calculated for forced expiratory flow volume in 1 s (DRSFEV1) and area under the flow-volume curve (DRSAEFV). Bronchial reactivity and its reproducibility were first tested by a standard methacholine provocation method. An abbreviated, single-dose method was used to measure the effect of salbutamol. The reproducibility of methacholine provocation was good, and the single-dose and standard methods gave comparable results. The DRS-values of all the doses of salbutamol differed significantly from placebo and from each other. AEFV did not show any advantage over the FEV1 in this context. A significant negative association between the dose of salbutamol (microgram/kg) and airway reactivity was observed. In conclusion, use of the DRS showed it possible to evaluate the protective efficacy of beta 2-adrenergic agonists against induced bronchoconstriction in healthy subjects.

Effects of apomorphine on blood levels of homovanillic acid, growth hormone and prolactin in medicated schizophrenics and healthy control subjects.

Two doses of apomorphine (0.005 mg/kg as a subcutaneous injection and 0.015 mg/kg as a 90 min i.v. infusion), and corresponding placebo treatments, were administered to 11 chronic medicated schizophrenic patients and to 8 healthy control subjects. The purpose of the study was to asses the usefulness of drug-induced alterations in the concentration of homovanillic acid (HVA) in plasma as indicators of dopamine autoreceptor sensitivity in the central nervous system. Growth hormone and prolactin in serum were also measured and used as indicators of postsynaptic dopaminergic drug effects. In the control subjects, i.v. apomorphine increased growth hormone in serum from 1.8 +/- 0.2 to 28.3 +/- 4.6 ng/ml and reduced prolactin by 57 +/- 7%. In the patients, apomorphine caused only weak neuroendocrine effects. HVA in plasma was not affected by apomorphine in either group of subjects. The results for growth hormone and prolactin indicate that postsynaptic dopamine receptors in the tubero-infundibular system are antagonized to a considerable degree also during chronic treatment with neuroleptics. The lack of effect of apomorphine on HVA levels suggests that HVA in plasma is not a sensitive indicator of the inhibition of dopamine release caused by small doses of apomorphine and mediated through dopamine auto-receptors. Supersensitivity of this class of receptors could not be demonstrated in our patients, which contrasts with some earlier results.