卡马西平致低钠血症4例

4例患者（3例男性,1例女性,年龄22～60岁）分别诊断为病毒性脑炎、症状性癫痫、三叉神经痛和脑出血,服用卡马西平0.1～0.2g,3次/d。1个月内均出现神志淡漠、嗜睡、食欲不振等,血钠水平分别从141.0、143.0、141.6和139.8mmol/L降至122.2、112.1、121.8和116.6mmol/L。4例患者遂即停用卡马西平,换用其他药物并接受对症支持治疗。1周后血钠水平分别恢复至138.0、144.0、139.2和144.2mmol/L。     

Physicochemical evaluation of carbamazepine microparticles produced by the rapid expansion of supercritical solutions and by spray-drying

PURPOSE: To compare the physical and physicochemical characteristics of carbamazepine microparticles prepared using two different methods: (1) the rapid expansion of supercritical solutions (RESS) and (2) the spray-drying process. METHODS: For both processes, microparticles were produced over a range of different temperatures (35 to 100 degrees C). For the RESS method, carbon dioxide was the solvent used over a pressure range of 2500 to 3500 psi. As for the spray-drying method, different organic solvents were used at atmospheric pressure. Comparison was based on morphology, crystalline structure, mean particle size, and size distribution of processed particles. The influence of process parameters on microparticles' characteristics was also investigated. Particles were analyzed using scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), thermogravimetric analyzer (TGA), and differential scanning calorimetry (DSC). RESULTS: The carbamazepine particles used as unprocessed starting material had a mean diameter of approximately 85 microm with a size distribution range between 15 and 336 microm. Microparticles produced by either the RESS or spray-drying method had a mean diameter smaller than 2 microm and a narrower size distribution range between 0.25 and 2.5 microm. SEM photomicrographs, X-ray diffractograms, and DSC spectra revealed that modification of crystal morphology was dependent on the operating conditions. CONCLUSIONS: Significant reduction in mean particle size and size distribution range of carbamazepine particles was observed by RESS and spray-drying methods. The results also demonstrate that the crystalline nature of carbamazepine particles depends on the method of production and on the operating parameters of pressure and temperature.     

HPLC法测定非诺贝特胶囊的含量

目的探讨非诺贝特胶囊中非诺贝特的含量测定方法.方法采用HPLC法,用CLC-ODS柱(250 mm×4.6 mm),以水(用磷酸调节pH为2.5)-乙腈(30:70)为流动相,用紫外检测器于286 nm波长处检测.结果线性范围为6.2～98.9 g·L-1(r=0.999 9,n=5).平均回收率为100.1%,RSD=0.43%(n=3).检测限为0.02 mg·L-1.结论HPLC法具有操作简便,分析快速准确、干扰小等优点.     

Biochemical properties of beta-lactamase produced by Bacteroides distasonis

Three of 29 clinical isolates of Bacteroides distasonis strains, GAI2095, GAI2361 and GAI6270 were found to produce high levels of beta-lactamase relative to the remaining 26 strains. The enzymes from these strains showed a broad substrate profile, hydrolyzing cephaloridine, cephalothin, cefazolin, oxyimino-cephalosporins such as cefuroxime, cefotaxime and cefmenoxime, and piperacillin at high rates. Examination of the substrate profiles indicated that the enzymes were mainly oxyimino-cephalosporinases. Inactivation of latamoxef over a long time by crude enzyme extracts of GAI2095 and GAI2361 was detected by a microbiological assay. The enzyme activities were inhibited by imipenem, cefoxitin, clavulanic acid and sulbactam but not by EDTA. The majority of beta-lactamase activity was found in the cell extract prepared by ultrasonic treatment, especially in the precipitate by ultracentrifugation including membrane fraction. When the cells of B. distasonis were subjected to osmotic shock, negligible levels of beta-lactamase activity were found in the supernatant fluid. The enzymes appeared to be tightly associated with the cell envelope since detergents were required to elute these activities.     

Physical stability of micronized powders produced by spray-freezing into liquid (SFL) to enhance the dissolution of an insoluble drug

PURPOSE: The objective of this study was to investigate the physical stability of micronized powders produced by the spray-freezing into liquid (SFL) particle engineeringtechnology. MATERIALS AND METHODS: Danazol was formulated with polyvinyl alcohol (MW 22,000), poloxamer 407, and polyvinylpyrrolidone K-15 to form a cosolvent solution that was SFL processed. The dried micronized SFL powders were sealed in glass vials with desiccant and exposed to 25 degrees C/60% RH for 3 and 6 mo, 40 degrees C/75% RH for 1, 2, 3, and 6 mo, and conditions where the temperature was cycled between -5 and +40 degrees C (6 cycles/24 hr) with constant 75% RH for 1, 2, 3 and 4 wk. The samples were characterized by using Karl-Fisher titration, differential scanning calorimetry, x-ray diffraction, specific surface area, scanning electron microscopy, and dissolution testing. RESULTS: Micronized SFL powders consisting of porous aggregates with small-particle domains were characterized as having high surface areas and consisted of amorphous danazol embedded within a hydrophilic excipient matrix. Karl-Fischer titration revealed no moisture absorption over the duration of the stability studies. Differential scanning calorimetry studies demonstrated high degrees of molecular interactions between danazol, PVA, poloxamer, and PVP. Scanning electron microscopy studies confirmed these interactions, especially those between danazol and poloxamer. These interactions facilitated API dissolution in the aqueous media. Powder surface area remained constant during storage at the various stability conditions, and danazol recrystallization did not occur during the entirety of the stability studies. Micronized SFL powders containing danazol dissolved rapidly and completely within 5 min in aqueous media. No differences were observed in the enhanced dissolution profiles of danazol after exposure to the storage conditions investigated. Physically stable micronized powders produced by the SFL particle engineering technology were produced for the purpose of enhancing the dissolution of an insoluble drug. CONCLUSIONS: The potential of the SFL particle-engineering technology as a micronization technique for enhancing the dissolution of hydrophobic drugs was demonstrated in this study. The robustness of the micronized SFL powders to withstand stressed storage conditions was shown.     

卡马西平致排尿困难

1例75岁男性前列腺癌患者,因带状疱疹后神经痛,服用卡马西平0.1 g,2次/d。2 d后,患者出现尿流变细、尿频无力和分段尿。5 d后,卡马西平增至0.2 g,2次/d,患者排尿困难加重,遂用导尿管排尿。停用该药,次日,患者自行排尿增多,第5天完全恢复正常。     

Influence of cohesive properties of micronized drug powders on particle size analysis

Particle size analysis results with respect to micronized, mean particle size below 10 μm, furosemide, chloramphenicol palmitate and acetaminophen particles are dealt with in this paper. Special consideration was given to the effect of the agglomeration of particles on data generated by three size measurement techniques. The physicochemical basis for preparing sufficiently well dispersed and stable suspensions for analysis by employing mechanical methods of pretreatment are shown. Furthermore, methods to determine the state of dispersion and methods to assess the individual particle size before size analysis are described. An attempt was also made to establish the statistical confidence that can be assigned to a particular instrument and the confidence level that may be placed on comparative data obtained with the different particle size analysers. Results especially showed the impact of the agglomeration of very small furosemide particles, mean size 3 μm, on particle size analysis and the importance of controlling the cohesive properties of this drug. To overcome the problems associated with agglomeration more attention must be paid to the physical properties of the drug substance. Combining particle size analysis with bulk density, surface area and microscopical studies also helped to identify potential problems.     

Physicochemical and mechanical properties of carbamazepine cocrystals with saccharin

The aim of present research was to investigate the physicochemical, mechanical properties, and stability characteristics of cocrystal of carbamazepine (CBZ) using saccharin (SAC) as a coformer. The cocrystals were prepared by solubility method and characterized by pH-solubility profile, intrinsic dissolution by static disk method, and surface morphology by scanning electron microscopy (SEM), crystallinity by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), and mechanical properties by Heckel analysis. Stability of the cocrystals were assessed by storing them at 60 (°)C for two weeks, 25 (°)C/60%RH, 40 (°)C/75%RH and 40 (°)C/94%RH for one month and compared with the stability of CBZ. The solubility profile of cocrystal was similar to CBZ. The cocrystal and CBZ have shown the same stability profile at all the conditions of studies except at 40 (°)C/94%RH. Unlike the CBZ, cocrystal was stable against dihydrate transformation. The compacts of cocrystal have a greater tensile strength and more compressibility. The Heckel analysis suggested that plastic deformation started at low compression pressure in the cocrystal than CBZ. In summary, the cocrystal form of carbamazepine provides another avenue for product development which is more stable than the parent drug.     

Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate

The dissolution behaviors of carbamazepine (CZP) polymorphs and pseudopolymorphs (form I, form III and dihydrate) and the bioavailabilities (BA) of each form in dogs after oral administration were investigated. Bioavailability tests were carried out at a dose of either 40 mg/body or 200 mg/body. The results of dissolution tests in JP13 first fluid (pH 1.2) at 37 degrees C indicated that the initial dissolution rate was in the order of form III>form I>dihydrate, while form III was transformed to dihydrate more rapidly than form I, resulting in decrease of the dissolution rate. The solubilities of both anhydrates (form I and form III), calculated from the initial dissolution rate of each anhydrate, were 1.5--1.6 times that of the dihydrate. At the dose of 40 mg/body, there were no significant differences in the area under the curve (AUC) between forms; their AUCs were nearly equal to that of CZP solution using polyethyleneglycol 400. These findings suggested that most crystalline powder of each form administered at the low dose was rapidly dissolved in gastrointestinal (GI) fluid. On the other hand, for the dose of 200 mg/body, significant differences in plasma concentration--time curves of CZP among polymorphic forms and dihydrate were observed. The order of AUC values was form I>form III>dihydrate. The inconsistency between the order of initial dissolution rates and that of AUC values at the high dose may have been due to rapid transformation from form III to dihydrate in GI fluids.     

Comparison of physical and inhalation properties of spray-dried and micronized terbutaline sulphate.

Terbutaline sulphate particles, for use in dry powder inhaler formulations, were prepared by spray-drying, using a Büchi 190 mini spray dryer. Spray-drying conditions were chosen to allow the production of spray-dried terbutaline sulphate with a size similar to micronized terbutaline sulphate, that is to say about 2.9mum of volume mean diameter. The physical properties and in vitro inhalation behaviour of micronized and spray-dried terbutaline sulphate were compared. X-ray diffraction, DSC, SEM and laser size analysis were investigated. Spray-dying produced spherically shaped particles with amorphous structure. After blending with different lactoses, adhesion and aerodynamic properties were investigated. Evaluation of adhesion was carried out with a mechanical sieve and an Alpine air-jet sieve. The adhesion of terbutaline sulphate on the lactoses tested was lower in the case of the spray-dried drug. Aerodynamic evaluation of fine particle dose and emitted dose was conducted using a twin stage impactor. The emitted doses and the fine particle doses were higher with the spray-dried terbutaline sulphate. The Alpine air-jet sieve assays showed that there was a correlation between drug separation from a carrier by sieving and that obtained from longer in vitro deposition studies. There was a linear relationship between the adhesion characteristics and the fine particle dose.     

卡马西平致重症多形红斑型药疹

患者男,33岁,体重72Kg。因三叉神经痛口服卡马西平0.3g·d-1治疗。1周后患者发现躯干、四肢等处出现散在红斑,稍痒痛,继而口腔糜烂,眼结膜充血,同时伴畏寒、高热、头痛、咽痛、吞咽困难等。于1998年7月26日来医院就诊。患者既往体健,有青霉素、磺胺类药物及环丙沙星过敏史。入院时查体:T40℃,P80次·min-1,R18次·min-1,BP135/80mmHg(1mmHg=0.133Kpa)。系统检查未见异常。皮肤科情况:患者全身泛发钱币大小散在圆形水肿性红斑,边界清,部分红斑中央有水疱或大疱,约黄豆至蚕豆大小,疱壁松弛,尼氏征(+),少数已破溃糜烂,部分皮疹相互融合成片…     

卡马西平致过敏反应综合征一例

患者,女,68岁,因三叉神经痛口服卡马西平,剂量从0.1 g,bid逐渐增至0.2 g,bid,第16天出现颌下、颈部淋巴结肿大;第28天出现发热、皮疹;第35天停药热退;第39天胃与食道不适、吞咽困难、内痔出血,3d后好转;皮疹1月余消退,后遗皮肤色素沉着及淋巴结肿大。     

The effect of homogenization method on the properties of carbamazepine microparticles prepared by spray congealing

Abstract

The aim of this study was to investigate the influence of ultrasound and high-shear mixing on the properties of microparticles obtained by spray congealing. Dispersions containing 10% carbamazepine and 90% carrier Gelucire® 50/13 (w/w) were prepared using magnetic stirring, high-shear mixing, or ultrasound. Each preparation was made using hot-melt mixing spray congealing to obtain the microparticles. All microparticles presented a spherical shape with high encapsulation efficiency (>99%). High-shear mixing and ultrasound promoted a decrease in the size of microparticles (D₉₀) to 62.8?±?4.1?μm and 64.9?±?3.3?μm, respectively, while magnetic stirring produced microparticles with a size of 84.1?±?1.4?µm. The use of ultrasound led to microparticles with increased moisture content as identified through sorption isotherm studies. In addition, rheograms showed distinct rheological behaviour among different dispersion preparations. Therefore, the technique used to prepare dispersions for spray congealing can affect specific characteristics of the microparticles and should be controlled during the preparation.     

Stevens-Johnson syndrome induced by carbamazepine

Stevens-Johnson syndrome (SJS) is a mucocutaneous disorder induced by an immune-complex-mediated hypersensitivity reaction. Nearly half of cases are caused by a reaction to drugs or appear during viral infections and malignancies. A very few cases are caused by a bacterial infection (Streptococcus) or Mycoplasma pneumoniae. Graft versus host disease is another well-established cause, independent of drugs. No specific etiology has been identified in up to half of cases. We report a 54-year-old man with SJS induced by carbamazepine. Reported patient had prodromal symptoms like fever, headache and polyarthralgia, which preceded mucocutaneous lesions by 3 days. Physical examination on admission, revealed asthenic male with a temperature of 37.2 degrees C and generalized dermatitis with positive Nikolsky sign, large erosions of the palms and soles, onychomadesis, numerous oral and vermilion border of the lips erosions. The patient was administered systemic steroidotherapy and carbamazepine dose was gradually decreased and finally replaced with valproic acid and valproate sodium. During the hospitalization, temperature normalized and the skin lesions disappeared after 3 weeks of treatment.     

超临界快速膨胀法制备厚朴SCF-CO2萃取物超微颗粒及其溶出度和药动学考察

应用超临界快速膨胀技术 (RESS) 制备中药厚朴超临界CO₂ (SCF-CO₂) 萃取物超微颗粒,初步探讨该技术应用于中药领域的可行性和优越性。以平均粒径、厚朴酚 (magnolol,MN) 及和厚朴酚 (honokiol,HN) 的总酚含量为考察指标, 采用L₉(3³) 正交实验,对影响RESS制备厚朴SCF-CO₂萃取物超微颗粒的因素 (萃取温度、萃取压力、喷嘴孔径）进行优选,并通过扫描电镜、HPLC、结合溶出度及体内动物实验对粒子各评价指标进行考察。该法最佳制备条件为:萃取温度T = 50 ℃、萃取压力P = 25 MPa、喷嘴孔径d = 100 μm;此条件下得到灰白色粒子, 电镜下观察为不规则的片状或块状,平均粒径为4.7 μm,粒子中总酚含量为91.2%。在15%甲醇中90 min内厚朴SCF-CO₂萃取物超微颗粒的溶出度为14.77 mg·L⁻¹,显著高于厚朴SCF-CO₂萃取物原料粒子的溶出度6.37 mg·L⁻¹  (P < 0.01);两组大鼠分别灌胃原料粒子混悬液和RESS粒子混悬液后,于不同时间测定血药浓度,得HN和MN的平均血药浓度-时间曲线,采用WINNONLN软件计算求得药动学参数,对两组药动学参数进行t检验,结果表明RESS粒子中HN、MN的AUC_0−t值 [(5.41 ± 0.63) 和 (7.24 ± 0.83) mg·h·L⁻¹]和C_max值 [(2.31 ± 0.17) 和 (2.84 ± 0.21) mg·L⁻¹] 均显著高于原料粒子组中HN、MN的AUC_0−t值 [(4.23 ± 0.36) 和 (5.46 ± 0.57) mg·h·L⁻¹] 和C_max值 [(1.55 ± 0.22) 和 (2.35 ± 0.14) mg·L⁻¹] (P < 0.05)。RESS技术可用于厚朴SCF-CO₂萃取物超微粒子的制备,得到的粒子粒径小,分布均匀,其溶出度、AUC和C_max值均明显高于普通工艺制备的厚朴提取物粒子,且操作温度低、工艺流程简单、对环境无污染及无有机溶剂残留。
     

Inhibition of phenprocoumon anticoagulation by carbamazepine.

Carbamazepine inhibits warfarin and dicoumarol anticoagulation through induction of cytochrome P450-enzymes. Inhibition of phenprocoumon anticoagulation by carbamazepine has been supposed in some reviews, however, without hard empirical evidence. We report a patient who was anticoagulated with phenprocoumon in whom carbamazepine produced a dramatic increase in prothrombin time ratio (Quick). After discontinuation of carbamazepine, Quick-values returned to therapeutic levels. Valproate did not affect phenprocoumol's anticoagulant properties. The potentially hazardous carbamazepine-phenprocoumon interaction should be emphasized in reference drug manuals.     

Effect of off-bottom clearance on properties of pellets produced by melt pelletization

This study examines the influence of off-bottom clearance on size and size distribution of pellets produced during melt pelletization at different postmelt impeller speeds and binder concentrations using lactose and polyethylene glycol. Melt pelletization of lactose powder 450 M in an 8-liter highshear mixer, the floor of which was made of polytetrafluoroethylene (PTFE), was carried out with polyethylene glycol 3000 as the meltable binder. Erosion of the PTFE floor of the mixer occurred with time of use and this caused a change in the off-bottom clearance. The findings showed that with a wider clearance, the size distribution of pellets was wider and pellets were much larger. These changes were the results of changes in the mixing intensity and impact frequency of the mass in relation to the eddies formed within the off-bottom clearance. The changes were not associated with the reduction in the circulating material load by entrapment into the off-bottom clearance. In the melt pelletization process, the quality of product was higher if the clearance was kept to a minimum. The off-bottom clearance was best measured at the beginning of each pelletization run because the PTFE floor of the mixer was prone to erosion.     

The influence of relative humidity on the cohesion properties of micronized drugs used in inhalation therapy

The influence of relative humidity (RH) on the cohesion properties of three drugs: salbutamol sulphate (SS), triamcinolone acetonide (TAA), and disodium cromoglycate (DSCG) was investigated using the atomic force microscope (AFM) colloidal probe technique. Micronized drug particles were mounted in heat-sensitive epoxy resin for immobilization. Multiple AFM force-distance curves were conducted between each drug probe and the immobilized drug particulates at 15, 45, and 75% RH using Force-Volume imaging. Clear variations in the cohesion profile with respect to RH were observed for all three micronized drugs. The calculated force and energy of cohesion to separate either micronized SS or DSCG increased as humidity was raised from 15 to 75% RH, suggesting capillary forces become a dominating factor at elevated RH. In comparison, the separation force and energy for micronized TAA particles decreased with increased RH. This behavior may be attributed to long-range attractive electrostatic interactions, which were observed in the approach cycle of the AFM force-distance curves. These observations correlated well with previous aerosolization studies of the three micronized drugs.     

Physicochemical properties and X-ray structural studies of the trigonal polymorph of carbamazepine

The trigonal polymorph of carbamazepine (alpha-carbamazepine) was obtained by crystallization from a number of solvents. It was characterized by means of differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, X-ray power diffraction, thermal microscopy, and powder and intrinsic dissolution rates. The crystal and molecular structures were determined by single-crystal, three-dimensional X-ray analysis. A comparison is drawn between the physicochemical properties of the monoclinic (beta) and trigonal (alpha) forms. Structural features of carbamazepine occurring in these forms and in the acetone solvate are compared. Substantial differences were detected between the two polymorphic forms with regard to infrared and differential scanning calorimetry data, thermomicroscopical behavior, morphology, and molecular conformation.