Flow-Through Versus Sidestream Capnometry for Detection of End Tidal Carbon Dioxide in the Sedated Patient

Background

End tidal carbon dioxide (ETCO₂) in non-intubated patients can be monitored using either sidestream or flow-through capnometry [Yamamori et al., J Clin Monit Comput 22(3):209–220, 2008]. The hypothesis of this validation study is that, flow-through capnometry will yield a more accurate estimate of ETCO₂ than sidestream capnometry when evaluated in a bench study during low tidal volumes and high oxygen administration via nasal cannula. Secondarily, when ETCO₂ from each is compared to arterial CO₂ (PaCO₂) during a study in which healthy, non-intubated volunteers are tested under normocapnic, hypocapnic and hypercapnic conditions, the flow-through capnometer will resemble PaCO₂ more closely than the sidestream capnometer. This will be especially true during periods of lower minute ventilation and high oxygen flow rates via mask in non-intubated, remifentanil sedated, healthy volunteers whose physiologic deadspace is small.

Methods

The performance of a flow-through (cap-ONE^®, Nihon Kohden, Tokyo, Japan) and a sidestream (Microcap^® Smart CapnoLine Plus^®, Oridion Inc., Needham, MA) capnometer were compared in a bench study and a volunteer trial. A bench study evaluated ETCO₂ accuracy using waveforms generated via mechanical lungs during low tidal volumes and high oxygen flow rates. A volunteer study compared the ETCO₂ for each capnometer against PaCO₂ during sedation in which 8 l O₂ was delivered via mask rather than the nasal cannula.

Results

In the bench study, the flow-through capnometer gave slightly higher values of ETCO₂ during high-flow oxygen and no discernable differences during variable tidal volumes. Bland and Altman plots comparing ETCO₂ to PaCO₂ showed essentially equal performance between the two capnometers in the volunteers.

Conclusions

Within a wide limit of agreement between the volunteer and bench study, flow-through and sidestream capnometry performed equally well during bench testing and in non-intubated, sedated patients.     

Does severe obstructive sleep apnea syndrome alter retrobulbar blood flow? A color Doppler ultrasound study

Purpose

To evaluate extraocular orbital vessels with color Doppler ultrasound (CDU) and investigate the effects of severe obstructive sleep apnea (OSA) on retrobulbar blood flow.

Methods

Between February 2014 and September 2015, 30 patients with severe OSA (apnea–hypopnea index (AHI) > 30) and 28 controls were prospectively included in this study. Intraocular pressure (IOP) was measured with a Goldmann applanation tonometer, and CDU was used to evaluate the retrobulbar vessels.

Results

The mean AHI score for the OSA group was 63.2 ± 21.5 per hour. The IOP values were significantly higher in the severe OSA group (p < 0.05). The central retinal artery peak systolic velocity (PSV) (p < 0.05) and end-diastolic velocity (EDV) (p < 0.02), and the ophthalmic artery (OA) PSV and EDV, were found to be significantly lower in the OSA group (p < 0.05).

Conclusion

Severe OSA causes an increase in IOP and a decrease in flow velocity in the retrobulbar circulation.

     

Pivotal Bioequivalence Study of Clopacin<Superscript>®</Superscript>, a Generic Formulation of Clopidogrel 75 mg Film-Coated Tablets

Introduction

Clopacin^® (Acino Pharma AG) is a proprietary, besylate salt and lactose-free formulation of the widely-used anti-platelet treatment, clopidogrel. This study aimed to evaluate the bioequivalence of Clopacin^® with the originator as reference drug, using a guideline-compliant trial design: open-labeled, randomized, single-dose (clopidogrel 75 mg tablet), two-period, crossover trial in 48 healthy male volunteers, with a 7 day wash-out period.

Methods

Plasma samples were collected at intervals and extracted before quantifying clopidogrel concentrations using a fully validated LC–MS/MS method. Bioequivalence of Clopacin^® and the reference drug was established by comparison of the primary pharmacokinetic parameters, C _max, AUC_0–t, and AUC_0–∞.

Results

The parameter values were similar for the two products (analysis of variance) and provided Clopacin/reference ratios (least squares means) of >90% and 90% confidence intervals (CIs 84.64–105.50%, 90.43–111.22%, 88.75–110.71%, respectively) that were well within the limits set for defining bioequivalence, according to international guidelines. The respective Clopacin^® and reference drug values for mean time to maximal plasma clopidogrel concentration (t _max) were 0.83 and 0.91 h, and for terminal elimination half-life were 3.99 and 3.51 h. The intra-subject coefficients of variability for maximal plasma clopidogrel concentration (C _max), area under the plasma clopidogrel concentration versus time curve, at 48 h (AUC_0–t) and extrapolated to infinity (AUC_0–∞) were 32.2%, 30.2%, and 28.9% (least square means), respectively, and the respective power values were 99.5%, 97.1%, and 95.3%.

Conclusion

This bioequivalence study provided robust clopidogrel pharmacokinetic data that established the bioequivalence of Clopacin^® and the reference originator drug.

Funding

Acino Pharma AG (formerly Cimex AG)

     

Laparoscopic Sleeve Gastrectomy Improves Excessive Daytime Sleepiness and Sleep Quality 6 Months Following Surgery: A Prospective Cohort Study

Introduction

Obstructive sleep apnea (OSA) is one of the most important co-morbid conditions related with morbid obesity. Bariatric procedures are associated with significant improvement in OSA. The aim of the current study was to evaluate the effect of bariatric surgery on daytime sleepiness and quality of sleep in patients that had undergone laparoscopic sleeve gastrectomy.

Methods

Fifty-nine patients were prospectively enrolled in the study. Pre-operative and post-operative (6 months) demographics, medical history, weight, and height of the patients were recorded, and patients were asked to complete Pittsburg Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) questionnaires. OSA screenings were performed using the STOP-Bang questionnaire.

Results

The mean age of the patients was 37.1 ± 1.2 years and 76% were female. Pre-operative and post-operative median (range) BMIs were 47 kg/m² (39–67 kg/m²) and 35 kg/m² (25–44 kg/m²), respectively (P < 0.001). The mean ± standard deviation excess weight loss was 51.6 ± 13.2%. In univariate analysis, total PSQI, STOP-Bang, and ESS scores were found to significantly improve 6 months after surgery (all P < 0.001). Multivariate mixed-model analysis showed a high correlation between the decrease in BMI and all key predictors. Mixed-model analysis revealed that every 1 kg/m² decrease in BMI was associated with a 0.32, 0.13, and 0.26 improvements in PSQI, STOP-Bang, and ESS scores, respectively (all P < 0.001).

Conclusion

Laparoscopic sleeve gastrectomy is associated with rapid weight loss and improvements in sleep quality, daytime sleepiness, and the risk of OSA 6 months after surgery.

     

Comparative Study of Tumor Targeting and Biodistribution of pH (Low) Insertion Peptides (pHLIP<Superscript>®</Superscript> Peptides) Conjugated with Different Fluorescent Dyes

Purpose

Acidification of extracellular space promotes tumor development, progression, and invasiveness. pH (low) insertion peptides (pHLIP^® peptides) belong to the class of pH-sensitive membrane peptides, which target acidic tumors and deliver imaging and/or therapeutic agents to cancer cells within tumors.

Procedures

Ex vivo fluorescent imaging of tissue and organs collected at various time points after administration of different pHLIP^® variants conjugated with fluorescent dyes of various polarity was performed. Methods of multivariate statistical analyses were employed to establish classification between fluorescently labeled pHLIP^® variants in multidimensional space of spectral parameters.

Results

The fluorescently labeled pHLIP^® variants were classified based on their biodistribution profile and ability of targeting of primary tumors. Also, submillimeter-sized metastatic lesions in lungs were identified by ex vivo imaging after intravenous administration of fluorescent pHLIP^® peptide.

Conclusions

Different cargo molecules conjugated with pHLIP^® peptides can alter biodistribution and tumor targeting. The obtained knowledge is essential for the design of novel pHLIP^®-based diagnostic and therapeutic agents targeting primary tumors and metastatic lesions.

     

Lack of agreement between thermodilution and electrical velocimetry cardiac output measurements

Objective

The modified algorithm for the non-invasive determination of cardiac output (CO) by electrical bioimpedance—electrical velocimetry (EV^®)—has been reported to give reliable results in comparison with echocardiography and pulmonary arterial thermodilution (PA-TD) in patients either before or after cardiac surgery. The present study was designed to determine whether EV^®-CO measurements reflect intraindividual changes in CO during cardiac surgery.

Design

Prospective, observational study.

Setting

Operating room (OR) and intensive care unit (ICU) of a university hospital.

Patients

Twenty-nine patients undergoing elective cardiac surgery.

Interventions

None.

Measurements

CO was determined simultaneously by PA-TD and EV^® after induction of anesthesia (t1) and 4.9?±?3.5?h after ICU admission (t2).

Results

TD-CO was 3.9?±?1.4 and 5.4?±?1.1 l/min at t1 and t2 (?p?®-CO was 4.3?±?1.1 and 4.9?±?1.5 l/min at t1 and t2 (?p?=?0.013). Bland–Altman analysis showed a bias of ?0.4 l/min and 0.4 l/min and a precision of 3.2 and 3.6 l/min (34.3% and 67.4%) at t1 and t2, respectively. Analysis of the individual pre- to postoperative changes in CO with both methods revealed bidirectional changes in n?=?12 patients and unidirectional changes with a difference greater than 50% and less than 50% in n?=?9 and n?=?8 patients, respectively.

Conclusions

The disagreement between PA-TD and EV^®-CO measurements after anesthesia induction and after ICU admission, as well as the fact that thoracic bioimpedance did not adequately reflect pre- to postoperative changes in CO, questions the reliability of EV^®-CO measurements in cardiac surgery patients and contrasts sharply with previous studies.

     

Effect of synbiotic therapy on the incidence of ventilator associated pneumonia in critically ill patients: a randomised,double-blind,placebo-controlled trial

Objective

To investigate the effect of enteral Synbiotic 2000 FORTE^® (a mixture of lactic acid bacteria and fibre) on the incidence of ventilator associated pneumonia (VAP) in critically ill patients.

Design

Prospective, randomised, double blind, placebo controlled trial.

Setting

Tertiary referral centre, general Adult Intensive Care Unit (ICU).

Patients and participants

259 enterally fed patients requiring mechanical ventilation for 48 h or more were enrolled.

Intervention

All patients were enterally fed as per a standard protocol and randomly assigned to receive either synbiotic 2000 FORTE^® (twice a day) or a cellulose-based placebo for a maximum of 28 days.

Measurements and results

Treatment group (n = 130) was well matched with placebo group (n = 129) for age (mean 49.5 and 50 years, respectively) and APACHE II score (median 17 for both). Oropharyngeal microbial flora and colonisation rates were unaffected by synbiotics. The overall incidence of VAP was lower than anticipated (11.2%) and no statistical difference was demonstrated between groups receiving synbiotic and placebo in the incidence of VAP (9 and 13%, P = 0.42), VAP rate per 1,000 ventilator days (13 and 14.6, P = 0.91) or hospital mortality (27 and 33%, P = 0.39), respectively.

Conclusions

Enteral administration of Synbiotic 2000 FORTE^® has no statistically significant impact on the incidence of VAP in critically ill patients.

     

A Comparison Between Rheological Properties of Intra-articular Hyaluronic Acid Preparations and Reported Human Synovial Fluid

Introduction

This study aims to compare the properties of currently available intra-articular hyaluronate (IA-HA) products widely available in the USA to those of healthy knee synovial fluid with respect to their bulk rheological properties. We hypothesize that products would have differing rheological properties, with some more closely resembling the properties and physiological aspects of healthy joint fluid HA.

Methods

We obtained reported HA product molecular weights, as well as measurements of the presence of cross-linking, zero shear rate viscosity, shear thinning ratio, and crossover frequency for the following IA-HA products available in the USA: Euflexxa^®, Orthovisc^®, Supartz^®, Monovisc^®, Synvisc^®, Synvisc-One^®, Gel-One^®, and Hyalgan^®.

Results

Differences were seen between the study products across all of the investigated parameters. Hyalgan, Supartz, Orthovisc, and Euflexxa had a linear chain structure, while Synvisc, Synvisc-One, and Monovisc were cross-linked in structure. Molecular weight, shear rates, and crossover frequencies ranged widely across tested products, with values ranging from below to above those reported for healthy knee synovial fluid HA. When compared to healthy knee parameter values reported within the current literature, observed parameters for Euflexxa and Orthovisc were typically seen to be the most similar to healthy knee synovial fluid. When comparing Euflexxa and Orthovisc directly, Euflexxa was more often similar to the properties of healthy knee synovial fluid with respect to the observed parameters of molecular structure, shear rates, and crossover frequency.

Conclusion

Available IA-HA products vary with respect to molecular weight, presence of cross-linking, shear rate dependency of viscosity, and crossover frequency. Since IA-HA treatment for osteoarthritis aims to restore synovial fluid back to original HA property characteristics, using HA supplements resembling healthy synovial fluid is a logical approach. Our findings demonstrate that Euflexxa is the most similar to healthy synovial fluid with respect to molecular structure, shear rates, and crossover frequency.

Funding

Ferring Pharmaceuticals, Inc.

     

Randomized Controlled Trial of Hyalobarrier<Superscript>®</Superscript> Versus No Hyalobarrier<Superscript>®</Superscript> on the Ovulatory Status of Women with Periovarian Adhesions: A Pilot Study

Introduction

Periadnexal adhesions are known to contribute to subfertility. The restoration of the tubo-ovarian anatomy is one the key principles in reproductive surgery, and this involves adhesiolysis. However, adhesion formation/reformation is very common after periovarian adhesiolysis. It is not known if the application of Hyalobarrier^®, an anti-adhesion gel, around the adnexal region postsurgery influences ovulatory status. The study is a pilot randomized controlled trial (RCT) randomizing women into the application of Hyalobarrier^® versus no Hyalobarrier^® at the time of laparoscopy, where postsurgical ovulatory status and pregnancy rates were evaluated.

Methods

This was a pilot RCT where women were recruited from the gynecological and subfertility clinic who were deemed to require an operative laparoscopy. If intraoperatively they were found to have periovarian adhesions, they were randomized into having adhesiolysis with and without usage of Hyalobarrier^®. Demographic details and intraoperative details including the severity, extent, and the ease of use of Hyalobarrier^® were recorded. Prior to the surgery and postoperatively, the participants had their serum hormonal status (day 2 FSH, LH and day 21 progesterone) evaluated. Postoperatively, they underwent a follicular tracking cycle at 3 months.

Results

Fifteen women were randomized into use of Hyalobarrier^® (study group) and 15 into the no Hyalobarrier^® group (control group) between December 2011 and January 2014. There was no difference in the patient characteristics in terms of age, BMI, the number of previous pregnancies, or the extent, site, and severity of adhesions between the two groups. There was no significant difference between the study versus control groups in terms of the hormonal profile (day 2 FSH and day 21 progesterone) before or after surgery. The 3-month postoperative day 10–12 follicular tracking findings and endometrial thickness were similar between the study and control groups. Four women were pregnant in the study group (24%) and one in the control group (7%) cumulatively over 2 years.

Conclusion

The use of Hyalobarrier^® post salpingo-ovariolysis did not influence follicular development as inferred from the results of the day 21 progesterone and folliculogram on day 10–12 3-month postsurgery.

Trial Registration

ISRCTN number, ISRCTN1833588.

Funding

Nordic Pharma.

     

Assessment of a new prototype hydrogel CO<Subscript><Emphasis Type="Bold">2</Emphasis></Subscript> sensor; comparison with air tonometry

Objective

Gastrointestinal ischemia is always accompanied by an increased luminal CO₂. Currently, air tonometry is used to measure luminal CO₂. To improve the response time a new sensor was developed, enabling continuous CO₂ measurement. It consists of a pH-sensitive hydrogel which swells and shrinks in response to luminal CO₂, which is measured by the pressure sensor. We evaluated the potential clinical value of the sensor during an in vitro and in vivo study.

Methods

The response time to immediate, and stepwise change in pCO₂ was determined between 5 and 15 kPa, as well as temperature sensitivity between 25 and 40 °C at two pCO₂ levels. Three sensors were compared to air tonometry (Tonocap^®) in healthy volunteers using a stepwise incremental exercise test, followed by a period of hyperventilation and an artificial CO₂-peak.

Results

The in vitro response time to CO₂ increase and decrease was mean 5.9 and 6.6 min. The bias, precision and reproducibility were +5%, 3% and 2%, resp. Increase of 1 °C at constant pCO₂ decreased sensor signal by 8%. In vivo tests: The relation with the Tonocap was poor during the exercise test. The response time of the sensor was 3 min during hyperventilation and the CO₂ peak.

Conclusion

The hydrogel carbon dioxide sensor enabled fast and accurate pCO₂ measurement in a controlled environment but is very temperature dependent. The current prototype hydrogel sensor is still too unstable for clinical use, and should therefore be improved.

     

Baseline [<Superscript>18</Superscript>F]FMISO μPET as a Predictive Biomarker for Response to HIF-1α Inhibition Combined with 5-FU Chemotherapy in a Human Colorectal Cancer Xenograft Model

Purpose

The purpose of this study was to characterize imaging biomarkers for the potential benefit of hypoxia-inducible factor-1 (HIF-1)α inhibition (by PX-12) during 5-fluorouracil (5-FU) chemotherapy in the treatment of colorectal cancer (CRC).

Procedures

Therapy response to 5-FU?±?PX-12 was assessed with baseline [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) and longitudinal 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) positron emission computed tomography (μPET/CT) in CRC xenograft model (n?=?36) during breathing of a hypoxic (10 % O₂) or normoxic (21 % O₂) atmosphere. Ex vivo, immunohistochemistry was performed.

Results

Baseline [¹⁸F]FMISO uptake and relative tumor volume (RTV) 2 days after 5-FU or 5-FU?+?PX-12 administration correlated significantly (p?≤?0.01). Under hypoxic breathing conditions, [¹⁸F]FDG uptake (?53.1?±?8.4 %) and Ki67 expression (?16 %) decreased and RTV stagnated in the 5-FU?+?PX-12 treatment group, but not in 5-FU alone-treated tumors. Under normoxic breathing, [¹⁸F]FDG uptake (?23.5?±?15.2 % and ?72.8?±?7.1 %) and Ki67 expression (?5 % and ?19 %) decreased and RTV stagnated in both the 5-FU and the combination treatment group, respectively.

Conclusion

Baseline [¹⁸F]FMISO μPET may predict the beneficial effect of HIF-1α inhibition during 5-FU chemotherapy in CRC.

     

Safety and efficacy of a fully closed-loop control ventilation (IntelliVent-ASV<Superscript>®</Superscript>) in sedated ICU patients with acute respiratory failure: a prospective randomized crossover study

Purpose

IntelliVent-ASV^® is a development of adaptive support ventilation (ASV) that automatically adjusts ventilation and oxygenation parameters. This study assessed the safety and efficacy of IntelliVent-ASV^® in sedated intensive care unit (ICU) patients with acute respiratory failure.

Methods

This prospective randomized crossover comparative study was conducted in a 12-bed ICU in a general hospital. Two periods of 2 h of ventilation in randomly applied ASV or IntelliVent-ASV^® were compared in 50 sedated, passively ventilated patients. Tidal volume (V _T), respiratory rate (RR), inspiratory pressure (P _INSP), SpO₂ and E_TCO₂ were continuously monitored and recorded breath by breath. Mean values over the 2-h period were calculated. Respiratory mechanics, plateau pressure (P _PLAT) and blood gas exchanges were measured at the end of each period.

Results

There was no safety issue requiring premature interruption of IntelliVent-ASV^®. Minute ventilation (MV) and V _T decreased from 7.6 (6.5–9.5) to 6.8 (6.0–8.0) L/min (p < 0.001) and from 8.3 (7.8–9.0) to 8.1 (7.7–8.6) mL/kg PBW (p = 0.003) during IntelliVent-ASV^® as compared to ASV. P _PLAT and FiO₂ decreased from 24 (20–29) to 20 (19–25) cmH₂O (p = 0.005) and from 40 (30–50) to 30 (30–39) % (p < 0.001) during IntelliVent-ASV^® as compared to ASV. RR, P _INSP, and PEEP decreased as well during IntelliVent-ASV^® as compared to ASV. Respiratory mechanics, pH, PaO₂ and PaO₂/FiO₂ ratio were not different but PaCO₂ was slightly higher during IntelliVent-ASV^® as compared to ASV.

Conclusions

In passive patients with acute respiratory failure, IntelliVent-ASV^® was safe and able to ventilate patients with less pressure, volume and FiO₂ while producing the same results in terms of oxygenation.

     

Study Design of VESUTO<Superscript>®</Superscript>: Efficacy of Tiotropium/Olodaterol on Lung Hyperinflation,Exercise Capacity,and Physical Activity in Japanese Patients with Chronic Obstructive Pulmonary Disease

Introduction

The superiority of tiotropium/olodaterol is demonstrated in improvement of lung function, dyspnea, lung hyperinflation, and quality of life compared with either monotherapy in patients with chronic obstructive pulmonary disease (COPD). Japanese Respiratory Society Guidelines for COPD management include improvement of exercise tolerance and daily physical activity as the treatment goals; however, there is limited evidence in Japanese patients with COPD.

Methods

A protocol is developed for the VESUTO^® study that investigates the efficacy of tiotropium/olodaterol fixed-dose combination (FDC) compared with tiotropium alone on inspiratory capacity (IC, volume from functional residual capacity to total lung capacity), exercise capacity, and daily physical activity in Japanese patients with COPD.

Results

A total of 180 Japanese patients with COPD, aged ≥40 years will be enrolled into the double-blind, multicenter, active-controlled, crossover study (NCT02629965) and will be randomized to receive either tiotropium/olodaterol FDC or tiotropium for 6 weeks each [two puffs via RESPIMAT^® (Boehringer Ingelheim, Ingelheim, Germany) inhaler in the morning]. The primary endpoint is IC at rest measured at 60 min post-dose after 6 weeks treatment. The secondary endpoints include the 6-min walk distance (6MWD) at 90 min post-dose and physical activity measured by the activity monitor in the last 2 weeks of the 6-week treatment periods. Lung function tests will also be assessed after 6 weeks treatment. A mixed-effects model repeated measures approach will be used for the primary and secondary endpoints.

Conclusion

The VESUTO^® study is the first randomized interventional study to investigate exercise capacity (6MWD) and physical activity measured by a 3-axis accelerometer in Japanese patients with COPD. The study could provide additional evidence of long-acting muscarinic antagonist (LAMA) + long-acting β₂-agonist (LABA) combination therapy on patients’ physical activities as well as lung function.

Trial registration

ClinicalTrials.gov: NCT02629965 (registered on December 1, 2015).

Funding

The VESUTO study was funded by Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan.

     

Distribution of lung ventilation in spontaneously breathing neonates lying in different body positions

Objective

The aim of our study was to determine the effect of the irregular spontaneous breathing pattern and posture on the spatial distribution of ventilation in neonates free from respiratory disease by the non-invasive imaging method of electrical impedance tomography (EIT). Scanning of spontaneously breathing neonates is the prerequisite for later routine application of EIT in babies with lung pathology undergoing ventilator therapy.

Design

Prospective study.

Setting

Neonatal intensive care unit at a university hospital.

Patients

Twelve pre-term and term neonates (mean age: 23 days; mean body weight: 2,465 g; mean gestational age: 34 weeks; mean birth weight: 2,040 g).

Interventions

Change in body position in the sequence: supine, right lateral, prone, supine.

Measurements and results

EIT measurements were performed using the Göttingen GoeMF I system. EIT scans of regional lung ventilation showing the distribution of respired air in the chest cross-section were generated during phases of rapid tidal breathing and deep breaths. During tidal breathing, 54.5±8.3%, 55.2±10.5%, 59.9±8.4% and 54.2±8.5% of inspired air (mean values ± SD) were directed into the right lung in the supine, right lateral, prone and repeated supine postures respectively. During deep inspirations, the right lung ventilation accounted for 52.6±7.9%, 68.5±8.5%, 55.4±8.2% and 50.5±6.6% of total ventilation respectively.

Conclusion

The study identified the significant effect of breathing pattern and posture on the spatial distribution of lung ventilation in spontaneously breathing neonates. The results demonstrate that changes in regional ventilation can easily be determined by EIT and bode well for the future use of this method in paediatric intensive care.

     

Zarzio<Superscript>®</Superscript>, biosimilar of filgrastim,in prophylaxis of chemotherapy-induced neutropenia in routine practice: a French prospective multicentric study

Purpose

Chemotherapy-induced neutropenia is a serious and potentially life-threatening consequence of cancer treatment. Prophylactic treatment with granulocyte-colony stimulating factor (G-CSF) decreases the incidence of febrile neutropenia, the rate of hospitalization, and the use of antibiotics in patients at risk. The aim of this study was to assess efficacy, safety, and use of Zarzio^®—biosimilar of Neupogen^® (G-CSF; filgrastim)—in prophylaxis of chemotherapy-induced neutropenia in current practice in cancer patients.

Methods

We conducted an observational, prospective, longitudinal, and multicentric study in France. The incidence of neutropenia was evaluated at each cycle of chemotherapy.

Results

One hundred eighty-four patients (women, 64.7 %; mean age, 61.7 years) with solid tumor (89.7 %; breast cancer, 50.5 %) or non-Hodgkin lymphoma (10.3 %) were included. The risk of febrile neutropenia based on chemotherapy regimen was >20 % for 32.1 % of patients. No case of febrile neutropenia was reported. Neutropenia was the cause of hospitalization and/or antibiotic therapy in 10 patients. The most frequent adverse events related to Zarzio^® were pain, in particular bone pain. No serious adverse event related to Zarzio^® was reported.

Conclusion

The results obtained in real-life conditions confirm that Zarzio^® is efficient and well tolerated in cancer patients.

     

Determination of functional residual capacity by oxygen washin-washout: a validation study

Objective

To validate a new system for functional residual capacity (FRC) measurements using oxygen washin/washout in spontaneously breathing humans. The system (LUFU, Drägerwerk AG, Lübeck, Germany) consists of an unmodified EVITA 4 ventilator, a side-stream paramagnetic oxygen sensor and a dedicated software.

Design

Laboratory study and measurements in spontaneously breathing volunteers.

Setting

Pulmonary function laboratory of a university hospital.

Participants

20 healthy and 15 lung diseased volunteers.

Interventions

FRC was measured by LUFU (LUFU-FRC) and by helium dilution (He-FRC); intra-thoracic gas volume (ITGV) was determined by body plethysmography. Each measurement cycle consisted of four independent LUFU-FRC determinations (step change of FiO₂ from 0.21 to 0.5 and back and from 0.21 to 1.0 and back), two helium-dilution runs and two body box measurements. Repeatability and agreement between methods were determined by comparing different measurements of one technique and by comparing different techniques among each other.

Measurements and results

Repeatability of LUFU-FRC was estimated by comparing washin to washout and the different FiO₂steps. The difference of the means was 3.7% at the most. Agreement between methods resulted in the following differences (mean?±?standard deviation of differences) for healthy and lung-diseased volunteers, respectively: LUFU-FRC vs. He-FRC –0.40?±?0.50?L (0.02?±?0.95?L), LUFU-FRC vs. ITGV –0.43?±?0.54?L (–0.18?±?0.61?L) and He-FRC vs. ITGV –0.03?±?0.43?L (–0.20?±?0.98?L).

Conclusions

LUFU is a non-invasive method for the determination of FRC that requires only minor additional equipment and no modification to the ventilator. It can be used in difficult conditions such as breathing patterns with variations from breath to breath. The results of this study show that LUFU is sufficiently reliable and repeatable to warrant its clinical application.

     

Evaluation of the Efficiency of Single-Inhaler Combination Therapy with Budesonide/Formoterol Fumarate in Patients with Bronchial Asthma in Daily Clinical Practice

Introduction

The effectiveness of single-inhaler budesonide/formoterol fumarate combination therapy for asthma has been previously shown for the original product. The aim of this nonrandomized, open-label, postauthorization efficacy study (PAES) real-life clinical assessment was to evaluate the clinical effectiveness of a second product (Bufomix Easyhaler^®) in the daily clinical practice of asthma therapy.

Methods

This multicenter PAES was conducted by 220 unselected allergologists and pulmonologists who enrolled 2200 adult outpatients (age 49.8 ± 17.9 years) with asthma treated with Bufomix Easyhaler^® for at least 14 days before enrolment. Asthma control was assessed during three subsequent visits with 8–12-week intervals on the basis of the Asthma Control Test (ACT). Adherence was assessed with the Medication Adherence Questionnaire. In addition, patient satisfaction with Bufomix Easyhaler^® was scored, and adverse drug reactions were recorded.

Results

The percentage of patients with well-controlled asthma or total control of asthma (ACT score 20-25 points) increased from 46.6% at the first visit to 90.8% at the third visit (p < 0.001). In addition, the percentage of patients with poor control of asthma (ACT score less than 15 points) decreased from 14.9% to 1.2% (p < 0.001). The adherence rate increased from 88% at the first visit to 95.3% at the third visit. Patient satisfaction with the use of this dry powder inhaler increased with the duration of its use. Only one adverse drug reaction was reported.

Conclusion

The results obtained confirm the effectiveness of Bufomix Easyhaler^® in the treatment of asthma in outpatient adults in daily clinical practice.

Funding

Orion Corporation

     

Clinical Effectiveness of Budesonide/Formoterol Fumarate Easyhaler<Superscript>®</Superscript> for Patients with Poorly Controlled Obstructive Airway Disease: a Real-World Study of Patient-Reported Outcomes

Introduction

The effectiveness of inhaled therapies can be influenced by many factors, including the type of inhaler, which may have clinical implications. We report a real-world, multicenter, open-label, non-randomized, non-interventional study conducted by 200 pulmonologists across 200 centers in Hungary. The effectiveness of budesonide/formoterol inhalation therapy in daily clinical practice, delivered via the Bufomix Easyhaler^®, was evaluated in patients with asthma, chronic obstructive pulmonary disease (COPD) and asthma-COPD overlap (ACO).

Methods

Effectiveness was assessed after 12 weeks of treatment by spirometry, the Asthma Control Test, mini-Asthma Quality of Life Questionnaire, COPD Assessment Test and modified Medical Research Council dyspnea scale. Patient satisfaction with the Bufomix Easyhaler^® and physicians’ assessments (ease of use and time taken to learn the technique) were also assessed.

Results

A total of 1498 patients with obstructive airway disease were evaluated (asthma: n?=?621; COPD: n?=?778; ACO: n?=?99), of whom 455 (30.4%) were newly diagnosed inhaler-naïve patients and 1043 (69.6%) were switching from other inhalers. Significant improvements in lung function, disease control and health-related quality of life measures (all p?≤?0.002) were reported after 12 weeks of Bufomix Easyhaler^® use. Improvements were observed in both inhaler-naïve patients and those who switched to a Bufomix Easyhaler^® from other devices. After switching, 72.4% of patients regarded the Bufomix Easyhaler^® as ‘very good’ and?>?90.0% of physicians described the Bufomix Easyhaler^® as easy to teach; 73.8% and 98.9% of patients learned the technique within 5 and 10 min of teaching, respectively.

Conclusion

Twelve weeks’ treatment with the Bufomix Easyhaler^® resulted in significant improvements in disease control and quality of life. The Bufomix Easyhaler^® was considered easy to use, and most patients were satisfied with the inhaler. Results confirm the real-world effectiveness of the Bufomix Easyhaler^® in the treatment of adult outpatients with obstructive airway disease.

Funding

Orion Corp., Orion Pharma.

     

Single-Dose Comparative Pharmacokinetics of Two Formulations of Lenalidomide 25 mg in Healthy Subjects: A Randomized Crossover Study

Background

Lenalidomide is used for the treatment of multiple myeloma in combination with dexamethasone. The purpose of this study was to compare the pharmacokinetics (PKs) and assess the bioequivalence of two formulations of lenalidomide 25 mg: Lenalid^® 25 mg tablet (test formulation) and Revlimid^® 25 mg capsule (reference formulation).

Methods

A randomized, single-dose, two-treatment, two-period, two-sequence crossover study was conducted in 42 healthy subjects. All subjects were randomly assigned to one of the two sequences, and they received a single dose of test or reference formulation in the first period and the alternative formulation during the next period under fasting conditions. Serial blood samples for PK evaluation were collected up to 24 h post-dose and the PK parameters were estimated by non-compartmental methods. Throughout the study, tolerability was assessed on the basis of adverse events, vital signs, and clinical laboratory tests.

Results

The test formulation showed similar PK profiles to those of the reference formulation. The geometric mean ratio and 90% confidence interval (CI) of the test formulation to the reference formulation for maximum plasma concentration (C_max) was 0.9995 (0.9250–1.0799) and the corresponding value for the area under the concentration–time curve from time zero to time of last quantifiable concentration (AUC_t) was 0.9648 (0.9451–0.9850). Both CIs were within the conventional bioequivalence range of 0.8–1.25. The tolerability profile was not significantly different between the two formulations.

Conclusion

This study found that the PKs of the two formulations of lenalidomide 25 mg were similar and the test formulation met the regulatory criteria for assuming bioequivalence with the reference formulation.

Funding

Samyang Biopharmaceutical Corp.

     

Tiotropium Respimat<Superscript>®</Superscript> Versus HandiHaler<Superscript>®</Superscript>: Comparison of Bronchodilator Efficacy of Various Doses in Clinical Trials

Introduction

The long-acting muscarinic antagonist tiotropium bromide is approved in many countries as maintenance therapy for chronic obstructive pulmonary disease (COPD). Tiotropium is available as a dry-powder formulation delivered via HandiHaler^® (18 μg once daily) and is now also approved as an aqueous solution delivered via the Respimat^® Soft Mist? Inhaler (5 μg once daily, 2 puffs of 2.5 µg). Several studies have compared the efficacy of tiotropium HandiHaler (18 μg once daily) with different doses of Respimat. We aimed to compare available bronchodilator efficacy data of once-daily Respimat 1.25, 2.5, 5, 10, 20 µg, and HandiHaler 18 µg to investigate which dose of tiotropium delivered by Respimat is the closest match to tiotropium HandiHaler.

Methods

Evaluation of six clinical trials (duration from 3 weeks to 2–3 years) that included lung function measures (trough forced expiratory volume in 1 s and trough forced vital capacity) as key outcomes.

Results

In the six trials, bronchodilator efficacy of Respimat 5 μg and HandiHaler 18 μg was similar; however, reduced bronchodilator efficacy was observed with lower doses of Respimat (1.25 and 2.5 μg).

Conclusion

These findings support the use of the marketed once-daily dose of Respimat 5 μg for the maintenance treatment of patients with COPD.

Funding

Boehringer Ingelheim.