Conversion to lacosamide monotherapy in the treatment of focal epilepsy: results from a historical-controlled, multicenter, double-blind study.

OBJECTIVE: To evaluate the efficacy and safety of conversion to lacosamide 400 mg/day monotherapy in adults with focal epilepsy. METHODS: This historical-controlled, double-blind study (NCT00520741) enrolled patients aged 16-70 years on stable doses of 1-2 antiepileptic drugs (AEDs) and experiencing 2-40 partial-onset seizures per 28 days during the 8-week prospective Baseline. Patients were randomized to lacosamide 400 or 300 mg/day (3:1 ratio), starting at 200 mg/day and titrated over 3 weeks to randomized dose. Patients then withdrew background AEDs over 6 weeks and entered a 10-week Monotherapy Phase. The primary assessment was the Kaplan-Meier-predicted percentage of patients on 400 mg/day in the full analysis set (FAS) meeting ≥ 1 predefined seizure-related exit criterion by day 112, compared with the historical-control threshold (65.3%). RESULTS: Four hundred twenty-five patients were enrolled and were eligible for safety analyses (400 mg/day, n = 319; 300 mg/day, n = 106). A total of 271 (63.8%) of 425 patients completed the Lacosamide Maintenance Phase (combined AED Withdrawal and Monotherapy Phases). Among 284 patients in the 400 mg/day group in the FAS, 82 (28.9%) met ≥ 1 exit criterion; the Kaplan-Meier-predicted exit percentage at day 112 for 400 mg/day (30.0%; 95% confidence interval [CI] 24.6-35.5%) was lower than the historical control. When exit events, withdrawal due to treatment-emergent adverse events (TEAEs), and withdrawal due to lack of efficacy were summed (n = 90), the predicted exit percentage (32.3%; 95% CI 26.8-37.8%) was also lower than the historical control. Most patients receiving 400 mg/day reported some improvement on the Clinical Global Impression of Change (75.4%) and Patient Global Impression of Change (74.3%). Overall, the most common (>10%) TEAEs were dizziness (24.0%), headache (14.4%), nausea (13.4%), convulsion (11.5%), somnolence (10.4%), and fatigue (10.1%); most (74.1%) were mild-to-moderate in intensity. Seventy-two patients (16.9%) discontinued due to TEAEs. Seventeen patients (4%, all receiving 400 mg/day) experienced serious AEs. SIGNIFICANCE: Lacosamide 400 mg/day monotherapy was effective, with a favorable safety profile in patients with focal epilepsy.

Evaluating the impact of a pharmacist's absence from an antimicrobial stewardship team.

PURPOSE: Results of a study to determine the impact of a clinical pharmacist's temporary absence from a hospital's antimicrobial stewardship team are presented. METHODS: A retrospective chart review was conducted to compare the appropriateness of the use of selected antimicrobial medications with and without regular pharmacist involvement on the hospital's antimicrobial stewardship team. The charts of two samples of patients were evaluated: (1) 119 patients who had received prolonged (≥72 hours) imipenem-cilastatin, linezolid, or micafungin therapy over a three-month period during which a clinical pharmacist routinely provided interventions to help ensure the drugs were used according to institutional guidelines and (2) 111 patients treated with one of the three drugs during a three-month period when the clinical pharmacist did not serve on the stewardship team. RESULTS: Relative to the period of active pharmacist involvement in antimicrobial stewardship, rates of inappropriate use of imipenem-cilastatin, linezolid, and micafungin during the pharmacist's absence were deemed to have increased by 27, 39, and 35 percentage points, respectively, with corresponding increases in the average duration of therapy of 0.7, 4.0, and 3.2 days; in addition, the number of cases of Clostridium difficile infection increased more than threefold (from 8 to 25) during the pharmacist's absence. CONCLUSION: The temporary absence of a pharmacist from the antimicrobial stewardship team was associated with increased rates of inappropriate use of restricted antimicrobial agents and consequent increases in average durations of therapy.

Quantification and structural elucidation of potential impurities in agomelatine active pharmaceutical ingredient.

Seven impurities in agomelatine drug substance were determined by a newly developed RP-HPLC method. Structures of potential impurities were confirmed by NMR and IR analysis. Efficient chromatographic separation was achieved on Hypersil BDS C18 column (250 mm × 4.6 mm, 5 µm) in gradient mode by using a binary mixture of potassium dihydrogen phosphate (15 mM, pH adjusted to 3.0) and acetonitrile at a flow rate of 1.0 ml/min. A photodiode array detector set at 230 nm was used for detection. Forced degradation studies showed that the proposed method was specific, and agomelatine was found to be susceptible to acidic and alkaline conditions. The method was validated according to ICH guidelines with respect to specificity, sensitivity, precision, linearity, accuracy, robustness and system suitability. Detection limit of impurities was in the range of 0.0008-0.0047%. Regression analysis showed correlation coefficient value greater than 0.999 for agomelatine and its seven impurities. Accuracy of the method was established based on the recovery obtained between 94.4% and 106.7% for all impurities. The validation results demonstrated that the developed method was suitable for the quantitative determination of potential impurities in agomelatine. A possible mechanism for the formation of impurities was proposed.

Development and validation of a stability-indicative agar diffusion assay to determine the potency of linezolid in tablets in the presence of photodegradation products.

Linezolid (LNZ) is one of the first commercially available (and most widely used) oxazolidinone antibiotics. This study describes the development and validation of a microbiological assay, applying the cylinder-plate method, for the determination of the antibiotic linezolid, as well as the evaluation of the ability of the method in determining the stability of linezolid in tablets. The validation method yielded good results and included linearity, precision, accuracy, robustness and selectivity. The assay is based on the inhibitory effect of LNZ upon the strain of Bacillus subtilis ATCC 9372 used as the test microorganism. The results of the assay were treated statistically by analysis of variance (ANOVA) and were found to be linear (r(2)=0.9998) in the range of 20-80 microg mL(-1), precise (inter-assay: R.S.D.=0.61) and accurate (R.S.D.=1.7). The method developed and validated proved to be indicative of stability and capable of determining the decay of linezolid in the presence of photodegradation products. Comparison of bioassay and liquid chromatography by ANOVA showed no significant difference between methodologies. The results demonstrated the validity of the proposed bioassay, which is a simple and useful alternative methodology for LNZ determination in routine quality control.

Determination of linezolid and its achiral impurities using sweeping preconcentration by micellar capillary electrophoresis.

Linezolid is the first compound of a truly new class of antibiotics--the oxazolidinones. The elaborated method of capillary electrophoresis (CE) of linezolid separation from its achiral impurities was successfully performed using sweeping preconcentration, followed by UV absorption detection at 254nm. The best results were obtained with 125mM Tris buffer, pH 2.0, with addition of 20% (v/v) methanol as background electrolyte. Sodium dodecyl sulfate (150mM) was added to the electrolyte in the inlet vial as the sweeping agent. The separation was carried out at negative polarity. Then, the optimized method was validated in terms of linearity, accuracy and precision. Sweeping preconcentration of linezolid provides detection limit at 0.05microg/ml level. The evaluated CE method was applied in the analysis of medicinal product containing linezolid-linezolid solution for infusion.

Monitoring of N,N-dimethylacetamide in children during i.v.-busulfan therapy by liquid chromatography-mass spectrometry.

Recently, an intravenous (i.v.) formulation of busulfan using the potentially hepatotoxic and neurotoxic N,N-dimethylacetamide (DMA) as a solvent was introduced. There is a need to assess the exposure of DMA in patients during the intravenous high dose therapy. A rapid and selective LC-MS method was developed to quantify relevant DMA concentration in plasma. After protein precipitation with trichloroacetic acid, the isocratic separation was achieved using a 150 mm x 2 mm C18 column and elution with a mobile phase containing 0.1% formic acid in water/acetonitrile (97:3). Detection of DMA was carried out with a ThermoFinnigan single-quadrupole mass spectrometer in selected-ion monitoring mode as H+ -adduct at m/z 88.2. Deuterium-labelled DMA was used as the internal standard. The LC-MS method was accurate, precise and reproducible in the range from 0.25 to 150 mg/l and met the generally accepted criteria for bioanalytical methods. Two calibration ranges from 0.25 to 7.5 mg/l and 7.5 to 150 mg/l were used. The intra- (n = 7) and interassay (n = 7) accuracy and precision were both < 7.7% and the limit of quantification is 0.25 mg/l. The method was successfully applied to investigate 203 plasma samples in children during the i.v.-busulfan therapy.

Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB)--a report of ten cases.

OBJECTIVES: Multidrug resistant tuberculosis (MDR-TB) is an increasing problem in many parts of the world and in Norway the increase has been substantial since 1998. New therapies for MDR-TB have not been introduced since the fluoroquinolones in the 1970s. The cure rate of this disease has been reported to be lower than for non-drug resistant TB, and the use of new experimental drugs in combination therapy is warranted. METHODS: Ten consecutive patients with culture proven MDR-TB were treated with the novel antibiotic drug linezolid in combination regimens for 6-40 (median 17) weeks and followed up 11-50 (median 24) months after end of treatment. All strains were sensitive to linezolid with MIC<4 mg/l. Treatment was given as direct observed therapy (DOT) and sputum cultures, blood chemistry and neurologic examination were undertaken on a regular basis. RESULTS: Nine patients were cured, one patient with poor adherence to treatment and advanced AIDS died. Seven of 10 patients experienced serious adverse events, which led to withdrawal of linezolid in all seven. Six patients developed peripheral neuropathy and five patients bone marrow depression, blood transfusions were given to three patients and in all five patients bone marrow function normalized after cessation of linezolid. Peripheral neuropathy was not fully reversed in all patients. CONCLUSION: Linezolid seems highly active in combination treatment of MDR-TB. Cultures became negative 10-37 days after the introduction of the drug. However, peripheral neuropathy and bone marrow depression led to linezolid withdrawal in seven patients, and neuropathy may not be fully reversible in all patients.