Stability of alprazolam, chloroquine phosphate, cisapride, enalapril maleate, and hydralazine hydrochloride in extemporaneously compounded oral liquids

The stability of five drugs commonly prescribed for use in oral liquid dosage forms but not commercially available as such was studied. Alprazolam 1 mg/mL, chloroquine phosphate 15 mg/mL, cisapride 1 mg/mL, enalapril maleate 1 mg/mL, and hydralazine hydrochloride 4 mg/mL were each prepared in a 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories), a 1:1 mixture of Ora-Sweet SF and Ora-Plus, and cherry syrup and placed in 120-mL amber clear polyethylene terephthalate bottles. Three bottles of each liquid were stored at 5 degrees C and three at 25 degrees C, all in the dark. Samples were taken initially and at various times up to 60 days for analysis by high-performance liquid chromatography and assessment of appearance and odor; pH was measured. A mean of at least 91% of the initial drug concentration was retained for 60 days in the alprazolam, chloroquine phosphate, cisapride, and enalapril maleate liquids. The hydralazine hydrochloride liquids retained more than 90% of the initial concentration for only one day at 5 degrees C when prepared with Ora-Sweet-Ora-Plus and two days when prepared with Ora-Sweet SF-Ora-Plus and for less than a day in these preparations at 25 degrees C and in cherry syrup at 5 and 25 degrees C. No substantial changes in the appearance, odor, or pH of any liquid were observed. Alprazolam 1 mg/mL, chloroquine phosphate 15 mg/mL, cisapride 1 mg/mL, and enalapril maleate 1 mg/mL were stable in three extemporaneously compounded oral liquids for 60 days at 5 and 25 degrees C; hydralazine hydrochloride 4 mg/mL was stable at 5 degrees C for one day in Ora-Sweet-Ora Plus and for two days in Ora-Sweet SF-Ora-Plus.     

Stability of vancomycin in an extemporaneously compounded ophthalmic solution

The stability of vancomycin 31 mg/mL (as the hydrochloride) in an artificial tears solution at -10, 4, 25, and 40 degrees C was studied. Vancomycin power was reconstituted with sterile water for injection to a concentration of 50 mg/mL. Artificial tears solution containing 0.3% hydroxypropyl methylcellulose, 0.1% dextran 70, 0.01% benzalkonium chloride, and 0.05% edetate disodium was used to produce a final concentration of 31 mg/mL. Triplicate solutions for each storage temperature and sampling time were prepared. The solutions were stored at -10, 4, 25, and 40 degrees C. Samples were taken initially and at 3, 7, 10, 21, 30, 45, and 60 days for visual inspection and analysis by high-performance liquid chromatography. All solutions remained clear and colorless at -10, 4, and 25 degrees C throughout the study period. By day 3, crystalline particles formed in the solutions stored at 40 degrees C. No substantial change in pH was observed at any time. At -10 degrees C, the solutions retained more than 90% of their initial vancomycin concentrations throughout the study period. The solutions retained a mean of at least 90% of the initial drug concentration for 21 days at 4 degrees C and for 7 days at 25 degrees C. For the solutions stored at 25 or 40 degrees C, less than 85% of the initial vancomycin concentration remained after 10 and 3 days, respectively. Vancomycin 31 mg/mL (as the hydrochloride) in an artificial tears solution was stable for 45 days at -10 degrees C, 10 days at 4 degrees C, and 7 days at 25 degrees C in the tears solution's original container.     

Solitary scapula mass: atypical presentation of esophageal adenocarcinoma

The stability of adenosine in various diluents in polypropylene syringes and polyvinyl chloride (PVC) bags at three temperatures was studied. Portions of pooled undiluted adenosine infusion (3 mg/ mL) were stored in 60-mL capped syringes, 20 for each storage condition. Adenosine infusions were prepared by mixing adenosine with 5% dextrose injection, 0.9% sodium chloride injection, lactated Ringer's injection, or 5% dextrose and lactated Ringer's injection to produce a concentration of 0.75 mg/mL. Samples of each infusion were stored in 60-mL capped syringes and 50-mL bags, 20 syringes and 20 bags for each storage condition. Syringes and bags were stored in the dark at 25, 5, and -15 degrees C. At various sampling times, three syringes and three bags of each infusion were removed for visual inspection, pH measurement, and high-performance liquid chromatographic analysis. At 10 and 16 days, fungal growth at 25 degrees C was suspected in the infusions prepared with 5% dextrose injection. For all other samples, there was no evidence of precipitation or change in pH. The concentration of adenosine remained constant in all samples at all storage conditions. Adenosine 3 mg/mL was stable in polypropylene syringes for 7 days at 25 degrees C, 14 days at 5 degrees C, and 28 days at -15 degrees C; adenosine 0.75 mg/ mL in 0.9% sodium chloride injection and in 5% dextrose injection was stable in polypropylene syringes and PVC bags for 16 days at 25, 5, and -15 degrees C; and adenosine 0.75 mg/mL in lactated Ringer's injection and in 5% dextrose and lactated Ringer's injection was stable in syringes and bags for 14 days at 25, 5, and -15 degrees C.     

Stability of enalapril maleate in three extemporaneously prepared oral liquids

The stability of enalapril 1 mg/mL (as the maleate) in deionized water, citrate buffer solution, and a sweetened suspending agent at two temperatures was studied. Twenty enalapril 10-mg tablets were crushed to a powder. Deionized water, citrate buffer solution, or sweetened vehicle was added to produce three 200-mL batches of each liquid; the expected final concentration of enalapril in each was 1 mg/mL. Each formulation was stored in 10 60-mL bottles, 5 of which were stored at 4 degrees C and 5 at 25 degrees C. Samples were collected on days 0, 7, 14, 28, 42, 56, 70, and 91 for visual inspection and analysis by high-performance liquid chromatography; pH was measured at each sampling time as well. The mean concentration of enalapril in the three liquids at 4 degrees C was > 94% of the initial concentration throughout the 91-day study period. At 25 degrees C, the mean concentration of enalapril was > 90% for 56 days and > 92% for 91 days in both citrate buffer solution and sweetened vehicle. The pH of the liquid prepared with deionized water and stored at 25 degrees C decreased by 2.0 pH units. Enalapril 1 mg/mL (as the maleate) in three extemporaneously compounded oral liquids was stable for 91 days at 4 and 25 degrees C with the exception of enalapril in deionized water, which was stable for only 56 days at 25 degrees C.     

Reduced progression-free survival in elderly patients receiving intensification with autologous peripheral blood stem cell reinfusion for multiple myeloma

The stability of cisatracurium besylate was studied. Cisatracurium (as besylate) 2 mg/mL in 5- and 10-mL unopened vials and 10 mg/mL in 20-mL unopened vials, as well as 3 mL of solution from additional 2-mg/mL vials, repackaged in 3-mL sealed plastic syringes, was stored at 4 and 23 degrees C in the dark and in normal fluorescent room light. Admixtures of cisatracurium (as besylate) 0.1, 2, or 5 mg/mL in polyvinyl chloride (PVC) minibags of 5% dextrose injection or 0.9% sodium chloride injection were stored at 4 and 23 degrees C in normal fluorescent room light. Triplicate samples for each storage condition were taken initially and at 1, 3, 5, 7, 14, 21, and 30 days; samples from vials were also removed at 45 and 90 days. Solutions were stored in sterile vials at -70 degrees C and then thawed at room temperature before analysis of chemical stability by high-performance liquid chromatography. Physical stability was assessed as well. Cisatracurium besylate was physically stable in all samples throughout the study. Cisatracurium (as besylate) 2 mg/mL exhibited drug losses at 23 degrees C in vials at 45 days and in syringes at 30 days. Cisatracurium (as besylate) 0.1, 2, and 5 mg/mL in 5% dextrose injection and in 0.9% sodium chloride injection was stable for at least 30 days at 4 degrees C, but substantial drug losses occurred at 23 degrees C. Admixtures prepared with cisatracurium (as besylate) 0.1 mg/mL and with 5% dextrose injection exhibited the greatest losses. Cisatracurium besylate was stable in most samples for at least 30 days at 4 and 23 degrees C; admixtures containing cisatracurium (as besylate) 0.1 or 2 mg/mL exhibited substantial drug loss at 23 degrees C.     

Stability of ondansetron hydrochloride and 12 medications in plastic syringes

The stability and compatibility of ondansetron hydrochloride with neostigmine methylsulfate, naloxone hydrochloride, midazolam hydrochloride, fentanyl citrate, alfentanil hydrochloride, atropine sulfate, morphine sulfate, meperidine hydrochloride, propofol, droperidol, metoclopramide monohydrochloride, and glycopyrrolate were studied. Ondansetron 1.33 or 1.0 mg/mL was combined with 0.9% sodium chloride injection and each of the 12 drugs in duplicate in plastic syringes (or glass for propofol). The syringes were stored at 21.8-23.4 or 4 degrees C in the dark, except for those containing propofol, which were stored at ambient temperature. Samples were removed at 0, 4, 8, and 24 hours for analysis by high-performance liquid chromatography and pH measurement; the propofol-containing samples were removed at 0, 1, 2, and 4 hours. Syringes were visually assessed for color and clarity, and particulate content was measured with a particle counter at the end of the study period. All solutions containing ondansetron retained more than 90% of their initial ondansetron concentration. Solutions containing each of the other drugs except droperidol retained more than 90% of their initial concentration of these drugs. The solutions containing droperidol retained more than 90% of their initial droperidol concentration for up to eight hours at ambient temperature but precipitated quickly at 4 degrees C. In combinations of ondansetron 1.33 or 1.0 mg/mL and 10 of 12 drugs, all drugs were stable for 24 hours in plastic syringes at 23 and 4 degrees C; ondansetron hydrochloride 1.0 mg/mL and propofol 1.0 and 5.0 mg/mL in admixtures were stable for 4 hours, and droperidol on its own and combined with ondansetron 1.0 mg/mL was stable for no more than 8 hours at ambient temperature.     

Microbial inhibitory properties and stability of topotecan hydrochloride injection

The viability of five microorganisms in topotecan 1 mg/mL (as the hydrochloride salt) in sterile water and the stability of the drug were studied. Duplicate portions of topotecan 1 mg/mL were inoculated with Escherichia coli. The process was repeated for Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Aspergillus niger. Samples were removed from each solution initially and after 6, 16, and 24 hours and 3, 7, 14, 21, and 28 days of incubation at 20-25 degrees C. To test stability, vials of reconstituted topotecan hydrochloride injection were stored at each of three temperatures--5, 25, and 30 degrees C--and other vials were used for time zero analysis. For each temperature, vials were removed at 1, 7, and 14 days and the remaining vials at 28 days for analysis by high-performance liquid chromatography and for visual and pH assessment. P. aeruginosa, S. aureus, and E. coli lost viability at 16 hours, 24 hours, and 28 days, respectively. C. albicans and A. niger did not lose viability, but their numbers did not grow. No differences in color or clarity were observed, and pH was constant. In all solutions, the topotecan concentration was > 98% of the initial concentration. Topotecan 1 mg/mL in sterile water stored at 20-25 degrees C for up t 28 days did not support growth of the five microorganisms studied; in solutions stored at 5, 25, or 30 degrees C for up to 28 days, topotecan 1 mg/mL remained stable.     

Stability and compatibility of granisetron hydrochloride in i.v. solutions and oral liquids and during simulated Y-site injection with selected drugs

The stability and compatibility of granisetron hydrochloride in common i.v. fluids and oral liquids and during simulated Y-site injection with selected drugs were studied. One milliliter of solution containing granisetron 1 mg (as the hydrochloride salt) was added to 50 mL of 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose and 0.45% sodium chloride injection, or 0.9% sodium chloride injection in polyvinyl chloride (PVC) bags and to 5 mL of 5% dextrose injection, 0.9% sodium chloride injection, or bacteriostatic water for injection in polypropylene syringes and stored at room temperature (20 degrees C) for 24 hours. One milliliter of the granisetron hydrochloride injection was added to 50 mL of apple juice, orange juice, cola, or an electrolyte replacement solution and stored for 60 minutes at room temperature. Twenty-nine drugs were mixed with the granisetron hydrochloride injection in 0.9% sodium chloride injection in volumes simulating Y-site injection and stored at room temperature. Finally, dexamethasone sodium phosphate injection 0.5 mL and 1 mL of the granisetron hydrochloride injection were added to 50 mL of 0.9% sodium chloride injection in a PVC bag and stored for 60 minutes. Drug concentrations were determined by high-performance liquid chromatography, and color, clarity, and pH were evaluated. Granisetron hydrochloride was stable in and compatible with all the i.v. solutions and oral liquids. Neither granisetron nor any of the drugs it was tested with during simulated Y-site injection showed any physical changes except for a slight Tyndall effect in the granisetron hydrochloride-doxorubicin hydrochloride combination; all the drugs retained at least 96% of initial concentrations. Granisetron and dexamethasone sodium phosphate were stable and compatible in the admixture. Granisetron 1 mg (as the hydrochloride salt) was stable for 24 hours in four i.v. infusion fluids in PVC bags and in 5% dextrose injection, 0.9% sodium chloride injection, and bacteriostatic water for injection in polypropylene syringes; for 1 hour in four oral liquids; for 4 hours in the presence of each of 29 drugs during simulated Y-site injection; and for 1 hour when mixed with dexamethasone sodium phosphate in 0.9% sodium chloride injection in a PVC bag.     

Stability of vinblastine sulphate in 0.9% sodium chloride in polypropylene syringes

The stability of vinblastine sulphate diluted in 0.9% sodium chloride solution for injection was studied. Vinblastine sulphate was reconstituted with 0.9% sodium chloride solution for injection to concentration of 1.0 mg/mL and stored in polypropylene syringes at 25 degrees C +/- 1 degree C protected from light. On different days the solutions were analysed and the vinblastine concentration was determined by high-performance liquid chromatography. An high-pressure liquid chromatographic method is described for the quantitative determination of vinblastine in the presence of its degradation products. The degradation of vinblastine was studied by examining the percentage changes from the theoretical concentrations for each solution. The results of these studies indicate that vinblastine solutions in 0.9% sodium chloride solution for injection (1 mg/mL) in polypropylene syringes at 25 degrees C +/- 1 degree C protected from light are stable for up to one month.     

Compatibility of ondansetron hydrochloride with meperidine hydrochloride for combined administration

OBJECTIVE: To determine the physical compatibility and chemical stability of ondansetron hydrochloride 0.1 and 1 mg/mL with meperidine hydrochloride 4 mg/mL admixed in NaCl 0.9% injection USP. DESIGN: Triplicate test solutions of the drugs in NaCl 0.9% injection USP were prepared and stored at 4, 22, and 32 degrees C. Samples were removed initially and at various time points over 31 days and were stored at -70 degrees C until they were analyzed. Physical compatibility was assessed by measuring solution turbidity with a color-correcting turbidimeter and particle content with a light-obscuration particle sizer/counter, as well as by visual assessment. Chemical stability of the drugs was determined using a stability-indicating HPLC analytic method. Duplicate determinations were performed on each sample to measure the concentration of each drug. RESULTS: All admixtures were found to exhibit no visual or subvisual changes of consequence in turbidity or particle content at all observation points. Further, little or no loss of any of the drugs occurred in any concentration throughout the study. CONCLUSIONS: The physical compatibility and chemical stability of ondansetron hydrochloride with meperidine hydrochloride under the conditions of this study have been established for 7 days at 32 degrees C and 31 days at 4 and 22 degrees C.     

Stability of mycophenolate mofetil in an extemporaneously compounded oral liquid

The stability of mycophenolate mofetil in an extemporaneously prepared 100-mg/mL oral liquid was studied. The contents of 80 250-mg capsules of mycophenolate mofetil were combined with sterile water for irrigation and cherry-flavored syrup to produce 200 mL of suspension. Six 1-mL samples were analyzed immediately, and the rest of the suspension was poured into 12 2-oz amber polyethylene terephthalate [corrected] G(PETG) bottles; six bottles were stored at 23-25 degrees C and six at 2-8 degrees C. Samples were removed on days 14, 21, 28, 35, 49, 63, 92, and 121 for analysis by high-performance liquid chromatography; pH was measured initially and at each sampling time. The pH of the suspension was initially 6.1 and remained unchanged throughout the study. The suspension retained more than 90% of its initial drug concentration for 121 days at 23-25 and 2-8 degrees C. There was no detectable change in color or odor and no visible microbial growth in any sample. Mycophenolate mofetil in a 100-mg/mL oral liquid prepared with cherry-flavored vehicle and stored in amber PETG bottles was stable for 121 days at 23-25 and 2-8 degrees C.     

Stability of cidofovir in 0.9% sodium chloride injection and in 5% dextrose injection

The stability of cidofovir in i.v. admixtures under refrigerator and room temperature conditions was studied. Admixtures of cidofovir 0.21 and 8.12 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection and of 0.085 and 3.51 mg/mL in 5% dextrose and 0.45% sodium chloride injection were prepared in triplicate in polyvinyl chloride (PVC) or polyethylene-polypropylene containers and i.v. administration sets and stored for 24 hours at 2-8 or 30 degrees C. The lower concentration of cidofovir corresponded to an assumed dose of 0.5 mg/kg for a 40-kg patient, and the higher concentration to an assumed dose of 10 mg/kg for a 100-kg patient. Samples were removed at 0 and 24 hours and analyzed for cidofovir concentration by high-performance liquid chromatography. Physical compatibility was also studied. The stability of cidofovir in 0.9% sodium chloride injection and in 5% dextrose injection at low- and high-dose concentrations was unaffected by storage at either temperature. All admixtures were clear, colorless, and free of visible particles or precipitation. There were no substantial changes in pH or number of particles of > or = 10 microns in diameter. Cidofovir 0.21 and 0.12 mg/mL was stable in 0.9% sodium chloride injection and 5% dextrose injection in PVC and polyethylene-polypropylene containers and i.v. administration sets for up to 24 hours at 2-8 and 30 degrees C. Cidofovir was compatible with the injectable solutions studied.     

Stability of thiopental sodium and propofol in polypropylene syringes at 23 and 4 degrees C

The stability of thiopental sodium and propofol in an admixture stored in polypropylene syringes at room temperature and under refrigeration was studied. Propofol injection 10 mg/ mL and thiopental sodium 25 mg/mL were mixed to final concentrations of 5 and 12.5 mg/mL, respectively. The admixture was put into 60-mL polypropylene syringes, and two syringes were stored at 23 degrees C and two at 4 degrees C. For solutions stored at 23 degrees C, samples were taken at 0, 4, 8, 24, 48, 72, 120, 168, 216, 240, and 264 hours, and for samples stored at 4 degrees C, samples were taken at 0, 4, 8, 24, 48, 72, 120, 168, 216, and 312 hours. Drug concentrations were determined by high-performance liquid chromatography. Thiopental sodium and propofol retained > 90% of their initial concentrations for up to 312 hours at 4 degrees C. At 23 degrees C, > 90% of the initial concentration was retained by propofol for up to 120 hours and by thiopental sodium for up to 240 hours. No visual changes or significant change in pH occurred in any sample. When mixed and stored in polypropylene syringes, propofol 5 mg/mL and thiopental sodium 12.5 mg/mL were stable for up to 312 hours at 4 degrees C and for up to 120 hours at 23 degrees C.     

Solubilization and stabilization of an anti-HIV thiocarbamate, NSC 629243, for parenteral delivery, using extemporaneous emulsions

The O-alkyl-N-aryl thiocarbamate, I, (2-chloro-5-[[(1-methyl-ethoxy)thioxomethyl]amino]benzoic acid, 1-methylethylester, NSC 629243, also known as Uniroyal Jr.) is an experimental anti-HIV drug with very low water solubility (1.5 micrograms/mL). Early clinical studies required an injectable solution at approximately 15 mg/mL, representing a solubility increase of approximately 10(4)-fold. Adequate solubilization of this hydrophobic drug was achieved in 20% lipid emulsions. Extemporaneous emulsions were prepared by adding a concentrated drug solution to a commercially available parenteral emulsion. Various methods of preparation to minimize drug precipitation during its addition and enhance redissolution of precipitated drug were evaluated. The stability and mechanism(s) of decomposition of NSC 629243 in both 20% lipid emulsions and in natural oil vehicles were examined. In lipid emulsions, the shelf life at 25 degrees C varied from 1 to > 10 weeks, depending on the extent to which air was excluded from the preparation. The shelf life of 50 mg/mL solutions in natural oils at 25 degrees C varied from < 1 to > 100 days depending on the oil and its supplier. A qualitative correlation was found between the initial rate of oxidation and the peroxide concentration in the oil. The primary degradation product in both systems was shown to be a disulfide dimer, II, formed via oxidation. Oxidation was inhibited by vacuum-sealing of emulsion formulations or incorporation of an oil-soluble thiol, thioglycolic acid (TGA), into oil formulations. TGA may inhibit oxidation by consuming free radicals or peroxide initiators or by reacting with the disulfide, II, to regenerate the starting drug.     

Influence of procainamide on sodium and potassium exchange and permeabilities in cultured human cells

The effects of quinidine and temperature on Na influx and contraction frequency of synchronously contracting rat myocardial cells in monolayer cultures were studied. Quinidine (10(-6) M to 10(-1) M) produced a prompt reduction in Na influx, maximum after 30 seconds of exposure, and dose-dependent along a sigmoid log dose-response curve. At 37 degrees C, Na influx (mumol/10(11) cells per sec) decreased from 30.19 to 24.70 (P less than 0.001) and 10.49 (P less than 0.001) on exposure to quinidine, 10(-6) and 10(-2) M, respectively. Simultaneously the contraction frequency decreased from a control of 120/min to 105/min and 48/min with 10(-6) M and 5 X 10(-4) M quinidine. At higher concentrations spontaneous contractions ceased. The effects on Na influx and contraction were reversible by washing the cells free of the drug (30 seconds). A temperature-dependent decrease in the Na influx between 37 degrees C and 22 degrees C also induced a decrease in contraction frequency. Between 25 degrees C and 35 degrees C the Q10 values for Na influx and contraction frequency were 2.41 and 2.44 respectively. Under all conditions tested there was a constant linear relationship (r = 0.98) between Na influx and contraction frequency for all values of Na influx greater than 11.82 mumol/10(11) cells per sec. Na influx and contraction frequency were insensitive to tetrodotoxin (10(-5) g/ml) but very sensitive to verapamil and to changes in extracellular Na. Quinidine affected only the verapamil-sensitive Na influx. The results indicate a close relationship between verapamil-sensitive inward Na movement and automaticity in these cells and demonstrate that the quinidine-induced changes in automaticity are closely linked to the effect on Na influx.     

Bacillus stearothermophilus sporulation response to different composition media

To evaluate the effectiveness of 11 commonly used ingredients to improve Bacillus stearothermophilus ATCC 7953 sporulation, with high spore yields in a short period of incubation, 32 composition media were set up by a fractional factorial 2IV11-6 design at two levels: D-glucose (0.018-0.25%), L-glutamic acid (0.040-0.10%), yeast extract (0.050-0.40%), peptone (0.30-0.50%), sodium chloride (0.001-1.0%), magnesium sulfate (0.001-0.20%), ammonium phosphate (0.010-0.035%), potassium phosphate monobasic (0.050-0.25%), calcium chloride (0.001-0.05%), ferrous sulfate (0.0003-0.002%), manganese sulfate (0.001-0.50%). The largest variation on Log10 CFU response took place due to sodium chloride main effect, by changing it from low to high levels. Magnesium sulfate, calcium chloride, and ferrous sulfate were split and exerted no detectable main effect influence on sporulation. Setting up two 16 runs for sodium chloride effect, in each of which the remainder levels were kept constant, other components contribution was studied. At low sodium chloride, best average 7.25 Log10 CFU yielded by fastening yeast extract and peptone at high level, and remainders at low level. Considering high level of sodium chloride, peptone, yeast extract and ammonium phosphate kept at high level and remainders at low level confirmed the best sporulation yield. Adjusted models evidenced a strong influence of joint yeast/peptone effect, associated to ammonium phosphate contributing positively. The reduced incubation period from 15 days to 3-6 days at 62 degrees C was attained for all 32 experimental runs.     

Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group

BACKGROUND: Donepezil hydrochloride (Aricept) is a selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer disease. This phase 3 study was 1 of 2 pivotal trials undertaken to establish the efficacy and safety of using donepezil in patients with mild to moderately severe Alzheimer disease. OBJECTIVES: To further examine the efficacy and safety of using donepezil in the treatment of patients with mild to moderately severe Alzheimer disease. To examine the relationships between plasma donepezil concentrations, inhibition of red blood cell acetylcholinesterase activity, and clinical response. METHODS: This was a 12-week, double-blind, placebo-controlled, parallel-group trial with a 3-week single-blind washout. Outpatients at 23 centers in the United States were randomized to receive placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride (5 mg/d during week 1 then 10 mg/d thereafter) administered once daily at bedtime. Primary efficacy was measured using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change including caregiver information (CIBIC plus). RESULTS: A total of 468 patients entered the study, more than 97% of whom were included in the intention-to-treat (end point) analyses. The use of donepezil produced statistically significant improvements in ADAS-cog, CIBIC plus, and Mini-Mental State Examination scores, relative to placebo. The mean drug-placebo differences, at end point, for the groups receiving 5 mg/d and 10 mg/d of donepezil hydrochloride were, respectively, 2.5 and 3.1 units for ADAS-cog (P<.001); 0.3 and 0.4 units for CIBIC plus (P< or =.008); and 1.0 and 1.3 units for Mini-Mental State Examination (P< or =.004). On the CIBIC plus scale, 32% and 38% of patients, respectively, treated with 5 mg/d and 10 mg/d of donepezil hydrochloride demonstrated clinical improvement (a score of 1, 2, or 3) compared with placebo (18%). The mean (+/-SEM) donepezil plasma concentrations at study end point were 25.9 +/- 0.7 ng/mL and 50.6 +/- 1.9 ng/mL in the groups receiving dosages of 5 mg/d and 10 mg/d, respectively. Corresponding mean (+/-SEM) percentages of inhibition of red blood cell acetylcholinesterase activity were 63.9% +/- 0.9% and 74.7% +/- 1.2% for these 2 dosages, respectively. There was a statistically significant positive correlation between plasma concentrations of donepezil and acetylcholinesterase inhibition; the EC50 (50% effect) was obtained at a concentration of 15.6 ng/mL. A plateau of inhibition (80%-90%) was reached at plasma donepezil concentrations higher than 50 ng/mL. The correlations between plasma drug concentrations and both ADAS-cog (P<.001) and CIBIC plus (P = .006) were also statistically significant, as were the correlations between red blood cell acetylcholinesterase inhibition and change in ADAS-cog (P<.001) and CIBIC plus (P = .005). The incidence of treatment-emergent adverse events with both dosages of donepezil (68%-78%) was comparable with that observed with placebo (69%). The use of 10 mg/d of donepezil hydrochloride was associated with transient mild nausea, insomnia, and diarrhea. There were no treatment-emergent clinically significant changes in vital signs or clinical laboratory test results. More important, the use of donepezil was not associated with the hepatotoxic effects observed with acridine-based cholinesterase inhibitors. CONCLUSION: Donepezil hydrochloride (5 and 10 mg) administered once daily is a well-tolerated and efficacious agent for treating the symptoms of mild to moderately severe Alzheimer disease.     

复合添加剂对交直流叠加电解精炼铜的影响

以氯化钾、明胶和硫脲为基础添加剂,复配聚丙烯酰胺、十二烷基苯磺酸钠、糖精和添加剂A中的一种或几种制得一系列复合添加剂,研究其对交直流叠加电解精炼铜的影响,并对复合添加剂的作用机理进行简单探讨。结果表明:自制复合添加剂均能不同程度的改善阴极铜质量,添加剂Ⅷ(含硫脲5 mg/L、聚丙烯酰胺10 mg/L和添加剂A 0.6 mL/L)和Ⅹ(含氯化钾10 mg/L、硫脲5 mg/L、明胶6 mg/L和添加剂A 0.6 mL/L)是两种作用效果较好的复合添加剂,可以明显改善阴极铜质量,有望成为未来铜电解精炼工艺中的新型复合添加剂。