PK/PD and safety of a single dose of TMX-67 (febuxostat) in subjects with mild and moderate renal impairment

A single oral dose of 20 mg febuxostat was administered to subjects with normal, mild or moderate impairment in renal function. There was less than a 2-fold difference in AUC of plasma unchanged febuxostat among the renal function groups, and changes in plasma urate levels from pre-dose levels were not significant. A total of five adverse events were reported with all mild in severity. The results indicate that renal impairment will have little clinical impact on the pharmacokinetics (PK), pharmacodynamics (PD) and safety of the study drug.     

Pharmacokinetics and biodistribution studies of Doxorubicin loaded poly(butyl cyanoacrylate) nanoparticles synthesized by two different techniques

The aim of the study is to determine and compare the pharmacokinetics and tissue distribution of Doxorubicin (Dox) delivered as solution or through nanoparticles after intravenous (i.v.) and intraperitoneal (i.p.) injection. Doxorubicin loaded poly(butyl cyanoacrylate) nanoparticles were synthesized by dispersion polymerization (DP) and emulsion polymerization (EP) techniques. The drug loaded DP and EP nanoparticles were administered by i.v. or i.p. routes and the respective pharmacokinetics and tissue distribution were determined. Both types of nanoparticles significantly enhanced the elimination half-life (T(1/2)), mean residence time (MRT) AUC(0-8), AUC(0-infinity) and AUMC(0-8) of Dox in blood after i.v. injection. Dox delivered through DP nanoparticles rapidly disappeared from blood and distributed to the organs of reticuloendothelial system (RES). But, the clearance of Dox delivered through EP nanoparticles from blood was slower than this of the DP nanoparticles and Dox solution. After i.p. injection, the Dox loaded into DP nanoparticles quickly appeared in blood and undergone rapid distribution to the organs of RES, while the Dox loaded into EP nanoparticles absorbed slowly into blood and remained in the circulation for longer time. The absorption into blood of Dox delivered through DP and EP nanoparticles after i.p. injection was relatively rapid and higher than Dox solution. The T(1/2), MRT, AUC(0-8), AUC(0-infinity) and AUMC(0-8) of Dox in blood were significantly higher and the clearance (Cl) was lower than for the Dox solution after i.p. injection. The tissue concentrations of Dox delivered through nanoparticles after i.p. injection were significantly lower than after i.v. injection. The bioavailability (F) of Dox was greatly enhanced by DP (approximately 1.9 fold) and EP nanoparticles (approximately 2.12 fold) compared to Dox solution after i.p. injection. EP nanoparticles significantly enhanced the bioavailability, MRT, T(1/2), AUC(0-8), AUC(0-infinity) and AUMC(0-8) of Dox than DP nanoparticles. This signifies the advantage of EP nanoparticles in increasing the elimination half-life of Dox both after i.v. and i.p. injection and enhanced bioavailability after i.p. injection, which is expected to improve the therapeutic efficacy of Dox and reduce the Dox-associated systemic toxicity. Importantly, both DP and EP nanoparticles greatly reduced the distribution of Dox to heart both after i.v. and i.p. injection, suggesting their potential in reducing Dox-associated cardiotoxicity.     

Bronchioalveolar carcinoma with renal and hepatic metastases in a degu (Octodon degus)

A primary bronchioloalveolar carcinoma with renal and hepatic metastases was diagnosed in a mature male degu (Octodon degus) that was found dead in a zoological exhibit (Buffalo Zoological Gardens, Buffalo, New York, USA). Grossly, a discrete 0.5 cm diameter nodule was seen in the lung. Smaller, but similar nodules were present scattered in the liver and kidneys. Histologically, nests and sheets of an infiltrating population of cuboidal to low columnar neoplastic epithelial cells partially effaced pulmonary architecture. Vascular invasion was evident. Similar nests and sheets of neoplastic cells were present within the renal cortex and medulla, and a small nest was present within the hepatic parenchyma. This is the first record of this neoplasm in a degu.     

(153)Sm(3+) and (111)In(3+) DTPA derivatives with high hepatic specificity: in vivo and in vitro studies

Two DTPA derivatives, a mono-amide derivative containing an iodinated synthon, DTPA-IOPsp (L(1)) and the ligand DTPA(BOM)(3) (BOM=benzyloxymethyl) (L(2)), radiolabelled with (153)Sm(3+) and (111)In(3+), were studied as potential hepatospecific gamma scintigraphic agents. In vivo studies with Wistar rats show that the main excretory pathway for all the chelates studied is the hepatobiliary system. The complexes of L(2) show even greater hepatobiliary specificity than L(1), perhaps as a consequence of longer blood circulation times due to their strong affinity towards HSA. The (153)Sm(3+) chelates are also more hepatospecific than the corresponding (111)In(3+) chelates. The La(3+) and In(3+) chelates of L(1) and L(2) show some structural and dynamic differences in aqueous solution, as studied by (1)H NMR spectroscopy. While only two nona-coordinated isomers were observed for the La(3+) complexes with both ligands, its number is much larger in the In(3+) complexes, with both octa- and hepta-coordinated species (with unbound side arms), as well as structural isomers for each coordination number.     

A comparative study of hepatic and epidermal histidase in the guinea-pig (Cavia porcellus)

Histidine ammonia lyase was purified to homogeneity from guinea-pig liver and epidermis. Both enzymes had similar molecular weights, subunit composition and pH optima. Km values for the two were similar at pH 9.2 but different at pH 7.0. Both enzymes were stimulated by low thiol concentrations and inhibited at higher concentrations, but to different extents. Antibody to the hepatic enzyme showed complete identity against hepatic enzyme but incomplete identity against epidermal enzyme.     

Long-term tolerability and maintenance of therapeutic response to sodium oxybate in an open-label extension study in patients with fibromyalgia

Introduction

The long-term safety and therapeutic response of sodium oxybate (SXB) in fibromyalgia syndrome (FM) patients were assessed for a combined period of up to 1 year in a prospective, multicenter, open-label, extension study in patients completing 1 of 2 phase 3 randomized, double-blind, controlled, 14-week trials that examined the efficacy and safety of SXB 4.5 g, SXB 6 g, and placebo for treatment of FM.

Methods

This extension study comprised an additional 38 weeks of treatment and was carried out at 130 clinical sites in 7 countries. Initial entry criteria for the previous 2 double-blind clinical trials required that patients aged ≥ 18 years met the American College of Rheumatology 1990 criteria for FM, had a body mass index (BMI) < 40 kg/m², and had a score ≥ 50 on a 100-mm pain visual analog scale (VAS) at baseline. All patients began treatment in the extension study with SXB 4.5 g/night (administered in 2 equally divided doses) for at least 1 week, followed by possible serial 1.5 g/night dose increases to 9 g/night (maximum) or reductions to 4.5 g/night (minimum).

Results

Of the 560 FM patients enrolled in this extension study, 319 (57.0%) completed the study. The main reason for early discontinuation was adverse events (AEs; 23.0% of patients). Patients were primarily middle-aged (mean 46.9 ± 10.8 years), female (91.1%), white (91.4%), with a mean duration of FM symptoms of 9.9 ± 8.7 years. Serious AEs were experienced by 3.6% of patients. The most frequently reported AEs (incidence ≥ 5% at any dose or overall) were nausea, headache, dizziness, nasopharyngitis, vomiting, sinusitis, diarrhea, anxiety, insomnia, influenza, somnolence, upper respiratory tract infection, muscle spasms, urinary tract infection, and gastroenteritis viral. Maintenance of SXB therapeutic response was demonstrated with continued improvement from controlled-study baseline in pain VAS, Fibromyalgia Impact Questionnaire (FIQ) total scores, and other measures. Responder analyses showed that 68.8% of patients achieved ≥ 30% reduction in pain VAS and 69.7% achieved ≥ 30% reduction in FIQ total score at study endpoint.

Conclusions

The long-term safety profile of SXB in FM patients was similar to that in the previously reported controlled clinical trials. Improvement in pain and other FM clinical domains was maintained during long-term use.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00423605","term_id":"NCT00423605"}}NCT00423605.     

Assessment of sleep in subjects with visual impairment: Comparison using subjective and objective methods

The objective of the present study was to verify the agreement between objective and subjective measures of sleep in people with and without visual impairment. Thirty-seven subjects with visual impairment participated in the study (19 blind without light perception and 18 low-vision), as well as 34 subjects with normal vision, with paired age and gender characteristics. For the subjective sleep evaluation, we used the Sleep Quality Index—PSQI and for the objective evaluation we used the ActiGraph GT3X+. Among the three analyzed groups, the blind was the only ones who presented differences between subjective and objective sleep duration (p = 0.021). Furthermore, the concordance between subjective and objective sleep duration (ICC = 0.388; p = 0.108) was not observed in blind subjects, and a greater variability of differences in sleep duration between the two methods was observed by the Bland Altman scatter plot. We concluded that the sleep duration obtained by PSQI did not show agreement for the objective sleep duration in blind subjects without light perception.     

Safety and tolerability of intrathecal delivery of autologous bone marrow nucleated cells in children with cerebral palsy: an open-label phase I trial

Background aimsCerebral palsy (CP) is related to severe perinatal hypoxia with permanent brain damage in nearly 50% of surviving preterm infants. Cell therapy is a potential therapeutic option for CP by several mechanisms, including immunomodulation through cytokine and growth factor secretion.MethodsIn this phase I open-label clinical trial, 18 pediatric patients with CP were included to assess the safety of autologous bone marrow–derived total nucleated cell (TNC) intrathecal and intravenous injection after stimulation with granulocyte colony-stimulating factor. Motor, cognitive, communication, personal-social and adaptive areas were evaluated at baseline and 1 and 6 months after the procedure through the use of the Battelle Developmental Inventory. Magnetic resonance imaging was performed at baseline and 6 months after therapy. This study was registered in ClinicaTrials.gov (NCT01019733).ResultsA median of 13.12 × 10⁸ TNCs (range, 4.83–53.87) including 10.02 × 10⁶ CD34+ cells (range, 1.02–29.9) in a volume of 7 mL (range, 4–10.5) was infused intrathecally. The remaining cells from the bone marrow aspirate were administered intravenously; 6.01 × 10⁸ TNCs (range, 1.36–17.85), with 3.39 × 10⁶ cells being CD34+. Early adverse effects included headache, vomiting, fever and stiff neck occurred in three patients. No serious complications were documented. An overall 4.7-month increase in developmental age according to the Battelle Developmental Inventory, including all areas of evaluation, was observed (±SD 2.63). No MRI changes at 6 months of follow-up were found.ConclusionsSubarachnoid placement of autologous bone marrow–derived TNC in children with CP is a safe procedure. The results suggest a possible increase in neurological function.     

Vitrification of dog spermatozoa: Effects of two cryoprotectants (sucrose or trehalose) and two warming procedures

Sperm vitrification is a low cost and simple technique that does not require special equipment and may represent an attractive alternative to the costly and time consuming conventional dog spermatozoa cryopreservation techniques. The objective of this study was to evaluate different cryoprotectants and warming temperatures on the vitrification of dog spermatozoa. Pooled semen samples from 10 beagle dogs were vitrified with four extenders, based on Tris, citric acid and glucose, 20% egg yolk (TCG-20% EY) and different combinations of sucrose and/or trehalose: 250 mM sucrose; 250 mM trehalose; 125 mM sucrose + 125 mM trehalose; 250 mM sucrose + 250 mM trehalose. Samples were vitrified by dropping 50 μL of sperm suspension directly into liquid nitrogen. After vitrification, warming was done either fast (at 65 °C for 2–5 s) or slow (at 37 °C for one minute). Motility was assayed using a computer-aided sperm analysis (CASA) system; membrane integrity and acrosomal status were analyzed by fluorescence microscopy. For comparison, samples were also conventionally frozen in liquid nitrogen vapor using a TCG-20% egg yolk extender plus 5% glycerol. Frozen straws were thawed in a water bath at 37 °C for 30 s. Poorer motility results (P < 0.05) but similar viability were obtained when vitrification was performed, compared to conventional freezing (P > 0.05). When vitrification was used, cryoprotectants containing either 250 mM sucrose or 250 mM trehalose and warmed at 37 °C returned the best sperm quality variables.     

Postural stability in subjects with temporomandibular disorders and healthy controls: A comparative assessment

Purpose of the studyThe influence of the stomatognathic apparatus on body posture is a continuously discussed topic with contrasting results. The aim of this study is to analyze differences in postural stability between subjects with and without myogenous TMD.Methods25 subjects affected by myogenous TMD according with DC/TMD (6 males, 19 females; mean age 31.75 ± 6.68 years) and a healthy control group of 19 subjects (4 Males, 15 Females; mean age 27.26 ± 3.85 years) were enrolled in the study.Both groups underwent a posturo-stabilometric force platform exam under different mandibular and visual conditions. Sway area and sway velocity of the COP (Center Of foot Pressure) posturo-stabilometric parameters were evaluated and compared applying Mann-U-Whitney statistical test.ResultsThe sway area and sway velocity parameters resulted statistically significantly higher in the TMD group (sway area p < 0.01; sway velocity p < 0.05) in mandibular maximum intercuspation and rest positions with eyes open.ConclusionsThis study demonstrates a significant difference in body postural stability between subjects with myogenous TMD and healthy controls. In particular, sway area and sway velocity postural parameters are increased in these subjects.     

Gene polymorphisms of CETP and apolipoprotein E in elderly subjects with cognitive impairment

The association of cholesteryl ester transfer protein (CETP) and apolipoprotein E (APOE) gene polymorphisms with mild cognitive impairment (MCI) is under debate. Our aim was to evaluate the relationship between APOE and CETP genotypes with healthy ageing. We analysed 267 elderly subjects (55 to 80+ years), 163 with MCI and 104 healthy, and 50 healthy control subjects (35 to 55 years) from a Romanian population. Biochemical parameters and thyroid hormones were assayed in plasma. APOE and CETP TaqIB gene polymorphisms were determined. Elderly subjects had higher frequency of ɛ3/ɛ2 genotype (14.6% vs. 4%, P<0.001) than controls. Elderly subjects with MCI had lower high density lipoproteins (HDL) cholesterol (P=0.031), apoA-I (P=0.018), T3 (P=0.002), T4 (P=0.028) and TSH (P=0.001) hormone levels, higher systolic blood pressure (P=0.005), lower frequency of CETP B2 allele than the age-matched subjects. Healthy elderly subjects had CETP B2 allele associated with higher plasma apoA-I (P=0.021), lower circulating collagen (P=0.001) levels, and an increased frequency of the combined APOE ɛ2- CETP B2 genotype (18.3%) relative to MCI elderly subjects (7.6%, P=0.011). Healthy elderly subjects are characterized by higher HDL cholesterol, apoA-I levels and higher frequency of the combined APOE ɛ2 and CETP B2 alleles, indicating this pattern as representative for healthy ageing.     

两种生物状态肠道益生菌的粘附和粘附拮抗效应的对比研究

目的:研究活菌和灭活菌两种生物状态的肠道主要益生菌--德氏乳杆菌、双歧杆菌和肠球菌对肠黏膜上皮细胞粘附性及其对肠道几种常见病原菌的粘附拮抗效应.方法:用光镜和电镜技术分析了两种生物状态的三种益生菌对肠黏膜上皮细胞的粘附指数,通过排除实验、竞争实验和替代实验研究了两种生物状态益生菌对侵袭性大肠埃希菌、产毒性大肠埃希菌和痢疾志贺菌的粘附拮抗效应,应用平板扩散法观察了三种益生菌的代谢乏液对上述肠道病原菌的抑制能力.结果:德氏乳杆菌和肠球菌的灭活状态较活菌状态对肠黏膜上皮细胞的粘附性显著增高,双歧杆菌经灭活后对细胞的粘附性与活菌相比差异无显著性,两种生物状态的三种益生菌对肠道致病菌均具有粘附拮抗作用.滤过后的德氏乳杆菌、双歧杆菌和肠球菌的代谢乏液对侵袭性大肠埃希菌、产毒性大肠埃希菌和痢疾志贺菌均具有较明显的抑制作用,经42℃、65℃和100℃加热不影响德氏乳杆菌和双歧杆菌代谢乏液的抑菌作用.结论:灭活状态的德氏乳杆菌、双歧杆菌和肠球菌是具有潜在开发价值的微生态制剂.