Objective Swallowing difficulties cause patients with amyotrophic lateral sclerosis (ALS) to crush oral medications, falling outside the labeling instructions and entailing some risks. To date, there is no evidence about consequences of crushing riluzole tablets in a home setting. This simulation experiment evaluated the loss of powder and active principle ingredient (API) mimicking the home setting with two alternative crushing methods (A and B). Methods The tests were carried out by 15 volunteers without experience in the preparation of medication. Each volunteer manually crushed 5 tablets with a meat tenderizer (method A) or two spoons pressed against each other (method B). Riluzole was weighed before (W1) and after crushing (W2). Then, a subsample of crushed tablets was analyzed by HPLC to measure API content. The loss of powder was calculated as a percentage of the intact tablet weight, and the loss of API as a percentage of the labeled API content. Results The quantitative analysis showed a mean percentage loss of 6.27% corresponding to a mean (SD) loss of powder of 13(±13) mg. The API loss was directly related to the powder loss: overall the mean percentage of API loss was 8.53% (corresponding to a mean API loss of 4.27 ± 4.50 mg). The difference in powder and API loss was highly statistically significant. Conclusion Crushing riluzole tablets in a simulated home setting determined a significant loss of powder and API. These results support neurologists to evaluate formulations that minimize the need to alter the product and can improve ALS patient journey.

Experimental determination of fluxes by (13)C-tracers relies on detection of (13)C-patterns in metabolites or by-products. In the field of (13)C metabolic flux analysis, the most recent developments point toward recording labeling patterns by liquid chromatography (LC)-mass spectrometry (MS)/MS directly in intermediates in central carbon metabolism (CCM) to increase temporal resolution. Surprisingly, the flux studies published so far with LC-MS measurements were based on intact metabolic intermediates-thus neglected the potential benefits of using positional information to improve flux estimation. For the first time, we exploit collisional fragmentation to obtain more fine-grained (13)C-data on intermediates of CCM and investigate their impact in (13)C metabolic flux analysis. For the case study of Bacillus subtilis grown in mineral medium with (13)C-labeled glucose, we compare the flux estimates obtained by iterative isotopologue balancing of (13)C-data obtained either by LC-MS/MS for solely intact intermediates or LC-MS/MS for intact and fragmented intermediates of CCM. We show that with LC-MS/MS data, fragment information leads to more precise estimates of fluxes in pentose phosphate pathway, glycolysis, and to the tricarboxylic acid cycle. Additionally, we present an efficient analytical strategy to rapidly acquire large sets of (13)C-patterns by tandem MS, and an in-depth analysis of the collisional fragmentation of primary intermediates. In the future, this catalogue will enable comprehensive in silico calculability analyses to identify the most sensitive measurements and direct experimental design.

This report describes the detailed conformational analysis and synthesis of a series of phthalazine phosphodiesterase-type (IV) (PDE IV) inhibitors bearing either mono- or dichloro 4-methylenepyridine at the ‘down’ position of the phthalazine nucleus or different heterocycles at the ‘top’ position 4 of the phthalazine moiety. Both the mono- and dichloro 4-methylenepyridine units linked at carbon C1 of the phthalazine nucleus show identical conformational behaviour with the substituent preferentially oriented towards the external part of the molecule and the pyridine plane almost orthogonal to that of phthalazine ring. The heterocyclic five-membered rings linked at carbon C4 of phthalazine show quite different conformational behaviour. The 1,3-thiazole ring exists in a well-defined conformation almost coplanar with respect to the phthalazine nucleus while the 1,2,4-triazole and the 1,3-diazole heterocycles show a great conformational freedom with large torsion angles. Compound 3 bearing the thiazole ring at C4 displays the major biological activity, thus suggesting that a planar and rather rigid conformation of the pentacycle should favour the PDE IV inhibition capacity of this class of compounds.

BackgroundMucosal delivery of therapeutic protein drugs or vaccines is actively investigated, in order to improve bioavailability and avoid side effects associated with systemic administration. Orally administered bacteria, engineered to produce anti-inflammatory cytokines (IL-10, IL-1Ra), have shown localised ameliorating effects in inflammatory gastro-intestinal conditions. However, the possible systemic effects of mucosally delivered recombinant bacteria have not been investigated.ResultsB. subtilis was engineered to produce the mature human IL-1 receptor antagonist (IL-1Ra). When recombinant B. subtilis was instilled in the distal colon of rats or rabbits, human IL-1Ra was found both in the intestinal lavage and in the serum of treated animals. The IL-1Ra protein in serum was intact and biologically active. IL-1-induced fever, neutrophilia, hypoglycemia and hypoferremia were inhibited in a dose-dependent fashion by intra-colon administration of IL-1Ra-producing B. subtilis. In the mouse, intra-peritoneal treatment with recombinant B. subtilis could inhibit endotoxin-induced shock and death. Instillation in the rabbit colon of another recombinant B. subtilis strain, which releases bioactive human recombinant IL-1β upon autolysis, could induce fever and eventually death, similarly to parenteral administration of high doses of IL-1β.ConclusionsA novel system of controlled release of pharmacologically active proteins is described, which exploits bacterial autolysis in a non-permissive environment. Mucosal administration of recombinant B. subtilis causes the release of cytoplasmic recombinant proteins, which can then be found in serum and exert their biological activity in vivo systemically.

This communication describes the synthesis and in vitro evaluation of a novel and potent series of phthalazine phosphodiesterase type (IV) (PDE4) inhibitors. The interaction with two distinct polar binding sites allowed us to eliminate the cyclopentyloxy substitution from rolipram-like analogues.

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This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described present substituents in position 4 of the phthalazine ring to replace the commonly observed cyclopentyloxy moiety of rolipram analogues. Preliminary evidences of reduced side effects compared to standards and improved pharmacokinetic properties for selected derivatives are also reported.

This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described represent conformationally constrained analogues of RP 73401, Piclamilast. Preliminary evidences of reduced side effects of 11 compared to standards are also reported.

Chronic bronchitis has a prevalence of approximately 11% in the population aged over 35 years and its frequent acute exacerbations (AECBs) are an important cause of morbidity and costs in health-care resources. Oral N -acetylcysteine (NAC) is administered during the winter months as a way of reducing AECBs. This cost-effectiveness analysis was done from the payers' point of view in the Swiss health-care system, based on a retrospective analysis of published placebo-controlled studies. The pooled data show that continuous administration of 400 mg day−1per os of NAC leads to a significant reduction in the number of AECBs (NAC: 16.2 vs 25.2% AECBs per month); a significantly smaller percentage of days of sick leave (NAC: 3.6 vs 5.3%) and a lower rate of hospitalizations (NAC: 1.5vs 3.5% over a period of 6 months). Taking into account the poor compliance of these patients, calculations assumed a compliance of 80%. Direct costs were those of an NAC treatment, the management of an AECB (biological tests in 59%, X-rays in 65% and pulmonary function tests in 45%; antibiotics 70%, bronchodilators in 89%, corticosteroids in 24% and `others' in 25% of the patients), and of hospitalizations (estimated at 10 days per case). Based on these figures, the mean direct costs of an untreated patient were CHF 869 vs CHF 700 in the NAC-treated patient. Univariate sensitivity analysis indicated that cost neutrality is reached with 0.6 (<0.25–1.94, 95% CI) AECBs per 6 months. Indirect costs (based on sick leave) were also significantly different; the mean in untreated patients was CHF 1324vs CHF 779 in the NAC-treated patients. Conclusion: Treating chronic bronchitis patients with NAC during the winter months is cost-effective both from the payer's and a social point of view.

Objective This meta-analysis was performed to assess the possible prophylactic benefit of prolonged treatment with oral N-acetylcysteine (NAC) in chronic bronchitis (CB) based on qualifying clinical trials. Treatment of acute exacerbations with NAC was not investigated. Background Prolonged treatment with oral NAC has been investigated in a number of studies of patients with CB. NAC prevented acute exacerbations and symptoms of CB in some but not all trials. Methods The trials included in this analysis were selected from a MEDLINE ® search of the period from January 1, 1980, through June 30, 1995; references in the articles retrieved in the initial search; and consultation with 2 experts. Selection was based on the following criteria: published, double-blind, placebo-controlled, chronic bronchopulmonary disease, duration of therapy ≥ 2 months, and data sufficient to calculate an outcome variable permitting direct comparison of studies (effect size) for both NAC and placebo groups. The primary end point was the incidence of acute exacerbations in 7 of 8 trials and clinical assessment in the other. In 7 studies, inclusion criteria were based on Medical Research Council criteria for CB, with an additional criterion in some trials. For the meta-analysis, the end points of individual trials were transformed into an effect size as a common outcome. Results Of 21 trials initially identified, 8 qualified for inclusion. References from the 8 papers and consultation with the experts produced 8 additional publications, 1 of which qualified for inclusion. NAC was administered orally at a daily dose of 400 mg (1 study), 600 mg (5 studies), or 1200 mg (1 study). One other trial used a dose of 600 mg 3 times per week. The duration of treatment was 3 months (1 study), ≥ 5 months (2 studies), or 6 months (7 studies). The results of this meta-analysis showed a statistically significant effect size for NAC compared with placebo. The overall value of effect size was −1.37 (95% CI, −1.5 to −1.25). Sensitivity analyses did not significantly alter these results. In a subset analysis of trials with the number of acute exacerbations as a clinical end point, a mean difference of −0.32 clinical event (95% CI, −0.50 to −0.18) was found (ie, a 23% decrease in the number of acute exacerbations compared with placebo). Conclusion These findings suggest that a prolonged course of oral NAC prevents acute exacerbations of CB, thus possibly decreasing morbidity and health care costs.