A phase IV, two-armed, randomized, cross-over study comparing compliance with once-a-month administration of vitamin D3 to compliance with daily administration of a fixed-dose combination of vitamin D3 and calcium during two 6-month periods.

UNLABELLED: In a randomized, cross-over study, once monthly administration of vitamin D3 was preferred over a once daily administration of a fixed-dose combination of vitamin D3 and calcium, with a better compliance but without any significant difference in the increase in vitamin D levels. INTRODUCTION: The aim of the present study was to compare a once-monthly administration of vitamin D3 to a daily administration of a fixed-dose combination of vitamin D3 and calcium during two treatment periods of 6 months. METHODS: One hundred volunteers aged 50 years old or older were randomized to receive either one drinkable ampoule containing 25,000 IU vitamin D3 (D-Cure®, SMB) once monthly (group VD) or one chewable tablet containing 1000 mg calcium carbonate + 800 IU vitamin D3 (Steovit Forte®, Takeda) once daily (group VDCa) during 6 months. After the first 6 months of treatment, the groups were reversed according to the randomized cross-over design. Treatment compliance (i.e. the primary outcome), preference, acceptability and vitamin D levels and adverse events were all collected. RESULTS: For the two periods, the patients had a significantly higher compliance in the VD group than in the VDCa group (p < 0.0001). During the study, 50 (56.8 %) patients preferred the VD treatment, 16 (18.2 %) patients preferred the VDCa, and for 22 (25.0 %) patients, neither treatment was preferred. At the end of the first 6 months of treatment, the mean (SD) increase of 25(OH)D was 6.57 ng/mL (8.19) in the VD group and 3.88 ng/mL (10.0) in the VDCa group (p = 0.16 between groups). CONCLUSION: In this study, a once-monthly administration of vitamin D3 was preferred over a once-daily administration of a fixed-dose combination of vitamin D3 and calcium, with a better compliance but without any significant difference in the increase in vitamin D levels.

Treatment of alcoholic polyneuropathy with vitamin B complex: a randomised controlled trial.

AIMS: To evaluate the therapeutic efficacy and safety of BEFACT Forte 'new formulation' and BEFACT Forte 'old formulation' in the treatment of sensory symptoms of alcoholic polyneuropathy. METHODS: A multi-centre, randomised, double-blind, placebo-controlled study was conducted on 325 patients with sensory symptoms and signs of alcoholic polyneuropathy. Patients were randomised to the 'old formulation' (i.e. vitamins B1, B2, B6, and B12), 'new formulation' [i.e. identical to the 'old formulation' with additional folic acid (vitamin B9)], or placebo in a 1:1:1 ratio. One tablet of the study medication ('new formulation' or 'old formulation') or placebo was taken orally, three times a day, over a 12-week treatment period. RESULTS: Therapeutic efficacy was assessed in 253 patients by measuring vibration perception threshold (biothesiometry), intensity of pain, sensory function, co-ordination, and reflex responses. Patients treated with the 'new formulation' or 'old formulation' showed significant improvement in the primary efficacy endpoint (vibration perception threshold at the big toe) and secondary efficacy endpoints in comparison to placebo. The active treatment groups were comparable to placebo in terms of safety. CONCLUSIONS: A specific vitamin B complex (with and without folic acid) significantly improved symptoms of alcoholic polyneuropathy over a 12-week treatment period.

Long-term tolerability of tramadol LP, a new once-daily formulation, in patients with osteoarthritis or low back pain.

INTRODUCTION: Tramadol hydrochloride is a centrally acting analgesic, which possesses opioid agonist properties and activates monoaminergic spinal inhibition of pain. An oral, once a day, sustained release formulation of tramadol is thought to be advantageous compared with immediate release preparations as it prevents plasma peaks associated with increased side-effects of the drug. It may also improve compliance. The purpose of the study was to assess the long-term safety of a new sustained-release formulation of tramadol (tramadol LP) in patients with knee or hip osteoarthritis and in patients with refractory low back pain. STUDY DESIGN: The design was a phase III, open, multicentre, international, tolerability study with tramadol LP at a dose titrated by the patient between 100 and 400 mg once daily, according to the intensity of pain. The treatment was administered for a continuous period of 4 weeks followed by an intermittent intake of 5 months in 204 patients. The safety criteria for evaluation were recording of adverse events, laboratory tests, electrocardiogram, radiography, global tolerability assessed by the patient and the investigators. RESULTS: Long-term use of tramadol LP was reasonably well tolerated. Most of the reported adverse events were expected and occurred within the first month of treatment. Roughly half of the patients (49%) reported adverse events, of which 66% were related to treatment. Gastrointestinal events (nausea and vomiting) were the most frequent. Serious adverse events were reported in 6.4% of patients, from which only two cases were related to treatment. There was no sign of tolerance development and the percentage of patients presenting withdrawal symptoms after the end of treatment was low (6%). CONCLUSION: Long-term treatment with tramadol LP once daily is generally safe in patients with osteoarthritis or refractory low back pain.

Dose-finding and 24-h monitoring for efficacy and safety of aerosolized Nacystelyn in cystic fibrosis.

The aim of the present studies was to investigate the tolerability and activity of a novel mucolytic drug, Nacystelyn (NAL), for the treatment of cystic fibrosis (CF) lung disease. In study 1, involving 10 CF patients, the main objective was to determine the tolerability and potential efficacy of a range of single doses of NAL in comparison to a placebo, in order to establish an optimal dose for further testing. On five consecutive scheduled treatment days, patients inhaled either from two (4 mg) to eight puffs (16 mg) of a single dose of NAL from the range, administered in an open-label fashion, or 12 puffs of active NAL (24 mg) versus 12 puffs of placebo, administered in a randomized double-blind fashion. Pulmonary function data were unaffected and clinically-adverse effects were limited to wheezing in some patients that inhaled 12 puffs of either placebo or active drug. Subsequent rheological analysis of their sputum showed a dose-dependent decrease in sputum viscoelasticity, accompanied by a decrease in sputum solids content and an increase in chloride and sodium concentrations. In study 2, involving 12 CF patients, the clinical safety and mucolytic activity of a single dose of NAL was monitored over 24 h. On different scheduled treatment days, 7 days apart, patients inhaled a single dose of 12 puffs of active NAL (24 mg) or 12 puffs of placebo drug in a randomized, double-blind sequence, with sputum samples taken at intervals before and after inhalation. Mucus rigidity decreased following NAL inhalation, with the maximum effect observed at 4 h; the 1-, 2- and 4-h NAL rheology results were significantly different from placebo. No adverse effects were observed. The drug was well tolerated in both studies. Sputum results were predictive of improved clearability by ciliary and cough transport mechanisms.

Nacystelyn, a novel lysine salt of N-acetylcysteine, to augment cellular antioxidant defence in vitro.

Nacystelyn (NAL), a recently-developed lysine salt of N-acetylcysteine (NAC), and NAG, both known to have excellent mucolytic capabilities, were tested for their ability to enhance cellular antioxidant defence mechanisms. To accomplish this, both drugs were tested in vitro for their capacity: (1) to inhibit O2- and H2O2 in cell-free assay systems; (2) to reduce O2- and H2O2 released by polymorphonuclear leukocytes (PMN); and (3) for their cellular glutathione (GSH) precursor effect. In comparison with GSH, NAL and NAC inhibited H2O2, but not O2-, in cell-free, in vitro test systems in a similar manner. The anti-H2O2 effect of these drugs was as potent as that of GSH, an important antioxidant in mammalian cells. To enhance cellular GSH levels, increasing concentrations (0-2 x 10(-4) mol l-1) of both substances were added to a transformed alveolar cell line (A549 cells). After NAC administration (2 x 10(-4) mol l-1), total intracellular GSH (GSH + 2GSSG) levels reached 4.5 +/- 1.1 x 10(-6) mol per 10(6) cells, whereas NAL increased GSH to 8.3 +/- 1.6 x 10(-6) mol per 10(6) cells. NAC and NAL administration also induced extracellular GSH secretion; about two-fold (NAC), and 1.5-fold (NAL), respectively. The GSH precursor potency of cystine was about two-fold higher than that of NAL and NAC, indicating that the deacetylation process of NAL and NAC slows the ability of both drugs to induce cellular glut production and secretion. Buthionine-sulphoximine, which is an inhibitor of GSH synthetase, blocked the cellular GSH precursor effect of all substances. In addition, these data demonstrate that NAC and NAL reduce H2O2 released by freshly-isolated cultured blood PMN from smokers with chronic obstructive pulmonary disease (COPD) (n = 10) in a similar manner (about 45% reduction of H2O2 activity by NAC or NAL at 4 x 10(-6) mol l-1). In accordance with the results obtained from cell-free, in vitro assays, O2- released by PMN was not affected. Ambroxol (concentrations: 10(-9)-10(-3) mol l-1) did not reduce activity levels of H2O2 and O2- in vitro. Due to the basic effect of dissolved lysine, which separates easily in solution from NAL, the acidic function of the remaining NAC molecule is almost completely neutralized [at concentration 2 x 10(-4) M: pH 3.6 (NAC), pH 6.4 (NAL)]. Due to their function as H2O2 scavengers, and due to their ability to enhance cellular glutathione levels, NAL and NAC both have potent antioxidant capabilities in vitro. The advantage of NAL over NAC is two-fold; it enhances intracellular GSH levels twice as effectively, and it forms neutral pH solutions whereas NAC is acidic. Concluding from these in vitro results, NAL could be an interesting alternative to enhance the antioxidant capacity at the epithelial surface of the lung by aerosol administration.

A comparison of a new mucolytic N-acetylcysteine L-lysinate with N-acetylcysteine: airway epithelial function and mucus changes in dog.

A newly synthesized mucolytic agent, N-acetylcysteine L-lysinate (Nacystelyn) was studied. Tracheal mucus velocity (TMV), transepithelial potential difference (PD), rheological properties, and ion content of collected airway secretions were evaluated in six healthy mongrel dogs after placebo, Nacystelyn (NAL) and acetylcysteine (NAC) metered dose inhaler (MDI) aerosols. Although TMV was increased and viscoelasticity decreased after both treatments, the treatment effect with NAL was significantly greater. Furthermore, NAL increased the negative PD and CI- content of secretions in the trachea, an effect not observed after NAC. Both compounds increased ciliary beat frequency (CBF) on the frog palate at a concentration range similar to that approximated in dog airways. The increased mucociliary clearance could be partially explained by favourable rheological changes combined with stimulation of CBF. Since both compounds break disulfide bonds in mucus polymers, the greater change in mucus rheology and clearance rate after NAL, without change in water content, could be explained by the increase in CI- content. Nacystelyn appears to combine different modes of action which synergistically cause an increase in the clearance rate of airway secretions.

Mucolytic treatment with N-acetylcysteine L-lysinate metered dose inhaler in dogs: airway epithelial function changes.

N-acetylcysteine L-lysinate Nacystelyn (L-NAC) is a newly synthesized mucolytic agent, of which the action in vivo has not been well defined. In six healthy mongrel dogs, the rheological properties of mucus, its mucociliary and cough clearability, and the transepithelial potential difference (PD) of the tracheobronchial epithelium were evaluated after placebo and L-NAC metered dose inhaler (MDI) aerosols. The principal index of mucus rigidity, log G*, decreased at all airway sites with L-NAC administration, i.e. the mucus became less rigid and more deformable (the overall change in G* was 0.29 log units, i.e. ca. twofold decrease). The viscoelasticity-derived mucus transportability parameters, mucociliary (MCI) and cough (CCI) clearability indices, increased with L-NAC MDI, particularly CCI, which predicts the effect of mucus rheology on cough clearability. PD increased significantly with L-NAC administration at all measurement sites, which appears to be a novel effect for a direct acting mucolytic agent. Tracheal mucus linear velocity (TMV) increased after L-NAC compared with placebo, as did the normalized frog palate transport rate (NFPTR). The increase in NFPTR was greater than that predicted from the mucus rheological properties alone, suggesting that L-NAC still resident in the collected mucus stimulated the frog palate cilia. The index of mucus flux, the collection rate in mg.min-1, was higher with L-NAC compared with placebo. From our results, we conclude that L-NAC shows potential benefit in terms of improving mucus rheological properties and clearability. It may act, in part, by stimulating the fresh secretion of mucus of lower viscoelasticity. The stimulation of mucociliary clearance could be related to ion flux changes, as indicated by the increase in PD.