Organic UV filters mixture exposure and childhood adiposity: A prospective follow-up study in China.

BACKGROUND: UV filters are emerging contaminants with endocrine disrupting effects, but little is known about their health effects, especially for children. OBJECTIVE: To assess the association between multiple organic UV filters exposure and adiposity measures and by gender in peripubertal children. METHODS: This prospective follow-up study included 327 children aged 7-15 years old. Urinary organic UV filters including benzophenone derivatives (BP-2, BP-3), octyl dimethyl para-aminobenzoic acid (OD-PABA), ethylhexyl methoxycinnamate (EHMC) and its metabolite (4-MCA and 4'-MAP) were quantified. Six adiposity biometrics including height, weight, waist and hip circumferences, and triceps and subscapular skinfold thickness were measured with 1.5-year duration. The Bayesian kernel machine regression method was used to estimate the associations of UV filters mixture with adiposity measurements, and longitudinal analyses were then considered to further evaluate the associations between individual UV filters and trajectories of growth development using linear mixed models or generalized linear mixed models. RESULTS: Exposure to mixture of UV filters was negatively associated with most adiposity measurements, with a reduction of 1.399 kg/m2 (95% CI: -2.246 to -0.551 kg/m2) in BMI, 0.674 (95% CI: -1.045 to -0.304) in BMI z-score, 0.033 BF% (95% CI: -0.053 to -0.013), and 2.301 mm (95% CI: -3.823 to -0.78) in subscapular skinfold thickness at baseline, comparing the 75th percentile to the 25th level of UV filters mixture exposure. Consistent associations were found at follow-up. Both baseline and follow-up results suggested that EHMC was identified as the most important contributor to lower adiposity measurements, which was also confirmed by linear mixed models in longitudinal analyses. No significant effects were found in girls. CONCLUSION: This study found that childhood organic UV filters exposure was negatively associated with adiposity measures in peripubertal boys, but not girls.

The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study.

Idasanutlin, an MDM2 antagonist, showed clinical activity and a rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/-intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily on days 1 through 5 of each 28-day cycle. The primary end point was composite response (hematocrit control and spleen volume reduction > 35%) in patients with splenomegaly and hematocrit control in patients without splenomegaly at week 32. Key secondary end points included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n = 27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n = 13), 9 (69%) attained any spleen volume reduction, and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥ 3 nausea or vomiting experienced by 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and was associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/- intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. This trial was registered at www.clinincaltrials.gov as #NCT03287245.

Inhaled Phosphodiesterase Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease.

Phosphodiesterase (PDE) 4 inhibitors prevent the metabolism of cyclic adenosine monophosphate, thereby reducing inflammation. Inhaled PDE4 inhibitors aim to restrict systemic drug exposure to enhance the potential for clinical benefits (in the lungs) versus adverse events (systemically). The orally administered PDE4 inhibitor roflumilast reduces exacerbation rates in the subgroup of chronic obstructive pulmonary disease patients with a history of exacerbations and the presence of chronic bronchitis, but can cause PDE4 related adverse effects due to systemic exposure. CHF6001 is an inhaled PDE4 inhibitor, while inhaled ensifentrine is an inhibitor of both PDE3 and PDE4; antagonism of PDE3 facilitates smooth muscle relaxation and hence bronchodilation. These inhaled PDE inhibitors have both reported positive findings from early phase clinical trials, and have been well tolerated. Longer term trials are needed to firmly establish the clinical benefits of these drugs.

Phase I study of daily and weekly regimens of the orally administered MDM2 antagonist idasanutlin in patients with advanced tumors.

Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days. We also analyzed p53 activation and the anti-proliferative effects of idasanutlin. Results The dose-escalation phase included 85 patients (QW × 3, n = 36; QD × 3, n = 15; QD × 5, n = 34). Daily MTD was 3200 mg (QW × 3), 1000 mg (QD × 3), and 500 mg (QD × 5). Most common adverse events were diarrhea, nausea/vomiting, decreased appetite, and thrombocytopenia. Dose-limiting toxicities were nausea/vomiting and myelosuppression; myelosuppression was more frequent with QD dosing and associated with pharmacokinetic exposure. Idasanutlin exposure was approximately dose proportional at low doses, but less than dose proportional at > 600 mg. Although inter-patient variability in exposure was high with all regimens, cumulative idasanutlin exposure over the whole 28-day cycle was greatest with a QD × 5 regimen. No major food effect on pharmacokinetic exposure occurred. MIC-1 levels were higher with QD dosing, increasing in an exposure-dependent manner. Best response was stable disease in 30.6% of patients, prolonged (> 600 days) in 2 patients with sarcoma. Conclusions Idasanutlin demonstrated dose- and schedule-dependent p53 activation with durable disease stabilization in some patients. Based on these findings, the QD × 5 schedule was selected for further development. TRIAL REGISTRATION: NCT01462175 (ClinicalTrials.gov), October 31, 2011.

Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia.

In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120-300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment-related adverse events in >20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%-47% (22%-54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967.

Be Aware of a Potential Pitfall in Oral and Dental Specimens: Alvogyl Fibers.

Alvogyl dressing is used to help control hemostasis, foster healing, and prevent complications after certain oral procedures. It is a paste composed of different antiseptic and analgesic substances, and fern-derived Penghawar djambi fibers that have styptic properties. It is claimed to be a resorbable and self-eliminating paste with little complications. However, some studies have demonstrated detrimental effects. We report 3 cases of postextraction nonhealing sockets after Alvogyl dressing. Histologically, they demonstrated residual Alvogyl fibers with foreign body giant cell stromal reaction and complications that were clinically confused with abscess, cysts, infections, and neoplastic lesions. Being unaware of their histopathologic appearances, the foreign bodies in 2 cases were initially confused with fungal hyphae, parasitic ova, vegetable material, and other surgical and nonsurgical materials. To add to our confusion, they were periodic acid-Schiff (PAS) and Grocott methenamine silver (GMS) positive, septated, spiked, and calcified. A history of Alvogyl dressing was retrospectively found. Learning from our mistakes and being aware of the histologic manifestations of Alvogyl fibers, the third case was correctly spotted. Because Alvogyl fibers are undissolvable and are not spontaneously eliminated, they may, if left for a long period, elicit tumefactive foreign body giant cell stromal and epithelial reactions that can be confused with inflammatory, infectious, and neoplastic lesions. Histologically, they can mimic infectious agents and noninfectious materials. Because history of dressing is not always provided, pathologists should be familiar with their histomorphologic features to avoid pitfalls and guide clinicians to correct diagnosis and management. In absence of history, certain histologic features are helpful hints.

Cytotoxicity and genotoxicity of DMABEE, a co-photoinitiator of resin polymerization, on CHO-K1 cells: Role of redox and carboxylesterase.

The 4-dimethylaminobenzoic acid ethyl ester (DMABEE) is an important co-initiator for resin polymerization in dental resinous materials. As a radical forming chemical with high lipophilicity, the genotoxicity and cytotoxicity of DMABEE deserve prudent investigation. In this study, we found that DMABEE reduced the viability and proliferation of Chinese hamster ovary (CHO-K1) cells in a dose-dependent manner, and altered cell morphology at higher concentrations. G0/G1 cell cycle arrest was induced by DMABEE at 0.25-0.75 mM, and cell proportion of sub-G0/G1 phase was significantly elevated at 1 mM while cell apoptosis was observed. Genotoxic effect was noted when cells were treated by 0.1 mM DMABEE, as revealed by increase of micronucleus formation. Reactive oxygen species overproduction was observed as cells treated with 0.75 and 1 mM, while elevation of intracellular glutathione was noticeable since 0.1 mM. Contrary to our expectation, pretreatment by N-acetyl-l-cysteine enhanced the toxicity of DMABEE on CHO-K1 cells. Catalase mildly reduced the toxic effect and carboxylesterase showed obvious ability to reverse the toxicity of DMABEE. These findings highlight the mechanism of DMABEE toxicity and provide clues for safety improvement of its application in clinical dental treatment.

Oral idasanutlin in patients with polycythemia vera.

A limited number of drugs are available to treat patients with polycythemia vera (PV) and essential thrombocythemia (ET). We attempted to identify alternative agents that may target abnormalities within malignant hematopoietic stem (HSCs) and progenitor cells (HPCs). Previously, MDM2 protein levels were shown to be upregulated in PV/ET CD34+ cells, and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53 pathway and selective depletion of PV HPCs/HSCs. This anticlonal activity was mediated by upregulation of p53 and potentiated by the addition of interferon-α2a (IFN-α2a). Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist idasanutlin (RG7388; Roche) in patients with high-risk PV/ET for whom at least 1 prior therapy had failed. Patients not attaining at least a partial response by European LeukemiaNet criteria after 6 cycles were then allowed to receive combination therapy with low-dose pegylated IFN-α2a. Thirteen patients with JAK2 V617F+ PV/ET were enrolled, and 12 (PV, n = 11; ET, n = 1) were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated; no dose-limiting toxicity was observed, but low-grade gastrointestinal toxicity was common. Overall response rate after 6 cycles was 58% (7 of 12) with idasanutlin monotherapy and 50% (2 of 4) with combination therapy. Median duration of response was 16.8 months (range, 3.5-26.7). Hematologic, symptomatic, pathologic, and molecular responses were observed. These data indicate that idasanutlin is a promising novel agent for PV; it is currently being evaluated in a global phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT02407080.

Safety, tolerability, and pharmacokinetics of single and repeat ascending doses of CHF6001, a novel inhaled phosphodiesterase-4 inhibitor: two randomized trials in healthy volunteers.

PURPOSE: The purpose of this study was to evaluate safety, tolerability, and pharmacokinetics (PK) of CHF6001, an inhaled phosphodiesterase-4 inhibitor. MATERIALS AND METHODS: Two healthy volunteer, randomized, double-blind, placebo-controlled studies were conducted. In each, Part 1 evaluated single ascending doses, with PK sampling up to 48 hours post-dose; Part 2 evaluated multiple ascending doses (Study 1, 7 days; Study 2, 14 days), with PK sampling up to 24 hours post-dose on first and last day of each period. In Study 1, treatments were administered via single-dose dry-powder inhaler (SDDPI; Aerolizer): Part 1, 20, 100, 200, 400, 800, 1,600, and 2,000 µg or placebo; Part 2, 100, 300, 600, 1,200, and 1,600 µg or placebo once daily (OD). In Study 2, treatments were administered via multi-dose dry-powder inhaler (MDDPI; NEXThaler): Part 1, 2,400, 4,000, and 4,800 µg or placebo; Part 2, 1,200, 2,000, or 2,400 µg twice daily (BID) or placebo. Modeling and simulation then compared OD and BID dosing via MDDPI. RESULTS: There was a clear correlation between CHF6001 dose and plasma concentration, following single and multiple doses and using SDDPI and MDDPI. CHF6001 plasma concentration area under the curve (AUC) was dose proportional, with steady state slopes of the fitted line of 0.95 (90% CI: 0.86, 1.04) for AUC0-24 h in Study 1, and 0.85 (90% CI: 0.38, 1.32) for AUC0-12 h in Study 2. Bioavailability was30% higher with MDDPI than SDDPI. The PK simulation confirmed dose proportionality; the same total daily dose OD or BID via MDDPI resulted in similar 24 hours exposure, with BID dosing providing smaller fluctuation and lower maximum concentration. CHF6001 was well tolerated with no relationship between dose and adverse events. CONCLUSION: CHF6001 demonstrated a good safety profile. There was a clear dose proportionality for systemic exposure, with higher bioavailability via MDDPI, suggesting that the MDDPI provides better pulmonary drug deposition. BID dosing was associated with a better exposure profile.

Photoprotection or photodamage: a direct observation of nonradiative dynamics from 2-ethylhexyl 4-dimethylaminobenzoate sunscreen agent.

Apart from being an analogue of the prototype for photoinduced intramolecular charge transfer (ICT), 2-ethylhexyl 4-dimethylaminobenzoate (EHDMABA) is also one of the earliest patented and most commonly used sunscreen components. There is, however, little documented information about the photophysics and factors affecting the photophysics of this molecule. Such information is of importance for both the understanding of the ICT reaction and assessing the underlying process of photoprotection, especially in view of the "sunscreen controversy" that has arisen from the contrasting in vivo vs. in vitro photobiological results on this and related UV filters. We report herein a femtosecond broadband time-resolved fluorescence (fs-TRF), complemented by transient absorption (fs-TA) to allow a full probe of the excited state cascades for EHDMABA and two of its derivatives in solvents of varied properties. The results provide direct evidence for a nearly solvent independent inner sphere ICT reaction occurring on the sub-picosecond time scale, and an ensuing solvent dictated deactivation of the ICT state. The ICT state in the aprotic solvent acetonitrile decayed solely through the intrinsic intersystem crossing (ISC) to produce a potentially harmful triplet excited state. In the protic solvent, the solvation and formation of ICT-induced solute-solvent hydrogen (H)-bonding opened the originally inaccessible internal conversion (IC) channel of the ICT state, leading to the rapid reformation of the ground state molecule with a unitary efficiency in the aqueous solution. This H-bonding-mediated IC restrained or eliminated the intrinsic ISC, providing a mechanism at the molecular level for the benign dissipation of the electronic excitation. The precise rate of IC was observed to vary with the alkoxy substituent and its efficiency was affected by the H-bonding capacity of the solvent. The findings of this work demonstrate the pivotal role of the microenvironment and the direct participation of solvent molecules through H-bonding in drastically altering the nonradiative dynamics and promoting or inhibiting photostability and photoprotection. This may assist in developing next-generation UV filters and help in improving formulation design for the optimal efficacy of sunscreen products. The pronounced H-bonding-induced fluorescence quenching and variation in the fluorescence wavelength imply that these molecules may also serve as a sensitive fluorescence probe for the H-bonding properties of the microenvironment.

Phase 1 summary of plasma concentration-QTc analysis for idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors and AML.

PURPOSE: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval. METHOD: Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from baseline (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed. RESULTS: A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation. CONCLUSION: The concentration-QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for clinical development.

First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-962212, a direct, reversible, small molecule factor XIa inhibitor in non-Japanese and Japanese healthy subjects.

AIMS: The aims of the present study were to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class factor XIa inhibitor, in Japanese and non-Japanese healthy subjects. METHODS: This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study of 2-h (part A) and 5-day (part B) intravenous (IV) infusions of BMS-962212. Part A used four doses (1.5, 4, 10 and 25 mg h-1 ) of BMS-962212 or placebo in a 6:2 ratio per dose. Part B used four doses (1, 3, 9 and 20 mg h-1 ) enrolling Japanese (n = 4 active, n = 1 placebo) and non-Japanese (n = 4 active, n = 1 placebo) subjects per dose. The PK, PD, safety and tolerability were assessed throughout the study. RESULTS: BMS-962212 was well tolerated; there were no signs of bleeding, and adverse events were mild. In parts A and B, BMS-962212 demonstrated dose proportionality. The mean half-life in parts A and B ranged from 2.04 to 4.94 h and 6.22 to 8.65 h, respectively. Exposure-dependent changes were observed in the PD parameters, activated partial thromboplastin time (aPTT) and factor XI clotting activity (FXI:C). The maximum mean aPTT and FXI:C change from baseline at 20 mg h-1 in part B was 92% and 90%, respectively. No difference was observed in weight-corrected steady-state concentrations, aPTT or FXI:C between Japanese and non-Japanese subjects (P > 0.05). CONCLUSION: BMS-962212 has tolerability, PK and PD properties suitable for investigational use as an acute antithrombotic agent in Japanese or non-Japanese subjects.

Effects of posaconazole (a strong CYP3A4 inhibitor), two new tablet formulations, and food on the pharmacokinetics of idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors.

PURPOSE: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. To optimize its dosing conditions, a number of clinical pharmacology characteristics were examined in this multi-center trial in patients with advanced solid tumors. METHOD: This was an open-label, single-dose, crossover clinical pharmacology study investigating the effects of strong CYP3A4 inhibition with posaconazole (Part 1), two new oral formulations (Part 2), as well as high-energy/high-fat and low-energy/low-fat meals (Part 3) on the relative bioavailability of idasanutlin. After completing Part 1, 2, or 3, patients could have participated in an optional treatment with idasanutlin. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) of MIC-1 elevation (Part 1 only), and safety/tolerability. RESULTS: The administration of posaconazole 400 mg BID × 7 days with idasanutlin 800 mg resulted in a slight decrease (7%) in Cmax and a modest increase (31%) in AUC for idasanutlin, a marked reduction in Cmax (~ 60%) and AUC0 (~ 50%) for M4 metabolite, and a minimal increase (~ 24%) in serum MIC-1 levels. Cmax and AUC were both 45% higher for the SDP formulation. While the low-fat meal caused a less than 20% increase in all PK exposure parameters with the 90% CI values just outside the upper end of the equivalence criteria (80-125%), the high-fat meal reached bioequivalence with dosing under fasting. CONCLUSION: In patients with solid tumors, multiple doses of posaconazole, a strong CYP3A4 inhibitor, minimally affected idasanutlin PK and PD without clinical significance. The SDP formulation improved rBA/exposures by ~ 50% without major food effect.

A novel inhaled phosphodiesterase 4 inhibitor (CHF6001) reduces the allergen challenge response in asthmatic patients.

CHF6001 is an inhaled phosphodiesterase 4 (PDE4) inhibitor in development for the treatment of obstructive lung diseases. The efficacy and safety of CHF6001 were investigated in a double blind, placebo controlled, 3-way cross-over study using the allergen challenge model. Thirty-six atopic asthmatics who were not taking inhaled corticosteroids and who demonstrated a late asthmatic response (LAR) to inhaled allergen at screening were randomised to receive CHF6001 400 µg or 1200 µg or placebo administered once a day using a dry powder inhaler. The three treatment periods were 9 days; allergen challenges were performed on day 9 and induced sputum was obtained after 10 h from challenge. Washout periods between treatments were up to 5 weeks. Both CHF6001 doses significantly attenuated the LAR; the primary endpoint analysis showed that CHF6001 400 µg and 1200 µg caused reductions of 19.7% (p = 0.015) and 28.2% (p < 0.001) respectively of the weighted FEV1 AUC4-10h compared with placebo. The difference between the CHF6001 doses was not statistically significant (p = 0.223). Compared with placebo, CHF6001 caused greater reduction in sputum eosinophil counts, although these changes were not statistically significant. CHF6001 was well tolerated, with similar numbers of adverse events in each treatment period. This inhaled PDE4 inhibitor has the potential to provide clinical benefits in patients with atopic asthma.

Evaluation of the Effects of CHF6001, an Inhaled PDE4 Inhibitor, on Cardiac Repolarization and Cardiac Arrhythmias in Healthy Volunteers.

Chronic obstructive pulmonary disease (COPD) is a multicomponent condition characterized by airway inflammation and associated to comorbidities, including cardiovascular diseases. Among anti-inflammatory agents in development for COPD, the phosphodiesterase inhibitors administrated by inhalation have the potential for increased efficacy and reduced systemic side effects. CHF6001 is an inhaled PDE4 inhibitor with proven anti-inflammatory properties in animal models. This randomized, double-blind, placebo-controlled study was aimed to demonstrate its cardiovascular safety and tolerability in healthy male volunteers with normal electrocardiogram and cardiac parameters. Single and multiple ascending doses (7 days of administration) of CHF6001 were administered. Three electrocardiograms were recorded at several pharmacokinetic time points and at each time points, postdose heart rate, QRS and PR intervals, and presence of arrhythmia were evaluated. In single ascending dose, QTcF intervals did not increase more than 30 milliseconds from the baseline, all heart rate was between 45 and 100 bpm, and no statistically significant differences were observed in PR and QRS intervals. In multiple ascending dose, cardiac parameters did not differ significantly from baseline. In the pharmacokinetic/pharmacodynamic analysis, no medically or clinically significant changes were found. Further studies are ongoing to demonstrate that CHF6001 is safe and well tolerated in COPD patients as well.

The use of hyaluronic and aminocaproic acid in the treatment of alveolar osteitis.

Background/Aim: Alveolar osteitis (AO), also known as "dry socket", is relatively common post-extraction complication. It probably occurs due to excessive fibrinolytic activity in the coagulum and is characterized by intense pain sensations. The aim of this clinical study was to examine the role of hyaluronic acid and aminocaproic acid in the treatment of AO. Methods: The study included 60 patients with the clinical diagnosis of AO. All the patients were divided into two groups of 30 patients each according to the applied non-pharmacological measure: irrigation ­ irrigation of dry socket with sterile saline; curettage ­ careful curettage. Both of these groups were further divided into three subgroups regarding the applied treatment (hyaluronic acid; hyaluronic acid + aminocaproic acid; Alvogyl ®, an anesthetic and antiseptic paste), each with 10 patients, according to the following protocol: 0.2 mL of hyaluronic acid in the form of a 0.8% gel; 2 mL of aminocaproic acid and hyaluronic acid; Alvogyl®. During each visit, scheduled for every two days until complete absence of painful sensations, the patients had the therapeutic method repeated as at the first examination. At each control visit the number of present symptoms and signs of AO was recorded, as well as the level of pain (measured with a visual analogue scale). Results: With the use of hyaluronic acid, with or without aminocaproic one, a statistically significantly faster reduction in pain sensations was achieved, along with the reduction in the number of symptoms and signs of AO compared to the use of Alvogyl®. Conclusion: Hyaluronic acid, applied alone or in combination with aminocaproic acid significantly reduces pain sensation, thus it can be successfully used in the treatment of AO.