The pharmacodynamic properties of azithromycin in a kinetics-of-kill model and implications for bacterial conjunctivitis treatment

Introduction

Antibiotics have traditionally been classified as bactericidal or bacteriostatic. Azithromycin belongs to the parent class of macrolides that are characteristically bacteriostatic. Some evidence suggests that this mol-ecule demonstrates bactericidal kill and has concentration-dependent effects. This study tests the hypothesis that azithromycin demonstrates a bactericidal, concentration-dependent antibiotic effect at concentrations corresponding to and exceeding published tear and conjunctival levels.

Methods

The antibacterial activity of different concentrations of azithromycin 1% in DuraSite® (AzaSite®; Inspire Pharmaceuticals Inc, Durham, NC, USA) was evaluated using a kinetics-of-kill model. Recent conjunctivitis isolates of Staphylococcus aureus, Streptococcus pneumoniae or Haemophilus influenzae were exposed to four concentrations of azithromycin (100, 250, 500 and 750 μg/ml). Starting concentrations were similar to the maximum concentrations (Cmax) that have been demonstrated in conjunctiva (83 μg/g) and tears (288 μg/ml) following topical ocular administration. The percentage of surviving bacteria at 30 and 60 minutes following exposure to each concentration were determined.

Results

Azithromycin failed to demonstrate bactericidal activity (i.e. a 3-log reduction in surviving bacteria) against S. aureus, S. pneumoniae or H. influenzae. Furthermore, the rate and extent of antibacterial activity with azithromycin did not change with higher concentrations, even at the highest tested concentration of 750 μg/ml.

Conclusion

Similar to the parent macrolide class, azithromycin demonstrates bacteriostatic activity against common conjunctival pathogens up to the maximum tested concentration of 750 μg/ml (i.e. 2.6-times and 9-times published Cmax tear and conjunctival concentration, respectively). Azithromycin’s bacteriostatic effects and prolonged elimination half-life will likely lead to a corresponding increase in the emergence of macrolide-resistant isolates.

     

Safety and tolerability of Kinesio<Superscript>®</Superscript> Taping in patients with arm lymphedema: medical device clinical study

Purpose

The aim of this study is to assess the safety and tolerability of Kinesio^® Taping (KT) in patients with arm lymphedema.

Method

Medical device clinical study in women with arm lymphedema. Kinesio^® Tex Gold bandage was applied by the KT technique. Assessments and interviews were carried out both at the beginning and 4 days after intervention. Skin disorders, reported tolerance and modification of limb volume and function after intervention were assessed. Changes in limb volume and functionality before and after intervention were compared by the Student’s t test and the Wilcoxon Signed-Rank test, considering significant p value <0.05.

Results

Twenty-four women were studied. After intervention, no patient had cutaneous lesions, vesicle or limb hyperthermia, and 4.2 % presented skin peeling and redness. Most patients reported no change in social life and that they felt safer in the daily activity and were very pleased with the treatment. The patients presented improvement of upper limb functionality after intervention (p?<?0.001). No difference of limb volume was found after intervention (p?=?0.639).

Conclusions

Kinesio^® Tex Gold bandage by the KT technique proved to be safe and tolerable in patients with lymphedema, with improved functionality and no change of the affected limb volume.

     

Prospective,Randomized, Single Masked,Parallel Study Exploring the Effects of a Preservative-Free Ophthalmic Solution Containing Hyaluronic Acid 0.4% and Taurine 0.5% on the Ocular Surface of Glaucoma Patients Under Multiple Long-Term Topical Hypotensive Therapy

Introduction

To compare the effects of a preservative-free (PF) ophthalmic solution containing hyaluronic acid (HA) 0.4% and taurine (TAU) 0.5% with those of a PF ophthalmic solution containing HA 0.2% on ocular surface signs, symptoms, and morphological parameters in glaucoma patients under multiple long-term topical hypotensive therapy.

Methods

Eligible patients underwent evaluation of ocular surface parameters by ocular surface disease index (OSDI) and glaucoma symptom scale (GSS) questionnaires, breakup time test (BUT), Schirmer I test, corneal and conjunctival staining (Oxford scale), and conjunctival in vivo confocal microscopy (Heidelberg Retina Tomograph 3, Heidelberg Engineering GmbH, Heidelberg, Germany). After the baseline visit, patients were randomized to use a PF ophthalmic solution containing HA 0.4% and TAU 0.5%, QID, in both eyes (group 1) or to use a PF ophthalmic solution containing HA 0.2%, QID (group 2) in addition to the ongoing preserved hypotensive treatment. Follow-up visits were scheduled at 30 and 90 days.

Results

Thirty-nine eyes of 39 glaucoma patients were included in the study. At baseline, results of study tests of both groups were similar. After 90 days in group 1 the BUT (p?=?0.01), the Oxford score (p?=?0.03), the conjunctival goblet cells (CGC) density (p?=?0.0005) ,and the two questionnaires score significantly improved (OSDI, p?=?0.003; GSS, p?=?0.003) compared to baseline values, while in group 2 all these parameters did not differ from baseline (BUT, p?=?0.39; Oxford score, p?=?0.54; CGC density, p?=?0.33, OSDI p?=?0.65, GSS, p?=?0.25). The BUT and the CGC density were statistically different between groups both at 30 and 90 days (p?=?0.04 and p?=?0.04, respectively). The Schirmer I test did not statistically change after 90 days in both groups.

Conclusions

The PF ophthalmic solution with HA 0.4% and TAU 0.5% seems to improve CGC density and reduce signs and symptoms of dry eye in glaucoma patients under long-term multiple preserved hypotensive therapy.

Trial registration

ClinicalTrials.gov identifier, NCT03480295.

     

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.

     

Comparative Effectiveness of <Emphasis Type="Italic">nab</Emphasis>-Paclitaxel Plus Gemcitabine vs FOLFIRINOX in Metastatic Pancreatic Cancer: A Retrospective Nationwide Chart Review in the United States

Introduction

nab-Paclitaxel plus gemcitabine (nab-P?+?G) and FOLFIRINOX (FFX) are among the most common first-line (1L) therapies for metastatic adenocarcinoma of the pancreas (MPAC), but real-world data on their comparative effectiveness are limited.

Methods

This retrospective cohort study compared the efficacy and safety of 1L nab-P?+?G versus FFX, overall and under specific treatment sequences. Medical records were reviewed by 215 US physicians who provided information on MPAC patients who initiated 1L therapy with nab-P?+?G or FFX between April 1, 2015 and December 31, 2015. Study outcomes were overall survival (OS) and tolerability. OS was compared using Kaplan–Meier curves and adjusted Cox proportional hazards models.

Results

In total, 654 medical records were reviewed, including those of 337 and 317 patients initiated on nab-P?+?G and FFX as 1L MPAC therapy, respectively. nab-P?+?G-initiated patients were older, less likely to have ECOG?≤?1, and had more comorbidities than FFX-initiated patients. Median OS (mOS) was 12.1 and 13.8 months for nab-P?+?G- and FFX-initiated patients, respectively (HR?=?0.99, P?=?0.96). Among patients with ECOG?≤?1, mOS was 14.1 and 13.7 months, respectively (HR?=?1.00, P?=?0.99). Among patients with 1L nab-P?+?G and FFX, 36.1% and 41.3% received 2L therapy and experienced mOS of 16.3 and 16.6 months, respectively (HR?=?1.04, P?=?0.76). The rates of diarrhea, fatigue, mucositis, and nausea and vomiting were significantly higher in the FFX than nab-P?+?G cohort.

Conclusion

The real-world survival was similar between patients receiving 1L nab-P?+?G or FFX both overall and among patients who received active 2L treatments. In addition, nab-P?+?G was associated with significantly lower rates of common AEs compared with FFX.

Funding

Celgene.

     

Effet des extraits de quelques plantes sur les bactéries pathogènes responsables de gastroentérites

Background

Phytochemicals are natural bioactive compounds that protect plants against the stress. These phytochemicals may also have other biological activities like, antibacterial activity.

Objective

The objective of this work is to study the antibacterial effect of aqueous and hydro-alcoholic extracts prepared from Thymus vulgaris, Aloysia triphylla, Pistacia lentiscus, Olea europaea leaves and Trigonella foenum-graecum seeds on some pathogenic bacteria responsible for gastroenteritis.

Result

The results obtained from the antibacterial effect showed a moderate activity against the strains studied with a diameters of inhibition zones ranging from 07.00 ± 0.8 to 16.00 ± 1.0 mm for aqueous extracts and vary between 07.00 ± 0.9 and 13.00 ± 1.0 mm for hydro-alcoholic extracts.

Conclusion

This study confirms the possibility of using these plants or components in the prevention of several diseases like, gastroenteritis.

     

Anti-Anginal Effectiveness and Tolerability of Trimetazidine Modified Release 80 Mg Once Daily in Stable Angina Patients in Real-World Practice

Introduction

Trimetazidine (TMZ) was shown to reduce angina symptoms and increase the exercise capacity in stable angina (SA) patients. A new formulation allowing a once-daily (od) dosage could improve patients’ satisfaction and adherence.

Methods

ODA was a 3-month, observational, multicenter, prospective Russian study in SA patients with persistent symptoms despite therapy. Angina attack frequency, short-acting nitrate (SAN) consumption, adherence to antianginal medications, and overall efficacy and tolerability of TMZ 80 mg od were assessed in a real-world setting.

Results

A total of 3066 patients were included (mean age 62.8, 48% male). After 3 months, TMZ 80 mg od treatment led to a significant (p?<?0.001) decrease in angina attack frequency (from 4.7?±?3.5 to 0.9?±?1.3/week) and SAN use (from 4.5?±?3.9 to 0.7?±?1.3/week). Overall tolerability and effectiveness were rated as “very good” by the majority of physicians. Medication adherence improved significantly, with good adherence reported by 56% of patients (vs. 24% at baseline, p?<?0.0001) and non-adherence by 3% (vs. 36% at baseline, p?<?0.0001) at month 3. Patient satisfaction with TMZ od was 9.5 [on a scale of 1 to 10 (very satisfied)]. Patients reported improved physical activity: more patients reported no limitations (15% vs. 1% at baseline p?<?0.01), slight limitation (46% vs. 5% at baseline, p?<?0.001) or moderate limitation (30% vs. 23%, p?<?0.01) and fewer patients reported substantial limitation (8% vs. 52% at baseline, p?<?0.001) or very marked reduction (1% vs. 19% at baseline, p?<?0.01) at month 3.

Conclusion

In this prospective, observational study, TMZ 80 mg od effectively reduced angina attacks and SAN consumption, improved physical activity and adherence and was well tolerated in chronic SA patients.

Trial Registration

ISRCTN registry Identifier, ISRCTN97780949.

Funding

Servier.

Plain Language Summary

Plain language summary available for this article.

     

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.

     

Effectiveness and Tolerability of Micafungin in Chinese Patients with Invasive Fungal Infections: A Retrospective,Multicenter Study

Introduction

Invasive fungal infections (IFIs) are a significant health problem in immunocompromised patients, resulting in substantial morbidity, mortality, and healthcare costs. Micafungin is a broad-spectrum echinocandin with activity against Candida and Aspergillus spp. This was a multicenter, non-comparative, retrospective observational study that evaluated the effectiveness and tolerability of intravenously administered micafungin for treating IFIs caused by Candida and Aspergillus spp.

Methods

Adult patients in China who had received at least one dose of intravenously administered micafungin were eligible. Retrospective data (May 2008–April 2015) were extracted from patients’ medical files and recorded using electronic data capture. The primary endpoint was overall success rate (patients with complete or partial response). Subgroup analyses determined effectiveness according to diagnostic certainty, fungal species, type of IFI, duration of micafungin treatment, and daily dose of micafungin. Tolerability, including the incidence of adverse events (AEs), was also assessed.

Results

Overall, 2555 patients who received at least one dose of micafungin were identified. The mean duration of treatment and mean daily dose were 10.2 days and 133.0 mg, respectively. The overall success rate was 60.8%; this was significantly higher in patients who received treatment for at least 1 week (range 67.9–71.6% [mean 69.2%]) compared with less than 1 week (47.8%; P?<?0.0001), and those who received 50–100 mg (65.7%) compared with other daily doses (range 42.9–60.1% [mean 59.0%]; P?=?0.0011). Success rates in Candida- and Aspergillus-infected patients were similar (61.9% and 56.8%, respectively). AEs and adverse drug reactions were observed in 36.2% and 4.5% of patients, respectively. The majority of AEs were mild, while discontinuation due to AEs was low (2.3%).

Conclusion

Micafungin is effective and well tolerated for the treatment of patients with IFIs in China, as demonstrated in Candida- and Aspergillus-infected adults. Subgroup analyses highlighted the potential benefits of treating IFIs with micafungin for a minimum of 1 week.

Trial registration

ClinicalTrials.gov identifier NCT02678598.

Funding

Astellas Pharma Inc.

     

Patterns of Vasculature in Mouse Models of Lung Cancer Are Dependent on Location

Purpose

Preclinical studies of hypoxia are generally done using ectopic xenograft tumors, which behave differently from human tumors. Our previous findings have shown that subcutaneously implanted lung tumors exhibit more hypoxia than their orthotopic implanted or spontaneous K-ras-induced counterparts. We hypothesize that differences in hypoxia are due to site-specific differences in vascularity and perfusion.

Procedures

To compare the presence and functionality of vessels in these tumor models, we studied vascular perfusion in vivo in real time.

Results

Orthotopically implanted and spontaneous K-ras-induced lung tumors showed elevated perfusion, demonstrating vasculature functionality. Little contrast agent uptake was observed within the subcutaneously implanted tumors, indicating vascular dysfunction. These findings were corroborated at the microscopic level with Hoechst 33342 and Meca-32 staining.

Conclusions

From these observations, we concluded that differences in hypoxia in experimental models is related to vessel perfusion. Thus, appropriate selection of preclinical lung tumor models is essential for the study of hypoxia, angiogenesis and therapies targeting these phenomena.

     

Effects of a self-managed home-based walking intervention on psychosocial health outcomes for breast cancer patients receiving chemotherapy: a randomised controlled trial

Purpose

This study evaluated the effectiveness of a self-managed home-based moderate intensity walking intervention on psychosocial health outcomes among breast cancer patients undergoing chemotherapy.

Methods

The randomised controlled trial compared a self-managed, home-based walking intervention to usual care alone among breast cancer patients receiving chemotherapy. Outcome measures included changes in self-report measures of anxiety, depression, fatigue, self-esteem, mood and physical activity. Fifty participants were randomised to either the intervention group (n?=?25), who received 12 weeks of moderate intensity walking, or the control group (n?=?25) mid-way through chemotherapy. Participants in the intervention group were provided with a pedometer and were asked to set goals and keep weekly diaries outlining the duration, intensity and exertion of their walking. Levels of psychosocial functioning and physical activity were assessed pre- and post-intervention in both groups.

Results

The intervention had positive effects on fatigue (F?=?5.77, p?=?0.02), self-esteem (F?=?8.93, p?≤?0.001), mood (F?=?4.73, p?=?0.03) and levels of physical activity (x ²?=?17.15, p?=?0.0011) but not anxiety (F?=?0.90, p?=?0.35) and depression (F?=?0.26, p?=?0.60) as assessed using the HADS. We found an 80 % adherence rate to completing the 12-week intervention and recording weekly logs.

Conclusion

This self-managed, home-based intervention was beneficial for improving psychosocial well-being and levels of physical activity among breast cancer patients treated with chemotherapy.

Trial registration

Current Controlled Trials ISRCTN50709297.

     

Quantitative [<Superscript>18</Superscript>F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer

Purpose

Evaluation of [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO)-positron emission tomography (PET) imaging as a metric for evaluating early response to trastuzumab therapy with histological validation in a murine model of HER2+ breast cancer.

Procedures

Mice with BT474, HER2+ tumors, were imaged with [¹⁸F]FMISO-PET during trastuzumab therapy. Pimonidazole staining was used to confirm hypoxia from imaging.

Results

[¹⁸F]FMISO-PET indicated significant decreases in hypoxia beginning on day 3 (P?<?0.01) prior to changes in tumor size. These results were confirmed with pimonidazole staining on day 7 (P?<?0.01); additionally, there was a significant positive linear correlation between histology and PET imaging (r ² ?=?0.85).

Conclusions

[¹⁸F]FMISO-PET is a clinically relevant modality which provides the opportunity to (1) predict response to HER2+ therapy before changes in tumor size and (2) identify decreases in hypoxia which has the potential to guide subsequent therapy.

     

Bioluminescence Imaging of Colonization and Clearance Dynamics of <Emphasis Type="Italic">Brucella Suis</Emphasis> Vaccine Strain S2 in Mice and Guinea Pigs

Purpose

The goal of this study was to develop a plasmid-based lux bio-reporter for use to obtain in vivo images of Brucella suis vaccine strain 2 (B.suis S2) infection with high resolution and good definition.

Procedures

The pBBR-lux (pBBR1MCS-2-lxCDABE) plasmid that carries the luxCDABE operon was introduced into B. suis S2 by electroporation yielding B. suis S2-lux. The spatial and temporal transit of B. suis S2 in mice and guinea pigs was monitored by bioluminescence imaging.

Results

The plasmid pBBR-lux is stable in vivo and does not appear to impact the virulence or growth of bacteria. This sensitive luciferase reporter could represent B. suis S2 survival in real time. B. suis S2 mainly colonized the lungs, liver, spleen, and uterus in mice and guinea pigs as demonstrated by bioluminescence imaging.

Conclusion

The plasmid-based lux bioreporter strategy can be used to obtain high resolution in vivo images of B. suis S2 infection in mice and guinea pigs.

     

Rate of bacterial eradication by ophthalmic solutions of fourth-generation fluoroquinolones

Introduction

Antibacterial activity of ophthalmic fourth-generation fluoroquinolones has traditionally been evaluated by comparing only their active ingredients, gatifloxacin and moxifloxacin. However, ophthalmic formulations of fourth-generation fluoroquinolones differ in terms of the inclusion of preservatives. While gatifloxacin ophthalmic solution 0.3% (Zymar®; Allergan, Inc., Irvine, CA, USA) contains 0.005% benzalkonium chloride (BAK), moxifloxacin ophthalmic solution 0.5% (Vigamox®; Alcon Laboratories, Inc., Fort Worth, TX, USA) is preservative-free. Recent studies have demonstrated that the presence of BAK dramatically affects the antibacterial activity of the ophthalmic formulation of gatifloxacin. This study was designed to compare the kill rates of ophthalmic solutions of fourth-generation fluoroquinolones against isolates of common ocular bacterial pathogens.

Methods

Approximately 5.6 log₁₀ colony-forming units (CFU)/mL of Haemophilus influenzae (n=1), Streptococcus pneumoniae (n=1), Staphylococcus aureus (n=2), methicillin-resistant Staphylococcus aureus (MRSA) (n=4), methicillinresistant Staphylococcus epidermidis (MRSE) (n=4), and fluoroquinolone-resistant S. epidermidis (n=1) were incubated with ophthalmic solutions of either gatifloxacin or moxifloxacin. Viable bacteria were quantified at specific time points up to 60 minutes.

Results

Gatifloxacin 0.3% completely eradicated H. influenzae and Strep. pneumoniae in 5 minutes, one of two S. aureus isolates in 15 minutes, and the other S. aureus isolate in 60 minutes. Gatifloxacin 0.3% completely killed all MRSA, MRSE, and fluoroquinolone-resistant S. epidermidis isolates in 15 minutes. Moxifloxacin 0.5% completely eradicated Strep. pneumoniae and one of four MRSA isolates in 60 minutes. All other isolates incubated with moxifloxacin 0.5% retained viable bacteria ranging from 1.8 to 4.4 log₁₀ CFU/mL.

Conclusions

The ophthalmic solution of gatifloxacin 0.3% eradicated bacteria that frequently cause postoperative ocular infections substantially faster than did the ophthalmic solution of moxifloxacin 0.5%.

     

Time to recovery in patients with acute painful musculoskeletal conditions treated with extended-release or immediate-release cyclobenzaprine

Introduction

This post-hoc analysis examined time to recovery in patients with acute, painful musculoskeletal conditions following cyclobenzaprine extended release (CER; AMRIX® Cephalon, Inc., Frazer, PA, USA), cyclobenzaprine immediate release (CIR; Flexeril® Pliva, Pomona, NY, USA), or placebo administration.

Methods

Data were pooled from two identically designed, double-blind, placebo-controlled, parallelgroup studies. Adults with acute, painful local muscle spasm were randomized to once-daily CER 15 mg, once-daily CER 30 mg, three-timesdaily CIR 10 mg, or placebo for 14 days. Efficacy assessments were time to first rating of “a lot” or “complete” relief from local pain or restriction of movement and patient-rated medication helpfulness.

Results

A total of 504 patients were randomized, and 330 (65.5%) completed the studies. Median times to “a lot” or “complete” relief from local pain were faster with CER 15 mg (6 days, P=0.016), CER 30 mg (5 days, P=0.002), and CIR (5 days, P=0.002) versus placebo (8 days). Time to “a lot” or “complete” relief from restriction of movement was faster with CER 30 mg (5 days, P=0.004) and CIR (5 days, P=0.009) versus placebo (7 days). Median times to “very good” or “excellent” medication helpfulness were 10 days (CER 15 mg, P=0.020), 8 days (CER 30 mg, P=0.004), and 7 days (CIR, P<0.001) versus >14 days (placebo). Dry mouth, constipation, dizziness, headache, and somnolence were the most commonly reported adverse events. Somnolence rates were lower with CER 15 mg (0.8%, P=0.008) and CER 30 mg (1.6%, P=0.028) versus CIR (7.3%).

Conclusion

Relief from local pain and restriction of movement occurred sooner with CER and CIR than placebo. CER was associated with less somnolence than CIR.

     

Efficacy of Ivabradine in Combination with Beta-Blockers Versus Uptitration of Beta-Blockers in Patients with Stable Angina (CONTROL-2 Study)

Introduction

Heart rate (HR) reduction is an integral part of antianginal therapy, but many patients do not reach the guideline-recommended target of less than 60 bpm despite high use of beta-blockers (BB). Failure to uptitrate BB doses may be partly to blame. To explore other options for lowering HR and improving angina control, CONTROL-2 was initiated to compare the efficacy and tolerability of the combination of BBs with ivabradine versus uptitration of BBs to maximal tolerated dose, in patients with stable angina.

Methods

This multicenter, open, randomized study included 1104 patients with Canadian Cardiovascular Society (CCS) class II or III stable angina, in sinus rhythm, and on background stable treatment with non-maximal recommended doses of BBs. Consecutive patients were allocated to ivabradine + BB or BB uptitration in a 4:1 ratio.

Results

At the end of the study (week 16), addition of ivabradine to BB treatment and BB uptitration resulted in reduction in HR (61 ± 6 vs. 63 ± 8 bpm; p = 0.001). At week 16, significantly more patients on ivabradine + BB were in CCS class I than with BB uptitration (37.1% vs. 28%; p = 0.017) and significantly more patients were angina-free (50.6% vs. 34.2%; p < 0.001). Patient health status based on the visual analogue scale (VAS) was also better in the ivabradine + BB group. Adverse events (AEs) were significantly more common with BB uptitration than with the ivabradine + BB combination (18.4% vs. 9.4%, p < 0.001).

Conclusion

In patients with stable angina, combination therapy with ivabradine + BB demonstrated good tolerability, safety, and more pronounced clinical improvement, compared to BB uptitration.

Trial Registration

ISRCTN30654443.

Funding

Servier.

     

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.

     

Dose Titration of Pregabalin in Patients with Painful Diabetic Peripheral Neuropathy: Simulation Based on Observational Study Patients Enriched with Data from Randomized Studies

Introduction

Achieving a therapeutic response to pregabalin in patients with painful diabetic peripheral neuropathy (pDPN) requires adequate upward dose titration. Our goal was to identify relationships between titration and response to pregabalin in patients with pDPN.

Methods

Data were integrated from nine randomized, placebo-controlled clinical trials as well as one 6-week open-label observational study conducted by 5808 physicians (2642 patients with pDPN) in standard outpatient settings in Germany. These studies evaluated pregabalin for treatment of pDPN. Using these data, we examined “what if” scenarios using a microsimulation platform that integrates data from randomized and observational sources as well as autoregressive–moving-average with exogenous inputs models that predict pain outcomes, taking into account weekly changes in pain, sleep interference, dose, and other patient characteristics that were unchanging.

Results

Final pain levels were significantly different depending on dose changes (P < 0.0001), with greater proportions improving with upward titration regardless of baseline pain severity. Altogether, 78.5% of patients with pDPN had 0–1 dose change, and 15.2% had ≥ 2 dose changes. Simulation demonstrated that the 4.8% of inadequately titrated patients who did not improve/very much improve their pain levels would have benefited from ≥ 2 dose changes. Patient satisfaction with tolerability (range 90.3–96.2%) was similar, regardless of baseline pain severity, number of titrations, or extent of improvement, suggesting that tolerability did not influence treatment response patterns.

Conclusion

Upward dose titration reduced pain in patients with pDPN who actually received it. Simulation also predicted pain reduction in an inadequately titrated nonresponder subgroup of patients had they actually received adequate titration. The decision not to uptitrate must have been driven by factors other than tolerability.

Funding

Pfizer, Inc.

     

High Impact of <Superscript>18</Superscript>F-FDG-PET on Management and Prognostic Stratification of Newly Diagnosed Small Cell Lung Cancer

Purpose

We evaluated whether ¹⁸F-FDG-PET altered stage classification, management, and prognostic stratification of newly diagnosed small cell lung cancer (SCLC).

Procedures

We identified 46 consecutive patients undergoing staging positron emission tomography for SCLC from 1993–2008 inclusive. Updated survival data from the state Cancer Registry was available on 42 of 46 patients.

Results

PET altered stage classification in 12 of 46 (26%) patients. PET altered treatment modality in nine patients, and the target mediastinal radiation field in another three patients. Therefore, PET altered management in 12 of 46 (26%) patients. Patients with limited disease (LD) on pre-PET staging had significantly longer overall survival (OS) than those upstaged to extensive disease (ED; median 18.6 months versus 5.7 months; log-rank p?versus 5.9 months; log-rank p?=?0.037).

Conclusion

PET had a major impact on stage classification, management, and prognostic stratification of newly diagnosed SCLC.