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To assess stability and degradation over time, of methadone alone, and mixed with lidocaine and ketamine, using various diluents and storage conditions.Solutions of methadone diluted in 0.9% NaCl, and methadone-lidocaine-ketamine diluted in 0.9% NaCl or Hartmann's solution, and stored at room temperature with exposure to light, or refrigerated at 4°C and protected from light, were maintained over 10 days. Chemical stability was determined using liquid chromatography immediately after preparation and following 4, 24, 48, 96 and 240 hours of storage. Physical stability of the solutions was evaluated by visual examination and absorbance of ultraviolet/visible light. A linear model assessed the impact of different diluent solutions and storage conditions on drug degradation over time.There was no evidence of physicochemical incompatibility for any solution. Methadone concentration, when diluted alone or in methadone-lidocaine-ketamine with Hartmann's solution at 4°C, did not decline over time. Ketamine and lidocaine decreased to a similar extent over time, regardless of the diluent used or storage method, while methadone in methadone-lidocaine-ketamine diluted with 0.9% NaCl or with Hartmann's solution at room temperature exposed to light, also declined over time; however, all three methadone-lidocaine-ketamine components retained acceptable stability (10% degradation) for at least 48 hours following preparation, irrespective of diluent or storage conditions.Regardless of the diluent or storage method, methadone-lidocaine-ketamine solutions degrade over time, but this only becomes clinically significant after 48 hours. Solutions of 1 mg/ml methadone in 0.9% NaCl are stable for at least 10 days under storage conditions likely to be encountered in general practice.

Data on the physical characteristics of North African hashish are scarce. This article exploits hashish seizure data collected over an 8-year period (2011-2018) in Algeria in order to establish a physical profile of North African hashish. The collected data were subjected to statistical analysis in order to characterize the three main forms in which North African hashish is packaged, namely hashish bags, hashish packets, and hashish units (slab bars). The study revealed that 82% of hashish bags weigh 25 kg that hashish bags are made either as a handbag or as a back bag that they are most often wrapped with woven plastic. Two hashish bag configurations were identified-Bag-Packet-Unit (79%) and Bag-Unit (21%)-and 81% of the total studied bags featured logos. Hashish packets contain the units, which are wrapped with three to five different types of packaging to constitute packets of 0.5 kg (65%) or 1 kg (32%), with two different configurations including 100- or 250-g units. Hashish packets are mainly covered with adhesive tape, and only 18% of them feature inscriptions. Hashish units are found in three different shapes: slab bar (most common), soap bar, and egg-shaped bar. Sixty-five percent of the North African hashish slab bars have a weight of 100 g; other weights are 250 g (20%), 90 g (10%), and 200 g (2%). Most of the 90-100 g units have a light brown color, and 200-250 g units are dark brown in color. Sixty-four percent of hashish units contain logos. Five logo classes were identified: letters (37%), numbers (27%), symbols (23%), animals (11%), and, more recently, "paper logos" at just 2%, exclusively reserved for high-quality hashish and entirely intended for the European market. The findings of this work allow for the establishment of a profiling platform of hashish seizures in this region and can be generalized to all countries that report this region as the primary source of seized hashish within their territory.

Purpose To investigate suicide-related over-the-counter (OTC) analgesic medication exposures among individuals ≥6 years old reported to United States (US) poison control centers. Methods Data from the National Poison Data System for the years 2000-2018 were retrospectively analyzed. Results From 2000 to 2018, US poison control centers recorded 549 807 suicide-related cases involving OTC analgesics, including 327 781 cases (59.6%) admitted to the hospital and 1745 deaths (0.3%). Most cases involved a single substance (67.5%) and occurred among females (72.7%) and individuals 6-19 years old (49.7%). Overall, the rate of exposures increased significantly by 33.5% from 2000 to 2018, primarily driven by the increasing exposure rate among 6- to 19-year-old females. From 2000 to 2018, exposure rates for acetaminophen and ibuprofen increased, while that for acetylsalicylic acid decreased. Additionally, the proportion of cases resulting in a serious medical outcome or healthcare facility admission increased for all types of OTC analgesics. Acetaminophen and acetylsalicylic acid accounted for 48.0% and 18.5% of cases, respectively, and 64.5% and 32.6% of deaths, respectively. Both acetaminophen and acetylsalicylic acid had greater odds of healthcare facility admission (ORs 2.56 and 2.63, respectively) and serious medical outcomes (ORs 2.54 and 4.90, respectively) compared with ibuprofen. Conclusions The rate of suicide-related OTC analgesic cases is increasing. Acetaminophen and acetylsalicylic acid cases are associated with greater morbidity and mortality. Prevention efforts should include implementing unit-dose packaging requirements and restrictions on package sizes and purchase quantities for acetaminophen and acetylsalicylic acid products to reduce access to large quantities of these analgesics.

High prevalence of Helicobacter pylori infection, the complexity for its treatment, poor correlation of registered drug packs or poor patient adherence to the treatment may contribute to antibiotic resistance and healthcare costs. The aim of the present study was to investigate whether registered drug packs are in accordance with European and national guidelines for H pylori eradication with reference to the number of drug units. In this study, we considered treatment options for the management of H pylori infection recommended by the Maastricht V/Florence Consensus Report and by national guidelines in the United Kingdom (UK), Croatia, Italy and Slovenia for adults. Drugs proposed by the guidelines were identified in national drug databases in July of 2019. When considering correlation for 10-day treatment regimens, drug packs registered in Croatia could not be matched with recommendations for sequential therapies. A number of proposed treatments could not be matched due to small variety of drug packs in Croatia. Drug packs registered in the UK more often matched recommended 14-day treatment regimens and national guidelines. With reference to European guidelines, 10-day treatments could more frequently be matched in Italy and in Slovenia. Furthermore, results of this study indicate that there is smaller variety in drug pack sizes registered in Croatia and Slovenia when compared to UK and Italy. Considering poor correlation of drug packs with treatment guidelines for H pylori, adherence to antimicrobial treatment and proper disposal of antimicrobials is warrant. Discussing adherence to antimicrobial treatment with patients should be introduced as a standard of patient care and education.

AIMS: Adequate user access to drug therapy can only be ensured when the drug can be removed from its package. The aim of this study was to investigate the influence of a variety of opening instructions on the ease of opening a user package and user satisfaction. METHODS: This experiment was conducted according to CEN/TS 15945. Ease of opening was defined as the ability to open a package within a defined time frame (effectiveness) and the learning effect by repeated opening (efficiency). (Dis)satisfaction ranged from −2 to +2. Empty bottles with left threat screw caps (rather than the standard right) were studied following 4 different types of instructions: none, arrow in the screw cap, package leaflet, video. Each instruction was studied in a group of 20 different healthy older adult volunteers (65–80 years). No opening aid was permitted. Data were captured in forms and on video. RESULTS: Nine (45%) participants could open the package without any instruction, 19 (95%) with an arrow marked bottle and 20 (100%) with a package leaflet or video. No notable differences were observed in median times for first and repeated opening. Participants were most often (n = 11) dissatisfied (score −2) without any instruction and neutral to most satisfied (0–2) with a video (n = 17). CONCLUSION: The effectiveness, efficiency and user satisfaction to open a package is strongly influenced by the type of opening instruction. This conclusion requires further consideration in drug product packaging and labelling.

We investigated whether low melting point phase-change waxes could be incorporated into emergency drug transport bags to attenuate the known temperature extremes their contents can be exposed to. We exposed two custom-made hollow-walled drug containers placed within a pair of drug transport bags to three day/night cycles including periods of direct radiant sunlight. The wall cavities of one contained air, whereas those of the other contained a paraffin wax (melting point of 44-46 °C) with a high latent heat of fusion (until fully melted, its temperature does not increase further). We collected 25,920 temperature datasets at six locations. We found that 97.8% and 84.7% of ampoule temperatures within the wax and air cavity containers, respectively, were within a target range of 15-40 °C over the study duration (Levene statistic W = 4279.1; Levene's test for equality of variance, p0.001). Ampoule temperatures in the wax cavity container only exceeded 40 °C for 1.7% of the time. Even when they did so, their temperature was attenuated to 40.3 °C, despite an ambient air temperature of40 °C for 6.4% of the time (peak 46.9 °C) and a bag surface temperature of40 °C for 17.2% of the time (peak 64.4 °C). In contrast, the ampoule temperature in the air cavity container exceeded 40 °C for 17.1% of the time (peak 54.1 °C). The latent heat of fusion of phase-change materials may be exploited in the design of drug transport bags to mitigate any temperature changes in the drugs stored within them.

In addition to degradation products, impurities, and exogenous contaminants, industries such as pharmaceutical, food, and others must concern themselves with leachables. These chemicals can derive from containers and closures or migrate from labels or secondary containers and packaging to make their way into products. Identification and quantification of extractables (potential leachables) and leachables, typically trace level analytes, is a regulatory expectation intended to ensure consumer safety and product fidelity. Mass spectrometry and related techniques have played a significant role in the analysis of extractables and leachables (E&L). This review provides an overview of how mass spectrometry is used for E&L studies, primarily in the context of the pharmaceutical industry. This review includes work flows, examples of how identification and quantification is done, and the importance of orthogonal data from several different detectors. E&L analyses are driven by the need for consumer safety. These studies are expected to expand in existing areas (e.g., food, textiles, toys, etc.) and into new, currently unregulated product areas. Thus, this topic is of interest to audiences beyond just the pharmaceutical and health care industries. Finally, the potential of universal detector approaches used in other areas is suggested as an opportunity to drive E&L research progress in this arguably understudied, under-published realm.

A simple and efficient method involving microwave-assisted extraction (MAE) combined with GC-MS was established to determine 1,3-di-tert-butylbenzene (DBB), 2,4-di-tert-butylphenol (DBP), 3,5-di-tert-butyl-4-hydroxybenzaldehyde (DBHBA) for evaluating the compatibility of antimicrobial peptide PL-5 spray with drug-packaging materials. In this study, the antimicrobial peptide PL-5 spray was purified using a Welchrom C18 column, and the high-density polyethylene spray bottle with liquid collection tube was first mixed with absolute ethanol, which would be subjected to MAE for further measurement by GC-MS. Various experimental parameters were systematically optimized, and good linearities were obtained within the range of 0.05-1.00 μg/mL for DBB and DBHBA and 0.50-10.00 μg/mL for DBP, with limits of detection (LODs) of 0.99 ng/mL (DBB), 16.34 ng/mL (DBP), and 1.64 ng/mL (DBHBA). Satisfactory recoveries that ranged from 96.0% to 107.2% were acquired, and the relative standard deviation was ≤ 4.7%. The results showed that the maximum daily usage of DBB, DBP, and DBHBA was 9.859, 163.445, and 16.399 ng, respectively, which was far below the corresponding permitted daily exposure values according to the safety assessment, indicating that the migration of analytes did not bring any potential safety risk. The compatibility between the drug and the packaging materials was favorable.

BACKGROUND Iatrogenic fluid overload is associated with increased mortality in the intensive care unit (ICU). Decisions on fluid therapy may, at times, be based on other factors than physiological endpoints. We hypothesized that because of psychological factors volume of available fluid bags would affect the amount of resuscitation fluid administered to ICU patients. METHODS We performed a prospective intervention cross-over study at 3 Swedish ICUs by replacing the standard resuscitation fluid bag of Ringer's Acetate 1000 mL with 500 mL bags (intervention group) for 5 separate months and then compared it with the standard bag size for 5 months (control group). Primary endpoint was the amount of Ringer's Acetate per patient during ICU stay. Secondary endpoints were differences between the groups in cumulative fluid balance and change in body weight, hemoglobin and creatinine levels, urine output, acute kidney failure (measured as the need for renal replacement therapy, RRT) and 90-day mortality. RESULTS Six hundred and thirty-five ICU patients were included (291 in the intervention group, 344 in the control group). There was no difference in the amount of resuscitation fluid per patient during the ICU stay (2200 mL [1000-4500 median IQR] vs 2245 mL [1000-5630 median IQR]), RRT rate (11 vs 9%), 90-day mortality (11 vs 10%) or total fluid balance between the groups. The daily amount of Ringer's acetate administered per day was lower in the intervention group (1040 (280-2000) vs 1520 (460-3000) mL; P = .03). CONCLUSIONS The amount of resuscitation fluid administered to ICU patients was not affected by the size of the available fluid bags. However, altering fluid bag size could have influenced fluid prescription behavior.

There are various factors that contribute to development of antimicrobial resistance. Overuse, inappropriate prescribing and extensive agricultural use of antibiotics are some of the factors which have been identified. Antibiotics are almost always universally packaged by manufacturers in packs that are heavily driven by cost of economies and convenience rather than by any scientific basis or duration of therapy. So, in this study, the correlation of the treatment guidelines with the choice of antibiotics and whether packing size contributes to leftover dosing units when used according to guideline recommendations were assessed.

Medicine counterfeiting is a current problem that the whole pharmaceutical field has to deal with. In 2014, counterfeits entered the legitimate supply chain in Europe. Quick and efficient action had to be taken. The aim of this paper is to explain which analytical strategy was chosen to deal with six of the cases concerned and which criteria have to be considered to provide quick and thorough information about the counterfeits. The evaluation of the packaging was performed in a first step, based on a comparison with genuine samples and evaluation of manipulation signs. Chemical methods were then used, consisting of near infrared and infrared spectroscopy, capillary zone electrophoresis and ultraviolet-visible spectrophotometry, in order to authenticate the samples and provide the chemical composition of the confirmed counterfeits. Among the 20 samples analyzed, 17 were confirmed as counterfeits. The counterfeits were the results of the manipulation of genuine samples, and one contained totally counterfeited parts. Several manipulation signs were asserted, like the addition of glue on the boxes and the vials. Genuine stolen goods had been diluted with water, while for an isolated case, a different active ingredient had been introduced in a vial. The analytical data generated were further investigated from a forensic intelligence perspective. Links could be revealed between the analyzed counterfeits, together with some interesting information about the modus operandi of the counterfeiters. The study was performed on a limited number of cases, and therefore encourages chemical and packaging profiling of counterfeits at a bigger scale. Copyright © 2015 John Wiley & Sons, Ltd. Language: en

Objectives: To determine the potential for a source of surplus antibiotics in the community to come from the mismatch between the recommended duration of antibiotic treatment for common indications in primary care and that dictated by default pharmaceutical industry packaging. Methods: Analysis of existing published information of: 1) the most common antibiotics prescribed in primary care in Australia; 2) their most common indications; 3) the guideline recommendations for their duration; and 4) the duration dictated by antibiotic packaging. Results: Of 32 common antibiotic prescribing scenarios, 10 had doses left over in surplus and 18 had a shortfall, leaving only four in which the packaging size matched the duration recommended by electronic Therapeutic Guidelines. Where there was a shortfall, this was only exactly accommodated by a repeat prescription in two cases. Conclusions: Mismatch contributes to a shortfall or excess of doses compared to recommended antibiotic treatment protocols and probably exaggerates redundant doses in the community from prescribed antibiotics dispensed and not consumed. Implications: Prescribers need to be aware that the mismatch between antibiotic pack sizes and guideline recommendations for their duration is contributing to antibiotic resistance in the community.

Counterfeit medicines are a global threat to public health. High amounts enter the European market, enforcing the need for simple techniques to help customs detect these pharmaceuticals. This study focused on physical profiling and IR spectroscopy to obtain a prime discrimination between genuine and illegal Viagra (R) and Cialis (R) medicines. Five post-tableting characteristics were explored: colour, mass, long length, short length, and thickness. Hypothesis testing showed that most illegal samples (between 60 and 100%) significantly differ from the genuine medicines, in particular for mass and long length. Classification and Regression Trees (CART) analysis resulted in a good discrimination between genuine and illegal medicines (98.93% correct classification rate for Viagra (R), 99.42% for Cialis (R)). Moreover, CART confirmed the observation that mass and long length are the key physical characteristics which determine the observed discrimination. IR analysis was performed on tablets without blister and on tablets in intact blister. These data were analyzed using Soft Independent Modelling of Class Analogy (SIMCA) and Partial Least Squares - Discriminant Analysis (PLS-DA). Supervised techniques needed to be applied since Principal Component Analysis (PCA) was not able to generate the desired discrimination. Our study shows that a perfect discrimination between genuine and illegal medicines can be made by both SIMCA and PLS-DA without removing the tablets from the blister. This approach has the advantage of keeping the blister intact. Our study demonstrates that these user friendly techniques are reliable methods to aid customs to obtain a prime distinction between genuine and illegal samples on the spot. Copyright (c) 2015 John Wiley & Sons, Ltd.

Objectives: To identify the practical problems that older people experience with the daily use of their medicines and their management strategies to address these problems and to determine the potential clinical relevance thereof. Design: Qualitative study with semistructured face-to-face interviews. Setting: A community pharmacy and a geriatric outpatient ward. Participants: Community-dwelling people aged 70 and older (N = 59). Measurements: Participants were interviewed at home. Two researchers coded the reported problems and management strategies independently according to a coding scheme. An expert panel classified the potential clinical relevance of every identified practical problem and associated management strategy using a 3-point scale. Results: Two hundred eleven practical problems and 184 management strategies were identified. Ninety-five percent of the participants experienced one or more practical problems with the use of their medicines: problems reading and understanding the instructions for use, handling the outer packaging, handling the immediate packaging, completing preparation before use, and taking the medicine. For 10 participants, at least one of their problems, in combination with the applied management strategy, had potential clinical consequences and 11 cases (5% of the problems) had the potential to cause moderate or severe clinical deterioration. Conclusion: Older people experience a number of practical problems using their medicines, and their strategies to manage these problems are sometimes suboptimal. These problems can lead to incorrect medication use with clinically relevant consequences. The findings pose a challenge for healthcare professionals, drug developers, and regulators to diminish these problems.

Summary We describe the management of a 62-year-old man who developed severe pain, cramps, paraplegia and pulmonary oedema after the accidental administration of potassium chloride into the subarachnoid space. In addition to supportive treatment, we performed cerebrospinal fluid lavage with saline 0.9%. The patient recovered well without any permanent injury.

Aims To examine whether tamper-resistant formulations (TRFs) of tapentadol hydrochloride extended-release (ER) 50 mg (TAP50) and tapentadol hydrochloride 250 mg (TAP250) could be converted into forms amenable to intranasal (study 1) or intravenous abuse (study 2). Design Randomized, repeated-measures study designs were employed. A non-TRF of OxyContin® 40 mg (OXY40) served as a positive control. No drug was taken in either study. Setting The studies took place in an out-patient setting in New York, NY. Participants Twenty-five experienced, healthy ER oxycodone abusers participated in each study. Measurements The primary outcome for study 1 was the percentage of participants who indicated that they would snort the tampered tablets, while the primary outcome for study 2 was the percentage yield of active drug in solution. Other descriptive variables, such as time spent manipulating the tablets, were also examined to characterize tampering behaviors more clearly. Findings Tampered TRF tablets were less desirable than the tampered OXY40 tablets. Few individuals were willing to snort the TRF particles (TAP50: 24%, TAP250: 16%; OXY40: 100% P < 0.001). There was less drug extracted from the TAP50 tablet than from the OXY40 tablet (3.52 versus 37.02%,P = 0.008), and no samples from the TAP250 tablets contained analyzable solutions of the drug. It took participants longer to tamper with the TAPs (study 1: TAP50 versus OXY40, P < 0.01; TAP250 versus OXY40, P < 0.01; study 2: TAP250 versus OXY40, P < 0.05). Conclusions Tamper-resistant formulations of tapten- tadol (pain relief) tablets do not appear to be well-liked by individuals who tamper regularly with extended-release oxycodone tablets. Employing tamper-resistant technology may be a promising approach towards reducing the abuse potential of tapentadol extended-release.

Handwritten recycled paper prescription for parenteral nutrition (PN) may become a concentrated source of viable contaminants, including pathogens. This study examined the effect of using fresh printouts of electronic prescriptions on these contaminants.Cellulose sponge stick swabs with neutralizing buffer were used to sample the surfaces of PN prescriptions (n = 32 handwritten recycled; n = 32 printed electronic) on arrival to the pharmacy or following printing and PN prescriptions and bags packaged together during delivery (n = 38 handwritten recycled; n = 34 printed electronic) on arrival to hospital wards. Different media plates and standard microbiological procedures identified the type and number of contaminants.Staphylococcus aureus, fungi, and mold were infrequent contaminants. nonspecific aerobes more frequently contaminated handwritten recycled than printed electronic prescriptions (into pharmacy, 94% vs 44%, fisher exact test P .001; onto wards, 76% vs 50%, p = .028), with greater numbers of colony-forming units (CFU) (into pharmacy, median 130 [interquartile range (IQR), 65260] VS 0 [075], Mann-Whitney U test, P .001; onto wards, median 120 [15320] vs 10 [040], P = .001). packaging with handwritten recycled prescriptions led to more frequent nonspecific aerobic bag surface contamination (63% vs 41%, fisher exact test P = .097), with greater numbers of CFU (median 40 [IQR, 080] VS 0 [040], Mann-Whitney U test, P = .036).The use of printed electronic PN prescriptions can reduce microbial loads for contamination of surfaces that compromises aseptic techniques.

Early‐stage prostate cancer is widely treated by iodine‐125 (I‐125) seed implantation. While quality assurance methods are in place to assure consistency in I‐125 seed source strength, current methods involve the breaking of the sterilization package, raising issues concerning sterility and time limitations. The purpose of this study was to develop a method of characterizing the total source strength of I‐125 seeds within a cartridge that has been sealed within a sterilization package and to evaluate the probability of detecting an out‐of‐calibration seed (aberrant seed). We defined a protocol to determine the ability of a well‐type ionization chamber to detect aberrant I‐125 seeds within a cartridge sealed in the sterilization package. A novel jig for a well‐type ionization chamber was designed to accommodate the sterilization package. One seed was chosen randomly from two cartridges containing five or 15 seeds (0.544 U source strength) and was exchanged with aberrant seeds of six different source strengths. The source strength was measured at each position within the cartridge. The results indicated that the response of the well chamber was sensitive to changes in the aberrant seed position within the cartridge and the source strength of the aberrant seed. The correlation coefficient between single seed and batch assay results was high (0.998). A novel jig and a measurement method using a well ionization chamber were developed, which allowed for a batch assay characterization of the total source strength of I‐125 seeds within a cartridge sealed within sterilization package. This method is simple, time‐saving, and offers greater practical application. PACS number: D6.20.Dk

Background European Council resolutions on tattoo ink introduce sterility and preservation of inks to protect customers. Inks used in Denmark are typically purchased over the internet from international suppliers and manufacturers from the US and the UK. In Denmark tattoo inks are regulated and labelled according to REACH as if they were plain chemicals. Objective The objective of this study was to check the microbial product safety of unopened and opened tattoo ink stock bottles. Packaging, labelling, preservation, sterility and contamination with micro-organisms were studied. Methods Physical inspection and culture of bacteria and fungi. Results Six of 58 unopened stock bottles (10%) were contaminated with bacteria and one of six samples (17%) of previously used stock bottles was contaminated. The bacterial species represented bacteria considered pathogenic in humans as well as non-pathogenic environmental bacteria. Yeast or moulds were detected in none of the samples. A total of 31% of the manufacturers informed only about the brand name. No information about content, sterility, risks or expiry date was indicated on the label. A total of 42% claimed sterility of their inks. A total of 54% labelled a maximum period of durability of typically 2–3 years. The physical sealing was leaking in 28% of the products. Conclusions The European Council resolutions regarding safety of tattoo inks are not effective. Stock bottles of tattoo ink may contain bacteria pathogenic to humans and environmental bacteria, and packaging, labelling and preservation of inks are of inadequate quality. Claim of sterility can be erroneous.

Ear cleaning solutions are designed for repeated use, which raises the possibility for bacterial contamination leading to recurrent or persistent infectious otitis. The purpose of this study was to investigate the prevalence of bacterial contamination of commercial ear cleaners following routine home use in dogs and to describe the characteristics that are associated with contamination. Used ear cleaner bottles and information regarding their use were obtained from canine owners visiting veterinary dermatologists. Both the bottle applicator tips and the solution contents were cultured for aerobic bacteria. Bacterial contamination was present on 10% of the bottle tips and in 2% of the solutions. Isolated bacteria included Staphylococcus pseudintermedius, Bacillus spp., coagulase-negative Staphylococcus spp., Micrococcus spp. and Burkholderia cepacia. The contamination rate was significantly higher on the applicator tips than in the solutions (P = 0.0076). The applicator tip contamination rate was significantly higher in expired samples (17%) than in-date samples (4%; P = 0.0277). The bottle sizes were significantly larger for the samples with contaminated applicator tips compared with noncontaminated tips (P = 0.0455). The contamination rate was significantly higher when Tris-EDTA was an ingredient. Cleanliness of the bottle, contact with the ear canal and infection status of the ear at time of culture had no bearing on the contamination rate. In summary, with routine home use of commercial ear cleaners, pathogenic bacterial contamination is of minor concern. This concern may increase when expired products or larger bottles of ear cleaner are used and when Tris-EDTA is an ingredient.

The daily requirement of intravenous (IV) lipid in pediatric patients is often less than the volumes and sizes available in prepackaged, commercially available preparations. In clinical practice, IV lipid emulsions (IVLEs) have been repackaged into syringes to prevent infusions from exceeding 12 hours, to reduce waste, and to improve patient safety. Recent data suggest an increasing risk of contamination when these preparations are repackaged manually. This study investigates the sterility of small volumes of IVLE that have been repackaged into empty IV bags by means of an automated compounding device (ACD).A total of 152 IVLE bags were repackaged with an ACD in an International Standards Organization class 5 environment. IVLE repackaging was conducted over a period of 3 weeks (week 1, n = 52; week 2, n = 52; week 3, n = 48). Forty commercially available bags of IVLE served as controls. At 0, 24, 48, and 120 hours after repackaging, IVLEs were filtered and placed onto blood agar medium.Microbial growth occurred in 12 of the 152 repackaged preparations compared with 0 of the 40 controls (7.9% vs 0%, P = .07). Positive cultures consisted of gram-positive cocci (n = 5, 3.3%), gram-positive rods (n = 5, 3.3%), and yeast (n = 2, 1.3%). There was no difference in positive bacterial or yeast growth between weeks 1, 2, and 3, suggesting an absence of outside contamination during preparation.The positive microbial growth suggests a concerning incidence of contamination of IVLEs repackaged with an ACD. Additional research is needed to further identify and validate the clinical impact of these preparations.

Background Saline nasal irrigation is a mainstay in the medical management of chronic rhinosinusitis (CRS) with proven efficacy. However, bacterial contamination of irrigation bottles has recently been reported and this may contribute to recurrent infections. Sterilization is effective but could a change in bottle design obviate the need for regular sterilization? Methods A total of 20 stable CRS patients were given a NasalCare® (Techworld Corporation, Inc., Downington, PA) irrigation bottle to use regularly for 1 week. This bottle incorporates a 1-way valve to prevent irrigant regurgitation. Swabs were taken from their sinonasal cavity and 3 sites on the bottle—nozzle, valve, and inner surface. Results This study cultured a range of organisms from all sites of the bottle, including common CRS pathogens such as S. aureus, P. aeruginosa, and E. coli. Whereas the bottle's inner surface had the lowest bacterial recovery rate, the frequent culture of organisms at this site suggests a 1-way valve cannot completely prevent irrigant reflux. The high rate of organism detection at the nozzle and valve of the bottle is concerning, as bacteria at these sites may be transported to the nose during nasal douching. Conclusion Saline irrigation will continue to be an essential component of CRS management. However, despite employing a 1-way liquid valve in this study, nasal irrigation bottles can still become contaminated with bacteria. Thus, patient education, irrespective of bottle design, will be essential in preventing bacterial contamination of nasal irrigation devices. The results of our survey suggest this message is not getting across to our patients. © 2011 ARS-AAOA, LLC.

Commercialization of protein-based therapeutics is a challenging task in part due to the difficulties in maintaining protein solutions safe and efficacious throughout the drug product development process, storage, transportation and patient administration. Bulk drug substance goes through a series of formulation, fill and finish operations to provide the final dosage form in the desired formulation and container or delivery device. Different process parameters during each of these operations can affect the purity, activity and efficacy of the final product. Common protein degradation pathways and the various physical and chemical factors that can induce such reactions have been extensively studied for years. This review presents an overview of the various formulation-fill-finish operations with a focus on processing steps and conditions that can impact product quality. Various manufacturing operations including bulk freeze-thaw, formulation, filtration, filling, lyophilization, inspection, labeling, packaging, storage, transport and delivery have been reviewed. The article highlights our present day understanding of protein instability issues during biopharmaceutical manufacturing and provides guidance on process considerations that can help alleviate these concerns.

Background Surface contamination with cytotoxic drug residue is a potential occupational health hazard to staff working in cytotoxic compounding areas and oncology wards. Aim To identify surfaces contaminated with cytotoxic drug residue and to indicate the risk of exposure to health workers handling cytotoxic drug residue. Method Wipe sampling was used to investigate surface contamination and occupational skin exposure to the marker cytotoxic drugs, fluorouracil (5-FU) and gemcitabine (GEM), in the pharmacy cytotoxic compounding section and oncology wards. Drug packaging, primary containers and gowns were also examined. Samples were analysed using a validated HPLC method. Repeat sampling was performed on selected surfaces to monitor any impact after implementing changes in practice. Results The majority of surfaces tested were contaminated. The cytotoxic work room (5-FU 56.7–320 μg/m2; GEM 75–370 μg/m2) and oncology wards had similar levels of contamination. Cytotoxic drug residue was detected on original containers and drug vials (5-FU < 3–6 μg; GEM 7.8–7.9 μg/wipe sample) stored in the cytotoxic work room but not on containers delivered directly from the distributor, suggesting that accidental contamination by pharmacy personnel does occur. Contamination was also detected on sections of the gowns (GEM around 0.9 mg/m2) worn by nurses in the oncology wards. Conclusion There is a risk of dermal contamination and accidental ingestion from inappropriate use of gloves, hand washing and cleaning, during and after preparation and administration of cytotoxic drugs. Implementing effective cleaning practices to decontaminate work surfaces is recommended in all cytotoxic drug compounding and administration areas. Regular environmental monitoring is warranted in these areas to ensure that background contamination is kept to a minimum and that decontamination protocols are adhered to.

A patient on an Intensive Care Unit who was recovering from multiple organ failure was being given an intravenous infusion of insulin to maintain normoglycaemia. On her 20th day in the unit, she suddenly became unresponsive. A cerebrovascular accident was suspected as other clinical and laboratory parameters remained normal apart from a blood glucose value of 20.6 mmol.l(-1). The insulin infusion rate had been increased to treat hyperglycaemia. Subsequent bedside finger prick blood testing suggested that the blood sugar was low but no numerical reading was provided. Repeat blood glucose analysis using a further sample drawn from the arterial line and measured in the blood gas analyser gave a value of 10.1 mmol.l(-1). Confirmatory laboratory blood tests revealed severe hypoglycaemia (0.1 mmol.l(-1)) and intravenous glucose 50% was given immediately. Examination showed that a glucose 5% solution had been inadvertently used in the arterial cannula flush system rather than saline, contaminating earlier samples drawn from the arterial line and giving falsely high blood glucose values. The prolonged period of severe hypoglycaemia led to neuroglycopaenia and irreversible brain injury. The patient died 9 days later without regaining consciousness. Such a complication has not previously been reported in this context and has particular significance given the increasing use of insulin therapy to maintain normoglycaemia in critically ill patients.

The United States Pharmacopeia (USP) has proposed large-globule-size limits to ensure the physical stability of lipid injectable emulsions, expressed as the percent fat5 microm, or PFAT(5), not exceeding 0.05%. Visibly obvious phase separation as free oil has been shown to occur in some samples if PFAT(5) is0.4%. We recently found that lipids, newly packaged in plastic (P), exceed the proposed USP limits and seem to produce less stable total nutrient admixtures compared with those made from conventional glass (G), which do meet proposed USP standards. We tested the possible stability differences between 20% lipid injectable emulsions in either P or G in a simulated neonatal syringe infusion study.Eighteen individual syringes were prepared from each 20% lipid injectable emulsion product (n = 36) and attached to a syringe pump set at an infusion rate of 0.5 mL/hour. The starting PFAT(5) levels were measured at time 0 and after 24 hours of infusion, using a laser-based light obscuration technique as described by the USP Chapter729. The data were assessed by a 2-way analysis of variance (ANOVA) with Container (G vs P) and Time as the independent variables and PFAT as the dependent variable.At time 0, the starting PFAT(5) level for lipids packaged in G was 0.006% +/- 0.001% vs 0.162% +/- 0.026% for P, whereas at the end of the infusion they were 0.013% +/- 0.003% and 0.328% +/- 0.046%, respectively. Significant differences were noted overall between groups for Container, Time, and Container-Time interaction (all p.001). Bonferroni tests showed significant differences in PFAT(5) levels between Containers at time 0 (T-0; p.001) and T-0 vs T-24 for P-based lipids (p.001), whereas no such differences were noted for Time for the G-based lipids. Similar results were noted for PFAT(10) levels.We confirm that presently available lipid injectable emulsions packaged in newly introduced plastic containers exceed the proposed USP729PFAT(5) limits and subsequently become significantly less stable during a simulated syringe-based infusion. Although modest growth (p = NS) in large-diameter fat globules was observed for the glass-based lipids, they remained within proposed USP globule size limits throughout the study. Glass-based lipids seem to be a more stable dosage form and potentially a safer way to deliver lipids via syringe infusion to critically ill neonates.

A large amount of heroin street doses are seized and examined for drug content by the Israel police. These are generally wrapped in heat-sealed plastic. Occasionally it is possible to visualize latent fingerprints on the plastic wrap itself, but the small size of the plastic item and the sealing process makes the success rate very low. In this study, the possibility of extracting and profiling DNA from the burnt edge of the plastic wrap was investigated. The idea was based on the assumption that epithelial cells might be trapped during the sealing process. The results show that there are sufficient quantities of DNA deposited at the "amorphic" burnt edges of sealed street doses for DNA profiling to be carried out. A controlled experiment using a known donor was performed. This subject carried out sealing of "street drug" packages and consequent DNA extractions were performed to show that known DNA profiles could be recovered from such packages, as a result of handling by the "packer." "Square-like" burnt edges did not yield DNA profiles, probably because of differences in the sealing process. It was also shown that DNA could be recovered from the plastic wrap itself and not only from the amorphic burnt edges. As heroin dealers and drug users are often involved in other crimes and run-ins with the law, the effective extraction and addition of their DNA profiles from such items of evidence to the newly established DNA database in Israel provides new avenues in the continued fight against crime and drug traffickers.

To describe how changes in legislation to restrict paracetamol sales have affected overdose discharges and death associated with the drug in Scotland.A descriptive analysis of routine death and hospital discharge data for the entire Scottish population between 1995 and 2004. Patients in Scotland participated who were discharged from hospital with a diagnosis of poisoning; deaths in Scotland from diagnosis of poisoning 1995-2003 were also analysed. Outcome measures were changes in mortality and overdose due to poisoning involving paracetamol. A comparison was made of in-hospital and out-of-hospital mortality in fatalities involving paracetamol.The majority of paracetamol-associated deaths were due to co-proxamol. Deaths associated with paracetamol alone or with ethanol occurred principally in hospital and were a minority of deaths overall. The proportion of in-hospital deaths attributed to paracetamol increased (post/pre ratio 1.347; 95% confidence interval 1.076, 1.639; P = 0.013). Overall numbers of cases discharged with poisoning fell. The proportion of these involving paracetamol in any form increased significantly in all groups except young men aged 10 to20 years.Legislation has not reduced mortality or proportional use of paracetamol in overdose, both of which appear to have increased in Scotland since pack-size limitations. Other approaches are necessary to reduce the death rate from overdoses involving paracetamol.

Patient adherence to immunosuppressive medications adherence is crucial to survival of the patient and a transplanted kidney, yet adherence is variable. Using a prospective, descriptive design, immunosuppressive medication adherence of 44 renal transplant recipients was followed for 6 months at a Midwestern transplant center using electronic monitoring. Four medication adherence patterns emerged from a hierarchical cluster analysis: those who took medications on time, those who took medications on time with late/missed doses, those who rarely took medications on time and who were late with morning and/or evening doses, and those who missed doses. This study is a step toward developing and implementing interventions targeted to specific patterns of poor adherence.

The main goals in the pharmacologic management of migraine headache are to avert or relieve debilitating pain, prevent escalating acute medication use, and improve day-to-day functioning. This review will examine the evidence supporting the early use of acute medication, usually when pain is mild, to enhance patient outcomes. We will also discuss imposed quantity limits as a practical impediment to the implementation of this strategy in the managed care setting, and will identify strategies for overcoming this barrier to effective care. Quantity limits imposed on triptan therapy by health plans can hinder the optimal acute treatment of migraine. A standard triptan quantity limit sufficient to permit early migraine treatment and a movement by manufacturers to provide blister packs consistent with a standard quantity limit should reduce patients costs, permit brand mobility when appropriate, and bolster long-term cost effectiveness by removing an important impediment to the use of triptans when they are most effective, early in the migraine attack when pain is often still mild.

Background Each year over 600 million prescription items are dispensed in community pharmacies in England and Wales. Despite this, there is little published evidence relating to dispensing errors and near misses occurring in this setting. This study sought to determine their incidence, nature and causes. Methods Prospective study over a 4-week period in 35 community pharmacies (9 independent pharmacies and 26 chain pharmacies) in the UK. Pharmacists recorded details of all incidents that occurred during the dispensing process, including information about: the stage at which the error was detected; who found the error; who made the error; type of error; reported cause of error and circumstances associated with the error. Results 125 395 prescribed items were dispensed during the study period and 330 incidents were recorded relating to 310 prescriptions. 280 (84.8%) incidents were classified as a near miss (rate per 10 000 items dispensed =22.33, 95%CI 19.79–25.10), while the remaining 50 (15.2%) were classified as dispensing errors (rate per 10 000 items dispensed =3.99, 95%CI 2.96–5.26). Selection errors were the most common types of incidents (199, 60.3%), followed by labeling (109, 33.0%) and bagging errors (22, 6.6%). Most of the incidents were caused either by misreading the prescription (90, 24.5%), similar drug names (62, 16.8%), selecting the previous drug or dose from the patient's medication record on the pharmacy computer (42, 11.4%) or similar packaging (28, 7.6%). Conclusions This study has demonstrated that a wide range of medication errors occur in community pharmacies. On average, for every 10 000 items dispensed, there are around 22 near misses and four dispensing errors. Given the current plans for reporting adverse events in the NHS, greater insight into the likely incidence and nature of dispensing errors will be helpful in designing effective risk management strategies in primary care. Copyright © 2004 John Wiley & Sons, Ltd.

We evaluate the effects of multilayered bags vs ethylvinyl-acetate bags on peroxidate formation of various emulsions for all-in-one total parenteral nutrition solutions (TPN) during storage.Twenty-four parenteral nutritions were prepared with 4 commercial i.v. lipid emulsions (Soyacal 20%, Grifols; Intralipid 20%, Fresenius-Kabi; Lipofundina 20%, Braun; and Clinoleic 20%, Clintex) and 2 different bags (multilayered [ML] bag, Miramed; and 1 ethylvinyl-acetate [EVA] bag, Miramed). Each kind of TPN was prepared in triplicate. Samples were taken at 3 different times: immediately after preparation (time 0), after 6 days at 4 degrees C and 48 hours at 37 degrees C (time 1), and finally after a total of 14 days at 37 degrees C (time 2). Oxidation of TPN was evaluated by analysis of hydroperoxides by ferrous oxidation-xylenol orange (FOX) reactive, lipoperoxides by thiobarbituric acid reactive species (TBARS), alpha-tocopherol by high-performance liquid chromatography (HPLC), and ascorbic acid and dehydroascorbic acid by HPLC.TPN admixtures in ML bag showed less oxidation evaluated by peroxide determination using FOX than EVA bag. Lipoperoxides by TBARS did not show significant differences between 2 bags. Ascorbic acid and dehydroascorbic acid disappeared in EVA bags at time 1. No important differences were found in alpha-tocopherol content.Multilayered bags minimize oxidation.

This document presents an ethnographic study of lay peoples classification of drug in malarial management in Suneka Division Kenya. Conducted over a 10-month period between February and November 1997 35 individuals were interviewed regarding malarial drugs and another 52 individuals were asked to pile sort the list of drugs procured during the interview according to familiarity. Results revealed that 58% of the respondents reported the correct dosage required for the treatment of malaria. On the other hand mixed feelings have been noted towards the new generation drugs. Lay people considered the age of the patient and whether he or she has fever pain or malaria when giving medication. Sometimes decisions were based on incorrect information given by friends and relatives causing prolonged suffering to the patient exacerbating chloroquine resistance and leading to resistance to the sulfodoxine/pyrymethamine drugs. A plan for the change of malaria drug policy has been suggested along with a careful examination of noncompliance drug packaging and drug of choice. Adoption of new drugs among lay people is dependent on the supply of affordable drugs with easy-to-follow instructions on the packaging material.

Objective Compare the risk of bacterial contamination of allergy immunotherapy vials prepared in-office versus those mixed under a ventilation hood. Study Design Prospective single-blinded study. Setting Tertiary otolaryngology outpatient clinic. Results Five hundred thirty-seven vials were prepared and cultured for aerobes and anaerobes over an 11-month period. Three hundred twenty vials were arbitrarily assigned to in-office preparation and 217 to under-hood preparation. A total of two positive cultures occurred in vials prepared in-office and one from under-hood preparation. Follow-up cultures of these three vials were all negative. No patients receiving injections had signs or symptoms of skin or systemic infections from the injections. Conclusion Our results suggest that the risk of bacterial contamination in immunotherapy vials in both groups is rare.

We have investigated the incidence of contamination of the contents of glass ampoules used for neuraxial injections, and whether this was reduced by wiping the outsides of the ampoules with isopropyl alcohol or using a filter straw. One hundred fentanyl and diamorphine ampoules used for routine regional anaesthesia were either wiped or not wiped with alcohol before their contents were aspirated, and the residual contents were swabbed and incubated. None of the swabs from the wiped ampoules grew organisms compared with nine (18%) from non-wiped ampoules (p = 0.004). In a second, laboratory study, 100 glass ampoules of saline were coated with Staphylococcus aureus and divided into four groups: wiped/not wiped with alcohol and with/without a filter straw. The contents of the ampoules were aspirated; the remnants and the aspirate were swabbed and incubated as before. Most contamination occurred in the unwiped groups and although numbers were small, filtering appeared to reduce contamination further. As filter straws also reduce the risk of injecting glass particles (even if not contaminated), our results suggest that wiping glass ampoules with isopropyl alcohol and using a filter straw should be part of routine practice when performing regional anaesthesia.