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Medication errors: an analysis comparing PHICO's closed claims data and PHICO's Event Reporting Trending System (PERTS).

Clinical pharmacologists are all dedicated to improving the use of medications and decreasing medication errors and adverse drug reactions. However, quality improvement requires that some significant parameters of quality be categorized, measured, and tracked to provide benchmarks to which future data (performance) can be compared. One of the best ways to accumulate data on medication errors and adverse drug reactions is to look at medical malpractice data compiled by the insurance industry. Using data from PHICO insurance company, PHICO's Closed Claims Data, and PHICO's Event Reporting Trending System (PERTS), this article examines the significance and trends of the claims and events reported between 1996 and 1998. Those who misread history are doomed to repeat the mistakes of the past. From a quality improvement perspective, the categorization of the claims and events is useful for reengineering integrated medication delivery, particularly in a hospital setting, and for redesigning drug administration protocols on low therapeutic index medications and "high-risk" drugs. Demonstrable evidence of quality improvement is being required by state laws and by accreditation agencies. The state of Florida requires that quality improvement data be posted quarterly on the Web sites of the health care facilities. Other states have followed suit. The insurance industry is concerned with costs, and medication errors cost money. Even excluding costs of litigation, an adverse drug reaction may cost up to $2500 in hospital resources, and a preventable medication error may cost almost $4700. To monitor costs and assess risk, insurance companies want to know what errors are made and where the system has broken down, permitting the error to occur. Recording and evaluating reliable data on adverse drug events is the first step in improving the quality of pharmacotherapy and increasing patient safety. Cost savings and quality improvement evolve on parallel paths. The PHICO data provide an excellent opportunity to review information that typically would not be in the public domain. The events captured by PHICO are similar to the errors and "high-risk" drugs described in the literature, the U.S. Pharmacopeia's MedMARx Reporting System, and the Sentinel Event reporting system maintained by the Joint Commission for the Accreditation of Healthcare Organizations. The information in this report serves to alert clinicians to the possibility of adverse events when treating patients with the reported drugs, thus allowing for greater care in their use and closer monitoring. Moreover, when using high-risk drugs, patients should be well informed of known risks, dosage should be titrated slowly, and therapeutic drug monitoring and laboratory monitoring should be employed to optimize therapy and minimize adverse effects.

Adverse Drug Reaction Reporting Systems↗

The second international standard for vitamin D: crystalline vitamin D3.

This report was presented to the Subcommittee on Fat-Soluble Vitamins of the WHO Expert Committee on Biological Standardization in 1949 by the Vitamin D Sub-Committee of the Accessory Food Factors Committee of the Medical Research Council of Great Britain and formed the evidence on which the first-mentioned subcommittee based its recommendation of the adoption of crystalline vitamin D(3) as the International Standard for Vitamin D, replacing the solution of irradiated ergosterol which had been adopted as Standard in 1931.The Vitamin D Sub-Committee organized a collaborative assay in which 32 laboratories in seven countries participated. In addition to 29g of crystalline vitamin D(3) generously contributed by five firms, the following preparations were compared for vitamin D activity by biological tests on rats or chicks or both: the then current International Standard, a preparation of the purest calciferol obtainable, the British Standards Institution (BSI) Standard, the United States Pharmacopeia (USP) Reference Cod Liver Oil, and the Swedish provisional standard.Altogether 29 rat assays and 25 chick assays were carried out, and the results were subjected to standard methods of analysis. The BSI Standard and the pure calciferol were found less potent than the Old Standard (potency ratios: 0.916 and 0.933, respectively); and the New Standard may be slightly less potent (0.981), but it is more potent than the BSI Standard (1.071). The USP Reference Oil is less potent than the BSI Standard (0.949), the Old Standard (0.896), and the New Standard (0.886). The fiducial range is generally less than 10%, but even where it is greater, it is still satisfactory for a biological test.

Animals↗

THE INTERNATIONAL STANDARD FOR NYSTATIN.

At the request of a WHO Expert Committee on Biological Standardization, a batch of nystatin, comparable in purity to material used therapeutically, was submitted to an international collaborative study in nine laboratories in six countries. In this study the material was assayed by the plate diffusion method (and in one laboratory also by a turbidimetric method) against the United States Pharmacopeia Reference Preparation of Nystatin. On the basis of the results obtained the material has been established as the International Standard for Nystatin, and the International Unit of Nystatin is defined as the activity in 0.000333 mg of the International Standard.

Biological Assay↗

[Determination of total alkaloid in seedling bulbs of Fritillaria thunbergii Miq].

This paper reports the determination of total alkaloid in the seedling bulbs and cultivars of the traditional Chinese medicine Fritillaria thunbergii. The result shows that the content of total alkaloid reaches the standard value specified in Chinese Pharmacopeia, and thus is useful for further production of sexual propagation.

Alkaloids↗

Analysis of the hypericin and pseudohypericin content of commercially available St John's Wort preparations.

CONTEXT: The use of herbal medications and supplements has been growing worldwide with over four billion dollars a year spent on alternative medicines in the United States. St John's wort herbal preparations are generally standardized to "total hypericins" as a means of illustrating a degree of quality control to the consumer. This standardization has been based on a nonspecific method that overestimates and sums the two major naphthodianthrone compounds (hypericin and pseudohypericin) that are found in these products. OBJECTIVE: To use a more specific and sensitive method to accurately determine the total hypericin content (sum of hypericin and pseudohypericin) in commercially available St John's wort herbal preparations. DESIGN: The current standard method for determining the naphthodianthrone content is a spectrophotometric method specified in the United States Pharmacopeia. Compounds other than hypericin and pseudohypericin can contribute falsely to the naphthodianthrone concentration, reducing this methods specificity. SETTING: Fifty-four commercially available St John's wort products were purchased in Canada and the United States. MAIN OUTCOME MEASURES: A specific and sensitive liquid chromatographic method with fluorescent detection was used to specifically quantify the hypericin and pseudohypericin content in commercially purchased St John's wort products. RESULTS: Analysis revealed large variations in total naphthodianthrone content, with the percentage of label claim varying from 0% to 108.62% for capsules, and from 31.34% to 80.18% for tablets. The content of tinctures varied from zero to 118.58 microg/ml. Only two products were observed to have a total naphthodianthrone concentrations within 10% of their label claim. CONCLUSIONS: When the active or marker compounds in an herbal or alternative medicine have been identified, standardization is an important step to ensure consistency from batch to batch. However, consistency is not apparent between brands and most products have inaccurate label claims. On average, most labels overestimate the hypericin and pseudohypericin content by a factor of almost two.

Anthracenes↗

Comparison of micellar electrokinetic chromatography, liquid chromatography, and microbiologic assay for analysis of cephalexin in oral suspensions.

Two well-accepted methodologies, based on a microbiologic assay (MA) and liquid chromatography (LC), and a novel methodology using micellar electrokinetic chromatography (MEKC), were compared for the determination of cephalexin in commercially available and simulated samples of oral suspensions. The MA, described in the Brazilian Pharmacopeia, was performed with a strain of Staphylococcus aureus ATCC 6538 as the test organism, following the cylinder-plate method. The LC analysis followed the European Pharmacopoeia, 3rd Ed., and was used with minor modifications. The MEKC analysis was based on a previous work of the group. Estimates of the repeatability relative standard deviations of the MA, LC, and MEKC methods in the analysis of a commercial sample were 0.34, 0.42, and 0.37%, respectively. The recovery obtained with LC was 99.90 +/- 1.11%; for MEKC, it was 100.09 +/- 0.56%. Although the 3 methodologies were statistically equivalent for the determination of cephalexin in oral suspensions, MA gave suitable repeatability despite being nonspecific and time-consuming. MEKC provided faster analysis and higher column efficiency, whereas LC presented superior sensitivity. The results indicated that MEKC can be used as an alternative method to MA and LC in routine quality control laboratories.

Anti-Bacterial Agents↗

Spectrophotometric, spectrofluorimetric, and densitometric methods for the determination of indapamide.

Three sensitive spectrophotometric, spectrofluorimetric, and densitometric methods are described for the determination of indapamide. The first and second methods are based on the oxidative coupling reaction of indapamide with 3-methyl-2-benzothiazolinone hydrazone HCl (MBTH) in the presence of cerium(IV) ammonium sulfate in an acidic medium. The absorbance of the reaction product is measured at the lambdamax, 601 nm. With the same reaction, indapamide is determined by its quenching effect on the fluorescence of excess cerous ions at the emission lambdamax, 350 nm, and the excitation at lambdamax, 300 nm. The reaction conditions were optimized, and Beer's law was obeyed for indapamide at 1.2-9.6 microg/mL with mean recoveries of 99.92 +/- 0.83 and 99.97 +/- 1.11%, respectively. The third method, a stability-indicating densitometric assay, was developed for the determination of indapamide, using toluene-ethyl acetate-glacial acetic acid (69 + 30 + 1, v/v/v) as the developing system and scanning at the lambdamax, 242 nm, in the presence of the degradation product and related substance; for the indapamide concentration range of 0.6-6 microg/spot, the mean recovery was 99.73 +/- 0.71%. The proposed methods were successfully applied to the determination of indapamide in bulk powder and commercial tablets, and the results of the analysis agreed statistically with those obtained with the official method. Furthermore, the methods were validated according to the guidelines of the U.S. Pharmacopeia and also assessed by applying the standard additions technique.

Antihypertensive Agents↗

[Stability of protein to digestion in vitro].

OBJECTIVE: To establish test model of stability of different protein to digestion in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). METHODS: The component of SGF and SIF being from the United States Pharmacopeia, the stability of various proteins were tested. The concentration of protein in SGF/SIF was 0.5mg/ml. At intervals of 0s, 15s, 30s, 60s, 2min, 4min, 8min, 15min, 30min and 60min, the samples were taken out. According to the results of SDS-PAGE, the stability of various proteins to digestion in SGF/SIF was observed. RESULTS: The experiment showed that trypsin inhibitor from soybean, beta-lactoglobulin A from bovine milk and beta-lactoglobulin B from bovine milk were stable within 60min in SGF. Peanut lectin was digested within 8min. Most soybean lectin was digested within 8min, but the degraded fragments still existed. Ovalbumin, ovomucoid, BSA, soybean lipoxygenase and potato acid phosphatase were digested within 15s. The results in SGF were not consistent with the results in SIF. Trypsin inhibitor from soybean, beta lactoglobulin A from bovine milk, beta-lactoglobulin B from bovine milk, BSA, ovalbumin, ovomucoid, soybean lectin and peanut lectin were stable for 60min in SIF. The degraded fragments of soybean lipoxygenase and potato acid phospatase exited within 60min. CONCLUSION: Different proteins showed different stability to SGF/SIF. According to the difference, model of evaluating the stability of protein to SGF/SIF was established.

Drug Stability↗

Development and validation of a liquid chromatographic method for fexofenadine hydrochloride in capsules.

This paper describes the development and validation of a new, simple, fast, and sensitive liquid chromatographic method for the determination of the antihistamine fexofenadine. Although widely used in the treatment of allergic diseases, fexofenadine is not listed in any pharmacopeia, and there are few methods in the literature for its quantitation in pharmaceutical dosage forms. In this work, a LiChrospher 100 RP-18 (250 x 4.0 mm, 5 microm) column was used as the stationary phase, and acetonitrile-5mM ammonium acetate buffer (50 + 50, v/v) at pH 3.2 was the mobile phase. Through the evaluation of the analytical parameters, it was shown that the method is linear (r = 0.9999) at concentrations ranging from 20.0 to 80.0 microg/mL, precise (intraday relative standard deviation [RSD] values = 0.85, 0.40, and 0.81%; interday RSD = 0.77%), accurate (mean recovery = 99.05%), specific, and robust. The detection and quantitation limits are 0.3409 and 1.033 microg/mL, respectively. These low values show the good sensitivity of the proposed method.

Capsules↗

[Study on the relativity between cultivated varieties and quality of Radix Glehniae].

OBJECTIVE: To study the relation between different cultivated varieties and quality of Radix Glehniae. METHODS: Polysaccharide, imperatorin and extractives in different varieties were detected according to document and Chinese Pharmacopeia. RESULTS: Each content of soluble carbohydrate, rough polysaccharide, total carbohydrate, water extractives and alcohol extractives in Baitiao is significantly higher than that in other two varieties (P < 0. 05). The content of imperatorin is highest in Dahongpao P < 0.05). CONCLUSION: It is more effective for Baitiao to restrain humor immunity,cell immunity and the overgrowth of T and B cells. Dahongpao is dominani as sedative, spasmolytic and abti-asthmatic.

Apiaceae↗

A generalized plate method for estimating total aerobic microbial count.

The plate method outlined in Chapter 61: Microbial Limit Tests of the U.S. Pharmacopeia (USP 61) provides very specific guidance for assessing total aerobic bioburden in pharmaceutical articles. This methodology, while comprehensive, lacks the flexibility to be useful in all situations. By studying the plate method as a special case within a more general family of assays, the effects of each parameter in the guidance can be understood. Using a mathematical model to describe the plate counting procedure, a statistical framework for making more definitive statements about total aerobic bioburden is developed. Such a framework allows the laboratory scientist to adjust the USP 61 methods to satisfy specific practical constraints. In particular, it is shown that the plate method can be conducted, albeit with stricter acceptance criteria, using a test specimen quantity that is smaller than the 10 g or 10 mL prescribed in the guidance. Finally, the interpretation of results proffered by the guidance is re-examined within this statistical framework and shown to be overly aggressive.

Air Microbiology↗

[Study on experimental factors for extraction of alkaloids from Aconitum carmichaili].

OBJECTIVE: To determine the suitable conditions for extracting alkaloidals from Aconitum carmichaili. METHOD: Using methods in Chinese Pharmacopeia for determining yields of extraction, which include spectrometry and single-factor tests, we investigated vavious factors that would affect the extraction of alkaloids from Aconiti. RESULT: The suitable extractant was 85% ethanol, starting material was medium-size powder of aconiti, 10 times of the volume of the solvent was used in extraction for twice 1.75 h each time. The extraction yield was 1.21%, with a content of 0.33% alkaloids. CONCLUSION: Extraction conditions determined with single factor test was consistent and feasible.

Aconitum↗

[A history of the research department of the Severance Union Medical College].

The Research Department of the Severance Union Medical College was founded on November 4th, 1914. Drs. R. G. Mills, J. D. VanBuskirk and A. I. Ludlow were the co-founders of the department. The department aimed at investigating the medical problems of Koreans which originated from the difference of diet, customs and habits. The main fields of the research were divided into three: traditional medicine, diet of the Koreans, and special diseases in Korea. As to the research of the traditional medicine, Mills conducted extensive investigations on the drugs mentioned in the pharmacopeia of the traditional medical texts. His work included the translation of the medical texts into English, which unfortunately was not published, and the collection of thousands traditional drugs and botanical specimens. To the second field, VanBuskirk contributed much. His research was mainly focused on investigating the characteristics of Korean diet, finding out its problems, and recommending more balanced diet. The third field was the research of the diseases specific in Korea. The diseases caused by various parasites were the main targets of the research. At first, the Research Department was a laboratory where research was actually being carried out. But, its nature has been changed as each department became the center of research activities. The Research Department became a research promoting center which provides research funds for each department or individual researchers. The founding of the Research Department of the Severance Union Medical College marks a turning point in the history of SUMC in the sense that academic activities began to become more important in the missionary institute.

History, 20th Century↗

Patient-controlled analgesia safety issues.

Patient controlled analgesia (PCA) offers meaningful advantages over traditional analgesia. However, PCA medical errors with PCA can be dangerous and even fatal. Errors associated with patient controlled analgesia (PCA) therapy are described as are ways to minimize such errors. This report is based on data from the United States Pharmacopeia (USP) and Institute for Safe Medication practices (ISMP) Medication Errors Reporting Program. PCA by proxy, appropriate patients selection for PCA, patient monitoring, patient education, medication mix ups and practice related errors are discussed. Staff training is addressed. Methods to minimize errors associated with pump purchasing, PCA prrescribing, initiation, and monitoring are described. Recommendations for pharmaceutical manufacturers elated to PCA therapy are provided.

Analgesia, Patient-Controlled↗

[Bioequivalence in vitro evaluation of some antibacterial generic dosage forms].

In this work, bioequivalence between generic and corresponding original brand-name dosage forms of some antibacterial drugs, frequently prescribed in developing countries, have been examined using in vitro dissolution testing. For this purpose, tablet or hard capsule formulations of five active substances (amoxycillin, ampicillin, co-trimoxazole (sulphamethoxazole/trimethoprim), metronidazole and penicillin V) have been retained. For each active substance, batch samples of three generic and one test formulations have been submitted to the pharmaceutical quality control and dissolution testing. Results obtained have shown that all samples examined met the specifications of quality edited by the pharmacopeias. On the other hand, interchangeability between generic and corresponding test formulations should be possible since their dissolution profiles are superposables enough.

Anti-Bacterial Agents↗

Quality control validation for exogenous natural surfactant labeled with 99mTc.

OBJECTIVE: Exogenous natural surfactant (ENS) labeled with 99mTc shows an elevated lung specificity allowing the acquisition of high-quality images for ventilation scintigraphy. METHODS: The methods for 99mTc-ENS quality control (physical properties, pH determination, radiochemical studies, and biologic studies) were evaluated and validated. RESULTS: The physical properties of the nonradioactive precursor and of the radiopharmaceutical were analyzed as general descriptors of the product. The pH of the radiopharmaceutical was determined by using pH test papers, a method described and validated in the United States Pharmacopeia. Chromatographic studies performed using the acetone/Whatman-1 paper system were validated as a method to evaluate the radiochemical purity of the 99mTc-ENS. Biodistribution studies on rats after intratracheal administration were validated as a method to estimate the radiopharmaceutical biodistribution in humans. CONCLUSION: The proposed method for 99mTc-ENS quality control studies and stability studies was evaluated and validated following international standards.

Animals↗

[In vitro and in vivo biopharmaceutical evaluation of lorazepam commercial tablets].

OBJECTIVE: Lorazepam (LZM) is a broadly used tranquillizer for the treatment of anxiety. Tavor is one of the most diffused registered drug products containing LZM. Lots of generic drug products containing LZM have been registered in Italy by several pharmaceutical groups and are present in the Italian market. Due to the wide medical prescription of products containing LZM, it seemed interesting, from a technological and biopharmaceutical point of view, to perform a comparative bioequivalence evaluation of a trade marked and generic tablet formulations containing LZM available in the Italian market. MATERIALS AND METHODS: The trial vas carried out on four preparations, including Tavor (1 mg) as reference product and three generics named A, B and C. In vitro technological parameters (dissolution, uniformity of content, uniformity of weight) and in vivo (pharmacokinetic on rabbit) studies were performed. RESULTS: All the examined brands passed technological tests according the European Pharmacopeia 5th ed. and USP25. Tavor ensures a faster dissolution behaviour than the tree generics in vitro. All the pharmacokinetic parameters were within the prescriptions of EMEA, even if the reference product showed the highest values of AUC0-infinity and of Cmax. CONCLUSIONS: Obtained results show that Tavor ensures a faster dissolution behaviour than the tree generics in vitro. Moreover, considering the pharmacokinetic data, it is possible to suppose that the generics B and C are not able to provide the same therapeutic effect as the reference product.

Analysis of Variance↗

Validation of UV spectrophotometric and nonaqueous titration methods for the determination of carvedilol in pharmaceutical formulations.

Ultraviolet (UV) spectrophotometric and nonaqueous volumetric methods are described for the determination of carvedilol in pharmaceutical formulations. Linearity, precision, and accuracy were evaluated according to the validation guidelines of the International Conference on Harmonization and the United States Pharmacopeia for both methods. The UV spectrophotometric procedure was performed in ethanol at 244 nm. Good linearity was obtained between 2 and 7 microg/mL with a correlation coefficient of 0.9999. The intra- and interday precision values were <2% for all samples analyzed. The accuracy, determined from recovery studies, was between 97.5 and 102.2%. The other procedure was based on the volumetric quantitation of carvedilol in a nonaqueous medium with 0.01 M perchloric acid and 1% violet crystal as the indicator. The validation of the volumetric method yielded good results that included linearity (r of > 0.999), precision (relative standard deviations of <2% for intra- and interday precision), and accuracy (96.4-102.4%). The methods were applied to tablets and compounded capsules. Statistical analysis by analysis of variance showed no significant difference between the results obtained by the proposed methods.

Capsules↗