Isolation, identification and structure elucidation of two novel process-related impurities of retigabine.

Retigabine was the first neuronal potassium channel opener for the treatment of epilepsy. During the manufacture of retigabine, two unknown impurities were present in laboratory batches in the range of 0.05-0.1% based upon HPLC analysis. These unknown impurities were obtained from the enriched reaction mother liquor by column chromatography. The structure of these process-related impurities were elucidated using FT-IR, (1)H NMR, (13)C NMR, 2D NMR (HSQC, HMBC, NOESY) and MS spectral data. Based on the complete spectral analysis and knowledge of the synthetic route of retigabine, these two new impurities were designated as ethyl 4-fluorobenzyl(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate (impurity-II) and diethyl 5-((ethoxycarbonyl)(4-fluorobenzyl)amino)-2-oxo-1H-benzo[d]imidazole-1,3(2H)-dicarboxylate (impurity-III). Impurity identification, structure elucidation and the formation of impurities were also discussed.

Long-term efficacy and safety of fosamprenavir plus ritonavir versus lopinavir/ritonavir in combination with abacavir/lamivudine over 144 weeks.

PURPOSE: The KLEAN study extension assessed the long-term efficacy and safety of fosamprenavir-ritonavir (FPV/r) and lopinavir-ritonavir (LPV/r), both administered with abacavir/lamivudine (ABC/3TC) fixed dose combination, over 144 weeks. METHODS: KLEAN was an open-label, noninferiority study that randomised antiretroviral-naïve patients to FPV/r twice daily (bid) or LPV/r bid with ABC/3TC once daily (qd). Patients with a viral load of <400 copies/mL at Week 48 were eligible to participate in the KLEAN study extension (up to 144 weeks) and continued with their previously randomised therapy. RESULTS: The KLEAN study extension (48 to 144 weeks) randomized 199 patients. The proportion of TLOVR responders (HIV-1 RNA <50 copies/mL) at Week 144 was 73% and 60% in the FPV/r and LPV/r arms, respectively. The proportion of TLOVR responders (<50 copies/mL) was the same irrespective of baseline HIV-1 RNA (>100,000 or 100,000 copies/mL). The Week 144 median (interquartile range) change from baseline CD4+ cell count was 300 (236-433) cells/mm3 and 335 (225-444) cells/mm3 in the FPV/r and LPV/r arms, respectively. Diarrhea was the most frequently reported adverse event. A small proportion of patients (FPV/r, 13%; LPV/r, 9%) discontinued study medication due to adverse events. Three patients (FPV/r, 1; LPV/r, 2) experienced virological failure between Week 48 and Week 144. CONCLUSION: The findings of the KLEAN study extension (48 to 144 weeks) support durable viral suppression with both FPV/r and LPV/r treatment regimens when used in combination with ABC/3TC irrespective of viral load at baseline. Both regimens were well tolerated and had similar safety profiles.

A comparative study of first-derivative spectrophotometry and column high-performance liquid chromatography applied to the determination of repaglinide in tablets and for dissolution testing.

A fast and reliable method for the determination of repaglinide is highly desirable to support formulation screening and quality control. A first-derivative UV spectroscopic method was developed for the determination of repaglinide in tablet dosage form and for dissolution testing. First-derivative UV absorbance was measured at 253 nm. The developed method was validated for linearity, accuracy, precision, limit of detection (LOD), and limit of quantitation (LOQ) in comparison to the U.S. Pharmacopeia (USP) column high-performance liquid chromatographic (HPLC) method. The first-derivative UV spectrophotometric method showed excellent linearity [correlation coefficient (r) = 0.9999] in the concentration range of 1-35 microg/mL and precision (relative standard deviation < 1.5%). The LOD and LOQ were 0.23 and 0.72 microg/mL, respectively, and good recoveries were achieved (98-101.8%). Statistical comparison of results of the first-derivative UV spectrophotometric and the USP HPLC methods using the t-test showed that there was no significant difference between the 2 methods. Additionally, the method was successfully used for the dissolution test of repaglinide and was found to be reliable, simple, fast, and inexpensive.

Comparison of chitin and Amberlite IRA-938 for alpha-galactosidase immobilization.

Watermelon alpha-galactosidase (EC 3.2.1.22) was immobilized on a natural (chitin) and a synthetic anion-exchange (Amberlite IRA-938) support by covalent coupling methods. The procedure entails the activation of supports with 1,1'-carbonyldiimidazole (CDI), followed by immobilization of the enzyme on to these supports without and with a spacer arm; gamma-aminobutyric acid (GABA). Optimization of activation was performed by changing the CDI concentrations and coupling efficiencies. The comparison of two immobilization techniques for both chitin and Amberlite IRA-938 was made by comparing different enzyme concentrations against enzyme activity yield. Furthermore, the storage stability of the immobilized enzymes was also investigated and chitin immobilized alpha-galactosidase was found to be better. Although the activity yield of immobilized enzymes were the same for both supports, the short storage stability of immobilized enzyme on Amberlite IRA-938 is currently a drawback to its applications.

Flexible prandial glucose regulation with repaglinide in patients with type 2 diabetes.

Repaglinide is a novel, rapid-acting prandial glucose regulator. To investigate the effect of repaglinide, 1 mg before each meal, in maintaining glycaemic control in Type 2 diabetic patients who either miss a meal or have an extra meal, 25 patients were randomized to either a fixed-meal regimen of three meals/day or one of two mixed-meal regimens consisting of repeating patterns of two, three or four meals/day over a 20-day period. On the 21st day each patient received three meals. Overall glycaemic control was assessed by weekly serum fructosamine concentrations and 13-point and 37-point serum glucose profiles. Mean fructosamine concentrations decreased significantly to normal values during the treatment period (from 3.10 to 2.68 mg/dl on the fixed-meal regimen and from 3.37 to 2.85 mg/dl on the mixed-meal regimens; P < 0.05), with no statistically significant difference in glucose control between the fixed-meal and mixed-meal regimen groups. Fasting serum glucose levels decreased slightly in both groups, but were not altered by the number of meals consumed. Similarly, serum glucose profiles were not altered significantly by the number of meals consumed. Repaglinide was well tolerated, and no hypoglycaemic events were reported. Serum cholesterol levels were significantly reduced (P < 0.05) in both the fixed-meal and mixed-meal groups, as were triglyceride levels in the mixed-meal group (P < 0.05). It was concluded that meal-associated treatment with repaglinide was well tolerated irrespective of the number of meals consumed/day. Thus, since missing or postponing a meal is a realistic scenario for many individuals, repaglinide offers an oral anti-diabetic treatment which can be adjusted to suit each individual's lifestyle.

[A method of quantitative analysis of bendiocarb in the air of the work area]. / Metodika kolichestvennogo opredeleniia bendiokarba v vozdukhe rabochei zony.

Proposed was a highly sensitive technique for a quantitative assessment of the newly developed insecticide bendiocarb++ in the working zone air (0.1 hg in the given air sample, or 0.025 mg/m3). The technique was tested in toxicological studies of bendiocarb++ contents in the working zone air.

Multicentre clinical trials of benzimidazole-carbamates in human cystic echinococcosis (phase 2).

A multicentre study which constituted the second phase of trials of the efficacy of albendazole and mebendazole in human cystic echinococcosis was coordinated by WHO. A total of 112 patients from four clinical centres in Beirut, Paris, Rome and Sofia completed standardized dosage of regimens of each drug and 68 patients were followed up for at least 12 months after treatment. Albendazole was more effective than mebendazole and adverse reactions were comparable with both treatment regimens. At least 12 months is needed after treatment for an objective evaluation of the efficacy of benzimidazoles. At present, treatment with albendazole or mebendazole should be reserved for inoperable cases of cystic echinococcosis (under strict medical supervision) and individualized according to the patient's response and the occurrence and severity of adverse reactions.

Multicentre clinical trials of benzimidazole-carbamates in human cystic echinococcosis

A multicentre study which constituted the second phase of trials of the efficacy of albendazole and mebendazole in human cystic echinococcosis ws coordinated by WHO. A total of 112 patients from four clinical centres in Beirut, Paris, Rome and Sofia completed standardized dosage regimens of each drug and 68 patients were followed up for at least 12 months after treatment

Albendazole was more effective than mebendazole and adverse reactions were comparable with both treatment regimens. At least 12 months is needed after treatment for an objective evaluation of the efficacy of benzimidazoles

At present, treatment with albendazole or mebendazole should be reserved for inoperable cases of cystic echinococcosis (under strict medical supervision) and individualized according to the patient's response and the occurrence and severity of adverse reactions(AU)