Influence of bone wax on bone healing: a case report and literature review.

The purposes of this article are to report the clinical case of a patient who exhibited a foreign body reaction associated with the use of bone wax after extraction of an impacted third molar and to present an integrative literature review addressing the possible influences of this hemostatic agent on bone healing. A 26-year-old woman who underwent the extraction of her mandibular right third molar developed intense alveolar bleeding during surgery, requiring the use of bone wax. In the 2-month postoperative period, the patient presented with intraoral edema and discharge of a purulent secretion via the alveolar route. After cone beam computed tomographic images revealed increased hyperdensity inside the alveolus, alveolar curettage was performed and the material that was obtained was submitted to histopathologic examination. The results of the histopathologic analysis proved conclusive for an inflammatory foreign body reaction associated with exogenous material. A search of the PubMed, SciELO, and LILACS databases identified 22 studies that evaluated the influence of this hemostatic agent on bone healing, and an integrative review involving 367 animals and 75 humans was compiled. Bone wax is a nonresorbable material capable of negatively influencing bone healing. It is suggested that the product be used cautiously in amounts that are just enough to promote the sealing of the bone channels.

Rg1 protects H9C2 cells from high glucose-/palmitate-induced injury via activation of AKT/GSK-3ß/Nrf2 pathway.

Our previous studies have assessed ginsenoside Rg1 (Rg1)-mediated protection in a type 1 diabetes rat model. To uncover the mechanism through which Rg1 protects against cardiac injury induced by diabetes, we mimicked diabetic conditions by culturing H9C2 cells in high glucose/palmitate. Rg1 had no toxic effect, and it alleviated the high glucose/palmitate damage in a dose-dependent manner, as indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and lactate dehydrogenase release to the culture medium. Rg1 prevented high glucose/palmitate-induced cell apoptosis, assessed using cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labelling staining. Rg1 also reduced high glucose-/palmitate-induced reactive oxygen species formation and increased intracellular antioxidant enzyme activity. We found that Rg1 activates protein kinase B (AKT)/glycogen synthase kinase-3 (GSK-3ß) pathway and antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, indicated by increased phosphorylation of AKT and GSK-3ß, and nuclear translocation of Nrf2. We used phosphatidylinositol-3-kinase inhibitor Ly294002 to block the activation of the AKT/GSK-3ß pathway and found that it partially reversed the protection by Rg1 and decreased Nrf2 pathway activation. The results suggest that Rg1 exerts a protective effect against high glucose and palmitate damage that is partially AKT/GSK-3ß/Nrf2-mediated. Further studies are required to validate these findings using primary cardiomyocytes and animal models of diabetes.

Effect of cis- and trans-Monounsaturated Fatty Acids on Palmitate Toxicity and on Palmitate-induced Accumulation of Ceramides and Diglycerides.

Dietary trans fatty acids (TFAs) have been implicated in serious health risks, yet little is known about their cellular effects and metabolism. We aim to undertake an in vitro comparison of two representative TFAs (elaidate and vaccenate) to the best-characterized endogenous cis-unsaturated FA (oleate). The present study addresses the possible protective action of TFAs on palmitate-treated RINm5F insulinoma cells with special regards to apoptosis, endoplasmic reticulum stress and the underlying ceramide and diglyceride (DG) accumulation. Both TFAs significantly improved cell viability and reduced apoptosis in palmitate-treated cells. They mildly attenuated palmitate-induced XBP-1 mRNA cleavage and phosphorylation of eukaryotic initiation factor 2α (eIF2α) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), but they were markedly less potent than oleate. Accordingly, all the three unsaturated FAs markedly reduced cellular palmitate incorporation and prevented harmful ceramide and DG accumulation. However, more elaidate or vaccenate than oleate was inserted into ceramides and DGs. Our results revealed a protective effect of TFAs in short-term palmitate toxicity, yet they also provide important in vitro evidence and even a potential mechanism for unfavorable long-term health effects of TFAs compared to oleate.

Metabolic signatures suggest o-phosphocholine to UDP-N-acetylglucosamine ratio as a potential biomarker for high-glucose and/or palmitate exposure in pancreatic ß-cells.

INTRODUCTION: Chronic exposure to high-glucose and free fatty acids (FFA) alone/or in combination; and the resulting gluco-, lipo- and glucolipo-toxic conditions, respectively, have been known to induce dysfunction and apoptosis of ß-cells in Diabetes. The molecular mechanisms and the development of biomarkers that can be used to predict similarities and differences behind these conditions would help in easier and earlier diagnosis of Diabetes. OBJECTIVES: This study aims to use metabolomics to gain insight into the mechanisms by which ß-cells respond to excess-nutrient stress and identify associated biomarkers. METHODS: INS-1E cells were cultured in high-glucose, palmitate alone/or in combination for 24 h to mimic gluco-, lipo- and glucolipo-toxic conditions, respectively. Biochemical and cellular experiments were performed to confirm the establishment of these conditions. To gain molecular insights, abundant metabolites were identified and quantified using 1H-NMR. RESULTS: No loss of cellular viability was observed in high-glucose while exposure to FFA alone/in combination with high-glucose was associated with increased ROS levels, membrane damage, lipid accumulation, and DNA double-strand breaks. Forty-nine abundant metabolites were identified and quantified using 1H-NMR. Chemometric pair-wise analysis in glucotoxic and lipotoxic conditions, when compared with glucolipotoxic conditions, revealed partial overlap in the dysregulated metabolites; however, the dysregulation was more significant under glucolipotoxic conditions. CONCLUSION: The current study compared gluco-, lipo- and glucolipotoxic conditions in parallel and elucidated differences in metabolic pathways that play major roles in Diabetes. o-phosphocholine and UDP-N-acetylglucosamine were identified as common dysregulated metabolites and their ratio was proposed as a potential biomarker for these conditions.

Bone wax migrates to the orbit in a patient with a frontal sinus abnormality: a case report.

BACKGROUND: Bone wax is the most widely used hemostatic bone sealant because of its availability, ease of use, immediate action, and minimal adverse effects. Several complications have been reported to be associated with the use of bone wax, such as infection, osteohypertrophy, pain, granuloma formation, allergic reaction, and thrombosis. Here, we present a rare complication, namely, bone wax migration, which developed after a craniotomy on a patient who had a frontal sinus abnormality. CASE PRESENTATION: A 51-year-old woman complained of pain and swelling in her left eye accompanied by difficulty opening the left eyelid after undergoing a craniotomy. An examination revealed left eye proptosis with ptosis, eyelid swelling, and increases in intraorbital pressure and intraocular pressure (IOP). According to a CT and an MRI of the orbit, we found that the intraoperative bone wax had migrated to the orbit, thereby causing compression. We also found that the basal frontal sinus of the patient was congenitally defective, which may have induced the migration of the bone wax. Given that the patient recently underwent a craniotomy and given the risks associated with orbital surgery, she refused to undergo a surgery to remove the bone wax. Thus, the patient was administered mannitol intravenously daily, accompanied by topical Timolol, to reduce the intraorbital pressure and IOP. This treatment led to a gradual decrease in IOP and intraorbital pressure, and these parameters remained stable after treatment ended. During the 6-month follow-up, the best corrected visual acuity improved, and ptosis and restricted eye movements also improved significantly. CONCLUSIONS: We report a case of bone wax migration that developed after a craniotomy on a patient who had a congenital defect in the basal frontal sinus. Extra caution should be taken when using bone wax, and a comprehensive understanding of the patient's intracranial anatomy is important for decreasing the incidence of bone wax migration. Additionally, when a patient presents with symptoms of ocular compression, bone wax migration should be considered in addition to typical radiological changes.

Taurine-Rich-Containing Hot Water Extract of Loliolus Beka Gray Meat Scavenges Palmitate-Induced Free Radicals and Protects Against DNA Damage in Insulin Secreting ß-Cells.

The loss of pancreatic ß-cells plays a central role in the pathogenesis of both type 1 and type 2 diabetes, and many studies have been focused on ways to improve glucose homeostasis by preserving, expanding and improving the function of ß-cell. Elevated levels of free fatty acids such as palmitate might contribute to the loss of ß-cells. A marine squid, Loliolus beka has long been used as a food in Korea, China, Japan and Europe due to its tender meat and high taurine content. Here, we investigated the protective effects of a hot water extract of Loliolus beka meat (LBM) against palmitate toxicity in Ins-1 cells, a rat ß-cell line. Treatment with LBM extract protected against palmitate-induced cytotoxicity and scavenged overproduction of nitric oxide, alkyl, and hydroxyl radicals. In addition, LBM extract protected against palmitate-induced DNA damage and ß-cell dysfunction. These findings suggest that LBM protects pancreatic ß-cells from palmitate-induced damage. LBM could be a potential therapeutic functional food for diabetes.

Chronic, Symptomatic Orbital Inflammation Resulting From Retained Bone Wax.

A 58-year-old man presented with a 9-month history of a chronically draining surgical wound and low-grade periorbital inflammation following a right lateral orbitotomy. Imaging of the right orbit revealed a peculiar lesion in the right lateral orbit that was hypointense on both T1- and T2-weighted MRI with peripheral enhancement. Exploratory orbitotomy and biopsy established the diagnosis of a chronic foreign body inflammatory reaction to bone wax; symptoms resolved following evacuation of the retained foreign material.A 58-year-old man developed a chronic, symptomatic, inflammatory reaction to bone wax following a lateral orbitotomy; only once previously has symptomatic orbital inflammation following orbital surgery as a result of bone wax been reported.

(-)-Epicatechin and its metabolites prevent palmitate-induced NADPH oxidase upregulation, oxidative stress and insulin resistance in HepG2 cells.

While diets rich in fruit and vegetables can decrease the risk for type 2 diabetes (T2D), diets rich in fat and carbohydrates can increase it. The flavanol-3-ol (-)-epicatechin (EC) can improve insulin sensitivity both in humans and animal models of T2D. NADPH oxidases and oxidative stress can contribute to the development of insulin resistance. This study investigated the capacity of EC and EC metabolites (ECM) to downregulate NADPH oxidases and oxidative stress, and its association to an improvement of insulin sensitivity. This was studied in in vivo (high fat-fed mice) and in vitro (HepG2 cells) conditions of hepatic lipid overload. EC decreased NOX3/NOX4 liver expression and mitigated oxidative stress in high fat-fed mice. In HepG2 cells, incubation with palmitate increased: i) lipid deposition, ii) NOX3/NOX4 expression, iii) NADPH oxidase activity, and iv) oxidative stress; promoting v) the activation of redox-sensitive kinases (JNK and IKK), and vi) impaired insulin responses. Physiological concentrations of EC and ECM, and NADPH oxidase inhibitors (apocynin, VAS2870) prevented all those deleterious effects of palmitate. The obtained results points to NADPH oxidases as an important target in the capacity of EC to improve insulin sensitivity in conditions of liver lipid overload, as those associated with Western-style diets.

An Unusual Complication of Bone Wax Utilization.

Bone wax is a commonly used hemostatic agent with minimal complications. Some of the known complications include inflammation, granuloma formation, infection, and impaired osteogenesis. Several clinical reports of bone wax migration have also been reported. In this paper, the authors present a rare patient of bone wax migration intracranially in a 6-year-old patient who initially underwent craniotomy for the evacuation of subdural hematoma and repair of depressed skull fracture. The patient then underwent craniotomy scalp scar revision several months later. Postoperatively he developed short-term memory loss, apraxia, and word finding difficulties. The imaging findings were consistent with the presence of a foreign body centered in the posterior aspect of the left middle temporal gyrus, which was surgically removed and found to be bone wax. The patient recovered well with complete improvement of his neurologic symptoms.

Involvement of Sphingosine 1-Phosphate in Palmitate-Induced Non-Alcoholic Fatty Liver Disease.

BACKGROUND/AIMS: Ectopic lipid accumulation in hepatocytes has been identified as a risk factor for the progression of liver fibrosis and is strongly associated with obesity. In particular, the saturated fatty acid palmitate is involved in initiation of liver fibrosis via formation of secondary metabolites by hepatocytes that in turn activate hepatic stellate cells (HSCs) in a paracrine manner. METHODS: α-smooth muscle actin-expression (α-SMA) as a marker of liver fibrosis was investigated via western blot analysis and immunofluorescence microscopy in HSCs (LX-2). Sphingolipid metabolism and the generation of the bioactive secondary metabolite sphingosine 1-phosphate (S1P) in response to palmitate were analyzed by LC-MS/MS in hepatocytes (HepG2). To identify the molecular mechanism involved in the progression of liver fibrosis real-time PCR analysis and pharmacological modulation of S1P receptors were performed. RESULTS: Palmitate oversupply increased intra- and extracellular S1P-concentrations in hepatocytes. Conditioned medium from HepG2 cells initiated fibrosis by enhancing α-SMA-expression in LX-2 in a S1P-dependent manner. In accordance, fibrotic response in the presence of S1P was also observed in HSCs. Pharmacological inhibition of S1P receptors demonstrated that S1P3 is the crucial receptor subtype involved in this process. CONCLUSION: S1P is synthesized in hepatocytes in response to palmitate and released into the extracellular environment leading to an activation of HSCs via the S1P3 receptor.

High-fat diet induces cardiomyocyte apoptosis via the inhibition of autophagy.

PURPOSE: Excessive fat intake induces obesity and causes cardiac injury. Intracellular degradation process involving destruction of long-lived proteins and organelles maintains homeostasis for cells under stress. The purpose of this study was to explore the relation of high-fat diet (HFD)-induced cardiac injury and intracellular degradation process with regard to autophagy and ER stress. METHODS AND RESULTS: HFD feeding for 24 weeks induced hyperglycemia, hyperlipidemia, and cardiac hypertrophy in adult male C57BL/6 mice. In the heart, PARP cleavage, an indicator of apoptosis, levels of LC3-II and p62, indicators of autophagy, and CHOP, indicator of ER stress, were increased. A palmitate-treated cardiomyoblast (H9C2) cell culture was examined to explore how HFD induced myocardial injury. Excessive palmitate (400 µM) treatment induced apoptosis and increased the number of autophagosomes and acid vacuoles of H9C2 cells. Besides, it elevated the expression of LC3-II, p62, and PARP cleavage. Induction of autophagy by rapamycin ameliorated palmitate-induced apoptosis, while inhibition of autophagy by 3-methyladenine or LC3 siRNA exacerbated palmitate-induced apoptosis. Palmitate treatment also induced CHOP expression which is associated with ER stress. CONCLUSION: HFD can cause cardiac injury by induction of apoptosis which is associated with autophagy dysregulation and ER stress. In addition, autophagy deficiency augments cardiac apoptosis, suggesting that autophagy serves as a pro-survival role in lipotoxic condition.

Curcumin protects hearts from FFA-induced injury by activating Nrf2 and inactivating NF-κB both in vitro and in vivo.

Obesity and increased free fatty acid (FFA) level are tightly linked, leading to the development of cardiovascular disorders. Curcumin is a natural product from Curcuma longa with multiple bioactivities and is known to have cardioprotective effects in several cellular and animal models. The current study was designed to evaluate the cardioprotective effects of curcumin and demonstrate the underlying mechanism in FFA-induced cardiac injury. Using cell culture studies and high fat in vivo model, we explored the mechanistic basis of anti-inflammatory and antioxidant activities of curcumin. We observed that palmitate (PA) treatment in cardiac derived H9C2 cells induced a marked increase in reactive oxygen species, inflammation, apoptosis and hypertrophy. All of these changes were effectively suppressed by curcumin treatment. In addition, oral administration of curcumin at 50mg/kg completely suppressed high fat diet-induced oxidative stress, inflammation, apoptosis, fibrosis, hypertrophy and tissue remodeling in mice. The beneficial actions of curcumin are closely associated with its ability to increase Nrf2 expression and inhibit NF-κB activation. Thus, both in vitro and in vivo studies showed a promising role of curcumin as a cardioprotective agent against palmitate and high fat diet mediated cardiac dysfunction. We indicated the regulatory roles of Nrf2 and NF-κB in obesity-induced heart injury, and suggested that they may be important therapeutic targets in the treatment of obesity-related disorders.

BAIBA attenuates insulin resistance and inflammation induced by palmitate or a high fat diet via an AMPK-PPARδ-dependent pathway in mice.

AIMS/HYPOTHESIS: We explored the effects of ß-aminoisobutyric acid (BAIBA) on hyperlipidaemic-condition-induced insulin resistance and inflammation as mediated through a signalling pathway involving AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor δ (PPARδ). METHODS: Mouse skeletal muscle C2C12 cells and C57BL/6J mice were treated with palmitate or a high-fat diet (HFD) and BAIBA. Inflammation and the expression of genes associated with insulin signalling were determined by western blot and quantitative real-time PCR. Selected genes from candidate pathways were evaluated by small interfering (si)RNA knockdown and specific inhibitors. RESULTS: BAIBA treatment ameliorated impairment of insulin receptor substrate (IRS)-1/Akt-mediated insulin signalling in palmitate-treated C2C12 myocytes and in skeletal muscle of HFD-fed mice. In addition, BAIBA treatment reversed HFD-induced increases in body weight and improved impaired glucose tolerance in mice. In vitro and in vivo, inhibitory κBα (IκBα) phosphorylation, nuclear factor κB (NFκB) nuclear translocation and downstream inflammatory cytokines were significantly suppressed by BAIBA. Furthermore, BAIBA treatment significantly induced AMPK phosphorylation and expression of PPARδ in C2C12 myocytes and in skeletal muscle of mice. Both compound C, an AMPK inhibitor, and Pparδ (also known as Ppard) siRNA abrogated the inhibitory effects of BAIBA on palmitate-induced inflammation and insulin resistance. BAIBA significantly induced the expression of genes associated with fatty acid oxidation, such as carnitine palmitoyltransferase 1 (Cpt1), acyl-CoA oxidase (Aco; also known as Acox1) and fatty acid binding protein 3 (Fabp3); this effect of BAIBA was significantly reduced by compound C and Pparδ siRNA. CONCLUSIONS/INTERPRETATION: These results are the first to demonstrate that BAIBA attenuates insulin resistance, suppresses inflammation and induces fatty acid oxidation via the AMPK-PPARδ pathway in skeletal muscle.

Group VIA phospholipase A2 mitigates palmitate-induced ß-cell mitochondrial injury and apoptosis.

Palmitate (C16:0) induces apoptosis of insulin-secreting ß-cells by processes that involve generation of reactive oxygen species, and chronically elevated blood long chain free fatty acid levels are thought to contribute to ß-cell lipotoxicity and the development of diabetes mellitus. Group VIA phospholipase A2 (iPLA2ß) affects ß-cell sensitivity to apoptosis, and here we examined iPLA2ß effects on events that occur in ß-cells incubated with C16:0. Such events in INS-1 insulinoma cells were found to include activation of caspase-3, expression of stress response genes (C/EBP homologous protein and activating transcription factor 4), accumulation of ceramide, loss of mitochondrial membrane potential, and apoptosis. All of these responses were blunted in INS-1 cells that overexpress iPLA2ß, which has been proposed to facilitate repair of oxidized mitochondrial phospholipids, e.g. cardiolipin (CL), by excising oxidized polyunsaturated fatty acid residues, e.g. linoleate (C18:2), to yield lysophospholipids, e.g. monolysocardiolipin (MLCL), that can be reacylated to regenerate the native phospholipid structures. Here the MLCL content of mouse pancreatic islets was found to rise with increasing iPLA2ß expression, and recombinant iPLA2ß hydrolyzed CL to MLCL and released oxygenated C18:2 residues from oxidized CL in preference to native C18:2. C16:0 induced accumulation of oxidized CL species and of the oxidized phospholipid (C18:0/hydroxyeicosatetraenoic acid)-glycerophosphoethanolamine, and these effects were blunted in INS-1 cells that overexpress iPLA2ß, consistent with iPLA2ß-mediated removal of oxidized phospholipids. C16:0 also induced iPLA2ß association with INS-1 cell mitochondria, consistent with a role in mitochondrial repair. These findings indicate that iPLA2ß confers significant protection of ß-cells against C16:0-induced injury.

MicroRNA 375 mediates palmitate-induced enteric neuronal damage and high-fat diet-induced delayed intestinal transit in mice.

BACKGROUND & AIMS: A high-fat diet (HFD) can cause serious health problems, including alteration of gastrointestinal transit, the exact mechanism of which is not clear. Several microRNAs (miRNAs) are involved in energy homeostasis, lipid metabolism, and HFD-induced weight gain. We investigated the role of miRNAs in HFD-induced damage to the enteric nervous system. METHODS: Male mice were fed a HFD (60% calories from fat) or regular diets (18% calories from fat) for 11 weeks. Mice on regular diets and HFDs were given intraperitoneal injections of Mir375 inhibitor or a negative control. Body weights, food intake, stool indices, and gastrointestinal transit (following Evans blue gavage) were measured. An enteric neuronal cell line (immorto-fetal enteric neuronal) and primary enteric neurons were used for in vitro studies. RESULTS: HFD delayed intestinal transit, which was associated with increased apoptosis and loss of colonic myenteric neurons. Mice fed a low-palmitate HFD did not develop a similar phenotype. Palmitate caused apoptosis of enteric neuronal cells associated with mitochondrial dysfunction and endoplasmic reticulum stress. Palmitate significantly increased the expression of Mir375 in vitro; transfection of cells with a Mir375 inhibitor prevented the palmitate-induced enteric neuronal cell apoptosis. Mir375 expression was increased in myenteric ganglia of mice fed HFD and associated with decreased levels of Mir375 target messenger RNAs, including Pdk1. Systemic injection of a Mir375 inhibitor for 5 weeks prevented HFD-induced delay in intestinal transit and morphologic changes. CONCLUSIONS: HFDs delay colonic transit, partly by inducing apoptosis in enteric neuronal cells. This effect is mediated by Mir375 and is associated with reduced levels of Pdk1. Mir375 might be targeted to increase survival of enteric neurons and gastrointestinal motility.

Establishment of a rat model for alveolar cleft with bone wax.

PURPOSE: Although treatment of cleft lip and cleft palate is becoming standardized, treatment of alveolar cleft remains controversial. Thus, preclinical animal work remains necessary to improve clinical outcome. This study established an alveolar cleft model in the rat. MATERIALS AND METHODS: Maxillary first molars were extracted to create a 4- × 4- × 3-mm complete alveolar cleft on the right and left sides in 25 8-week-old Sprague-Dawley rats. The left cleft was filled with bone wax and the right side remained untreated. Animals were sacrificed at 0, 4 and 8 weeks after surgery. Harvested alveolar cleft samples were evaluated by micro-computed tomographic and histologic analyses. RESULTS: The healing rate and osteoblast activity of the left cleft were less than those of the right cleft. CONCLUSION: This model of a critical-size alveolar cleft can be used efficiently for the therapeutic evaluation of novel techniques for the treatment of alveolar cleft.

Body mass index and metabolic parameters in patients with schizophrenia during long-term treatment with paliperidone palmitate.

BACKGROUND: There is a strong association between weight gain and metabolic events in patients with schizophrenia receiving many of the second-generation antipsychotic agents. We explored the relationship between body mass index (BMI) and metabolic events in patients with schizophrenia receiving long-acting injectable paliperidone palmitate (PP) in a long-term trial. METHODS: We conducted a post hoc analysis of data from a PP study that included a 33-week open-label transition (TR) and maintenance phase; a variable duration, randomized, double-blind (DB), placebo-controlled phase and a 52-week open-label extension (OLE) phase. Overall, 644 patients received PP continuously from study entry through discontinuation or study completion and were grouped by baseline BMI (kg/m2): underweight (BMI <19; n = 29, 4.5%), normal-weight (BMI 19- < 25; n = 229, 35.6%), overweight (BMI 25- < 30; n = 232, 36.0%) and obese (BMI ≥ 30; n = 154, 23.9%). Metabolic treatment-emergent adverse events (TEAEs) and changes in related laboratory results from TR baseline were analyzed. RESULTS: PP exposure was similar across BMI groups; overall mean (SD) dose/month was 70.3 (17.17) mg eq. [109.6 (26.78) mg]; median duration of exposure was 204 days (6 to 1009 days). Occurrences of metabolic TEAEs overall by group were 0% (underweight), 14.9% (normal-weight), 14.7% (overweight), and 24.0% (obese). The most common (≥ 2%) metabolic TEAE were weight gain and elevated blood levels of glucose, lipids, and insulin. Mean BMI and weight increased in normal-weight and overweight groups at DB endpoint, and in underweight, normal-weight and overweight groups at OLE endpoint (p ≤ 0.05). No consistent trend for increased metabolic-related laboratory values by baseline BMI group was observed. Homeostatic model assessments for insulin resistance indicated preexisting insulin resistance at baseline, with minimal changes at OLE endpoint across baseline BMI groups. CONCLUSION: Occurrences of metabolic-related TEAEs trended with greater BMI status in patients with schizophrenia treated with PP; consistent trends in metabolic-related laboratory values were not observed. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT 00518323).

Pharmacokinetics and tolerability of paliperidone palmitate injection in Chinese subjects.

OBJECTIVE: The objective of this study was to characterize the pharmacokinetics of 25, 100, and 150 mg equivalents (eq.) of paliperidone long-acting injection in Chinese subjects with schizophrenia. METHODS: This was an open-label, randomized, parallel group, multicenter study. A total of 48 patients were randomized in a 1:1:1 ratio to one of three groups. Sequential blood samples were collected immediately before injection on day 1 and up to 210 days after the first injection. The plasma paliperidone concentrations were determined by a validated high-performance liquid chromatography/tandem mass spectrometry method. RESULTS: A total of 47 patients received at least one injection of the study medication, and 43 completed the study. The pharmacokinetic (PK) parameters, such as time to maximum concentration, t1/2, and CL/F, were comparable across the three treatment groups (p = 0.935, 0.349, and 0.794, respectively). The differences in maximum plasma concentration, AUC (035 days), AUC (0-210 days), and AUC (0-∞) were significant (p < 0.001) and dose proportional. The inter-individual variation of PK parameters was large. The most frequent treatment-emergent adverse events were prolactin level increasing, injection site pain, tremor, dry mouth, and constipation. CONCLUSIONS: The pharmacokinetics of paliperidone palmitate are linear with respect to time in Chinese subjects with schizophrenia at injections from 25 to 150 mg eq.

Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial.

IMPORTANCE: Long-acting injectable antipsychotics are used to reduce medication nonadherence and relapse in schizophrenia-spectrum disorders. The relative effectiveness of long-acting injectable versions of second-generation and older antipsychotics has not been assessed. OBJECTIVE: To compare the effectiveness of the second-generation long-acting injectable antipsychotic paliperidone palmitate with the older long-acting injectable antipsychotic haloperidol decanoate. DESIGN, SETTING, AND PARTICIPANTS: Multisite, double-blind, randomized clinical trial conducted from March 2011 to July 2013 at 22 US clinical research sites. Randomized patients (n = 311) were adults diagnosed with schizophrenia or schizoaffective disorder who were clinically assessed to be at risk of relapse and likely to benefit from a long-acting injectable antipsychotic. INTERVENTIONS: Intramuscular injections of haloperidol decanoate 25 to 200 mg or paliperidone palmitate 39 to 234 mg every month for as long as 24 months. MAIN OUTCOME MEASURES: Efficacy failure, defined as a psychiatric hospitalization, a need for crisis stabilization, a substantial increase in frequency of outpatient visits, a clinician's decision that oral antipsychotic could not be discontinued within 8 weeks after starting the long-acting injectable antipsychotics, or a clinician's decision to discontinue the assigned long-acting injectable due to inadequate therapeutic benefit. Key secondary outcomes were common adverse effects of antipsychotic medications. RESULTS: There was no statistically significant difference in the rate of efficacy failure for paliperidone palmitate compared with haloperidol decanoate (adjusted hazard ratio, 0.98; 95% CI, 0.65-1.47). The number of participants who experienced efficacy failure was 49 (33.8%) in the paliperidone palmitate group and 47 (32.4%) in the haloperidol decanoate group. On average, participants in the paliperidone palmitate group gained weight and those in the haloperidol decanoate group lost weight; after 6 months, the least-squares mean weight change for those taking paliperidone palmitate was increased by 2.17 kg (95% CI, 1.25-3.09) and was decreased for those taking haloperidol decanoate (-0.96 kg; 95% CI, -1.88 to -0.04). Patients taking paliperidone palmitate had significantly higher maximum mean levels of serum prolactin (men, 34.56 µg/L [95% CI, 29.75-39.37] vs 15.41 µg/L [95% CI, 10.73-20.08]; P <.001, and for women, 75.19 [95% CI, 63.03-87.36] vs 26.84 [95% CI, 13.29-40.40]; P<.001). Patients taking haloperidol decanoate had significantly larger increases in global ratings of akathisia (0.73 [95% CI, 0.59-0.87] vs 0.45 [95% CI, 0.31-0.59]; P=.006). CONCLUSIONS AND RELEVANCE: In adults with schizophrenia or schizoaffective disorder, use of paliperidone palmitate vs haloperidol decanoate did not result in a statistically significant difference in efficacy failure, but was associated with more weight gain and greater increases in serum prolactin, whereas haloperidol decanoate was associated with more akathisia. However, the CIs do not rule out the possibility of a clinically meaningful advantage with paliperidone palmitate. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01136772.

Safety and efficacy of bone wax in patients on oral anticoagulant therapy.

Cardiovascular conditions, apart from neoplastic diseases, remain the major cause of death in developed countries; therefore, the number of patients receiving oral anticoagulants is constantly increasing. Anticoagulant therapy considerably reduced mortality in patients with history of myocardial infarction among others. Although many interventions may be performed without withdrawal of the anticoagulant and tooth extraction was qualified as a procedure of low hemorrhage risk, a majority of dentists refer the patient to a cardiologist several days before the elective tooth extraction to withdraw anticoagulants. The aim of the study was to evaluate the efficacy and safety of bone wax used to stop bleeding after dental procedures in a group of patients on chronic anticoagulant therapy and find an answer to a question, whether it is justified to temporarily withdraw anticoagulants for this type of procedures. The study involved 176 patients on chronic anticoagulant therapy undergoing tooth extraction (154 subjects) or surgical extraction of a retained tooth (48 subjects). After the procedure, in each case the alveolus was filled with bone wax to stop bleeding. In all patients involved in the study bleeding from the alveolus was successfully stopped during the procedure. None of the subjects reported increased bleeding from the operational site after coming back home. Bone wax is a good, efficient, and safe material to block bleeding from the alveolus following tooth extractions, also in patients on chronic anticoagulant therapy. The study demonstrated that withdrawal or adjustment of anticoagulant therapy is not necessary before an elective tooth extraction.