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Utility of an online medication-error-reporting system.

PURPOSE: The utility of an online medication-error-reporting program was evaluated. METHODS: A survey regarding the utility of Medmarx was developed and mailed to 550 hospitals and health systems that used the medication-error-reporting program. Primary contact persons were identified and asked to gather and report the necessary information to adequately characterize medication-error reporting in their institution before and after implementing the Medmarx system. Potential respondents were contacted four times during the survey period by the United States Pharmacopeia. RESULTS: Of the 550 surveys sent, 200 were returned and 25 were undeliverable, resulting in a response rate of 38%. The average number of medication errors reported internally increased twofold after the adoption of the Medmarx system. Pharmacy departments were most often reported as responsible for medication-safety oversight activities after Medmarx implementation. Most facilities (94%) generated reports from the medication-error database, and 75% used this information to identify 7.0+/-8.1 opportunities to improve their medication-use system annually. Most respondents believed that Medmarx played an integral role in preparing their facility for Joint Commission accreditation surveys (65%), provided a tool for root-cause analysis (71%), and helped identify problems in the medication-use process (85%). The annual costs of the subscription and staff time required to use the system was estimated to be 16,756 dollars+/-21,108 dollars. Sixty-six percent of users were satisfied with the impact the system has had on improving the medication-use process. CONCLUSION: Implementation of the Medmarx system led to an increase in the number of reported medication errors and improvements in the medication-use process.

Adverse Drug Reaction Reporting Systems↗

I.V. admixture contamination rates: traditional practice site versus a class 1000 cleanroom.

PURPOSE: The contamination rates associated with the preparation of medium-risk i.v. admixtures in a traditional practice site and in a class 1000 cleanroom were compared. METHODS: Simulated product media fills served as the samples. Each investigator, a pharmacist and a pharmacy technician, prepared 500 vials and 500 small-volume parenteral (SVP) bags in five separate runs at a traditional practice site and in a cleanroom. United States Pharmacopeia chapter 797 medium-risk compounding procedures were followed, and strict adherence to aseptic technique was employed. Single-strength tryptic soy broth was substituted for the drug and diluent in the admixtures. Positive and negative controls were also prepared and stored for the duration of the study. The pharmacist and technician prepared a total of 4057 samples: 2027 samples (1014 vials and 1013 SVP bags) were prepared in a class 1000 cleanroom, and 2030 (1014 vials and 1016 SVP bags) were prepared at a traditional practice site. RESULTS: Contamination rates did not significantly differ between the traditional practice site (0.296%) and the cleanroom environment (0.344%) (p = 1.0). A significant difference in the number of contaminated samples was found between the two investigators (2 of 2057 were contaminated by the pharmacist and 11 of 2000 were contaminated by the technician) (p = 0.012). Contamination rates by the pharmacist (p = 1.0) and technician (p = 1.0) did not significantly differ between sites. CONCLUSION: The most important variable affecting microbial contamination of admixtures was the aseptic technique of personnel, not the environment in which the drugs were compounded.

Asepsis↗

Improving the safety of neuromuscular blocking agents: a statement from the USP Safe Medication Use Expert Committee.

PURPOSE: Recommendations of the interdisciplinary Safe Medication Use Expert Committee of the United States Pharmacopeia (USP) to assist health care professionals, manufacturers, and organizations in handling neuromuscular blocking agents (NMBAs) safely and effectively are discussed. SUMMARY: Review and analysis of the USP Medication Errors Reporting Program and MEDMARX program databases showed a continuing risk of patient harm or death due to errors with NMBAs. Medication errors involving wrong concentrations, wrong doses, wrong drugs, look-alike packaging, and sound-alike names, combined with lack of monitoring and communication, have been associated with the use of NMBAs in health care institutions. Serious adverse events occur when NMBAs are used without adequate safeguards. Recommendations for improving safety were developed through review and discussion of root causes and areas of concern with these medications. CONCLUSION: Medical errors with NMBAs continue to result in patient morbidity and mortality. Increased awareness and action on the part of all parties involved are needed to improve the safety of this class of medications.

Drug Labeling↗

Interrater agreement with a standard scheme for classifying medication errors.

PURPOSE: The interrater agreement for and reliability of the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) index for categorizing medication errors were determined. METHODS: A letter was sent by the U.S. Pharmacopeia to all 550 contacts in the MEDMARX system user database. Participants were asked to categorize 27 medication scenarios using the NCC MERP index and were randomly assigned to one of three tools (the index alone, a paper-based algorithm, or a computer-based algorithm) to assist in categorization. Because the NCC MERP index accounts for harm and cost, and because categories could be interpreted as substantially similar, study results were analyzed after the nine error categories were collapsed to six. The interrater agreement was measured using Cohen's kappa value. RESULTS: Of 119 positive responses, 101 completed surveys were returned for a response rate of 85%. There were no significant differences in baseline demographics among the three groups. The overall interrater agreement for the participants, regardless of group assignment, was substantial at 0.61 (95% confidence interval [CI], 0.41-0.81). There was no difference among the kappa values of the three study groups and the tools used to aid in medication error classification. When the index was condensed from nine categories to six, the interrater agreement increased with a kappa value of 0.74 (95% CI, 0.56-0.90). CONCLUSION: Overall interrater agreement for the NCC MERP index for categorizing medication errors was substantial. The tool provided to assist with categorization did not influence overall categorization. Further refining of the scale could improve the usefulness and validity of medication error categorization.

Adverse Drug Reaction Reporting Systems↗

Rational limits for drug impurities.

The United States Pharmacopeia (USP) has developed policies on drug substance purity and organic volatile impurities. This paper will include the historical background and the scientific basis of these policies and will give several examples of how they are reflected in the tests that are included in USP monographs. Data on the types of analytical methods used in assessing the purity of compendial articles will also be presented.

Chemical Phenomena↗

Comparative potency and dissolution performance of internationally available piroxicam products.

Generic drug products are marketed throughout the world and are generally regarded as being equivalent to the name brand product. Piroxicam is a widely prescribed nonsteroidal anti-inflammatory drug and is marketed under the Pfizer tradename Feldene or Felden . In countries with no patent laws or where the Feldene patent has expired, the drug is available under various trademarks by many different producers. Differences in formulations produced by different manufacturers can be assessed by measuring dissolution rate and potency. In this study, the United States Pharmacopeia (USP) dissolution and potency tests were applied to 85 generic piroxicam products obtained from 21 countries in an attempt to evaluate if the available formulations met standard quality assurance tests. The results show that of the 85 piroxicam products tested, 17 products met the USP dissolution standards and 68 products failed. Of the 85 products tested for potency as a percentage of label claim, 50 products failed the USP criteria. Overall, 91% of the generic piroxicam products evaluated failed to meet the routine in vitro USP quality assurance criteria for potency and/or dissolution. The substantial differences observed in this study regarding performance of piroxicam dosage forms available worldwide have possible implications in terms of product equivalency and standards at an international level. While these results cannot be used to draw clinical conclusions without bioavailability data, they should nonetheless be kept in mind by healthcare practitioners.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemistry, Pharmaceutical↗

Bacteriocins as oral and gastrointestinal antibiotics: theoretical considerations, applied research, and practical applications.

Bacteriocins, specific and highly potent protein antibiotics, have been long been expected to enter the working pharmacopeia. Despite laboratory experiments demonstrating their effectiveness against a wide range of gastrointestinal pathogens, attempts to reproduce such killing activity by using live bacteriocin-producing bacteria in animal gastrointestinal systems repeatedly failed. This raised doubts about the potential of the bacteriocins as in vivo antibiotics. Thus, though some bacteriocins have been employed in food preservation and processing, none have been applied directly as medicine. Recent experiments, based on an improved theoretical understanding of microbial ecology, demonstrate the in vivo activity of bacteriocins, the potential importance of bacteriocins as antibiotics, and the role that bacteriocins play in antibiotic resistance. Meanwhile, several kinds of bacteriocins have been proposed for applications in gastrointestinal microbiology, as well as for the use of probiotics to reduce dental caries and improve oral hygiene. Unfortunately, much of the probiotic-oriented research appears to be pursued without reference to resistance and the role of the bacteriocins in a community of bacteria. This leads to continued confusion regarding the interpretation of experimental results and mistaken assessments, positive and negative, of bacteriocins' therapeutic potential. A study of microbial ecology should be incorporated in the drug development process in order to apply bacteriocins most effectively.

Animals↗

Biochemical and pharmacologic heterogeneity in low molecular weight heparins. Impact on the therapeutic profile.

Ever since the introduction of low molecular weight heparins (LMWHs) for clinical use, one of the major questions raised relates to product interchangeability and the differences between each of the individual LMWH preparations. Although differences between various commercially available products have been described in terms of molecular weight profile and biologic properties, very limited information on the direct comparison of individual products in a defined clinical setting is available at this time. European Pharmacopeia (EP) and the World Health Organization (WHO) have developed guidelines to characterize these agents in terms of molecular weight and biologic profiles. On a gravimetric basis, these potency assignments differ for anti-Xa and anti-IIa activities in terms of U potency per mg. The relative distribution of various molecular weight components has also been reported to vary. The oligosaccharide composition, microstructural differences in terms of specific sugars and the presence of unique structural features and the interaction with endogenous mediators such as antithrombin (AT) and heparin cofactor II (HC II) also differ. At equivalent anti-Xa levels, the amount of the anti-IIa activity and anticoagulant activity differs. Since the bioavailability and relative pharmacokinetics of the anti-Xa and anti-IIa effects are different, the specific pharmacodynamic effects of these drugs also differ. A large preclinical data base is now available on the differences between various LMWHs. However, only limited clinical data is available in the current literature. To date, the LMWHs have been primarily used for the management of post-surgical DVT. Only smaller dosages (30-40 mg or 2,500 to 4,000 anti-Xa U total dose) have been used. In these studies, because of the low dose and subcutaneous route of administration, the differences in clinical effects are rather small. Since LMWHs are now developed for therapeutic use, where relatively higher doses are used, these pharmacokinetic/pharmacodynamic differences will become more apparent. The reported differences in the clinical efficacy of LMWHs in such indications as unstable angina may be due to their pharmacologic properties and molecular composition. There are also major differences in the non-anticoagulant actions of these agents such as their ability to interact with growth factors and antithrombotic effects. Based on the available literature, it can be concluded that each product exhibits individuality.

Anticoagulants↗

New World plants; New World drugs.

The "discovery" and eventual colonization and exploitation of the New World by Europeans created the opportunity for the development of medicines from numerous plants native to the Western Hemisphere. Many of these plants had been employed by native cultures for centuries or millenia. The plants and, eventually, isolated drugs derived from them were incorporated into the materia media of the Europeans both in Europe and in the new colonies. Many became official in the United States Pharmacopeia (USP); a few still remain today. In all, 30 plants and/or their derivatives are briefly profiled. The subjects of plant-based medicines is becoming more timely as millions of Europeans and Americans begin to seek "natural" remedies for self-medication. Unfortunately, lack of patentability and high new-drug approval costs keep many traditional plant medicines from obtaining proper recognition.

Americas↗

Preparation and performance of cross-linked agar encapsulated activated charcoal (CAAC-III).

A technique is described to encapsulate activated charcoal for hemoperfusion to be used in an artificial liver support. Spherical activated charcoal was coated with agar and shaped in organic solvent, as well as cross-linked by epichlorohydrin (40-50 degrees C). The product withstood autoclaving at 121 degrees C for 0.5 hours, and had a good adsorption ability for compounds with molecular weight ranging from 113-5200. The adsorption kinetic showed pore diffusion limitation to compounds of small molecular weight, and film diffusion limitation to compounds of large molecular weight. Microparticles of charcoal release were greatly reduced, and within the permissible range according to the requirements in the U.S. Pharmacopeia (1985).

Agar↗

Role of endogenous brain "ouabain" in the sympathoexcitatory and pressor effects of sodium.

Endogenous cardiac glycoside inhibitors of the Na, K-ATPase (called "ouabain" here) with structures similar to plant ouabain have been isolated in several tissues, including the adrenal cortex and the brain. Recent studies have demonstrated that "ouabain" in the anteroventral third ventricle (AV3V) region of the hypothalamus mediates the sympathoexcitatory and pressor responses to a high sodium diet in Dahl salt-sensitive (Dahl-S) and spontaneously hypertensive (SHR) rats. Although the mechanisms regulating the biosynthesis, release and deactivation of CNS "ouabain" remain unknown, the discovery of the importance of brain "ouabain" in cardiovascular regulation creates a novel path for the development of antihypertensive pharmacopeia.

Animals↗

Introduction of dissolution error as a result of different openings in vessel covers.

Vessel covers are required in dissolution studies to retard solvent evaporation. Sufficient openings on the cover are required by the current United States Pharmacopeia (USP) "to allow ready insertion of a thermometer and for withdrawal of specimens/samples." However, the area of the opening has not been regulated by the USP. The purpose of this work was to measure the loss of the dissolution solvent as a result of openings in vessel covers and to investigate errors caused by the solvent loss. The method used in the study involved measurements of the opening areas in three commercial vessel covers and determinations of solvent loss under a typical dissolution condition. The results showed that the openings in the three covers varied from 75 mm2 to 2285 mm2; this was 1-30% of the total vessel open area for a USP standard vessel. The volume of the dissolution solvent was reduced by 0.6-3.4% for an 8-hr dissolution study, and 1.7-9.7% for a 24-hr study when the three different vessel covers were used. The rate of solvent loss exhibited a linear relationship with the area of the opening in the covers. A slower rate of reduction was found for a smaller initial volume of the solvent. The conclusion was that higher dissolution results were produced if the solvent loss was not considered.

Chemistry, Pharmaceutical↗

Effects of activated charcoal and sorbitol on sodium pentobarbital absorption in the rat.

Three activated charcoals were tested for their ability to reduce the oral absorption of sodium pentobarbital (SP) in rats. Fasted adult, male rats were given 40 mg/kg of C-14 labelled SP by gavage (2 ml). Five minutes after drug administration, the animals were given 40 mg of either Darco (G-60), United States Pharmacopeia (USP) or SuperChar (SC) activated charcoals. The charcoals were administered as a slurry in either 1 ml of water, or 1 ml of 70 percent (w/v) sorbitol solution. Water (control) and sorbitol given alone were tested separately. Various pharmacokinetic parameters were calculated from the plasma concentration of SP determined at various time intervals after drug administration. When given in water, only SC significantly (p less than .01) reduced the peak plasma concentration and oral bioavailability of SP. Sorbitol given alone produced diarrhea but did not affect drug absorption. However, sorbitol selectively enhanced the effectiveness of G-60 and USP charcoals and, as a result, all charcoals significantly reduced SP absorption when given along with the cathartic. The results suggest that when given in water, charcoal antidotal effectiveness is proportional to absorptive surface area, and that sorbitol may enhance the antidotal effectiveness of some charcoals but not others.

Administration, Oral↗

In vitro effect of a buffered chelating agent and neomycin or oxytetracycline on bacteria associated with diseases of fish.

The antimicrobial agents used to treat bacterial fish diseases are archaic, and their uses may result in the emergence of drug-resistant bacterial strains. This study evaluated the in vitro antimicrobial activity of combinations of Tricide and neomycin or oxytetracycline on common disease-causing bacteria of fish and its possible use as an alternative treatment of these diseases. Tricide solutions containing of 8 mM United States Pharmacopeia (USP) disodium ethylenediaminetetraacetate dehydrate (chelator) and 20 mM USP 2-amino-2-hydroxymethyl-1,3-propanediol (buffer) potentate the antimicrobial action of neomycin and oxytetracycline when reacted in vitro with Aeromonas hydrophila, Streptococcus iniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Serial passage of the test organisms in Tricide or Tricide and neomycin or oxytetracycline did not result in the development of resistant forms. Combinations of Tricide and neomycin or oxytetracycline reduced the amount of antibiotics necessary for fish therapy, render drug-resistant bacteria sensitive to antimicrobial therapy, may be used to decontaminate recently shipped fish, and should reduce the formation of antibiotic-resistant forms.

Animals↗

Correlation of biological value of feed phosphates with their solubility in water, dilute hydrogen chloride, dilute citric acid, and neutral ammonium citrate.

Relative biological values (BV) of 36 feed phosphates were determined with female turkeys in bioassays of 21-day duration using three response criteria: weight gain, tibia ash percentage, and gain:feed ratio. Calcium phosphate, dibasic dihydrate (United States Pharmacopeia) was the reference standard. Nine mono-dicalcium phosphates (M-DCP, 21.0% phosphorus), 13 di-monocalcium phosphates (D-MCP, 18.5% phosphorus), and 14 defluorinated phosphates (DFP, 18.0% phosphorus) were evaluated. The average relative BV for M-DCP, D-MCP, and DFP samples were 97.6, 94.6, and 90.8%, respectively. Solubility of phosphates was determined by four recognized methods. The solvents were water, .4% HCl, 2.0% citric acid (CA), and neutral ammonium citrate (NAC). Water solubility of M-DCP samples was greater (67.5%) than that of D-MCP (38.8%) and DFP (8.9%) samples. Correlation of water solubility of phosphates to their relative BV was quite low, and water solubility was a poor indicator of BV. When .4% HCl was the solvent, correlation coefficients (r) were .55, .33, and .72 for M-DCP, D-MCP, and DFP, respectively. Based on these results and prediction equations, .4% HCl solubility would be inappropriate for estimating BV of M-DCP and D-MCP samples. Solubility of feed phosphates (mainly D-MCP and DFP) in 2.0% CA or NAC was positively correlated with BV; the r values were .87 to .95. Both of these solubility tests provided a good index of BV. However, it would seem inappropriate and risky to replace bioassays totally with these tests. Feed phosphate users could perform either the 2.0% CA or NAC solubility test easily as a screen for BV along with other quality control procedures (i.e., phosphorus, calcium, sodium, and fluoride determinations).

Animal Feed↗

Biological value of bone-precipitated dicalcium phosphate in turkey starter diets.

A study was conducted to determine the relative biological value (RBV) of phosphorus from two bone-precipitated dicalcium phosphates (DCP-BP) in turkey starter diets. An estimated 40,000 metric tons of DCP-BP are produced annually in the United States as a by-product of gelatin production. The two DCP-BP sources were compared to commercial feed phosphates. Two bioassay experiments of 21-d duration were conducted with female turkeys. Phosphate sources were each fed at three levels (.18, .24, and .36% added total phosphorus) in a corn-soybean meal diet. Calcium level was maintained constant at 1.0% in all diets by adjusting the level of ground limestone. Four replicate pens of six poults were randomly assigned at 1 d of age to each level of each phosphorus source in each bioassay. The reference standard was United States Pharmacopeia (USP) grade calcium phosphate, dibasic dihydrate. Data representing three response criteria (weight gain, gain:feed ratio, and tibia ash percentage at 21 d) were combined to calculate a biological value (BV) for each test source and the reference standard phosphate. A RBV was then computed for each test source. The RBV of the two DCP-BP sources were 98.8 and 99.1, as compared to 100.0 for the reference standard, and 86.7, 87.1, and 88.4 for three commercial, thermochemically produced defluorinated phosphates. The RBV of one commercial mono-dicalcium phosphate, and three di-monocalcium phosphates were: 96.4, and 91.2, 94.7, and 101.5, respectively. The two DCP-BP sources compared favorably to commercial feed phosphates, and would be satisfactory supplements in diets for starting chicks, poults, pigs, and other species.

Animal Feed↗

Syrup of ipecacuanha as an emetic in adults.

The emetic actions of syrup of ipecacuanha have been evaluated in 105 adult patients presenting at the emergency department of the Royal Perth Hospital with a diagnosis of accidental or intentional poisoning. The australian Pharmaceutical Formulary (APF) and the United States Pharmacopeia (USP) formulations of the syrup were compared and gave similar overall emetic responses of 88% and 89% respectively at a dose level of 15 ml. A 30 ml dose regimen of the APF formulation gave a slightly but not significantly increased overall emetic response of 96%. There were no differences between the three groups of patients in the time taken to vomit, the duration of vomiting or the volume of stomach contents recovered.

Adolescent↗

Oral thyroxine: variation in biologic action and tablet content.

Thirty-two patients with primary hypothyroidism were given oral thyroxine as Levothroid or Synthroid to see if the two preparations had similar effects. The serum thyroxine was used as an index of bioavailability and the serum thyrotrophin as an index of biologic activity. The serum thyroxine was lower in all 32 patients when taking Synthroid than when taking Levothroid. In 15 patients the serum thyroxine level fell low enough to raise the serum thyrotrophin; in all 15 the serum thyrotrophin rose when taking Synthroid. Direct measurement of thyroxine in the tablets showed that the tablets of Synthroid contained 20% to 30% less thyroxine than their stated content. Thus, the decreased bioavailability (lower serum thyroxine) and decreased biologic action (higher serum thyrotrophin) of Synthroid were due to the lower content of thyroxine. An incidental observation is that the range of serum thyroxine in treated hypothyroid patients is 7.6 to 16.6 micrograms/dL, higher than in normal persons. Because oral thyroxine is widely used, a cooperative effort among manufacturers, the United States Pharmacopeia and Food and Drug Administration, and clinicians to ensure the potency and biologic action of oral thyroxine is in order. Meanwhile, it seems reasonable to use oral thyroxine that is close to the stated content.

Biological Availability↗