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SHetA2 is a small molecule drug with promising cancer prevention and therapeutic activity and a high preclinical safety profile. The study objectives were to perform interspecies scaling and pharmacokinetic (PK) modeling of SHetA2 for human PK prediction. The PK data obtained from mice, rats, and dogs after intravenous and oral doses were used for simultaneous fitting to PK models. The disposition of SHetA2 was best described by a two-compartment model. The absorption kinetics was well characterized with a first-order absorption model for mice and rats, and a gastrointestinal transit model for dogs. Oral administration of SHetA2 showed a relatively fast absorption in mice, prolonged absorption (i.e., flip-flop kinetics) toward high doses in rats, and an early peak followed by a secondary peak at high doses in dogs. The oral bioavailability was 17.7–19.5% at 20–60 mg/kg doses in mice, <1.6% at 100–2000 mg/kg in rats, and 11.2% at 100 mg/kg decreasing to 3.45% at 400 mg/kg and 1.11% at 1500 mg/kg in dogs. The disposition parameters were well correlated with the body weight for all species using the allometric equation, which predicted values of CL (17.3 L/h), V1 (36.2 L), V2 (68.5 L) and CLD (15.2 L/h) for a 70-kg human. The oral absorption rate and bioavailability of SHetA2 was highly dependent on species, doses, formulations, and possibly other factors. The limited bioavailability at high doses was taken into consideration for the suggested first-in-human dose, which was much lower than the dose estimated based on toxicology studies. In summary, the present study provided the PK model for SHetA2 that depicted the disposition and absorption kinetics in preclinical species, and computational tools for human PK prediction. [ABSTRACT FROM AUTHOR]

Viral vectors are extensively purified for use in biomedical research, in order to separate biologically active virus particles and to eliminate production related impurities that are assumed to be detrimental to the host. For recombinant adeno-associated virus (rAAV) vectors this is typically accomplished using density gradient-based methods, which are tedious and require specialized ultracentrifugation equipment. In order to streamline the preparation of rAAV vectors for pilot and small animal studies, we recently devised a simple ultrafiltration approach that permits rapid virus concentration and partial removal of production-related impurities. Here we show that systemic administration of such rapidly prepared (RP) rAAV8 vectors in mice is safe and efficiently transduces the liver. Across a range of doses, delivery of RP rAAV8-CMV-eGFP vector induced enhanced green fluorescent protein (eGFP) expression in liver that was comparable to that obtained from a conventional iodixanol gradient-purified (IP) vector. Surprisingly, no liver inflammation or systemic cytokine induction was detected in RP rAAV injected animals, revealing that residual impurities in the viral vector preparation are not deleterious to the host. Together, these data demonstrate that partially purified rAAV vector can be safely and effectively administered in vivo. The speed and versatility of the RP method and lack of need for cumbersome density gradients or expensive ultracentrifuge equipment will enable more widespread use of RP prepared rAAV vectors, such as for pilot liver gene transfer studies. [ABSTRACT FROM AUTHOR]

Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+ cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr-1+ cell populations in naïve mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post-influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-γ and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr-1+ cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (Lineage−HLA-DR−CD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+ cells essential for the immunomodulatory properties of macrolides. [ABSTRACT FROM AUTHOR]

Cinacalcet hydrochloride (cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral calcimimetic agent, with a wider safety margin. [ABSTRACT FROM AUTHOR]

Preservation of residual hearing after cochlear implant is an important issue with regards to hearing performance. Various methods of steroid administration have been widely used in clinical practice to reduce inflammation and preserve residual hearing. Here we compare the effect of different routes of dexamethasone administration on intracochlear inflammation and residual hearing in guinea pig ears. Dexamethasone was delivered into the guinea pigs either through intracochlear, intratympanic or systemic route. The intracochlear concentration of dexamethasone, residual hearing, inflammatory cytokines and histopathologic changes were evaluated over time. A higher intracochlear dexamethasone concentration was observed after intracochlear administration than through the other routes. Residual hearing was better preserved with local dexamethasone administration as was supported by the reduced inflammatory cytokines, more hair cell survival and less severe intracochlear fibrosis and ossification concurrently seen in the local delivery group than in the systemic group. The results demonstrate that local dexamethasone delivery can reduce intracochlear inflammation and preserve residual hearing better than in systemically administered dexamethasone. [ABSTRACT FROM AUTHOR]

Multiple sclerosis is a chronic, progressive, and common disease affecting the central nervous system in young adults. Interferon-beta is one of the most widely used medicines to reduce the disease progression. Given the variety of drugs in this category, we aimed to identify the preferences of patients for IFN-β that play an important role in policymaking in this area. Discrete choice experiment method was used in the present study to identify and prioritize those attributes that are of interest to MS patients and increases the utility of the use of IFN-β in their treatment. Questionnaires were given to 358 patients in Isfahan-Iran, who were asked to choose between the two treatment choices in each scenario. The results of the logit model showed that the changes in the efficacy lead to the most changes in the patient utility. Changes in side effects and ease of injection have been placed in the next rankings. Considering the drug attributes considered more desirable by patients can lead to greater medication adherence and possibly better treatment outcomes. Also, pharmaceutical companies, the health ministry, the Food and Drug Administration, insurance organizations, and neurologists can benefit from this information in production and importation, policymaking, and prescription. [ABSTRACT FROM AUTHOR]

Pantoea agglomerans (P. agglomerans) is a Gram-negative bacterium that grows symbiotically with various edible plants, and the oral or sublingual administration of lipopolysaccharide derived from P. agglomerans (LPSp) have been suggested to contribute to prevention of immune-related diseases. Our previous study indicated that orally administered LPSp was shown to exhibit an LDL-lowering effect in hyperlipidemic volunteers; however, a preventive effect of LPSp on atherosclerosis is unclear. The present study attempted to evaluate the anti-atherosclerotic effect by LPSp in a mouse model of high-fat diet (HFD)-induced atherosclerosis. For 16 weeks, apoE-deficient mice were fed an HFD and received drinking water containing LPSp (0.3 or 1 mg/kg body weight/day). The results showed that the orally administered LPSp decreased body weight. A significant reduction in atherosclerotic plaque deposition was observed even with the lower dose of LPSp. The biochemical analyses showed that LPSp markedly improved glucose tolerance and reduced plasma LDL and oxidized LDL levels. In addition, LPSp significantly reduced the production of pro-inflammatory mediators including MCP-1 (in the plasma), TNF-α and IL-6 (in the colon), and decreased the oxidative burst activities in the peripheral blood sample. Taken together, these results suggest the possibility that oral administration of LPSp can effectively ameliorate HFD-induced hyperlipidemia and inflammatory/oxidative responses to prevent atherosclerosis and related metabolic disorders. [ABSTRACT FROM AUTHOR]

The natural alkaloid berberine has been ascribed numerous health benefits including lipid and cholesterol reduction and improved insulin sensitivity in diabetics. However, oral (PO) administration of berberine is hindered by poor bioavailability and increasing dose often elicits gastro-intestinal side effects. To overcome the caveats associated with oral berberine, we developed transdermal (TD) formulations of berberine (BBR) and the berberine precursor dihydroberberine (DHB). These formulations were compared to oral BBR using pharmacokinetics, metabolism, and general safety studies in vivo. To complete this work, a sensitive quantitative LC-MS/MS method was developed and validated according the FDA guidelines for bioanalytical methods to simultaneously measure berberine, simvastatin, and simvastatin hydroxy acid with relative quantification used for the berberine metabolite demethylene berberine glucuronide (DBG). Acute pharmacokinetics in Sprague-Dawley rats demonstrated a statistically relevant ranking for berberine bioavailability based upon AUC0-8 as DHB TD > BBR TD >> BBR PO with similar ranking for the metabolite DBG, indicating that transdermal administration achieves BBR levels well above oral administration. Similarly, chronic administration (14 days) resulted in significantly higher levels of circulating BBR and DBG in DHB TD treated animals. Chronically treated rats were given a single dose of simvastatin with no observed change in the drugs bioavailability compared with control, suggesting the increased presence of BBR had no effect on simvastatin metabolism. This observation was further supported by consistent CYP3A4 expression across all treatment groups. Moreover, no changes in kidney and liver biomarkers, including alanine aminotransferase and alkaline phosphatase, were observed between treatment formats, and confirming previous reports that BBR has no effect on HMG-CoA expression. This study supports the safe use of transdermal compositions that improve on the poor bioavailability of oral berberine and have the potential to be more efficacious in the treatment of dyslipidemia or hypercholesterolemia. [ABSTRACT FROM AUTHOR]

The purpose of the study was to develop Tizanidine HCl (TZN) and Meloxicam (MLX) loaded bilayer mucoadhesive films intended for buccal administration, aiming to enhance the bioavailability. Bilayer films were prepared by solvent evaporation technique selecting arabinoxylan (ARX) as a sustained release (SR) layer forming polymer and hydroxypropyl methylcellulose (HPMC) E-15 as an immediate release (IR) layer-forming polymer. Prepared films were subjected to in-vitro drug release, surface morphology, mechanical strength, compatibility of the ingredients, drug contents, ex-vivo mucoadhesion strength and drug permeation. Crossover study design was applied to study the in-vivo pharmacokinetics by using albino rabbits. Various pharmacokinetic parameters including AUC, Cmax, tmax and t1/2 of both drugs loaded in films were compared with standard solution/dispersion administered to the rabbits at the dose of 1mg/kg. The results unveiled instant release and permeation of MLX from IR layer, while good controlled release and permeation characteristics of TZN from SR films over 8 h. films were of uniform thickness with smooth surface and satisfactory mechanical strength. Mucoadhesion strength was sufficient to provide suitable contact time with mucosal membrane. The pharmacokinetic study exhibited prompt absorption of MLX with better AUC 0-t (6655.64 ng/ml*h vs 6538.99 ng/ml*h) and Cmax (436.98 ng/ml vs 411.33 ng/ml) from oral dispersion. Similarly buccal films has shown enhanced half-life (9.91hr vs 2.51 hr), AUC 0-t (1043.4 ng/ml*h vs 149.1 ng/ml*h) and Cmax (91.92 ng/ml vs 42.29 ng/ml) from oral solution. A statistical investigation disclosed a significantly improved pharmacokinetics of TZN and MLX after their absorption across buccal route following administration of buccal film (p<0.05). ARX proved expedient and bilayer buccal films as a drug delivery system ascertained the dual effect of providing instant release of one active agent and persistent release of another one with improved pharmacokinetics. [ABSTRACT FROM AUTHOR]

The environmental fates of pharmaceuticals and the effects of crop protection products on non-target species are subjects that are undergoing intense review. Since measuring the concentrations and effects of xenobiotics on all affected species under all conceivable scenarios is not feasible, standard laboratory animals such as rabbits are tested, and the observed adverse effects are translated to focal species for environmental risk assessments. In that respect, mathematical modelling is becoming increasingly important for evaluating the consequences of pesticides in untested scenarios. In particular, physiologically based pharmacokinetic/toxicokinetic (PBPK/TK) modelling is a well-established methodology used to predict tissue concentrations based on the absorption, distribution, metabolism and excretion of drugs and toxicants. In the present work, a rabbit PBPK/TK model is developed and evaluated with data available from the literature. The model predictions include scenarios of both intravenous (i.v.) and oral (p.o.) administration of small and large compounds. The presented rabbit PBPK/TK model predicts the pharmacokinetics (Cmax, AUC) of the tested compounds with an average 1.7-fold error. This result indicates a good predictive capacity of the model, which enables its use for risk assessment modelling and simulations. [ABSTRACT FROM AUTHOR]

Seizure clustering is a common and significant phenomenon in patients with epilepsy. The clustering of spontaneous recurrent seizures (SRSs) in animal models of epilepsy, including mouse pilocarpine models, has been reported. However, most studies have analyzed seizures for a short duration after the induction of status epilepticus (SE). In this study, we investigated the detailed characteristics of seizure clustering in the chronic stage of a mouse pilocarpine-induced epilepsy model for an extended duration by continuous 24/7 video-EEG monitoring. A seizure cluster was defined as the occurrence of one or more seizures per day for at least three consecutive days and at least five seizures during the cluster period. We analyzed the cluster duration, seizure-free period, cluster interval, and numbers of seizures within and outside the seizure clusters. The video-EEG monitoring began 84.5±33.7 days after the induction of SE and continued for 53.7±20.4 days. Every mouse displayed seizure clusters, and 97.0% of the seizures occurred within a cluster period. The seizure clusters were followed by long seizure-free periods of 16.3±6.8 days, showing a cyclic pattern. The SRSs also occurred in a grouped pattern within a day. We demonstrate that almost all seizures occur in clusters with a cyclic pattern in the chronic stage of a mouse pilocarpine-induced epilepsy model. The seizure-free periods between clusters were long. These findings should be considered when performing in vivo studies using this animal model. Furthermore, this model might be appropriate for studying the unrevealed mechanism of ictogenesis. [ABSTRACT FROM AUTHOR]

We previously demonstrated that patients with multiple sclerosis (MS) of high serum Sema4A levels are resistant to IFN-β therapy. To further elucidate the role of serum Sema4A as a biomarker for therapeutic stratification in MS patients, it is important to clarify the efficacy of other disease-modifying drugs (DMD) in those with high serum Sema4A levels. Thus, in this study we investigated whether fingolimod has beneficial effects on MS patients with high Sema4A levels. We retrospectively analyzed annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) change in 56 relapsing—remitting multiple sclerosis (RRMS) patients who had been treated with fingolimod, including those who switched from IFN-β therapy. The levels of Sema4A in the sera were measured by sandwich ELISA. The implications of Sema4A on the efficacy of fingolimod were investigated by administering recombinant Sema4A-Fc and fingolimod to mice with experimental autoimmune encephalomyelitis (EAE). Retrospective analysis of MS cohort (17 high Sema4A and 39 low Sema4A) demonstrated the effectiveness of fingolimod in those with high serum Sema4A levels, showing reduction of ARR (from 1.21 to 0.12) and EDSS progression (from 0.50 to 0.04). Consistent with this observation, improvement in the disease severity of EAE mice receiving recombinant Sema4A-Fc was also observed after fingolimod treatment. These data suggest that fingolimod could serve as a candidate DMD for managing the disease activity of MS patients with high Sema4A levels. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials (RCTs) have compared mechanical endovascular therapy (MET) in addition to intravenous tissue plasminogen activator (IVtPA) to IVtPA alone for the management of acute ischemic stroke (AIS). Direct comparative studies between individual METs are not available. In lieu of head-to-head randomized control trials, we performed an adjusted indirect treatment comparison (ITC) meta-analysis to assess the comparative efficacy and safety of different METs, Solitaire+IVtPA and Penumbra+IVtPA in AIS patients. Methods and findings: We searched MEDLINE, the Cochrane Central Register of Controlled Trials and Embase from January 1, 2005 through April 1, 2017 for RCTs in AIS patients, comparing a single MET+IVtPA to IVtPA alone and reporting shift in ordinal modified Rankin Scale (mRS) score at 90 days. Secondary endpoints included 90 day mortality and symptomatic intracranial hemorrhage (sICH). Endpoints were pooled using traditional random effects meta-analysis methods, producing odds ratios and 95% confidence intervals. Adjusted ITCs using pooled estimates were then performed. Three studies (SWIFT PRIME, EXTEND-IA, THERAPY) were included; two evaluating the Solitaire stent retriever and one the Penumbra system. Traditional meta-analysis demonstrated that each MET+IVtPA resulted in increased odds of improving ordinal mRS score vs. IVtPA alone, but did not alter the odds of death or sICH. Adjusted ITC showed no significant difference between the METs for any outcome. Conclusion: No significant difference in efficacy or safety between the Solitaire and Penumbra devices was observed. [ABSTRACT FROM AUTHOR]

Fonsecaea pedrosoi (F. pedrosoi) is the most common agent of chromoblastomycosis. Transformation of this fungus from its saprophytic phase into pathogenic sclerotic cells in tissue is an essential link to the refractoriness of this infection. Experimental studies in murine models have shown that the absence of CD4+ T cells impairs host defense against F. pedrosoi infection. Clinical research has also suggested that a relatively low level of the Th1 cytokine INF-γ and inefficient T cell proliferation are simultaneously present in patients with severe chromoblastomycosis upon in vitro stimulation with ChromoAg, an antigen prepared from F. pedrosoi. In the present study, we show that in mice intraperitoneally infected with F. pedrosoi-spores, -hyphae or in vitro-induced sclerotic cells respectively, the transformation of this causative agent into sclerotic cells contributes to a compromised Th1 cytokine production in the earlier stage of infection with impaired generation of neutrophil reactive oxygen species (ROS) and pan-inhibition of Th1/Th2/Th17 cytokine production with disseminated infection in the later stage by using a CBA murine Th1/Th2/Th17 cytokine kit. In addition, we have further demonstrated that intraperitoneal administration of recombinant mouse IFN-γ (rmIFN-γ) effectively reduces the fungal load in the infected mouse spleen, and dampens the peritoneal dissemination of F. pedrosoi-sclerotic cells. Meanwhile, exogeneous rmIFN-γ contributes to the formation and maintenance of micro-abscess and restores the decrease in neutrophil ROS generation in the mouse spleen infected with F. pedrosoi-sclerotic cells. Of note, we have once again demonstrated that it is a chitin-like component, but not β-glucans or mannose moiety, that exclusively accumulates on the outer cell wall of F. pedrosoi-sclerotic cells which were induced in vitro or isolated from the spleens of intraperitoneally infected BALB/c mice. In addition, our results indicate that decreased accumulation of chitin on the surface of live F. pedrosoi-sclerotic cells after chitinase treatment can be self-compensated in a time-dependent manner. Importantly, we have for the first time demonstrated that exclusive accumulation of chitin on the transformed sclerotic cells of F. pedrosoi is involved in an impaired murine Th1 cytokine profile, therefore promoting the refractoriness of experimental murine chromoblastomycosis. [ABSTRACT FROM AUTHOR]

Effective inhibitors of invasion and metastasis represent a serious unmet clinical need. We have recently identified 4-fluoro-3’,4’,5’-trimethoxychalcone or C16 as a potent anti-invasive molecule. In this paper, we report on the development of an optimized vehicle for oral administration of C16. We also explore its pharmacokinetic and toxicity profile in rodents as a prelude to a broad-scope evaluation as a pharmacological tool in animal models of disease. C16 showed suboptimal pharmacokinetics with limited oral bioavailability and whole blood stability. Rapid metabolism with elimination via glutathione conjugation was observed. An oral dosing routine using medicated gels was developed to overcome bioavailability issues and yielded sustained whole blood levels above the half maximal effective concentration (EC50) in a 7-day study. The compound proved well-tolerated in acute and chronic experiments at 300 mg/kg PO dosing. The medicated gel formulation is highly suitable for evaluation of C16 in animal models of disease. [ABSTRACT FROM AUTHOR]

Rhabdomyolysis (RM) may cause kidney damage and results primarily in acute kidney injury (AKI). Complement is implicated in the pathogenesis of renal diseases and ischemia-reperfusion injury (IRI), but the role of complement, especially its activation pathway(s) and its effect in RM-induced AKI, is not clear. This study established a rat model of AKI induced by RM via intramuscular treatment with glycerol. Cobra venom factor (CVF) was administered via tail vein injection to deplete complement 12 h prior to intramuscular injection of glycerol. We found that the complement components, including complement 3 (C3), C1q, MBL-A, factor B(fB), C5a, C5b-9, and CD59, were significantly increased in rat kidneys after intramuscular glycerol administration. However, the levels of serum BUN and Cr, renal tubular injury scores, and the number of TUNEL-positive cells decreased significantly in the CVF+AKI group. These results suggest that complement plays an important role in RM-induced AKI and that complement depletion may improve renal function and decrease renal tissue damage by reducing the inflammatory response and apoptosis. [ABSTRACT FROM AUTHOR]

Background & aims: Prophylactic injections of factor VIII reduce the incidence of bleeds and slow the development of joint damage in people with hemophilia. The aim of this study was to identify optimal person-specific prophylaxis regimens for children with hemophilia A. Methods: Analytic and numerical methods were used to identify prophylaxis regimens which maximize the time for which plasma factor VIII concentrations exceed a threshold, maximize the lowest plasma factor VIII concentrations, and minimize risk of bleeds. Results: It was demonstrated analytically that, for any injection schedule, the regimen that maximizes the lowest factor VIII concentration involves sharing doses between injections so that all of the trough concentrations in a prophylaxis cycle are equal. Numerical methods were used to identify optimal prophylaxis schedules and explore the trade-offs between efficacy and acceptability of different prophylaxis regimens. The prophylaxis regimen which minimizes risk of bleeds depends on the person’s pattern of physical activity and may differ greatly from prophylaxis regimens that optimize pharmacokinetic parameters. Prophylaxis regimens which minimize risk of bleeds also differ from prophylaxis regimens that are typically prescribed. Predictions about which regimen is optimal are sensitive to estimates of the effects on risk of bleeds of factor VIII concentration and physical activity. Conclusion: The methods described here can be used to identify optimal, person-specific prophylaxis regimens for children with hemophilia A. [ABSTRACT FROM AUTHOR]

TopicalPdb () is a repository of experimentally verified topically delivered peptides. Data was manually collected from research articles. The current release of TopicalPdb consists of 657 entries, which includes peptides delivered through the skin (462 entries), eye (173 entries), and nose (22 entries). Each entry provides comprehensive information related to these peptides like the source of origin, nature of peptide, length, N- and C-terminal modifications, mechanism of penetration, type of assays, cargo and biological properties of peptides, etc. In addition to natural peptides, TopicalPdb contains information of peptides having non-natural, chemically modified residues and D-amino acids. Besides this primary information, TopicalPdb stores predicted tertiary structures as well as peptide sequences in SMILE format. Tertiary structures of peptides were predicted using state-of-art method PEPstrMod. In order to assist users, a number of web-based tools have been integrated that includes keyword search, data browsing, similarity search and structural similarity. We believe that TopicalPdb is a unique database of its kind and it will be very useful in designing peptides for non-invasive topical delivery. [ABSTRACT FROM AUTHOR]

The rates of opioid prescription and use have continued to increase over the last few decades resulting in a greater number of opioid tolerant patients. Treatment of acute pain from surgery and injury is a clinical challenge for these patients. Several pain management strategies including prescribing increased opioids are used clinically with limited success; all currently available strategies have significant limitations. Many opioids are a substrate for p-glycoprotein (p-gp), an efflux transporter at the blood-brain barrier (BBB). Increased p-gp is associated with a decreased central nervous system uptake and analgesic efficacy of morphine. Our laboratory previously found that acute peripheral inflammatory pain (PIP) induces p-gp trafficking from the nucleus to the luminal surface of endothelial cells making up the BBB concomitant with increased p-gp activity and decreased morphine analgesic efficacy. In the current study, we tested whether PIP-induced p-gp trafficking could contribute to decreased opioid efficacy in morphine tolerant rats. A 6-day continuous dosing of morphine from osmotic minipumps was used to establish morphine tolerance in female rats. PIP induced p-gp trafficking away from nuclear stores showed a 2-fold increase in morphine tolerant rats. This observation suggests that p-gp trafficking contributes to the decreased morphine analgesic effects in morphine tolerant rats experiencing an acute pain stimulus. Attenuating p-gp trafficking during an acute pain stimulus could improve pain management by increasing the amount of opioid that could reach CNS analgesic targets and decrease the need for the dose escalation that is a serious challenge in pain management. [ABSTRACT FROM AUTHOR]

To date, good experimental animal models of renal anemia are not available. Therefore, the purpose of this study was to establish a novel approach to induce chronic kidney disease (CKD) with severe anemia by oral administration of adenine in rodents. Adenine was administered to 6-week-old male C57BL/6 mice (25 and 50 mg/kg body weight) by oral gavage daily for 28 days. Serum creatinine and BUN as well as hematocrit, hemoglobin (Hb) and plasma erythropoietin (EPO) levels were monitored to assess renal function and anemia, respectively. Adenine at 25 mg/kg for 28 days slightly increased plasma creatinine levels, but did not induce anemia. In contrast, 50 mg/kg of adenine daily for 28 days showed severe renal dysfunction (plasma creatinine 1.9 ± 0.10 mg/dL) and anemia (hematocrit 36.5 ± 1.0% and EPO 28 ± 2.4 pg/mL) as compared with vehicle-treated mice (0.4 ± 0.02 mg/dL, 49.6 ± 1.6% and 61 ± 4.0 pg/mL, respectively). At the end of experiment, level of Hb also significantly reduced in 50 mg/kg adenine administration group. Remarkable histological changes of kidney tissues characterized by interstitial fibrosis and cystic appearance in tubules were observed in 50 mg/kg of adenine treatment group. These results have demonstrated that oral dosing with adenine at 50 mg/kg for 28 days is suitable to induce a stable anemia associated with CKD in mice. [ABSTRACT FROM AUTHOR]

Background: Cannabis use is common, and associated with adverse health outcomes. 'Routes of administration' (ROAs) for cannabis use have increasingly diversified, in part influenced by developments towards legalization. This paper sought to review data on prevalence and health outcomes associated with different ROAs.Methods: This scoping review followed a structured approach. Electronic searches for English-language peer-reviewed publications were conducted in primary databases (i.e., MEDLINE, EMBASE, PsycINFO, Google Scholar) based on pertinent keywords. Studies were included if they contained information on prevalence and/or health outcomes related to cannabis use ROAs. Relevant data were screened, extracted and narratively summarized under distinct ROA categories.Results: Overall, there is a paucity of rigorous and high-quality data on health outcomes from cannabis ROAs, especially in direct and quantifiable comparison. Most data exist on smoking combusted cannabis, which is associated with various adverse respiratory system outcomes (e.g., bronchitis, lung function). Vaporizing natural cannabis and ingesting edibles appear to reduce respiratory system problems, but may come with other risks (e.g., delayed impairment, use 'normalization'). Vaporizing cannabis concentrates can result in distinct acute risks (e.g., excessive impairment, injuries). Other ROAs are uncommon and under-researched.Conclusions: ROAs appear to distinctly influence health outcomes from cannabis use, yet systematic data for comparative assessments are largely lacking; these evidence gaps require filling. Especially in emerging legalization regimes, ROAs should be subject to evidence-based regulation towards improved public health outcomes. Concretely, vaporizers and edibles may offer potential for reduced health risks, especially concerning respiratory problems. Adequate cannabis product regulation (e.g., purity, labeling, THC-restrictions) is required to complement ROA-based effects. [ABSTRACT FROM AUTHOR]

Prothionamide (PTH), a second line antitubercular drug is used to administer in conventional oral route. However, its unpredictable absorption and frequent administration limit its use. An alternate approach was thought of administering PTH through pulmonary route in a form of nanoparticles, which can sustain the release for several hours in lungs. Chitosan, a bio-degradable polymer was used to coat PTH and further freeze dried to prepare dry powder inhaler (DPI) with aerodynamic particle size of 1.76μm. In vitro release study showed initial burst release followed by sustained release up to 96.91% in 24h. In vitro release further correlated with in vivo study. Prepared DPI maintained the PTH concentration above MIC for more than 12h after single dose administration and increased the PTH residency in the lungs tissue more than 24h. Animal study also revealed the reduction of dose in pulmonary administration, which will improve the management of tuberculosis. [ABSTRACT FROM AUTHOR]

In the present study, the DPPH and ABTS+ radical scavenging activity of eight types of apples decreased (P < 0.05) during the 70-day storage at 4°C. The Fushi (F2) apples from Xin Jiang showed the highest radical scavenging activity. For in vivo study, 40 male Kunming mice (body weight 20–25 g) were selected and randomly assigned to four groups (10 mice per group). The F2 groups (F2S, F2 + sterile saline and F2L, F2 + lipopolysaccharide) were administered with 0.3 mL F2 filtrate via gastric intubation daily for 28 days. The control groups (CS, CON + sterile saline and CL, CON + lipopolysaccharide) were treated with sterile saline at the same volume. At day 29, mice of F2L and CL groups were injected with 100 μg/kg body weight of lipopolysaccharide (LPS) intraperitoneally, while those of F2S and CS groups were injected equal volume of sterile saline. In comparison to the CS group, the CL group showed a decrease (P < 0.05) in serum, liver, and hepatic mitochondrial antioxidant capacity, reduction (P < 0.05) in the expression of hepatic antioxidant-related genes, and an increase (P < 0.05) in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), protein carbonyl (PC), and reactive oxygen species (ROS). In comparison to the CL group, the F2L group showed lower (P < 0.05) levels of serum ALT, AST, and ROS, higher (P < 0.05) level of serum, liver, and hepatic mitochondrial antioxidant capacity, increased mitochondrial membrane potential (MMP), and enhanced (P < 0.05) expression of hepatic antioxidant-related genes. These results suggest that F2 may exert protective effect against LPS-induced oxidative damage by improving the antioxidant capacity. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the effect of concomitant dipeptidyl peptidase IV inhibitor (DPPIVi) use on efficacy and safety of insulin glargine 300 U/mL (Gla-300) versus glargine 100 U/mL (Gla-100) in people with type 2 diabetes on oral antihyperglycaemic drugs. Methods: A post hoc patient-level meta-analysis was performed using data from EDITION 2 (basal insulin [N = 811]) and EDITION 3 (insulin-naïve [N = 878]), multicentre, randomised, open-label, parallel-group, phase 3a trials of similar design. Endpoints analysed included HbA1c, hypoglycaemia and adverse events, investigated in subgroups of participants with and without concomitant DPPIVi use. Results: Of 1689 participants randomised, 107 (13%, Gla-300) and 133 (16%, Gla-100) received DPPIVi therapy. The least squares mean change in HbA1c (baseline to month 6) was comparable between treatment groups, irrespective of DPPIVi use (no evidence of heterogeneity of treatment effect across subgroups, p = 0.753), although group sizes were unbalanced. The cumulative mean number of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemic events, and the risk and annualised rate of such events, were consistently lower for Gla-300 than Gla-100 during the night (between 00:00 and 05:59 h) or at any time of day (24 h period), irrespective of DPPIVi use. Severe hypoglycaemia occurred in 8/838 and 10/844 participants in the Gla-300 and Gla-100 groups, respectively, and was not affected by DPPIVi use. The adverse event profile was similar between treatment groups and DPPIVi subgroups. Conclusions: Glycaemic control with Gla-300 was comparable to Gla-100, with less hypoglycaemia during the night and at any time of day (24 h), irrespective of concomitant DPPIVi use. Trial registration: ClinicalTrials.gov ; [ABSTRACT FROM AUTHOR]

2,4-Dichlorophenoxyacetic acid (2,4-D) is a chlorophenoxy herbicide used worldwide. We describe a high-performance liquid chromatography (HPLC) method with UV detection for the determination of 2,4-D in female and male rat serum. This allows to observe the change of serum 2,4-D concentration in rats with time and its pharmacokinetics characteristics with a simple, rapid, optimized and validated method. The serum samples are pretreated and introduced into the HPLC system. The analytes are separated in a XDB-C18 column with a mobile phase of acetonitrile (solvent A) and 0.02 M ammonium acetate (containing 0.1% formic acid) (solvent B) using a gradient elution at a flow rate of 1.0 mL/min. The wavelength for UV detection was set at 230 nm. Calibration curve for 2,4-D was constructed over a range of 0.1–400 mg/L. The method was successfully applied to study the pharmacokinetics of 2,4-D in rats in this study. After oral administration of 300 mg/kg and 60 mg/kg 2,4-D, the mean Cmax values were 601.9 and 218.4 mg/L, the AUC0→∞ values were 23,722 and 4,127 mg×h/L and the clearance (Cl) were 1.10 and 0.02 L/(h×kg), respectively. The developed method was found to be specific, precise, reproducible and rapid. [ABSTRACT FROM AUTHOR]

Filarial parasites can be targeted by antibiotic treatment due to their unique endosymbiotic relationship with Wolbachia bacteria. This finding has led to successful treatment strategies in both, human onchocerciasis and lymphatic filariasis. A 4–6 week treatment course using doxycycline results in long-term sterility and safe macrofilaricidal activity in humans. However, current treatment times and doxycycline contraindications in children and pregnant women preclude widespread administration of doxycycline in public health control programs; therefore, the search for shorter anti-wolbachial regimens is a focus of ongoing research. We have established an in vivo model for compound screening, using mice infected with Litomosoides sigmodontis. We could show that gold standard doxycycline treatment did not only deplete Wolbachia, it also resulted in a larval arrest. In this model, combinations of registered antibiotics were tested for their anti-wolbachial activity. Administration of rifamycins in combination with doxycycline for 7 days successfully depleted Wolbachia by > 2 log (>99% reduction) and thus resulted in a significant reduction of the treatment duration. Using a triple combination of a tetracycline (doxycycline or minocycline), a rifamycin and a fluoroquinolone (moxifloxacin) led to an even greater shortening of the treatment time. Testing all double combinations that could be derived from the triple combinations revealed that the combination of rifapentine (15mg/kg) and moxifloxacin (2 x 200mg/kg) showed the strongest reduction of treatment time in intraperitoneal and also oral administration routes. The rifapentine plus moxifloxacin combination was equivalent to the triple combination with additional doxycycline (>99% Wolbachia reduction). These investigations suggest that it is possible to shorten anti-wolbachial treatment times with combination treatments in order to achieve the target product profile (TPP) requirements for macrofilaricidal drugs of no more than 7–10 days of treatment. [ABSTRACT FROM AUTHOR]

Introduction: Hospitals have seen a rise in Medical Emergency Team (MET) reviews. We hypothesised that the commonest MET calls result in similar treatments. Our aim was to design a pre-emptive management algorithm that allowed direct institution of treatment to patients without having to wait for attendance of the MET team and to model its potential impact on MET call incidence and patient outcomes. Methods: Data was extracted for all MET calls from the hospital database. Association rule data mining techniques were used to identify the most common combinations of MET call causes, outcomes and therapies. Results: There were 13,656 MET calls during the 34-month study period in 7936 patients. The most common MET call was for hypotension [31%, (2459/7936)]. These MET calls were strongly associated with the immediate administration of intra-venous fluid (70% [1714/2459] v 13% [739/5477] p<0.001), unless the patient was located on a respiratory ward (adjusted OR 0.41 [95%CI 0.25–0.67] p<0.001), had a cardiac cause for admission (adjusted OR 0.61 [95%CI 0.50–0.75] p<0.001) or was under the care of the heart failure team (adjusted OR 0.29 [95%CI 0.19–0.42] p<0.001). Modelling the effect of a pre-emptive management algorithm for immediate fluid administration without MET activation on data from a test period of 24 months following the study period, suggested it would lead to a 68.7% (2541/3697) reduction in MET calls for hypotension and a 19.6% (2541/12938) reduction in total METs without adverse effects on patients. Conclusion: Routinely collected data and analytic techniques can be used to develop a pre-emptive management algorithm to administer intravenous fluid therapy to a specific group of hypotensive patients without the need to initiate a MET call. This could both lead to earlier treatment for the patient and less total MET calls. [ABSTRACT FROM AUTHOR]

Background: Patients with gastrointestinal disease may have comorbid iron deficiency anaemia (IDA) and an increased risk of hospitalisation and re-attendance in hospital. The purpose of this study was to determine if oral and intravenous (IV) treatment of IDA in patients with gastrointestinal disease attending hospital were associated with differential rates of subsequent re-attendance. Methods and findings: Data from the Clinical Practice Research Datalink (primary care) and Hospital Treatment Insights (secondary care) databases in England were used to conduct this retrospective cohort study. Patients with a coded gastrointestinal disease and IDA who attended hospital (inpatient or outpatient) and were dispensed oral or IV iron between 01/01/2010-31/10/2013 were included. Elective and emergency re-attendances in secondary care within 30 days of the initial attendance were determined. Demographics, medical diagnoses and treatments were extracted. Re-attendance rates following oral or IV iron were compared using chi-square tests and a step-wise logistic regression model to adjust for confounders. 2,844 patients contributed 6,294 initial attendances; 80% of patients received oral iron, 14% received intravenous iron, and 6% received both. Of initial attendances recording oral iron, 77% resulted in re-attendance in hospital, compared to 34% of those recording IV iron (unadjusted odds ratio [OR]: 0.16; adjusted OR: 0.52 [95% CI: 0.44–0.61]). Initial attendances using IV treatment were more likely to result in elective re-attendance (84%) than those recording oral treatment (43%) (p<0.001). Median length of stay in hospital tended to be shorter for patients using IV iron (1.4 days; interquartile range 0.5–3.6 days; oral iron: 5.1 days; interquartile range: 2.2–9.6 days). Conclusions: Patients with gastrointestinal disease and IDA who received IV iron were less likely to re-attend hospital, more likely to re-attend electively, and tended to have a shorter length of stay in hospital. The mode of IDA treatment could have a real-world impact on healthcare utilisation. [ABSTRACT FROM AUTHOR]

The molecular mechanisms of strain-specific probiotic effects and the impact of the oral administration of probiotic strains on the host’s gene expression are not yet well understood. The aim of this study was to investigate the strain-specific effects of probiotic strain intake on gene expression in the murine small intestine. Two distinct strains of lactic acid bacteria, Lactobacillus rhamnosus GG (GG) and Lactococcus lactis subsp. lactis C59 (C59), were orally administered to BALB/c mice, daily for 2 weeks. The total RNA was isolated from the upper (including the duodenum) and lower (the terminal ileum) small intestine, and gene expression was assessed by microarray analysis. The data revealed (1) oral administration of C59 and GG markedly down-regulated the expression of genes encoding fibrinogen subunits and plasminogen in the upper small intestine; (2) administration of more than 1 × 107 CFU/day of GG changed the gene expression of the host ileum. (3) strain- and dose-related effects on various GO biological processes; and (4) enrichment for B cell-related Gene Ontology terms among up-regulated genes in the terminal ileum of mice administered the 1 × 109 CFU/day of GG. The distinct effects of GG and C59 on gene expression in the intact small intestine provide clues to understand how the health beneficial effects of specific strains of probiotic bacteria are mediated by interactions with intestinal cells. [ABSTRACT FROM AUTHOR]

Background & aims: High cure rates are achieved in HCV genotype-1b patients treated with daclatasvir and asunaprevir, DCV/ASV. Here we analyzed early HCV kinetics in genotype-1b infected Japanese subjects treated with DCV/ASV and retrospectively projected, using mathematical modeling, whether shorter treatment durations might be effective. Methods: HCV RNA levels were measured frequently during DCV/ASV therapy in 95 consecutively treated patients at a single center in Japan. Mathematical modeling was used to predict the time to cure, i.e, <1 virus copy in the extracellular body fluid. Patients with HCV<15 IU/ml at week 1 (n = 27) were excluded from modeling analysis due to insufficient HCV RNA data points. Results: Eighty nine of the 95 included patients (94%) achieved cure, 3 (3%) relapsed due to treatment-emergent resistance, and 3 (3%) completed therapy but were lost during follow up. Model fits from 68 patients with sufficient data points indicate that after a short pharmacological delay (15.4 min [relative standard error, rse = 26%]), DCV/ASV effectiveness in blocking HCV production was 0.999 [rse~0%], HCV half-life in blood was t1/2 = 1.7 hr [rse = 21%], and HCV-infected cell loss rate was 0.391/d [rse = 5%]. Modeling predicted that 100% and 98.5% of patients who had HCV<15 IU/ml at days 14 and 28 might have been cured with 6 and 8 weeks of therapy, respectively. There was a trend (p = 0.058) between younger age and shorter time to cure. Conclusion: Modeling early HCV kinetics under DCV/ASV predicts that most patients would achieve cure with short treatment durations, suggesting that 24 weeks of DCV/ASV treatment can be significantly shortened. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells are being the focus of connective tissue technology and regenerative medicine, presenting a good choice cell source for improving old and well recognized techniques of cartilage defect repair. For instance, the autologous chondrocyte transplantation using new concepts of regenerative medicine. The present study investigated the risk of xenogenicity of human synovial membrane-derived MSCs, injected into the monkeys using intravenous and intra-articular administration. The animal models used were adult monkeys Rhesus which had been injured into the left knee to create an Osteoarthritis (OA) animal model. CD105+-MSCs were injected twice into the OA monkeys with an interval of one week between them. The animals were euthanized one month after treatment. Immunohistochemistry analysis of different organs: spleen, heart, fat, liver, gut, pancreas, lung, skeletal muscle and kidney from the animals revealed that CD105+-MSCs migrated towards the injured knee joint. MSCs naive were found statistically significant increased in the injured knee in front of healthy one. CD105+-MSCs were negatives for CD68 and the area where CD105+-MSCs were found presented SDF-1 increased levels in front of healthy knee. We concluded that a characterized MSCs subset could be a safe alternative for cell therapy in clearly localized pathologies. [ABSTRACT FROM AUTHOR]

Troxerutin, a semi-synthetic derivative of the natural bioflavanoid rutin, has been reported to possess many beneficial effects in human bodies, such as vasoprotection, immune support, anti-inflammation and anti-aging. However, the effects of troxerutin on genome-wide transcription in blood cells are still unknown. In order to find out effects of troxerutin on gene transcription, a high-throughput RNA sequencing was employed to analysis differential gene expression in blood cells consisting of leucocytes, erythrocytes and platelets isolated from the mice received subcutaneous injection of troxerutin. Transcriptome analysis demonstrated that the expression of only fifteen genes was significantly changed by the treatment with troxerutin, among which 5 genes were up-regulated and 10 genes were down-regulated. Bioinformatic analysis of the fifteen differentially expressed genes was made by utilizing the Gene Ontology (GO), and the differential expression induced by troxerutin was further evaluated by real-time quantitative PCR (Q-PCR). [ABSTRACT FROM AUTHOR]

Background: Erythropoiesis-stimulating agents (ESAs) are recommended for treating anemia in patients with chronic kidney disease and end-stage renal disease. However, misappropriate and over-use of these agents can be costly and unnecessary in some settings. Objective: The primary aim was to identify predictors of adherence to a newly approved ESA inpatient ordering policy. The secondary aims were to evaluate the impact of a 5-day delay in the initiation of ESA therapy on ESA usage, hemoglobin (Hb) levels, and costs. Methods: This retrospective observational record review included a sample of adult patients admitted to four tertiary care hospitals from November 1, 2013 to August 31, 2014. Multivariable logistic and linear regression analyses were used to calculate the odds of adherence to the new ESA inpatient ordering policy and the impact of this policy on discharge Hb level, respectively. Results: A total of 242 patients were included. The majority of the prescribers (77%) adhered to the new ESA ordering policy. Hemoglobin (OR = 1.306; 95% CI: 1.03–1.65) and ferritin (OR = 3.91; 95% CI: 1.23–12.51) levels at admission and length of hospital stay were positively correlated with the odds of patients receiving ESAs after day 5 (OR = 1.12; 95% CI:1.05–1.20). Furthermore, adherence to the new policy did not have a significant impact on discharge Hb level (β = 0.02349; P = 0.895). Conclusions: Prescribers were adherent to a 5-day delay in the initiation of ESA therapy policy which resulted in a reduction in ESA usage, did not impact the discharge Hb levels, and was proven to be cost effective. [ABSTRACT FROM AUTHOR]

Background: Sepsis-induced neuroinflammation plays an important role in sepsis-related brain dysfunction. However, the molecules that are targeted during neuroinflammation resulting from sepsis-induced brain dysfunction remain unclear. Herein, we tried to investigate the expression and roles of NMDA receptor subunits during sepsis-related brain dysfunction. Methods: Sepsis was induced by cecal ligation and perforation (CLP) or by a single intraperitoneal injection of lipopolysaccharide (LPS, 8 mg/kg) in C57BL/6J mice. The NMDA receptor co-agonist D-serine was injected intraperitoneally for 3 days (500 mg/kg/day) to compensate for the loss of NMDA receptors. The behaviors of mice were tested in the Barnes maze and in the open field test. The mice were euthanized at the indicated time points. The brains were collected to detect the following: the levels of synaptophysin and NMDA receptor subunits GluN2A, GluN2B and GluN1 (by Western blot and RT-PCR); the number of CA1 neurons (by Nissl staining); neuronal activity (by p-CREB staining); neuroinflammation (by staining of Iba-1 and inflammatory factors IL-1β, TNF-α, NLRP3); and the levels of oxidative stress [by dihydroethidium (DHE)]. Results: Sepsis selectively decreased the protein and mRNA levels of GluN2A, GluN2B and GluN1 but not the levels of synaptophysin or the neuronal number in the hippocampus of mice in either of the classic CLP-induced or LPS-induced sepsis models during the first 7 days after sepsis. Intraperitoneal injection of D-serine obviously limited the lipopolysaccharide-induced changes, including the impairment of learning and memory, the loss of NMDA receptor subunits, robust neuroinflammation, the levels of ROS stress and the decrease of p-CREB in the hippocampus of mice. Conclusion: These data suggest that the sepsis-induced selective loss of NMDA receptors modulates hippocampal neuropathology in the mice that survived sepsis, and the data show that NMDA receptors are potential targets for the improvement of brain dysfunction in sepsis survivors. [ABSTRACT FROM AUTHOR]

Objective: M10 is a ten amino acid peptide generated from the intracellular cytoplasmic tail of the hepatocyte growth factor (HGF) receptor c-Met following cleavage by caspase-3. Recently we reported that M10 interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo and can be advanced into a novel antifibrotic remedy. The current study was undertaken to develop an immunoassay to measure M10 concentration in biological specimens. Experimental design: An Indirect Enzyme-Linked Immunosorbent Assay (ELISA) for detection of M10 in biological fluids was developed using pharmaceutical grade synthetic M10 as a calibrator and commercially available anti-c-Met C12 antibody. Results: M10 ELISA specifically detected in plasma M10, but not a scrambled peptide, following a single intraperitoneal administration of M10 (1mg/kg) to mice. The detection limit was 9.6 ng/ml, and the measuring limit was between 15 ng/ml and 200 ng/ml. The recovery limits of M10 were between 80% and 120%; intra-assay coefficient of variation was between 5.3% and 6.3%; inter-assay coefficient of variation was between 5.0% and 8.0% over the buffer concentration tested in the range from 15 ng /ml to 250 ng /ml. The peak of M10 concentration following a single intraperitoneal injection (1mg/kg) was achieved within 6 hours and declined to minimal levels by 48 hours. The experimentally obtained half-life for M10 was comparable to the theoretically predicted half-life for M10. Conclusions: We have established a highly sensitive ELISA to detect the antifibrotic peptide M10 in plasma samples, which should prove to be a novel tool to study the pharmacokinetics and efficacy of M10 in the treatment of fibroproliferative disorders. [ABSTRACT FROM AUTHOR]

Background: Intravenous glucocorticoids are recommended for multiple sclerosis (MS). However, they can be inconvenient and expensive. Due to their convenience and low cost, oral glucocorticoids may be an alternative treatment. Recently, several studies have shown that there is no difference in efficacy and safety between oral methylprednisolone (oMP) and intravenous methylprednisolone (ivMP). Objectives: We sought to assess the clinical efficacy, safety and tolerability of oral methylprednisolone versus intravenous methylprednisolone for MS relapses in this meta-analysis. Methods: Randomized controlled trials (RCTs) evaluating the clinical efficacy, safety and tolerability of oral methylprednisolone versus intravenous methylprednisolone for MS relapses were searched in PubMed, Cochrane Library, Medline, EMBASE and China Biology Medicine until October 25, 2016, without language restrictions. The proportion of patients who had improved by day 28 was chosen as the efficacy outcome. We chose the risk ratio (RR) to analyze each trial with the 95% confidence interval (95% CI). We also used the fixed-effects model (Mantel–Haenszel approach) to calculate the pooled relative effect estimates. Results: A total of 5 trials were identified, which included 369 patients. The results of our meta-analysis revealed that no significant difference existed in relapse improvement at day 28 between oMP and ivMP (RR 0.96, 95% CI 0.84 to 1.10). No evidence of heterogeneity existed among the trials (P = 0.45, I2 = 0%). Both treatments were equally safe and well tolerated except that insomnia was more likely to occur in the oMP group compared to the ivMP group. Conclusion: Our meta-analysis reveals strong evidence that oMP is not inferior to ivMP in increasing the proportion of patients experiencing clinical improvement at day 28. In addition, both routes of administration are equally well tolerated and safe. These findings suggest that we may be able to replace ivMP with oMP to treat MS relapses. [ABSTRACT FROM AUTHOR]

Background: Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT.Methods and Findings: Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI -0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0-5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, -4.41 years; 95% CI -7.14 to -1.68) and haemorrhagic stroke-free (first PD, -9.51 years; 95% CI -12.77 to -6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, -1.97 years; 95% CI -3.81 to -0.13), but not with a shorter stroke-free period (fifth PD, -1.21 years; 95% CI -3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out.Conclusions: When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0-5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk. [ABSTRACT FROM AUTHOR]

Background: VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro and protects against simian-human immunodeficiency virus (SHIV) when delivered parenterally to nonhuman primates. It has been shown to be safe and well tolerated after short-term administration in humans; however, its clinical and functional activity after longer-term administration has not been previously assessed.Methods and Findings: HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01 administered either subcutaneously or by intravenous (IV) infusion and to assess the pharmacokinetics and in vitro immunologic activity of the different dosing regimens. Additionally, this study aimed to assess the effect that the human body has on the functional activities of VRC01 as measured by several in vitro assays. Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6 United States clinical research sites affiliated with the HVTN between September 9, 2014, and July 15, 2015. The median age of enrollees was 27 years (range, 18-50); 52% were White (non-Hispanic), 25% identified as Black (non-Hispanic), 11% were Hispanic, and 11% were non-Hispanic people of diverse origins. Participants were randomized to receive the following: a 40 mg/kg IV VRC01 loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment group 1 [T1], n = 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 [T3], n = 20); placebo (placebo group 3 [P3], n = 4) doses every 2 weeks; or three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 [T2], n = 20). Treatment groups T4 and T5 (n = 12 each) received three 10 or 30 mg/kg IV VRC01 doses every 8 weeks, respectively. Participants were followed for 32 weeks after their first VRC01 administration and received a total of 249 IV infusions and 208 SC injections, with no serious adverse events, dose-limiting toxicities, nor evidence for anti-VRC01 antibodies observed. Serum VRC01 levels were detected through 12 weeks after final administration in all participants who received all scheduled doses. Mean peak serum VRC01 levels of 1,177 μg/ml (95% CI: 1,033, 1,340) and 420 μg/ml (95% CI: 356, 494) were achieved 1 hour after the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively. Mean trough levels at week 24 in the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively, were 16 μg/ml (95% CI: 10, 27) and 6 μg/ml (95% CI: 5, 9) levels, which neutralize a majority of circulating strains in vitro (50% inhibitory concentration [IC50] > 5 μg/ml). Post-infusion/injection serum VRC01 retained expected functional activity (virus neutralization, antibody-dependent cellular cytotoxicity, phagocytosis, and virion capture). The limitations of this study include the relatively small sample size of each VRC01 administration regimen and missing data from participants who were unable to complete all study visits.Conclusions: VRC01 administered as either an IV infusion (10-40 mg/kg) given monthly or bimonthly, or as an SC injection (5 mg/kg) every 2 weeks, was found to be safe and well tolerated. In addition to maintaining drug concentrations consistent with neutralization of the majority of tested HIV strains, VRC01 concentrations from participants' sera were found to avidly capture HIV virions and to mediate antibody-dependent cellular phagocytosis, suggesting a range of anti-HIV immunological activities, warranting further clinical trials.Trial Registration: Clinical Trials Registration: NCT02165267. [ABSTRACT FROM AUTHOR]

Background: Continuous infusion of doxorubicin has been a strategy to reduce cardiotoxicity. Epirubicin is another anthracycline in common clinical use. However, evidence is lacking regarding whether this strategy can reduce cardiotoxicity of epirubicin without compromising antineoplastic efficacy. Design and methods: Healthy rats were randomized into groups: epirubicin (8 mg/kg) delivered intraperitoneally via micro osmotic pumps (MOP), epirubicin (8 mg/kg) by intraperitoneal (IP) bolus injection, and placebo control. Blood samples were collected for analyzing biomarkers of myocardial injury and pharmacokinetics. At chosen times, sub-groups of animals were sacrificed for histopathology. A mouse breast cancer cell line (4T1), stably transfected with luciferase, was orthotopically allografted in female mice, and treated in three groups as described above for the rats. Tumor growth was monitored by measuring tumor size as well as bioluminescence. Results: Delivery by IP bolus and by MOP achieved essentially the same area under the curve of epirubicin plasma concentration time profile. Blood biomarkers showed that the degree of myocardial injury in MOP group was lower than that of IP group. Histopathology showed that there was less eosinophilic enhancement, interstitial hemorrhage and necrotizing muscle atrophy in MOP group than IP group. In the orthotopic breast cancer allograft mouse model, the antineoplastic effect of epirubicin by MOP was not different from that by IP as measured by tumor weights or by in vivo bioluminescence. Conclusion: Slow delivery of epirubicin by MOP reduced cardiotoxicity without compromising the antineoplastic effect compared to IP bolus delivery. These in vivo data support our previous clinical data that continuous intravenous infusion of epirubicin using micro infusion pumps over 48–96 hours had less cardiotoxicity than intravenous bolus injections. However, whether multiple doses of epirubicin given by MOP result in a lower magnitude of long term cardiomyopathy remains to be further investigated. [ABSTRACT FROM AUTHOR]

Patients with stage IV non-small cell lung cancer (NSCLC) comprise a heterogeneous group, and the optimal treatment for this group of patients is complex and debatable. We aimed to assess the effect of local thoracic therapy combined with chemotherapy on cancer specific survival (CSS). To evaluate the CSS of four subgroups of patients with stage IV NSCLC according to four different treatment modalities: combined modality of Chemotherapy, Surgery, and Radiation (Chem+Sur+RT), Chemotherapy and Radiation (Chem+RT), Chemotherapy and Surgery (Chem+Sur), and Chemotherapy only (Chem Only) by analyzing the Surveillance, Epidemiology, and End Results (SEER)-registered database. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of survival outcomes and risk factors. The 3-year CSS was 33.5% in “Chem+Sur+RT” group, 9.3% in “Chem+RT” group, 42.7% in “Chem+Sur” group and 11.8% in “Chem Only” group, which had significant difference in univariate log-rank test (P<0.001) and multivariate Cox regression (P<0.001). Moreover, we observed significant survival benefits in “Chem+Sur” group in all stage of T/N categories, including stage I, stage II, stage IIIa and stage IIIb (all P<0.001). Multimodality therapy, especially combined thoracic surgery and chemotherapy is associated with dramatically improved prognosis for patients with stage IV NSCLC. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus is a progressive disease caused by the destruction of pancreatic β-cells, resulting in insulin dependency and hyperglycemia. While transplanted bone marrow-derived mesenchymal stem/stromal cells (BMMSCs) have been explored as an alternative therapeutic approach for diseases, the choice of delivery route may be a critical factor determining their sustainability. This study evaluated the effects of intrapancreatic and intravenous injection of human BMMSCs (hBMMSCs) in streptozotocin (STZ)-induced type 1 diabetic mouse model. C57/BL6 mice were intraperitoneally injected with 115 mg/kg STZ on day 0. hBMMSCs (1 × 106 cells) or vehicle were injected into the pancreas or jugular vein on day 7. Intrapancreatic, but not intravenous, hBMMSC injection significantly reduced blood glucose levels on day 28 compared with vehicle injection by the same route. This glucose-lowering effect was not induced by intrapancreatic injection of human fibroblasts as the xenograft control. Intrapancreatically injected fluorescence-labeled hBMMSCs were observed in the intra- and extra-lobular spaces of the pancreas, and intravenously injected cells were in the lung region, although the number of cells mostly decreased within 2 weeks of injection. For hBMMSCs injected twice into the pancreatic region on days 7 and 28, the injected mice had further reduced blood glucose to borderline diabetic levels on day 56. Animals injected with hBMMSCs twice exhibited increases in the plasma insulin level, number and size of islets, insulin-positive proportion of the total pancreas area, and intensity of insulin staining compared with vehicle-injected animals. We found a decrease of Iba1-positive cells in islets and an increase of CD206-positive cells in both the endocrine and exocrine pancreas. The hBMMSC injection also reduced the number of CD40-positive cells merged with glucagon immunoreactions in the islets. These results suggest that intrapancreatic injection may be a better delivery route of hBMMSCs for the treatment of type 1 diabetes mellitus. [ABSTRACT FROM AUTHOR]

TW-37 is a novel, potent and non-peptide Bcl-2 small-molecule inhibitor. Its activity in colorectal cancer (CRC) cells is studied. In both HCT-116 cells and primary human colon cancer cells, treatment with TW-37 at only nM concentration efficiently inhibited cell survival and proliferation. TW-37 also induced caspase-3/9 and apoptosis activation in CRC cells. Feedback autophagy activation was observed in TW-37-treated CRC cells. Reversely pharmacological autophagy inhibition or Beclin-1 knockdown by targeted-shRNA potentiated TW-37-induced apoptosis and killing of CRC cells. In vivo, intravenous injection of TW-37 inhibited HCT-116 tumor growth in mice. TW-37’s anti-tumor activity was further potentiated against Beclin-1-silenced HCT-116 tumors. Together, targeting Bcl-2 family protein by TW-37 efficiently inhibits CRC cell growth in vitro and in vivo. Inhibition of feedback autophagy activation could further sensitize TW-37. [ABSTRACT FROM AUTHOR]

Background: Treatment satisfaction in patients with relapsing-remitting multiple sclerosis (RRMS) may impact adherence and thus clinical outcomes. The objective of this study was to measure the satisfaction of patients with RRMS with injectable disease-modifying therapies (DMTs) and to evaluate the factors associated with treatment satisfaction. Material and methods: In this observational retrospective study conducted in the neurology departments of 35 hospitals throughout Spain, demographic data, disease characteristics, and information on treatment with injectable DMTs were collected at a single scheduled visit. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM), version 1.4. Patients also answered complementary questions about the factors that might affect treatment satisfaction. The data collected were analyzed descriptively. A regression model was used to explore the factors associated with treatment satisfaction. Results: The study included 445 patients (mean±SD age, 41±10.2 years; two-thirds women). The percentages treated with each DMT were Avonex 28.5%, Rebif 44 μg 24.5%, Copaxone 22.5%, Betaferon 13.0%, Rebif22 μg 8.3% and Extavia 3.1%. The mean±SD overall satisfaction according to the TSQM was 68.8±18.6 and the highest overall satisfaction was reported for Rebif 22 μg (72.4±20.3) and the lowest for Extavia (61.7±23.7). In the regression analysis, rehabilitation, interference with social life, pain on injection and number of MS treatments received were significantly associated with a decrease in overall TSMQ score. A small but significant negative correlation was found between EDSS scores and TSMQ scores (rho = –0.11, p = 0.02) and effectiveness (rho = –0.17, p<0.001). A perceived inconvenience of injections was reflected by the stated preference of 83% for once-daily oral treatment over other administration routes. Conclusions: Patients on stable injectable DMT therapy were reasonably satisfied with their treatment. Our results suggest that the main source of dissatisfaction with the current treatment is the inconvenience of the administration regimen. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact and cost-benefit of clinical pharmacist interventions on inappropriate use of prophylactic acid suppressant in hepatobiliary surgical patients in a Chinese tertiary hospital. Methods: A retro-prospective intervention study of patients undergoing elective operations was performed in the Department of Hepatobiliary Surgery of the Affiliated Hospital of Southwest Medical University. Patients admitted from October to December 2015 and from October to December 2016, served as the pre-intervention and the post-intervention group, respectively. Clinical pharmacist interventions in the post-intervention group included real-time monitoring medical records and recommending that surgeons prescribe prophylactic acid suppressants according to the criteria established by the hospital administration. Then, the clinical outcomes of post-intervention group were compared with the pre-intervention group which lacked pharmacist interventions. In addition, cost-benefit analysis was conducted to determine the economic effects of implementing the clinical pharmacist interventions in acid suppressant prophylaxis in perioperative period. Results: Clinical pharmacist interventions significantly decreased the rate of the use of no indications for prophylactic acid suppressant and of the cases of inappropriate drug selection, dose, route, replacement and prolonged duration of prophylaxis (P < 0.05 or P < 0.001), resulting in significant increase by 10.65% in the percentage of cases adhering to all the criteria (P < 0.001). Moreover, significant reductions were found in the average usage quantity (P<0.001), mean cost (P = 0.03) and mean duration (P < 0.001) of prophylaxis acid suppressant. The ratio of the mean cost savings for acid suppressants to the mean cost of pharmacist time was 13.61:1. Conclusion: The clinical pharmacist’s real-time interventions facilitated the rational use of prophylactic acid suppressant and resulted in favorable economic outcomes in hepatobiliary surgery. [ABSTRACT FROM AUTHOR]

To address the role of Toll-like receptor 4 (TLR4) single nucleotide polymorphisms (SNP) in lipopolysaccharide (LPS) recognition, we generated mice that differed only in the sequence of TLR4. We used a bacterial artificial chromosome (BAC) transgenic approach and TLR4/MD-2 knockout mice to specifically examine the role of human TLR4 variants in recognition of LPS. Using in vitro and in vivo assays we found that the expression level rather than the sequence of TLR4 played a larger role in recognition of LPS, especially hypoacylated LPS. [ABSTRACT FROM AUTHOR]

Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints. Despite many treatment options for gout, there is a substantial need for alternative treatments for patients unresponsive to current therapies. Tyrosine kinase inhibitors have demonstrated therapeutic benefit in experimental models of antibody-dependent arthritis and in rheumatoid arthritis in humans, but to date, the potential effects of such inhibitors on gouty arthritis has not been evaluated. Here we demonstrate that treatment with the tyrosine kinase inhibitor imatinib mesylate (imatinib) can suppress inflammation induced by injection of MSU crystals into subcutaneous air pouches or into the ankle joint of wild type mice. Moreover, imatinib treatment also largely abolished the lower levels of inflammation which developed in IL-1R1-/- or KitW-sh/W-sh mice, indicating that this drug can inhibit IL-1-independent pathways, as well as mast cell-independent pathways, contributing to pathology in this model. Imatinib treatment not only prevented ankle swelling and synovial inflammation when administered before MSU crystals but also diminished these features when administrated after the injection of MSU crystals, a therapeutic protocol more closely mimicking the clinical situation in which treatment occurs after the development of an acute gout flare. Finally, we also assessed the efficiency of local intra-articular injections of imatinib-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles in this model of acute gout. Treatment with low doses of this long-acting imatinib:PLGA formulation was able to reduce ankle swelling in a therapeutic protocol. Altogether, these results raise the possibility that tyrosine kinase inhibitors might have utility in the treatment of acute gout in humans. [ABSTRACT FROM AUTHOR]