French recommendations for the diagnosis and management of lymphangioleiomyomatosis.

BACKGROUND: The present article is an English-language version of the French National Diagnostic and Care Protocol, a pragmatic tool to optimize and harmonize the diagnosis, care pathway, management and follow-up of lymphangioleiomyomatosis in France. METHODS: Practical recommendations were developed in accordance with the method for developing a National Diagnosis and Care Protocol for rare diseases of the Haute Autorité de Santé and following international guidelines and literature on lymphangioleiomyomatosis. It was developed by a multidisciplinary group, with the help of patient representatives and of RespiFIL, the rare disease network on respiratory diseases. RESULTS: Lymphangioleiomyomatosis is a rare lung disease characterised by a proliferation of smooth muscle cells that leads to the formation of multiple lung cysts. It occurs sporadically or as part of a genetic disease called tuberous sclerosis complex (TSC). The document addresses multiple aspects of the disease, to guide the clinicians regarding when to suspect a diagnosis of lymphangioleiomyomatosis, what to do in case of recurrent pneumothorax or angiomyolipomas, what investigations are needed to make the diagnosis of lymphangioleiomyomatosis, what the diagnostic criteria are for lymphangioleiomyomatosis, what the principles of management are, and how follow-up can be organised. Recommendations are made regarding the use of pharmaceutical specialties and treatment other than medications. CONCLUSION: These recommendations are intended to guide the diagnosis and practical management of pulmonary lymphangioleiomyomatosis.

Air travel and incidence of pneumothorax in lymphangioleiomyomatosis.

BACKGROUND: Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease of women characterized by multiple lung cysts leading to respiratory insufficiency and frequent pneumothorax (PT). Air travel (AT) could increase the risk of PT in LAM through rupture of subpleural cysts induced by atmospheric pressure changes in aircraft cabin. To determine whether AT increases the risk of PT in LAM, we performed a retrospective survey of members of European LAM patient associations. A flight-related PT was defined as occurring ≤30 days after AT. RESULTS: 145 women reported 207 PT. In 128 patients with available data, the annual incidence of PT was 8% since the first symptoms of LAM and 5% since LAM diagnosis, compared to 0.006% in the general female population. Following surgical or chemical pleurodesis, the probability of remaining free of PT recurrence was respectively 82, 68, and 59% after 1, 5 and 10 years, as compared to only 55, 46 and 39% without pleurodesis (p = 0.026). 70 patients with available data performed 178 AT. 6 flight-related PT occurred in 5 patients. PT incidence since first symptoms of LAM was significantly higher ≤30 days after AT as compared to non-flight periods (22 versus 6%, risk ratio 3.58, confidence interval 1.40-7.45). CONCLUSIONS: The incidence of PT in LAM is about 1000 times higher than in the general female population, and is further increased threefold after AT. Chemical or surgical pleurodesis partly reduces the risk of PT recurrence in LAM.

The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo.

Roflumilast is a new phosphodiesterase 4 (PDE4) inhibitor developed by Byk Gulden Pharmaceuticals for the treatment of chronic obstructive pulmonary disease and asthma. A placebo-controlled, randomized, double-blind, two-period crossover study was performed to investigate the safety and efficacy of roflumilast in 16 patients with exercise-induced asthma. The patients received placebo or roflumilast (500 microg/day) for 28 days, each according to the randomly determined treatment sequences roflumilast/placebo and placebo/roflumilast. In both study periods, exercise challenge was performed 1 hour after dosing on days 1, 14, and 28. FEV1 was measured before exercise challenge, immediately after the end of exercise challenge, and then at 1, 3, 5, 7, 9, and 12 minutes after the end of challenge. Blood samples for the determination of lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) in whole blood ex vivo as a surrogate marker for the inhibition of inflammatory cell activation were taken predose on days 1 and 28. Serial safety measurements were performed during both study periods. Analysis of variance for the crossover design showed a significant superiority of roflumilast over placebo on day 28. The mean percentage fall of FEV1 after exercise was reduced by 41% as compared to placebo (p = 0.021). An improvement of lung function during roflumilast treatment was also observed on days 1 and 14. The median TNF-alpha level decreased by 21% (p = 0.009) during roflumilast treatment but remained essentially constant under placebo. It is concluded that roflumilast is effective in the treatment of exercise-induced asthma. This result was accompanied by a significant reduction of TNF-alpha levels ex vivo. Treatment with roflumilast was safe and well tolerated.

Pharmacokinetics and safety of the ketolide telithromycin in patients with renal impairment.

The pharmacokinetics and safety of the ketolide telithromycin were evaluated in two separate studies after single and repeat oral dosing in patients with varying degrees of renal impairment and in subjects with normal renal function. The single-dose study was an open-label, nonrandomized, parallel-group design in which all 40 patients received a single oral dose of telithromycin 800 mg. The repeat-dose study was an open-label study with a randomized, balanced, incomplete three-block treatment crossover design. In this study, each of the 36 patients received two of three telithromycin regimens (400, 600, or 800 mg once daily for 5 days), with a washout period of >/= 7 days between treatments. Telithromycin was well tolerated. Adverse events were generally mild in severity, and no serious drug-related adverse events were reported. Plasma exposure to telithromycin (C(max), AUC) showed a tendency to increase with increasing severity of renal impairment in both studies. In patients with severe renal impairment (CL(CR) < 30 mL/min) receiving telithromycin 800 mg in the repeat-dose study, C(max,ss) and AUC((0-24 h)ss) increased 1.5-fold (p < 0.05) to 2.0-fold (p = 0.0005), respectively, compared with healthy subjects. The percentage of dose excreted in urine and renal clearance (CL(R)) of telithromycin was found to decrease significantly with increasing severity of renal impairment in both studies, and CL(R) was found to be independent of telithromycin dose in the repeat-dose study. In conclusion, telithromycin dosage adjustment is not necessary in patients with mild to moderate renal impairment (CL(CR) >/= 30 mL/min). In patients with severe renal impairment (CL(CR) < 30 mL/min), dosage adjustment could be considered.

The effects of renal impairment on the pharmacokinetics and safety of fosfluconazole and fluconazole following a single intravenous bolus injection of fosfluconazole.

AIMS: Fosfluconazole is a phosphate prodrug of fluconazole (FLCZ). This study was conducted to investigate the effect of renal impairment on the pharmacokinetics of fosfluconazole and FLCZ, and to assess the safety and toleration of fosfluconazole following a single intravenous bolus injection of fosfluconazole in subjects with normal and impaired renal function. METHODS: In an open, parallel-group, two-centre study, subjects with normal and impaired renal function received a single 1000-mg bolus intravenous injection of fosfluconazole. Subjects were categorized as Normal (> 80 ml min(-1)), Mild (51-80 ml min(-1)), Moderate (30-50 ml min(-1)) or Severe (< 30 ml min(-1)) impairment group according to their Cockcroft and Gault creatinine clearance (CLcr) values. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 240 h and 48 h postdose, respectively. RESULTS: Fosfluconazole plasma concentrations were very similar across the four groups, and there was no apparent relationship between any of the fosfluconazole pharmacokinetic parameters with increasing renal impairment. The conversion of fosfluconazole to FLCZ was unaffected by the degree of renal impairment. Only small amounts of fosfluconazole were excreted in the urine suggesting almost complete conversion to FLCZ. FLCZ concentrations were still detected in plasma after 240 h postdose and remained higher at the later sampling times in subjects in the Moderate and Severe groups. The area under the plasma concentration vs. time curve between time zero and infinity (AUC), the terminal elimination phase half-life (t(1/2)) and the mean residence time (MRT) of FLCZ all increased with the degree of renal impairment. The ratios (95% confidence interval) for AUC (Renal impairment group/Normal group) were 112.8% (89.5, 142.1), 240.6% (128.2, 451.4) and 355.1% (259.3, 486.3) for the Mild, Moderate and Severe impairment groups, respectively. There was a linear relationship between CLcr with AUC, t(1/2), MRT and the total plasma clearance of FLCZ (CL/F). Both the amount excreted over 48 h in the urine and the renal clearance of FLCZ decreased with an increase in renal impairment. The adverse events reported were mild to moderate in intensity, and there was no observed relationship with impairment group. There were no severe or serious adverse events, and in general fosfluconazole was well tolerated. CONCLUSIONS: The pharmacokinetics of fosfluconazole, including its efficient conversion into FLCZ, were unaffected by renal impairment. For FLCZ, there was a significant linear relationship between CLcr and AUC, t(1/2), MRT and CL/F, with AUC, t(1/2) and MRT increasing and CL/F decreasing as renal impairment increased. The dose adjustment used for FLCZ (half normal dose for patients with CLcr at