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Gastroenterology Nursing : the Official... 2014
Topics: Desoximetasone; Granisetron; Humans; Indoles; Isoquinolines; Nausea; Ondansetron; Palonosetron; Quinolizines; Quinuclidines; Serotonin Antagonists; Vomiting
PubMed: 24691090
DOI: 10.1097/SGA.0000000000000040 -
AAPS PharmSciTech Jun 2014It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development...
It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development program. However, we are unaware of efforts to classify drugs into a Biopharmaceutics Classification System (BCS) framework for pediatric patients. The objective was to classify five drugs into a potential BCS. These five drugs were selected since both oral and intravenous pharmacokinetic data were available for each drug, and covered the four BCS classes in adults. Literature searches for each drug were conducted using Medline and applied to classify drugs with respect to solubility and permeability in pediatric subpopulations. Four pediatric subpopulations were considered: neonates, infants, children, and adolescents. Regarding solubility, dose numbers were calculated using a volume for each subpopulation based on body surface area (BSA) relative to 250 ml for a 1.73 m(2) adult. Dose numbers spanned a range of values, depending upon the pediatric dose formula and subpopulation. Regarding permeability, pharmacokinetic literature data required assumptions and decisions about data collection. Using a devised pediatric BCS framework, there was agreement in adult and pediatric BCS class for two drugs, azithromycin (class 3) and ciprofloxacin (class 4). There was discordance for the three drugs that have high adult permeability since all pediatric permeabilities were low: dolasetron (class 3 in pediatric), ketoprofen (class 4 in pediatric), and voriconazole (class 4 in pediatric). A main contribution of this work is the identification of critical factors required for a pediatric BCS.
Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Age Factors; Azithromycin; Biological Availability; Biopharmaceutics; Body Surface Area; Child; Child, Preschool; Ciprofloxacin; Drug Dosage Calculations; Humans; Indoles; Infant; Infant, Newborn; Ketoprofen; Models, Biological; Pediatrics; Permeability; Quinolizines; Risk Assessment; Solubility; Terminology as Topic; Voriconazole
PubMed: 24557773
DOI: 10.1208/s12249-014-0084-0 -
Hospital Pharmacy Jan 2014The physical and chemical compatibility of intravenous acetaminophen with commonly administered injectable medications was evaluated.
PURPOSE
The physical and chemical compatibility of intravenous acetaminophen with commonly administered injectable medications was evaluated.
METHODS
Simulated Y-site evaluation was accomplished by mixing 2 mL of acetaminophen (10 mg/mL) with 2 mL of an alternative intravenous medication and subsequently storing the mixture in a polypropylene syringe for 4 hours. The aliquot solutions were visually inspected and evaluated for crystal content at 4 hours by infusing 4 mL of the medication mixture through a 0.45-μm nitrocellulose filter disc. Medication mixtures that were selected for chemical stability testing were analyzed by high-performance liquid chromatography at 0, 1, and 4 hours using a Zorbax Eclipse Plus C18, 4.6 x 100 mm, 3.5-μm column for separation of analytes with subsequent diode-array detection. Medications were considered chemically compatible if the concentrations of all components were >90% of the original concentrations during the 4 hour simulated Y-site compatibility test.
RESULTS
U.S. Pharmacopeial Convention (USP) standards for physical particle counts were met for acetaminophen injection (10 mg/mL) when combined with cefoxitin, ceftriaxone, clindamycin, dexamethasone, diphenhydramine, dolasetron, fentanyl, granisetron, hydrocortisone, hydromorphone, ketorolac, meperidine, methylprednisolone, midazolam, morphine, nalbuphine, ondansetron, piperacillin/tazobactam, ranitidine, and vancomycin. Injectable acetaminophen is incompatible with acyclovir and diazepam and therefore should not be administered concomitantly with either of these products. Further testing confirmed the chemical compatibility of acetaminophen with ceftriaxone, diphenhydramine, granisetron, ketorolac, nalbuphine, ondansetron, piperacillin/tazobactam, and vancomycin.
CONCLUSION
All medications tested with acetaminophen were physically compatible except for acyclovir and diazepam. All 8 medications tested for chemical compatibility with acetaminophen were stable over the 4 hour simulated Y-site administration study.
PubMed: 24421562
DOI: 10.1310/hpj4901-42 -
Mayo Clinic Proceedings Jan 2014To test the primary hypothesis that ondansetron or dolasetron extends the rate-corrected QT electrocardiographic interval (QTc) greater than 60 milliseconds or increases... (Comparative Study)
Comparative Study
OBJECTIVE
To test the primary hypothesis that ondansetron or dolasetron extends the rate-corrected QT electrocardiographic interval (QTc) greater than 60 milliseconds or increases the fraction of patients with QTc greater than 500 milliseconds in patients having noncardiac surgery, and the secondary hypothesis that QTc prolongation is worse in diabetic patients.
PATIENTS AND METHODS
We extracted data from the Cleveland Clinic's Perioperative Health Documentation System between March 25, 2006, and September 30, 2010, and additional perioperative medications from Cleveland Clinic pharmacy's Epic Cost of Goods Sold (COGS) system. We searched for patients who had a preoperative electrocardiogram within 1 month of surgery and postoperatively within 2 hours. We excluded patients given an antiemetic drug other than ondansetron or dolasetron perioperatively, and those given amiodarone.
RESULTS
A total of 1429 patients given serotonin-3 receptor (5HT3R) antagonists and 1022 controls met the enrollment criteria. Seventeen percent of patients given 5HT3R antagonists (n=242) and 22% of controls (n=220) had postoperative QTc exceeding 500 milliseconds. Mean ± SD presurgical and postsurgical QTc, respectively, were 438±37 milliseconds and 464±41 milliseconds for 5HT3R antagonist patients and 443±40 milliseconds and 469±47 milliseconds for control patients. Univariable mean ± SD perioperative increases in QTc were 26±39 and 26±48 milliseconds in the 2 groups. After adjusting for confounding variables, there were no differences in the mean increase in QTc in patients who were and were not given 5HT3R antagonists: -0.1 milliseconds (97.5% CI, -5.2 to 5.0 milliseconds; multivariable P=.97). The QTc was prolonged, but not significantly, in diabetic patients given 5HT3R antagonists (P=.16).
CONCLUSIONS
The average QTc prolongation from baseline was only 6%. Perioperative use of ondansetron or dolasetron was not associated with extended QT prolongation, and these results did not vary by diabetic status. Perioperative use of 5HT3R antagonists does not produce potentially dangerous perioperative electrocardiographic changes and does not seem to warrant a drug safety warning from the Food and Drug Administration.
Topics: Aged; Aged, 80 and over; Female; Heart Rate; Humans; Indoles; Long QT Syndrome; Male; Middle Aged; Ondansetron; Postoperative Complications; Postoperative Period; Preoperative Care; Quinolizines; Serotonin 5-HT3 Receptor Antagonists; Young Adult
PubMed: 24388024
DOI: 10.1016/j.mayocp.2013.10.008 -
Journal of Anaesthesiology, Clinical... Oct 2013Postoperative nausea and vomiting (PONV) is common after ambulatory surgery performed under general anesthesia. Anecdotal evidence suggests that caffeine may be useful...
CONTEXT
Postoperative nausea and vomiting (PONV) is common after ambulatory surgery performed under general anesthesia. Anecdotal evidence suggests that caffeine may be useful in preventing PONV.
AIMS
The aim of the study was to determine efficacy of intravenous (IV) caffeine given prior to surgery is effective prophylaxis against PONV.
SETTINGS AND DESIGN
We conducted a prospective, randomized, double-blind, placebo-controlled study.
SUBJECT AND METHODS
Patients at moderate or high risk of PONV were randomized to receive IV caffeine (500 mg) or saline placebo during general anesthesia; all patients received dexamethasone and dolasetron.
STATISTICAL ANALYSIS
Statistical comparisons were tested using bivariable linear and logistic regression for each outcome and then adjusted for high/low risk.
RESULTS
Nausea in the postanesthesia care unit (PACU) was more common in the caffeine (16 of 62 patients) than the placebo group (seven of 69; P = 0.02). There were no significant differences in the use of rescue antiemetics in the PACU, in the incidence of nausea or vomiting over 24 h postoperatively, nor in other outcomes (headache, fatigue, or overall satisfaction) either in the PACU or at 24 h; time-to-discharge was similar for both groups.
CONCLUSION
Caffeine was not effective in the prevention of PONV or headache, and did not improve time-to-discharge or patient satisfaction.
PubMed: 24249992
DOI: 10.4103/0970-9185.119170 -
European Journal of Pharmacology Jan 2014Nausea and vomiting are major side effects of chemotherapy and one key reason for non-compliance with cancer treatment. The introduction of 5-HT3 receptor antagonists in... (Review)
Review
Nausea and vomiting are major side effects of chemotherapy and one key reason for non-compliance with cancer treatment. The introduction of 5-HT3 receptor antagonists in the 1990s was a major advance in the prevention of acute emesis, and highlighted the critical role of serotonin in the emetic response. The next major advance in the treatment of chemotherapy induced nausea and vomiting (CINV) occurred in 2003 with the introduction of aprepitant, a tachykinin 1 (NK1) receptor antagonist. Aprepitant not only reduced acute emesis but also helped in the reduction of delayed emesis. Also in 2003, palonosetron, a second generation 5-HT3 receptor antagonist became available. Unlike the first generation 5-HT3 receptor antagonists, palonosetron demonstrated efficacy in preventing both acute and delayed emesis. This review focuses on the mechanism of action of 5-HT3 and NK1 receptor antagonists in acute and delayed CINV prevention. We discuss first, the medicinal chemistry that led to the discovery of these antagonists to underline their common structural features. Second, we discuss their performance in the clinic and what it tells us about the emetic response. Finally, we present recent mechanistic studies that help provide a rationale for efficacy differences between palonosetron and other 5-HT3 receptor antagonists in the clinic. In vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT3 receptor. The crossroads of acute and delayed emesis seem to include interactions among the 5-HT3 and NK1 receptor signaling pathways and inhibitions of these interactions could lead to improved treatment of CINV.
Topics: Animals; Drug Discovery; Humans; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-1; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 24184669
DOI: 10.1016/j.ejphar.2013.08.049 -
Supportive Care in Cancer : Official... Feb 2014Preventing chemotherapy-induced nausea and vomiting (CINV) is integral to treatment success in patients with cancer. This analysis was undertaken to assess the relative... (Randomized Controlled Trial)
Randomized Controlled Trial
Pooled analysis of phase III clinical studies of palonosetron versus ondansetron, dolasetron, and granisetron in the prevention of chemotherapy-induced nausea and vomiting (CINV).
PURPOSE
Preventing chemotherapy-induced nausea and vomiting (CINV) is integral to treatment success in patients with cancer. This analysis was undertaken to assess the relative efficacy and safety of palonosetron versus older 5HT3 RAs in preventing CINV associated with moderately or highly emetogenic chemotherapy.
METHODS
Patient-level data from four randomized, double-blind, phase III trials comparing palonosetron 0.25 or 0.75 mg with ondansetron 32 mg, dolasetron 100 mg, or granisetron 40 μg/kg were analyzed. Endpoints included complete response (CR: no emesis and no rescue antiemetics) in the acute (0-24 h), delayed (>24-120 h), and overall (0-120 h) postchemotherapy periods (primary), complete control (CC: no emesis, no rescue antiemetics, and no more than mild nausea), number of emetic episodes, and nausea severity.
RESULTS
CR rates were significantly higher for palonosetron (n = 1,787) versus older 5HT3 RAs (n = 1,175) in the delayed (57 vs 45 %, P < 0.0001) and overall periods (51 vs 40 %, P < 0.0001); odds ratios (95 % CI) in the acute, delayed, and overall periods were 1.15 (0.98-1.34), 1.62 (1.40-1.88), and 1.56 (1.34-1.81), respectively. Significant differences in CC rates and nausea severity were observed for the delayed and overall periods and in emetic episodes for all three periods. The incidence of treatment-related adverse events was similar with palonosetron (0.25 mg, 20.0 %; 0.75 mg, 26.5 %) and older 5HT3 RAs (27.5 %).
CONCLUSIONS
Palonosetron is more effective than older 5HT3 RAs for controlling CINV in the delayed and overall postchemotherapy periods.
Topics: Antiemetics; Antineoplastic Agents; Double-Blind Method; Female; Granisetron; Humans; Indoles; Isoquinolines; Male; Middle Aged; Nausea; Neoplasms; Ondansetron; Palonosetron; Quinolizines; Quinuclidines; Serotonin Antagonists; Treatment Outcome; Vomiting
PubMed: 24141698
DOI: 10.1007/s00520-013-1999-9 -
Expert Review of Anticancer Therapy Aug 2013Chemotherapy-induced nausea and vomiting (CINV) remains both a feared side effect of cancer treatment and a focus of many supportive care initiatives/guidelines. The... (Review)
Review
Chemotherapy-induced nausea and vomiting (CINV) remains both a feared side effect of cancer treatment and a focus of many supportive care initiatives/guidelines. The class of medications known as serotonin receptor antagonists (5-HT3RAs) are integral in the prevention of CINV from both moderately and highly emetogenic chemotherapy. Palonosetron (ALOXI(®)), a second-generation 5-HT3RA, has a higher affinity for the 5-HT3 receptor, has a longer half-life and has unique interactions with the 5-HT3 receptor compared with the current first-generation 5-HT3RA such as ondansetron, granisetron, dolasetron and tropisetron. This may allow palonosetron an advantage in control of CINV. This review article examines the available evidence, the pharmacokinetics and the safety and tolerability of palonosetron in the prevention of CINV.
Topics: Antineoplastic Agents; Humans; Induction Chemotherapy; Isoquinolines; Nausea; Neoplasms; Palonosetron; Quinuclidines; Vomiting
PubMed: 23984894
DOI: 10.1586/14737140.2013.814412 -
BMC Health Services Research Jul 20121st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy... (Comparative Study)
Comparative Study
BACKGROUND
1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions.
METHODS
Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics' (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables.
RESULTS
Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p<0.05). The BC and LC-carboplatin palonosetron groups experienced 50% and 30% fewer CINV days than the generic 5-HT3 RA group (p<0.05).
CONCLUSIONS
Patients with breast or lung cancer initiated and maintained on palonosetron were at significantly lower risk for potentially costly CINV versus those on older 5-HT3 RAs. Further studies on impact of step therapy policy are warranted in order to minimize the clinical and economic burden of CINV.
Topics: Adult; Antineoplastic Agents; Breast Neoplasms; Carboplatin; Cisplatin; Female; Health Care Surveys; Hospitalization; Humans; Isoquinolines; Logistic Models; Lung Neoplasms; Male; Middle Aged; Nausea; Palonosetron; Quinuclidines; Retrospective Studies; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 22823909
DOI: 10.1186/1472-6963-12-215 -
Journal of Chromatographic Science Oct 2012A high-performance liquid chromatographic method coupled with electrospray mass spectrometry was developed for the simultaneous determination of dolasetron and its major... (Comparative Study)
Comparative Study
A high-performance liquid chromatographic method coupled with electrospray mass spectrometry was developed for the simultaneous determination of dolasetron and its major metabolite, hydrodolasetron, in human plasma. A new sample pretreatment method, i.e., salt induced phase separation extraction (SIPSE), was proposed and compared with four other methods, i.e., albumin precipitation, liquid-liquid extraction, hydrophobic solvent-induced phase separation extraction and subzero-temperature induced phase separation extraction. Among these methods, SIPSE showed the highest extraction efficiency and the lowest matrix interferences. The extraction recoveries obtained from the SIPSE method were all more than 96% for dolasetron, hydrodolasetron and ondansetron (internal standard). The SIPSE method is also very fast and easy because protein precipitation, analyte extraction and sample cleanup are combined into one simple process by mixing acetonitrile with plasma and partitioning with 2 mol/L sodium carbonate aqueous solution. The correlation coefficients of the calibration curves were all more than 0.997, in the range of 7.9-4750.0 ng/mL and 4.8-2855.1 ng/mL for dolasetron and hydrodolasetron, respectively. The limits of quantification were 7.9 and 4.8 ng/mL for dolasetron and hydrodolasetron, respectively. The intra-day and inter-day repeatability were all less than 10%. The method was successfully applied to the pharmacokinetic study of dolasetron.
Topics: Carbonates; Chemical Fractionation; Chromatography, High Pressure Liquid; Drug Stability; Humans; Indoles; Quinolizines; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization
PubMed: 22645289
DOI: 10.1093/chromsci/bms065