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.

     

Reliability and Responsiveness of NutriQoL<Superscript>®</Superscript> Questionnaire

Introduction

NutriQoL^® (Nestlé Health Science, Vevay, Switzerland) is a questionnaire developed to assess the health-related quality-of-life (HRQoL) of patients with home enteral nutrition (HEN) irrespective of their underlying condition and route of administration. The aim of this work is assessing the questionnaire’s reliability and responsiveness to change.

Methods

Two cohorts of patients with HEN and their primary caregivers were enrolled to assess reliability and responsiveness, respectively. All participants had to be 18 years of age or older, without mental deterioration (≤3 or 4 errors in the Pfeiffer’s test) and with sufficient functional status (>40 points on Karnovsky’s performance status scale). When the patients’ ability to respond to the questionnaire was impaired due to underlying disease, their caregivers answered on their behalf. NutriQoL was administered in two and three visits to reliability and responsiveness cohorts, respectively. Test–retest reliability and internal consistency were assessed by the intra-class correlation coefficient (ICC) and the Cronbach’s α, respectively. Responsiveness was evaluated by standardized effect size and standardized response mean between basal visit and third visit. Finally, the minimal clinically important difference (MCID) was estimated.

Results

A total of 54 and 86 participants were recruited to the reliability and responsiveness cohort, respectively. Thirty-five caregivers were selected to assess the inter-observer reliability. ICC values confirmed the good reproducibility level (ICC >0.75) of the questionnaire in both “physical functioning and activities of daily living” and “social life” domains and total score. The assessment of internal consistency in both domains of the questionnaire showed good internal consistency in visit 2. ICC showed the excellent agreement level between caregiver and patient in the global NutriQoL score. Finally, patients classified as having a minimal change in their health reported a mean (standard deviation) MCID in NutriQoL score of 0.63 (11.51).

Conclusion

NutriQoL is a reliable and unique instrument to measure the HRQoL in HEN patients. NutriQoL detects changes in the health status of the patient. Nevertheless, further research is needed to determine the full extent of the questionnaire responsiveness.

     

Gluten and Aluminum Content in Synthroid<Superscript>®</Superscript> (Levothyroxine Sodium Tablets)

Introduction

Inquiries from healthcare providers and patients about the gluten and aluminum content of Synthroid^® (levothyroxine sodium tablets) have increased. The objective of this study was to measure and evaluate the gluten content of the raw materials used in the manufacturing of Synthroid. Additionally, this study determined the aluminum content in different strengths of Synthroid tablets by estimating the amount of aluminum in the raw materials used in the manufacturing of Synthroid.

Methods

Gluten levels of three lots of the active pharmaceutical ingredient (API) and one lot of each excipient from different vendors were examined. The ingredients in all current Synthroid formulations (strengths) were evaluated for their quantity of aluminum.

Results

Gluten concentrations were below the lowest limit of detection (<3.0 ppm) for all tested lots of the API and excipients of Synthroid tablets. Aluminum content varied across tablet strengths (range 19–137 µg/tablet). Gluten levels of the API and excipients were found to be below the lowest level of detection and are considered gluten-free based on the US Food and Drug Administration (FDA) definition for food products. Across the various tablet strengths of Synthroid, the maximum aluminum levels were well below the FDA-determined minimal risk level for chronic oral aluminum exposure (1 mg/kg/day).

Conclusion

These data demonstrate that Synthroid tablets are not a source for dietary gluten and are a minimal source of aluminum.

Funding

AbbVie 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.

     

Evaluation of the Responsiveness of the SarQoL<Superscript>®</Superscript> Questionnaire,a Patient-Reported Outcome Measure Specific to Sarcopenia

Introduction

The Sarcopenia Quality of Life (SarQoL^®) questionnaire was developed to provide a patient-reported outcome measure specific to sarcopenia. Its psychometric properties indicate that it is a valid and reliable instrument. However, until now, its ability to detect change over time has not been examined. Therefore, the objective of this study is to evaluate the responsiveness (also known as sensitivity to change) of the SarQoL^® questionnaire in a prospective, longitudinal cohort of community-dwelling, older, sarcopenic subjects.

Methods

Sarcopenic subjects from the SarcoPhAge (Sarcopenia and Physical impairment with advancing Age) study were included. Responsiveness was evaluated with nine pre-specified hypotheses on the correlation between the evolution of the SarQoL^® scores after a 2-year interval and the evolution of the scores on the Short Form-36 (SF-36) and the Euroqol 5-dimension (EQ-5D) questionnaires. This technique considers responsiveness to be a form of longitudinal validity. Additionally, standardized response means were also calculated to compare the quantity of change measured by the different questionnaires.

Results

A total of 42 sarcopenic subjects were included. The median age of the sample was 72.9 (68.9–78.8) years, 59.5% were female, and the mean body mass index was 23.3 (20.4–25.7) kg/m². A good responsiveness was observed, as evidenced by the confirmation of eight out of nine hypotheses, well above the 75% confirmation threshold. The standardized response mean of the Overall SarQoL^® score was significantly higher than those of the SF-36 Physical Component Summary (p?=?0.005), the EQ-5D Utility Index (p?<?0.001) and the Euroqol visual analogue scale (p?=?0.003).

Conclusion

The first data available on the ability of the SarQoL^® questionnaire to detect change over time indicates that the questionnaire has good responsiveness. This, together with the previously established psychometric properties, confirms that the SarQoL^® questionnaire is a relevant instrument for the assessment of quality of life in sarcopenic populations.

     

Prospective Evaluation of Two iStent<Superscript>®</Superscript> Trabecular Stents,One iStent Supra<Superscript>®</Superscript> Suprachoroidal Stent,and Postoperative Prostaglandin in Refractory Glaucoma: 4-year Outcomes

Introduction

This study evaluates long-term outcomes of two trabecular micro-bypass stents, one suprachoroidal stent, and postoperative prostaglandin in eyes with refractory open angle glaucoma (OAG).

Methods

Prospective ongoing 5-year study of 80 eligible subjects (70 with 4-year follow-up) with OAG and IOP ≥ 18 mmHg after prior trabeculectomy and while taking 1–3 glaucoma medications. Subjects received two iStent^® trabecular micro-bypass stents, one iStent Supra^® suprachoroidal stent, and postoperative travoprost. Postoperative IOP was measured with medication and annually following medication washouts. Performance was measured by the proportion of eyes with ≥ 20% IOP reduction on one medication (the protocol-specified prostaglandin) versus preoperative medicated IOP (primary outcome); and the proportion of eyes with postoperative IOP ≤ 15 and ≤ 18 mmHg on one medication (secondary outcome). Additional clinical and safety data included medications, visual field, pachymetry, gonioscopy, adverse events, visual acuity, and slit-lamp and fundus examinations.

Results

Preoperatively, mean medicated IOP was 22.0 ± 3.1 mmHg on 1.2 ± 0.4 medications, and mean unmedicated IOP was 26.4 ± 2.4 mmHg. Postoperatively, among eyes without later cataract surgery, mean medicated IOP at all visits through 48 months was ≤ 13.7 mmHg (≥ 37% reduction), and annual unmedicated IOP was ≤ 18.4 mmHg (reductions of ≥ 30% vs. preoperative unmedicated IOP and ≥ 16% vs. preoperative medicated IOP). At all postoperative visits among eyes without additional surgery or medication, ≥ 91% of eyes had ≥ 20% IOP reduction on one medication versus preoperative medicated IOP. At month 48, 97 and 98% of eyes achieved IOP ≤ 15 and ≤ 18 mmHg, respectively, on one medication. Six eyes required additional medication, no eyes required additional glaucoma surgery, and safety measurements were favorable throughout follow-up.

Conclusion

IOP control was achieved safely with two trabecular micro-bypass stents, one suprachoroidal stent, and postoperative prostaglandin. This microinvasive, ab interno approach introduces a possible new treatment option for refractory disease.

Trial Registration

NCT01456390.

Funding

Glaukos Corporation.

     

In vitro performance of prefilled CO<Subscript>2</Subscript> absorbers with the Aisys<Superscript>®</Superscript>

Low flow anesthesia increases the use of CO₂ absorbents, but independent data that compare canister life of the newest CO₂ absorbents are scarce. Seven different pre-packed CO₂ canisters were tested in vitro: Amsorb Plus, Spherasorb, LoFloSorb, Medisorb, Medisorb EF, LithoLyme, and SpiraLith. CO₂ (160 mL min^?1) flowed into the tip of a 2 L breathing bag that was ventilated with a tidal volume of 500 mL, a respiratory rate of 10/min, and an I:E ratio of 1:1 using the controlled mechanical ventilation mode of the Aisys ^® (GE, Madison, WI, USA). In part I, canister life of each brand (all of the same lot) was tested with 12 different fresh gas flows (FGF) ranging from 0.25 to 4 L min^?1. In part II, canister life of six canisters each of two different lots of each brand were tested with a 350 mL min^?1 FGF. Canister life is presented as “FCU”, fractional canister usage, the fraction of a canister used per hour, and is defined for the inspired CO₂ concentration (F_ICO₂) that denotes exhaustion. In part III, canister life per 100 g fresh granule content was calculated. FCU decreased linearly with increasing FGF. The relative position of the FCU–FGF curves of the different brands depends on the F_ICO₂ threshold because the exhaustion rate (the rate of rise once F_ICO₂ starts to increase) differs among the brands. Intra-lot variability was 18 % or less. The different prepacks can be ranked according their efficiency (least to most efficient) as follows: Amsorb Plus = Medisorb EF < LoFloSorb < Medisorb = Spherasorb = LithoLyme < SpiraLith (all for an F_ICO₂ threshold = 0.5 %). Canister life per 100 g fresh granule content is almost twice as long when LiOH is used as the primary absorbent. The most important factors that determine canister life of prepacks in a circle breathing system are the chemical composition of the canister, the absolute amount of absorbent present in the canister, and the F_ICO₂ replacement threshold. The use of the fractional canister usage allows cost comparisons among different prepacks. Results should not be extrapolated to prepacks that fit onto other anesthesia machines.     

Efficacy of a Novel Prefilled,Single-Use,Needle-Free Device (Zeneo<Superscript>®</Superscript>) in Achieving Intramuscular Agent Delivery: An Observational Study

Background

It is recognized that, as a result of variation in tissue anatomy, current auto-injectors may have insufficient needle length to achieve successful intramuscular agent delivery in a number of patients. The Zeneo^® auto-injector is a novel prefilled, single-use, needle-free device currently in development for intradermal, subcutaneous, and intramuscular agent delivery across a variety of clinical indications. We aimed to evaluate delivery depth of the device calibrated at pressure appropriate for intramuscular (IM) administration.

Methods

This was a prospective single-center study in healthy adult volunteers, in whom each received a single injection of saline into the anterolateral thigh. Using sequential MRI scans, we measured skin-to-muscle distance (STMD) agent delivery depth, and the success of IM agent penetration. Device dynamic pressure measurements were also recorded.

Results

Results are reported for 37 subjects with evaluable MRI scans; 19 men, 18 women; mean age 38 years (range 20–58); mean BMI 27.0 kg/m² (range 21.2–30.8 kg/m²). Mean STMD values were 18.6 mm (range 13.4–23.6 mm) in women and 10.0 mm (range 5.0–21.7 mm) in men, with gender differences due primarily to greater subcutaneous thickness in women. A trend for greater STMD in subjects with BMI greater than 25 kg/m² was seen. Mean injectate penetration depths of 30.1 mm (range 20.2–45.6 mm) were observed with values similar in male and female subjects. Successful IM delivery was reported in 95% of subjects. When failure occurred, this was not due to inadequate injection depth. Device pressure (P _max) had the greatest influence on injectate muscle penetration.

Conclusion

Use of the Zeneo^® auto-injector achieves delivery depth that ensures intramuscular delivery in both men and women, regardless of BMI. Consistent with other reported data, STMD is greater in women.

Funding

Crossject.

     

Automated,continuous and non-invasive assessment of pulse pressure variations using CNAP<Superscript>®</Superscript> system

Non-invasive respiratory variations in arterial pulse pressure using infrared-plethysmography (PPV_CNAP) are able to predict fluid responsiveness in mechanically ventilated patients. However, they cannot be continuously monitored. The present study evaluated a new algorithm allowing continuous measurements of PPV_CNAP (PPV_CNAPauto) (CNSystem, Graz, Austria). Thirty-five patients undergoing vascular surgery were studied after induction of general anaesthesia. Stroke volume was measured using the Vigileo^TM/FloTrac^TM. Invasive pulse pressure variations were manually calculated using an arterial line (PPV_ART) and PPV_CNAPauto was continuously displayed. PPV_ART and PPV_CNAPauto were simultaneously recorded before and after volume expansion (500 ml hydroxyethylstarch). Subjects were defined as responders if stroke volume increased by ≥15 %. Twenty-one patients were responders. Before volume expansion, PPV_ART and PPV_CNAPauto exhibited a bias of 0.1 % and limits of agreement from ?7.9 % to 7.9 %. After volume expansion, PPV_ART and PPV_CNAPauto exhibited a bias of ?0.4 % and limits of agreement from ?5.3 % to 4.5 %. A 14 % baseline PPV_ART threshold discriminated responders with a sensitivity of 86 % (95 % CI 64–97 %) and a specificity of 100 % (95 % CI 77–100 %). Area under the receiver operating characteristic (ROC) curve for PPV_ART was 0.93 (95 % CI 0.79–0.99). A 15 % baseline PPV_CNAPauto threshold discriminated responders with a sensitivity of 76% (95 % CI 53–92 %) and a specificity of 93 % (95 % CI 66–99 %). Area under the ROC curves for PPV_CNAPauto was 0.91 (95 % CI 0.76–0.98), which was not different from that for PPV_ART. When compared with PPV_ART, PPV_CNAPauto performs satisfactorily in assessing fluid responsiveness in hemodynamically stable surgical patients.     

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.

     

Cardiac output monitoring in septic shock: evaluation of the third-generation Flotrac-Vigileo<Superscript>®</Superscript>

Continuous cardiac index (CI) monitoring is frequently used in critically ill patients. Few studies have compared the pulse contour-based device FloTrac/Vigileo^® to pulmonary artery thermodilution (PAC) in terms of accuracy for CI monitoring in septic shock. The aim of our study was to compare the third-generation FloTrac/Vigileo^® to PAC in septic shock. Eighteen patients with septic shock requiring monitoring by PAC were included in this study. We monitored CI using both FloTrac/Vigileo^® and continuous thermodilution (PAC-CI). Hemodynamic data were recorded every hour or every 2 min during fluid challenges. The primary endpoint was the global agreement of all CI-paired measurements determined using the Bland–Altman method adapted to replicated data. We tested the linearity of the bias by regression analysis, and compared the reactivity of the 2 techniques during fluid challenges. A receiver operating characteristic (ROC) curve analysis tested the ability of FloTrac/Vigileo^® to detect concordant and significative CI changes, using PAC-CI as the reference method. Overall, 1,201 paired CI measurements were recorded. The Bland–Altman analysis for global agreement of the 2 techniques showed a bias of ?0.1 ± 2.1 L min^?1 m^?2 and a percentage error of 64 %. The overall correlation coefficient between PAC-CI and FloTrac/Vigileo^® CI was 0.47 (p < 0.01), with r² = 0.22. The area under the curve of the ROC curve for detecting concordant and significant changes in CI was 0.72 (0.53; 0.87). In our study, third-generation Flowtrac-Vigileo^® appears to be too inaccurate to be recommended for CI monitoring in septic shock.     

Two patterns of contrast-enhanced ultrasonography with Sonazoid<Superscript>®</Superscript> in spontaneous rupture of hepatocellular carcinoma: a report of four cases

Spontaneous rupture is a life-threatening complication of hepatocellular carcinoma (HCC). Detecting active bleeding is critical. Color Doppler and contrast-enhanced ultrasonography (CEUS) with Levovist^® are reported to be useful for detecting active bleeding. A few reports have described using Sonazoid^® to detect bleeding in ruptured HCC. This report describes two distinctive patterns of bleeding from ruptured HCC observed in CEUS with Sonazoid^®. Four patients with suspected HCC rupture were examined by gray-scale ultrasonography (US) and then CEUS with Sonazoid^®. Two patterns of bleeding were observed with CEUS: jet-like extravasation (n = 2) and bubble leakage (n = 2). While contrast-enhanced computed tomography and angiography revealed active bleeding in only one patient, CEUS detected active bleeding and enabled the bleeding site to be estimated in all patients. Transcatheter arterial embolization was performed based on the findings of CEUS, and hemostasis was achieved in all patients. CEUS using Sonazoid^® could demonstrate active bleeding as two patterns, and these findings enabled us to detect the rupture site of HCC more confidently than with other modalities.     

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.

     

Incidence of late occurring bradyarrhythmias after TAVI with the self-expanding CoreValve<Superscript>®</Superscript> aortic bioprosthesis

Objectives  

Analysis of timing, type, electrocardiographic and patient characteristics of postinterventional bradyarrhythmias after CoreValve implantation.     

Nonclinical Evaluation of PF-06438179: A Potential Biosimilar to Remicade<Superscript>®</Superscript> (Infliximab)

Introduction

PF-06438179, a potential biosimilar to Remicade^® (infliximab, Janssen Biotech, Inc.), is a chimeric mouse–human monoclonal antibody targeting human tumor necrosis factor alpha (TNF).

Methods

Analytical (small subset reported here) and nonclinical studies compared the structural, functional, and in vivo nonclinical similarity of PF-06438179 with Remicade sourced from the United States (infliximab-US) and/or European Union (infliximab-EU).

Results

The peptide map profiles were superimposable, and peptide masses were the same, indicating identical amino acid sequences. Data on post-translational modifications, biochemical properties, and biological function provided strong support for analytical similarity. Administration of a single intravenous (IV) dose (10 or 50 mg/kg) of PF-06438179 or infliximab-EU to male rats was well tolerated. There were no test article-related clinical signs or effects on body weight or food consumption. Systemic exposures [maximum drug concentration (C _max) and area under the concentration–time curve (AUC)] in rats administered PF-06438179 or infliximab-EU were similar, with mean exposure ratio of PF-06438179 relative to infliximab-EU ranging from 0.88 to 1.16. No rats developed anti-drug antibodies. A 2-week IV toxicity study was conducted with once-weekly administration of 10 or 50 mg/kg of PF-06438179 to male and female rats. PF-06438179-related hyperplasia of sinusoidal cells occurred in the liver in rats administered 50 mg/kg, but was not adverse based on its minimal to mild severity. The no-observed adverse-effect level for PF-06438179 was 50 mg/kg. At this dose, C _max was 1360 µg/mL and AUC at 168 h was 115,000 µg h/mL on day 8.

Conclusions

The analytical and nonclinical studies have supported advancement of PF-06438179 into global comparative clinical trials.

Funding

Pfizer Inc.

     

Evaluation of left atrial functions by color tissue Doppler imaging in adults with body mass indexes ≥30 kg/m<Superscript>2</Superscript> versus those <30 kg/m<Superscript>2</Superscript>

Evaluation of atrial function has received less attention than that of the ventricle although normal atrial function is required for optimal overall cardiac function. Obesity is associated with increased cardiovascular morbidity and mortality. In this study, we compared left atrial functions in obese adults (body mass index = BMI ≥30 kg/m²) with those in non-obese adults (BMI <30 kg/m²) by color tissue Doppler parameters. There were 37 adults with BMI ≥30 kg/m² (mean age 36 ± 11 years) and 26 adults with BMI <30 kg/m² (mean age 35 ± 5 years). Mean BMI was 38 ± 6 kg/m² in the obese group whereas that was 24 ± 2 kg/m² in the non-obese group. For color tissue Doppler imaging, sample volumes were placed on the mid left atrium at the septum, lateral, inferior, and anterior walls. The peak systolic strain (S _s), peak systolic strain rate (SR_s), peak early diastolic SR (SR_e), peak late diastolic SR (SR_a), peak systolic tissue velocity (TV_s), peak early diastolic TV (TV_e) and peak late diastolic TV (TV_a) values were measured. For each measurement, values in three consecutive cardiac cycles were measured and then averaged. To simplify the analysis, the values at each wall were combined and averaged to obtain mean values. All left atrial systolic function parameters (S _s, SR_s, TV_s) were similar between the groups. In addition, there was no statistically significant difference at left atrial diastolic function parameters (SR_e, SR_a, TV_e, TV_a). We could not find any significant difference between obese and non-obese adults at left atrial functions assessed by color tissue Doppler parameters.