Dry powder inhalation versus wet nebulisation delivery of antibiotics in cystic fibrosis patients.

Inhalation of antipseudomonal antibiotics is a cornerstone in treating cystic fibrosis patients. It has shown to be effective in slowing down the process of pulmonary deterioration and decreasing the incidence of infectious exacerbations. The focus is now on innovating drug delivery devices, sometimes combined with specific drug formulations, which allow for the administration of large doses in a short time frame and in a reproducible way. Adaptive aerosol delivery devices are promising, but do not have a distinct position as yet because of the lack of long-term data. The position of dry powder inhalation of antibiotics in cystic fibrosis treatment is still confined to pilot studies. Until more clinical data are available, the suboptimal, conventional jet nebulisers are the mainstay in antipseudomonal inhalation therapy in cystic fibrosis.

Dry powder inhalation of colistin sulphomethate in healthy volunteers: A pilot study.

BACKGROUND: Pulmonary administration of the antimicrobial drugs colistin sulphomethate and tobramycin has been shown to be effective in slowing down pulmonary deterioration in cystic fibrosis (CF) patients. Both drugs are administered by liquid nebulisation, a technique known to have disadvantages. Dry powder inhalation may be an attractive alternative. We investigated inhalation of colistin sulphomethate dry powder using a newly developed Twincer device in healthy volunteers. METHODS: Eight healthy volunteers inhaled a single dose of 25mg colistin sulphomethate dry powder each, using the Twincer inhaler. The median diameter (X(50)) of the dry powder was 1.6 microm (X(10)=0.7 microm, X(90)=3.1 microm), measured by laser diffraction technique. Pulmonary function tests were performed before, 5 and 30 min after inhalation. Serum samples were drawn at t=15 min, 45 min, 1.5h, 2.5h, 3.5h, 5.5h, 7.5h and 24h after inhalation. RESULTS: The colistin sulphomethate dry powder inhaler was well tolerated: no clinically relevant effect on FEV(1) was observed nor did the volunteers experience adverse effects. CONCLUSION: Dry powder inhalation of colistin sulphomethate using the Twincer inhaler is well tolerated by healthy volunteers. A pilot study in cystic fibrosis patients is therefore considered safe in developing a dry powder inhalation of colistin for everyday CF treatment.

Dry powder inhalation of colistin in cystic fibrosis patients: a single dose pilot study.

BACKGROUND: Dry powder inhalation (DPI) may be an alternative to nebulisation of drugs in the treatment of chest infections in cystic fibrosis (CF) patients. In a pilot study the feasibility of a colistin dry powder inhaler (prototype Twincer) by a single dose in CF-patients was assessed and compared to nebulised colistin. METHODS: Ten CF-patients, chronically infected with P. aeruginosa, participated in a randomised cross over study. On two visits to the outpatient clinic, patients inhaled colistin sulphomethate as 25 mg dry powder (Twincer) or as 158 mg nebulised solution (Ventstream nebuliser, PortaNeb compressor). Pulmonary function tests were performed before, 5 and 30 min after inhalation. Serum samples were drawn prior to each dose and at 15, 45 min, 1.5; 2.5; 3.5 and 5.5 h after inhalation. RESULTS: The DPI was well tolerated by the patients: no significant reduction in FEV1 was observed. Relative bioavailability of DPI to nebulisation was approx. 140% based on actual dose and approx. 270% based on drug dose label claim. CONCLUSIONS: The colistin DPI (Twincer inhaler) is well tolerated and appreciated by CF-patients. Optimisation with respect to particle size and internal resistance of the inhaler is necessary to attain equivalent pulmonary deposition to liquid nebulisation.

Quetiapine in overdosage: a clinical and pharmacokinetic analysis of 14 cases.

Data on quetiapine overdosage are only sparsely available in the literature. This study provides additional data on the pharmacokinetics and clinical effects of intoxication with this atypical antipsychotic drug. The authors performed a retrospective analysis of all quetiapine intoxications reported to and screened by the toxicological laboratory of the Central Hospital Pharmacy The Hague between January 1999 and December 2003. Cases with known suggested amount of intake and medical outcome were included. From the patient's medical record and from the toxicological laboratory findings, patient demographic characteristics (gender, age), details of quetiapine intoxication (estimated time of ingestion, estimated amount of ingestion, and coingested drugs) and clinical parameters were obtained. Severity of intoxication was graded by the Poisoning Severity Score (PSS). Individual pharmacokinetic parameter values were calculated using a one-compartment open model and a Bayesian fitting procedure. Out of a total of 21 intoxications with quetiapine, 14 fulfilled the inclusion criteria. The ingested dose ranged from 1200 to 18,000 mg. The blood concentration ranged from 1.1 to 8.8 mg/L with a lag time of 1 to 26.2 hours between time of ingestion and blood sampling at the emergency ward. The most frequent findings were somnolence and tachycardia. The PSS was minor in 6 patients (43%), moderate in 5 patients (36%), and severe in 3 patients (21%). Severity of intoxication was not associated with a higher amount of quetiapine intake. The authors found no correlation between the serum concentration of quetiapine and the amount ingested. Elimination t(1/2) was not prolonged. It can be concluded that quetiapine intoxications appear to proceed mildly. Tachycardia and somnolence were the main clinical symptoms in our case series. No fatalities occurred. The severity of clinical symptoms was not associated with either a high serum concentration or the suggested amount ingested of quetiapine.

Effect of nebulized colistin sulphate and colistin sulphomethate on lung function in patients with cystic fibrosis: a pilot study.

BACKGROUND: Pulmonary administration of colistin is one of the antimicrobial treatments used in Cystic Fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. Dry powder inhalation of colistin may be an attractive alternative to nebulization of colistin. However, nebulized colistin can cause bronchoconstriction in CF patients. Therefore, in the progress of developing a dry powder formula, the choice of the inhaler and its contents should be guided by optimal efficacy and the least possible side effects. To investigate the side effects, a study was initiated to compare the tolerability of colistin sulphate to colistin sulphomethate per nebulization in CF-patients. METHODS: Nine CF-patients chronically infected with P. aeruginosa participated in a double blind, randomized cross over study. On two visits to the outpatient clinic, patients were submitted to either nebulized colistin sulphate or colistin sulphomethate solution. Lung function tests were performed immediately before and 15 and 30 min after nebulization. RESULTS: Nebulization of colistin sulphate caused a significant larger mean decrease in lung function compared to nebulized colistin sulphomethate. A significant decrease in mean changes (SD) in FEV1 at 30 min and FVC at 15 and 30 min after nebulization compared to baseline of -7.3% (8.6%), -5.7% (7.3%) and -8.4% (7.5%) respectively was seen after colistin sulphate nebulization compared to colistin sulphomethate (P < 0.05). Seven patients were not able to complete the nebulization of colistin sulphate because of throat irritation and severe cough. CONCLUSION: Based on these results it was concluded that inhalation with nebulized colistin sulphate is not suitable for treatment of CF patients chronically infected with P. aeruginosa. Colistin sulphomethate is the drug of choice for pulmonary administration of colistin.

Neuropathologic findings in multi-infarct dementia associated with anticardiolipin antibody. Evidence for endothelial injury as the primary event.

OBJECTIVE: There are few reports describing histopathologic changes associated with the antiphospholipid antibody syndrome. We describe a patient with multi-infarct dementia and antiphospholipid antibody syndrome, in whom a brain biopsy was performed. METHODS: Biopsy material from the left frontal cortex, including meninges, cortex, and underlying subcortical white matter, was investigated. Microscopic examination and special staining were performed. RESULTS: Microscopic examination showed lumenal occlusion by thrombi, and marked endothelial hyperplasia of small meningeal and cortical arterioles. CONCLUSION: These findings suggest that the pathogenesis of this cerebral vasculopathy is noninflammatory and is associated with reactive endothelial hyperplasia and thrombosis of small arterioles.