Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.

BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.

Stability of Generic Formulations of Bortezomib 1.0 and 2.5 mg/mL in Vials and Syringes Stored at 4°C and Room Temperature (23°C or 25°C).

BACKGROUND: The availability of generic versions of bortezomib raises questions about the reliability of extrapolating stability data from one brand to another. OBJECTIVE: To evaluate the stability of bortezomib formulations available from Janssen, Teva Canada, Actavis Pharma, Dr. Reddy's Laboratories, Apotex, and MDA, reconstituted with 0.9% sodium chloride (normal saline) to produce solutions of either 1.0 or 2.5 mg/mL and stored over at least 21 days under refrigeration (4°C) or at room temperature (either 23°C or 25°C) in the manufacturer's original glass vials or in polypropylene syringes. METHODS: On study day 0, solutions with concentration 1.0 mg/mL or 2.5 mg/mL of the Teva, Actavis, Dr. Reddy's, Apotex, and MDA generic formulations were prepared. Three units of each type of container (glass vials and syringes) were stored at 4°C and 3 units at room temperature. Concentration and physical inspection were completed on at least 8 study days (including day 0) over a 21- to 84-day study period. Bortezomib concentrations were determined by a validated stability-indicating liquid chromatographic method with ultraviolet detection. The end point of these studies was the time to reach 90% of the initial concentration (T-90) with 95% confidence, which is expressed as "T-9095%CI", where CI refers to the confidence interval. In addition to estimating the T-9095%CI, differences in stability among products from all manufacturers were compared using multiple linear regression. Previously published data for the Janssen product were included in the overall comparisons. RESULTS: In all of the studies, the analytical method separated degradation products from bortezomib, such that the concentration of bortezomib was measured specifically, accurately (deviations < 2.5%), and reproducibly (average replicate error 2.5%). During all studies, solutions retained more than 94% of the initial concentration at 4°C. The T-9095%CI exceeded the study period for all formulations under all combinations of concentration, container, and temperature, except the 84-day study for the MDA product. Multiple linear regression showed no significant differences among manufacturers (p = 0.57). CONCLUSIONS: In this study, formulations of bortezomib currently marketed in Canada (by Janssen, Teva Canada, Actavis Pharma, Dr. Reddy's Laboratories, Apotex, and MDA) were pharmaceutically equivalent and interchangeable. Given that there was no difference in stability related to manufacturer, nominal concentration, or container, we conclude that these formulations are physically and chemically stable for at least 35 days under refrigeration and at least 25 days at room temperature.

CONTEXTE: La disponibilité de versions génériques de bortezomib soulève des questions relatives à la fiabilité de l'extrapolation des données concernant la stabilité d'une marque à l'autre. OBJECTIF: Évaluer la stabilité des formules de bortezomib de Janssen, de Teva Canada, d'Actavis Pharma, des Laboratoires du Dr Reddy, d'Apotex et de MDA, reconstituées avec 0,9 % de chlorure de sodium (solution saline normale) pour produire des solutions de 1 ou de 2,5 mg/mL et réfrigérées au moins 21 jours à 4 °C ou à température ambiante (23 °C ou 25 °C), dans des fioles en verre du fabricant ou dans des seringues en polypropylène. MÉTHODES: La préparation des solutions avec une concentration de 1 mg/mL ou 2,5 mg/mL des formules génériques de Teva, d'Actavis, du Dr Reddy, d'Apotex et de MDA a eu lieu le jour 0 de l'étude. Trois unités de chaque contenant (fioles en verre et seringues) étaient stockées à 4 °C et 3 unités, à température ambiante. L'inspection de la concentration et l'inspection physique ont été réalisées pendant au moins 8 jours (y compris le jour 0) de l'étude qui a duré de 21 à 84 jours. Les concentrations de bortezomib ont été déterminées par une méthode chromatographique liquide validée, indiquant la stabilité à l'aide d'une détection par rayons ultraviolets. Le point final de ces études était le temps nécessaire pour que le produit atteigne 90 % de la concentration initiale (T-90) avec un seuil de confiance de 95 %, exprimé par T-90IC 95 %, IC indiquant l'intervalle de confiance. En plus de l'estimation du T-90IC 95 %, les différences de stabilité des produits de tous les fabricants ont été comparées à l'aide d'une régression linéaire multiple. Les données publiées précédemment sur le produit Jansen sont incluses dans les comparaisons globales. RÉSULTATS: La méthode analytique de toutes les études qui ont été menées a séparé les produits de dégradation du bortezomib de telle manière que la concentration était mesurée de manière spécifique, précise (déviations < 2,5 %) et reproductible (erreur de réplique 2,5 %). Tout au long des études, les solutions ont retenu plus de 94 % de la concentration initiale à 4 °C. Le T-90IC 95 % de toutes les formules dans toutes les combinaisons de concentration, de contenant et de température, dépassait la durée des études, à l'exception du produit MDA dans l'étude de 84 jours. La régression linéaire multiple n'a indiqué aucune différence importante parmi les fabricants (p = 0,57). CONCLUSIONS: Dans cette étude, les formules de bortezomib actuellement commercialisées au Canada (par Janssen, Teva Canada, Actavis Pharma, les Laboratoires du Dr Reddy, Apotex et MDA) étaient équivalentes et interchangeables d'un point de vue pharmaceutique. Puisqu'aucune différence de stabilité, de concentration nominale ou de contenant liée à l'un ou l'autre des fabricants n'a été révélée, nous concluons que ces formules sont physiquement et chimiquement stables pendant au moins 35 jours sous réfrigération et au moins 25 jours à température ambiante.

Development of Stable and Simple Finasteride 333-µg/mL Suspensions that Minimize Occupational Exposure.

Finasteride is not commercially available in a liquid format, which stimulated the development of a stable and simple finasteride suspension formulation. The objectives of this work were to develop and test a finasteride suspension for 1) simplicity to compound, 2) pharmaceutical acceptability, 3) stability, and 4) potential for occupational exposure. The stability of commercial 5-mg finasteride tablets (50 mg/150 mL) was evaluated in water, Oral Mix, and OralMix SF in amber polyethylene terephthalate bottles at 25°C or 4°C. Additional stability studies were carried out using sugar-free Finasteride Powder USP in amber polyethylene terephthalate bottles and tablets in water in polypropylene oral syringes. On study days 0, 1, 3, 7, 14, 28, 38, 49, 63, and 90, the finasteride concentration was determined using a validated stability-indicating liquid chromatographic method. The potential occupational airborne exposure was evaluated by attempting to measure finasteride in 1000 liters of room air following shaking and nebulization. Finasteride suspension/dispersion formulations were prepared in water, Oral Mix, and Oral Mix SF from tablets and pure powder. All formulations retained more than 94.3% of the initial finasteride concentration, with 95% confidence, when stored for up to 90 days at room temperature or 4°C. Simulations of occupational exposure failed to demonstrate the presence of finasteride in room air following attempts to nebulize finasteride mixtures. We conclude that 333-µg/mL suspension/dispersions of finasteride in water or Oral Mix products will have more than 94.3% of the initial finasteride concentration remaining after 90 days, regardless of the formulation, container, or storage temperature. Although we could not detect finasteride in room air, given the analytical limits of the study, we estimate that exposure would unlikely exceed 3.6-µg/1000 liters of room air. Nevertheless, since current regulations are based on "no safe limit," use of primary engineering controls and personal protective equipment as appropriate is recommended.

Nitrous oxide as a putative novel dual-mechanism treatment for bipolar depression: Proof-of-concept study design and methodology.

INTRODUCTION: Depressive symptoms predominate in the course of bipolar disorder (BD) and there is an urgent need to evaluate novel application of repurposed compounds that act on pre-specified treatment targets. Several lines of reasoning suggest that nitrous oxide (N2O) is an ideal medication to study as a potential treatment and as a strategy to identify the underlying pathophysiology of bipolar depression. N2O is a potent cerebral vasodilator and there is compelling evidence of reduced frontal cerebral blood flow (CBF; i.e. hypoperfusion) in depression. Therefore, N2O may increase CBF and thereby improve symptoms of depression. The goal of this randomized, double-blind trial is to study the effect of a single administration of N2O versus the active comparator midazolam on mood and CBF in adults with treatment-resistant bipolar depression. METHODS: Participants with BD-I/-II currently experiencing a major depressive episode will be randomized to one of two conditions (n = 20/group): 1) inhaled N2O plus intravenous saline, or 2) inhaled room air plus intravenous midazolam. Montgomery-Asberg Depression Rating Scale scores will serve as the primary endpoint. CBF will be measured via arterial spin labelling magnetic resonance imaging. CONCLUSIONS: N2O is a potential novel treatment for bipolar depression, as it causes cerebral vasodilation. This proof-of-concept study will provide valuable information regarding the acute impact of N2O on mood and on CBF. If N2O proves to be efficacious in future larger-scale trials, its ubiquity, safety, low cost, and ease of use suggest that it has great potential to become a game-changing acute treatment for bipolar depression.

Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial.

BACKGROUND: Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28 days in patients with sepsis. METHODS: LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n = 800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24 h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6 months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned. DISCUSSION: This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis. TRIAL REGISTRATION: clinicaltrials.gov, NCT03680274, first posted 21 September 2018.

Administration of Intravenous Ascorbic Acid-Practical Considerations for Clinicians.

Emerging data suggest that intravenous ascorbic acid (AA) may be beneficial in patients with sepsis. Clinicians require data on stability of diluted AA for safe administration. We evaluated the stability of AA diluted in normal saline (NS) or 5% dextrose in water (D5W) solutions over 14 days at 25 °C and at 4 °C, protected from light, using concentrations of 37 mg/mL and 77 mg/mL (Sandoz) and 40 mg/mL and 92 mg/mL (Mylan). We also assessed stability of a 40 mg/mL solution (Mylan) at 25 °C exposed to light for 75 h. Concentrations were measured using liquid chromatographic separation with ultraviolet light detection on days 0, 0.33, 1, 1.33, 2, 3, 4, 7, 10 and 14. By day 14, solutions at 4 °C retained >97.72% of the initial concentration; at 25 °C, solutions retained >88.02% of the initial concentration, but visual changes were evident after day 2. Multiple linear regression demonstrated that study day and temperature (p < 0.001) but not solution type (p = 0.519), concentration (p = 0.677) or manufacturer (p = 0.808) were associated with the percentage remaining. At 75 h, degradation rates were similar in solutions protected from vs. exposed to light. In conclusion, AA solutions are stable for at least 14 days at 4 °C, with protection from light.

Extended Stability of Sodium Phosphate Solutions in Polyvinyl Chloride Bags.

BACKGROUND: Sodium phosphate injection is used to treat moderate to severe hypophosphatemia. There have been no published reports documenting the physical compatibility or chemical stability of sodium phosphate injection in IV solutions. OBJECTIVE: To evaluate the physical compatibility and chemical stability of 30 and 150 mmol/L solutions of phosphate, prepared from sodium phosphate injection, in 5% dextrose in water (D5W) and in 0.9% sodium chloride (normal saline [NS]) and stored in polyvinyl chloride (PVC) bags at 23°C or 4°C over 63 days. METHODS: On study day 0, solutions of phosphate 30 and 150 mmol/L in D5W or NS were prepared in PVC bags and stored at 4°C and 23°C. On prespecified days during the 63-day study period, the concentrations of sodium and phosphate were determined, and admixture weight was checked to assess moisture loss during storage without a plastic overwrap. Chemical stability was calculated from the intersection of the lower 95% confidence limit of the degradation rate and the lower limit of acceptability (90%) for concentration remaining. RESULTS: The analytical methods for both sodium and phosphate were found to be precise (coefficient of variation averaging less than 1% for pre-study validation samples). Both sodium and phosphate retained more than 94% of the initial concentration over the 63-day study period. With 95% confidence, the time to achieve 90% of the initial concentration of both sodium and phosphate approached or exceeded the 63-day study period, regardless of temperature, concentration, or base solution. CONCLUSIONS: Sodium phosphate solutions at a phosphate concentration of 30 or 150 mmol/L in either NS or D5W retained more than 94% of the initial concentration of both sodium and phosphate over 63 days when stored at 23°C or 4°C. In compliance with United States Pharmacopeia General Chapter <797> recommendations, a beyond-use date of 14 days (with refrigeration) or 48 h (room temperature) may be applied. Extending the beyond-use date beyond these limits may be considered, if a validated sterility test is performed.

CONTEXTE: Le phosphate de sodium injectable est employé pour traiter l'hypophosphatémie modérée et grave. À ce jour, aucun rapport portant sur la compatibilité physique ou la stabilité chimique du phosphate de sodium injectable contenu dans les solutions intraveineuses n'a été publié. OBJECTIF: Évaluer la compatibilité physique et la stabilité chimique de solutions de phosphate à des concentrations de 30 et de 150 mmol/L préparées à partir de phosphate de sodium injectable dilué dans du dextrose à 5 % dans l'eau (D5E) ou du chlorure de sodium à 0,9 % (solution physiologique salée [SP]) puis rangées dans des sacs de polychlorure de vinyle (PVC) à des températures de 4 °C ou de 23 °C pendant 63 jours. MÉTHODES: Au jour 0 de l'étude, les solutions de phosphate à des concentrations de 30 et de 150 mmol/L ont été préparées avec du D5E ou de la SP dans des sacs de PVC, puis entreposées à des températures de 4 °C ou de 23 °C. À des jours donnés pendant la période de 63 jours de l'étude, on a évalué les concentrations de sodium et de phosphate et l'on a pesé les mélanges pour vérifier la perte d'humidité pendant un entre-posage n'utilisant pas de suremballage de plastique. La stabilité chimique était calculée au point d'intersection entre la limite inférieure de confiance à 95 % du taux de dégradation et la limite inférieure d'acceptabilité (90 %) de la concentration restante. RÉSULTATS: Les méthodes analytiques employées pour évaluer le sodium et le phosphate se sont révélées précises (coefficient de variation moyen inférieur à 1 % pour les échantillons aux fins de validation avant l'étude). Le sodium et le phosphate conservaient chacun plus de 94 % de leurs concentrations initiales pendant la période d'étude de 63 jours. Avec un niveau de confiance de 95 %, le temps nécessaire pour atteindre 90 % de la concentration initiale pour le sodium et pour le phosphate approchait ou dépassait les 63 jours de la période d'étude, peu importe la température, la concentration ou la solution de base. CONCLUSIONS: Les solutions de phosphate de sodium dont la concentration en phosphate est de 30 ou de 150 mmol/L, qu'elles soient à base de D5E ou de SP, conservaient plus de 94 % des concentrations initiales de sodium et de phosphate pendant 63 jours, qu'elles soient entreposées à des températures de 4 °C ou de 23 °C. Conformément aux recommandations contenues dans le chapitre <797> de la United States Pharmacopeia, une date limite d'utilisation de 14 jours (sous réfrigération) ou de 48 heures (à température ambiante) peut être utilisée. Allonger la date limite d'utilisation au-delà des bornes fixées par l'organisme américain peut être envisageable si une épreuve validée de stérilité est réalisée.

Stability of Ertapenem 100 mg/mL in Manufacturer's Glass Vials or Syringes at 4°C and 23°C.

BACKGROUND: Prophylactic administration of ertapenem as a single 1-g IV dose has been shown to reduce sepsis after prostate biopsy. OBJECTIVE: To evaluate the stability of ertapenem after reconstitution with 0.9% sodium chloride to a final concentration of 100 mg/mL and storage in the manufacturer's original glass vials or polypropylene syringes. METHODS: On study day 0, 100 mg/mL solutions of ertapenem were retained in the manufacturer's glass vials or packaged in polypropylene syringes and stored at 4°C or 23°C without protection from fluorescent room light. Samples were assayed periodically over 18 days using a validated, stability-indicating liquid chromatographic method with ultra-violet detection. A beyond-use date was determined as the time for the concentration to decline to 90% of the initial (day 0) concentration, based on the fastest degradation rate, with 95% confidence. RESULTS: Reconstituted solutions stored in the manufacturer's glass vials or polypropylene syringes exhibited a first-order degradation rate, such that 10% of the initial concentration was lost in the first 2.5 days when stored at 4°C or within the first 6.75 h when stored at room temperature (23°C). Analysis of variance showed differences in the percentage remaining due to temperature (p < 0.001) and study day (p < 0.001) but not type of container (p = 0.98). When a 95% CI for the degradation rate was calculated and used to determine a beyond-use date, it was established that more than 90% of the initial concentration would remain for 2.35 days at 4°C and for 0.23 day (about 5 h, 30 min) at room temperature. CONCLUSIONS: A 100 mg/mL ertapenem solution stored in the manufacturer's glass vial or a polypropylene syringe will retain more than 90.5% of the initial concentration when stored for 48 h at 4°C and for an additional 1 h at 23°C.

CONTEXTE: Il a été démontré que l'administration prophylactique d'une dose unique de 1 g d'ertapénem par voie intraveineuse réduit les risques de sepsis après une biopsie de la prostate. OBJECTIF: Évaluer la stabilité de l'ertapénem reconstitué avec une solution de chlorure de sodium à 0,9 % pour atteindre une concentration finale de 100 mg/mL et placé dans les fioles de verre d'origine du fabricant ou dans des seringues de polypropylène. MÉTHODES: Au jour 0 de l'étude, des solutions de 100 mg/mL d'ertapénem ont été conservées dans les fioles de verre d'origine du fabricant ou conditionnées dans des seringues de polypropylène. Elles ont ensuite été entreposées à des températures de 4 °C ou de 23 °C sans protection contre la lumière des lampes fluorescentes de la pièce. Les échantillons ont été dosés périodiquement pendant 18 jours à l'aide d'une épreuve validée mesurant la stabilité par chromatographie liquide avec détection ultraviolette. Une date limite d'utilisation a été établie comme étant le temps nécessaire pour atteindre 90 % de la concentration initiale (jour 0), et ce, en fonction du taux de dégradation le plus rapide, avec un niveau de confiance de 95 %. RÉSULTATS: Les solutions reconstituées placées dans les fioles de verre du fabricant ou dans les seringues de polypropylène ont présenté un taux de dégradation de premier ordre, de sorte que la concentration initiale avait chuté de 10 % après les 2,5 premiers jours d'entreposage à 4 °C ou après les 6,75 premières heures d'entreposage à température ambiante (23 °C). L'analyse de variance a montré des différences dans le pourcentage restant qui étaient associées à la température (p < 0,001) et au jour de l'étude (p < 0,001), mais pas au type de contenant (p = 0,98). Lorsqu'un intervalle de confiance de 95 % pour le taux de dégradation a été calculé et utilisé pour déterminer la date limite d'utilisation, on a établi qu'il resterait plus de 90 % de la concentration initiale pendant 2,35 jours à 4 °C et pendant 0,23 jour (environ 5 heures 30 minutes) à température ambiante. CONCLUSIONS: Une solution de 100 mg/mL d'ertapénem placée dans la fiole de verre du fabricant ou dans une seringue de polypropylène conserve plus de 90,5 % de sa concentration initiale après avoir été entreposée pendant 48 heures à 4 °C et pendant 1 heure additionnelle lorsqu'elle est entreposée à 23 °C.

Does warfarin use impact hospital length of stay? A retrospective study looking at patients treated for atrial fibrillation.

The authors received anecdotal practice information from clinicians indicating that when warfarin was initiated in the hospital setting, it may be associated with an increased length of stay (LOS): specifically to achieve a desired minimum international normalized ratio (INR) of 2.0 before discharge in a subset of patients where clinicians perceived follow-up after discharge was not deemed optimal. Given that oral thromboprophylactic anticoagulation with warfarin is the mainstay treatment for the prevention of stroke in atrial fibrillation (AF), the authors decided to look at hospitalized patients from this population to determine if a subset of these patients experienced an increased LOS. The study design entailed a retrospective chart review of consecutive patients admitted to a large, tertiary care, academic center. Patients were included if they were admitted with a primary, secondary, or most responsible diagnosis of paroxysmal or chronic AF. Medical records were audited over an 18-month period (February 1, 2009, to July 31, 2010) to determine the average LOS and to identify patients with a documented prolonged LOS secondary due to subtherapeutic INR at the time of potential discharge. Our final study cohort of 189 patients had an average LOS of 5.2 days (SD = 5.2). However, for eight (4.2%) of these patients discharge was delayed an additional 2.25 days (SD = 1.3) for reasons solely attributed to achieving a therapeutic INR.

Stability of Ibuprofen solutions in normal saline or 5% dextrose in water.

BACKGROUND: A shortage of the standard medication for treatment of patent ductus arteriosus has necessitated use of parenteral ibuprofen, which is equally efficacious for this indication. The beyond-use date recommended by the manufacturer is very short and has implications for resource allocation and wastage. OBJECTIVE: To evaluate the stability of ibuprofen (undiluted or diluted in either 0.9% sodium chloride [normal saline; NS] or 5% dextrose in water [D5W]) with storage for up to 21 days under refrigeration or at room temperature in glass vials or polypropylene syringes. METHODS: Six glass vials, each containing undiluted ibuprofen (5 mg/mL), were prepared. In addition, ibuprofen was diluted to 2.5 mg/mL in NS or D5W, and 6 syringes were prepared for each diluent (total of 12 syringes). Finally, 6 extension tubes were each primed with 1 mL of ibuprofen (duplicates of undiluted solution and solutions diluted to 2.5 mg/mL in NS or D5W). Half of the vials, syringes, and tubes were stored under refrigeration (4°C) and the other half at room temperature (23°C). The concentration of ibuprofen was determined by a validated, stability-indicating liquid chromatographic method on study days 0, 1, 2, 3, 6, 8, 10, 13, 17, and 21 for samples stored in vials and syringes, or at time 0, 6, 24, and 30 h for samples stored in tubes. RESULTS: Analysis of variance showed differences in the percentage of ibuprofen remaining due to study day (p < 0.001) and diluent (p < 0.005), but no differences due to concentration (p = 0.06) or temperature (p = 0.12). All solutions of ibuprofen were stable throughout the study period, retaining at least 90% of their initial concentration. CONCLUSIONS: Undiluted ibuprofen (5 mg/mL) stored in glass vials and ibuprofen diluted to 2.5 mg/mL with either NS or D5W and stored in polypropylene syringes will retain more than 92% of its initial concentration with storage for up to 14 days at 4°C. A beyond-use date of 14 days would allow for up to 24 h storage at 23°C during this 14-day period. Storage of ibuprofen solutions in extension tubing should not exceed 29 h at 4°C or 17 h at 23°C. Beyond-use dates should be applied only after consideration of US Pharmacopeia Revised General Chapter <797> guidelines for compounding of sterile preparations.

Stability of norepinephrine solutions in normal saline and 5% dextrose in water.

BACKGROUND: Most previous stability studies for norepinephrine have reported the percentage of drug remaining in IV solutions after only 24 h. No previously published study has evaluated the effect of light on the stability of this drug. OBJECTIVE: To evaluate the stability of norepinephrine (64 mg/L) in either normal saline (NS; 0.9% sodium chloride) or 5% dextrose in water (D5W) with storage at either 4°C or room temperature (23°C) in polyvinyl chloride (PVC) bags exposed to or protected from normal room lighting for 2 months. METHODS: Thirty-two PVC bags were prepared, each containing norepinephrine at 64 mg/L; half of the bags had normal saline as the diluent and the other half had D5W. The bags were stored at either 4°C or room temperature (23°C), with protection from or exposure to ambient fluorescent room light. Overall, there were 4 bags for each combination of diluent, temperature, and light condition. The concentration of norepinephrine in each bag was determined by a validated, stability-indicating liquid chromatographic method on study days 0, 1, 2, 3, 4, 8, 9, 10, 11, 14, 18, 21, 23, 25, 28, 30, 36, 42, and 61. RESULTS: Analysis of variance revealed differences in percentage remaining as a function of study day (p < 0.001) and light conditions (p < 0.001), but not diluent (p = 0.06) or storage temperature (p > 0.99). CONCLUSIONS: Solutions of norepinephrine 64 mg/L in NS or D5W can be stored in PVC bags at 4°C for up to 61 days with protection from light. This expiry date allows for up to 24 h storage at 23°C. Solutions that are not protected from light will retain only 90% of the initial concentration after storage for 39 days at 4°C. This storage period could include up to 24 h at room temperature, without protection from light.

Stability of commonly used antibiotic solutions in an elastomeric infusion device.

BACKGROUND: The Accufuser silicone-based elastomeric infusion device has recently been approved for the Canadian market. OBJECTIVE: To evaluate the stability of 5 antibiotics (cefazolin, ceftazidime, ceftriaxone, clindamycin, and vancomycin) in either 5% dextrose in water (D5W) or 0.9% sodium chloride in water (NS) after storage in Accufuser disposable silicone balloon infusers. METHODS: The study drugs were reconstituted, according to the manufacturers' directions, in polyvinyl chloride minibags with either D5W or NS, at 2 different concentrations. The resulting solutions were transferred to disposable silicone balloon infusers for storage at 4°C or at room temperature (23°C). The concentration of each drug in each solution was determined by validated stability-indicating liquid chromatographic methods after storage for 14 to 31 days. RESULTS: Solutions of ceftriaxone in either diluent retained more than 95.2% of the initial concentration for 2 days at room temperature and more than 91.6% of the initial concentration for 14 days at 4°C. Solutions of cefazolin in D5W or NS retained more than 90% of the initial concentration for at least 3 days at room temperature and for at least 26 days at 4°C. Solutions of ceftazidime in D5W or NS retained more than 90% of the initial concentration for only 1 day when stored at room temperature and for at least 4 days at 4°C. Solutions of clindamycin or vancomycin in D5W or NS retained 90% of the initial concentration for at least 7.5 days at room temperature and at least 90% of the initial concentration for at least 27.8 days at 4°C. CONCLUSIONS: Previously reported expiration dates for solutions stored in elastomeric infusion devices were not based on 95% confidence intervals and were often longer than expiration dates determined from the studies reported here, which are based on 95% confidence intervals. Comparison of the observed concentrations remaining between previously published studies and the studies reported here indicates that the Accufuser elastomeric infusion device did not adversely affect the stability of these drugs.

A randomized double-blind trial of the effects of hormone therapy on delayed verbal recall in older women.

We examined whether estradiol and norethindrone hormone therapy (HT) prevented decline in delayed verbal recall in older women with normal to mildly impaired memory functioning. This was a 2-year, randomized, double-blind, placebo-controlled trial of 142 women aged 61-87, randomly assigned to receive 1 mg 17-beta estradiol daily and 0.35 mg norethindrone 3 days/week or daily placebo for 2 years. The primary outcome was short-delay verbal recall of the California Verbal Learning Test (CVLT). To look for differences in response to HT by baseline short-delay recall, we examined the primary outcome in participants grouped according to whether their baseline scores were below average for the age group or greater than or equal to this score and according to whether they met criteria for Mild Cognitive Impairment (MCI) or not. 133 women completed 1 year of the trial and 128 completed 2 years. Prespecified covariates in all repeated measures analyses of covariance (RANCOVA) included age, education, APOE epsilon4, and prior HT use. RANCOVA showed no overall significant treatment effects at year 1 or year 2. After testing for an interaction, which was significant (p=0.02), we found that women in the HT group who scored at or above the average showed significantly less decline than the placebo group in short-delay verbal recall after 1 year, p=0.007 and 2 years, p=0.01. No treatment effects were found in women below the average in either year. When grouped according to whether the participant met criteria for MCI, the interaction between treatment group and MCI subgroup was not significant. These results suggest that benefits of estrogen exposure may be limited to those with average to above average scores on the delayed verbal recall. HT dose and formulation may have contributed to these beneficial outcomes. Replication is warranted before recommendations can be made in the clinical setting.

Extended stability of pantoprazole for injection in 0.9% sodium chloride or 5% dextrose at 4°c and 23°c.

BACKGROUND: The pantoprazole product available in Canada for IV administration has recently been reformulated to include ethylenediaminetetra-acetic acid (EDTA). The purpose of this study was to determine if the chemical stability of pantoprazole for injection containing EDTA (PANTO IV), admixed in polyvinyl chloride (PVC) minibags at concentrations of 0.16 mg/mL and 0.80 mg/mL in 5% dextrose in water (D5W) or 0.9% sodium chloride for injection (normal saline [NS]) and stored at 4°C or 23°C, could be extended beyond the manufacturer's expiry period of 24 hours. METHODS: Sodium pantoprazole was reconstituted in NS or D5W, and 32 PVC minibags were prepared, 16 containing pantoprazole at a nominal concentration of 0.16 mg/mL (8 in NS, 8 in D5W) and 16 containing pantoprazole at a nominal concentration of 0.80 mg/mL (8 in NS, 8 in D5W). Half of the minibags for each diluent-concentration combination were stored at 4°C and half at room temperature (23°C). The concentration of pantoprazole in each minibag was determined by a validated, stability-indicating liquid chromatographic method on study days 0, 1, 2, 4, 7, 9, 11, 14, and 21. RESULTS: Analysis of variance revealed differences in the percentage of drug remaining in relation to temperature (p < 0.001), study day (p = 0.001), concentration (p = 0.007), and diluent (p = 0.008). CONCLUSIONS: Solutions of pantoprazole in D5W with concentration between 0.16 mg/mL and 0.80 mg/mL can be stored for a maximum of 11 days at 4°C plus an additional 6 h at 23°C. The saline solutions degraded more slowly, and pantoprazole admixtures in NS with concentration between 0.16 mg/mL and 0.80 mg/mL can be stored for 20 days at 4°C plus an additional 6 h at 23°C. Under these conditions, more than 90% of the initial concentration will remain (with 95% confidence).

Severe Raynaud's phenomenon with yohimbine therapy for erectile dysfunction.

Yohimbine is a selective alpha-2 adrenergic antagonist that has been used in the pharmacologic management of erectile dysfunction (ED). We describe a patient with CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) who paradoxically experienced worsening of Raynaud's phenomenon when using yohimbine for ED.