[Investigation on the recommended dose of prebiotic in health food in China in 1996-2022].

OBJECTIVE: To understand the recommended dose distribution of prebiotic-containing health food in China. METHODS: The overall recommended dose of prebiotic health food was available from the label information of approved prebiotic health food from 1996 to 2022; the recommended dose distribution of prebiotic-containing health food was analyzed from different healthy functions and different ways of addition. RESULTS: There were 174 prebiotic-containing health food products with clear dose information, respectively, involving 5 prebiotics including Fructooligosaccharides, Galactooligosaccharides, Isomaltooligosaccharides, Xylo-oligosaccharides and Polydextrose, and the majority of prebiotics were added in combination, with 159 products. The recommended dose range of prebiotic-containing health food products was wide, and in general, the dose of prebiotic-containing health food products used alone was higher than the dose used in combination. The recommended daily intake range of health food containing Fructooligosaccharides was 5.28-17 500 mg/d, the recommended daily intake range of health food containing Isomaltooligosaccharides was 220-28 000 mg/d, the dose range of health food containing Xylo-oligosaccharides was 8.4-2 800 mg/d, the dose range of health food containing Polydextrose was 4-12 120 mg/d, the number of Galacto-Oligosaccharides products Only two kinds of products were included, with doses of 259.8 mg/d and 3500 mg/d, respectively. The claimed functions of prebiotic health food products were focused on laxative function, immunity enhancement, and regulation of intestinal flora. The application dose of prebiotic health food with different functional compounding additions was close to the overall dose. CONCLUSION: The recommended dosage range of prebiotics in health food containing prebiotics in China is large, and prebiotics in products are mainly added by compounding.

An Investigation in the Comparability of the Exposure and Recommended Dose of Selected Pfizer Drugs in East Asian Countries: Is Mutual Usage of Clinical Data Among East Asian Countries Feasible?

The current regulatory path for new drug registration in East Asian countries has led to significant delay of the new medicines in these countries. A unified regulatory path and allowance of mutual usage of clinical data in East Asian countries would lead to cost saving in drug development and expedite the new drug registration in these countries. The objectives of the present analysis are to compare the approval dates of a selection of products developed by Pfizer in the United States and East Asian countries (China, Japan, Korea) and compare the pharmacokinetics and recommended doses of these products in East Asian countries. Eighteen products (20 drugs, 2 products with 2 combination drugs) with exposure data available in at least 2 of the 3 East Asian countries across different therapeutic areas were included in the analyses. The results showed that most products had delayed approval in East Asian countries (up to 8 years) after US or EU approval. No distinct differences were observed in the drug exposure and recommended doses for the selected products in East Asian countries. These results together with literature data of genetic similarity of the East Asian populations support the mutual usage of the clinical data in the East Asian countries for expedited regulatory submission and approval.

Optimal dose and type of exercise to reduce pain, anxiety and increase quality of life in patients with fibromyalgia. A systematic review with meta-analysis.

The aim of our meta-analysis was to compile the available evidence to evaluate the effect of physical exercise-based therapy (PEBT) on pain, impact of the disease, quality of life (QoL) and anxiety in patients with fibromyalgia syndrome (FMS), to determine the effect of different modes of physical exercise-based therapy, and the most effective dose of physical exercise-based therapy for improving each outcome. A systematic review and meta-analysis was carried out. The PubMed (MEDLINE), SCOPUS, Web of Science, CINAHL Complete and Physiotherapy Evidence Database (PEDro) databases were searched up to November 2022. Randomized controlled trials (RCTs) comparing the effects of physical exercise-based therapy and other treatments on pain, the impact of the disease, QoL and/or anxiety in patients with FMS were included. The standardized mean difference (SMD) and a 95% CI were estimated for all the outcome measures using random effect models. Three reviewers independently extracted data and assessed the risk of bias using the PEDro scale. Sixty-eight RCTs involving 5,474 participants were included. Selection, detection and performance biases were the most identified. In comparison to other therapies, at immediate assessment, physical exercise-based therapy was effective at improving pain [SMD-0.62 (95%CI, -0.78 to -0.46)], the impact of the disease [SMD-0.52 (95%CI, -0.67 to -0.36)], the physical [SMD 0.51 (95%CI, 0.33 to 0.69)] and mental dimensions of QoL [SMD 0.48 (95%CI, 0.29 to 0.67)], and the anxiety [SMD-0.36 (95%CI, -0.49 to -0.25)]. The most effective dose of physical exercise-based therapy for reducing pain was 21-40 sessions [SMD-0.83 (95%CI, 1.1--0.56)], 3 sessions/week [SMD-0.82 (95%CI, -1.2--0.48)] and 61-90 min per session [SMD-1.08 (95%CI, -1.55--0.62)]. The effect of PEBT on pain reduction was maintained up to 12 weeks [SMD-0.74 (95%CI, -1.03--0.45)]. Among patients with FMS, PEBT (including circuit-based exercises or exercise movement techniques) is effective at reducing pain, the impact of the disease and anxiety as well as increasing QoL. Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021232013.

Ondansetron: recommended antiemetics for patients with acute pancreatitis? a population-based study.

Objective: Ondansetron administration is a common antemetic of acute pancreatitis therapy in the intensive care unit (ICU), but its actual association with patients' outcomes has not been confirmed. The study is aimed to determine whether the multiple outcomes of ICU patients with acute pancreatitis could benefit from ondansetron. Methods: 1,030 acute pancreatitis patients diagnosed in 2008-2019 were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database as our study cohort. The primary outcome we considered is the 90-day prognosis, and secondary outcomes included in-hospital survival and overall prognosis. Results: In MIMIC-IV, 663 acute pancreatitis patients received ondansetron administration (OND group) during their hospitalization, while 367 patients did not (non-OND group). Patients in the OND group presented better in-hospital, 90-day, and overall survival curves than the non-OND group (log-rank test: in-hospital: p < 0.001, 90-day: p = 0.002, overall: p = 0.009). After including covariates, ondansetron was associated with better survival in patients with multiple outcomes (in-hospital: HR = 0.50, 90-day: HR = 0.63, overall: HR = 0.66), and the optimal dose inflection points were 7.8 mg, 4.9 mg, and 4.6 mg, respectively. The survival benefit of ondansetron was unique and stable in the multivariate analyses after consideration of metoclopramide, diphenhydramine, and prochlorperazine, which may also be used as antiemetics. Conclusion: In ICU acute pancreatitis patients, ondansetron administration was associated with better 90-day outcomes, while results were similar in terms of in-hospital and overall outcomes, and the recommended minimum total dose might be suggested to be 4-8 mg.

Toxicological assessment compilation of selected examples of raw materials for homeopathic and anthroposophic medicinal products - Part 2.

The present successor article comprises more than 180 substances representing a continuative compilation of toxicologically evaluated starting materials prompted by the wide use and high number of homeopathic and anthroposophic medicinal products (HMP) on the market together with the broad spectrum of active substances of botanical, mineral, chemical or animal origin contained therein, and by the equally important requirement of applying adequate safety principles as with conventional human medicinal products in line with the European regulatory framework. The February 2019 issue of the Regulatory Toxicology and Pharmacology journal includes the antecedent article bearing the same title and entailing safety evaluations of more than 170 raw materials processed in HMP. This part 2 article highlights scientific evaluation following recognized methods used in toxicology with a view to drug-regulatory authority's assessment principles and practice in the context of HMP, and offers useful systematic, scientifically substantiated and simultaneously pragmatic approaches in differentiated HMP risk assessment. As a unique feature, both articles provide the most extensive publicly available systematic compilation of a considerable number of substances processed in HMP as a transparent resource for applicants, pharmaceutical manufacturers, the scientific community and healthcare authorities to actively support regulatory decision making in practice.

Phase I trial of concurrent chemoradiotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF-CRT) for locally advanced squamous cell carcinoma of the external auditory canal.

PURPOSE: Chemoradiotherapy with docetaxel (DOC), cisplatin (CDDP), and 5-FU (TPF-CRT) for locally advanced external auditory canal cancer (EACC) has favorable oncological and functional outcomes. To establish TPF-CRT as a standard of care for advanced EACC, we conducted this study to determine the maximum tolerated (MTD) and recommended dose (RD) of DOC in TPF-CRT for locally advanced EACC. METHODS: To determine the recommended (RD) and maximum tolerated dose (MTD) of DOC in TPF-CRT for EACC, a phase I trial was conducted using the standard "3 + 3" design for maximum dose finding. DOC was administered twice every 4 weeks, CDDP at 70 mg/m2 and 5-FU at 700 mg/m2; patients were also receiving radiotherapy (66 Gy). Eight patients with T3 or T4 EACC were prospectively enrolled. RESULTS: Two patients treated with DOC, 50 mg/m2, and one out of six patients treated with DOC, 40 mg/m2, had dose-limiting toxicities. Prolonged febrile neutropenia was observed in three patients. Grade 3 non-hematological toxicities were observed in only three patients. At study completion, six patients survived, five of whom were disease free. CONCLUSION: The RD and MTD of DOC in TPF-CRT for locally advanced EACC are 40 mg/m2 when doses of CDDP and 5-FU are 70 mg/m2 and 700 mg/m2, respectively.

Toxicological safety assessment of essential oils used as food supplements to establish safe oral recommended doses.

Essential oils (EOs) are increasingly consumed as food supplements. The few published recommended doses available generally lack details both on the methodology used and concentration limits for substances of concern, including genotoxic carcinogens. We propose a tiered approach based on the toxicological evaluation of maximized concentrations of each constituent present in the EO investigated. The genotoxic potential of each constituent is assessed using literature data or QSAR analyses. Genotoxic constituents are evaluated according to the methodology provided in the ICHM7 guideline. A Toxicological Reference Value (TRV) is associated to each non-genotoxic constituent, using one of the following methodologies (decision-tree successive steps): extraction from recognized databases or clinical studies, application of adequate safety factors to NOAELs established in animal studies, read-across analyses and when none was possible, TTC of Cramer classes. An EO recommended dose is considered safe when the safety margin (ratio between TRV and systemic exposure) for all constituents is all at least equal to 1. In conclusion, this methodology has proven to be robust to establish safe recommended doses for EOs used as food supplements, consistent with those publicly available, and avoiding unnecessary dedicated new animal testing.

Anticoccidial Activity of Qinghao Powder Against Eimeria tenella in Broiler Chickens.

Artemisia annua (AAH) is traditionally used as an anti-malarial, expectorant and antipyretic Chinese medicine. The aim of this study was to explore the therapeutic effect of Qinghao Powder (QHP) on chicken coccidiosis, evaluate the safe dosage of QHP, and provide test basis for clinical medication. High-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) were used to detect artemisinin in Qinghao Powder (QHP) for quality control. The level of artemisinin in QHP was 81.03 mg/g. A total of 210 chicks (14 days of age) were divided randomly into seven groups: three QHP treatments (0.15, 0.30, and 0.60 g/kg), a toltrazuril control (1.00 mL/L), a sulfachloropyrazine sodium control (SSC, 0.30 g/L), an E. tenella-infected control, and a healthy control group. All the groups were inoculated orally with 7 × 104 E. tenella oocysts except for the healthy control group. After seven days of administration, compared with the infected control group, chicks which were administered QHP, SS, and toltrazuril showed less bloody feces, oocyst output, and cecal lesions, and the protection rates were improved. The maximum rBWG and ACI were found in the SS-medicated group, followed by the groups medicated with 0.60 and 0.30 g/kg QHP. Therefore, a 0.30 g/kg dose level of QHP in the feed was selected as the recommend dose (RD) in the target animal safety test, in which 80 broiler chicks (14 days of age) were randomly divided into four major groups (I-healthy control group; II-1× RD; III-3× RD; IV-6× RD), with each group subdivided into two subgroups (A and B) consisting of 10 chicks each. After 7-day (for sub-group A) or 14-day (for sub-group B) administration, compared with the healthy control, treatment-related changes in BWG, feed conversion ratio (FCR), relative organ weight (ROW) of the liver, WBC counts, and levels of RBC, HGB, ALT, AST, and TBIL were detected in the 3× and 6× RD groups. No differences were noted in necropsy for all doses, and histopathological examinations exhibited no QHP-associated signs of toxicity or abnormalities in the liver or kidney. The findings suggest that QHP at a dose of 0.30 g/kg feed would be appropriate for therapy and intermittent treatment of E. tenella-infected chicks, the dosage in clinical applications should be set according to the recommended dose to ensure animal safety.

Alpelisib in combination with everolimus ± exemestane in solid tumours: Phase Ib randomised, open-label, multicentre study.

BACKGROUND AND PURPOSE: Combined mTORC1 inhibition with everolimus (EVE) and phosphatidylinositol 3-kinase catalytic subunit p110α blockade with alpelisib (ALP) has demonstrated synergistic efficacy in preclinical models and supports testing the combination of ALP and EVE in the clinical setting. The primary objective was to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of ALP in combination with EVE and in combination with EVE and exemestane (EXE) and subsequently assess safety, preliminary efficacy and effect of ALP on the pharmacokinetics of EVE and determine the magnitude of the drug-drug interaction. PATIENTS AND METHODS: Dose escalation phases were conducted in patients with advanced solid tumours and in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). The dose expansion phase was conducted in patients with pancreatic neuroendocrine tumour and renal cell carcinoma (RCC) (both mechanistic target of rapamycin inhibitor [mTORi]-naive), in patients with mTORi-pretreated solid tumours and in postmenopausal women with HR+, HER2- ABC. RESULTS: During the doublet escalation phase, dose-limiting toxicities (DLTs) were reported in 5 of 10 (50%) patients: one patient had grade (Gr) 2 hyperglycemia and one patient had Gr 3 diarrhoea in the 300 mg dose group, one patient had Gr 2 hyperglycemia and one patient had Gr 4 hypocalcaemia in the 250 mg dose group, and one patient in the 200 mg dose group had Gr 3 diarrhoea and Gr 3 stomatitis. The combination of ALP 250 mg + EVE 2.5 mg was declared as the MTD/RDE in subjects with advanced solid tumours. In the triplet escalation phase, one patient who received ALP 200 mg + EVE 2.5 mg + EXE 25 mg had a DLT of Gr 3 acute kidney injury. This dose combination was declared as the MTD and RDE in subjects with advanced HR-positive HER2-negative BC. The common adverse events (≥30% patients), occurring across all phases, were hyperglycaemia, stomatitis, diarrhoea, nausea, asthenia, decreased appetite and fatigue. The sixteen-week progression-free survival rate was 52.4% (90% confidence interval [CI]: 32.8, 71.4) in the RCC cohort, 35.3% (90% CI: 16.6, 58.0) in the prior pNET cohort and 30.0% (90% CI: 8.7, 60.7) in the prior mTORi cohort. The pharmacokinetics of 2.5 mg of EVE was largely unchanged in the presence of ALP, independent of the dose (250 mg or 300 mg). There were no clinically relevant drug-drug interactions observed between ALP and EVE. CONCLUSION: The overall safety profile of ALP with EVE and EXE is manageable and reversible; no unexpected safety signals were noted compared with the individual safety profiles. Pharmacokinetics of ALP, EVE and EXE was largely unchanged in combination with each other.

Recommended dose of sufentanil during induction of general anesthesia to avoid coughing and drastic hemodynamic fluctuations in patients undergoing surgery.

BACKGROUND: Sufentanil-induced cough (SIC) is a common complication during anesthesia induction. We explored the recommended sufentanil dose that effectively avoids cough during general anesthesia using a clinical trial to analyze the effective dose (ED)50 and ED95 of sufentanil that avoids cough, hemodynamic fluctuations, and adverse reactions. METHODS: On the basis of sufentanil dose, 136 patients (ASA class I-II) were randomly allocated into the following groups: I, 0.1 µg/kg; II, 0.3 µg/kg; III, 0.5 µg/kg; or IV, 1.0 µg/kg. The number of coughing incidents, dizziness, panic, and chest tightness within 1 minute after sufentanil injection, and the patient's heart rate (HR) and blood pressure 5 minutes after intubation were recorded and analyzed. Cough was assessed as follows: none, 0 times; mild, 1 to 2 times/minute; moderate, 3 to 4 times/minute; and severe, 5 times/minute or more. RESULTS: The ED50 and ED95 of cough incidence induced by intravenous sufentanil in patients during general anesthesia induction was 0.332 µg/kg and 1.423 µg/kg, respectively. The cough rate in group I was lower than the other groups. The incidence of dizziness, panic, chest tightness, hypertension, bradycardia, and tachycardia were not significantly different. CONCLUSIONS: The recommended sufentanil dose during general anesthesia induction is 0.1 µg/kg.

Efficacy and Safety of Non-recommended Dose of New Oral Anticoagulants in Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis.

Introduction: The real-world treatment of atrial fibrillation (AF) often involves the prescription of new oral anticoagulants (NOACs) using dosing both lower and higher than recommended guidelines. Our study aimed to evaluate the efficacy and safety of non-recommended dosage of NOACs in AF patients. Methods: A systematic search was performed for relevant studies across multiple electronic databases (PubMed, Embase, Cochrane Library, Clinical Trials Registry) from inception to May 1, 2021. Multicenter randomized trials and observational studies were selected with key reporting measures for inclusion involved efficacy outcomes including stroke or systemic thromboembolism along with safety endpoints assessing major or clinically relevant bleeding events. Results: A total of 11 eligible studies were included involving 48,648 patients receiving recommended dose of NOACs and 50,116 patients receiving non-recommended dosage. Compared to AF patients treated with recommended dose regimens, administration of low dose of NOACs was associated with higher risk of stroke/systemic embolism (RR = 1.24, 95% CI 1.14-1.35, P < 0.00001), but without reducing bleeding risk (RR = 1.18, 95% CI 0.91-1.53, P = 0.21) and a higher risk of all-cause mortality (RR = 1.58, 95% CI 1.25-1.99, P = 0.0001). Moreover, high dose of NOACs was associated with higher risk of stroke and systemic embolism efficacy (RR = 1.71, 95% CI 1.06-2.76, P = 0.03) and a non-significant trend to a greater risk of major or clinically relevant bleeding (RR = 1.57, 95% CI 0.96-2.58, P = 0.07). Conclusions: AF patients treated with low dose of NOACs showed equivalent safety but with worse efficacy compared with recommended dose. High dose of NOACs was not superior to recommended dose regimens in preventing stroke/systemic embolism outcomes in AF patients.

Toxicological assessment compilation of selected examples of raw materials for homeopathic medicinal products.

The considerable number of homeopathic medicinal products (HMP) on the German market and the staggering breadth of active substances of various origin along with the specific legal requirements of adequate safety principles posed the need to compile data on toxicologically evaluated raw materials. In line with the European regulatory framework, HMP applications must consider appropriate safety standards in analogy to conventional human medicinal products. This review presents an option for a systematic and scientifically substantiated approach for regulatory use. Furthermore, this paper provides a multitude of data for selected raw materials processed in HMP with up to now rather scarce knowledge and, thus, aims at filling data gaps on acceptable amounts per day (AAD). The inclusion of raw materials into the compilation was determined considering the frequencies of their occurrence in HMP in Germany along with the availability of appropriate safety assessments. This safety evaluation compilation represents a practical, fairly comprehensive and systematic set of more than 170 raw materials. It is designed to both effectively support regulatory decision making and to be recognized and exploited by applicants, stakeholders and the scientific community.

Individualized Dosing of Axitinib Based on First-Dose Area Under the Concentration-Time Curve for Metastatic Renal-Cell Carcinoma.

BACKGROUND: Previous studies have revealed that higher exposure of axitinib leads to better prognosis in metastatic renal-cell carcinoma. We thus assessed individualized dosing of axitinib on the basis of the first-dose area under the concentration-time curve from 0 to 12 hours (AUC0-12) for sunitinib-pretreated metastatic renal-cell carcinoma patients. PATIENTS AND METHODS: In this prospective single-arm trial, the starting dose of axitinib was 5 mg twice daily. A series of blood samples were taken at predetermined times after the first dose to calculate AUC0-12. On day 15 of axitinib administration, the dose was adjusted to ensure ≥ 150 ng·h/mL AUC0-12 at steady state according to first-dose AUC0-12. The primary end point was the 6-month progression-free survival rate. RESULTS: Twenty-six Japanese patients were enrolled. The median recommended dose based on the first-dose AUC0-12 was 2.5 mg (range, 1-16 mg) twice daily. The 6-month progression-free survival rate for all enrolled patients and per-protocol set, from which 3 patients were excluded for not adjusting to the recommended dose on day 15, was 84.6% (95% confidence interval, 65.5-94.1) and 82.6% (95% confidence interval, 61.8-93.3), respectively. The most common nonhematologic adverse events were hypertension, hand-foot syndrome, fatigue, and decreased appetite. Eighteen patients (75%) developed grade 3 hypertension; however, actual blood pressure could be controlled using antihypertensive agents. Other adverse events were manageable during the protocol treatment. CONCLUSION: Individualized dosing of axitinib based on the first-dose AUC0-12 might have promising efficacy and manageable toxicity.

Analysis of Real-World Dosing Patterns for the 3 FDA-Approved Medications in the Treatment of Fibromyalgia.

BACKGROUND: Fibromyalgia is a chronic condition characterized by widespread pain, fatigue, and sleep disturbances that affects approximately 2% to 4% of the adult population in the United States, with minimal real-world data related to the use of medications and associated dosages for this condition. OBJECTIVE: To analyze the real-world dosing patterns of the 3 medications approved by the US Food and Drug Administration for fibromyalgia-pregabalin, duloxetine, and milnacipran. METHODS: Using QuintilesIMS' (now IQVIA) electronic medical record data linked to administrative claims, we identified adults with fibromyalgia who were newly prescribed pregabalin, duloxetine, or milnacipran between January 1, 2006, and December 31, 2014. We summarized and compared the starting and maximum doses with United States prescribing information (USPI) dosing recommendations. RESULTS: In all, 1043 patients who were receiving pregabalin, 1281 receiving duloxetine, and 326 patients receiving milnacipran with similar age and comorbidity profiles were included in the study. The mean starting dose was 176 mg daily, 56 mg daily, and 95 mg daily for pregabalin, duloxetine, and milnacipran, respectively. More patients receiving pregabalin (35%) had a starting dose lower than recommended compared with patients receiving duloxetine (7%) or milnacipran (17%; P <.0001). Of the patients who received pregabalin, 27% had USPI-recommended maintenance dosing versus 91% of patients who received duloxetine and 80% who received milnacipran (P <.0001). The mean duration of treatment was longer for duloxetine (205 days; P <.0001) than for pregabalin (167 days) and milnacipran (167 days). The duration of using the maximum dose of each medication as a percentage of the total time of medication use was 77% for pregabalin, 84% for duloxetine, and 90% for milnacipran (P <.0001). CONCLUSIONS: Patients using pregabalin were the most likely of the 3 cohorts to receive lower than label-recommended starting doses and the least likely to receive the recommended maintenance doses during follow-up compared with those receiving duloxetine or milnacipran. Real-world prescribing patterns indicate that factors other than label recommendations may be influencing prescribed dosing.

Image guidance doses delivered during radiotherapy: Quantification, management, and reduction: Report of the AAPM Therapy Physics Committee Task Group 180.

BACKGROUND: With radiotherapy having entered the era of image guidance, or image-guided radiation therapy (IGRT), imaging procedures are routinely performed for patient positioning and target localization. The imaging dose delivered may result in excessive dose to sensitive organs and potentially increase the chance of secondary cancers and, therefore, needs to be managed. AIMS: This task group was charged with: a) providing an overview on imaging dose, including megavoltage electronic portal imaging (MV EPI), kilovoltage digital radiography (kV DR), Tomotherapy MV-CT, megavoltage cone-beam CT (MV-CBCT) and kilovoltage cone-beam CT (kV-CBCT), and b) providing general guidelines for commissioning dose calculation methods and managing imaging dose to patients. MATERIALS & METHODS: We briefly review the dose to radiotherapy (RT) patients resulting from different image guidance procedures and list typical organ doses resulting from MV and kV image acquisition procedures. RESULTS: We provide recommendations for managing the imaging dose, including different methods for its calculation, and techniques for reducing it. The recommended threshold beyond which imaging dose should be considered in the treatment planning process is 5% of the therapeutic target dose. DISCUSSION: Although the imaging dose resulting from current kV acquisition procedures is generally below this threshold, the ALARA principle should always be applied in practice. Medical physicists should make radiation oncologists aware of the imaging doses delivered to patients under their care. CONCLUSION: Balancing ALARA with the requirement for effective target localization requires that imaging dose be managed based on the consideration of weighing risks and benefits to the patient.

Feasibility of olanzapine, multi acting receptor targeted antipsychotic agent, for the prevention of emesis caused by continuous cisplatin- or ifosfamide-based chemotherapy.

Background To determine the feasibility and efficacy of olanzapine, which is approved by the Pharmaceuticals and Medical Devices Agency as multi acting receptor targeted antipsychotic agent of the thienobenzodiazepine class, for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients undergoing continuous five-day chemotherapy. Patients and methods This study was a prospective dose escalation study at a single center (UMIN ID: UMIN000015386). Patients received a combination of adriamycin and ifosfamide (AI) or a combination of bleomycin, etoposide, and cisplatin (BEP). On days 1-5, all patients received intravenous granisetron (1 mg) and intravenous dexamethasone sodium phosphate (24 mg). Olanzapine was administrated on day-1 to day5 at bedtime. The dose of olanzapine followed a dose-escalation scheme, with monitoring of safety and tolerability at each dose. A 3 + 3 cohort design was used, with three to six patients per cohort. Results Nine patients were enrolled (three for each cohort). No patients experienced dose-limiting toxicity (DLT). The most frequent adverse events were dry mouth and constipation. In each cohort, the maximum severity of nausea was Grade 2, and no patients experienced a vomiting episode. Conclusion A 2.5 mg/day dosage of olanzapine is sufficient to prevent from CINV in Japanese patients receiving continuous five-day chemotherapy. A dose of 10 mg/day, which is recommended by international CINV guidelines, is also tolerated. If CINV is not controlled by an initial dose of 2.5 mg/day of olanzapine, dosage escalation is encouraged. Future studies should compare olanzapine with aprepitant.

Disminución de la tasa de errores en la medicación luego de la incorporación de la recomendación de la posología en un sistema de prescripción electrónica / Diminuição da taxa de erro de medicação após incorporar a recomendação de dosagem numa prescrição eletrônica / Reduction in the rate of errors in medication doses after the incorporation of a recommended posology in a prescription system

Los errores en la medicación son comunes en la práctica médica, más aún en los hospitales universitarios. Aquellos asociados con la dosis de los fármacos son los más frecuentes. Los sistemas computarizados de prescripción médica (CPOE, sigla en inglés para Computerized provider order entry) han demostrado mejorar la tasa de error e incrementar la calidad de cuidado médico. Nuestro hospital desarrolló su propia Historia Clínica Electrónica con un completo CPOE. Los farmacéuticos validan todas las prescripciones y rechazan aquellas que contienen errores, siendo los más frecuentes los vinculados conerrores en la dosis. Un grupo multidisciplinario acordó una lista de posología recomendada de fármacos que se ofrece a los médicos tratantes luego de que seleccionan la droga a prescribir. El objetivo de este estudio es describir el desarrollo e implementación de una estrategia de prevención de error que incorpora dosis recomendada en el proceso de prescripción electrónica.

Os erros de medicação são comuns na prática médica, ainda mais em hospitais universitários. Aqueles associados com a dose das drogas são as mais freqüentemente. Os sistemas informatizados de prescrição médica (CPOE,sigla em inglês para entrada de pedido do provedor informatizado) foram mostrados para melhorar a taxa de erro e aumentar a qualidade dos cuidados médicos. Nosso hospital desenvolveu a sua própria registros médicos eletrônicos com uma completa CPOE. Farmacêuticos valida todas as prescrições e rejeitar aqueles que contêm erros, sendo os mais freqüentes aqueles relacionados com erros na dose. Um grupo de trabalho multidisciplinar chegou a acordo sobre uma lista de dose recomendada de drogas que é oferecido aos médicos que depois que selecionar a droga de prescrever.

Medication errors are common in medical practice, even more in teaching hospitals. The errors associated with drugs doses are the most common. Computerized provider order entry (CPOE) has demonstrated that could improvethe error rate and increase the quality of medical care. Our hospital developed its own Electronic Health Record(EHR) with a full implemented CPOE. Pharmacists validate all the prescriptions, and reject those that contain errors,the most frequent errors are related to dose. A multidisciplinary group agreed on a list of recommended dose of drugs, that is offered to the treating physicians after selecting the drugs to prescribe. The aim of this study is to describe the development and implementation of a prevention strategy that incorporates recommended error in the process of electronic prescribing doses. The aim of this study is to describe the development and implementation strategy of error prevention that incorporates recommended dose in the prescription process electronics.

Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer.

PURPOSE: To evaluate safety of TAS-102 administered twice daily (bid) on days 1-5 and 8-12 of a 4-week cycle, confirm feasibility of the Japanese recommended dose (RD), 35 mg/m(2), in Western patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies, and describe preliminary antitumor activity. METHODS: This open-label, dose-escalation phase 1 study was conducted at four US centers. Patients were enrolled into two sequential cohorts [30 (cohort 1) or 35 mg/m(2)/dose bid (cohort 2)]; dose-limiting toxicities (DLT) were evaluated during cycle 1 in dose-escalation cohorts. At RD, 15 additional patients were enrolled in an expansion cohort. RESULTS: Patients (N = 27) with refractory mCRC received TAS-102; 74 % had received ≥4 prior regimens. DLT was not observed in three patients in cohort 1, and was in one out of nine patients in cohort 2 (grade 3 febrile neutropenia). Therefore, RD was identified as 35 mg/m(2) bid. At RD, fatigue (63 %), gastrointestinal disturbances and nausea (46 %), vomiting (46 %), and diarrhea (42 %) were common but rarely grade 3/4. Grade 3/4 nausea, vomiting, and diarrhea occurred at 4 % each. Grade 3/4 toxicity was predominantly hematologic [neutropenia (71 %), anemia (25 %)]; febrile neutropenia was observed in two patients. Stable disease lasting ≥6 weeks was achieved by 16 evaluable patients (70 %); median progression-free survival and overall survival were 5.3 and 7.5 months, respectively. CONCLUSIONS: TAS-102 has an acceptable safety profile and preliminary evidence of disease stabilization in Western patients with refractory mCRC. Results from a randomized phase 3 study have shown survival benefit with disease stabilization evidence in this population.

Phase I dose-escalation study of cyclophosphamide combined with bortezomib and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma.

The present study was conducted to determine the recommended dose (RD) of cyclophosphamide (CPM) in the CBD regimen, a triplet combination of CPM, bortezomib (BTZ), and dexamethasone (Dex), for relapsed and/or refractory multiple myeloma (RRMM). Patients received intravenous CPM on days 1 and 8 at one of three dose levels: 300, 400, or 500 mg/m(2), with dose escalation in a 3 + 3 design. BTZ at 1.3 mg/m(2) was given twice weekly in 3-week cycles, with Dex at 20 mg/m(2) on the day of and day after BTZ. Of 16 patients enrolled, 15 eligible patients were allocated to the study. Dose-limiting toxicities (DLTs) were seen in two patients: one in dose level 1 with increased γ-GTP and the other in dose level 3 with increased γ-GTP and ALT. Both patients spontaneously recovered from DLT. Neither therapy-related mortality nor severe adverse events were reported during the study. Therefore, the RD of CPM was determined as 500 mg/m(2). Overall, 2 (13.3 %), 1 (6.7 %), and 8 (53.3 %) patients achieved CR, VGPR, and PR, respectively. The regimen was well tolerated and showed promising activity in patients with RRMM.

Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma.

AIM: To evaluate the safety, pharmacokinetics and antitumor activity of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma (HCC). METHODS: HCC patients of Child-Pugh A or B who progressed on, or were intolerant to, sorafenib were eligible for this phase 1 trial. We used a standard 3 + 3 dose-escalation design with a 28-day cycle at dose levels of 50, 100, 200 and 400 mg/day. Tumor responses were assessed using the modified Response Evaluation Criteria in Solid Tumors. RESULTS: Twenty-four patients were enrolled, of whom 23 received OPB-31121 (20 males; median age, 65 years). The most common adverse drug reactions were nausea (87.0%), vomiting (82.6%), diarrhea (69.6%), fatigue/malaise (52.2%), anorexia (47.8%) and peripheral sensory neuropathy (26.1%). The recommended dose for OPB-31121 was determined to be 200 mg. Six patients had stable disease for 8 weeks or more, resulting in disease control rates of 25.0-42.9%. In the 200-mg dose cohort, three of seven patients had stable disease and a median time to progression of 61.0 days. The maximum concentration and area under the plasma concentration-time curve of OPB-31121 were dose proportional. CONCLUSION: OPB-31121 demonstrated insufficient antitumor activity for HCC. Furthermore, peripheral nervous system-related toxicities may negatively affect long-term administration of OPB-31121. Therefore, it was deemed difficult to continue the clinical development of OPB-31121 for treating advanced HCC and further investigation is expected in the agent with favorable profile in this category.