Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 Genotype and Methadone Therapy.

Methadone is a mu (µ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP). Genetic variation in the CYP2B6 gene has been investigated in the context of implications for methadone pharmacokinetics, dose, and clinical outcomes. Most CYP2B6 variants result in diminished or loss of CYP2B6 enzyme activity, which can lead to higher plasma methadone concentrations (affecting S- more than R-methadone). However, the data do not consistently indicate that CYP2B6-based metabolic variability has a clinically significant effect on methadone dose, efficacy, or QTc prolongation. Expert analysis of the published literature does not support a change from standard methadone prescribing based on CYP2B6 genotype (updates at www.cpicpgx.org).

Provider-directed analgesia for dental pain.

INTRODUCTION: Extraction of impacted molar teeth is a common procedure performed by oral surgeons and general dentists, with postoperative pain being a significant adverse event post-surgery. If mismanaged, pain can lead to complications that impact oral and systemic health. The current scourge of the opioid epidemic has ushered in a new era of provider-directed analgesic (PDA) therapy in dentistry. AREAS COVERED: This article provides an in-depth review on the major pharmacological and therapeutic properties of established and alternative analgesics used to manage dental pain. EXPERT OPINION: Substantial evidence-based literature shows a combination of a non-steroidal anti-inflammatory drug (NSAID; e.g. ibuprofen) and acetaminophen provides superior pain relief than single-agent or combination opioid regimens. However, there are clinical scenarios (e.g. severe pain) where a short-course opioid prescription is appropriate in select patients, for which a 2-3-day treatment duration is typically sufficient. Alternative agents (e.g. caffeine, gabapentin, phytotherapies), typically in combination with established agents, can mitigate postoperative dental pain. Some evidence suggests preemptive therapies (e.g. corticosteroids, NSAIDs) reduce amounts of postsurgical analgesic consumption and might lessen opioid prescription burden. In summary, this comprehensive review provides an opportune update on the evolving landscape of pharmacotherapy for acute postsurgical dental pain, informing best practices for PDA in the dental setting.

The impact of coronavirus disease 2019 pandemic on dental school assessments - Current status and future perspectives.

PURPOSE: To evaluate course directors' feedback on the assessment methods used during the coronavirus disease 2019 (COVID-19) pandemic and identify effective approaches for future assessments in dental education. METHODS: Course directors at the US dental schools were surveyed for changes in assessments implemented during the early stages of the pandemic (March-July 2020) using the Qualtrics platform. The survey questions addressed assessment methods utilized in didactic, preclinical, and clinical arenas pre-COVID-19 (before March 2020) and during the early phase of the pandemic (between March and July 2020) and identified any sustained changes in assessments post-COVID-19. Of the 295 responses for the type of courses directed, 48%, 22%, and 30% responses were for didactic, pre-clinical, and clinical assessments, respectively. Chi-square tests and 95% confidence intervals were used to assess quantitative differences. RESULTS: Computer-based un-proctored and remote- proctored assessments increased whereas paper-based in-person proctored assessments decreased during an early pandemic. For pre-clinical and clinical courses, objective-structured clinical exams and case-based assessments increased whereas, for didactic courses, the number of presentations, short-answer, and multiple-choice questions-based assessments increased. Specimen-based assessments and patient-based encounters decreased significantly in didactic and clinical courses, respectively. Manikin-based exams increased in clinical but not in pre-clinical courses. Survey respondents disagreed that alternative assessments helped students learn better, resulted in better course evaluations, or were an equivalent replacement for pre-COVID-19 assessments. Interestingly, 49% of respondents indicated a likelihood of continuing alternative assessments whereas 36% were unlikely and 15% were neutral. CONCLUSIONS: A combination of effective pre-pandemic and innovative alternative assessments developed during the pandemic may be the new normal in the dental education curriculum.

Interactions of Betel Quid Constituents with Drug Disposition Pathways: An Overview.

Global estimates indicate that over 600 million individuals worldwide consume the areca (betel) nut in some form. Nonetheless, its consumption is associated with a myriad of oral and systemic ailments, such as precancerous oral lesions, oropharyngeal cancers, liver toxicity and hepatic carcinoma, cardiovascular distress, and addiction. Users commonly chew slivers of areca nut in a complex consumable preparation called betel quid (BQ). Consequently, the user is exposed to a wide array of chemicals with diverse pharmacokinetic behavior in the body. However, a comprehensive understanding of the metabolic pathways significant to BQ chemicals is lacking. Henceforth, we performed a literature search to identify prominent BQ constituents and examine each chemical's interplay with drug disposition proteins. In total, we uncovered over 20 major chemicals (e.g., arecoline, nicotine, menthol, quercetin, tannic acid) present in the BQ mixture that were substrates, inhibitors, and/or inducers of various phase I (e.g., CYP, FMO, hydrolases) and phase II (e.g., GST, UGT, SULT) drug metabolizing enzymes, along with several transporters (e.g., P-gp, BCRP, MRP). Altogether, over 80 potential interactivities were found. Utilizing this new information, we generated theoretical predictions of drug interactions precipitated by BQ consumption. Data suggests that BQ consumers are at risk for drug interactions (and possible adverse effects) when co-ingesting other substances (multiple therapeutic classes) with overlapping elimination mechanisms. Until now, prediction about interactions is not widely known among BQ consumers and their clinicians. Further research is necessary based on our speculations to elucidate the biological ramifications of specific BQ-induced interactions and to take measures that improve the health of BQ consumers.

Effect of imatinib on oral wound healing after extraction: A rare case report.

BACKGROUND: Proper tissue repair and healing after oral surgery are vital to achieve optimal outcomes. Certain medications may interfere with wound healing, but this debilitating adverse drug reaction is often not reported in the literature. It is unknown whether imatinib (Gleevec; Novartis Pharmaceuticals) interferes with gingival healing after oral surgery. CASE DESCRIPTION: A 58-year-old man with a dislodged crown and core buildup of tooth no. 19 sought treatment at a prosthodontic clinic. After examination, the patient consented to extraction, ridge preservation, and future implant placement. He had previous surgical resection of a gastrointestinal stromal tumor and was taking 400 mg of imatinib daily. After extraction and ridge preservation, delayed soft-tissue healing and loss of the coronal portion of bone graft were observed at 8 weeks after surgery. Delayed wound healing was observed again after revision surgery. After imatinib therapy was paused, the adverse effect subsided and the wound healed properly. On the basis of causality assessment and clinical judgment, the authors determined that imatinib was the probable cause of this adverse drug reaction. To their best knowledge, this is the first report of delayed gingival healing after oral surgery secondary to imatinib. PRACTICAL IMPLICATIONS: Dental practitioners should consider the possibility of impaired healing among their patients taking imatinib, especially before procedures that damage gingival tissue, although this adverse drug reaction is not reported in the drug's package insert. Consult with the patient's oncologist is advised before dental manipulations; temporary discontinuation (or dose reductions) of imatinib may be warranted until wounded tissue heals properly.

Metabolism of the areca alkaloids - toxic and psychoactive constituents of the areca (betel) nut.

Areca nut (AN) is consumed by millions of people for its therapeutic and psychoactive effects, making it one of the most widely self-administered psychoactive substances in the world. Even so, AN use/abuse is associated with myriad oral and systemic side effects, affecting most organ systems in the body. Alkaloids abundant in the nut (e.g. arecoline, arecaidine, guvacoline, and guvacine), collectively called the areca alkaloids, are presumably responsible for the major pharmacological effects experienced by users, with arecoline being the most abundant alkaloid with notable toxicological properties. However, the mechanisms of arecoline and other areca alkaloid elimination in humans remain poorly documented. Therefore, the purpose of this review is to provide an in-depth review of areca alkaloid pharmacokinetics (PK) in biological systems, and discuss mechanisms of metabolism by presenting information found in the literature. Also, the toxicological relevance of the known and purported metabolic steps will be reviewed. In brief, several areca alkaloids contain a labile methyl ester group and are susceptible to hydrolysis, although the human esterase responsible remains presumptive. Other notable mechanisms include N-oxidation, glutathionylation, nitrosamine conversion, and carbon-carbon double-bond reduction. These metabolic conversions result in toxic and sometimes less-toxic derivatives. Arecoline and arecaidine undergo extensive metabolism while far less is known about guvacine and guvacoline. Metabolism information may help predict drug interactions with human pharmaceuticals with overlapping elimination pathways. Altogether, this review provides a first-of-its-kind comprehensive analysis of AN alkaloid metabolism, adds perspective on new mechanisms of metabolism, and highlights the need for future metabolism work in the field.

Chemical Degradation of Intravenous Chemotherapy Agents and Opioids by a Novel Instrument.

Purpose: To assess chemical degradation of various liquid chemotherapy and opioid drugs in the novel RxDestruct™ instrument. Methods: Intravenous (IV) drug solutions for chemotherapy and pain management were prepared using 0.9% normal saline in Excel® bags to a final volume of 500 mL. We investigated duplicate IV solutions of methotrexate (0.1 mg/mL), etoposide (0.4 mg/mL), doxorubicin (0.25 mg/mL), cladribine (12.4 µg/mL), fentanyl (1.0 µg/mL), and hydromorphone (12.0 µg/mL) in this study. Solutions were poured into an automated instrument to undergo pulsatile chemical treatment (Fenton reactions) for 20 minutes, and then discharged from the instrument through a waste outlet. Extent of intact drug degradation was determined by measuring concentrations of drugs before entry into the instrument and after chemical treatment in the filtrate using high-performance liquid-chromatography with ultraviolet detection (HPLC-UV). Results: Following chemical reactions (Fenton processes) in the automated instrument, infusion solutions containing methotrexate, etoposide, doxorubicin, and cladribine had levels below the HPLC-UV limit of quantification (LOQ), indicating <50 ppb of each. This equated to >99.5%, 99.99%, 99.9%, and 99.8% intact drug loss, respectively. Likewise, processed samples of fentanyl and hydromorphone contained levels below the LOQ (78 and 98 ng/mL, respectively), indicating extensive degradation (>92.2% and 99.2% intact drug loss, respectively). Conclusion: The novel instrument was capable of degrading intact chemotherapy and opioid drugs prepared in infusion solutions to undetectable quantities by HPLC-UV. RxDestruct™ is a possible alternative for disposal of aqueous medication waste.

Retail Availability and Characteristics of Addictive Areca Nut Products in a US Metropolis.

Consumption of the areca (betel) nut is the world's fourth-most common addictive habit, only after caffeine, alcohol, and nicotine. Mastication of the nut releases psychoactive alkaloids that produce greater alertness, a tingling sensation in the body, and euphoria. Consumption is prevalent in many Asia-Pacific countries, but also within immigrant populations in Europe and North America. Regarding use/abuse in the US, data are limited to mostly case/anecdotal reports, and some published literature. Little is known about the retail availability and product characteristics of areca products in the US. In this field observational study, we found that areca products were relatively inexpensive, readily available, and easily purchased in grocery stores visited in Houston, TX. Almost entirely, no hindrances or warnings for purchasing occurred, which is concerning since it is well-established that consumption is associated with substance abuse and untoward oral/systemic health effects. Several products contained the sweetening agent sodium cyclamate, a substance currently banned by the FDA. Others products contain menthol, the role of which in areca addiction is unknown. Collectively, our findings support the need for future psychopharmacological and public health research, as well as closer investigation by US policy makers and statewide/federal regulatory agencies.

Electrophilic reactivity of the Busulfan metabolite, EdAG, towards cellular thiols and inhibition of human thioredoxin-1.

Busulfan is an alkylating agent used in chemotherapy conditioning regimens prior to hematopoietic stem cell transplantation (HSCT). However, its administration is associated with a great risk of adverse toxicities, which have been historically attributed to busulfan's mechanism of non-specific DNA alkylation. A phase II generated metabolite of busulfan, EdAG (γ-glutamyldehydroalanylglycine), is a dehydroalanine analog of glutathione (GSH) with an electrophilic moiety, suggesting it may bind to proteins and disrupt biological function. However, EdAG's reactions with common cellular thiols such as glutathione (GSH) and l-cysteine are understudied, along with possible inhibition of glutathionylation-dependent enzymes (with active site cysteine residues). We established a physiologically-relevant in vitro model to readily measure thiol loss over time. Using this model, we compared the apparent rates of thiol depletion in the presence of EdAG or arecoline, a toxic constituent of the areca (betel) nut and known GSH depletor. Simulated kinetic modeling revealed that the mean (±SE) alpha (α) second order rate constants describing GSH and l-cysteine depletion in the presence of EdAG were 0.00522 (0.00845) µM-1∙min-1 and 0.0207 (0.00721) µM-1∙min-1, respectively; in the presence of arecoline, the apparent rates of depletion were 0.0619 (0.009) µM-1∙min-1 and 0.2834 (0.0637) µM-1∙min-1 for GSH and l-cysteine, respectively. Under these experimental conditions, we conclude that EdAG was a weaker electrophile than arecoline. Arecoline and EdAG both depleted apparent l-cysteine concentrations to a much greater extent than GSH, approximately 4.58-fold and 3.97-fold change greater, respectively. EdAG modestly inhibited (∼20%) the human thioredoxin-1 (hTrx-1) catalyzed reduction of insulin with a mean IC50 of 93 µM [95% CI: 78.6-110 µM). In summary, EdAG's ability to spontaneously react with endogenous thiols and inhibit hTrx-1 are potentially biochemically relevant in humans. These findings continue to support the growing concept that EdAG, an underrecognized phase II metabolite of busulfan, plays a role in untoward cellular toxicities during busulfan pharmacotherapy.

A rare case of methotrexate and primaquine co-administration in a mantle cell lymphoma patient.

WHAT IS KNOWN AND OBJECTIVE: High-dose methotrexate (HD-MTX) is associated with a plethora of adverse drug reactions and potential drug interactions (DIs). But there is a paucity of information regarding the safety of co-administering primaquine with HD-MTX. CASE SUMMARY: A 65-year-old male patient was diagnosed with mantle cell lymphoma (MCL) with CNS involvement and treated with three cycles of IV HD-MTX. His case was further complicated by fungal pneumonia treated with primaquine during cycle-2. Serial blood sampling and subsequent population pharmacokinetics (PK) modelling suggests a possible distribution-mediated DI between the two drugs. WHAT IS NEW AND CONCLUSION: This is the first case report to highlight the safe co-administration of MTX and primaquine, despite a possible PK interaction.

Pharmacokinetics: Unique Challenges in Blood Monitoring for Oncology Nurses.

BACKGROUND: Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion of drugs. Many chemotherapeutic agents have a sensitive PK index, in which a small margin in blood concentrations is the difference between nontherapeutic, therapeutic, and adverse outcomes. OBJECTIVES: This article will provide an overview of evidence-based approaches to the collection of PK samples, monitoring of PK levels, and the resulting management of patients undergoing PK testing. METHODS: A case study involving busulfan, an alkylating agent used in the pre-stem cell transplantation setting, will highlight the cross-contamination of samples while a drug is being infused through a central venous catheter with PK sample collection from a proximal peripherally inserted central catheter. The influence of false elevations in drug concentrations on PK-guided dose adjustments will also be emphasized. FINDINGS: Imprecise blood collections or cross-contamination of samples may lead to inaccurate drug concentration results and, subsequently, undesired low or high drug dosage calculations.

Interdisciplinary implementation of tacrolimus intravenous standard concentration in hematopoietic stem cell transplantation recipients.

Purpose Reduction in waste of intravenous (IV) tacrolimus, an immunosuppressant used to prevent graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients, was evaluated after standardizing the concentration. Methods A single-center, retrospective cohort study at a large academic comprehensive cancer center was performed comparing patient-specific intravenous tacrolimus doses (tacrolimus doses in 50, 100, or 250 mL of normal saline based on manufacturer's recommended concentration) to tacrolimus intravenous standard concentration (tacrolimus 1 mg in 250 mL of normal saline) continuous intravenous infusion titrated to prescribed dose. The cohort study was performed on two hematopoietic stem cell transplantation nursing units consisting of a prepilot phase during which time patient-specific intravenous tacrolimus doses were compounded and administered, followed by the pilot phase during which patients received tacrolimus intravenous standard concentration. The primary endpoint was reduction in tacrolimus intravenous bags wasted. Secondary endpoints were drug cost savings, decreased intravenous infusion line supplies, decrease in time needed to execute dose changes, reduction in infusion pump alerts, and number of patient safety events. Results Compared to the prepilot phase, there was a 64% reduction in tacrolimus intravenous bags wasted during the pilot phase ( p = 0.029), resulting in a mean monthly total cost savings of $224.31 for pilot units. Intravenous pump line use was reduced by 18% ( p = 0.067), yielding a monthly total cost savings of $84.02 for pilot units. The median time needed to execute dose changes and intravenous pump overrides was significantly reduced ( p < 0.0001, p < 0.0001, respectively). Conclusion This interdisciplinary quality improvement initiative led to increased efficiency, reduction in waste, and decreased intravenous pump alerts utilizing tacrolimus intravenous standard concentration.

Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review.

INTRODUCTION: Busulfan (Bu) is an alkylating agent with a limited therapeutic margin and exhibits inter-patient variability in pharmacokinetics (PK). Despite decades of use, mechanisms of Bu PK-based drug-drug interactions (DDIs), as well as the negative downstream effects of these DDIs, have not been fully characterized. Areas covered: This article provides an overview of Bu PK, with a primary focus on how known and potentially unknown drug metabolism pathways influence Bu-associated DDIs. In addition, pharmacogenomics of Bu chemotherapy and Bu-related DDIs observed in the stem cell transplant clinic (SCT) are summarized. Finally the increasing importance of Bu therapeutic drug monitoring is highlighted. Expert opinion: Mechanistic studies of Bu metabolism have shown that in addition to GST isoenzymes, other oxidative enzymes (CYP, FMO) and ABC/MDR drug transporters likely contribute to the overall clearance of Bu. Despite many insights, results from clinical studies, especially in polypharmacy settings and between pediatric and adult patients, remain conflicting. Further basic science and clinical investigative efforts are required to fully understand the key factors determining Bu PK characteristics and its effects on complications after SCT. Improved TDM strategies are promising components to further investigate, for instance DDI mechanisms and patient outcomes, in the highly complex SCT treatment setting.

Solubilization and Stability of Mitomycin C Solutions Prepared for Intravesical Administration.

BACKGROUND: Mitomycin C (MMC) is an antitumor agent that is often administered intravesically to treat bladder cancer. Pharmacologically optimized studies have suggested varying methods to optimize delivery, with drug concentration and solution volume being the main drivers. However, these MMC concentrations (e.g. 2.0 mg/mL) supersede its solubility threshold, raising major concerns of inferior drug delivery. OBJECTIVE: In this study, we seek to confirm that the pharmacologically optimized MMC concentrations are achievable in clinical practice through careful modifications of the solution preparation methods. METHODS: MMC admixtures (1.0 and 2.0 mg/mL) were prepared in normal saline using conventional and alternative compounding methods. Conventional methodology resulted in poorly soluble solutions, with many visible particulates and crystallates. However, special compounding methods, which included incubation of solutions at 50 °C for 50 min followed by storage at 37 °C, were sufficient to solubilize drug. Chemical degradation of MMC solutions was determined over 6 h using high-performance liquid chromatography (HPLC) analytics, while physical stability was tested in parallel. RESULTS: Immediately following the 50 min incubation, both MMC solutions exhibited approximately 5-7% drug degradation. Based on the measured concentrations and linear regression of degradation plots, additional storage of these solutions at 37 °C for 5 h retained chemical stability criterion (< 10% overall drug loss). No physical changes were observed in any solutions at any test time points. CONCLUSION: We recommend that the described alternative preparation methods may improve intravesicular delivery of MMC in this urological setting, and advise that clinicians employing these changes should closely monitor patients for MMC toxicities and pharmacodynamics (change in clinical outcomes) that result from the potential enhancement of MMC exposure in the bladder.

Stability of tacrolimus injection diluted in 0.9% sodium chloride injection and stored in Excel bags.

PURPOSE: The chemical stability and physical compatibility of tacrolimus i.v. infusion solutions prepared in Excel bags and stored at 23 or 4 °C for up to nine days were studied. METHODS: Tacrolimus admixtures (2, 4, and 8 µg/mL) were prepared in Excel bags using 0.9% sodium chloride injection and stored at 23 °C without protection from light or at 4 °C in the dark. Test samples were withdrawn from triplicate bag solutions immediately after preparation and at predetermined time intervals (1, 3, 5, 7, and 9 days). Chemical stability was assessed by measuring tacrolimus concentrations using a validated stability-indicating high-performance liquid chromatography assay. The physical stability of the admixtures was assessed by visual examination and by measuring turbidity, particle size, and drug content. RESULTS: All test solutions stored at 23 or 4 °C had a no greater than 6% loss of the initial tacrolimus concentration throughout the nine-day study period. All test samples of tacrolimus admixtures, under both storage conditions, were without precipitation and remained clear initially and throughout the nine-day observation period. Changes in turbidities were minor; measured particulates remained few in number in all samples throughout the study. CONCLUSION: Extemporaneously prepared infusion solutions of tacrolimus 2, 4, and 8 µg/mL in 0.9% sodium chloride injection in Excel bags were chemically and physically stable for at least nine days when stored at room temperature (23 °C) without protection from light and when stored in a refrigerator (4 °C) in the dark.

Erratum to: Pharmacokinetic evaluation of nanoparticle albumin-bound paclitaxel delivered via hepatic arterial infusion in patients with predominantly hepatic metastases.

In the original article, corresponding author's given name and family name are flipped. It should be "Siqing Fu" rather than "Fu Siqing".

Pharmacokinetic evaluation of nanoparticle albumin-bound paclitaxel delivered via hepatic arterial infusion in patients with predominantly hepatic metastases.

PURPOSE: Cancer patients with predominantly hepatic metastases have poor outcomes and limited options. Hepatic arterial infusion (HAI) of a therapeutic agent may be an appropriate option for producing increased drug concentrations at the tumor sites while reducing systemic adverse effects in normal tissues. METHODS: Patients with predominantly hepatic metastases (n = 48) were placed in 6 groups according to nanoparticle albumin-bound paclitaxel (nab-paclitaxel) dose level using a 3 + 3 design plus dose expansion for responsive tumor types. We evaluated the toxicity, antitumor activity, and pharmacokinetics of nab-paclitaxel delivered via HAI. RESULTS: Thirty-eight and ten patients underwent HAI over 1 and 4 h, respectively, at doses of up to 300 mg/m(2). The treatment was safe and exhibited antitumor activity. Pharmacokinetic analyses revealed that HAI of nab-paclitaxel over 4 h resulted in markedly lower peak drug concentrations (C max) and longer times to peak concentration (T max) than that over 1 h. The self-control pharmacokinetic studies showed that HAI of nab-paclitaxel led to much lower C max and areas under the curve (AUC), compared with intravenous infusion. CONCLUSIONS: HAI of nab-paclitaxel at up to 300 mg/m(2) over 4 h was well tolerated. Pharmacokinetic evaluation of C max, T max, and AUC implied that 4-h HAI enhanced hepatic extraction of nab-paclitaxel. Further preclinical and clinical studies are required to develop reliable methods of evaluation of hepatic extraction (clinicaltrials.gov registration number NCT00732836, first registered on August 8, 2008, and last updated on October 27, 2014).

Physical and chemical stability of proflavine contrast agent solutions for early detection of oral cancer.

BACKGROUND AND PURPOSE: Proflavine hemisulfate solution is a fluorescence contrast agent to visualize cell nuclei using high-resolution optical imaging devices such as the high-resolution microendoscope. These devices provide real-time imaging to distinguish between normal versus neoplastic tissue. These images could be helpful for early screening of oral cancer and its precursors and to determine accurate margins of malignant tissue for ablative surgery. Extemporaneous preparation of proflavine solution for these diagnostic procedures requires preparation in batches and long-term storage to improve compounding efficiency in the pharmacy. However, there is a paucity of long-term stability data for proflavine contrast solutions. METHODS: The physical and chemical stability of 0.01% (10 mg/100 ml) proflavine hemisulfate solutions prepared in sterile water was determined following storage at refrigeration (4-8℃) and room temperature (23℃). Concentrations of proflavine were measured at predetermined time points up to 12 months using a validated stability-indicating high-performance liquid chromatography method. RESULTS: Proflavine solutions stored under refrigeration were physically and chemically stable for at least 12 months with concentrations ranging from 95% to 105% compared to initial concentration. However, in solutions stored at room temperature increased turbidity and particulates were observed in some of the tested vials at 9 months and 12 months with peak particle count reaching 17-fold increase compared to baseline. Solutions stored at room temperature were chemically stable up to six months (94-105%). CONCLUSION: Proflavine solutions at concentration of 0.01% were chemically and physically stable for at least 12 months under refrigeration. The solution was chemically stable for six months when stored at room temperature. We recommend long-term storage of proflavine solutions under refrigeration prior to diagnostic procedure.

Stability study of carboplatin infusion solutions in 0.9% sodium chloride in polyvinyl chloride bags.

BACKGROUND AND PURPOSE: Carboplatin is a platinum-containing compound with efficacy against various malignancies. The physico-chemical stability of carboplatin in dextrose 5% water (D5W) has been thoroughly studied; however, there is a paucity of stability data in clinically relevant 0.9% sodium chloride infusion solutions. The manufacturer's limited stability data in sodium chloride solutions hampers the flexibility of carboplatin usage in oncology patients. Hence, the purpose of this study is to determine the physical and chemical stability of carboplatin-sodium chloride intravenous solutions under different storage conditions. METHODS: The physico-chemical stability of 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL carboplatin-sodium chloride solutions prepared in polyvinyl chloride bags was determined following storage at room temperature under ambient fluorescent light and under refrigeration in the dark. Concentrations of carboplatin were measured at predetermined time points up to seven days using a stability-indicating high-performance liquid chromatography method. RESULTS: All tested solutions were found physically stable for at least seven days. The greatest chemical stability was observed under refrigerated storage conditions. At 4℃, all tested solutions were found chemically stable for at least seven days, with nominal losses of ≤6%. Following storage at room temperature exposed to normal fluorescent light, the chemical stability of 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL solutions was three days, five days, and seven days, respectively. CONCLUSION: The extended physico-chemical stability of carboplatin prepared in sodium chloride reported herein permits advance preparation of these admixtures, facilitating pharmacy utility and operations. Since no antibacterial preservative is contained within these carboplatin solutions, we recommend storage, when prepared under specified aseptic conditions, no greater than 24 h at room temperature or three days under refrigeration.