Tapentadol Prolonged Release for Long-Term Treatment of Pain in Children.

PURPOSE: Investigation of the efficacy and safety of tapentadol prolonged release (PR) compared with morphine PR for long-term treatment of pain in children. PATIENTS AND METHODS: Children aged 6 to <18 years requiring long-term treatment with opioids were studied in a 12-month, 2-part, multi-center trial: Part 1, 14-day open-label, randomized, active-controlled, parallel group non-inferiority trial comparing twice daily tapentadol PR with morphine PR; Part 2, open-label treatment with tapentadol PR for up to 12 months or no treatment "safety observation period". Pain intensity was rated with visual analogue scale or Faces Pain Scale-Revised, and non-inferiority was assessed by comparison of "treatment responders" (those completing the 14-day treatment period and showing pre-defined changes in pain rating) in each group. RESULTS: Twenty-three of 48 centers enrolled 73 patients. In Part 1, 45 and 24 patients received tapentadol or morphine, respectively, of which 40 and 22 completed 14-day treatment. In Part 2, thirty-six and 58 patients entered the tapentadol PR or observation periods, respectively, with 20/36 completing at least 12 weeks of treatment; 10 of the 36 had received morphine in Part 1. Forty-four of the 58 patients in the safety observation period had received tapentadol. Tapentadol PR was non-inferior to morphine PR (lower limit of confidence interval above negative non-inferiority margin of -0.2) in Part 1. Rates of adverse events were as expected with nausea (22.2%) and constipation (15.6%) in the tapentadol PR group, and with vomiting (33.3%), nausea and constipation (each 16.7%) in the morphine PR group. No new safety issues were identified; the safety profile of tapentadol over the 12 months treatment and observation periods was comparable to that established in subjects >18 years old. CONCLUSION: Tapentadol PR was well tolerated and equivalent to morphine PR for both efficacy and safety in children (6 to <18 years old) requiring long-term treatment with opioids.

Study on the kinetics and influence of feline platelet aggregation and deaggregation.

BACKGROUND: Feline platelets are prone to clumping after blood collection, rendering the determination of accurate platelet counts difficult for clinical laboratories and resulting in a high incidence of pseudothrombocytopenia in feline haematology reports. No information is available about the kinetics of platelet aggregate formation in feline ethylenediaminetetraacetic acid blood and the course of platelet counts over a clinically relevant time period. The aim of the present study was to determine platelet counts in healthy cats over a time period of 24 h after blood collection at 9 time points; to assess potential effects of platelet aggregates, anaesthesia and bleeding conditions on feline platelets and white blood cell counts; and finally, to investigate if glucose concentration is associated with the presence of aggregates. From 30 clinically healthy cats, blood samples were analysed at 9 different time points using two different haematology instruments (using fluorescence and impedance-based flow cytometry) in the counting chamber and by blood smear evaluation. RESULTS: Fourteen of the 30 samples were thrombocytopenic at one to 8 time points after collection as analysed on a fluorescence flow cytometry haematology analyser. At the 24-h timepoint, all thrombocytopenic samples had returned to normal platelet counts. Seventeen of the 30 samples showed platelet aggregates in the counting chamber. Significant differences in platelet counts were associated with the presence and size of aggregates and time since bleeding. No statistically significant differences in counts were found with regard to the quality of blood collection or the use of anaesthesia. Platelet aggregation and, therefore, pseudothrombocytopenia occurred in 57 % of the investigated samples at different time points. CONCLUSION: For the first time, deaggregation of feline platelet aggregates could be demonstrated as a reversible effect of platelet aggregation. For clinical laboratories or veterinarians, it may be helpful to rerun feline samples with pseudothrombocytopenia to obtain a more reliable platelet count. The quality of blood collection seems not to be causative for platelet aggregation. Blood smear evaluation is absolutely indicated in cases when haematology instruments give PLT counts below the reference interval.

Effective prevention of pseudothrombocytopenia in feline blood samples with the prostaglandin I2 analogue Iloprost.

BACKGROUND: In vitro platelet aggregation in feline blood samples is a well-known phenomenon in veterinary clinical laboratories resulting in high numbers of pseudothrombocytopenia. Several attempts have been made to prevent or dissolve platelet aggregates in feline blood samples and to increase the reliability of feline platelet counts. Prostaglandin I2 (PGI2) is the most powerful endogenous inhibitor of platelet aggregation but unstable. Iloprost is a stable PGI2 analogue. The aims of the present study were (1) to evaluate the anti-aggregatory effect of Iloprost on feline platelet counts and to determine a useful concentration to inhibit platelet aggregation in EDTA samples from clinically healthy cats, (2) to investigate the effect of Iloprost on hematological blood parameters, and (3) to determine stability of Iloprost in K3-EDTA tubes for up to 16 weeks. From 20 clinically healthy cats blood was drawn from the jugular vein and immediately distributed in a 1.3 ml K3-EDTA tube, and two 1.3 ml K3-EDTA tubes containing 20 ng and 200 ng Iloprost, respectively. A complete blood cell count was performed on the Sysmex XT-2000iV and the Mythic 18 on eight consecutive time points after collection. Blood smears were evaluated for the presence of PLT aggregates. RESULTS: In the absence of Iloprost, pseudothrombocytopenia was observed in 50% of the investigated samples that led to significantly decreased optical PLT counts by a mean of 105 x10(3)/µl, which could be prevented by the addition of 1 µL (20 ng) Iloprost leading to an increase in PLT counts by a mean of 108 x10(3)/µl. CONCLUSION: This is the first study showing an anti-aggregatory effect of the PGI2-analogue Iloprost in feline EDTA blood. In all clinically healthy cats investigated, pseudothrombocytopenia was prevented by adding Iloprost to EDTA tubes prior to blood collection. Furthermore, Iloprost was very useful in preventing falsely increased WBC counts in samples with platelet aggregates analyzed on impedance-based hematological instruments. Iloprost is preferable to PGI2 or PGE1 due to its stability and easy and safe handling properties. Cytological evaluations of blood smears as well as other hematological parameters were not influenced to a clinically significant degree by the presence of Iloprost.

Evaluation of the Mythic 18 hematology analyzer for use with canine, feline, and equine samples.

The Mythic 18 is a fully automated hematology bench-top analyzer using impedance technology for a complete blood cell count (CBC) and a 3-part white blood cell count (WBC) differential. The purpose of the current study was to evaluate the Mythic for assessment of agreement, precision, linearity, carry-over, stability, and usability under practice conditions. Ethylenediamine tetra-acetic acid-blood samples from 122 dogs, 140 cats, and 123 horses were analyzed with the Mythic and reference methods (Sysmex XT-2000iV, manual hematocrit, and microscopic WBC differentiation). Pearson's coefficient of correlation, Passing-Bablok regression analysis, and Bland-Altman difference plots were performed to determine agreement. For precision, standard deviation and coefficients of variation were calculated. Linearity was determined according to Emancipator-Kroll. Red blood cell parameters showed excellent correlation and small biases, except for red cell distribution width and mean corpuscular hemoglobin concentration. Total WBC correlated excellently in canine and equine and very well in feline samples. In 23 feline specimens with platelet aggregates, the Mythic overestimated WBC. In all 3 species, absolute granulocyte counts correlated excellently. Equine lymphocyte counts showed good correlation whereas canine and feline lymphocyte counts correlated poorly. Feline platelets showed good correlation with a negative bias. The instrument showed good to excellent precision. The whole 3-part differential was found to be accurate in horses. In dogs and cats, absolute granulocyte counts were reliable. As with all impedance-based hematological instruments, evaluation of a blood smear is absolutely indicated to check for the presence of platelet aggregates, to verify WBC differentiation, and to identify possible abnormalities.