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Sample records for awake intranasal insulin

  1. Awake Intranasal Insulin Delivery Modifies Protein Complexes and Alters Memory, Anxiety, and Olfactory Behaviors

    PubMed Central

    Marks, D.R.; Tucker, K.; Cavallin, M.A.; Mast, T.G.; Fadool, D.A.

    2009-01-01

    The role of insulin pathways in olfaction is of significant interest with the widespread pathology of Diabetes mellitus and its associated metabolic and neuronal co-morbidities. The insulin receptor kinase (IR) is expressed at high levels in the olfactory bulb (OB), where it suppresses a dominant Shaker ion channel (Kv1.3) via tyrosine phosphorylation of critical N- and C-terminal residues. We optimized a seven day intranasal insulin delivery (IND) in awake mice to ascertain the biochemical and behavioral effects of insulin to this brain region, given that nasal sprays for insulin have been marketed notwithstanding our knowledge of the role of Kv1.3 in olfaction, metabolism, and axon targeting. IND evoked robust phosphorylation of Kv1.3, as well as increased channel protein-protein interactions with IR and post-synaptic density 95. IND-treated mice had an increased short- and long-term object memory recognition, increased anxiolytic behavior, and an increased odor-discrimination using an odor habituation protocol but only moderate change in odor threshold using a two-choice paradigm. Unlike Kv1.3 gene-targeted deletion that alters metabolism, adiposity, and axonal targeting to defined olfactory glomeruli, suppression of Kv1.3 via IND had no effect on body weight nor the size and number of M72 glomeruli or the route of its sensory axon projections. There was no evidence of altered expression of sensory neurons in the epithelium. In mice made pre-diabetic via diet-induced obesity, IND was no longer effective in increasing long-term object memory recognition nor increasing anxiolytic behavior, suggesting state dependency or a degree of insulin resistance related to these behaviors. PMID:19458242

  2. New strategies to improve the intranasal absorption of insulin.

    PubMed

    Duan, Xiaopin; Mao, Shirui

    2010-06-01

    Recently, intranasal delivery of insulin as an alternative route of parenteral administration has been widely studied because it bears close resemblance to the 'pulsatile' pattern of endogenous insulin secretion during meal time. However, insulin is not well absorbed through nasal mucosa because of its large molecular size, hydrophilicity and low permeability through the membrane. This review describes the main barriers preventing nasal insulin absorption, and special attention is given to new approaches to improve the intranasal absorption of insulin, including the application of new safe absorption enhancers and the use of appropriate delivery systems. It seems that bioadhesive delivery systems or water-insoluble powders with absorption enhancers are the most promising methods for intranasal delivery of insulin. PMID:20359545

  3. Plasma and CSF oxytocin levels after intranasal and intravenous oxytocin in awake macaques.

    PubMed

    Freeman, Sara M; Samineni, Sridhar; Allen, Philip C; Stockinger, Diane; Bales, Karen L; Hwa, Granger G C; Roberts, Jeffrey A

    2016-04-01

    Oxytocin (OT) is a neuropeptide that mediates a variety of complex social behaviors in animals and humans. Intranasal OT has been used as an experimental therapeutic for human conditions characterized by deficits in social functioning, especially autism spectrum disorder and schizophrenia. However, it is currently under intense debate whether intranasal delivery of OT reaches the central nervous system. In this study, four female rhesus macaques were implanted with chronic intrathecal catheters and used to investigate the pharmacokinetic profile of OT in the central nervous system and the peripheral vasculature following intravenous (IV) and intranasal (IN) administration of OT. In a randomized, crossover design, OT was given to four awake monkeys at three different doses based on body weight (0.1 IU/kg; 1 IU/kg; 5 IU/kg). A time course of concurrent cerebrospinal fluid (CSF) and plasma samples were taken following administration. We found a dose-dependent effect of IV OT treatment on plasma OT levels, which peaked at 5 min post-dose and gradually returned to baseline by 120 min. In contrast, a change in CSF OT was only observed at the highest IV dose (5 IU/kg) at 15 min post-dose and gradually returned to baseline by 120 min. After IN administration, there was no significant change in plasma OT at any of the three doses. However, at the highest dose level, we found a significant increase in CSF OT at 15-30 min post- dose. The results of this study in light of recent, similar publications highlight the importance of methodological consistency across studies. This study also establishes a non-human primate model that can provide a stable platform for carrying out serial sampling from the central nervous system and peripheral vasculature concurrently. PMID:26826355

  4. Intranasal Insulin and Insulin-Like Growth Factor 1 as Neuroprotectants in Acute Ischemic Stroke.

    PubMed

    Lioutas, Vasileios-Arsenios; Alfaro-Martinez, Freddy; Bedoya, Francisco; Chung, Chen-Chih; Pimentel, Daniela A; Novak, Vera

    2015-08-01

    Treatment options for stroke remain limited. Neuroprotective therapies, in particular, have invariably failed to yield the expected benefit in stroke patients, despite robust theoretical and mechanistic background and promising animal data. Insulin and insulin-like growth factor 1 (IGF-1) play a pivotal role in critical brain functions, such as energy homeostasis, neuronal growth, and differentiation. They may exhibit neuroprotective properties in acute ischemic stroke based upon their vasodilatory, anti-inflammatory and antithrombotic effects, as well as improvements of functional connectivity, neuronal metabolism, neurotransmitter regulation, and remyelination. Intranasally administered insulin has demonstrated a benefit for prevention of cognitive decline in older people, and IGF-1 has shown potential benefit to improve functional outcomes in animal models of acute ischemic stroke. The intranasal route presents a feasible, tolerable, safe, and particularly effective administration route, bypassing the blood-brain barrier and maximizing distribution to the central nervous system (CNS), without the disadvantages of systemic side effects and first-pass metabolism. This review summarizes the neuroprotective potential of intranasally administered insulin and IGF-1 in stroke patients. We present the theoretical background and pathophysiologic mechanisms, animal and human studies of intranasal insulin and IGF-1, and the safety and feasibility of intranasal route for medication administration to the CNS. PMID:26040423

  5. Effects of intranasal insulin on hepatic fat accumulation and energy metabolism in humans.

    PubMed

    Gancheva, Sofiya; Koliaki, Chrysi; Bierwagen, Alessandra; Nowotny, Peter; Heni, Martin; Fritsche, Andreas; Häring, Hans-Ulrich; Szendroedi, Julia; Roden, Michael

    2015-06-01

    Studies in rodents suggest that insulin controls hepatic glucose metabolism through brain-liver crosstalk, but human studies using intranasal insulin to mimic central insulin delivery have provided conflicting results. In this randomized controlled crossover trial, we investigated the effects of intranasal insulin on hepatic insulin sensitivity (HIS) and energy metabolism in 10 patients with type 2 diabetes and 10 lean healthy participants (CON). Endogenous glucose production was monitored with [6,6-(2)H2]glucose, hepatocellular lipids (HCLs), ATP, and inorganic phosphate concentrations with (1)H/(31)P magnetic resonance spectroscopy. Intranasal insulin transiently increased serum insulin levels followed by a gradual lowering of blood glucose in CON only. Fasting HIS index was not affected by intranasal insulin in CON and patients. HCLs decreased by 35% in CON only, whereas absolute hepatic ATP concentration increased by 18% after 3 h. A subgroup of CON received intravenous insulin to mimic the changes in serum insulin and blood glucose levels observed after intranasal insulin. This resulted in a 34% increase in HCLs without altering hepatic ATP concentrations. In conclusion, intranasal insulin does not affect HIS but rapidly improves hepatic energy metabolism in healthy humans, which is independent of peripheral insulinemia. These effects are blunted in patients with type 2 diabetes. PMID:25576060

  6. Position on zinc delivery to olfactory nerves in intranasal insulin phase I-III clinical trials.

    PubMed

    Hamidovic, A

    2015-11-01

    Zinc in pancreatic insulin is essential for processing and action of the peptide, while in commercial preparations zinc promotes hexameric structure and prevents aggregate formation. In 2002, for the first time, insulin was delivered to humans intranasally with resulting cerebrospinal fluid insulin increases, but steady peripheral insulin levels. The novel method of increasing brain insulin levels without changes in the periphery resulted in an expansion of brain insulin research in clinical trials. As pre-clinical research has shown that brain insulin modulates a number functions, including food cravings and eating behavior, learning and memory functions, stress and mood regulation; realization of beneficial effects of insulin in modulating these functions in clinical populations became a possibility with the new direct-to-brain insulin delivery methodology. However, zinc, being integral to insulin structure and function, is neurotoxic, and has resulted in adverse effects to human health. In the last century, intranasal zinc was given preventively during the time of polio outbreak, and in the 21st century intranasal zinc was widely used over the counter to prevent common cold. In both cases, patients experienced partial or complete loss of smell. This paper is the first one to analyze zinc salts and concentrations of those two epidemiological adversities and directly compare formulations distributed to the public with animal toxicity data. The information gained from animal and epidemiological data provides a foundation for the formation of opinion given in this paper regarding safety of intranasal zinc in emerging clinical trials with intranasal insulin. PMID:26386292

  7. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype.

    PubMed

    Reger, M A; Watson, G S; Frey, W H; Baker, L D; Cholerton, B; Keeling, M L; Belongia, D A; Fishel, M A; Plymate, S R; Schellenberg, G D; Cherrier, M M; Craft, S

    2006-03-01

    Raising insulin acutely in the periphery and in brain improves verbal memory. Intranasal insulin administration, which raises insulin acutely in the CNS without raising plasma insulin levels, provides an opportunity to determine whether these effects are mediated by central insulin or peripheral processes. Based on prior research with intravenous insulin, we predicted that the treatment response would differ between subjects with (epsilon4+) and without (epsilon4-) the APOE-epsilon4 allele. On separate mornings, 26 memory-impaired subjects (13 with early Alzheimer's disease and 13 with amnestic mild cognitive impairment) and 35 normal controls each underwent three intranasal treatment conditions consisting of saline (placebo) or insulin (20 or 40 IU). Cognition was tested 15 min post-treatment, and blood was acquired at baseline and 45 min after treatment. Intranasal insulin treatment did not change plasma insulin or glucose levels. Insulin treatment facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults. These effects were stronger for memory-impaired epsilon4- subjects than for memory-impaired epsilon4+ subjects and normal adults. Unexpectedly, memory-impaired epsilon4+ subjects showed poorer recall following insulin administration on one test of memory. These findings suggest that intranasal insulin administration may have therapeutic benefit without the risk of peripheral hypoglycemia and provide further evidence for apolipoprotein E (APOE) related differences in insulin metabolism. PMID:15964100

  8. Postprandial Administration of Intranasal Insulin Intensifies Satiety and Reduces Intake of Palatable Snacks in Women

    PubMed Central

    Hallschmid, Manfred; Higgs, Suzanne; Thienel, Matthias; Ott, Volker; Lehnert, Hendrik

    2012-01-01

    The role of brain insulin signaling in the control of food intake in humans has not been thoroughly defined. We hypothesized that the hormone contributes to the postprandial regulation of appetite for palatable food, and assessed the effects on appetite and snack intake of postprandial versus fasted intranasal insulin administration to the brain in healthy women. Two groups of subjects were intranasally administered 160 IU insulin or vehicle after lunch. Two hours later, consumption of cookies of varying palatability was measured under the pretext of a taste test. In a control study, the effects of intranasal insulin administered to fasted female subjects were assessed. Compared with placebo, insulin administration in the postprandial but not in the fasted state decreased appetite as well as intake and rated palatability of chocolate chip cookies (the most palatable snack offered). In both experiments, intranasal insulin induced a slight decrease in plasma glucose but did not affect serum insulin concentrations. Data indicate that brain insulin acts as a relevant satiety signal during the postprandial period, in particular reducing the intake of highly palatable food, and impacts peripheral glucose homeostasis. Postprandial intranasal insulin administration might be useful in curtailing overconsumption of snacks with accentuated rewarding value. PMID:22344561

  9. Postprandial administration of intranasal insulin intensifies satiety and reduces intake of palatable snacks in women.

    PubMed

    Hallschmid, Manfred; Higgs, Suzanne; Thienel, Matthias; Ott, Volker; Lehnert, Hendrik

    2012-04-01

    The role of brain insulin signaling in the control of food intake in humans has not been thoroughly defined. We hypothesized that the hormone contributes to the postprandial regulation of appetite for palatable food, and assessed the effects on appetite and snack intake of postprandial versus fasted intranasal insulin administration to the brain in healthy women. Two groups of subjects were intranasally administered 160 IU insulin or vehicle after lunch. Two hours later, consumption of cookies of varying palatability was measured under the pretext of a taste test. In a control study, the effects of intranasal insulin administered to fasted female subjects were assessed. Compared with placebo, insulin administration in the postprandial but not in the fasted state decreased appetite as well as intake and rated palatability of chocolate chip cookies (the most palatable snack offered). In both experiments, intranasal insulin induced a slight decrease in plasma glucose but did not affect serum insulin concentrations. Data indicate that brain insulin acts as a relevant satiety signal during the postprandial period, in particular reducing the intake of highly palatable food, and impacts peripheral glucose homeostasis. Postprandial intranasal insulin administration might be useful in curtailing overconsumption of snacks with accentuated rewarding value. PMID:22344561

  10. Intranasal Insulin Improves Age-Related Cognitive Deficits and Reverses Electrophysiological Correlates of Brain Aging.

    PubMed

    Maimaiti, Shaniya; Anderson, Katie L; DeMoll, Chris; Brewer, Lawrence D; Rauh, Benjamin A; Gant, John C; Blalock, Eric M; Porter, Nada M; Thibault, Olivier

    2016-01-01

    Peripheral insulin resistance is a key component of metabolic syndrome associated with obesity, dyslipidemia, hypertension, and type 2 diabetes. While the impact of insulin resistance is well recognized in the periphery, it is also becoming apparent in the brain. Recent studies suggest that insulin resistance may be a factor in brain aging and Alzheimer's disease (AD) whereby intranasal insulin therapy, which delivers insulin to the brain, improves cognition and memory in AD patients. Here, we tested a clinically relevant delivery method to determine the impact of two forms of insulin, short-acting insulin lispro (Humalog) or long-acting insulin detemir (Levemir), on cognitive functions in aged F344 rats. We also explored insulin effects on the Ca(2+)-dependent hippocampal afterhyperpolarization (AHP), a well-characterized neurophysiological marker of aging which is increased in the aged, memory impaired animal. Low-dose intranasal insulin improved memory recall in aged animals such that their performance was similar to that seen in younger animals. Further, because ex vivo insulin also reduced the AHP, our results suggest that the AHP may be a novel cellular target of insulin in the brain, and improved cognitive performance following intranasal insulin therapy may be the result of insulin actions on the AHP. PMID:25659889

  11. Intranasal Insulin Therapy for Cognitive Impairment and Neurodegeneration: Current State of the Art

    PubMed Central

    de la Monte, Suzanne M.

    2015-01-01

    Introduction Growing evidence supports the concept that insulin resistance plays an important role in the pathogenesis of cognitive impairment and neurodegeneration, including in Alzheimer's disease (AD). The metabolic hypothesis has led to the development and utilization of insulin- and insulin agonist-based treatments. Therapeutic challenges faced include the ability to provide effective treatments that do not require repeated injections and also minimize potentially hazardous off-target effects. Areas covered This review covers the role of intra-nasal insulin therapy for cognitive impairment and neurodegeneration, particularly Alzheimer's disease. The literature reviewed focuses on data published within the past 5 years as this field is evolving rapidly. The author provides evidence that brain insulin resistance is an important and early abnormality in Alzheimer's disease, and that increasing brain supply and utilization of insulin improves cognition and memory. Emphasis was placed on discussing outcomes of clinical trials and interpreting discordant results to clarify the benefits and limitations of intranasal insulin therapy. Expert Opinion Intranasal insulin therapy can efficiently and directly target the brain to support energy metabolism, myelin maintenance, cell survival, and neuronal plasticity, which begin to fail in the early stages of neurodegeneration. Efforts must continue toward increasing the safety, efficacy, and specificity of intranasal insulin therapy. PMID:24215447

  12. Intranasal Insulin Suppresses Food Intake via Enhancement of Brain Energy Levels in Humans

    PubMed Central

    Jauch-Chara, Kamila; Friedrich, Alexia; Rezmer, Magdalena; Melchert, Uwe H.; G. Scholand-Engler, Harald; Hallschmid, Manfred; Oltmanns, Kerstin M.

    2012-01-01

    Cerebral insulin exerts anorexic effects in humans and animals. The underlying mechanisms, however, are not clear. Because insulin physiologically facilitates glucose uptake by most tissues of the body and thereby fosters intracellular energy supply, we hypothesized that intranasal insulin reduces food consumption via enhancement of the neuroenergetic level. In a double-blind, placebo–controlled, within-subject comparison, 15 healthy men (BMI 22.2 ± 0.37 kg/m2) aged 22–28 years were intranasally administered insulin (40 IU) or placebo after an overnight fast. Cerebral energy metabolism was assessed by 31P magnetic resonance spectroscopy. At 100 min after spray administration, participants consumed ad libitum from a test buffet. Our data show that intranasal insulin increases brain energy (i.e., adenosine triphosphate and phosphocreatine levels). Cerebral energy content correlates inversely with subsequent calorie intake in the control condition. Moreover, the neuroenergetic rise upon insulin administration correlates with the consecutive reduction in free-choice calorie consumption. Brain energy levels may therefore constitute a predictive value for food intake. Given that the brain synchronizes food intake behavior in dependence of its current energetic status, a future challenge in obesity treatment may be to therapeutically influence cerebral energy homeostasis. Intranasal insulin, after optimizing its application schema, seems a promising option in this regard. PMID:22586589

  13. Brain delivery of insulin boosted by intranasal coadministration with cell-penetrating peptides.

    PubMed

    Kamei, Noriyasu; Takeda-Morishita, Mariko

    2015-01-10

    Intranasal administration is considered as an alternative route to enable effective drug delivery to the central nervous system (CNS) by bypassing the blood-brain barrier. Several reports have proved that macromolecules can be transferred directly from the nasal cavity to the brain. However, strategies to enhance the delivery of macromolecules from the nasal cavity to CNS are needed because of their low delivery efficiencies via this route in general. We hypothesized that the delivery of biopharmaceuticals to the brain parenchyma can be facilitated by increasing the uptake of drugs by the nasal epithelium including supporting and neuronal cells to maximize the potentiality of the intranasal pathway. To test this hypothesis, the CNS-related model peptide insulin was intranasally coadministered with the cell-penetrating peptide (CPP) penetratin to mice. As a result, insulin coadministered with l- or d-penetratin reached the distal regions of the brain from the nasal cavity, including the cerebral cortex, cerebellum, and brain stem. In particular, d-penetratin could intranasally deliver insulin to the brain with a reduced risk of systemic insulin exposure. Thus, the results obtained in this study suggested that CPPs are potential tools for the brain delivery of peptide- and protein-based pharmaceuticals via intranasal administration. PMID:25445695

  14. Intranasal Insulin Prevents Anesthesia-Induced Spatial Learning and Memory Deficit in Mice

    PubMed Central

    Zhang, Yongli; Dai, Chun-ling; Chen, Yanxing; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2016-01-01

    Elderly individuals are at increased risk of cognitive decline after anesthesia. General anesthesia is believed to be a risk factor for Alzheimer’s disease (AD). At present, there is no treatment that can prevent anesthesia-induced postoperative cognitive dysfunction. Here, we treated mice with daily intranasal administration of insulin (1.75 U/day) for one week before anesthesia induced by intraperitoneal injection of propofol and maintained by inhalation of sevoflurane for 1 hr. We found that the insulin treatment prevented anesthesia-induced deficit in spatial learning and memory, as measured by Morris water maze task during 1–5 days after exposure to anesthesia. The insulin treatment also attenuated anesthesia-induced hyperphosphorylation of tau and promoted the expression of synaptic proteins and insulin signaling in the brain. These findings show a therapeutic potential of intranasal administration of insulin before surgery to reduce the risk of anesthesia-induced cognitive decline and AD. PMID:26879001

  15. Intranasal insulin prevents anesthesia-induced hyperphosphorylation of tau in 3xTg-AD mice

    PubMed Central

    Chen, Yanxing; Run, Xiaoqin; Liang, Zhihou; Zhao, Yang; Dai, Chun-ling; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2014-01-01

    Background: It is well documented that elderly individuals are at increased risk of cognitive decline after anesthesia. General anesthesia is believed to be a risk factor for Alzheimer’s disease (AD). Recent studies suggest that anesthesia may increase the risk for cognitive decline and AD through promoting abnormal hyperphosphorylation of tau, which is crucial to neurodegeneration seen in AD. Methods: We treated 3xTg-AD mice, a commonly used transgenic mouse model of AD, with daily intranasal administration of insulin (1.75 U/day) for one week. The insulin- and control-treated mice were then anesthetized with single intraperitoneal injection of propofol (250 mg/kg body weight). Tau phosphorylation and tau protein kinases and phosphatases in the brains of mice 30 min and 2 h after propofol injection were then investigated by using Western blots and immunohistochemistry. Results: Propofol strongly promoted hyperphosphorylation of tau at several AD-related phosphorylation sites. Intranasal administration of insulin attenuated propofol-induced hyperphosphorylation of tau, promoted brain insulin signaling, and led to up-regulation of protein phosphatase 2A, a major tau phosphatase in the brain. Intranasal insulin also resulted in down-regulation of several tau protein kinases, including cyclin-dependent protein kinase 5, calcium/calmodulin-dependent protein kinase II, and c-Jun N-terminal kinase. Conclusion: Our results demonstrate that pretreatment with intranasal insulin prevents AD-like tau hyperphosphorylation. These findings provide the first evidence supporting that intranasal insulin administration might be used for the prevention of anesthesia-induced cognitive decline and increased risk for AD and dementia. PMID:24910612

  16. Influence of hemorrhage on adrenal secretion, blood glucose and serum insulin in the awake pig.

    PubMed Central

    Carey, L C; Curtin, R; Sapira, J D

    1976-01-01

    A study was performed to quantitate the adrenal medullary and cortical response to hemorrhage in awake animals bled at different rates and to relate these responses to simultaneous changes in blood glucose and serum insulin. A series of awake pigs were bled either slowly or rapidly of 30% of their calculated blood volume. Infusions of exogenous epinephrine were performed in an additional series of unbled animals and infusions of epinephrine plus hydrocortisone were similarly performed in an additonal series. Increase in blood glucose and epinephrine secretion rate following hemorrhage were found to be significantly dependent upon the rate of initial hemorrhage. Cortisol secretion was found to rise significantly during and following hemorrhage in both rapidly and slowly bled animals. Serum insulin levels remained at baseline levels during shock, despite the presence of significant hyperglycemia. In unbled animals infused with epinephrine at rates comparable to those measured in shock, elevations in blood glucose were markedly lower, shifting to the right of the dose-response curve during hemorrhage. Simultaneous infusions of cortisol and epinephrine resulted in a dose-response curve which did not differ significantly from that following infusion of epinephrine alone. Images Fig. 2. PMID:1247317

  17. Intranasal Insulin Prevents Cognitive Decline, Cerebral Atrophy and White Matter Changes in Murine Type I Diabetic Encephalopathy

    ERIC Educational Resources Information Center

    Francis, George J.; Martinez, Jose A.; Liu, Wei Q.; Xu, Kevin; Ayer, Amit; Fine, Jared; Tuor, Ursula I.; Glazner, Gordon; Hanson, Leah R.; Frey, William H., II; Toth, Cory

    2008-01-01

    Insulin deficiency in type I diabetes may lead to cognitive impairment, cerebral atrophy and white matter abnormalities. We studied the impact of a novel delivery system using intranasal insulin (I-I) in a mouse model of type I diabetes (streptozotocin-induced) for direct targeting of pathological and cognitive deficits while avoiding potential…

  18. Pharmacokinetics and Pharmacodynamics of Intranasal Insulin Spray (Nasulin™) Administered to Healthy Male Volunteers:

    PubMed Central

    Leary, Andrew C.; Dowling, Muiris; Cussen, Kathleen; O'Brien, Jackie; Stote, Robert M.

    2008-01-01

    Background The pharmacokinetics and pharmacodynamics of a Bentley Pharmaceuticals proprietary intranasal (IN) insulin formulation (Nasulin™) were studied in healthy volunteers. Methods Thirteen fasting healthy male volunteers received five doses of medication (one dose of 4 international units [IU] subcutaneous (SC) regular insulin and four doses of 25 IU IN insulin) at least 48 h apart. Serum insulin, serum C-peptide, and plasma glucose were measured in the 4 h after dosing. Profiles were compared for IN insulin spray following administration into the dominant nostril (more open at time of dosing) and into the nondominant nostril (less open at time of dosing). Results The formulation was generally well tolerated. A rise in serum insulin levels accompanied by a decrease in plasma glucose was seen following all doses. For IN doses, peak insulin levels were generally attained in 10–20 min and remained elevated for approximately 40–50 min; the resultant effect on glucose peaked at 40 min and waned approximately 2 h postdosing. As reported in other studies, the interindividual response to insulin was variable. The comparative absorption of IN insulin relative to SC insulin was 12.0% (dominant nostril) or 15.4% (nondominant nostril) over 2 h. This increased somewhat if sneezers and volunteers with moderately blocked nostrils were removed from the analysis. Conclusions This IN formulation was generally well tolerated and relatively well absorbed. While both insulin data (maximal plasma concentration and area under the plasma concentration time curve) and glucose data (% fall) support a trend toward better absorption from the nondominant nostril, this did not reach statistical significance. Nasulin can be administered without reference to the nasal cycle. PMID:19885293

  19. Intranasal insulin protects against substantia nigra dopaminergic neuronal loss and alleviates motor deficits induced by 6-OHDA in rats.

    PubMed

    Pang, Y; Lin, S; Wright, C; Shen, J; Carter, K; Bhatt, A; Fan, L-W

    2016-03-24

    Protection of substantia nigra (SN) dopaminergic (DA) neurons by neurotrophic factors (NTFs) is one of the promising strategies in Parkinson's disease (PD) therapy. A major clinical challenge for NTF-based therapy is that NTFs need to be delivered into the brain via invasive means, which often shows limited delivery efficiency. The nose to brain pathway is a non-invasive brain drug delivery approach developed in recent years. Of particular interest is the finding that intranasal insulin improves cognitive functions in Alzheimer's patients. In vitro, insulin has been shown to protect neurons against various insults. Therefore, the current study was designed to test whether intranasal insulin could afford neuroprotection in the 6-hydroxydopamine (6-OHDA)-based rat PD model. 6-OHDA was injected into the right side of striatum to induce a progressive DA neuronal lesion in the ipsilateral SN pars compact (SNc). Recombinant human insulin was applied intranasally to rats starting from 24h post lesion, once per day, for 2 weeks. A battery of motor behavioral tests was conducted on day 8 and 15. The number of DA neurons in the SNc was estimated by stereological counting. Our results showed that 6-OHDA injection led to significant motor deficits and 53% of DA neuron loss in the ipsilateral side of injection. Treatment with insulin significantly ameliorated 6-OHDA-induced motor impairments, as shown by improved locomotor activity, tapered/ledged beam-walking performance, vibrissa-elicited forelimb-placing, initial steps, as well as methamphetamine-induced rotational behavior. Consistent with behavioral improvements, insulin treatment provided a potent protection of DA neurons in the SNc against 6-OHDA neurotoxicity, as shown by a 74.8% increase in tyrosine hydroxylase (TH)-positive neurons compared to the vehicle group. Intranasal insulin treatment did not affect body weight and blood glucose levels. In conclusion, our study showed that intranasal insulin provided strong

  20. The intra-nasal administration of insulin induces significant hypoglycaemia and classical counterregulatory hormonal responses in normal man.

    PubMed

    Paquot, N; Scheen, A J; Franchimont, P; Lefebvre, P J

    1988-01-01

    The present study aimed at investigating the metabolic and hormonal consequences of intra-nasal administration of insulin in normal man. Lyophylisated regular porcine insulin (Insuline Ordinaire Organon) diluted with a non ionic detergent (Laureth-9 0,25%) was administered intra-nasally in 8 overnight fasted healthy volunteers using a calibrated aerosol delivery device (90 microliters = 9 U of insulin/spray) up to a total insulin dose close to 1 U/kg body weight. After intra-nasal insulin administration, plasma insulin levels rose from 5 +/- 1 to 38 +/- 10 mU/l (2p less than 0.01) at min 15, blood glucose concentrations decreased from 4.4 +/- 0.2 to 3.2 +/- 0.3 mmol/l (2p less than 0.01) at min 45, plasma C-peptide levels diminished from 327 +/- 31 to 174 +/- 28 mumol/l (2p less than 0.01) at min 60 and plasma free fatty acids concentrations fell from 336 +/- 109 to 130 +/- 31 mumol/l (2p less than 0.05) at min 30. The fall in blood glucose resulted in a prompt increase in plasma glucagon levels (from 78 +/- 28 to 150 +/- 24 ng/l at min 45; 2p less than 0.05) and in later rises in plasma growth hormone and cortisol concentrations. There was a close relationship between the individual maximal decreases in blood glucose levels and the individual maximal increases in plasma insulin (r = 0.81), glucagon (r = 0.88), cortisol (r = 0.87) and growth hormone (r = 0.76) concentrations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3292305

  1. Impact of Intranasal Insulin on Insulin Antibody Affinity and Isotypes in Young Children With HLA-Conferred Susceptibility to Type 1 Diabetes

    PubMed Central

    Ryhänen, Samppa J.; Härkönen, Taina; Siljander, Heli; Näntö-Salonen, Kirsti; Simell, Tuula; Hyöty, Heikki; Ilonen, Jorma; Veijola, Riitta; Simell, Olli; Knip, Mikael

    2011-01-01

    OBJECTIVE Despite promising results from studies on mouse models, intranasal insulin failed to prevent or delay the development of type 1 diabetes in autoantibody-positive children with HLA-conferred disease susceptibility. To analyze whether the insulin dose was inadequate to elicit an immunomodulatory response, we compared the changes observed in insulin antibody (IA) affinity and isotypes after treatment with nasal insulin or placebo. RESEARCH DESIGN AND METHODS Ninety-five children (47 in the placebo group and 48 in the insulin group of the total of 224 children randomized for the trial) with HLA-conferred susceptibility to type 1 diabetes derived from the intervention arm of the Finnish Type 1 Diabetes Prediction and Prevention study were included in these analyses. Blood samples drawn before or at the beginning of the treatment and after treatment for 3 and 6 months were analyzed for IA affinity and isotype-specific IAs (IgG1–4, IgA, IgM, and IgE). RESULTS IgG3- and IgA-IA levels (P = 0.031 and 0.015, respectively) and the number of IgG3-IA–positive subjects (P = 0.022) were significantly higher at 6 months after the initiation of the treatment in the insulin group. No significant differences were observed between the two groups in IA affinity or other IA isotypes. CONCLUSIONS The insulin dose administered induced a modest change in the IA isotype profile. The lack of impact of nasal insulin on IA affinity implies that the immune response of study subjects was already mature at the beginning of the intervention. PMID:21515841

  2. Enhanced Absorption of Nasulin™, an Ultrarapid-Acting Intranasal Insulin Formulation, Using Single Nostril Administration in Normal Subjects

    PubMed Central

    Stote, Robert; Miller, Michael; Marbury, Thomas; Shi, Leon; Strange, Poul

    2011-01-01

    Background This pharmacokinetic (PK) study was designed to investigate the maximum intranasal insulin dose that could be achieved by repeated doses in a single nostril of a nasal spray of recombinant regular human insulin 1% in combination with cyclopentadecalactone (CPE-215) 2%, a compound that enhances absorption of molecules across mucous membranes (Nasulin™, CPEX Pharmaceuticals, Inc.). Method A nine-period crossover study of 8 healthy, nonsmoking subjects (ages 18–50, body mass index <33 kg/m2, weight >70 kg) were studied. In a fasted state, subjects were randomly given 25, 50, and 75 U in a single nostril on the first day and randomly given 50, 75, and 100 U doses utilizing both nostrils on two subsequent days. After a 45-minute PK assessment, subjects were given a meal. To determine the mechanism of enhanced absorption in a single nostril, a second study utilizing 24 subjects under similar conditions received 25 U, placebo (P) that included CPE-215 plus 25 U, and 50 U in a single nostril. Results Single nostril administration revealed enhanced absorption with maximum concentrations (Cmax) of 13, 65, and 96 µU/ml for the 25, 50, and 75 U doses, respectively. Dual nostril administration in two cohorts resulted in Cmax of 31/42, 65/52, and 88/79 µU/ml for the 50, 75, and 100 U, respectively. In the second cohort, Cmax was 23, 19, 56 µU/ml for the 25, P + 25, and 50 U doses, respectively. Conclusions Repeated dosing in a single nostril resulted in enhanced absorption; this was not due to the increased CPE-215 but to the increased insulin administered. PMID:21303633

  3. Intranasal Glucagon

    PubMed Central

    2014-01-01

    Prevention of diabetic complications is mainly obtained through optimal control of blood glucose levels. With hypoglycemic drugs like beta-cell stimulating drugs and especially insulin, the limit to treatment is represented by hypoglycemia, a life-threatening occurrence that is dangerous itself and can induce fear of other episodes. Glucagon, injected subcutaneously (SC) or intramuscularly (IM), is the treatment of choice for severe hypoglycemia outside of the hospital setting. However, due to practical aspects such as preparation of solutions for administration and injection by untrained persons, there are obstacles to its routine use. This review focuses on the current status of alternative routes of administration of peptide hormones, and in particular the intranasal (IN) route of glucagon, as a promising approach for the treatment of severe hypoglycemia. PMID:25385946

  4. Insulin

    MedlinePlus

    ... pump is connected to your body by a flexible tube that has a tip that sticks under your skin. A cartridge of insulin is put in the pump. The insulin flows through the tube into your body. The pump controls how much insulin goes into your body. The ...

  5. Comparison Pharmacokinetics of Two Concentrations (0.7% and 1.0%) of Nasulin™, an Ultra-Rapid-Acting Intranasal Insulin Formulation

    PubMed Central

    Stote, Robert; Marbury, Thomas; Shi, Leon; Miller, Michael; Strange, Poul

    2010-01-01

    Background This pharmacokinetic (PK) study was designed to characterize the dose response of two concentrations (0.7% and 1%) of a nasal spray of recombinant regular human insulin in combination with cyclopentadecalactone (CPE-215), a compound that enhances absorption of molecules across mucous membranes (Nasulin™, CPEX Pharmaceuticals). Nasulin has been effective in lowering blood glucose in both normal subjects and diabetes patients, and additional dosing options would allow greater titration flexibility. Method A five-period crossover study of 24 healthy, nonsmoking subjects (ages 18-50, basal metabolic index <33 kg/m2, weight >70 kg) were studied. Subjects were in a fasted state for 5 h before and 45 min after administration for PK assessment and were then given a meal. Each spray contained 100 μl. Doses tested were 25, 35, 50, 70, and 100 U. Maximum concentration (Cmax) and area under the curve (AUC) were estimated for each dose group. Glucose measurements were also performed. Results A dose response (slope of the natural log response versus dose) was demonstrated by baseline-adjusted Cmax of 22, 27, 56, 62, and 84 μU/ml for the 25, 35, 50, 70, and 100 U doses (p < .0001), respectively, and by baseline-adjusted AUC(0–45 min) values of 491, 592, 1231, 1310, and 1894 μU/ml/min (p < .0001). Glucose AUC(0–45 min) determinations also demonstrated a pharmacodynamic (PD) dose response. Conclusions Proportional and linear dose responses for both PK and PD parameters were demonstrated for the two concentrations, making multiple doses available for clinical development. PMID:20513326

  6. Insulin

    NASA Technical Reports Server (NTRS)

    2004-01-01

    The manipulation of organic materials--cells, tissues, and even living organisms--offers many exciting possibilities for the future from organic computers to improved aquaculture. Commercial researchers are using the microgravity environment to produce large near perfect protein crystals Research on insulin has yielded crystals that far surpass the quality of insulin crystals grown on the ground. Using these crystals industry partners are working to develop new and improved treatments for diabetes. Other researchers are exploring the possibility of producing antibiotics using plant cell cultures which could lead to both orbital production and the improvement of ground-based antibiotic production.

  7. Awake right hemisphere brain surgery.

    PubMed

    Hulou, M Maher; Cote, David J; Olubiyi, Olutayo I; Smith, Timothy R; Chiocca, E Antonio; Johnson, Mark D

    2015-12-01

    We report the indications and outcomes of awake right hemispheric brain surgery, as well as a rare patient with crossed aphasia. Awake craniotomies are often performed to protect eloquent cortex. We reviewed the medical records for 35 of 96 patients, in detail, who had awake right hemisphere brain operations. Intraoperative cortical mapping of motor and/or language function was performed in 29 of the 35 patients. A preoperative speech impairment and left hand dominance were the main indicators for awake right-sided craniotomies in patients with right hemisphere lesions. Four patients with lesion proximity to eloquent areas underwent awake craniotomies without cortical mapping. In addition, one patient had a broncho-pulmonary fistula, and another had a recent major cardiac procedure that precluded awake surgery. An eloquent cortex representation was identified in 14 patients (48.3%). Postoperatively, seven of 17 patients (41.1%) who presented with weakness, experienced improvements in their motor functions, 11 of 16 (68.7%) with seizures became seizure-free, and seven of nine (77.7%) with moderate to severe headaches and one of two with a visual field deficit improved significantly. There were also improvements in speech and language functions in all patients who presented with speech difficulties. A right sided awake craniotomy is an excellent option for left handed patients, or those with right sided cortical lesions that result in preoperative speech impairments. When combined with intraoperative cortical mapping, both speech and motor function can be well preserved. PMID:26279501

  8. Pitfalls of intranasal naloxone.

    PubMed

    Zuckerman, Matthew; Weisberg, Stacy N; Boyer, Edward W

    2014-01-01

    We present a case of failed prehospital treatment of fentanyl induced apnea with intranasal (IN) naloxone. While IN administration of naloxone is becoming more common in both lay and pre-hospital settings, older EMS protocols utilized intravenous (IV) administration. Longer-acting, higher potency opioids, such as fentanyl, may not be as easily reversed as heroin, and studies evaluating IN administration in this population are lacking. In order to contribute to our understanding of the strengths and limitations of IN administration of naloxone, we present a case where it failed to restore ventilation. We also describe peer reviewed literature that supports the use of IV naloxone following heroin overdose and explore possible limitations of generalizing this literature to opioids other than heroin and to IN routes of administration. PMID:24830404

  9. Evaluation of Gastrointestinal Motility in Awake Rats: A Learning Exercise for Undergraduate Biomedical Students

    ERIC Educational Resources Information Center

    Souza, M. A. N.; Souza, M. H. L. P.; Palheta, R. C., Jr.; Cruz, P. R. M.; Medeiros, B. A.; Rola, F. H.; Magalhaes, P. J. C.; Troncon, L. E. A.; Santos, A. A.

    2009-01-01

    Current medical curricula devote scarce time for practical activities on digestive physiology, despite frequent misconceptions about dyspepsia and dysmotility phenomena. Thus, we designed a hands-on activity followed by a small-group discussion on gut motility. Male awake rats were randomly submitted to insulin, control, or hypertonic protocols.…

  10. Associations of Sleep Quality and Awake Physical Activity with Fluctuations in Nocturnal Blood Pressure in Patients with Cardiovascular Risk Factors

    PubMed Central

    Kadoya, Manabu; Koyama, Hidenori; Kurajoh, Masafumi; Naka, Mariko; Miyoshi, Akio; Kanzaki, Akinori; Kakutani, Miki; Shoji, Takuhito; Moriwaki, Yuji; Yamamoto, Tetsuya; Inaba, Masaaki; Namba, Mitsuyoshi

    2016-01-01

    Background Sleep quality and awake physical activity are important behavioral factors involved in the occurrence of cardiovascular diseases, potentially through nocturnal blood pressure (BP) changes. However, the impacts of quantitatively measured sleep quality and awake physical activity on BP fluctuation, and their relationships with several candidate causal factors for nocturnal hypertension are not well elucidated. Methods This cross-sectional study included 303 patients registered in the HSCAA study. Measurements included quantitatively determined sleep quality parameters and awake physical activity obtained by actigraph, nocturnal systolic BP (SBP) fall [100 × (1- sleep SBP/awake SBP ratio)], apnea hypopnea index, urinary sodium and cortisol secretion, plasma aldosterone concentration and renin activity, insulin resistance index, parameters of heart rate variability (HRV), and plasma brain-derived neurotrophic factor (BDNF). Results Simple regression analysis showed that time awake after sleep onset (r = -0.150), a parameter of sleep quality, and awake physical activity (r = 0.164) were significantly correlated with nocturnal SBP fall. Among those, time awake after sleep onset (β = -0.179) and awake physical activity (β = 0.190) were significantly and independently associated with nocturnal SBP fall in multiple regression analysis. In a subgroup of patients without taking anti-hypertensive medications, both time awake after sleep onset (β = -0.336) and awake physical activity (β = 0.489) were more strongly and independently associated with nocturnal SBP falls. Conclusion Sleep quality and awake physical activity were found to be significantly associated with nocturnal SBP fall, and that relationship was not necessarily confounded by candidate causal factors for nocturnal hypertension. PMID:27166822

  11. Intranasal scopolamine preparation and method

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi (Inventor); Cintron, Nitza M. (Inventor)

    1991-01-01

    A new method and preparation for intranasal delivery of scopolamine provides a safe and effective treatment for motion sickness and other conditions requiring anticholinergic therapy. The preparation can be in the form of aqueous nasal drops, mist spray, gel or oinment. Intranasal delivery of scopolamine has similar bioavailability and effect of intravenous delivery and is far superior to oral dosage. Scopolamine is prepared in a buffered saline solution at the desired dosage rate for effective anticholinergic response.

  12. Intranasal Delivery of Exendin-4 Confers Neuroprotective Effect Against Cerebral Ischemia in Mice.

    PubMed

    Zhang, Huinan; Meng, Jingru; Zhou, Shimeng; Liu, Yunhan; Qu, Di; Wang, Ling; Li, Xubo; Wang, Ning; Luo, Xiaoxing; Ma, Xue

    2016-03-01

    Exendin-4 is now considered as a promising drug for the treatment of cerebral ischemia. To determine the neuroprotective effects of intranasal exendin-4, C57BL/6J mice were intranasally administered with exendin-4 daily for 7 days before middle cerebral artery occlusion (MCAO) surgery. Intranasally administered exendin-4 produced higher brain concentrations and lower plasma concentrations when compared to identical doses administered interperitoneally. Neurological deficits and volume of infarcted lesions were analyzed 24 h after ischemia. Intranasal administration of exendin-4 exhibited significant neuroprotection in C57BL/6 mice subjected to MCAO by reducing neurological deficit scores and infarct volume. The neuroprotective effects of exendin-4 were blocked by the knockdown of GLP-1R with shRNA. However, exendin-4 has no impact on glucose and insulin levels which indicated that the neuroprotective effect was mediated by the activation of GLP-1R in the brain. Exendin-4 intranasal administration restored the balance between pro- and anti-apoptotic proteins and decreased the expression of Caspase-3. The anti-apoptotic effect was mediated by the cAMP/PKA and PI3K/Akt pathway. These findings provided evidence that exendin-4 intranasal administration exerted a neuroprotective effect mediated by an anti-apoptotic mechanism in MCAO mice and protected neurons against ischemic injury through the GLP-1R pathway in the brain. Intranasal delivery of exendin-4 might be a promising strategy for the treatment of ischemic stroke. PMID:26689204

  13. Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases.

    PubMed

    Meredith, M Elizabeth; Salameh, Therese S; Banks, William A

    2015-07-01

    The blood-brain barrier (BBB) is a major impediment to the therapeutic delivery of peptides and proteins to the brain. Intranasal delivery often provides a non-invasive means to bypass the BBB. Advantages of using intranasal delivery include minimizing exposure to peripheral organs and tissues, thus reducing systemic side effects. It also allows substances that typically have rapid degradation in the blood time to exert their effect. Intranasal delivery provides the ability to target proteins and peptides to specific regions of the brain when administered with substrates like cyclodextrins. In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP. We have described their rationale for use, distribution in the brain after intranasal injection, how intranasal administration differed from other modes of delivery, and their use in clinical trials, if applicable. Intranasal delivery of drugs, peptides, and other proteins could be very useful in the future for the prevention or treatment of brain related diseases. PMID:25801717

  14. Intranasal therapies for acute seizures.

    PubMed

    Kälviäinen, Reetta

    2015-08-01

    Most seizure emergencies occur outside of the hospital, and there is a need for treatment interventions that can be administered quickly and safely by nonclinical caregivers. Intranasal benzodiazepine administration does not require intravenous access and offers rapid seizure cessation. Intranasal midazolam is faster at aborting seizure activity than rectal diazepam and quicker to administer than intravenous diazepam. Although time to seizure cessation varies from study to study, intranasal midazolam is efficacious when administered not only by emergency department personnel but also by paramedics and caregivers in out-of-hospital and home settings. Absorption of midazolam intranasal formulations appears to be relatively rapid compared to diazepam formulations. Its shorter elimination half-life may also be beneficial in that patients may more quickly return to normal function because of rapid offset of effect. On the other hand, the faster rate of elimination of midazolam may expose patients to a higher rate of seizure recurrence compared with diazepam. Two diazepam formulations and one midazolam formulation are being currently developed for intranasal use. This article is part of a Special Issue entitled "Status Epilepticus". PMID:26022649

  15. Awake operative videothoracoscopic pulmonary resections.

    PubMed

    Pompeo, Eugenio; Mineo, Tommaso C

    2008-08-01

    The authors' initial experience with awake videothoracoscopic lung resection suggests that these procedures can be easily and safely performed under sole thoracic epidural anesthesia with no mortality and negligible morbidity. One major concern was that operating on a ventilating lung would render surgical maneuvers more difficult because of the lung movements and lack of a sufficient operating space. Instead, the open pneumothorax created after trocar insertion produces a satisfactory lung collapse that does not hamper surgical maneuvers. These results contradict the accepted assumption that the main prerequisite for allowing successful thoracoscopic lung surgery is general anesthesia with one-lung ventilation. No particular training is necessary to accomplish an awake pulmonary resection for teams experienced in thoracoscopic surgery, and conversions to general anesthesia are mainly caused by the presence of extensive fibrous pleural adhesions or the development of intractable panic attacks. Overall, awake pulmonary resection is easily accepted and well tolerated by patients, as confirmed by the high anesthesia satisfaction score, which was better than in nonawake control patients. Nonetheless, thoracic epidural anesthesia has potential complications, including epidural hematoma, spinal cord injury, and phrenic nerve palsy caused by inadvertently high anesthetic level, but these never occurred in the authors' experience. Further concerns relate to patient participation in operating room conversations or risk for development of perioperative panic attacks. However, the authors have found that reassuring the patient during the procedure, explaining step-by-step what is being performed, and even showing the ongoing procedure on the operating video can greatly improve the perioperative wellness and expectations of patients, particularly if the procedure is performed for oncologic diseases. Panic attacks occurred in few patients and could be usually managed through

  16. Calcitonin intranasal--unigene: Salcatonin intranasal--unigene.

    PubMed

    2004-01-01

    An intranasal spray formulation of recombinant salmon calcitonin [salcatonin] is in development with Unigene Laboratories as therapy for postmenopausal osteoporosis. Calcitonin is an endogenous polypeptide hormone that regulates calcium and bone metabolism. It is produced by the parafollicular cells of the thyroid gland in humans and other species. Calcitonin inhibits bone loss through the suppression of osteoclast activity. Salmon calcitonin is approximately 40-50 times more potent than natural human calcitonin at inhibiting osteoclast function. It can be obtained naturally from salmon or can be synthesised with the same chemical structure. Calcitonin was originally available only as an injectable formulation, but in recent years more convenient formulations have become available. Unigene is actively seeking to license its intranasal calcitonin product in Europe and other territories outside the US. nigene licensed its intranasal calcitonin product to Upsher-Smith Laboratories in December 2002, under a $US10 million exclusive US licensing agreement. Under the terms of the agreement, Unigene received an upfront payment of $US3 million from Upsher-Smith and will be eligible to receive milestone payments and royalty payments on product sales. Unigene will be responsible for manufacturing the product at its Boonton facility in New Jersey, USA, and will sell finished calcitonin product to Upsher-Smith. Upsher-Smith will package, market and distribute the product nationwide. Unigene granted an exclusive license to Faran Laboratories in September 2003 for its intranasal calcitonin osteoporosis product in Greece. Unigene will sell the finished product to Faran, who will promote and market it throughout the country after Unigene obtains European regulatory approval and local pricing approval. Unigene will receive an upfront payment and is eligible to receive milestone payments prior to product launch. Faran will pay Unigene a fixed price for each unit of product received

  17. [Intranasal opioids for acute pain].

    PubMed

    Añez Simón, C; Rull Bartomeu, M; Rodríguez Pérez, A; Fuentes Baena, A

    2006-12-01

    Intranasal drug administration is an easy, well-tolerated, noninvasive transmucosal route that avoids first-pass metabolism in the liver. The nasal mucosa provides an extensive, highly vascularized surface of pseudostratified ciliated epithelium. It secretes mucus that is subjected to mucociliary movement that can affect the time of contact between the drug and the surface. Absorption is influenced by anatomical and physiological factors as well as by properties of the drug and the delivery system. We review the literature on intranasal administration of fentanyl, meperidine, diamorphine, and butorphanol to treat acute pain. The adverse systemic effects are similar to those described for intravenous administration, the most common being drowsiness, nausea, and vomiting. Local effects reported are a burning sensation with meperidine and a bad taste. PMID:17302079

  18. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  19. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  20. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  1. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  2. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  3. Evaluation of Language Function under Awake Craniotomy

    PubMed Central

    KANNO, Aya; MIKUNI, Nobuhiro

    2015-01-01

    Awake craniotomy is the only established way to assess patients’ language functions intraoperatively and to contribute to their preservation, if necessary. Recent guidelines have enabled the approach to be used widely, effectively, and safely. Non-invasive brain functional imaging techniques, including functional magnetic resonance imaging and diffusion tensor imaging, have been used preoperatively to identify brain functional regions corresponding to language, and their accuracy has increased year by year. In addition, the use of neuronavigation that incorporates this preoperative information has made it possible to identify the positional relationships between the lesion and functional regions involved in language, conduct functional brain mapping in the awake state with electrical stimulation, and intraoperatively assess nerve function in real time when resecting the lesion. This article outlines the history of awake craniotomy, the current state of pre- and intraoperative evaluation of language function, and the clinical usefulness of such functional evaluation. When evaluating patients’ language functions during awake craniotomy, given the various intraoperative stresses involved, it is necessary to carefully select the tasks to be undertaken, quickly perform all examinations, and promptly evaluate the results. As language functions involve both input and output, they are strongly affected by patients’ preoperative cognitive function, degree of intraoperative wakefulness and fatigue, the ability to produce verbal articulations and utterances, as well as perform synergic movement. Therefore, it is essential to appropriately assess the reproducibility of language function evaluation using awake craniotomy techniques. PMID:25925758

  4. Changes in insulin and insulin signaling in Alzheimer's disease: cause or consequence?

    PubMed

    Stanley, Molly; Macauley, Shannon L; Holtzman, David M

    2016-07-25

    Individuals with type 2 diabetes have an increased risk for developing Alzheimer's disease (AD), although the causal relationship remains poorly understood. Alterations in insulin signaling (IS) are reported in the AD brain. Moreover, oligomers/fibrils of amyloid-β (Aβ) can lead to neuronal insulin resistance and intranasal insulin is being explored as a potential therapy for AD. Conversely, elevated insulin levels (ins) are found in AD patients and high insulin has been reported to increase Aβ levels and tau phosphorylation, which could exacerbate AD pathology. Herein, we explore whether changes in ins and IS are a cause or consequence of AD. PMID:27432942

  5. Awake Craniotomy: A New Airway Approach.

    PubMed

    Sivasankar, Chitra; Schlichter, Rolf A; Baranov, Dimitry; Kofke, W Andrew

    2016-02-01

    Awake craniotomies have been performed regularly at the University of Pennsylvania since 2004. Varying approaches to airway management are described for this procedure, including intubation with an endotracheal tube and use of a laryngeal mask airway, simple facemask, or nasal cannula. In this case series, we describe the successful use (i.e., no need for endotracheal intubation related to inadequate gas exchange) of bilateral nasopharyngeal airways in 90 patients undergoing awake craniotomies. The use of nasopharyngeal airways can ease the transition between the asleep and awake phases of the craniotomy without the need to stimulate the airway. Our purpose was to describe our experience and report adverse events related to this technique. PMID:26579845

  6. Awake animal SPECT: Overview and initial results

    SciTech Connect

    Weisenberger, A G; Majewski, S; McKisson, J; Popov, V; Proffitt, J; Stolin, A; Baba, J S; Goddard, J S; Lee, S J; Smith, M F; Tsui, B; Pomper, M

    2009-02-01

    A SPECT / X-ray CT system configured at Johns Hopkins University to image the biodistribution of radiopharmaceuticals in unrestrained, un-anesthetized mice has been constructed and tested on awake mice. The system was built by Thomas Jefferson National Accelerator Facility and Oak Ridge National Laboratory. SPECT imaging is accomplished using two gamma cameras, 10 cm × 20 cm in size based on a 2 × 4 array of Hamamatsu H8500 flat panel position sensitive photomultiplier tubes. A real-time optical tracking system utilizing three infrared cameras provides time stamped pose data of an awake mouse head during a SPECT scan. The six degrees of freedom (three translational and three rotational) pose data are used for motion correction during 3-D tomographic list-mode iterative image reconstruction. SPECT reconstruction of awake, unrestrained mice with motion compensation for head movement has been accomplished.

  7. Intranasal treatment of central nervous system dysfunction in humans.

    PubMed

    Chapman, Colin D; Frey, William H; Craft, Suzanne; Danielyan, Lusine; Hallschmid, Manfred; Schiöth, Helgi B; Benedict, Christian

    2013-10-01

    One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke. PMID:23135822

  8. Intranasal IGF-1 Reduced Rat Pup Germinal Matrix Hemorrhage.

    PubMed

    Lekic, Tim; Flores, Jerry; Klebe, Damon; Doycheva, Desislava; Rolland, William B; Tang, Jiping; Zhang, John H

    2016-01-01

    Germinal matrix hemorrhage (GMH) is the most devastating neurological problem of premature infants. Current treatment strategies are ineffective and brain injury is unpreventable. Insulin-like growth factor 1 (IGF-1) is an endogenous protein shown to have multiple neuroprotective properties. We therefore hypothesized that IGF-1 would reduce brain injury after GMH. Neonatal rats (P7 age) received stereotactic collagenase into the right ganglionic eminence. The following groups were studied: (1) sham, (2) GMH + vehicle, (3) GMH + intranasal IGF-1. Three days later, the animals were evaluated using the righting-reflex (early neurobehavior), Evans blue dye leakage (blood-brain barrier (BBB) permeability), brain water content (edema), and hemoglobin assay (extent of bleeding). Three weeks later, juvenile rats were tested using a water maze (delayed neurobehavior), and then were sacrificed on day 28 for assessment of hydrocephalus (ventricular size). Intranasal IGF-1 treated animals had improved neurological function, and amelioration of BBB permeability, edema, and re-bleeding. IGF-1 may play a part in protective brain signaling following GMH, and our observed protective effect may offer new promise for treatment targeting this vulnerable patient population. PMID:26463950

  9. Intranasal glucagon: a promising approach for treatment of severe hypoglycemia.

    PubMed

    Pontiroli, Antonio E

    2015-01-01

    Prevention of diabetic complications is mainly obtained through optimal control of blood glucose levels. With hypoglycemic drugs like beta-cell stimulating drugs and especially insulin, the limit to treatment is represented by hypoglycemia, a life-threatening occurrence that is dangerous itself and can induce fear of other episodes. Glucagon, injected subcutaneously (SC) or intramuscularly (IM), is the treatment of choice for severe hypoglycemia outside of the hospital setting. However, due to practical aspects such as preparation of solutions for administration and injection by untrained persons, there are obstacles to its routine use. This review focuses on the current status of alternative routes of administration of peptide hormones, and in particular the intranasal (IN) route of glucagon, as a promising approach for the treatment of severe hypoglycemia. PMID:25385946

  10. Reading Wide Awake: Politics, Pedagogies, and Possibilities

    ERIC Educational Resources Information Center

    Shannon, Patrick

    2011-01-01

    In his new book, popular author Patrick Shannon examines reading as agency--why reading critically is essential to civic engagement and a healthy democracy. We follow the author on a journey of self discovery as he practices "wide-awake reading" with a variety of everyday texts, from radio programs to legal documents to more traditional books and…

  11. [Development of formulations of desmopressin intranasal drops].

    PubMed

    Gerbutaviciene, Rima; Klimas, Rimantas; Savickas, Arūnas; Maciulevicius, Jonas

    2002-01-01

    In recent years synthetic vasopressin analogues (particularly desmopressin) emerged as safe and effective representatives of this class of drugs for same clinical indications as natural hormone. It was imperative to create intranasal drug form using synthetic desmopressin compound. The purpose of this work was to develop formulations of intranasal desmopressin drug using synthetic active compound with optimal composition. Aquatic desmopressin intranasal solution was prepared in 0.05 mg/ml concentration using phosphate buffer (pH 4.5-5.5) and following preservatives: nipagin-nipazol 7:3--0.1% or benzalkonium chloride 0.01%. Sterility is the main condition for intranasal drops and hormones as a raw material are thermolabile so it is not possible to apply a thermic sterilisation. Polymeric membrane filters of 0.22 micron pore size were employed as sterilizing filters. In order to control the quality, to determine the stability of desmopressin intranasal drops at long-lasting storage (24 months) and to evaluate the influence of the technological factors we have developed the analytical methods of quality control. According to our quality control data, desmopressin intranasal drops are stable for two years and remain sterile during storage and administration of the drug. PMID:12474688

  12. Awake, Offline Processing during Associative Learning.

    PubMed

    Bursley, James K; Nestor, Adrian; Tarr, Michael J; Creswell, J David

    2016-01-01

    Offline processing has been shown to strengthen memory traces and enhance learning in the absence of conscious rehearsal or awareness. Here we evaluate whether a brief, two-minute offline processing period can boost associative learning and test a memory reactivation account for these offline processing effects. After encoding paired associates, subjects either completed a distractor task for two minutes or were immediately tested for memory of the pairs in a counterbalanced, within-subjects functional magnetic resonance imaging study. Results showed that brief, awake, offline processing improves memory for associate pairs. Moreover, multi-voxel pattern analysis of the neuroimaging data suggested reactivation of encoded memory representations in dorsolateral prefrontal cortex during offline processing. These results signify the first demonstration of awake, active, offline enhancement of associative memory and suggest that such enhancement is accompanied by the offline reactivation of encoded memory representations. PMID:27119345

  13. Path to AWAKE: Evolution of the concept

    NASA Astrophysics Data System (ADS)

    Caldwell, A.; Adli, E.; Amorim, L.; Apsimon, R.; Argyropoulos, T.; Assmann, R.; Bachmann, A.-M.; Batsch, F.; Bauche, J.; Berglyd Olsen, V. K.; Bernardini, M.; Bingham, R.; Biskup, B.; Bohl, T.; Bracco, C.; Burrows, P. N.; Burt, G.; Buttenschön, B.; Butterworth, A.; Cascella, M.; Chattopadhyay, S.; Chevallay, E.; Cipiccia, S.; Damerau, H.; Deacon, L.; Dirksen, P.; Doebert, S.; Dorda, U.; Elsen, E.; Farmer, J.; Fartoukh, S.; Fedosseev, V.; Feldbaumer, E.; Fiorito, R.; Fonseca, R.; Friebel, F.; Geschonke, G.; Goddard, B.; Gorn, A. A.; Grulke, O.; Gschwendtner, E.; Hansen, J.; Hessler, C.; Hillenbrand, S.; Hofle, W.; Holloway, J.; Huang, C.; Hüther, M.; Jaroszynski, D.; Jensen, L.; Jolly, S.; Joulaei, A.; Kasim, M.; Keeble, F.; Kersevan, R.; Kumar, N.; Li, Y.; Liu, S.; Lopes, N.; Lotov, K. V.; Lu, W.; Machacek, J.; Mandry, S.; Martin, I.; Martorelli, R.; Martyanov, M.; Mazzoni, S.; Meddahi, M.; Merminga, L.; Mete, O.; Minakov, V. A.; Mitchell, J.; Moody, J.; Müller, A.-S.; Najmudin, Z.; Noakes, T. C. Q.; Norreys, P.; Osterhoff, J.; Öz, E.; Pardons, A.; Pepitone, K.; Petrenko, A.; Plyushchev, G.; Pozimski, J.; Pukhov, A.; Reimann, O.; Rieger, K.; Roesler, S.; Ruhl, H.; Rusnak, T.; Salveter, F.; Savard, N.; Schmidt, J.; von der Schmitt, H.; Seryi, A.; Shaposhnikova, E.; Sheng, Z. M.; Sherwood, P.; Silva, L.; Simon, F.; Soby, L.; Sosedkin, A. P.; Spitsyn, R. I.; Tajima, T.; Tarkeshian, R.; Timko, H.; Trines, R.; Tückmantel, T.; Tuev, P. V.; Turner, M.; Velotti, F.; Verzilov, V.; Vieira, J.; Vincke, H.; Wei, Y.; Welsch, C. P.; Wing, M.; Xia, G.; Yakimenko, V.; Zhang, H.; Zimmermann, F.

    2016-09-01

    This paper describes the conceptual steps in reaching the design of the AWAKE experiment currently under construction at CERN. We start with an introduction to plasma wakefield acceleration and the motivation for using proton drivers. We then describe the self-modulation instability - a key to an early realization of the concept. This is then followed by the historical development of the experimental design, where the critical issues that arose and their solutions are described. We conclude with the design of the experiment as it is being realized at CERN and some words on the future outlook. A summary of the AWAKE design and construction status as presented in this conference is given in Gschwendtner et al. [1].

  14. Awake, Offline Processing during Associative Learning

    PubMed Central

    Nestor, Adrian; Tarr, Michael J.; Creswell, J. David

    2016-01-01

    Offline processing has been shown to strengthen memory traces and enhance learning in the absence of conscious rehearsal or awareness. Here we evaluate whether a brief, two-minute offline processing period can boost associative learning and test a memory reactivation account for these offline processing effects. After encoding paired associates, subjects either completed a distractor task for two minutes or were immediately tested for memory of the pairs in a counterbalanced, within-subjects functional magnetic resonance imaging study. Results showed that brief, awake, offline processing improves memory for associate pairs. Moreover, multi-voxel pattern analysis of the neuroimaging data suggested reactivation of encoded memory representations in dorsolateral prefrontal cortex during offline processing. These results signify the first demonstration of awake, active, offline enhancement of associative memory and suggest that such enhancement is accompanied by the offline reactivation of encoded memory representations. PMID:27119345

  15. Influenza (Flu) vaccine (Live, Intranasal): What you need to know

    MedlinePlus

    ... is taken in its entirety from the CDC Influenza Live, Intranasal Flu Vaccine Information Statement (VIS): www.cdc.gov/vaccines/ ... flulive.html . CDC review information for Live, Intranasal Influenza VIS: Vaccine Information Statement Influenza Page last reviewed: ...

  16. Population Pharmacokinetics of Intranasal Scopolamine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Chow, D. S. L.; Putcha, L.

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

  17. Human Cortical Excitability Increases with Time Awake

    PubMed Central

    Huber, Reto; Mäki, Hanna; Rosanova, Mario; Casarotto, Silvia; Canali, Paola; Casali, Adenauer G.; Tononi, Giulio

    2013-01-01

    Prolonged wakefulness is associated not only with obvious changes in the way we feel and perform but also with well-known clinical effects, such as increased susceptibility to seizures, to hallucinations, and relief of depressive symptoms. These clinical effects suggest that prolonged wakefulness may be associated with significant changes in the state of cortical circuits. While recent animal experiments have reported a progressive increase of cortical excitability with time awake, no conclusive evidence could be gathered in humans. In this study, we combine transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to monitor cortical excitability in healthy individuals as a function of time awake. We observed that the excitability of the human frontal cortex, measured as the immediate (0–20 ms) EEG reaction to TMS, progressively increases with time awake, from morning to evening and after one night of total sleep deprivation, and that it decreases after recovery sleep. By continuously monitoring vigilance, we also found that this modulation in cortical responsiveness is tonic and not attributable to transient fluctuations of the level of arousal. The present results provide noninvasive electrophysiological evidence that wakefulness is associated with a steady increase in the excitability of human cortical circuits that is rebalanced during sleep. PMID:22314045

  18. Ammonia encephalopathy and awake craniotomy for brain language mapping: cause of failed awake craniotomy.

    PubMed

    Villalba Martínez, G; Fernández-Candil, J L; Vivanco-Hidalgo, R M; Pacreu Terradas, S; León Jorba, A; Arroyo Pérez, R

    2015-05-01

    We report the case of an aborted awake craniotomy for a left frontotemporoinsular glioma due to ammonia encephalopathy on a patient taking Levetiracetam, valproic acid and clobazam. This awake mapping surgery was scheduled as a second-stage procedure following partial resection eight days earlier under general anesthesia. We planned to perform the surgery with local anesthesia and sedation with remifentanil and propofol. After removal of the bone flap all sedation was stopped and we noticed slow mentation and excessive drowsiness prompting us to stop and control the airway and proceed with general anesthesia. There were no post-operative complications but the patient continued to exhibit bradypsychia and hand tremor. His ammonia level was found to be elevated and was treated with an infusion of l-carnitine after discontinuation of the valproic acid with vast improvement. Ammonia encephalopathy should be considered in patients treated with valproic acid and mental status changes who require an awake craniotomy with patient collaboration. PMID:25475698

  19. Enhanced insulin absorption in the rabbit airways and lung by sodium dioctyl sulfosuccinate.

    PubMed

    Dahlbäck, Magnus; Eirefelt, Stefan; Bäckström, Kjell; Larsson, Per; Almér, Lars-Olof; Wollmer, Per; Jonson, Björn

    2002-01-01

    The objective of this investigation was to study regional absorption of inhaled insulin together with an enhancer (sodium di-octyl-sulfosuccinate [DOSS]) in the rabbit airways and lung. Insulin was administered with or without DOSS by aerosol inhalation, intratracheal infusion, intranasally, sublingually, and without DOSS intravenously. Blood glucose and plasma levels of insulin were measured during 100 min from the start of administration. Inhalation of insulin (3 U) with 0.25% or 1% DOSS decreased average blood glucose levels significantly more than inhalation of insulin (3 U) without DOSS. Intratracheal administration of 1.5 U of insulin with 0.25% DOSS in 0.3 mL of vehicle decreased the average blood glucose level significantly compared with intratracheal administration of 1.5 U of insulin and no DOSS in 0.3 mL of vehicle and compared with 1.5 U of insulin with 0.25% DOSS in 0.15 mL of vehicle. Intravenous insulin (1.5 U) and inhaled (1.5 U) insulin in 0.25% DOSS decreased average blood glucose levels significantly compared with intratracheal (0.15 mL), intranasal, and sublingual administration of 1.5 U of insulin with 0.25% DOSS. The bioavailability of inhaled insulin (1.5 U) with 0.25% DOSS was estimated to be 16% in comparison with 7% for intratracheally (0.15 mL), 1% intranasally, and 0.8% sublingually administered insulin (1.5 U with 0.25% DOSS), respectively. Inhaled insulin together with the absorption enhancer DOSS decreased the blood glucose level more effectively than insulin given intratracheally, intranasally, or sublingually. The effect on blood glucose reflected the difference in plasma insulin concentration for the different routes of administration. PMID:12006143

  20. Awake hippocampal sharp-wave ripples support spatial memory.

    PubMed

    Jadhav, Shantanu P; Kemere, Caleb; German, P Walter; Frank, Loren M

    2012-06-15

    The hippocampus is critical for spatial learning and memory. Hippocampal neurons in awake animals exhibit place field activity that encodes current location, as well as sharp-wave ripple (SWR) activity during which representations based on past experiences are often replayed. The relationship between these patterns of activity and the memory functions of the hippocampus is poorly understood. We interrupted awake SWRs in animals learning a spatial alternation task. We observed a specific learning and performance deficit that persisted throughout training. This deficit was associated with awake SWR activity, as SWR interruption left place field activity and post-experience SWR reactivation intact. These results provide a link between awake SWRs and hippocampal memory processes, which suggests that awake replay of memory-related information during SWRs supports learning and memory-guided decision-making. PMID:22555434

  1. Preparing to perform an awake fiberoptic intubation.

    PubMed Central

    Walsh, M. E.; Shorten, G. D.

    1998-01-01

    Fiberoptically guided tracheal intubation represents one of the most important advances in airway management to occur in the past thirty years. Perhaps its most important role is in management of the anticipated difficult airway. This is a situation in which the dangers of encountering the life-threatening "can't intubate, can't ventilate" situation can be avoided by placement of an endotracheal tube while the patient is awake. Although skill at the procedure of endoscopy is obviously necessary in this setting, these authors hold that success or failure of the technique frequently depends on the adequacy of preparation. These measures include 1) pre-operative assessment of the patient; 2) careful explanation of what lies in store; 3) "setting the stage"; 4) preparing the equipment to be used; and 5) preparing the patient (antisialogue, sedation, application of topical anesthesia to the upper airway). If these preparatory measures are carried out meticulously, the likelihood of performing a successful and comfortable awake fiberoptic tracheal intubation is greatly increased. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:10604785

  2. Visualization and Quantitative Assessment of the Brain Distribution of Insulin through Nose-to-Brain Delivery Based on the Cell-Penetrating Peptide Noncovalent Strategy.

    PubMed

    Kamei, Noriyasu; Shingaki, Tomotaka; Kanayama, Yousuke; Tanaka, Misa; Zochi, Riyo; Hasegawa, Koki; Watanabe, Yasuyoshi; Takeda-Morishita, Mariko

    2016-03-01

    Our recent work suggested that intranasal coadministration with the cell-penetrating peptide (CPP) penetratin increased the brain distribution of the peptide drug insulin. The present study aimed to distinctly certify the ability of penetratin to facilitate the nose-to-brain delivery of insulin by quantitatively evaluating the distribution characteristics in brain using radioactive (64)Cu-NODAGA-insulin. Autoradiography and analysis using a gamma counter of brain areas demonstrated that the accumulation of radioactivity was greatest in the olfactory bulb, the anterior part of the brain closest to the administration site, at 15 min after intranasal administration of (64)Cu-NODAGA-insulin with l- or d-penetratin. The brain accumulation of (64)Cu-NODAGA-insulin with penetratin was confirmed by ELISA using unlabeled insulin in which intact insulin was delivered to the brain after intranasal coadministration with l- or d-penetratin. By contrast, quantification of cerebrospinal fluid (CSF) samples showed increased insulin concentration in only the anterior portion of the CSF at 15 min after intranasal coadministration with l-penetratin. This study gives the first concrete proof that penetratin can accelerate the direct transport of insulin from the nasal cavity to the brain parenchyma. Further optimization of intranasal administration with CPP may increase the efficacy of delivery of biopharmaceuticals to the brain while reducing the risk of systemic drug exposure. PMID:26795701

  3. Intranasal Osteopontin for Rodent Germinal Matrix Hemorrhage.

    PubMed

    Malaguit, Jay; Casel, Darlene; Dixon, Brandon; Doycheva, Desislava; Tang, Jiping; Zhang, John H; Lekic, Tim

    2016-01-01

    Germinal matrix hemorrhage (GMH) is the most common and devastating neurological problem of premature infants. Current treatment is largely ineffective and GMH has been nonpreventable. Osteopontin (OPN) is an endogenous protein that has been shown to be neuroprotective, however, it has not been tested in GMH. P7 neonatal rats were subjected to stereotactic ganglionic eminence collagenase infusion. Groups were as follows: (1) sham, (2) GMH + vehicle, (3) GMH + intranasal OPN. Seventy-two hours later, the animals were evaluated using righting reflex, blood-brain barrier (BBB) permeability by Evans blue dye leakage, brain water content, and hemoglobin assay. Intranasal OPN improved outcomes after GMH by attenuation of brain swelling, BBB function, re-bleeding, and neurological outcomes. OPN may play an important role in enhancing neuroprotective brain signaling following GMH. These observed effects may offer novel possibilities for therapy in this patient population. PMID:26463952

  4. Drug development of intranasally delivered peptides.

    PubMed

    Campbell, Catherine; Morimoto, Bruce H; Nenciu, Daniela; Fox, Anthony W

    2012-04-01

    Intranasal drug delivery has attracted increasing attention as a noninvasive route of administration for therapeutic proteins and peptides. The delivery of therapeutic peptides through the nasal route provides an alternative to intravenous or subcutaneous injections. This review highlights the drug-development considerations unique to nasal therapeutics and discusses some of the factors and strategies that affect and can improve nasal absorption of peptides. The selectivity and good safety profile typical of peptide therapeutics, along with the dose limitation for intranasal administration, can provide challenges in drug development. Therefore, nasal peptide therapeutics often require special considerations in the nonclinical safety evaluations, such as determining drug exposure in the context of the maximum feasible dose in order to adequately prepare nasal products for clinical studies. PMID:22834082

  5. The Insulin-Mediated Modulation of Visually Evoked Magnetic Fields Is Reduced in Obese Subjects

    PubMed Central

    Tschritter, Otto; Rogic, Maja; Heni, Martin; Stingl, Katarina; Hallschmid, Manfred; Häring, Hans-Ulrich; Fritsche, Andreas; Preissl, Hubert; Hennige, Anita M.

    2011-01-01

    Background Insulin is an anorexigenic hormone that contributes to the termination of food intake in the postprandial state. An alteration in insulin action in the brain, named “cerebral insulin resistance”, is responsible for overeating and the development of obesity. Methodology/Principal Findings To analyze the direct effect of insulin on food-related neuronal activity we tested 10 lean and 10 obese subjects. We conducted a magnetencephalography study during a visual working memory task in both the basal state and after applying insulin or placebo spray intranasally to bypass the blood brain barrier. Food and non-food pictures were presented and subjects had to determine whether or not two consecutive pictures belonged to the same category. Intranasal insulin displayed no effect on blood glucose, insulin or C-peptide concentrations in the periphery; however, it led to an increase in the components of evoked fields related to identification and categorization of pictures (at around 170 ms post stimuli in the visual ventral stream) in lean subjects when food pictures were presented. In contrast, insulin did not modulate food-related brain activity in obese subjects. Conclusions/Significance We demonstrated that intranasal insulin increases the cerebral processing of food pictures in lean whereas this was absent in obese subjects. This study further substantiates the presence of a “cerebral insulin resistance” in obese subjects and might be relevant in the pathogenesis of obesity. PMID:21589921

  6. Intranasal Neuropeptide Administration To Target the Human Brain in Health and Disease.

    PubMed

    Spetter, Maartje S; Hallschmid, Manfred

    2015-08-01

    Central nervous system control of metabolic function relies on the input of endocrine messengers from the periphery, including the pancreatic hormone insulin and the adipokine leptin. This concept primarily derives from experiments in animals where substances can be directly applied to the brain. A feasible approach to study the impact of peptidergic messengers on brain function in humans is the intranasal (IN) route of administration, which bypasses the blood-brain barrier and delivers neuropeptides to the brain compartment, but induces considerably less, if any, peripheral uptake than other administration modes. Experimental IN insulin administration has been extensively used to delineate the role of brain insulin signaling in the control of energy homeostasis, but also cognitive function in healthy humans. Clinical pilot studies have found beneficial effects of IN insulin in patients with memory deficits, suggesting that the IN delivery of this and other peptides bears some promise for new, selectively brain-targeted pharmaceutical approaches in the treatment of metabolic and cognitive disorders. More recently, experiments relying on the IN delivery of the hypothalamic hormone oxytocin, which is primarily known for its involvement in psychosocial processes, have provided evidence that oxytocin influences metabolic control in humans. The IN administration of leptin has been successfully tested in animal models but remains to be investigated in the human setting. We briefly summarize the literature on the IN administration of insulin, leptin, and oxytocin, with a particular focus on metabolic effects, and address limitations and perspectives of IN neuropeptide administration. PMID:25880274

  7. Anaesthesia for awake craniotomy: A retrospective study of 54 cases

    PubMed Central

    Sokhal, Navdeep; Rath, Girija Prasad; Chaturvedi, Arvind; Dash, Hari Hara; Bithal, Parmod Kumar; Chandra, P Sarat

    2015-01-01

    Background and Aims: The anaesthetic challenge of awake craniotomy is to maintain adequate sedation, analgesia, respiratory and haemodynamic stability in an awake patient who should be able to co-operate during intraoperative neurological assessment. The current literature, sharing the experience on awake craniotomy, in Indian context, is minimal. Hence, we carried out a retrospective study with the aim to review and analyse the anaesthetic management and perioperative complications in patients undergoing awake craniotomy, at our centre. Methods: Medical records of 54 patients who underwent awake craniotomy for intracranial lesions over a period of 10 years were reviewed, retrospectively. Data regarding anaesthetic management, intraoperative complications and post-operative course were recorded. Results: Propofol (81.5%) and dexmedetomidine (18.5%) were the main agents used for providing conscious sedation to facilitate awake craniotomy. Hypertension (16.7%) was the most commonly encountered complication during intraoperative period, followed by seizures (9.3%), desaturation (7.4%), tight brain (7.4%), and shivering (5.6%). The procedure had to be converted to general anaesthesia in one of patients owing to refractory brain bulge. The incidence of respiratory and haemodynamic complications were comparable in the both groups (P > 0.05). There was less incidence of intraoperative seizures in patients who received propofol (P = 0.03). In post-operative period, 20% of patients developed new motor deficit. Mean intensive care unit stay was 2.8 ± 1.9 day (1–14 days) and mean hospital stay was 7.0 ± 5.0 day (3–30 days). Conclusions: ‘Conscious sedation’ was the technique of choice for awake craniotomy, at our institute. Fentanyl, propofol, and dexmedetomidine were the main agents used for this purpose. Patients receiving propofol had less incidence of intraoperative seizure. Appropriate selection of patients, understanding the procedure of surgery, and judicious

  8. Awake craniotomy: A qualitative review and future challenges

    PubMed Central

    Ghazanwy, Mahmood; Chakrabarti, Rajkalyan; Tewari, Anurag; Sinha, Ashish

    2014-01-01

    Neurosurgery in awake patients incorporates newer technologies that require the anesthesiologists to update their skills and evolve their methodologies. They need effective communication skills and knowledge of selecting the right anesthetic drugs to ensure adequate analgesia, akinesia, along with patient satisfaction with the anesthetic conduct throughout the procedure. The challenge of providing adequate anesthetic care to an awake patient for intracranial surgery requires more than routine vigilance about anesthetic management. PMID:25422613

  9. Molecular Imaging of Conscious, Unrestrained Mice with AwakeSPECT

    PubMed Central

    Baba, Justin S.; Endres, Christopher J.; Foss, Catherine A.; Nimmagadda, Sridhar; Jung, Hyeyun; Goddard, James S.; Lee, Seungjoon; McKisson, John; Smith, Mark F.; Stolin, Alexander V.; Weisenberger, Andrew G.; Pomper, Martin G.

    2014-01-01

    We have developed a SPECT imaging system, AwakeSPECT, to enable molecular brain imaging of untrained mice that are conscious, unanesthetized, and unrestrained. We accomplished this with head tracking and motion correction techniques. Methods: The capability of the system for motion-corrected imaging was demonstrated with a 99mTc-pertechnetate phantom, 99mTcmethylene diphosphonate bone imaging, and measurement of the binding potential of the dopamine transporter radioligand 123I-ioflupane in mouse brain in the awake and anesthetized (isoflurane) states. Stress induced by imaging in the awake state was assessed through measurement of plasma corticosterone levels. Results: AwakeSPECT provided high-resolution bone images reminiscent of those obtained from CT. The binding potential of 123I-ioflupane in the awake state was on the order of 50% of that obtained with the animal under anesthesia, consistent with previous studies in nonhuman primates. Levels of stress induced were on the order of those seen in other behavioral tasks and imaging studies of awake animals. Conclusion: These results demonstrate the feasibility of SPECT molecular brain imaging of mice in the conscious, unrestrained state and demonstrate the effects of isoflurane anesthesia on radiotracer uptake. PMID:23536223

  10. Molecular Imaging of Conscious, Unrestrained Mice with AwakeSPECT

    SciTech Connect

    Baba, Justin S.; Endres, Christopher J.; Foss, Catherine A.; Nimmagadda, Sridhar; Jung, Hyeyun; Goddard, James S.; Lee, Seung Joon; McKisson, John; Smith, Mark F.; Stolin, Alexander V.; Weisenberger, Andrew G.; Pomper, Martin G.

    2013-06-01

    We have developed a SPECT imaging system, AwakeSPECT, to enable molecular brain imaging of untrained mice that are conscious, unanesthetized, and unrestrained. We accomplished this with head tracking and motion correction techniques. Methods: The capability of the system for motion-corrected imaging was demonstrated with a ^99mTc-pertechnetate phantom, ^99mTc-methylene diphosphonate bone imaging, and measurement of the binding potential of the dopamine transporter radioligand ^123I-ioflupane in mouse brain in the awake and anesthetized (isoflurane) states. Stress induced by imaging in the awake state was assessed through measurement of plasma corticosterone levels. Results: AwakeSPECT provided high-resolution bone images reminiscent of those obtained from CT. The binding potential of ^123I-ioflupane in the awake state was on the order of 50% of that obtained with the animal under anesthesia, consistent with previous studies in nonhuman primates. Levels of stress induced were on the order of those seen in other behavioral tasks and imaging studies of awake animals. Conclusion: These results demonstrate the feasibility of SPECT molecular brain imaging of mice in the conscious, unrestrained state and demonstrate the effects of isoflurane anesthesia on radiotracer uptake.

  11. Molecular Imaging of Conscious, Unrestrained Mice with AwakeSPECT

    SciTech Connect

    Baba, Justin S; Endres, Christopher; Foss, Catherine; Nimmagadda, Sridhar; Jung, Hyeyun; Goddard Jr, James Samuel; Lee, Seung Joon; McKisson, John; Smith, Mark F.; Stolin, Alexander; Weisenberger, Andrew G.; Pomper, Martin

    2013-01-01

    We have developed a SPECT imaging system, AwakeSPECT, to enable molecular brain imaging of untrained mice that are conscious, unanesthetized, and unrestrained. We accomplished this with head tracking and motion correction techniques. Methods: The capability of the system for motion-corrected imaging was demonstrated with a 99mTc-pertechnetate phantom, 99mTcmethylene diphosphonate bone imaging, and measurement of the binding potential of the dopamine transporter radioligand 123I-ioflupane in mouse brain in the awake and anesthetized (isoflurane) states. Stress induced by imaging in the awake state was assessed through measurement of plasma corticosterone levels. Results: AwakeSPECT provided high-resolution bone images reminiscent of those obtained from CT. The binding potential of 123I-ioflupane in the awake state was on the order of 50% of that obtained with the animal under anesthesia, consistent with previous studies in nonhuman primates. Levels of stress induced were on the order of those seen in other behavioral tasks and imaging studies of awake animals. Conclusion: These results demonstrate the feasibility of SPECT molecular brain imaging of mice in the conscious, unrestrained state and demonstrate the effects of isoflurane anesthesia on radiotracer uptake.

  12. Sedation in pediatric imaging using intranasal midazolam.

    PubMed

    Harcke, H T; Grissom, L E; Meister, M A

    1995-01-01

    Intranasal midazolam offers an attractive alternative for use as a sedative agent for medical imaging studies in children. Its convenient administration and rapid onset are significant advantages over intravenous and oral agents. Because of its short duration, it is effective only for short procedures and as an adjunct to other sedative agents. When younger children present with such requirements, a dose of 0.2 mg/kg has been safe and effective in our experience. We advocate its use with adherence to guidelines for sedation published by the American Academy of Pediatrics. PMID:7567258

  13. [Development of intranasal lactocin (oxytocin) drops technology].

    PubMed

    Klimas, Rimantas; Baranauskas, Algirdas; Gendrolis, Antanas

    2002-01-01

    Pure oxytocin substance was obtained from posterior part of cattle pituitary gland by high pressure liquid chromatography. Biological activity of the substance--450-500 IU/mg. Chromatographically pure Oxytocin substance was used in developing two different compositions of Lactocin intranasal drops (40 IU/ml). Stability evaluation was performed for 2 year period. The technical documentation was prepared on the basis of the research results. Lactocin is active preparation helping lactation and is indicated for lactostasis treatment and its prophylaxis after delivery. PMID:12474675

  14. Central Nervous Insulin Signaling in Sleep-Associated Memory Formation and Neuroendocrine Regulation

    PubMed Central

    Feld, Gordon B; Wilhem, Ines; Benedict, Christian; Rüdel, Benjamin; Klameth, Corinna; Born, Jan; Hallschmid, Manfred

    2016-01-01

    The neurochemical underpinnings of sleep's contribution to the establishment and maintenance of memory traces are largely unexplored. Considering that intranasal insulin administration to the CNS improves memory functions in healthy and memory-impaired humans, we tested whether brain insulin signaling and sleep interact to enhance memory consolidation in healthy participants. We investigated the effect of intranasal insulin on sleep-associated neurophysiological and neuroendocrine parameters and memory consolidation in 16 men and 16 women (aged 18–30 years), who learned a declarative word-pair task and a procedural finger sequence tapping task in the evening before intranasal insulin (160 IU) or placebo administration and 8 h of nocturnal sleep. On the subsequent evening, they learned interfering word-pairs and a new finger sequence before retrieving the original memories. Insulin increased growth hormone concentrations in the first night-half and EEG delta power during the second 90 min of non-rapid-eye-movement sleep. Insulin treatment impaired the acquisition of new contents in both the declarative and procedural memory systems on the next day, whereas retrieval of original memories was unchanged. Results indicate that sleep-associated memory consolidation is not a primary mediator of insulin's acute memory-improving effect, but that the peptide acts on mechanisms that diminish the subsequent encoding of novel information. Thus, by inhibiting processes of active forgetting during sleep, central nervous insulin might reduce the interfering influence of encoding new information. PMID:26448203

  15. Central Nervous Insulin Signaling in Sleep-Associated Memory Formation and Neuroendocrine Regulation.

    PubMed

    Feld, Gordon B; Wilhem, Ines; Benedict, Christian; Rüdel, Benjamin; Klameth, Corinna; Born, Jan; Hallschmid, Manfred

    2016-05-01

    The neurochemical underpinnings of sleep's contribution to the establishment and maintenance of memory traces are largely unexplored. Considering that intranasal insulin administration to the CNS improves memory functions in healthy and memory-impaired humans, we tested whether brain insulin signaling and sleep interact to enhance memory consolidation in healthy participants. We investigated the effect of intranasal insulin on sleep-associated neurophysiological and neuroendocrine parameters and memory consolidation in 16 men and 16 women (aged 18-30 years), who learned a declarative word-pair task and a procedural finger sequence tapping task in the evening before intranasal insulin (160 IU) or placebo administration and 8 h of nocturnal sleep. On the subsequent evening, they learned interfering word-pairs and a new finger sequence before retrieving the original memories. Insulin increased growth hormone concentrations in the first night-half and EEG delta power during the second 90 min of non-rapid-eye-movement sleep. Insulin treatment impaired the acquisition of new contents in both the declarative and procedural memory systems on the next day, whereas retrieval of original memories was unchanged. Results indicate that sleep-associated memory consolidation is not a primary mediator of insulin's acute memory-improving effect, but that the peptide acts on mechanisms that diminish the subsequent encoding of novel information. Thus, by inhibiting processes of active forgetting during sleep, central nervous insulin might reduce the interfering influence of encoding new information. PMID:26448203

  16. Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression.

    PubMed

    Andrade, Chittaranjan

    2015-05-01

    Intranasal drug delivery (INDD) systems offer a route to the brain that bypasses problems related to gastrointestinal absorption, first-pass metabolism, and the blood-brain barrier; onset of therapeutic action is rapid, and the inconvenience and discomfort of parenteral administration are avoided. INDD has found several applications in neuropsychiatry, such as to treat migraine, acute and chronic pain, Parkinson disease, disorders of cognition, autism, schizophrenia, social phobia, and depression. INDD has also been used to test experimental drugs, such as peptides, for neuropsychiatric indications; these drugs cannot easily be administered by other routes. This article examines the advantages and applications of INDD in neuropsychiatry; provides examples of test, experimental, and approved INDD treatments; and focuses especially on the potential of intranasal ketamine for the acute and maintenance therapy of refractory depression. PMID:26035196

  17. Patient experiences during awake mechanical ventilation

    PubMed Central

    Prime, Danille; Arkless, Paul; Fine, Jonathan; Winter, Stephen; Wakefield, Dorothy B.; Scatena, Robyn

    2016-01-01

    Background Sedation practices in an ICU have shifted significantly in the past 20 years toward the use of minimizing sedation in mechanically ventilated patients. While minimizing sedation is clearly in the best interest of patients, data are lacking about how this approach affects patients’ experiences. Methods We interviewed mechanically ventilated patients receiving minimal sedation, over a 6-month period in an ICU, in order to explore their emotional, comfort, and communication experiences. Their responses were compared with the responses of their available family members regarding their attitudes and perceptions of the patients’ experiences. Results Seventy-five percent of the patients agreed or strongly agreed that they experienced pain, and 50% agreed or strongly agreed that they were comfortable. Half of the patients agreed or strongly agreed that they preferred to be kept awake. Five patients (31%) indicated that they were frustrated while 17 relatives (89%) agreed or strongly agreed that the patients were frustrated. When controlling for age and gender of respondents, family members perceived higher levels of patient pain (least square [LS] mean [95% CI]: 4.2 [3.7, 4.7] vs. 3.1 [2.5, 3.8]; p=0.022), frustration (LS mean [95% CI]: 4.2 [3.7, 4.6] vs. 3.2 [2.6, 3.9]; p=0.031), and adequate communication with nurses and doctors (LS mean [95% CI]: 3.9 [3.5, 4.4] vs. 3.1 [2.4, 3.7]; p=0.046) than the patients themselves. Conclusion Patients tolerated minimal sedation without significant frustration while mechanically ventilated despite experiencing discomfort. Patient and family member perceptions of the patient experience may differ, especially in regards to pain and frustration. The use of a communication tool can facilitate understanding of patient experiences and preferences. PMID:26908386

  18. Intranasal medications for the treatment of migraine and cluster headache.

    PubMed

    Rapoport, Alan M; Bigal, Marcelo E; Tepper, Stewart J; Sheftell, Fred D

    2004-01-01

    Intranasal medications for the treatment of headache have recently received increased attention. This paper reviews intranasal formulations of a variety of available medications (dihydroergotamine mesylate [dihydroergotamine mesilate], sumatriptan, zolmitriptan, butorphanol, capsaicin and lidocaine [lignocaine]) and one experimental medication (civamide, a cis-isomer of capsaicin) for the treatment of migraine and cluster headache. Although the efficacy of intranasal agents varies with the product used, intranasal delivery may be both convenient and more effective than other modes of drug delivery for a variety of reasons: (i) intranasal administration bypasses small bowel gastrointestinal tract absorption, which is often significantly delayed during the acute phase of a migraine attack; (ii) nauseated patients may prefer non-oral formulations as they decrease the chance of vomiting and are more rapidly effective; (iii) intranasal administration causes no pain or injection site reaction and is easier and more convenient to administer than injection or suppository and so may be used earlier in a migraine attack, resulting in better efficacy; (iv) intranasal medication produces the same number or fewer adverse events than injections; and (v) intranasal formulations offer a more rapid onset of action than oral medications, for some of the above reasons and, as such, may be more useful in patients with cluster headache, although this needs to be verified. However, it is important to emphasise that a preference study showed that most patients prefer oral tablets to an intranasal formulation. Also, some nasal preparations have significant adverse effects or are not well absorbed and therefore do not work consistently; others are more challenging to administer as a result of their delivery apparatus. Nevertheless, it is our opinion that nasal preparations increase therapeutic options and may result in faster response times and better efficacy than oral formulations and

  19. Implantable electrode for recording nerve signals in awake animals

    NASA Technical Reports Server (NTRS)

    Ninomiya, I.; Yonezawa, Y.; Wilson, M. F.

    1976-01-01

    An implantable electrode assembly consisting of collagen and metallic electrodes was constructed to measure simultaneously neural signals from the intact nerve and bioelectrical noises in awake animals. Mechanical artifacts, due to bodily movement, were negligibly small. The impedance of the collagen electrodes, measured in awake cats 6-7 days after implantation surgery, ranged from 39.8-11.5 k ohms at a frequency range of 20-5 kHz. Aortic nerve activity and renal nerve activity, measured in awake conditions using the collagen electrode, showed grouped activity synchronous with the cardiac cycle. Results indicate that most of the renal nerve activity was from postganglionic sympathetic fibers and was inhibited by the baroceptor reflex in the same cardiac cycle.

  20. Dual-headed SPECT for awake animal brain imaging

    SciTech Connect

    Lee, Seung Joon; Weisenberger, A G; McKisson, J; Goddard Jr, James Samuel; Baba, Justin S; Smith, M F

    2011-01-01

    Abstract- Motion-corrected awake animal imaging is needed for normal-state investigations of models of neurological disease and brain activity. The awake animal brain SPECT/CT system, AwakeSPECT at Johns Hopkins University has in the past used a single gamma camera for imaging. Enhancements have been made by adding a pinhole collimator to the second gamma camera at the opposite side which has been previously equipped parallel hole collimator. Geometry calibration was performed using a custom built quality control phantom containing three Co-57 point sources and applied to the tomographic reconstruction code. Hot-rod phantom scans with Tc-99m were performed to test sensitivity and resolution improvements. The reconstruction results show significant resolution and sensitivity improvements.

  1. Dual-headed SPECT for awake animal brain imaging

    SciTech Connect

    S. Lee, B. Kross, D. Weisenberger, J. McKisson, J.S. Goddard, J.S. Baba, M.S. Smith

    2012-02-01

    Motion-corrected awake animal imaging is needed for normal-state investigations of models of neurological disease and brain activity. The awake animal brain SPECT/CT system, AwakeSPECT at Johns Hopkins University has in the past used a single gamma camera for imaging. Enhancements have been made by adding a pinhole collimator to the second gamma camera at the opposite side which has been previously equipped parallel hole collimator. Geometry calibration was performed using a custom built quality control phantom containing three Co-57 point sources and applied to the tomographic reconstruction code. Hot-rod phantom scans with Tc-99m were performed to test sensitivity and resolution improvements. The reconstruction results show significant resolution and sensitivity improvements.

  2. Intranasal vaccination with proinsulin DNA induces regulatory CD4+ T cells that prevent experimental autoimmune diabetes.

    PubMed

    Every, Alison L; Kramer, David R; Mannering, Stuart I; Lew, Andrew M; Harrison, Leonard C

    2006-04-15

    Insulin, an autoantigen in type 1 diabetes, when administered mucosally to diabetes-prone NOD mice induces regulatory T cells (T(reg)) that protect against diabetes. Compared with protein, Ag encoded as DNA has potential advantages as a therapeutic agent. We found that intranasal vaccination of NOD mice with plasmid DNA encoding mouse proinsulin II-induced CD4+ T(reg) that suppressed diabetes development, both after adoptive cotransfer with "diabetogenic" spleen cells and after transfer into NOD mice given cyclophosphamide to accelerate diabetes onset. In contrast to prototypic CD4+ CD25+ T(reg), CD4+ T(reg) induced by proinsulin DNA were both CD25+ and CD25- and not defined by markers such as glucocorticoid-induced TNFR-related protein (GITR), CD103, or Foxp3. Intriguingly, despite induction of T(reg) and reduced islet inflammation, diabetes incidence in proinsulin DNA-treated mice was unchanged. However, diabetes was prevented when DNA vaccination was performed under the cover of CD40 ligand blockade, known to prevent priming of CTL by mucosal Ag. Thus, intranasal vaccination with proinsulin DNA has therapeutic potential to prevent diabetes, as demonstrated by induction of protective T(reg), but further modifications are required to improve its efficacy, which could be compromised by concomitant induction of pathogenic immunity. PMID:16585551

  3. Decrease in glucose-stimulated insulin secretion with aging is independent of insulin action.

    PubMed

    Muzumdar, Radhika; Ma, Xiaohui; Atzmon, Gil; Vuguin, Patricia; Yang, Xiaoman; Barzilai, Nir

    2004-02-01

    While the incidence of diabetes increases with age, a decrease in beta-cell function independent of age-related insulin resistance has not been conclusively determined. We studied insulin secretion (by hyperglycemic clamp) in 3-, 9-, and 20-month-old chronically catheterized, awake, Sprague Dawley (SD) rats (n = 78). Insulin action was modulated in a group of old rats by caloric restriction (CR) or by surgical removal of visceral fat (VF-). During the first 2 h of the clamp (11 mmol/l glucose), insulin secretion and insulin resistance (S(i hyper clamp)) demonstrated the characteristic hyperbolic relationship. However, after hyperglycemia for an additional 2 h, the ability to maintain insulin secretion, commensurate with the degree of insulin resistance, was decreased in all aging rats (P < 0.05). Increasing plasma glucose levels to 18 mmol/l glucose, after clamp at 11 mmol/l, increased insulin secretion by approximately threefold in young rats, but failed to induce similar magnitude of response in the aging rats ( approximately 50%). However, elevation of plasma free fatty acid (FFA) levels by twofold (by intralipid infusion during 11 mmol/l glucose clamp) resulted in a robust, approximate twofold response in both young and old rats. Thus, prolonged stimulation by hyperglycemia unveiled a functional defect in insulin secretion with aging. This age-related defect is independent of insulin action and is specific to glucose and not FFAs. We suggest that prolonged hyperglycemic stimulation can be a tool to identify functional defects in insulin secretion, particularly in the context of the hyperbolic relationship with insulin action, in elderly subjects or those at risk for type 2 diabetes. PMID:14747296

  4. [Awake intubation using Pentax Airway Scope as an alternative to awake fiberoptic intubation in management of anticipated difficult tracheal intubation in major burn patients].

    PubMed

    Fayolle-Pivot, L; Magnin, C; Tissot, S; Bertin-Maghit, M; Allaouchiche, B

    2013-05-01

    Intubating patients with facial burn is difficult to most anesthesiologists. Awake flexible fiberoptic intubation is the gold standard for management of anticipated difficult tracheal intubation. However, serious facial burn and dysmorphic syndrome can make fiberoptic intubation more difficult or impossible. We report the use of awake oral intubation using the Pentax-Airway Scope (AWS) in two major burn patients with facial injury, in whom awake fiberoptic intubation was impossible. As shown in morbidly obese patient and in patients with unstable necks, AWS could be useful to facilitate tracheal intubation in awake, facial burn patients presenting with a potentially difficult airway. Awake AWS intubation seems as a potential alternative to awake fiberoptic intubation. PMID:23453928

  5. Non-Clinical Safety Evaluation of Intranasal Iota-Carrageenan

    PubMed Central

    Hebar, Alexandra; Koller, Christiane; Seifert, Jan-Marcus; Chabicovsky, Monika; Bodenteich, Angelika; Bernkop-Schnürch, Andreas; Grassauer, Andreas; Prieschl-Grassauer, Eva

    2015-01-01

    Carrageenan has been widely used as food additive for decades and therefore, an extended oral data set is available in the public domain. Less data are available for other routes of administration, especially intranasal administration. The current publication describes the non-clinical safety and toxicity of native (non-degraded) iota-carrageenan when applied intranasally or via inhalation. Intranasally applied iota-carrageenan is a topically applied, locally acting compound with no need of systemic bioavailability for the drug’s action. Animal experiments included repeated dose local tolerance and toxicity studies with intranasally applied 0.12% iota-carrageenan for 7 or 28 days in New Zealand White rabbits and nebulized 0.12% iota-carrageenan administered to F344 rats for 7 days. Permeation studies revealed no penetration of iota-carrageenan across nasal mucosa, demonstrating that iota-carrageenan does not reach the blood stream. Consistent with this, no relevant toxic or secondary pharmacological effects due to systemic exposure were observed in the rabbit or rat repeated dose toxicity studies. Data do not provide any evidence for local intolerance or toxicity, when carrageenan is applied intranasally or by inhalation. No signs for immunogenicity or immunotoxicity have been observed in the in vivo studies. This is substantiated by in vitro assays showing no stimulation of a panel of pro-inflammatory cytokines by iota-carrageenan. In conclusion, 0.12% iota-carrageenan is safe for clinical use via intranasal application. PMID:25875737

  6. Inside the brachycephalic nose: intranasal mucosal contact points.

    PubMed

    Schuenemann, Riccarda; Oechtering, Gerhard U

    2014-01-01

    The purpose of this study was to evaluate the prevalence of intranasal mucosal contact points in brachycephalic and normocephalic dogs. In total, 82 brachycephalic dogs (42 pugs and 40 French bulldogs) were evaluated by rhinoscopy for their intranasal mucosal contact and 25 normocephalic dogs were evaluated as a control group. Of those, 162 brachycephalic nasal cavities were evaluable and 140 had contact between intranasal structures (87%). Intraconchal and septoconchal mucosal contact points were the most commonly detected sites of contact. French bulldogs had a significantly higher prevalence of mucosal contact and had 3 mean contact points compared with 1.7 mean contact points per nasal cavity in pugs. Septal deviations were present in 62% of brachycephalic dogs. In the control group, mucosal contact points were present in only 7 of 50 nasal cavities (14%), and septal deviations occurred in 16% of those cases. Contact point average was 0.1 in large and 0.3 in small normocephalic dogs. Intranasal mucosal contact was identified as a common and previously unreported problem in brachycephalic dogs. Numerous contact points reduce the lumen of the intranasal passageways and indicate potential intranasal obstruction. Affected dogs might benefit from removal of obstructing conchae, potentially using laser-assisted turbinectomy. PMID:24659729

  7. Oral Insulin

    PubMed Central

    2010-01-01

    Oral insulin is an exciting area of research and development in the field of diabetology. This brief review covers the various approaches used in the development of oral insulin, and highlights some of the recent data related to novel oral insulin preparation. PMID:21059246

  8. PATTERN REVERSAL VISUAL EVOKED POTENTIALS IN AWAKE RATS

    EPA Science Inventory

    A method for recording pattern reversal evoked potentials (PREPs) from awake restrained rats has been developed. The procedure of Onofrj et al. was modified to eliminate the need for anesthetic, thereby avoiding possible interactions of the anesthetic with other manipulations of ...

  9. Intrinsic Temporal Patterning in the Spontaneous Movement of Awake Neonates.

    ERIC Educational Resources Information Center

    Robertson, Steven S.

    1982-01-01

    The temporal organization of spontaneous movement in healthy, awake neonates was studied on the second or third day after birth. Movement was recorded using time lapse photography and quantified as a function of time. Evidence of intrinsic temporal organization among subjects was found. (MP)

  10. Awake craniotomy using electromagnetic navigation technology without rigid pin fixation.

    PubMed

    Morsy, Ahmed A; Ng, Wai Hoe

    2015-11-01

    We report our institutional experience using an electromagnetic navigation system, without rigid head fixation, for awake craniotomy patients. The StealthStation® S7 AxiEM™ navigation system (Medtronic, Inc.) was used for this technique. Detailed preoperative clinical and neuropsychological evaluations, patient education and contrast-enhanced MRI (thickness 1.5mm) were performed for each patient. The AxiEM Mobile Emitter was typically placed in a holder, which was mounted to the operating room table, and a non-invasive patient tracker was used as the patient reference device. A monitored conscious sedation technique was used in all awake craniotomy patients, and the AxiEM Navigation Pointer was used for navigation during the procedure. This offers the same accuracy as optical navigation, but without head pin fixation or interference with intraoperative neurophysiological techniques and surgical instruments. The application of the electromagnetic neuronavigation technology without rigid head fixation during an awake craniotomy is accurate, and offers superior patient comfort. It is recommended as an effective adjunctive technique for the conduct of awake surgery. PMID:26249245

  11. Targeting Insulin Signaling for the Treatment of Alzheimer's Disease.

    PubMed

    Chen, Yanxing; Zhang, Jianfang; Zhang, Baorong; Gong, Cheng-Xin

    2016-01-01

    Sporadic Alzheimer's disease (AD) is caused by multiple etiological factors, among which impaired brain insulin signaling and decreased brain glucose metabolism are important metabolic factors. Contrary to previous belief that insulin would not act in the brain, studies in the last three decades have proven important roles of insulin and insulin signaling in various biological functions in the brain. Impaired brain insulin signaling or brain insulin resistance and its role in the molecular pathogenesis of sporadic AD have been demonstrated. Thus, targeting brain insulin signaling for the treatment of cognitive impairment and AD has now attracted much attention in the field of AD drug discovery. This article reviews recent studies that target brain insulin signaling, especially those investigations on intranasal insulin administration and drugs that improve insulin sensitivity, including incretins, dipeptidyl peptidase IV inhibitors, thiazolidinediones, and metformin. These drugs have been previously approved for the treatment of diabetes mellitus, which could expedite their development for the treatment of AD. Although larger clinical trials are needed for validating their efficacy for the treatment of cognitive impairment and AD, results of animal studies and clinical trials available to date are encouraging. PMID:26268336

  12. Aberrant insulin signaling in Alzheimer's disease: current knowledge

    PubMed Central

    Bedse, Gaurav; Di Domenico, Fabio; Serviddio, Gaetano; Cassano, Tommaso

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia affecting elderly people. AD is a multifaceted pathology characterized by accumulation of extracellular neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neuronal loss mainly in the cortex and hippocampus. AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated. For long time, it was considered that insulin signaling has only peripheral actions but now it is widely accepted that insulin has neuromodulatory actions in the brain. Insulin signaling is involved in numerous brain functions including cognition and memory that are impaired in AD. Recent studies suggest that AD may be linked to brain insulin resistance and patients with diabetes have an increased risk of developing AD compared to healthy individuals. Indeed insulin resistance, increased inflammation and impaired metabolism are key pathological features of both AD and diabetes. However, the precise mechanisms involved in the development of AD in patients with diabetes are not yet fully understood. In this review we will discuss the role played by aberrant brain insulin signaling in AD. In detail, we will focus on the role of insulin signaling in the deposition of neuritic plaques and intracellular NFTs. Considering that insulin mitigates beta-amyloid deposition and phosphorylation of tau, pharmacological strategies restoring brain insulin signaling, such as intranasal delivery of insulin, could have significant therapeutic potential in AD treatment. PMID:26136647

  13. Intranasal oxytocin effects on social cognition: a critique

    PubMed Central

    Evans, Simon L.; Monte, Olga Dal; Noble, Pamela; Averbeck, Bruno B.

    2014-01-01

    The last decade has seen a large number of published findings supporting the hypothesis that intranasally delivered oxytocin (OT) can enhance the processing of social stimuli and regulate social emotion-related behaviors such as trust, memory, fidelity, and anxiety. The use of nasal spray for administering OT in behavioral research has become a standard method, but many questions still exist regarding its action. OT is a peptide that cannot cross the blood-brain barrier, and it has yet to be shown that it does indeed reach the brain when delivered intranasally. Given the evidence, it seems highly likely that OT does affect behavior when delivered as a nasal spray. These effects may be driven by at least three possible mechanisms. First, the intranasally delivered OT may diffuse directly into the CNS where it directly engages OT receptors. Second, the intranasally delivered OT may trigger increased central release via an indirect peripheral mechanism. And third, the indirect peripheral effects may directly lead to behavioral effects via some mechanism other than increased central release. Although intranasally delivered OT likely affects behavior, there are conflicting reports as to the exact nature of those behavioral changes: some studies suggest that OT effects are not always “pro-social” and others suggest effects on social behaviors are due to a more general anxiolytic effect. In this critique, we draw from work in healthy human populations and the animal literature to review the mechanistic aspects of intranasal OT delivery, and to discuss intranasal OT effects on social cognition and behavior. We conclude that future work should control carefully for anxiolytic and gender effects, which could underlie inconsistencies in the existing literature. PMID:24239931

  14. Biosimilar Insulins

    PubMed Central

    Hompesch, Marcus

    2014-01-01

    Until now most of the insulin used in developed countries has been manufactured and distributed by a small number of multinational companies. Beyond the established insulin manufacturers, a number of new players have developed insulin manufacturing capacities based on modern biotechnological methods. Because the patents for many of the approved insulin formulations have expired or are going to expire soon, these not yet established companies are increasingly interested in seeking market approval for their insulin products as biosimilar insulins (BI) in highly regulated markets like the EU and the United States. Differences in the manufacturing process (none of the insulin manufacturing procedures are 100% identical) can lead to insulins that to some extent may differ from the originator insulin. The key questions are if subtle differences in the structure of the insulins, purity, and so on are clinically relevant and may result in different biological effects. The aim of this article is to introduce and discuss basic aspects that may be of relevance with regard to BI. PMID:24876530

  15. Biosimilar insulins.

    PubMed

    Heinemann, Lutz

    2012-08-01

    Until now most insulin used in developed countries is manufactured and distributed by a small number of multinational companies. Other pharmaceutical companies - many of these are located in countries such as India or China - are also able to manufacture insulin with modern biotechnological methods. Additionally, the patents for many insulin formulations have expired or are going to expire soon. This enables such companies to produce insulins and to apply for market approval of these as biosimilar insulins (BIs) in highly regulated markets such as the EU or the US. To understand the complexity of BIs' approval and usage, scientific and regulatory aspects have to be discussed. Differences in the manufacturing process (none of the insulin-manufacturing procedures are identical) result in the fact that all insulin that might become BIs differ from the originator insulin to some extent. The question is, have such differences in the structure of the insulin molecule and or the purity and so on clinically relevant consequences for the biological effects induced or not. The guidelines already in place in the EU for market approval require that the manufacturer demonstrates that his insulin has a safety and efficacy profile that is similar to that of the 'original' insulin formulation. Recently guidelines for biosimilars were issued in the US; however, these do not cover insulin. Although a challenging approval process for insulins to become BI might be regarded as a hurdle to keep companies out of certain markets, it is fair to say that the potential safety and efficacy issues surrounding BI are substantial and relevant, and do warrant a careful and evidence-driven approval process. Nevertheless, it is very likely that in the next years, BIs will come to the market also in highly regulated markets. PMID:22583127

  16. The use of Midazolam as an Intranasal Sedative in Dentistry.

    PubMed

    Greaves, Anwen

    2016-01-01

    The administration of midazolam intranasally exploits the unique structure of the nasopharynx thus ensuring rapid delivery to the systemic circulation (The Nose - Brain Pathway). The absorption of midazolam nasally is influenced by the volume and concentration of midazolam, its physicochemical properties and the characteristics of the nasal mucosa. Delivering midazolam intranasally is non-titratable. The level of conscious sedation may be equivalent to that achieved by intravenous routes but is approached in a less controlled manner. Randomised Control trials using intranasal sedation in children have shown the technique to be safe and effective in secondary care for dental procedures at concentrations varying from 0.2 mg/kg to 0.5 mg/kg. A combined technique of intranasal midazolam (to facilitate cannulation) and intravenous midazolam is used for adults with moderate to severe learning disabilities. This has revolutionised dental treatment for this group of patients as treatment under General Anaesthesia (GA) may be avoided. Intranasal delivery of midazolam is emerging as a significant tool in our dental armamentarium for the treatment of anxious children, phobic adult patients and patients with learning disabilities. PMID:27145560

  17. Pharmacokinetics of Intranasal Scopolamine Gel Formulation (Inscop)

    NASA Technical Reports Server (NTRS)

    Boyd, Jason L.; Du, Brian; Daniels, Vernie; Simmons, Rita; Buckey, Jay; Putcha, Lakshmi

    2009-01-01

    Space Motion Sickness (SMS) is commonly experienced by astronauts and often requires treatment with medications during early flight days of space missions. Orally administered scopolamine is commonly used by astronauts to prevent SMS. Bioavailability of oral (PO) SMS medications is often low and highly variable. Intranasal (IN) administration of medications achieves higher and more reliable bioavailability than from an equivalent PO dose. Methods: To test the safety and reliability of INSCOP, two clinical studies were performed, a dose escalation study and a comparison study administering INSCOP during normal ambulation and head down tilt bedrest. Efficacy was evaluated by testing INSCOP with two, different motion sickness inducing paradigms. Results: Preliminary results indicate that INSCOP demonstrates linear pharmacokinetics and a low side effect profile. In head down tilt bedrest, relative bioavailability of INSCOP was increased for females at both doses (0.2 and 0.4 mg) and for males at the higher dose (0.4 mg) but is reduced at the lower dose (0.2 mg) compared to normal ambulation. INSCOP displays gender specific differences during ABR. One of the treatment efficacy trials conducted at Dartmouth Hitchcock Medical Center demonstrated that INSCOP is efficacious at both doses (0.2 and 0.4 mg) in suppressing motion sickness symptoms as indicated by longer chair ride times with INSCOP administration than with placebo, and efficacy increases with dose. Similar results were seen using another motion sickness simulator, the motion simulator dome, at the Naval Aerospace Medical Research Laboratory, with significantly increased time in the dome in motion-susceptible subjects when using INSCOP compared to untreated controls. Conclusion: Higher bioavailability, linear pharmacokinetics, a low incidence of side effects, and a favorable efficacy profile make INSCOP a desirable formulation for prophylactic and rescue treatment of astronauts in space and military personnel on

  18. Awake Nonhuman Primate Brain PET Imaging with Minimal Head Restraint: Evaluation of GABAA Benzodiazepine Binding with [11C]Flumazenil in Awake and Anesthetized Animals

    PubMed Central

    Sandiego, Christine M.; Jin, Xiao; Mulnix, Tim; Fowles, Krista; Labaree, David; Ropchan, Jim; Huang, Yiyun; Cosgrove, Kelly; Castner, Stacy A.; Williams, Graham V.; Wells, Lisa; Rabiner, Eugenii A.; Carson, Richard E.

    2013-01-01

    Neuroreceptor imaging in the nonhuman primate (NHP) is valuable for translational research approaches in humans. However, the majority of NHP studies are conducted under anesthesia, which affects the interpretability of receptor binding measures. The aims of this study are to develop awake NHP imaging with minimal head restraint and to compare in vivo binding of GABAA-benzodiazepine radiotracer [11C]flumazenil under anesthetized and awake conditions. We hypothesized that [11C]flumazenil binding potential (BPND) would be higher in isoflurane-anesthetized monkeys. Methods The Focus-220 small animal PET scanner was fitted to a mechanical device that raised and tilted the scanner 45° while the awake NHP was tilted back 35° in a custom chair for optimal brain positioning. This required acclimation of the animals to the chair, touch-screen tasks, i.v. catheter insertion, and tilting. For PET studies, the bolus plus constant infusion (B/I) method was used for [11C]flumazenil administration. Two rhesus monkeys were scanned under the awake (n=6 scans) and isoflurane-anesthetized (n=4 scans) conditions. The Vicra infrared camera was used to track head motion during PET scans. Under the awake condition, emission and head motion-tracking data were acquired for 40-75 min post-injection. Anesthetized monkeys were scanned for 90 min. Cortisol measurements were acquired during awake and anesthetized scans. Equilibrium analysis was used for both the anesthetized (n=4) and awake (n=5) datasets to compute mean BPND images in NHP template space, using the pons as a reference region. Percent change per min (%Δ/min) in radioactivity concentration was calculated in high and low binding regions to assess the quality of equilibrium. Results The monkeys acclimated to procedures in the NHP chair necessary to perform awake PET imaging. Image quality was comparable between awake and anesthetized conditions. The relationship between awake and anesthetized values was BPND(awake)=0.94BPND

  19. Avoidance and management of trigeminocardiac reflex complicating awake-craniotomy.

    PubMed

    Prabhu, Vikram C; Bamber, Norman I; Shea, John F; Jellish, W Scott

    2008-12-01

    The trigeminocardiac reflex occurs from manipulation or stimulation of peripheral branches or the central component of the trigeminal nerve and consists of bradycardia, hypotension, apnea, and increased gastric motility. The efferent limb of the response is mediated by the vagus nerve. This 65-year-old Caucasian male suffered an episode of bradycardia progressing to transient asystole during the course of an awake-craniotomy procedure for tumor resection. The cardiac rhythm changes resolved with administration of intravenous atropine, removal of the precipitating stimulus, and application of topical anesthetic on the dura of the middle cranial fossa. The trigeminocardiac response may complicate the course of a craniotomy and may place an awake, unintubated patient at increased risk for morbidity. The reflex may be prevented by anesthetizing the dura innervated by the trigeminal nerve via injection or topical application of local anesthetic. If encountered, removal of the stimulus, airway protection, and administration of vagolytic medications are measures that need to be considered. PMID:18845385

  20. Sonographically guided superior laryngeal nerve block during awake fiberoptic intubation.

    PubMed

    Sawka, Andrew; Tang, Raymond; Vaghadia, Himat

    2015-04-15

    We report 5 patients who underwent ultrasound-guided superior laryngeal nerve block before awake intubation and general anesthesia. We used a 8- to 15-MHz hockey stick-shaped ultrasound transducer (HST15-8/20 linear probe, Ultrasonix) to visualize the superior laryngeal nerve. A 3.8-cm 25-G needle was inserted in real time and directed toward the superior laryngeal nerve followed by circumferential placement of local anesthetic. All 5 patients tolerated subsequent awake fiberoptic intubation with either minimal or no sedation. Sonographically guided superior laryngeal nerve block may be useful in patients where identification of landmarks in the neck is difficult as a result of patient anatomy. PMID:25867195

  1. Enclosure for small animals during awake animal imaging

    SciTech Connect

    Goddard, Jr., James S

    2013-11-26

    An enclosure or burrow restrains an awake animal during an imaging procedure. A tubular body, made from a radiolucent material that does not attenuate x-rays or gamma rays, accepts an awake animal. A proximal end of the body includes an attachment surface that corresponds to an attachment surface of an optically transparent and optically uniform window. An anti-reflective coating may be applied to an inner surface, an outer surface, or both surfaces of the window. Since the window is a separate element of the enclosure and it is not integrally formed as part of the body, it can be made with optically uniform thickness properties for improved motion tracking of markers on the animal with a camera during the imaging procedure. The motion tracking information is then used to compensate for animal movement in the image.

  2. Intranasal curcumin and its evaluation in murine model of asthma.

    PubMed

    Subhashini; Chauhan, Preeti S; Kumari, Sharda; Kumar, Jarajana Pradeep; Chawla, Ruchi; Dash, D; Singh, Mandavi; Singh, Rashmi

    2013-11-01

    Curcumin, a phytochemical present in turmeric, rhizome of Curcuma longa, has been shown to have a wide variety of pharmacological activities including anti-inflammatory, anti-allergic and anti-asthmatic properties. Curcumin is known for its low systemic bioavailability and rapid metabolization through oral route and has limited its applications. Over the recent decades, the interest in intranasal delivery as a non-invasive route for drugs has increased as target tissue for drug delivery since nasal mucosa offers numerous benefits. In this study, we evaluated intranasal curcumin following its absorption through nasal mucosa by a sensitive and validated high-performance liquid chromatography (HPLC) method for the determination of intranasal curcumin in mouse blood plasma and lung tissue. Intranasal curcumin has been detected in plasma after 15 min to 3 h at pharmacological dose (5 mg/kg, i.n.), which has shown anti-asthmatic potential by inhibiting bronchoconstriction and inflammatory cell recruitment to the lungs. At considerably lower doses has proved better than standard drug disodium cromoglycate (DSCG 50 mg/kg, i.p.) by affecting inflammatory cell infiltration and histamine release in mouse model of asthma. HPLC detection revealed that curcumin absorption in lungs has started after 30 min following intranasal administration and retained till 3h then declines. Present investigations suggest that intranasal curcumin (5.0 mg/kg, i.n.) has effectively being absorbed and detected in plasma and lungs both and suppressed airway inflammations at lower doses than the earlier doses used for detection (100-200 mg/kg, i.p.) for pharmacological studies (10-20 mg/kg, i.p.) in mouse model of asthma. Present study may prove the possibility of curcumin as complementary medication in the development of nasal drops to prevent airway inflammations and bronchoconstrictions in asthma without any side effect. PMID:24021755

  3. Real-Time Dopamine Measurement in Awake Monkeys

    PubMed Central

    Schluter, Erik W.; Mitz, Andrew R.; Cheer, Joseph F.; Averbeck, Bruno B.

    2014-01-01

    Fast-scan cyclic voltammetry (FSCV) is often used to measure real-time dopamine (DA) concentrations in awake, behaving rodents. Extending this technique to work in monkeys would provide a platform for advanced behavioral studies and a primate model for preclinical research. The present study demonstrates the feasibility of DA recordings in two awake monkeys (Macaca mulatta) using a mixture of techniques adapted from rodent, primate and brain slice work. We developed a long carbon fiber electrode to operate in the larger primate brain. This electrode was lowered into the striatum each day using a recording chamber and a detachable micromanipulator system. A manipulator also moved one or more tungsten stimulating electrodes into either the nearby striatum or the ventral tegmental area/substantia nigra pars compacta (VTA/SNc). We developed an electrical stimulation controller to reduce artifacts during electrical stimulation. We also introduce a stimulation-based methodology for estimating distances between electrodes in the brain. Dopamine responses within the striatum were evoked by either stimulation of the striatum near the FSCV electrode, or stimulation within the VTA/SNc. Unexpected juice rewards also evoked dopamine responses in the ventral striatum. Thus, we demonstrate that robust dopamine responses can be recorded from awake, behaving primates with FSCV. In addition, we describe how a stimulation technique borrowed from the neuroprosthetics field can activate the distributed monkey midbrain dopamine system in a way that mimics rodent VTA stimulation. PMID:24921937

  4. Presurgical Rehearsals for Patients Considering "Awake" Deep Brain Stimulation.

    PubMed

    Falconer, Ramsey A; Rogers, Sean L; Brewer, Cristie M; Piscitani, Franco; Shenai, Mahesh B

    2016-01-01

    Simulated surgical environments are rapidly gaining adoption in training students, residents, and members of specialized surgical teams. However, minimal attention has been given to the use of simulated surgical environments to educate patients on surgical processes, particularly procedures that require the active participation of the patient. "Awake" neurosurgery provides a unique situation in which patients openly participate in their operation. We describe a case report, in which a 62-year-old male was referred for "awake" deep brain stimulation implantation, in relation to medically refractory Parkinson's disease. The patient had significant concerns regarding anxiety and claustrophobia, and toleration of the "awake" procedure. Consequently, we designed a simulated OR environment and process, to recreate the physical experience of the procedure, with minimal cost or risk. This experience was crucial in determining the care plan, as after this experience, the patient opted for an "asleep" alternative. Thus, in certain settings, presurgical rehearsals may have a dramatic impact in the overall course of care. PMID:27532036

  5. Real-time dopamine measurement in awake monkeys.

    PubMed

    Schluter, Erik W; Mitz, Andrew R; Cheer, Joseph F; Averbeck, Bruno B

    2014-01-01

    Fast-scan cyclic voltammetry (FSCV) is often used to measure real-time dopamine (DA) concentrations in awake, behaving rodents. Extending this technique to work in monkeys would provide a platform for advanced behavioral studies and a primate model for preclinical research. The present study demonstrates the feasibility of DA recordings in two awake monkeys (Macaca mulatta) using a mixture of techniques adapted from rodent, primate and brain slice work. We developed a long carbon fiber electrode to operate in the larger primate brain. This electrode was lowered into the striatum each day using a recording chamber and a detachable micromanipulator system. A manipulator also moved one or more tungsten stimulating electrodes into either the nearby striatum or the ventral tegmental area/substantia nigra pars compacta (VTA/SNc). We developed an electrical stimulation controller to reduce artifacts during electrical stimulation. We also introduce a stimulation-based methodology for estimating distances between electrodes in the brain. Dopamine responses within the striatum were evoked by either stimulation of the striatum near the FSCV electrode, or stimulation within the VTA/SNc. Unexpected juice rewards also evoked dopamine responses in the ventral striatum. Thus, we demonstrate that robust dopamine responses can be recorded from awake, behaving primates with FSCV. In addition, we describe how a stimulation technique borrowed from the neuroprosthetics field can activate the distributed monkey midbrain dopamine system in a way that mimics rodent VTA stimulation. PMID:24921937

  6. The evolution of brain surgery on awake patients.

    PubMed

    Surbeck, Werner; Hildebrandt, Gerhard; Duffau, Hugues

    2015-01-01

    In the early days of modern neurological surgery, the inconveniences and potential dangers of general anesthesia by chloroform and ether using the so-called "open-drop technique" led to the quest for alternative methods of anesthesia. Besides preventing the feared side effects, the introduction of regional anesthesia revealed another decisive advantage over general anesthesia in neurosurgery: While intraoperative direct cortical stimulation under general anesthesia could only delineate the motor area (by evocation of contralateral muscular contraction), now, the awake patients were able to report sensations elicited by this method. These properties advanced regional anesthesia to the regimen of choice for cranial surgeries in the first half of the 20th century. While technical advances and new drugs led to a progressive return to general anesthesia for neurosurgical procedures, the use of regional anesthesia for epilepsy surgery has only decreased in recent decades. Meanwhile, awake craniotomies regained popularity in oncologically motivated surgeries, especially in craniotomies for diffuse low-grade gliomas. Intraoperative mapping of brain functions using electrical stimulation in awake patients enables not only for increased tumor removal while preserving the functional status of the patients but also opens a window to cognitive neuroscience. Observations during such interventions and their correlation with both pre - and postoperative neuropsychological examinations and functional neuroimaging is progressively leading to new insights into the complex functional anatomy of the human brain. Furthermore, it broadens our knowledge on cerebral network reorganization in the presence of disease-with implications for all disciplines of clinical neuroscience. PMID:25352088

  7. Demystifying FluMist, a new intranasal, live influenza vaccine.

    PubMed

    Mossad, Sherif B

    2003-09-01

    FluMist--a cold-adapted, live-attenuated, trivalent, intranasal influenza virus vaccine approved by the US Food and Drug Administration on June 17, 2003--has been shown to be safe and effective, but its role in the general prevention of influenza is yet to be defined. Intranasal administration is expected to be more acceptable than parenteral, particularly in children, but the potential for the shedding of live virus may pose a risk to anyone with a compromised immune system. PMID:14518575

  8. Intranasal midazolam for rapid sedation of an agitated patient

    PubMed Central

    Shrestha, Gentle Sunder; Joshi, Pankaj; Bhattarai, Krishna; Chhetri, Santosh; Acharya, Subhash Prasad

    2015-01-01

    Rapidly, establishing a difficult intravenous access in a dangerously agitated patient is a real challenge. Intranasal midazolam has been shown to be effective and safe for rapidly sedating patients before anesthesia, for procedural sedation and for control of seizure. Here, we report a patient in intensive care unit who was on mechanical ventilation and on inotropic support for management of septic shock and who turned out extremely agitated after accidental catheter removal. Intravenous access was successfully established following sedation with intranasal midazolam, using ultrasound guidance. PMID:26195863

  9. Chronic invasive fungal sinusitis associated with intranasal drug use.

    PubMed

    Pekala, Kelly R; Clavenna, Matthew J; Shockley, Ross; Weiss, Vivian L; Turner, Justin H

    2015-12-01

    Chronic invasive fungal sinusitis (CIFS) is a rare but potentially aggressive form of invasive fungal disease that occurs in immunocompetent patients. We report a case of CIFS in an otherwise healthy young adult associated with intranasal illicit drug abuse. The patient presented with nonhealing nasal septal and palatal perforations. Biopsy demonstrated invasive Aspergillus flavus requiring surgical debridement and extended intravenous antifungal therapy. Tissue necrosis and ulceration related to intranasal drug use should be recognized as a potential risk factor for invasive fungal sinusitis. PMID:26153255

  10. Nonobese, insulin-deficient Ins2Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling.

    PubMed

    Hong, Eun-Gyoung; Jung, Dae Young; Ko, Hwi Jin; Zhang, Zhiyou; Ma, Zhexi; Jun, John Y; Kim, Jae Hyeong; Sumner, Andrew D; Vary, Thomas C; Gardner, Thomas W; Bronson, Sarah K; Kim, Jason K

    2007-12-01

    Although insulin resistance has been traditionally associated with type 2 diabetes, recent evidence in humans and animal models indicates that insulin resistance may also develop in type 1 diabetes. A point mutation of insulin 2 gene in Ins2(Akita) mice leads to pancreatic beta-cell apoptosis and hyperglycemia, and these mice are commonly used to investigate type 1 diabetes and complications. Since insulin resistance plays an important role in diabetic complications, we performed hyperinsulinemic-euglycemic clamps in awake Ins2(Akita) and wild-type mice to measure insulin action and glucose metabolism in vivo. Nonobese Ins2(Akita) mice developed insulin resistance, as indicated by an approximately 80% reduction in glucose infusion rate during clamps. Insulin resistance was due to approximately 50% decreases in glucose uptake in skeletal muscle and brown adipose tissue as well as hepatic insulin action. Skeletal muscle insulin resistance was associated with a 40% reduction in total GLUT4 and a threefold increase in PKCepsilon levels in Ins2(Akita) mice. Chronic phloridzin treatment lowered systemic glucose levels and normalized muscle insulin action, GLUT4 and PKCepsilon levels in Ins2(Akita) mice, indicating that hyperglycemia plays a role in insulin resistance. Echocardiography showed significant cardiac remodeling with ventricular hypertrophy that was ameliorated following chronic phloridzin treatment in Ins2(Akita) mice. Overall, we report for the first time that nonobese, insulin-deficient Ins2(Akita) mice develop type 2 diabetes phenotypes including peripheral and hepatic insulin resistance and cardiac remodeling. Our findings provide important insights into the pathogenesis of metabolic abnormalities and complications affecting type 1 diabetes and lean type 2 diabetes subjects. PMID:17911348

  11. Intranasal H5N1 vaccines, adjuvanted with chitosan derivatives, protect ferrets against highly pathogenic influenza intranasal and intratracheal challenge.

    PubMed

    Mann, Alex J; Noulin, Nicolas; Catchpole, Andrew; Stittelaar, Koert J; de Waal, Leon; Veldhuis Kroeze, Edwin J B; Hinchcliffe, Michael; Smith, Alan; Montomoli, Emanuele; Piccirella, Simona; Osterhaus, Albert D M E; Knight, Alastair; Oxford, John S; Lapini, Giulia; Cox, Rebecca; Lambkin-Williams, Rob

    2014-01-01

    We investigated the protective efficacy of two intranasal chitosan (CSN and TM-CSN) adjuvanted H5N1 Influenza vaccines against highly pathogenic avian Influenza (HPAI) intratracheal and intranasal challenge in a ferret model. Six groups of 6 ferrets were intranasally vaccinated twice, 21 days apart, with either placebo, antigen alone, CSN adjuvanted antigen, or TM-CSN adjuvanted antigen. Homologous and intra-subtypic antibody cross-reacting responses were assessed. Ferrets were inoculated intratracheally (all treatments) or intranasally (CSN adjuvanted and placebo treatments only) with clade 1 HPAI A/Vietnam/1194/2004 (H5N1) virus 28 days after the second vaccination and subsequently monitored for morbidity and mortality outcomes. Clinical signs were assessed and nasal as well as throat swabs were taken daily for virology. Samples of lung tissue, nasal turbinates, brain, and olfactory bulb were analysed for the presence of virus and examined for histolopathological findings. In contrast to animals vaccinated with antigen alone, the CSN and TM-CSN adjuvanted vaccines induced high levels of antibodies, protected ferrets from death, reduced viral replication and abrogated disease after intratracheal challenge, and in the case of CSN after intranasal challenge. In particular, the TM-CSN adjuvanted vaccine was highly effective at eliciting protective immunity from intratracheal challenge; serologically, protective titres were demonstrable after one vaccination. The 2-dose schedule with TM-CSN vaccine also induced cross-reactive antibodies to clade 2.1 and 2.2 H5N1 viruses. Furthermore ferrets immunised with TM-CSN had no detectable virus in the respiratory tract or brain, whereas there were signs of virus in the throat and lungs, albeit at significantly reduced levels, in CSN vaccinated animals. This study demonstrated for the first time that CSN and in particular TM-CSN adjuvanted intranasal vaccines have the potential to protect against significant mortality and

  12. Insulin resistance and insulin sensitizers.

    PubMed

    Stumvoll, M; Häring, H

    2001-01-01

    Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-alpha and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) gamma is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in beta-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARgamma-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance. PMID:11684868

  13. Insulin improves memory and reduces chronic neuroinflammation in the hippocampus of young but not aged brains.

    PubMed

    Adzovic, Linda; Lynn, Ashley E; D'Angelo, Heather M; Crockett, Alexis M; Kaercher, Roxanne M; Royer, Sarah E; Hopp, Sarah C; Wenk, Gary L

    2015-01-01

    The role of insulin in the brain is still not completely understood. In the periphery, insulin can decrease inflammation induced by lipopolysaccharide (LPS); however, whether insulin can reduce inflammation within the brain is unknown. Experiments administrating intranasal insulin to young and aged adults have shown that insulin improves memory. In our animal model of chronic neuroinflammation, we administered insulin and/or LPS directly into the brain via the fourth ventricle for 4 weeks in young rats; we then analyzed their spatial memory and neuroinflammatory response. Additionally, we administered insulin or artificial cerebral spinal fluid (aCSF), in the same manner, to aged rats and then analyzed their spatial memory and neuroinflammatory response. Response to chronic neuroinflammation in young rats was analyzed in the presence or absence of insulin supplementation. Here, we show for the first time that insulin infused (i.c.v.) to young rats significantly attenuated the effects of LPS by decreasing the expression of neuroinflammatory markers in the hippocampus and by improving performance in the Morris water pool task. In young rats, insulin infusion alone significantly improved their performance as compared to all other groups. Unexpectedly, in aged rats, the responsiveness to insulin was completely absent, that is, spatial memory was still impaired suggesting that an age-dependent insulin resistance may contribute to the cognitive impairment observed in neurodegenerative diseases. Our data suggest a novel therapeutic effect of insulin on neuroinflammation in the young but not the aged brain. PMID:25889938

  14. Intranasal flunisolide treatment in children with adenoidal hypertrophy.

    PubMed

    Ciprandi, G; Varricchio, A; Capasso, M; Varricchio, A M; De Lucia, A; Ascione, E; Avvisati, F; Capristo, C; Marseglia, G L; Barillari, U

    2007-01-01

    Adenoidal hypertrophy (AH) represents one of the most frequent indications for surgery in children and it has been proposed that treatment with intranasal corticosteroids can decrease the size of AH. Therefore, the aim of the study is to evaluate the effect of the use of intranasal flunisolide among children affected by AH. 178 children with AH were evaluated in this randomised and controlled study. Inclusion criteria for the study required that each patient had to have a III or IV degree of AH on the initial endoscopic examination. Children were treated with intranasal flunisolide or isotonic saline solution for 8 weeks. After treatment, endoscopy was performed to re-evaluate AH degree. Flunisolide treatment was associated with significant (p less than 0.04) reduction of AH degree. There was moreover a consistent reduction of children (46 out of 58) proposed to adenoidectomy. No clinically important adverse events were reported. In conclusion, this preliminary study demonstrates that an 8-week treatment with intranasal flunisolide is significantly associated with reduction of AH, thus preventing the recurrence to adenoidectomy, and is safe. PMID:18179756

  15. Ready-to-use colloidal adjuvant systems for intranasal immunization.

    PubMed

    Lee, Jeong-Jun; Shim, Aeri; Lee, Song Yi; Kwon, Bo-Eun; Kim, Seong Ryeol; Ko, Hyun-Jeong; Cho, Hyun-Jong

    2016-04-01

    Adjuvant systems based on oil-in-water (o/w) microemulsions (MEs) for vaccination via intranasal administration were prepared and evaluated. A ready-to-use blank ME system composed of mineral oil (oil), Labrasol (surfactant), Tween 80 (cosurfactant), and water was prepared and blended with antigen (Ag) solution prior to use. The o/w ME system developed exhibited nano-size droplets within the tested range of Ag concentrations and dilution factors. The maintenance of primary, secondary, and tertiary structural stability of ovalbumin (OVA) in ME, compared with OVA in solution, was demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism (CD), and fluorescence intensity measurements, respectively. The uptake efficiency in RAW 264.7 cells, evaluated by flow cytometry, of OVA in the ME group was significantly higher than that of the OVA solution group (p<0.05). In an intranasal immunization study with OVA ME in mice, elevated adjuvant effects in terms of mucosal immunization and Th1-dominant cell-mediated immune responses were identified. Given the convenience of use (simply mixing with Ag solution prior to use) and the adjuvant effects after intranasal immunization, the new o/w ME may be a practical and efficient adjuvant system for intranasal vaccination. PMID:26775242

  16. Pharmacodynamics and toxicity of vasoactive intestinal peptide for intranasal administration.

    PubMed

    Cui, Xu; Cao, De-Ying; Wang, Zhi-Min; Zheng, Ai-Ping

    2013-01-01

    The aim of this work was to study the nasal route for the delivery of vasoactive intestinal peptide (VIP) to the brain and to evaluate the toxicity of VIP nasal spray. Mice were injected intracerebroventricularly with the aggregated Abeta25-35 to mimic Alzheimer's disease. Following administration, different groups of mice were treated over one week, and their spatial learning and memory capacities were evaluated by the Morris water maze test. The toxicity of VIP nasal spray was evaluated by examining the morphology of individual rat nasal mucosa cilia and the pathology of rat nasal mucosa. Rats receiving intranasal VIP (40 microg/ml) showed good spatial memory relative to the Abeta25-35 model group, but the escape latency did not show any statistically significant difference. Intranasal administration of VIP nasal spray (200 microg/ml) improved deficits in spatial memory to the point that test animals receiving intranasal VIP showed no statistically significant differences from the normal control group in escape latency. This indicated that the nasal spray method could increase the quantity of VIP entering the brain and protect the central nervous systems of mice. Toxicity evaluation showed that the preparation could cause minor irritation, which resolved spontaneously within a week at the end of treatment. In conclusion, VIP can be delivered successfully to the brain using the intranasal route. PMID:23444784

  17. Acute Physiological and Behavioral Effects of Intranasal Methamphetamine in Humans

    PubMed Central

    Hart, Carl L; Gunderson, Erik W; Perez, Audrey; Kirkpatrick, Matthew G; Thurmond, Andrew; Comer, Sandra D; Foltin, Richard W

    2016-01-01

    Intranasal methamphetamine abuse has increased dramatically in the past decade, yet only one published study has investigated its acute effects under controlled laboratory conditions. Thus, the current study examined the effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Eleven nontreatment-seeking methamphetamine abusers (two females, nine males) completed this four-session, in-patient, within-participant, double-blind study. During each session, one of four intranasal methamphetamine doses (0, 12, 25, and 50 mg/70 kg) was administered and methamphetamine plasma concentrations, cardiovascular, subjective, and psychomotor/cognitive performance effects were assessed before drug administration and repeatedly thereafter. Following drug administration, methamphetamine plasma concentrations systematically increased for 4 h postdrug administration then declined. Methamphetamine dose dependently increased cardiovascular measures and ‘positive’ subjective effects, with peaks occurring approximately 5–15 min after drug administration, when plasma levels were still ascending. In addition, cognitive performance on less complicated tasks was improved by all active methamphetamine doses, whereas performance on more complicated tasks was improved only by the intermediate doses (12 and 25 mg). These results show that intranasal methamphetamine produced predictable effects on multiple behavioral and physiological measures before peak plasma levels were observed. Of interest is the dissociation between methamphetamine plasma concentrations with cardiovascular measures and positive subjective effects, which might have important implications for potential toxicity after repeated doses. PMID:17851535

  18. Distinct BOLD Activation Profiles Following Central and Peripheral Oxytocin Administration in Awake Rats

    PubMed Central

    Ferris, Craig F.; Yee, Jason R.; Kenkel, William M.; Dumais, Kelly Marie; Moore, Kelsey; Veenema, Alexa H.; Kulkarni, Praveen; Perkybile, Allison M.; Carter, C. Sue

    2015-01-01

    A growing body of literature has suggested that intranasal oxytocin (OT) or other systemic routes of administration can alter prosocial behavior, presumably by directly activating OT sensitive neural circuits in the brain. Yet there is no clear evidence that OT given peripherally can cross the blood–brain barrier at levels sufficient to engage the OT receptor. To address this issue we examined changes in blood oxygen level-dependent (BOLD) signal intensity in response to peripheral OT injections (0.1, 0.5, or 2.5 mg/kg) during functional magnetic resonance imaging (fMRI) in awake rats imaged at 7.0 T. These data were compared to OT (1 μg/5 μl) given directly to the brain via the lateral cerebroventricle. Using a 3D annotated MRI atlas of the rat brain segmented into 171 brain areas and computational analysis, we reconstructed the distributed integrated neural circuits identified with BOLD fMRI following central and peripheral OT. Both routes of administration caused significant changes in BOLD signal within the first 10 min of administration. As expected, central OT activated a majority of brain areas known to express a high density of OT receptors, e.g., lateral septum, subiculum, shell of the accumbens, bed nucleus of the stria terminalis. This profile of activation was not matched by peripheral OT. The change in BOLD signal to peripheral OT did not show any discernible dose–response. Interestingly, peripheral OT affected all subdivisions of the olfactory bulb, in addition to the cerebellum and several brainstem areas relevant to the autonomic nervous system, including the solitary tract nucleus. The results from this imaging study do not support a direct central action of peripheral OT on the brain. Instead, the patterns of brain activity suggest that peripheral OT may interact at the level of the olfactory bulb and through sensory afferents from the autonomic nervous system to influence brain activity. PMID:26441574

  19. Insulin Test

    MedlinePlus

    ... people with type 2 diabetes , polycystic ovarian syndrome (PCOS) , prediabetes or heart disease , or metabolic syndrome . A ... resistance), especially in obese individuals and those with PCOS . This test involves an IV-infusion of insulin, ...

  20. Characterizing Awake and Anesthetized States Using a Dimensionality Reduction Method.

    PubMed

    Mirsadeghi, M; Behnam, H; Shalbaf, R; Jelveh Moghadam, H

    2016-01-01

    Distinguishing between awake and anesthetized states is one of the important problems in surgery. Vital signals contain valuable information that can be used in prediction of different levels of anesthesia. Some monitors based on electroencephalogram (EEG) such as the Bispectral (BIS) index have been proposed in recent years. This study proposes a new method for characterizing between awake and anesthetized states. We validated our method by obtaining data from 25 patients during the cardiac surgery that requires cardiopulmonary bypass. At first, some linear and non-linear features are extracted from EEG signals. Then a method called "LLE"(Locally Linear Embedding) is used to map high-dimensional features in a three-dimensional output space. Finally, low dimensional data are used as an input to a quadratic discriminant analyzer (QDA). The experimental results indicate that an overall accuracy of 88.4 % can be obtained using this method for classifying the EEG signal into conscious and unconscious states for all patients. Considering the reliability of this method, we can develop a new EEG monitoring system that could assist the anesthesiologists to estimate the depth of anesthesia accurately. PMID:26573650

  1. Mapping oxygen concentration in the awake mouse brain

    PubMed Central

    Lyons, Declan G; Parpaleix, Alexandre; Roche, Morgane; Charpak, Serge

    2016-01-01

    Although critical for brain function, the physiological values of cerebral oxygen concentration have remained elusive because high-resolution measurements have only been performed during anesthesia, which affects two major parameters modulating tissue oxygenation: neuronal activity and blood flow. Using measurements of capillary erythrocyte-associated transients, fluctuations of oxygen partial pressure (Po2) associated with individual erythrocytes, to infer Po2 in the nearby neuropil, we report the first non-invasive micron-scale mapping of cerebral Po2 in awake, resting mice. Interstitial Po2 has similar values in the olfactory bulb glomerular layer and the somatosensory cortex, whereas there are large capillary hematocrit and erythrocyte flux differences. Awake tissue Po2 is about half that under isoflurane anesthesia, and within the cortex, vascular and interstitial Po2 values display layer-specific differences which dramatically contrast with those recorded under anesthesia. Our findings emphasize the importance of measuring energy parameters non-invasively in physiological conditions to precisely quantify and model brain metabolism. DOI: http://dx.doi.org/10.7554/eLife.12024.001 PMID:26836304

  2. Robust Reproducible Resting State Networks in the Awake Rodent Brain

    PubMed Central

    Becerra, Lino; Pendse, Gautam; Chang, Pei-Ching; Bishop, James; Borsook, David

    2011-01-01

    Resting state networks (RSNs) have been studied extensively with functional MRI in humans in health and disease to reflect brain function in the un-stimulated state as well as reveal how the brain is altered with disease. Rodent models of disease have been used comprehensively to understand the biology of the disease as well as in the development of new therapies. RSN reported studies in rodents, however, are few, and most studies are performed with anesthetized rodents that might alter networks and differ from their non-anesthetized state. Acquiring RSN data in the awake rodent avoids the issues of anesthesia effects on brain function. Using high field fMRI we determined RSNs in awake rats using an independent component analysis (ICA) approach, however, ICA analysis can produce a large number of components, some with biological relevance (networks). We further have applied a novel method to determine networks that are robust and reproducible among all the components found with ICA. This analysis indicates that 7 networks are robust and reproducible in the rat and their putative role is discussed. PMID:22028788

  3. Intrinsic Feature Pose Measurement for Awake Animal SPECT Imaging

    SciTech Connect

    Goddard Jr, James Samuel; Baba, Justin S; Lee, Seung Joon; Weisenberger, A G; Stolin, A; McKisson, J; Smith, M F

    2009-01-01

    New developments have been made in optical motion tracking for awake animal imaging that measures 3D position and orientation (pose) for a single photon emission computed tomography (SPECT) imaging system. Ongoing SPECT imaging research has been directed towards head motion measurement for brain studies in awake, unrestrained mice. In contrast to previous results using external markers, this work extracts and tracks intrinsic features from multiple camera images and computes relative pose from the tracked features over time. Motion tracking thus far has been limited to measuring extrinsic features such as retro-reflective markers applied to the mouse s head. While this approach has been proven to be accurate, the additional animal handling required to attach the markers is undesirable. A significant improvement in the procedure is achieved by measuring the pose of the head without extrinsic markers using only the external surface appearance. This approach is currently being developed with initial results presented here. The intrinsic features measurement extracts discrete, sparse natural features from 2D images such as eyes, nose, mouth and other visible structures. Stereo correspondence between features for a camera pair is determined for calculation of 3D positions. These features are also tracked over time to provide continuity for surface model fitting. Experimental results from live images are presented.

  4. Improvements in Intrinsic Feature Pose Measurement for Awake Animal Imaging

    SciTech Connect

    Goddard Jr, James Samuel; Baba, Justin S; Lee, Seung Joon; Weisenberger, A G; McKisson, J; Smith, M F; Stolin, Alexander

    2010-01-01

    Development has continued with intrinsic feature optical motion tracking for awake animal imaging to measure 3D position and orientation (pose) for motion compensated reconstruction. Prior imaging results have been directed towards head motion measurement for SPECT brain studies in awake unrestrained mice. This work improves on those results in extracting and tracking intrinsic features from multiple camera images and computing pose changes from the tracked features over time. Previously, most motion tracking for 3D imaging has been limited to measuring extrinsic features such as retro-reflective markers applied to an animal s head. While this approach has been proven to be accurate, the use of external markers is undesirable for several reasons. The intrinsic feature approach has been further developed from previous work to provide full pose measurements for a live mouse scan. Surface feature extraction, matching, and pose change calculation with point tracking and accuracy results are described. Experimental pose calculation and 3D reconstruction results from live images are presented.

  5. Improvements in intrinsic feature pose measurement for awake animal imaging

    SciTech Connect

    J.S. Goddard, J.S. Baba, S.J. Lee, A.G. Weisenberger, A. Stolin, J. McKisson, M.F. Smith

    2011-06-01

    Development has continued with intrinsic feature optical motion tracking for awake animal imaging to measure 3D position and orientation (pose) for motion compensated reconstruction. Prior imaging results have been directed towards head motion measurement for SPECT brain studies in awake unrestrained mice. This work improves on those results in extracting and tracking intrinsic features from multiple camera images and computing pose changes from the tracked features over time. Previously, most motion tracking for 3D imaging has been limited to measuring extrinsic features such as retro-reflective markers applied to an animal's head. While this approach has been proven to be accurate, the use of external markers is undesirable for several reasons. The intrinsic feature approach has been further developed from previous work to provide full pose measurements for a live mouse scan. Surface feature extraction, matching, and pose change calculation with point tracking and accuracy results are described. Experimental pose calculation and 3D reconstruction results from live images are presented.

  6. Robust reproducible resting state networks in the awake rodent brain.

    PubMed

    Becerra, Lino; Pendse, Gautam; Chang, Pei-Ching; Bishop, James; Borsook, David

    2011-01-01

    Resting state networks (RSNs) have been studied extensively with functional MRI in humans in health and disease to reflect brain function in the un-stimulated state as well as reveal how the brain is altered with disease. Rodent models of disease have been used comprehensively to understand the biology of the disease as well as in the development of new therapies. RSN reported studies in rodents, however, are few, and most studies are performed with anesthetized rodents that might alter networks and differ from their non-anesthetized state. Acquiring RSN data in the awake rodent avoids the issues of anesthesia effects on brain function. Using high field fMRI we determined RSNs in awake rats using an independent component analysis (ICA) approach, however, ICA analysis can produce a large number of components, some with biological relevance (networks). We further have applied a novel method to determine networks that are robust and reproducible among all the components found with ICA. This analysis indicates that 7 networks are robust and reproducible in the rat and their putative role is discussed. PMID:22028788

  7. Diabetes and Insulin

    MedlinePlus

    ... years, but may eventually need insulin to maintain glucose control. What are the different types of insulin? Different ... glulisine • Short-acting: regular human insulin Basal insulin. Controls blood glucose levels between meals and throughout the night. This ...

  8. Intranasal midazolam for seizure cessation in the community setting

    PubMed Central

    Zelcer, Michal; Goldman, Ran D.

    2016-01-01

    Question There are times when parents arrive to my clinic after their child has had a seizure and a second seizure takes place in the clinic. While waiting for transport to the hospital, are there ways to stop the seizures without the need to obtain intravenous access in the clinic? Answer Intravenous diazepam has been a first-line therapy to stop seizures in children for many years. Other routes of drug administration such as intramuscular, rectal, and buccal are available but have several limitations. More evidence suggests that the intranasal route to administer drugs is quick and effective in children, and the use of midazolam has been continuing to show promise in seizure cessation. With its good safety profile, intranasal midazolam can be used in the clinic and prehospital setting for seizure cessation in children. PMID:27412207

  9. Assessment of the pharmacodynamics of intranasal, intravenous and oral scopolamine

    NASA Technical Reports Server (NTRS)

    Tietze, Karen J.

    1990-01-01

    Space motion sickness is an important issue in the space medical sciences program. One of the objectives of the ongoing clinical experimental protocol Pharmacokinetics of Intranasal Scopolamine in Normal Subjects is to evaluate the pharmacodynamics of scopolamine using salivary flow rate and pH profiles and cognitive performance tests as pharmacodynamic parameters. Normal volunteers collected saliva and performed the NTI Multiresource Performance Battery tests at designed time intervals to establish control saliva flow rates, salivary pH profiles, and the characteristics of the learning curve for the performance program under normal conditions. In the clinical part of the study, saliva samples and performance test scores are collected from healthy nonsmoking subjects after receiving a single 0.4 mg dose of either intranasal, intravenous, or oral scopolamine.

  10. Targeting glioblastoma via intranasal administration of Ff bacteriophages

    PubMed Central

    Dor-On, Eyal; Solomon, Beka

    2015-01-01

    Bacteriophages (phages) are ubiquitous viruses that control the growth and diversity of bacteria. Although they have no tropism to mammalian cells, accumulated evidence suggests that phages are not neutral to the mammalian macro-host and can promote immunomodulatory and anti-tumorigenic activities. Here we demonstrate that Ff phages that do not display any proteins or peptides could inhibit the growth of subcutaneous glioblastoma tumors in mice and that this activity is mediated in part by lipopolysaccharide molecules attached to their virion. Using the intranasal route, a non-invasive approach to deliver therapeutics directly to the CNS, we further show that phages rapidly accumulate in the brains of mice and could attenuate progression of orthotopic glioblastoma. Taken together, this study provides new insight into phages non-bacterial activities and demonstrates the feasibility of delivering Ff phages intranasally to treat brain malignancies. PMID:26074908

  11. Intranasal substituted cathinone "bath salts" psychosis potentially exacerbated by diphenhydramine.

    PubMed

    Gunderson, Erik W; Kirkpatrick, Matthew G; Willing, Laura M; Holstege, Christopher P

    2013-01-01

    In this report, we describe a case of intranasal "bath salts"-associated psychosis. Symptoms developed during a 3-week binge and were potentially exacerbated by oral diphenhydramine taken for insomnia. The clinical case conference includes expert discussion from 3 disciplines: emergency medicine toxicology, behavioral pharmacology, and addiction medicine. It is hoped that the discussion will provide insight into the clinical aspects and challenges of addressing acute substituted cathinone toxicity, including acute psychosis, a major adverse effect of bath salts consumption. PMID:23732955

  12. Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Tam, V.; Chow, Diana S. L.; Putcha, Lakshmi

    2014-01-01

    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials with an Investigative New Drug (IND). The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial with INSCOP.

  13. Pharmaceutical Product Development: Intranasal Scopolamine (INSCOP) Metered Dose Spray

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi; Crady, Camille; Putcha, Lakshmi

    2012-01-01

    Motion sickness (MS) has been a problem associated with space flight, the modern military and commercial air and water transportation for many years. Clinical studies have shown that scopolamine is the most effective medication for the prevention of motion sickness (Dornhoffer et al, 2004); however, the two most common methods of administration (transdermal and oral) have performance limitations that compromise its utility. Intranasal administration offers a noninvasive treatment modality, and has been shown to counter many of the problems associated with oral and transdermal administration. With the elimination of the first pass effect by the liver, intranasal delivery achieves higher and more reliable bioavailability than an equivalent oral dose. This allows for the potential of enhanced efficacy at a reduced dose, thus minimizing the occurrence of untoward side effects. An Intranasal scopolamine (INSCOP) gel formulation was prepared and tested in four ground-based clinical trials under an active Investigational New Drug (IND) application with the Food and Drug Administration (FDA). Although there were early indicators that the intranasal gel formulation was effective, there were aspects of formulation viscosity and the delivery system that were less desirable. The INSCOP gel formulation has since been reformulated into an aqueous spray dosage form packaged in a precise, metered dose delivery system; thereby enhancing dose uniformity, increased user satisfaction and palatability, and a potentially more rapid onset of action. Recent reports of new therapeutic indications for scopolamine has prompted a wide spread interest in new scopolamine dosage forms. The novel dosage form and delivery system of INSCOP spray shows promise as an effective treatment for motion sickness targeted at the armed forces, spaceflight, and commercial sea, air, and space travel markets, as well as prospective psychotherapy for mental and emotional disorders.

  14. Best evidence topic report. Intranasal midazolam in patients with fits.

    PubMed

    Smith, Martin; Carley, Simon

    2005-06-01

    A short cut review was carried out to establish whether intranasal midazolam was effective for stopping fits. Altogether 36 papers were found using the reported search, of which four presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these best papers are tabulated. A clinical bottom line is stated. PMID:15911956

  15. Microdialysis pharmacokinetic study of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration.

    PubMed

    Wei, Yan; Ying, Mingzhen; Xu, Shuai; Wang, Feng; Zou, Aifeng; Cao, Shilei; Jiang, Xinguo; Wang, Yajie

    2016-01-01

    The purpose of this study was to investigate the microdialysis pharmacokinetic of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration. The pharmacokinetic study of subcutaneous and oral administration was also performed in rats. From the in vivo results, scopolamine intranasal administration can avoid hepatic first-pass effect. Tmax plasma samples after intranasal administration were significantly faster than oral administration and subcutaneous injection. The relative bioavailability of intranasal administrations was 51.8-70% when compared with subcutaneous injection. Moreover, one can see that in comparison with scopolamine subcutaneous administration, scopolamine intranasal gel and solutions can increased drug target index (DTI) with olfactory bulb 1.69 and 2.05, vestibule 1.80 and 2.15, respectively. The results indicated that scopolamine can be absorbed directly through the olfactory mucosa into the olfactory bulb, and then transported to various brain tissue after intranasal administration, with the characteristics of brain drug delivery. PMID:24865285

  16. Dose escalation pharmacokinetics of intranasal scopolamine gel formulation.

    PubMed

    Wu, Lei; Boyd, Jason L; Daniels, Vernie; Wang, Zuwei; Chow, Diana S-L; Putcha, Lakshmi

    2015-02-01

    Astronauts experience Space Motion Sickness requiring treatment with an anti-motion sickness medication, scopolamine during space missions. Bioavailability after oral administration of scopolamine is low and variable, and absorption form transdermal patch is slow and prolonged. Intranasal administration achieves faster absorption and higher bioavailability of drugs that are subject to extrahepatic, first pass metabolism after oral dosing. We examined pharmacokinetics of 0.1, 0.2, and 0.4 mg doses of the Investigational New Drug formulation of intranasal scopolamine gel (INSCOP) in 12 healthy subjects using a randomized, double-blind cross-over study design. Subjects received one squirt of 0.1 g of gel containing either 0.1 mg or 0.2 mg/0.1 mL scopolamine or placebo in each nostril. Serial blood samples and total urine voids were collected after dosing and drug concentrations were determined using a modified LC-MS-MS method. Results indicate dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range tested. Plasma drug concentrations were significantly lower in females than in males after administration of 0.4 dose. All three doses were well tolerated with no unexpected or serious adverse side effects reported. These results suggest that intranasal scopolamine gel formulation (INSCOP) offers a fast, reliable, and safe alternative for the treatment of motion sickness. PMID:25187210

  17. Preparation and evaluation of fexofenadine microemulsion for intranasal delivery.

    PubMed

    Piao, Hong-Mei; Balakrishnan, Prabagar; Cho, Hyun Jong; Kim, Hyunjun; Kim, You Sun; Chung, Suk-Jae; Shim, Chang-Koo; Kim, Dae-Duk

    2010-06-01

    To enhance the solubility and bioavailability of poorly absorbable fexofenadine, microemulsion system composed of oil, surfactant and co-surfactant was developed for intranasal delivery. Phase behavior, particle size, viscosity and solubilization capacity of the microemulsion system were characterized. Histopathology and in vivo nasal absorption of the optimized microemulsion formulations were also investigated in rats. A single isotropic region was found in the pseudo-ternary phase diagrams developed at various ratios with Lauroglycol 90 as oil, Labrasol as surfactant and Plurol oleiqueCC49 or its mixture with PEG-400 (1:1) as cosurfactant. An increase in the microemulsion region in pseudo-ternary phase systems was observed with increased surfactant concentration. The optimized microemulsion formulations showed higher solubulization of fexofenadine, i.e., F1 (22.64mg/mL) and F2 (22.98mg/mL), compared to its intrinsic water solubility (1.51mg/mL). Nasal absorption of fexofenadine from these microemulsions was found to be fairly rapid. T(max) was observed within 5min after intranasal administration at 1.0mg/kg dose, and the absolute bioavailability (0-4h) was about 68% compared to the intravenous administration in rats. Our results suggested that these microemulsion formulations could be used as an effective intranasal dosage form for the rapid-onset delivery of fexofenadine. PMID:20685383

  18. Preparation and evaluation of fexofenadine microemulsions for intranasal delivery.

    PubMed

    Piao, Hong-Mei; Balakrishnan, Prabagar; Cho, Hyun-Jong; Kim, Hyunjun; Kim, You-Sun; Chung, Suk-Jae; Shim, Chang-Koo; Kim, Dae-Duk

    2010-08-16

    To enhance the solubility and bioavailability of poorly absorbable fexofenadine, microemulsion system composed of oil, surfactant and co-surfactant was developed for intranasal delivery. Phase behavior, particle size, viscosity and solubilization capacity of the microemulsion system were characterized. Histopathology and in vivo nasal absorption of the optimized microemulsion formulations were also investigated in rats. A single isotropic region was found in the pseudo-ternary phase diagrams developed at various ratios with Lauroglycol 90 as oil, Labrasol as surfactant and Plurol Oleique CC49 or its mixture with PEG-400 (1:1) as cosurfactant. An increase in the microemulsion region in pseudo-ternary phase systems was observed with increased surfactant concentration. The optimized microemulsion formulations showed higher solubulization of fexofenadine, i.e., F1 (22.64 mg/mL) and F2 (22.98 mg/mL), compared to its intrinsic water solubility (1.51 mg/mL). Nasal absorption of fexofenadine from these microemulsions was found to be fairly rapid. Tmax was observed within 5 min after intranasal administration at 1.0 mg/kg dose, and the absolute bioavailability (0-4 h) was about 68% compared to the intravenous administration in rats. Our results suggested that these microemulsion formulations could be used as an effective intranasal dosage form for the rapid-onset delivery of fexofenadine PMID:20635476

  19. Residual effects of intranasal methamphetamine on sleep, mood, and performance

    PubMed Central

    Perez, Audrey; Kirkpatrick, Matthew G.; Gunderson, Erik W.; Marrone, Gina; Silver, Rae; Foltin, Richard W.; Hart, Carl L.

    2008-01-01

    Although intranasal methamphetamine abuse has increased, there are no published data investigating the residual effects of the drug under controlled conditions. Thus, the current study examined the residual effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Non-treatment seeking methamphetamine abusers (n = 11) completed this two-week, in-patient, within-participant, double-blind study. The study consisted of 4 two-day blocks of sessions; each block was separated by at least 24 hrs. At approximately 1000 hrs, on the first day of each block, participants received one of four intranasal methamphetamine doses (0, 12, 25, 50 mg/70 kg). Lights were turned out at 2300 hrs that evening and sleep measures were assessed. On the morning of the second day of each block, methamphetamine plasma levels, cardiovascular measures, mood, subjective reports of the previous evening's sleep, and psychomotor performance were assessed to determine residual drug effects. The larger methamphetamine doses (25 and 50 mg) markedly disrupted subjective measures of that night's sleep and some indices of next-day mood, but only the largest dose (50 mg) dose decreased objective measures of that night's sleep and increased next-day physiological measures. Methamphetamine did not produce any negative residual effects on early next-day performance. Future studies should assess methamphetamine-related residual effects following repeated doses administered over consecutive days. PMID:18078723

  20. Urgent awake thoracoscopic treatment of retained haemothorax associated with respiratory failure.

    PubMed

    Pompeo, Eugenio; Cristino, Benedetto; Rogliani, Paola; Dauri, Mario

    2015-05-01

    A number of video-assisted thoracoscopic surgery (VATS) procedures are being increasingly performed by awake anesthesia in an attempt of minimizing the surgical- and anesthesia-related traumas. However, so far the usefulness of awake VATS for urgent management of retained haemothorax has been scarcely investigated. Herein we present two patients with retained haemothorax following previous thoracentesis and blunt chest trauma, respectively, who developed acute respiratory failure and underwent successful urgent awake VATS management under local anesthesia through a single trocar access. PMID:26046053

  1. WIDE AWAKE mediates the circadian timing of sleep onset.

    PubMed

    Liu, Sha; Lamaze, Angelique; Liu, Qili; Tabuchi, Masashi; Yang, Yong; Fowler, Melissa; Bharadwaj, Rajnish; Zhang, Julia; Bedont, Joseph; Blackshaw, Seth; Lloyd, Thomas E; Montell, Craig; Sehgal, Amita; Koh, Kyunghee; Wu, Mark N

    2014-04-01

    How the circadian clock regulates the timing of sleep is poorly understood. Here, we identify a Drosophila mutant, wide awake (wake), that exhibits a marked delay in sleep onset at dusk. Loss of WAKE in a set of arousal-promoting clock neurons, the large ventrolateral neurons (l-LNvs), impairs sleep onset. WAKE levels cycle, peaking near dusk, and the expression of WAKE in l-LNvs is Clock dependent. Strikingly, Clock and cycle mutants also exhibit a profound delay in sleep onset, which can be rescued by restoring WAKE expression in LNvs. WAKE interacts with the GABAA receptor Resistant to Dieldrin (RDL), upregulating its levels and promoting its localization to the plasma membrane. In wake mutant l-LNvs, GABA sensitivity is decreased and excitability is increased at dusk. We propose that WAKE acts as a clock output molecule specifically for sleep, inhibiting LNvs at dusk to promote the transition from wake to sleep. PMID:24631345

  2. The electron accelerator for the AWAKE experiment at CERN

    NASA Astrophysics Data System (ADS)

    Pepitone, K.; Doebert, S.; Burt, G.; Chevallay, E.; Chritin, N.; Delory, C.; Fedosseev, V.; Hessler, Ch.; McMonagle, G.; Mete, O.; Verzilov, V.; Apsimon, R.

    2016-09-01

    The AWAKE collaboration prepares a proton driven plasma wakefield acceleration experiment using the SPS beam at CERN. A long proton bunch extracted from the SPS interacts with a high power laser and a 10 m long rubidium vapour plasma cell to create strong wakefields allowing sustained electron acceleration. The electron bunch to probe these wakefields is supplied by a 20 MeV electron accelerator. The electron accelerator consists of an RF-gun and a short booster structure. This electron source should provide beams with intensities between 0.1 and 1 nC, bunch lengths between 0.3 and 3 ps and an emittance of the order of 2 mm mrad. The wide range of parameters should cope with the uncertainties and future prospects of the planned experiments. The layout of the electron accelerator, its instrumentation and beam dynamics simulations are presented.

  3. Technosphere insulin: an inhaled prandial insulin product.

    PubMed

    Neumiller, Joshua J; Campbell, R Keith

    2010-06-01

    Given the important role of insulin in the treatment of diabetes mellitus and in light of common barriers to insulin use, new strategies for insulin delivery by routes other than intravenous and subcutaneous injection have been investigated since the discovery of insulin in the 1920s. Most companies researching and developing pulmonary administration systems for the use of insulin announced the termination of product development following the failure of the first US FDA-approved inhaled insulin product, Exubera. One company in particular continued their pursuit of a useful inhaled insulin product. MannKind Corporation has developed a powder formulation of insulin that allows for a high percentage of the administered insulin to be absorbed via the lung. Their product, AFREZZA (Technosphere insulin), is currently under review by the FDA for use in patients with diabetes. Technosphere insulin appears to overcome some of the barriers that contributed to the market withdrawal of Exubera by the manufacturer. Studies with Technosphere insulin have shown it to be a unique insulin formulation in that it is very rapid acting, has a relatively short duration of action, and is efficacious in terms of improved glycemic control without contributing to increased weight gain or the incidence of hypoglycemia when compared with other prandial insulin products. Additionally, Technosphere insulin has demonstrated a favorable safety and tolerability profile in clinical studies to date. PMID:20462282

  4. Pediatric awake craniotomy for seizure focus resection with dexmedetomidine sedation-a case report.

    PubMed

    Sheshadri, Veena; Chandramouli, B A

    2016-08-01

    Resection of lesions near the eloquent cortex of brain necessitates awake craniotomy to reduce the risk of permanent neurologic deficits during surgery. There are limited reports of anesthetic management of awake craniotomy in pediatric patients. This report is on use of dexmedetomidine sedation for awake craniotomy in a 11-year-old child, without any airway adjuncts throughout the procedure. Dexmedetomidine infusion administered at a dosage of 0.2 to 0.7μg kg(-1) h(-1) provided adequate sedation for the entire procedure. There were no untoward incidents or any interference with electrocorticography, intraoperative stimulation, and functional mapping. Adequate preoperative visits and counseling of patient and parents regarding course and nature of events along with well-planned intraoperative management are of utmost importance in a pediatric age group for successful intraoperative awake craniotomy. PMID:27290976

  5. Long-term imaging in awake mice using removable cranial windows

    PubMed Central

    Glickfeld, Lindsey L.; Kerlin, Aaron M.; Reid, R. Clay; Bonin, Vincent; Schafer, Dorothy P.; Andermann, Mark L.

    2015-01-01

    Cranial window implants in head-fixed rodents are becoming a preparation of choice for stable optical access to large areas of cortex over extended periods of time. Here, we provide a highly detailed and reliable surgical protocol for a cranial window implantation procedure for chronic widefield and cellular imaging in awake, head-fixed mice, which enables subsequent window removal and replacement in the weeks and months following the initial craniotomy. This protocol has facilitated awake, chronic imaging in adolescent as well as adult mice over several months from a large number of cortical brain regions; targeted virus and tracer injections from data obtained using prior awake functional mapping; and functionally-targeted two-photon imaging across all cortical layers in awake mice using a microprism attachment to the cranial window. Collectively, these procedures extend the reach of chronic imaging of cortical function and dysfunction in behaving animals. PMID:25275789

  6. New intranasal formulations for the treatment of allergic rhinitis.

    PubMed

    Meltzer, Eli O; Bensch, Greg W; Storms, William W

    2014-01-01

    Intranasal corticosteroids (INSs) have been effectively used for >40 years for the treatment of seasonal allergic rhinitis (SAR) and perennial AR (PAR). Following the Montreal Protocol, the initial aerosol formulations using chlorofluorocarbon (CFC) propellants were phased out. For the past 20 years, aqueous solutions have been the only available option for INS treatment. In 2012, the U.S. Food and Drug Administration approved two new nonaqueous aerosol AR treatments that use a hydrofluoroalkane (HFA) propellant. In 2012, the first intranasal aqueous combination product was also approved. This article reviews the clinical profiles of HFA beclomethasone dipropionate (BDP) and HFA ciclesonide (CIC) and the aqueous combination intranasal antihistamine (INA)/INS formulation of azelastine hydrochloride/fluticasone propionate (AZE/FP). The medical literature was searched for clinical trials investigating the use of BDP, CIC, and AZE/FP in SAR and PAR. Clinical trials involving aqueous solutions and CFC propellant or HFA propellant delivery were included. Data from prescribing information and published efficacy and safety data were presented as part of the clinical profile for the reviewed agents. AZE/FP has shown efficacy and safety comparable or greater with the current AR treatment options. Although efficacy comparisons of new HFA formulations have not been investigated in head-to-head clinical trials with aqueous formulations, HFA formulations have shown similar efficacy rates. Furthermore, HFA formulations may have some additional benefits, including a preferable sensory profile for some patients. These new formulations will provide additional options for clinicians and patients to better individualize therapy for control of AR. PMID:25582157

  7. Computed Intranasal Spray Penetration: Comparisons Before and After Nasal Surgery

    PubMed Central

    Frank, Dennis O.; Kimbell, Julia S.; Cannon, Daniel; Rhee, John S.

    2012-01-01

    Background Quantitative methods for comparing intranasal drug delivery efficiencies pre- and postoperatively have not been fully utilized. The objective of this study is to use computational fluid dynamics techniques to evaluate aqueous nasal spray penetration efficiencies before and after surgical correction of intranasal anatomic deformities. Methods Ten three-dimensional models of the nasal cavities were created from pre- and postoperative computed tomography scans in five subjects. Spray simulations were conducted using a particle size distribution ranging from 10–110μm, a spray speed of 3m/s, plume angle of 68°, and with steady state, resting inspiratory airflow present. Two different nozzle positions were compared. Statistical analysis was conducted using Student T-test for matched pairs. Results On the obstructed side, posterior particle deposition after surgery increased by 118% and was statistically significant (p-value=0.036), while anterior particle deposition decreased by 13% and was also statistically significant (p-value=0.020). The fraction of particles that by-passed the airways either pre- or post-operatively was less than 5%. Posterior particle deposition differences between obstructed and contralateral sides of the airways were 113% and 30% for pre- and post-surgery, respectively. Results showed that nozzle positions can influence spray delivery. Conclusions Simulations predicted that surgical correction of nasal anatomic deformities can improve spray penetration to areas where medications can have greater effect. Particle deposition patterns between both sides of the airways are more evenly distributed after surgery. These findings suggest that correcting anatomic deformities may improve intranasal medication delivery. For enhanced particle penetration, patients with nasal deformities may explore different nozzle positions. PMID:22927179

  8. Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization.

    PubMed

    Achenbach, Peter; Barker, Jennifer; Bonifacio, Ezio

    2008-04-01

    Mucosal administration of insulin represents an attractive antigen-specific therapeutic approach to preventing type 1 diabetes. It can prevent autoimmune diabetes in animal models, but although it has been shown to be safe, it has not yet been proven effective in human studies. Efficacy may depend on the dose and route at which insulin is administered, the stage in type 1 diabetes pathogenesis at which treatment is initiated, and the study cohort that is treated. We have proposed Pre-POINT (Primary Oral/intranasal INsulin Trial), a dose-finding safety and immune efficacy pilot study for primary mucosal insulin therapy in islet autoantibody-negative children at high genetic risk for type 1 diabetes who naturally first develop autoimmunity to insulin. Pre-POINT aims to identify an optimal insulin dose and route of application (orally or intranasally) that is well tolerated and can induce an immune response to insulin for additional use in a phase II/III primary prevention trial in children at risk. PMID:18445349

  9. Serospecific protection of mice against intranasal infection with Bordetella pertussis.

    PubMed

    Robinson, A; Gorringe, A R; Funnell, S G; Fernandez, M

    1989-08-01

    The ability of purified serospecific agglutinogens from Bordetella pertussis to protect mice against intranasal infection has been examined. Immunization with agglutinogen 2 protected mice against infection with 1.2.0 or 1.2.3 serotypes of B. pertussis, whereas immunization with agglutinogen 3 protected mice against infection with all serotypes. More importantly immunization with serospecific agglutinogen resulted in immune selection so that organisms recovered following infection did not express the immunizing antigen. The results are consistent with the suggestions that protection of children with whole cell pertussis vaccine is to some extent serospecific and that agglutinogens should be considered as constituents of acellular pertussis vaccines. PMID:2573215

  10. Intranasal Delivery of pGDNF Nanoparticles for Parkinson's Disease

    NASA Astrophysics Data System (ADS)

    Harmon, Brendan Trevor

    Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects the dopaminergic A9 nigrostriatal tract. For dopamine neurons specifically, glial cell-derived neurotrophic factor (GDNF) has been shown to promote their survival and proliferation both in culture and in vivo. GDNF has also proven to be neuroprotective and restorative in various animal models of PD and some human clinical trials. However, its delivery to the brain has required invasive surgical routes which are not clinically practical for many patients. The main objective of this project was to test intranasal delivery to the brain of a nanoparticle vector incorporating an expression plasmid for GDNF (pGDNF). The intranasal route circumvents the blood-brain barrier, allowing larger sized vectors into the central nervous system while avoiding peripheral distribution. This approach would provide a renewable source of GDNF within the target areas of the brain, the striatum and the substantia nigra (SN) without the need for surgical injections or frequent re-dosing. A PEGylated polylysine compacted plasmid nanoparticle vector (PEG-CK30), developed by Copernicus Therapeutics, Inc., has been shown to transfect neurons and glial cells in vivo while lacking the safety issues present with other vectors. The first goal of this work was to determine if these PEG-CK30 compacted plasmid nanoparticles can successfully transfect cells and express the reporter protein, enhanced green fluorescent protein (eGFP) in the rat brain after intranasal administration. Initial in vivo experiments utilized the expression plasmid pCG, expressing eGFP under the fast-acting cytomegalovirus (CMV) promoter. Intranasal administration of pCG nanoparticles resulted in evidence of transfection of brain cells, as shown both qualitatively, by GFP-immunohistochemistry, and quantitatively, by GFP-ELISA. Expression was detected throughout the rat brain two days post-administration. Following the proof

  11. [Potential for the clinical use of intranasal rifathyroin for diagnosis and treatment].

    PubMed

    Starkova, N T; Butrova, S A; Surkov, S I; Kotova, G A; Nazarov, A N; Bobrovskaia, T A

    1991-01-01

    It has been shown that stimulated TSH and prolactin levels in intranasal administration of rifathyroin are comparable with the results of i.v. administration of the drug. Intranasal administration can be used for both therapeutic and diagnostic purposes. PMID:1788208

  12. Pentax-AWS videolaryngoscope for awake nasal intubation in patients with unstable necks.

    PubMed

    Asai, T

    2010-01-01

    In patients with unstable necks and at risk of pulmonary aspiration, awake fibreoptic intubation is often appropriate. However, stabilization of the neck can make fibreoptic intubation more difficult. I report the use of awake nasal intubation using the Pentax-Aiway Scope (AWS) in three patients with restricted neck movement, in whom awake fibreoptic intubation had failed. Case 1: a 59-yr-old man, at risk of aspiration, required an emergency cervical laminectomy. Awake fibreoptic intubation was attempted while a Halo vest was being applied, but it was impossible to see the glottis, mainly due to pharyngeal and laryngeal oedema. The Pentax-AWS was easily inserted orally, and nasotracheal intubation was achieved within 20 s. Case 2: an 85-yr-old woman with neck injury required emergency surgical stabilization. A retropharyngeal haematoma prevented a fibreoptic bronchoscope from being advanced beyond the epiglottis. Nasotracheal intubation using the Pentax-AWS (with the aid of a gum elastic bougie) was achieved within 1 min. Case 3: a 22-yr-old man, with partial spinal cord damage, was undergoing cervical laminoplasty. He was at risk of aspiration and had an oedematous larynx. Although it was possible to insert a fibreoptic bronchoscope into the trachea while the neck was stabilized with a Halo vest, it was impossible to advance a tube over the fibrescope. Awake nasotracheal intubation using the Pentax-AWS was achieved within 15 s. The Pentax-AWS may be useful for nasotracheal intubation in awake patients with restricted necks. PMID:19923133

  13. Awake tracheal intubation using Pentax airway scope in 30 patients: A Case series

    PubMed Central

    Kajekar, Payal; Mendonca, Cyprian; Danha, Rati; Hillermann, Carl

    2014-01-01

    Background and Aims: Pentax airway scope (AWS) has been successfully used for managing difficult intubations. In this case series, we aimed to evaluate the success rate and time taken to complete intubation, when AWS was used for awake tracheal intubation. Methods: We prospectively evaluated the use of AWS for awake tracheal intubation in 30 patients. Indication for awake intubation, intubation time, total time to complete tracheal intubation, laryngoscopic view (Cormack and Lehane grade), total dose of local anaesthetic used, anaesthetists rating and patient's tolerance of the procedure were recorded. Results: The procedure was successful in 25 out of the 30 patients (83%). The mean (standard deviation) intubation time and total time to complete the tracheal intubation was 5.4 (2.4) and 13.9 (3.7) min, respectively in successful cases. The laryngeal view was grade 1 in 24 and grade 2 in one of 25 successful intubations. In three out of the five patients where the AWS failed, awake tracheal intubation was successfully completed with the assistance of flexible fibre optic scope (FOS). Conclusion: Awake tracheal intubation using AWS was successful in 83% of patients. Success rate can be further improved using a combination of AWS and FOS. Anaesthesiologists who do not routinely use FOS may find AWS easier to use for awake tracheal intubation using an oral route. PMID:25197114

  14. The efficacy of combined regional nerve blocks in awake orotracheal fiberoptic intubation

    PubMed Central

    Chatrath, Veena; Sharan, Radhe; Jain, Payal; Bala, Anju; Ranjana; Sudha

    2016-01-01

    Aims of Study: To evaluate the efficacy, hemodynamic changes, and patient comfort during awake fiberoptic intubation done under combined regional blocks. Materials and Methods: In the present observational study, 50 patients of American Society of Anesthesiologists ( ASA) Grade I–II, Mallampati Grade I–IV were given nerve blocks - bilateral glossopharyngeal nerve block, bilateral superior laryngeal nerve block, and recurrent laryngeal nerve block before awake fiberoptic intubation using 2% lidocaine. Results: Procedure was associated with minimal increases in hemodynamic parameters during the procedure and until 3 min after it. Most of the intubations were being carried out within 3 min. Patient comfort was satisfactory with 90% of patients having favorable grades. Discussion: The most common cause of mortality and serious morbidity due to anesthesia is from airway problems. One-third of all anesthetic deaths are due to failure to intubate and ventilate. Awake flexible fiberoptic intubation under local anesthesia is now an accepted technique for managing such situations. In awake patient's anatomy, muscle tone, airway protection, and ventilation are preserved, but it is essential to sufficiently anesthetize the upper airway before the performance of awake fiberoptic bronchoscope-guided intubation to ensure patient comfort and cooperation for which in our study we used the nerve block technique. Conclusion: A properly performed technique of awake fiberoptic intubation done under combined regional nerve blocks provides good intubating conditions, patient comfort and safety and results in minimal hemodynamic changes. PMID:27212757

  15. Insulin Human Inhalation

    MedlinePlus

    Insulin inhalation is used in combination with a long-acting insulin to treat type 1 diabetes (condition in which the body does not produce insulin and therefore cannot control the amount of sugar ...

  16. Giving an insulin injection

    MedlinePlus

    ... One Type of Insulin Wash your hands with soap and water. Dry them well. Check the insulin ... syringe before injecting it. Wash your hands with soap and water. Dry them well. Check the insulin ...

  17. Insulin Lispro Injection

    MedlinePlus

    ... is a short-acting, man-made version of human insulin. Insulin lispro works by replacing the insulin ... niacin (Niacor, Niaspan, in Advicor); certain medications for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) ...

  18. Intranasally Administered Adjunctive Dexmedetomidine Reduces Perioperative Anesthetic Requirements in General Anesthesia

    PubMed Central

    Wu, Xiang; Hang, Li-Hua; Wang, Hong; Shao, Dong-Hua; Xu, Yi-Guo; Cui, Wei

    2016-01-01

    Purpose Intranasal dexmedetomidine is an effective sedative for premedication and is regularly used to reduce preoperative tension and anxiety in children. This study aimed to assess the effect of intranasally adjunctive dexmedetomidine on perioperative sedative and analgesic requirements in adults. Materials and Methods Patients were randomly divided into four groups to receive preoperative administration of saline, intranasal dexmedetomidine 1 µg/kg and 2 µg/kg, and intravenous dexmedetomidine 1 µg/kg, respectively. Propofol and remifentanil were target-controlled infused to maintain intraoperative bispectral index at 45–55 and blood pressure at baseline value±20%. Sufentanil was administered to maintain postoperative visual analogue scale ≤3. Perioperative anesthetics requirements were compared using nonparametric tests. Results Intranasal dexmedetomidine significantly attenuated propofol requirements for anesthesia induction and maintenance in a dose-dependent manner. Patients given intranasal dexmedetomidine 2 µg/kg required less remifentanil for anesthesia maintenance. The first postoperative request for sufentanil analgesia was delayed in patients given intranasal dexmedetomidine 2 µg/kg. The anesthetics-sparing effect of intranasal dexmedetomidine was significantly weaker than intravenous dexmedetomidine at the same dose of 1 µg/kg. The incidences of adverse events, including hemodynamic instability and delayed recovery, were comparable with and without intranasal dexmedetomidine. Conclusion Intranasal administration of dexmedetomidine can reduce perioperative anesthetic requirements, and a dose of dexmedetomidine 2 µg/kg produces a better effect in adults. The anesthetics-sparing effect of intranasal dexmedetomidine 1 µg/kg is less than that with the same intravenous dose of dexmedetomidine. PMID:27189297

  19. Central nervous insulin administration does not potentiate the acute glucoregulatory impact of concurrent mild hyperinsulinemia.

    PubMed

    Ott, Volker; Lehnert, Hendrik; Staub, Josefine; Wönne, Kathrin; Born, Jan; Hallschmid, Manfred

    2015-03-01

    Experiments in rodents suggest that hypothalamic insulin signaling essentially contributes to the acute control of peripheral glucose homeostasis. Against this background, we investigated in healthy humans whether intranasal (IN) insulin, which is known to effectively reach the brain compartment, impacts systemic glucose metabolism. Twenty overnight-fasted healthy, normal-weight men were IN administered 210 and 420 international units [IU] (10 and 20 IU every 15 min) of the insulin analog aspart (ins-asp) and placebo, respectively, during experimental sessions lasting 6 h. The use of ins-asp rather than human insulin enabled us to disentangle exogenous and endogenous insulin kinetics. IN insulin dose-dependently decreased plasma glucose concentrations while reducing C-peptide and attenuating endogenous insulin levels. However, we also observed a slight dose-dependent permeation of ins-asp into the circulation. In control experiments mimicking the systemic but not the central nervous uptake of the IN 210 IU dose via intravenous infusion of ins-asp at a dose of 0.12 IU/kg/24 h (n = 10), we obtained essentially identical effects on fasting plasma glucose concentrations. This pattern indicates that sustained IN insulin administration to the human brain to enhance central nervous insulin signaling does not acutely alter systemic glucose homeostasis beyond effects accounted for by concurrent mild hyperinsulinemia. PMID:25277390

  20. Bioavailability of intranasal promethazine dosage forms in dogs

    NASA Technical Reports Server (NTRS)

    Ramanathan, R.; Geary, R. S.; Bourne, D. W.; Putcha, L.

    1998-01-01

    Intramuscular promethazine (PMZ) is used aboard the US Space Shuttle to ameliorate symptoms of space motion sickness. Bioavailability after an oral dose of PMZ during space flight is thought to be impaired because of gastrointestinal disturbances associated with weightlessness and space motion sickness. In an attempt to find an alternative dosage form for use in space, we evaluated two intranasal (i.n.) dosage forms of PMZ in dogs for absorption and bioavailability relative to that of an equivalent intramuscular dose. Promethazine (5 mg kg-1) was administered as two intranasal dosage forms and as an intramuscular (i.m.) dose to three dogs in a randomised cross-over design. Serial blood samples were taken and analysed for PMZ concentrations and the absorption and bioavailability of PMZ were calculated for the three dosage forms. PMZ absorption from the carboxymethyl cellulose microsphere i.n. dosage form was more rapid and complete than from the myverol cubic gel formulation or from an i.m. injection. Bioavailability of the microsphere formulation was also greater than that of the gel formulation (AUC 3009 vs 1727 ng h ml-1). The bioavailability of the two i.n. dosage forms (relative to that of the i.m. injection) were 94% (microsphere) and 54% (gel). The i.n. microsphere formulation of PMZ offers great promise as an effective non-invasive alternative for treating space motion sickness due to its rapid absorption and bioavailability equivalent to the i.m. dose.

  1. Host resistance to intranasal Acinetobacter baumannii reinfection in mice.

    PubMed

    Qiu, Hongyu; Li, Zack; KuoLee, Rhonda; Harris, Greg; Gao, Xiaoling; Yan, Hongbin; Xu, H Howard; Chen, Wangxue

    2016-07-01

    Acinetobacter baumannii is a major causative agent of healthcare-associated infection and develops multidrug resistance rapidly. However, little is known in the host defense mechanisms against this infection. In this study, we examined if mice recovered from a previous intranasal A. baumannii infection (recovered mice) are fully protected against a subsequent reinfection. We found that, despite the presence of specific serum IgG and mucosal IgA responses prior to the reinfection, the recovered mice were only marginally better protected against intranasal challenge with low doses of homologous or heterologous A. baumannii strains than the naïve mice. Post-challenge immune and inflammatory (cells and cytokines) responses were generally comparable between recovered and naïve mice although the recovered mice produced significantly higher amounts of IFN-γ and IL-17 and had higher percentages and numbers of resident lung CD44(hi)CD62L(-)CD4(+) and CD19(+) B lymphocytes. Taken together, our results suggest that mice recovered from a previous A. baumannii infection remain susceptible to reinfection, indicating the complexity of immune protection mechanism for this Gram-negative, multidrug-resistant emerging pathogen. PMID:27194730

  2. Clinical implications for breath-powered powder sumatriptan intranasal treatment.

    PubMed

    Tepper, Stewart J

    2013-09-01

    The acute treatment of migraine requires matching patient need to drug and formulation. In particular, nausea and vomiting, quick time to peak intensity, and the common gastroparesis of migraineurs, all call for a variety of non-oral formulations for treatment of attacks. A novel breath-powered powder sumatriptan intranasal treatment offers an improvement, at least in pharmacokinetics, over conventional liquid nasal sumatriptan spray. The device for delivery in this breath-powered nasal sumatriptan uses natural nose anatomy to close the soft palate and propel the sumatriptan high up in the nasal cavity on one side with bidirectional airflow coming out the other side. This approach has the potential to reduce adverse events and improve efficacy. Phase 3 data on this system are in press at the time of this writing and results appear promising. The clinical role for a fast acting non-oral nasal formulation will be in those for whom tablets are bound to fail, that is, in the setting of nausea and vomiting or when the time to central sensitization, allodynia, and disabling migraine is too short for the patient to respond to a tablet. This review provides a clinical perspective on the breath-powered powder sumatriptan intranasal treatment. PMID:23809006

  3. Intranasal scopolamine affects the semicircular canals centrally and peripherally.

    PubMed

    Weerts, Aurélie P; Putcha, Lakshmi; Hoag, Stephen W; Hallgren, Emma; Van Ombergen, Angelique; Van de Heyning, Paul H; Wuyts, Floris L

    2015-08-01

    Space motion sickness (SMS), a condition caused by an intravestibular conflict, remains an important obstacle that astronauts encounter during the first days in space. Promethazine is currently the standard treatment of SMS, but scopolamine is used by some astronauts to prevent SMS. However, the oral and transdermal routes of administration of scopolamine are known to have substantial drawbacks. Intranasal administration of scopolamine ensures a fast absorption and rapid onset of therapeutic effect, which might prove to be suitable for use during spaceflights. The aim of this study was to evaluate the effects of intranasally administered scopolamine (0.4 mg) on the semicircular canals (SCCs) and the otoliths. This double-blind, placebo-controlled study was performed on 19 healthy male subjects. The function of the horizontal SCC and the vestibulo-ocular reflex, as well as the saccular function and utricular function, were evaluated. Scopolamine turned out to affect mainly the SCCs centrally and peripherally but also the utricles to a lesser extent. Centrally, the most probable site of action is the medial vestibular nucleus, where the highest density of muscarinic receptors has been demonstrated and afferent fibers from the SCCs and utricles synapse. Furthermore, our results suggest the presence of muscarinic receptors in the peripheral vestibular system on which scopolamine has a suppressive effect. Given the depressant actions on the SCCs, it is suggested that the pharmacodynamic effect of scopolamine may be attributed to the obliteration of intravestibular conflict that arises during (S)MS. PMID:25953832

  4. Clinical utility of insulin and insulin analogs

    PubMed Central

    Sanlioglu, Ahter D.; Altunbas, Hasan Ali; Balci, Mustafa Kemal; Griffith, Thomas S.; Sanlioglu, Salih

    2013-01-01

    Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes. PMID:23584214

  5. Influenza virus vaccine live intranasal--MedImmune vaccines: CAIV-T, influenza vaccine live intranasal.

    PubMed

    2003-01-01

    submitting a licence application in Europe, a $US27.5 million payment for approval of a refrigerator-stable liquid formulation of FluMist and as much as $US50 million for licensing of FluMist internationally. In July 2003 MedImmune announced that it had received approximately $US28 million in milestone payments during Q2 of 2003 for the approval of FluMist. CSL Ltd of Australia will collaborate on the development, sale and distribution of MedImmune Vaccine's vaccine in Australia, New Zealand and certain countries in the South Pacific. MedImmune is to acquire vaccine research programmes in respiratory syncytial virus and cytomegalovirus from MedImmune Vaccines. The company's primary interest is in FluMist. In May 2002, MedImmune licensed exclusive rights to Crucell's proprietary human cell line PER.C6 for use in its influenza vaccine programmes. On 11 March 2002, American Home Products changed its name and the names of its subsidiaries Wyeth-Ayerst and Wyeth-Lederle to Wyeth. Wyeth's vaccines division is called Wyeth Vaccines. On 29 September 2000, Aviron announced that it had been awarded a $US2.7 million Challenge Grant from NIAID for development of vaccines against pandemic strains of influenza based on FluMist intranasal technology. The cold-adapted live influenza vaccine has been widely evaluated in the US and Japan since 1975 in clinical trials involving several thousand people. Aviron completed phase II clinical trials in adults in the US and phase III trials in US children aged 15-71 months. Additional phase III trials in adults and the elderly are ongoing. Aviron also commenced phase III trials to test the safety of its intranasal live vaccine in children with moderate to severe asthma. The vaccine is delivered using the AccuSpray nasal delivery system by Becton Dickinson, which will supply the system for FluMist through the 2001-2002 influenza season under an agreement with Aviron made in August 1998. On 7 March 2000, Aviron announced that Wyeth-Lederle Vaccines

  6. Functional Connectivity Hubs and Networks in the Awake Marmoset Brain

    PubMed Central

    Belcher, Annabelle M.; Yen, Cecil Chern-Chyi; Notardonato, Lucia; Ross, Thomas J.; Volkow, Nora D.; Yang, Yihong; Stein, Elliot A.; Silva, Afonso C.; Tomasi, Dardo

    2016-01-01

    In combination with advances in analytical methods, resting-state fMRI is allowing unprecedented access to a better understanding of the network organization of the brain. Increasing evidence suggests that this architecture may incorporate highly functionally connected nodes, or “hubs”, and we have recently proposed local functional connectivity density (lFCD) mapping to identify highly-connected nodes in the human brain. Here, we imaged awake nonhuman primates to test whether, like the human brain, the marmoset brain contains FC hubs. Ten adult common marmosets (Callithrix jacchus) were acclimated to mild, comfortable restraint using individualized helmets. Following restraint training, resting BOLD data were acquired during eight consecutive 10 min scans for each subject. lFCD revealed prominent cortical and subcortical hubs of connectivity across the marmoset brain; specifically, in primary and secondary visual cortices (V1/V2), higher-order visual association areas (A19M/V6[DM]), posterior parietal and posterior cingulate areas (PGM and A23b/A31), thalamus, dorsal and ventral striatal areas (caudate, putamen, lateral septal nucleus, and anterior cingulate cortex (A24a). lFCD hubs were highly connected to widespread areas of the brain, and further revealed significant network-network interactions. These data provide a baseline platform for future investigations in a nonhuman primate model of the brain’s network topology. PMID:26973476

  7. Carotid endarterectomy in awake patients: safety, tolerability and results

    PubMed Central

    Mendonça, Célio Teixeira; Fortunato Jr, Jerônimo A.; de Carvalho, Cláudio A.; Weingartner, Janaina; Filho, Otávio R. M.; Rezende, Felipe F.; Bertinato, Luciane P.

    2014-01-01

    Objective To analyze the results of 125 carotid endarterectomies under loco-regional anesthesia, with selective use of shunt and bovine pericardium patch. Methods One hundred and seventeen patients with stenosis ≥ 70% in the internal carotid artery on duplex-scan + arteriography or magnetic resonance angiography underwent 125 carotid endarterectomies. Intraoperative pharmacological cerebral protection included intravenous administration of alfentanil and dexametasone. Clopidogrel, aspirin and statins were used in all cases. Seventy-seven patients were males (65.8%). Mean age was 70.8 years, ranging from 48 to 88 years. Surgery was performed to treat symptomatic stenosis in 69 arteries (55.2%) and asymptomatic stenosis in 56 arteries (44.8%). Results A carotid shunt was used in 3 cases (2.4%) due to signs and symptoms of cerebral ischemia after carotid artery clamping during the operation, and all 3 patients had a good outcome. Bovine pericardium patch was used in 71 arteries ≤ 6 mm in diameter (56.8%). Perioperative mortality was 0.8%: one patient died from a myocardial infarction. Two patients (1.6%) had minor ipsilateral strokes with good recovery, and 2 patients (1.6%) had non-fatal myocardial infarctions with good recovery. The mean follow-up period was 32 months. In the late postoperative period, there was restenosis in only three arteries (2.4%). Conclusion Carotid artery endarterectomy can be safely performed in the awake patient, with low morbidity and mortality rates. PMID:25714212

  8. Brainstem areas activated by intermittent apnea in awake unrestrained rats.

    PubMed

    Ferreira, C B; Schoorlemmer, G H; Rossi, M V; Takakura, A C; Barna, B F; Moreira, T S; Cravo, S L

    2015-06-25

    We investigated the role of the autonomic nervous system to cardiovascular responses to obstructive apnea in awake, unrestrained rats, and measured expression of Fos induced by apnea in the brainstem. We implanted a tracheal balloon contained in a rigid tube to allow the induction of apnea without inducing pain in the trachea. During bouts of 15s of apnea, heart rate fell from 371±8 to 161±11bpm (mean±SEM, n=15, p<0.01) and arterial pressure increased from 115±2 to 131±4mmHg (p<0.01). Bradycardia was due to parasympathetic activity because it was blocked by the muscarinic antagonist, methylatropine. The pressor response was due to vasoconstriction caused by sympathetic activation because it was blocked by the α1 antagonist, prazosin. Apnea induced Fos expression in several brainstem areas involved in cardiorespiratory control such as the nucleus of the solitary tract (NTS), ventrolateral medulla (VLM), and pons. Ligation of the carotid body artery reduced apnea-induced bradycardia, blocked heart rate responses to i.v. injection of cyanide, reduced Fos expression in the caudal NTS, and increased Fos expression in the rostral VLM. In conclusion, apnea activates neurons in regions that process signals from baroreceptors, chemoreceptors, pulmonary receptors, and regions responsible for autonomic and respiratory activity both in the presence and absence of carotid chemoreceptors. PMID:25862588

  9. Effect of nitroglycerin on myocardial collateral conductance in awake dogs

    SciTech Connect

    Brazzamano, S.; Rembert, J.C.; Greenfield, J.C. Jr. )

    1988-04-01

    Conductance of the coronary collateral circulation during the course of two abrupt circumflex coronary occlusions was measured in awake dogs {approximately} 2 wk after collateral vessels were stimulated to develop. The pressure gradient from the central aorta to the distal circumflex coronary artery was measured, and myocardial blood flow was determined by 9-{mu}m radioactive microspheres at 30 s and 4 min after coronary occlusions. Collateral conductance was calculated as mean collateral blood flow divided by the mean aorta-coronary pressure gradient. Before nitroglycerin, collateral conductance increased in all eight dogs from 30 s to 4 min. After nitroglycerin administration, the conductance at 30 s increased from the prenitroglycerin control value to 0.014 {+-} 0.012 ml{center dot}min{sup {minus}1}{center dot}g{sup {minus}1}{center dot}mmHg{sup {minus}1}. The mean change in conductance from 30 s to 4 min postnitroglycerin was significantly less than during prenitroglycerin. These data indicate that an increase in conductance during coronary occlusion occurs even in the immature collateral circulation. This effect presumably takes place in the arterial smooth muscle at the origin of the collateral vasculature.

  10. Neural representation of face familiarity in an awake chimpanzee.

    PubMed

    Fukushima, Hirokata; Hirata, Satoshi; Matsuda, Goh; Ueno, Ari; Fuwa, Kohki; Sugama, Keiko; Kusunoki, Kiyo; Hiraki, Kazuo; Tomonaga, Masaki; Hasegawa, Toshikazu

    2013-01-01

    Evaluating the familiarity of faces is critical for social animals as it is the basis of individual recognition. In the present study, we examined how face familiarity is reflected in neural activities in our closest living relative, the chimpanzee. Skin-surface event-related brain potentials (ERPs) were measured while a fully awake chimpanzee observed photographs of familiar and unfamiliar chimpanzee faces (Experiment 1) and human faces (Experiment 2). The ERPs evoked by chimpanzee faces differentiated unfamiliar individuals from familiar ones around midline areas centered on vertex sites at approximately 200 ms after the stimulus onset. In addition, the ERP response to the image of the subject's own face did not significantly diverge from those evoked by familiar chimpanzees, suggesting that the subject's brain at a minimum remembered the image of her own face. The ERPs evoked by human faces were not influenced by the familiarity of target individuals. These results indicate that chimpanzee neural representations are more sensitive to the familiarity of conspecific than allospecific faces. PMID:24392287

  11. Dynamic Resting State Functional Connectivity in Awake and Anesthetized Rodents

    PubMed Central

    Liang, Zhifeng; Liu, Xiao; Zhang, Nanyin

    2014-01-01

    Since its introduction, resting-state functional magnetic resonance imaging (rsfMRI) has been a powerful tool for investigating functional neural networks in both normal and pathological conditions. When measuring resting-state functional connectivity (RSFC), most rsfMRI approaches do not consider its temporal variations and thus only provide the averaged RSFC over the scan time. Recently, there has been a surge of interest to investigate the dynamic characteristics of RSFC in humans, and promising results have been yielded. However, our knowledge regarding the dynamic RSFC in animals remains sparse. In the present study we utilized the single-volume coactivation method to systematically study the dynamic properties of RSFC within the networks of infralimbic cortex (IL) and primary somatosensory cortex (S1) in both awake and anesthetized rats. Our data showed that both IL and S1 networks could be decomposed into several spatially reproducible but temporally changing co-activation patterns (CAPs), suggesting that dynamic RSFC was indeed a characteristic feature in rodents. In addition, we demonstrated that anesthesia profoundly impacted the dynamic RSFC of neural circuits subserving cognitive and emotional functions but had less effects on sensorimotor systems. Finally, we examined the temporal characteristics of each CAP, and found that individual CAPs exhibited consistent temporal evolution patterns. Together, these results suggest that dynamic RSFC might be a general phenomenon in vertebrate animals. In addition, this study has paved the way for further understanding the alterations of dynamic RSFC in animal models of brain disorders. PMID:25315787

  12. Concentrated insulins: the new basal insulins

    PubMed Central

    Lamos, Elizabeth M; Younk, Lisa M; Davis, Stephen N

    2016-01-01

    Introduction Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed. Areas covered This review highlights the published reports of the pharmacokinetic (PK) and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market. Conclusion Humulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration. PMID:27022271

  13. Intranasal leptin reduces appetite and induces weight loss in rats with diet-induced obesity (DIO).

    PubMed

    Schulz, Carla; Paulus, Kerstin; Jöhren, Olaf; Lehnert, Hendrik

    2012-01-01

    Resistance to brain-mediated effects of leptin is a characteristic feature of obesity, resulting from alterations in leptin receptor signaling in hypothalamic neurons and/or transport across the blood-brain-barrier. We have shown previously, that the latter can be circumvented by intranasal (i.n.) application of leptin in lean rats. This prompted us to test i.n. leptin in animals with diet-induced obesity (DIO) as a basis for future human administration. DIO was induced in male Wistar rats by feeding a cafeteria diet for 25 or 32 wk, respectively. Consecutively, these DIO animals (seven to eight per treatment) and standard diet rats (lean) (14-15 per treatment, matched for age and diet duration) were treated with 0.1, 0.2 mg/kg leptin, or control solution i.n. daily for 4 wk before onset of dark period. Energy intake and body weight were measured daily; blood glucose, serum insulin, and leptin were measured before and after treatment. Expression of hypothalamic neuropeptides was assessed by quantitative real-time PCR. We demonstrate, for the first time, that i.n. leptin reduces appetite and induces weight loss in DIO to the same extent as in lean rats. Our findings are supported accordingly by an altered expression pattern of anorexigenic and orexigenic neuropeptides in the hypothalamus, e.g. proopiomelanocortin, cocaine and amphetamine-related transcript, neuropeptide Y, agouti-related protein. It now appears clear that i.n. leptin is effectively acting in obese animals in the same fashion as in their lean counterparts. These findings now clearly warrant studies in humans and may open new perspectives in the treatment of obesity. PMID:22128019

  14. Awake craniotomy induces fewer changes in the plasma amino acid profile than craniotomy under general anesthesia.

    PubMed

    Hol, Jaap W; Klimek, Markus; van der Heide-Mulder, Marieke; Stronks, Dirk; Vincent, Arnoud J; Klein, Jan; Zijlstra, Freek J; Fekkes, Durk

    2009-04-01

    In this prospective, observational, 2-armed study, we compared the plasma amino acid profiles of patients undergoing awake craniotomy to those undergoing craniotomy under general anesthesia. Both experimental groups were also compared with a healthy, age-matched and sex-matched reference group not undergoing surgery. It is our intention to investigate whether plasma amino acid levels provide information about physical and emotional stress, as well as pain during awake craniotomy versus craniotomy under general anesthesia. Both experimental groups received preoperative, perioperative, and postoperative dexamethasone. The plasma levels of 20 amino acids were determined preoperative, perioperative, and postoperatively in all groups and were correlated with subjective markers for pain, stress, and anxiety. In both craniotomy groups, preoperative levels of tryptophan and valine were significantly decreased whereas glutamate, alanine, and arginine were significantly increased relative to the reference group. Throughout time, tryptophan levels were significantly lower in the general anesthesia group versus the awake craniotomy group. The general anesthesia group had a significantly higher phenylalanine/tyrosine ratio, which may suggest higher oxidative stress, than the awake group throughout time. Between experimental groups, a significant increase in large neutral amino acids was found postoperatively in awake craniotomy patients, pain was also less and recovery was faster. A significant difference in mean hospitalization time was also found, with awake craniotomy patients leaving after 4.53+/-2.12 days and general anesthesia patients after 6.17+/-1.62 days; P=0.012. This study demonstrates that awake craniotomy is likely to be physically and emotionally less stressful than general anesthesia and that amino acid profiling holds promise for monitoring postoperative pain and recovery. PMID:19295387

  15. Intranasal oxytocin increases social grooming and food sharing in the common vampire bat Desmodus rotundus.

    PubMed

    Carter, Gerald G; Wilkinson, Gerald S

    2015-09-01

    Intranasal oxytocin (OT) delivery has been used to non-invasively manipulate mammalian cooperative behavior. Such manipulations can potentially provide insight into both shared and species-specific mechanisms underlying cooperation. Vampire bats are remarkable for their high rates of allogrooming and the presence of regurgitated food sharing among adults. We administered intranasal OT to highly familiar captive vampire bats of varying relatedness to test for an effect on allogrooming and food sharing. We found that intranasal OT did not have a detectable effect on food-sharing occurrence, but it did increase the size of regurgitated food donations when controlling for dyad and amount of allogrooming. Intranasal OT in females increased the amount of allogrooming per partner and across all partners per trial, but not the number of partners. We also found that the peak effect of OT treatments occurred 30-50min after administration, which is consistent with the reported latency for intranasal OT to affect relevant brain areas in rats and mice. Our results suggest that intranasal OT is a potential tool for influencing dyadic cooperative investments, but measuring prior social relationships may be necessary to interpret the results of hormonal manipulations of cooperative behavior and it may be difficult to alter partner choice in vampire bats using intranasal OT alone. PMID:26475061

  16. Comparative efficacy of intranasal and oral vaccines against Bordetella bronchiseptica in dogs.

    PubMed

    Ellis, J A; Gow, S P; Waldner, C L; Shields, S; Wappel, S; Bowers, A; Lacoste, S; Xu, Z; Ball, E

    2016-06-01

    In order to determine the comparative efficacy of vaccines administered intranasally or orally to protect puppies from disease subsequent to experimental infection with Bordetella bronchiseptica (Bb), a randomized controlled trial was performed using 48 approximately 8-week-old specific pathogen free, Bb naive Beagle puppies. Puppies were randomized into three groups and administered vaccines containing Bb intranasally or orally, or a placebo intranasally. Twenty-one days later, all dogs were challenge exposed via aerosol administration of Bb. Clinical signs, nasal bacterial shedding and immune responses were monitored for 28 days after challenge. Intranasally vaccinated puppies had significantly lower rates of coughing, nasal discharge, retching and sneezing (i.e. were less sick clinically) than control puppies. The distinction between the orally vaccinated puppies and the control puppies was less consistent. The orally vaccinated puppies had less coughing and less retching than the control puppies, but nasal discharge and sneezing did not differ from control animals. Orally vaccinated puppies had higher rates of coughing, nasal discharge, retching and sneezing than the intranasally vaccinated puppies. Although both intranasal and oral Bb vaccines stimulated immune responses associated with disease sparing following Bb infection, the intranasal route of delivery conferred superior clinical outcomes. The observed difference in clinical efficacy suggests the need to question the rationale for the use of currently available orally administered Bb vaccines. PMID:27256028

  17. The Rationale for Insulin Therapy in Alzheimer's Disease.

    PubMed

    Ribarič, Samo

    2016-01-01

    Alzheimer's disease (AD) is the most common form of dementia, with a prevalence that increases with age. By 2050, the worldwide number of patients with AD is projected to reach more than 140 million. The prominent signs of AD are progressive memory loss, accompanied by a gradual decline in cognitive function and premature death. AD is the clinical manifestation of altered proteostasis. The initiating step of altered proteostasis in most AD patients is not known. The progression of AD is accelerated by several chronic disorders, among which the contribution of diabetes to AD is well understood at the cell biology level. The pathological mechanisms of AD and diabetes interact and tend to reinforce each other, thus accelerating cognitive impairment. At present, only symptomatic interventions are available for treating AD. To optimise symptomatic treatment, a personalised therapy approach has been suggested. Intranasal insulin administration seems to open the possibility for a safe, and at least in the short term, effective symptomatic intervention that delays loss of cognition in AD patients. This review summarizes the interactions of AD and diabetes from the cell biology to the patient level and the clinical results of intranasal insulin treatment of cognitive decline in AD. PMID:27240327

  18. Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning.

    PubMed

    Krishnan, Jishnu K S; Arun, Peethambaran; Appu, Abhilash P; Vijayakumar, Nivetha; Figueiredo, Taíza H; Braga, Maria F M; Baskota, Sudikshya; Olsen, Cara H; Farkas, Natalia; Dagata, John; Frey, William H; Moffett, John R; Namboodiri, Aryan M A

    2016-03-01

    Intranasal delivery is an emerging method for bypassing the blood brain barrier (BBB) and targeting therapeutics to the CNS. Oximes are used to counteract the effects of organophosphate poisoning, but they do not readily cross the BBB. Therefore, they cannot effectively counteract the central neuropathologies caused by cholinergic over-activation when administered peripherally. For these reasons we examined intranasal administration of oximes in an animal model of severe organophosphate poisoning to determine their effectiveness in reducing mortality and seizure-induced neuronal degeneration. Using the paraoxon model of organophosphate poisoning, we administered the standard treatment (intramuscular pralidoxime plus atropine sulphate) to all animals and then compared the effectiveness of intranasal application of obidoxime (OBD) to saline in the control groups. Intranasally administered OBD was effective in partially reducing paraoxon-induced acetylcholinesterase inhibition in the brain and substantially reduced seizure severity and duration. Further, intranasal OBD completely prevented mortality, which was 41% in the animals given standard treatment plus intranasal saline. Fluoro-Jade-B staining revealed extensive neuronal degeneration in the surviving saline-treated animals 24h after paraoxon administration, whereas no detectable degenerating neurons were observed in any of the animals given intranasal OBD 30min before or 5min after paraoxon administration. These findings demonstrate that intranasally administered oximes bypass the BBB more effectively than those administered peripherally and provide an effective method for protecting the brain from organophosphates. The addition of intranasally administered oximes to the current treatment regimen for organophosphate poisoning would improve efficacy, reducing both brain damage and mortality. PMID:26751814

  19. Topical and Intranasal Analgesic Therapy in a Woman with Refractory Postherpetic Neuralgia

    PubMed Central

    Hohmeier, Kenneth C.; Almon, Lyndsey M.

    2015-01-01

    A patient-specific, stepped approach to topical and intranasal analgesic pharmacotherapy was effective in reducing refractory postherpetic neuralgia (PHN) not responding to the current standard of care for PHN. The use of topical analgesic therapy allowed for higher concentrations of medication locally while reducing the likelihood of systemic side effects common to the drugs used. No adverse effects were noted for either topical or intranasal drug therapy. The patient-specific, stepped approach resulted in clinically significant decreases in pain on visual analog scale (VAS), with the use of intranasal ketamine 10% solution and topical gabapentin 6%, ketoprofen 10%, lidocaine 5%, and ketamine 10% cream. PMID:25949241

  20. Awake brain tumor resection during pregnancy: Decision making and technical nuances.

    PubMed

    Meng, Lingzhong; Han, Seunggu J; Rollins, Mark D; Gelb, Adrian W; Chang, Edward F

    2016-02-01

    The co-occurrence of primary brain tumor and pregnancy poses unique challenges to the treating physician. If a rapidly growing lesion causes life-threatening mass effect, craniotomy for tumor debulking becomes urgent. The choice between awake craniotomy versus general anesthesia becomes complicated if the tumor is encroaching on eloquent brain because considerations pertinent to both patient safety and oncological outcome, in addition to fetal wellbeing, are involved. A 31-year-old female at 30 weeks gestation with twins presented to our hospital seeking awake craniotomy to resect a 7 × 6 × 5 cm left frontoparietal brain tumor with 7 mm left-to-right subfalcine herniation on imaging that led to word finding difficulty, dysfluency, right upper extremity paralysis, and right lower extremity weakness. She had twice undergone tumor debulking under general anesthesia during the same pregnancy at an outside hospital at 16 weeks and 28 weeks gestation. There were considerations both for and against awake brain tumor resection over surgery under general anesthesia. The decision-making process and the technical nuances related to awake brain tumor resection in this neurologically impaired patient are discussed. Awake craniotomy benefits the patient who harbors a tumor that encroaches on the eloquent brain by allowing a greater extent of resection while preserving the language and sensorimotor function. It can be successfully done in pregnant patients who are neurologically impaired. The patient should be motivated and well informed of the details of the process. A multidisciplinary and collaborative effort is also crucial. PMID:26498092

  1. Anaphylaxis following intranasal challenge of mice sensitized with ovalbumin.

    PubMed Central

    McCaskill, A C; Hosking, C S; Hill, D J

    1984-01-01

    Mice sensitized with two intraperitoneal injections of ovalbumin and challenged intranasally with the same antigen developed a non-fatal anaphylactic shock peaking in severity 30 min after challenge. Increases in haematocrit were noted which corresponded to the severity of signs of shock displayed by mice. Severity of shock also correlated with IgE and IgG levels. Sensitization by the nasal route, and use of B. pertussis vaccine as adjuvant had no qualitative effect upon the response. Cobra venom factor depletion of C3 in vivo did not alter the response of mice, which suggests anaphylaxis did not involve complement activation. Sensitivity was not transferrable to non-immune mice with serum. Passive sensitization with polyclonal and monoclonal antibodies produced inconsistent results. Possible mechanisms of anaphylaxis are discussed. PMID:6706376

  2. Meal-contingent intestinal lymph sampling from awake, unrestrained rats.

    PubMed

    Arnold, Myrtha; Dai, Yunting; Tso, Patrick; Langhans, Wolfgang

    2012-06-15

    Standard procedures for intestinal lymph collection involve continuous, quantitative drainage of the lymph fluid in anesthetized or restrained animals that are often euthanized within 48 h. We here describe a novel technique for the nonocclusive cannulation of the major intestinal lymph duct in rats that allows for repetitive in vivo sampling of intestinal lymph from unrestrained, awake, and ad libitum-fed animals. The distinctive feature of this novel technique is that a 5- to 7-mm long piece of Vialon tubing (OD/ID: 0.8/0.7 mm) with a small hole in its wall is first implanted into the major intestinal lymph duct for stabilization. The tapered tip (OD: ≈0.1 mm) of the catheter is then inserted into the hole of the tubing and fixed in place with a polyamid suture and a drop of tissue glue. In our hands, catheters implanted this way remain patent for up to 6 wk after surgery. In an initial experiment we collected lymph from six adult rats before (0) and 15, 30, 45, 60, 75, 90, 120, and 180 min (120 μl, each) after the onset of isocaloric (12.5 kcal) low-fat (LF) or high-fat (HF) test meals and measured active glucagon-like peptide-1 (GLP-1). Intestinal lymphatic GLP-1 concentration increased (P < 0.05) from ≈4 pmol/l (0 min) to a peak of 33 ± 6 (means ± SE) or 22 ± 4 pmol/l at 15 (HF) or 30 min (LF) after meal onset and gradually returned to baseline levels by 180 min. With this new technique fewer animals are required to generate physiologically relevant data for various aspects of gastrointestinal physiology that involve the lymphatic system. Furthermore, the advantage of this system is that the animal can act as its own control when the effect of different experimental protocols is tested. PMID:22513747

  3. Thermoreversible nanoethosomal gel for the intranasal delivery of Eletriptan hydrobromide.

    PubMed

    Shelke, Santosh; Shahi, Sadhana; Jadhav, Kiran; Dhamecha, Dinesh; Tiwari, Roshan; Patil, Hemlata

    2016-06-01

    The objective of the current study was to formulate and characterize thermoreversible gel of Eletriptan Hydrobromide for brain targeting via the intranasal route. Ethosomes were prepared by 3(2) factorial design with two independent variables (concentration of soya lecithin and ethanol) and two response variables [percent entrapment efficiency and vesicle size (nm)] using ethanol injection method. Formulated ethosomes were evaluated for preliminary microscopic examination followed by percent drug entrapment efficiency, vesicle size analysis, zeta potential, polydispersibility index and Transmission electron microscopy (TEM). TEM confirms spherical morphology of ethosomes, whereas Malvern zeta sizer confirms that the vesicle size was in the range of 191 ± 6.55-381.3 ± 61.0 nm. Ethosomes were incorporated in gel using poloxamer 407 and carbopol 934 as thermoreversible and mucoadhesive polymers, respectively. Ethosomal gels were evaluated for their pH, viscosity, mucoadhesive strength, in vitro drug release and ex vivo drug permeation through the sheep nasal mucosa. Mucoadhesive strength and pH was found to be 4400 ± 45 to 5500 ± 78.10 dynes/cm(2) and 6.0 ± 0.3 to 6.2 ± 0.1, respectively. In-vitro drug release from the optimized ethosomal gel formulation (G4) was found to be almost 100 % and ex vivo permeation of 4980 µg/ml with a permeability coefficient of 11.94 ± 0.04 × 10(-5) cm/s after 24 h. Histopathological study of the nasal mucosa confirmed non-toxic nature of ethosomal gels. Formulated EH loaded ethosomal thermoreversible gel could serve as the better alternative for the brain targeting via the intranasal route which in turn could subsequently improve its bioavailability. PMID:27091045

  4. Guinea Pig Lung Lavage Cells After Intranasal BCG Sensitization

    PubMed Central

    Terai, T.; Ganguly, Rama; Waldman, Robert H.

    1979-01-01

    Recent studies have suggested that intranasal administration of antigen can induce local cell-mediated immunity in lung lavage cells. The present study was designed to examine the changes in composition of lung lavage cells and their capacity to produce the lymphokine migration inhibitory factor after intranasal immunization with BCG in guinea pigs. Results indicate that guinea pigs responded to respiratory tract BCG infection with an increase in immunocompetent cells in the bronchoalveolar tract and with production of migration inhibitory factor. After local pulmonary BCG administration, the total number of cells increased as compared with that of the uninfected animals, the increase being statistically significant within 2 weeks. This marked increase in the total cell population is due to a more than doubling of the number of macrophages in the lavage fluid. Animals also developed at this time positive delayed hypersensitivity to intradermally administered purified protein derivative. A significant increase in the total lymphoid cells and macrophage population was observed again at 6 weeks after sensitization, suggesting that the response is biphasic in nature. At 6 weeks, however, there was also a significant rise in total lymphocytes and T cell population in addition to macrophage numbers. This increase in T cells correlated with an increase in production of migration inhibitory factor in the presence of purified protein derivative. These data suggest that the immune response of the respiratory tract after BCG challenge involves increased recruitment of immunocompetent cells locally at the site of infection and that these cells are capable of producing effector molecules in terms of the elaboration of migration inhibitory factor. PMID:387595

  5. Plasma oxytocin concentrations following MDMA or intranasal oxytocin in humans

    PubMed Central

    Kirkpatrick, Matthew G.; Francis, Sunday M.; Lee, Royce; de Wit, Harriet; Jacob, Suma

    2014-01-01

    MDMA (±3,4-methylenedioxymethamphetamine, ‘ecstasy’) is reportedly used recreationally because it increases feelings of sociability and interpersonal closeness. Prior work suggests that the pro-social effects of MDMA may be mediated by release of oxytocin. A direct examination of plasma levels of oxytocin after acute doses of oxytocin and MDMA, in the same individuals, would provide further evidence for the idea that MDMA produces its prosocial effects by increasing oxytocin. Fourteen healthy MDMA users participated in a 4-session, double-blind study in which they received oral MDMA (0.75 and 1.5 mg/kg), intranasal oxytocin (20 IU or 40 IU), and placebo. Plasma oxytocin concentrations, as well as cardiovascular and subjective effects were assessed before and at several time points after drug administration. MDMA (1.5 mg/kg only) increased plasma oxytocin levels to a mean peak of 83.7 pg/ml at approximately 90–120 minutes, compared to 18.6 pg/ml after placebo. Intranasal oxytocin (40 IU, but not 20 IU) increased plasma oxytocin levels to 48.0 pg/ml, 30–60 min after nasal spray administration. MDMA dose-dependently increased heart rate, blood pressure, feelings of euphoria (e.g., ‘High’ and ‘Like Drug’), and feelings of sociability, whereas oxytocin had no cardiovascular or subjective effects. The subjective and cardiovascular responses to MDMA were not related to plasma oxytocin levels, although the N was small for this analysis. Future studies examining the effects of oxytocin antagonists on responses to MDMA will help to determine the mechanism by which MDMA produces pro-social effects. PMID:24882155

  6. Intranasal Delivery of pGDNF Nanoparticles for Parkinson's Disease

    NASA Astrophysics Data System (ADS)

    Harmon, Brendan Trevor

    Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects the dopaminergic A9 nigrostriatal tract. For dopamine neurons specifically, glial cell-derived neurotrophic factor (GDNF) has been shown to promote their survival and proliferation both in culture and in vivo. GDNF has also proven to be neuroprotective and restorative in various animal models of PD and some human clinical trials. However, its delivery to the brain has required invasive surgical routes which are not clinically practical for many patients. The main objective of this project was to test intranasal delivery to the brain of a nanoparticle vector incorporating an expression plasmid for GDNF (pGDNF). The intranasal route circumvents the blood-brain barrier, allowing larger sized vectors into the central nervous system while avoiding peripheral distribution. This approach would provide a renewable source of GDNF within the target areas of the brain, the striatum and the substantia nigra (SN) without the need for surgical injections or frequent re-dosing. A PEGylated polylysine compacted plasmid nanoparticle vector (PEG-CK30), developed by Copernicus Therapeutics, Inc., has been shown to transfect neurons and glial cells in vivo while lacking the safety issues present with other vectors. The first goal of this work was to determine if these PEG-CK30 compacted plasmid nanoparticles can successfully transfect cells and express the reporter protein, enhanced green fluorescent protein (eGFP) in the rat brain after intranasal administration. Initial in vivo experiments utilized the expression plasmid pCG, expressing eGFP under the fast-acting cytomegalovirus (CMV) promoter. Intranasal administration of pCG nanoparticles resulted in evidence of transfection of brain cells, as shown both qualitatively, by GFP-immunohistochemistry, and quantitatively, by GFP-ELISA. Expression was detected throughout the rat brain two days post-administration. Following the proof

  7. [Awake intubation with landiolol and dexmedetomidine in a patient with anxiety neurosis].

    PubMed

    Nagamine, Tatsunari; Komasawa, Nobuyasu; Fujitate, Yasutaka; Kuzukawa, Yosuke; Kitano, Manabu; Minami, Toshiaki

    2014-08-01

    We report a successful case of awake intubation in a patient with anxiety neurosis via continuous administration of landiolol and dexmedetomidine. A 52-year-old woman weighing 46.8 kg with anxiety neurosis experienced postoperative bleeding after left-side thyroidectomy and was scheduled for emergent hemostasis under general anesthesia Due to swelling of the neck, we anticipated a difficult airway and decided to perform awake intubation. She showed extreme insecurity and shivering, and initially did not agree to the procedure. To calm her anxiety and panic, we continuously administered 10 microg x kg(-1). min(-1) landiolol and 1.0 microg x kg(-1) hr(-1) dexmedetomidine. After 10 minutes, her shivering disappeared, and she agreed to undergo awake intubation, which was performed with the Pentax-AWS Airwayscope and thin Intlock blade. The patient bucked slightly during intubation but hemodynamic changes were minimal. PMID:25199332

  8. AWAKE, The Advanced Proton Driven Plasma Wakefield Acceleration Experiment at CERN

    NASA Astrophysics Data System (ADS)

    Gschwendtner, E.; Adli, E.; Amorim, L.; Apsimon, R.; Assmann, R.; Bachmann, A.-M.; Batsch, F.; Bauche, J.; Berglyd Olsen, V. K.; Bernardini, M.; Bingham, R.; Biskup, B.; Bohl, T.; Bracco, C.; Burrows, P. N.; Burt, G.; Buttenschön, B.; Butterworth, A.; Caldwell, A.; Cascella, M.; Chevallay, E.; Cipiccia, S.; Damerau, H.; Deacon, L.; Dirksen, P.; Doebert, S.; Dorda, U.; Farmer, J.; Fedosseev, V.; Feldbaumer, E.; Fiorito, R.; Fonseca, R.; Friebel, F.; Gorn, A. A.; Grulke, O.; Hansen, J.; Hessler, C.; Hofle, W.; Holloway, J.; Hüther, M.; Jaroszynski, D.; Jensen, L.; Jolly, S.; Joulaei, A.; Kasim, M.; Keeble, F.; Li, Y.; Liu, S.; Lopes, N.; Lotov, K. V.; Mandry, S.; Martorelli, R.; Martyanov, M.; Mazzoni, S.; Mete, O.; Minakov, V. A.; Mitchell, J.; Moody, J.; Muggli, P.; Najmudin, Z.; Norreys, P.; Öz, E.; Pardons, A.; Pepitone, K.; Petrenko, A.; Plyushchev, G.; Pukhov, A.; Rieger, K.; Ruhl, H.; Salveter, F.; Savard, N.; Schmidt, J.; Seryi, A.; Shaposhnikova, E.; Sheng, Z. M.; Sherwood, P.; Silva, L.; Soby, L.; Sosedkin, A. P.; Spitsyn, R. I.; Trines, R.; Tuev, P. V.; Turner, M.; Verzilov, V.; Vieira, J.; Vincke, H.; Wei, Y.; Welsch, C. P.; Wing, M.; Xia, G.; Zhang, H.

    2016-09-01

    The Advanced Proton Driven Plasma Wakefield Acceleration Experiment (AWAKE) aims at studying plasma wakefield generation and electron acceleration driven by proton bunches. It is a proof-of-principle R&D experiment at CERN and the world's first proton driven plasma wakefield acceleration experiment. The AWAKE experiment will be installed in the former CNGS facility and uses the 400 GeV/c proton beam bunches from the SPS. The first experiments will focus on the self-modulation instability of the long (rms ~12 cm) proton bunch in the plasma. These experiments are planned for the end of 2016. Later, in 2017/2018, low energy (~15 MeV) electrons will be externally injected into the sample wakefields and be accelerated beyond 1 GeV. The main goals of the experiment will be summarized. A summary of the AWAKE design and construction status will be presented.

  9. Anti-obesity effect of intranasal administration of galanin-like peptide (GALP) in obese mice.

    PubMed

    Kageyama, Haruaki; Shiba, Kanako; Hirako, Satoshi; Wada, Nobuhiro; Yamanaka, Satoru; Nogi, Yukinori; Takenoya, Fumiko; Nonaka, Naoko; Hirano, Tsutomu; Inoue, Shuji; Shioda, Seiji

    2016-01-01

    Galanin-like peptide (GALP) has an anti-obesity effect in rats and mice. It has been reported that the uptake of GALP by the brain is higher after intranasal administration than with intravenous injection. This study therefore aimed to clarify the effect of intranasal administration of GALP on the feeding behavior of lean and obese mice. Autoradiography revealed the presence of (125)I-GALP in the olfactory bulb and the brain microcirculation. The body weights of ob/ob mice gradually increased during vehicle treatment, but remained unchanged in response to repeated intranasal administration of GALP, with both ob/ob and diet-induced obese mice displaying significantly decreased food intake, water intake and locomotor activity when treated with GALP. These results suggest that intranasal administration is an effective route whereby GALP can exert its effect as an anti-obesity drug. PMID:27323911

  10. The effect of long-term use of intranasal steroids on intraocular pressure

    PubMed Central

    Şimşek, Ali; Bayraktar, Cem; Doğan, Sedat; Karataş, Mehmet; Sarıkaya, Yasin

    2016-01-01

    Long-term use of topical nasal steroids (especially older generation steroids) has been shown to elevate intraocular pressure (IOP), but newer intranasal steroids are thought to have a minimal effect on IOP because of their low bioavailability. This study aimed to investigate alterations in IOP with two commonly used intranasal steroids for a 6-month period of time. One-hundred allergic rhinitis patients, divided equally into two groups, used mometasone furoate and fluticasone furoate intranasal steroids for 6 months. IOPs were measured before treatment and repeated at the 3rd, 6th, 12th, and 24th weeks of treatment. The IOPs of the groups were then compared. No statistically significant alteration was observed between the groups during the treatment time period. It was found that new generation intranasal steroids can be used safely, and there may not be an increased risk of IOP elevation in prolonged use in normal healthy people. PMID:27354761

  11. Anti-obesity effect of intranasal administration of galanin-like peptide (GALP) in obese mice

    PubMed Central

    Kageyama, Haruaki; Shiba, Kanako; Hirako, Satoshi; Wada, Nobuhiro; Yamanaka, Satoru; Nogi, Yukinori; Takenoya, Fumiko; Nonaka, Naoko; Hirano, Tsutomu; Inoue, Shuji; Shioda, Seiji

    2016-01-01

    Galanin-like peptide (GALP) has an anti-obesity effect in rats and mice. It has been reported that the uptake of GALP by the brain is higher after intranasal administration than with intravenous injection. This study therefore aimed to clarify the effect of intranasal administration of GALP on the feeding behavior of lean and obese mice. Autoradiography revealed the presence of 125I-GALP in the olfactory bulb and the brain microcirculation. The body weights of ob/ob mice gradually increased during vehicle treatment, but remained unchanged in response to repeated intranasal administration of GALP, with both ob/ob and diet-induced obese mice displaying significantly decreased food intake, water intake and locomotor activity when treated with GALP. These results suggest that intranasal administration is an effective route whereby GALP can exert its effect as an anti-obesity drug. PMID:27323911

  12. Intranasal epidermoid cyst causing upper airway obstruction in three brachycephalic dogs.

    PubMed

    Murgia, D; Pivetta, M; Bowlt, K; Volmer, C; Holloway, A; Dennis, R

    2014-08-01

    This case report describes three brachycephalic dogs with intranasal epidermoid cysts that were causing additional upper airway obstruction. Although epidermoid cysts have been described in several locations in dogs, to the authors' knowledge intranasal epidermoid cysts have not been previously reported. All dogs had mucopurulent to haemorrhagic nasal discharge. Magnetic resonance imaging of the head revealed the presence of unilateral or bilateral intranasal cystic lesions obstructing the nasal cavities partially or completely, with atrophy of the ipsilateral nasal turbinates. The cystic lesions were surgically excised in all dogs using a modified lateral alveolar mucosal approach to the affected nasal cavity. Aerobic, anaerobic and fungal culture of the cystic contents were negative and histology of the excised tissue was consistent with a benign intranasal epidermoid cyst in each dog. Upper airway obstruction was clinically improved in two dogs. PMID:24697627

  13. Insulin pumps.

    PubMed

    Pickup, J

    2011-02-01

    The last year has seen a continued uptake of insulin pump therapy in most countries. The USA is still a leader in pump use, with probably some 40% of type 1 diabetic patients on continuous subcutaneous insulin infusion (CSII), but the large variation in usage within Europe remains, with relatively high use (> 15%) in, for example, Norway, Austria, Germany and Sweden and low use (< 5%) in Spain, the UK, Finland and Portugal. There is much speculation on the factors responsible for this variation, and the possibilities include physician attitudes to CSII and knowledge about its benefits and indications for its use (and inappropriate beliefs about dangers), the availability of reimbursement from insurance companies or funding from national health services, the availability of sufficient diabetes nurse educators and dietitians trained in pump procedures, and clear referral pathways for the pump candidate from general practitioner or general hospital to specialist pump centre. There are now several comprehensive national guidelines on CSII use (see ATTD Yearbook 2009) but more work needs to be done in unifying uptake and ensuring all those who can benefit do so. Technology developments recently include increasing use of pumps with continuous glucose monitoring (CGM) connectivity (see elsewhere in this volume) and the emergence of numerous manufacturers developing so-called 'patch pumps', often for the type 2 diabetes market. Interestingly, the evidence base for CSII in this group is not well established, and for this reason the selected papers on CSII in this section include several in this area. The use of CSII in diabetic pregnancy is a long-established practice, in spite of the lack of evidence that it is superior to multiple daily injections (MDI), and few randomised controlled trials have been done in recent years. Several papers in this field this year continue the debate about the usefulness of CSII in diabetic pregnancy and are reviewed here. It is pleasing

  14. Effect of anaesthesia on insulin-induced hypoglycemia in rabbits.

    PubMed

    Haynes, F J; Cheema-Dhadli, S; Halperin, R M; Zettle, R; Robinson, L; Halperin, M L

    1988-12-01

    The aim of this study was to determine how anaesthetized rabbits survive much longer than awake rabbits after receiving an insulin overdose. Insulin appeared to act in both groups of rabbits because there was a prompt fall in circulating glucose, free fatty acids, and beta-hydroxybutyrate concentrations. Carbohydrate appeared to be the principal energy source for anaesthetized rabbits because their respiratory quotient approached unity. Although the fall in glycemia was similar in both groups of rabbits, the circulating lactate concentration rose only in the anaesthetized group. This rise in lactate in the initial 60 min after insulin was given could account for most of the fall in glycemia if the source of lactate was the glucose pool. The decline in hepatic glycogen was close to 100 mumol/g liver; this would account for about one-third of the total energy turnover and close to one-half of the measured glucose appearance in these anaesthetized rabbits. As judged from the rate of oxygen consumption, muscle glycogen seemed to supply two-thirds of the fuel to be oxidized in these rabbits. However, only one-third of the lactate released from muscle was first converted to glucose and the remainder was oxidized directly to CO2. Although insulin provided the metabolic setting for a rapid rate of glucose oxidation, this rate appeared to be diminished when the overall rate of oxygen consumption was lower during anaesthesia. PMID:3067835

  15. [Intranasal administration of immunoglobulins--perspectives for use in medical practice].

    PubMed

    Novikova, L I; Aleshkin, V A; Borisova, I V; Zueva, M M

    2008-01-01

    Effectiveness of topical use of immunoglobulines in respiratory infections along with preparations for parenteral use is discussed. Immunoglobuline preparations for intranasal use (drops, spays, aerosols) should take place among preparations intended for prevention and treatment of influenza, parainfluenza, respiratory syncitial virus infection and others. Potential to intranasal use of complex immunoglobulin preparation containing polymeric and monomeric antibodies of different isotypes is also discussed. PMID:19004281

  16. Sampling phasic dopamine signaling with fast-scan cyclic voltammetry in awake behaving rats

    PubMed Central

    Fortin, SM; Cone, JJ; Ng-Evans, S; McCutcheon, JE; Roitman, MF

    2015-01-01

    Fast-scan cyclic voltammetry (FSCV) is an electrochemical technique which permits the in vivo measurement of extracellular fluctuations in multiple chemical species. The technique is frequently utilized to sample sub-second (phasic) concentration changes of the neurotransmitter dopamine in awake and behaving rats. Phasic dopamine signaling is implicated in reinforcement, goal-directed behavior, and locomotion and FSCV has been used to investigate how rapid changes in striatal dopamine concentration contribute to these and other behaviors. This unit describes the instrumentation and construction, implantation, and use of necessary components required to sample and analyze dopamine concentration changes in awake rats with FSCV. PMID:25559005

  17. Awake surgery between art and science. Part I: clinical and operative settings

    PubMed Central

    Talacchi, Andrea; Santini, Barbara; Casagrande, Francesca; Alessandrini, Franco; Zoccatelli, Giada; Squintani, Giovanna M.

    Summary Awake surgery requires coordinated teamwork and communication between the surgeon and the anesthesiologist, as he monitors the patient, the neuroradiologist as he interprets the images for intraoperative confirmation, and the neuropsychologist and neurophysiologist as they evaluate in real-time the patient’s responses to commands and questions. To improve comparison across published studies on clinical assessment and operative settings in awake surgery, we reviewed the literature, focusing on methodological differences and aims. In complex, interdisciplinary medical care, such differences can affect the outcome and the cost-benefit ratio of the treatment. Standardization of intraoperative mapping and related controversies will be discussed in Part II. PMID:24139657

  18. Photoacoustic detection of functional responses in the motor cortex of awake behaving monkey during forelimb movement

    NASA Astrophysics Data System (ADS)

    Jo, Janggun; Zhang, Hongyu; Cheney, Paul D.; Yang, Xinmai

    2012-11-01

    Photoacoustic (PA) imaging was applied to detect the neuronal activity in the motor cortex of an awake, behaving monkey during forelimb movement. An adult macaque monkey was trained to perform a reach-to-grasp task while PA images were acquired through a 30-mm diameter implanted cranial chamber. Increased PA signal amplitude results from an increase in regional blood volume and is interpreted as increased neuronal activity. Additionally, depth-resolved PA signals enabled the study of functional responses in deep cortical areas. The results demonstrate the feasibility of utilizing PA imaging for studies of functional activation of cerebral cortex in awake monkeys performing behavioral tasks.

  19. Tumescent Local Anesthesia for Hand Surgery: Improved Results, Cost Effectiveness, and Wide-Awake Patient Satisfaction

    PubMed Central

    Martin, Alison

    2014-01-01

    This is a review article of the wide-awake approach to hand surgery. More than 95% of all hand surgery can now be performed without a tourniquet. Epinephrine is injected with lidocaine for hemostasis and anesthesia instead of a tourniquet and sedation. This is sedation-free surgery, much like a visit to a dental office. The myth of danger of using epinephrine in the finger is reviewed. The wide awake technique is greatly improving results in tendon repair, tenolysis, and tendon transfer. Here, we will explain its advantages. PMID:25075350

  20. [Awake Nasotracheal Intubation for a 4-Year-old Boy with an Oral Penetrating Toothbrush Injury].

    PubMed

    Kobayashi, Naoya; Ando, Kokichi; Saito, Kazutomo; Toyama, Hiroaki; Fudeta, Hiroto; Yamauchi, Masanori

    2015-09-01

    We report a case of an oral penetrating injury caused by a toothbrush in a 4-year-old 17-kg boy. The toothbrush was lodged in the right cervical region through the oral cavity, and emergency surgery for removal was planned under general anesthesia. Although mask ventilation was not possible because of the protruding toothbrush handle, awake nasotracheal intubation was successfully performed with a fiber-scope and intravenous fentanyl 25 μg. We conclude that appropriate analgesics could facilitate awake intubation in pediatric patients. PMID:26466500

  1. The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study

    PubMed Central

    Riediger, Christine; Haschke, Manuel; Bitter, Christoph; Fabbro, Thomas; Schaeren, Stefan; Urwyler, Albert; Ruppen, Wilhelm

    2015-01-01

    Objectives Ketamine is a well-known analgesic and dose-dependent anesthetic used in emergency and disaster medicine. Recently, a new formulation of S-ketamine, as an intranasal spray, was developed and tested in our institution in healthy volunteers. The authors investigated the effect of intranasal S-ketamine spray combined with midazolam intranasal spray in postoperative spinal surgery patients. Materials and methods In this prospective, computer-randomized, double-blinded noninferiority study in spinal surgery patients, the effects of intranasal S-ketamine and midazolam were compared with standard morphine patient-controlled analgesia (PCA). The primary end point was the numeric rating scale pain score 24 hours after surgery. Results Twenty-two patients finished this study, eleven in each group. There were similar numeric rating scale scores in the morphine PCA and the S-ketamine-PCA groups at 1, 2, 4, 24, 48, and 72 hours after surgery during rest as well as in motion. There were no differences in the satisfaction scores at any time between the groups. The number of bolus demands and deliveries was not significantly different. Discussion In our study, we found that an S-ketamine intranasal spray combined with intra-nasal midazolam was similar in effectiveness, satisfaction, number of demands/deliveries of S-ketamine and morphine, and number/severity of adverse events compared with standard intravenous PCA with morphine. S-ketamine can be regarded as an effective alternative for a traditional intravenous morphine PCA in the postoperative setting. PMID:25709497

  2. Role of intranasal fentanyl in breakthrough pain management in cancer patients

    PubMed Central

    Leppert, Wojciech

    2010-01-01

    Fentanyl is a strong opioid analgesic, which is commonly used in the form of a transdermal patch for the treatment of chronic cancer pain. An intranasal route of fentanyl administration is a novel treatment for breakthrough cancer pain (BTCP). The prevalence, assessment, and management of BTCP is outlined in this paper, and basic pharmacodynamic and pharmacokinetic properties, dosing guidelines, and clinical experience with the use of intranasal fentanyl in this indication are discussed. Intranasal fentanyl is an attractive and convenient mode of BTCP treatment in opioid-tolerant patients due to its quick onset and short duration of action, noninvasive administration route, high bioavailability, and avoidance of a hepatic first-pass effect. Until now, few clinical trials have been conducted with intranasal fentanyl, but all have confirmed its usefulness and acceptability in BTCP treatment. Intranasal fentanyl may be used in opioid-tolerant patients without nasal pathologies. The dose should be titrated in each patient regardless of the regular opioid dose administered. Future studies should compare intranasal fentanyl with other fentanyl formulations used for BTCP management, and with analgesia, adverse effects, and quality of life taken into consideration. PMID:21188114

  3. New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163

    PubMed Central

    Hashizume, Rintaro; Ozawa, Tomoko; Gryaznov, Sergei M.; Bollen, Andrew W.; Lamborn, Kathleen R.; Frey, William H.; Deen, Dennis F.

    2008-01-01

    The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are greatly needed for brain-tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain and could provide an alternative to intravenous injection and convection-enhanced delivery. We treated rats bearing intracerebral human tumor xeno-grafts intranasally with GRN163, an oligonucleotide N3′→P5′thio-phosphoramidate telomerase inhibitor. 3′-Fuorescein isothiocyanate (FITC)–labeled GRN163 was administered intranasally every 2 min as 6 μl drops into alternating sides of the nasal cavity over 22 min. FITC-labeled GRN163 was present in tumor cells at all time points studied, and accumulation of GRN163 peaked at 4 h after delivery. Moreover, GRN163 delivered intranasally, daily for 12 days, significantly prolonged the median survival from 35 days in the control group to 75.5 days in the GRN163-treated group. Thus, intranasal delivery of GRN163 readily bypassed the blood-brain barrier, exhibited favorable tumor uptake, and inhibited tumor growth, leading to a prolonged lifespan for treated rats compared to controls. This delivery approach appears to kill tumor cells selectively, and no toxic effects were noted in normal brain tissue. These data support further development of intranasal delivery of tumor-specific therapeutic agents for brain tumor patients. PMID:18287341

  4. New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163.

    PubMed

    Hashizume, Rintaro; Ozawa, Tomoko; Gryaznov, Sergei M; Bollen, Andrew W; Lamborn, Kathleen R; Frey, William H; Deen, Dennis F

    2008-04-01

    The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are greatly needed for brain-tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain and could provide an alternative to intravenous injection and convection-enhanced delivery. We treated rats bearing intracerebral human tumor xenografts intranasally with GRN163, an oligonucleotide N3'-->P5'thio-phosphoramidate telomerase inhibitor. 3'-Fuorescein isothiocyanate (FITC)-labeled GRN163 was administered intranasally every 2 min as 6 microl drops into alternating sides of the nasal cavity over 22 min. FITC-labeled GRN163 was present in tumor cells at all time points studied, and accumulation of GRN163 peaked at 4 h after delivery. Moreover, GRN163 delivered intranasally, daily for 12 days, significantly prolonged the median survival from 35 days in the control group to 75.5 days in the GRN163-treated group. Thus, intranasal delivery of GRN163 readily bypassed the blood-brain barrier, exhibited favorable tumor uptake, and inhibited tumor growth, leading to a prolonged lifespan for treated rats compared to controls. This delivery approach appears to kill tumor cells selectively, and no toxic effects were noted in normal brain tissue. These data support further development of intranasal delivery of tumor-specific therapeutic agents for brain tumor patients. PMID:18287341

  5. Intranasal delivery of nanomicelle curcumin promotes corneal epithelial wound healing in streptozotocin-induced diabetic mice.

    PubMed

    Guo, Chuanlong; Li, Mengshuang; Qi, Xia; Lin, Guiming; Cui, Fenghua; Li, Fengjie; Wu, Xianggen

    2016-01-01

    Corneal nerves are mainly derived from the ophthalmic branch of the trigeminal ganglion (TG). Corneal neuropathy contributes to epithelial degenerative changes in diabetic keratopathy. Efficient drug delivery to TG may be beneficial for the treatment of diabetic keratopathy. This article described intranasal delivery of nanomicelle curcumin to correct pathophysiological conditions in TG to promote corneal epithelial/nerve wound healing in streptozotocin-induced diabetic mice. A diabetic mice model with corneal epithelium abrasion was established. Ocular topical and/or intranasal nanomicelle curcumin treatments were performed, and treatment efficacy and mechanisms of action were explored. Results showed that intranasal nanomicelle curcumin treatment promoted corneal epithelial wound healing and recovery of corneal sensation. Enhanced accumulation of reactive oxygen species, reduced free radical scavengers, increased mRNA expressions of inflammatory cytokines, and decreased mRNA expressions of neurotrophic factors in the cornea and TG neuron were observed in diabetic mice with corneal epithelium abrasions. Intranasal nanomicelle curcumin treatment effectively recovered these pathophysiological conditions, especially that of the TG neuron, and a strengthened recovery was observed with ocular topical combined with intranasal treatment. These findings indicated that intranasal curcumin treatment effectively helped promote diabetic corneal epithelial/nerve wound healing. This novel treatment might be a promising strengthened therapy for diabetic keratopathy. PMID:27405815

  6. Rapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration

    PubMed Central

    Lochhead, Jeffrey J; Wolak, Daniel J; Pizzo, Michelle E; Thorne, Robert G

    2015-01-01

    The intranasal administration route is increasingly being used as a noninvasive method to bypass the blood–brain barrier because evidence suggests small fractions of nasally applied macromolecules may reach the brain directly via olfactory and trigeminal nerve components present in the nasal mucosa. Upon reaching the olfactory bulb (olfactory pathway) or brainstem (trigeminal pathway), intranasally delivered macromolecules appear to rapidly distribute within the brains of rodents and primates. The mechanisms responsible for this distribution have yet to be fully characterized. Here, we have used ex vivo fluorescence imaging to show that bulk flow within the perivascular space (PVS) of cerebral blood vessels contributes to the rapid central distribution of fluorescently labeled 3 and 10 kDa dextran tracers after intranasal administration in anesthetized adult rats. Comparison of tracer plasma levels and fluorescent signal distribution associated with the PVS of surface arteries and internal cerebral vessels showed that the intranasal route results in unique central access to the PVS not observed after matched intravascular dosing in separate animals. Intranasal targeting to the PVS was tracer size dependent and could be regulated by modifying nasal epithelial permeability. These results suggest cerebral perivascular convection likely has a key role in intranasal drug delivery to the brain. PMID:25492117

  7. Rapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration.

    PubMed

    Lochhead, Jeffrey J; Wolak, Daniel J; Pizzo, Michelle E; Thorne, Robert G

    2015-03-01

    The intranasal administration route is increasingly being used as a noninvasive method to bypass the blood-brain barrier because evidence suggests small fractions of nasally applied macromolecules may reach the brain directly via olfactory and trigeminal nerve components present in the nasal mucosa. Upon reaching the olfactory bulb (olfactory pathway) or brainstem (trigeminal pathway), intranasally delivered macromolecules appear to rapidly distribute within the brains of rodents and primates. The mechanisms responsible for this distribution have yet to be fully characterized. Here, we have used ex vivo fluorescence imaging to show that bulk flow within the perivascular space (PVS) of cerebral blood vessels contributes to the rapid central distribution of fluorescently labeled 3 and 10 kDa dextran tracers after intranasal administration in anesthetized adult rats. Comparison of tracer plasma levels and fluorescent signal distribution associated with the PVS of surface arteries and internal cerebral vessels showed that the intranasal route results in unique central access to the PVS not observed after matched intravascular dosing in separate animals. Intranasal targeting to the PVS was tracer size dependent and could be regulated by modifying nasal epithelial permeability. These results suggest cerebral perivascular convection likely has a key role in intranasal drug delivery to the brain. PMID:25492117

  8. Human insulin genome sequence map, biochemical structure of insulin for recombinant DNA insulin.

    PubMed

    Chakraborty, Chiranjib; Mungantiwar, Ashish A

    2003-08-01

    Insulin is a essential molecule for type I diabetes that is marketed by very few companies. It is the first molecule, which was made by recombinant technology; but the commercialization process is very difficult. Knowledge about biochemical structure of insulin and human insulin genome sequence map is pivotal to large scale manufacturing of recombinant DNA Insulin. This paper reviews human insulin genome sequence map, the amino acid sequence of porcine insulin, crystal structure of porcine insulin, insulin monomer, aggregation surfaces of insulin, conformational variation in the insulin monomer, insulin X-ray structures for recombinant DNA technology in the synthesis of human insulin in Escherichia coli. PMID:12769691

  9. Giving an insulin injection

    MedlinePlus

    ... room temperature for a month. Gather your supplies: insulin, needles, syringes, alcohol wipes, and a container for used needles ... the plunger to get the right dose of insulin into the syringe. Check the syringe for air bubbles. If there ...

  10. Inflammation and Insulin Resistance

    PubMed Central

    de Luca, Carl; Olefsky, Jerrold M.

    2008-01-01

    Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and the Metabolic syndrome. In this review, we focus on the interconnection between obesity, inflammation and insulin resistance. Pro-inflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction. The sources of cytokines in insulin resistant states are the insulin target tissue themselves, primarily fat and liver, but to a larger extent the activated tissue resident macrophages. While the initiating factors of this inflammatory response remain to be fully determined, chronic inflammation in these tissues could cause localized insulin resistance via autocrine/paracrine cytokine signaling and systemic insulin resistance via endocrine cytokine signaling all of which contribute to the abnormal metabolic state. PMID:18053812

  11. High-mix insulins

    PubMed Central

    Kalra, Sanjay; Farooqi, Mohammad Hamed; El-Houni, Ali E.

    2015-01-01

    Premix insulins are commonly used insulin preparations, which are available in varying ratios of different molecules. These drugs contain one short- or rapid-acting, and one intermediate- or long-acting insulin. High-mix insulins are mixtures of insulins that contain 50% or more than 50% of short-acting insulin. This review describes the clinical pharmacology of high-mix insulins, including data from randomized controlled trials. It suggests various ways, in which high-mix insulin can be used, including once daily, twice daily, thrice daily, hetero-mix, and reverse regimes. The authors provide a rational framework to help diabetes care professionals, identify indications for pragmatic high-mix use. PMID:26425485

  12. Insulin pump (image)

    MedlinePlus

    The catheter at the end of the insulin pump is inserted through a needle into the abdominal ... with diabetes. Dosage instructions are entered into the pump's small computer and the appropriate amount of insulin ...

  13. a-Band Oscillations in Intracellular Membrane Potentials of Dentate Gyrus Neurons in Awake Rodents

    ERIC Educational Resources Information Center

    Anderson, Ross W.; Strowbridge, Ben W.

    2014-01-01

    The hippocampus and dentate gyrus play critical roles in processing declarative memories and spatial information. Dentate granule cells, the first relay in the trisynaptic circuit through the hippocampus, exhibit low spontaneous firing rates even during locomotion. Using intracellular recordings from dentate neurons in awake mice operating a…

  14. "Awake" extracorporeal membrane oxygenation (ECMO): pathophysiology, technical considerations, and clinical pioneering.

    PubMed

    Langer, Thomas; Santini, Alessandro; Bottino, Nicola; Crotti, Stefania; Batchinsky, Andriy I; Pesenti, Antonio; Gattinoni, Luciano

    2016-01-01

    Venovenous extracorporeal membrane oxygenation (vv-ECMO) has been classically employed as a rescue therapy for patients with respiratory failure not treatable with conventional mechanical ventilation alone. In recent years, however, the timing of ECMO initiation has been readdressed and ECMO is often started earlier in the time course of respiratory failure. Furthermore, some centers are starting to use ECMO as a first line of treatment, i.e., as an alternative to invasive mechanical ventilation in awake, non-intubated, spontaneously breathing patients with respiratory failure ("awake" ECMO). There is a strong rationale for this type of respiratory support as it avoids several side effects related to sedation, intubation, and mechanical ventilation. However, the complexity of the patient-ECMO interactions, the difficulties related to respiratory monitoring, and the management of an awake patient on extracorporeal support together pose a major challenge for the intensive care unit staff. Here, we review the use of vv-ECMO in awake, spontaneously breathing patients with respiratory failure, highlighting the pros and cons of this approach, analyzing the pathophysiology of patient-ECMO interactions, detailing some of the technical aspects, and summarizing the initial clinical experience gained over the past years. PMID:27357690

  15. Noninvasive high-speed photoacoustic tomography of cerebral hemodynamics in awake-moving rats

    PubMed Central

    Tang, Jianbo; Xi, Lei; Zhou, Junli; Huang, Hua; Zhang, Tao; Carney, Paul R; Jiang, Huabei

    2015-01-01

    We present a noninvasive method of photoacoustic tomography (PAT) for imaging cerebral hemodynamics in awake-moving rats. The wearable PAT (wPAT) system has a size of 15 mm in height and 33 mm in diameter, and a weight of ~8 g (excluding cabling). The wPAT achieved an imaging rate of 3.33 frames/s with a lateral resolution of 243 μm. Animal experiments were designed to show wPAT feasibility for imaging cerebral hemodynamics on awake-moving animals. Results showed that the cerebral oxy-hemoglobin and deoxy-hemoglobin changed significantly in response to hyperoxia; and, after the injection of pentylenetetrazol (PTZ), cerebral blood volume changed faster over time and larger in amplitude for rats in awake-moving state compared with rats under anesthesia. By providing a light-weight, high-resolution technology for in vivo monitoring of cerebral hemodynamics in awake-behaving animals, it will be possible to develop a comprehensive understanding on how activity alters hemodynamics in normal and diseased states. PMID:26082016

  16. Awake nasotracheal fiberoptic intubation and self-positioning followed by anesthesia induction in prone patients

    PubMed Central

    Heng, Lei; Wang, Ming-Yu; Sun, Hou-Liang; Zhu, Shan-Shan

    2016-01-01

    Abstract Anesthesia followed by placement in the prone position takes time and may result in complications. This study aimed to evaluate the feasibility of awake nasotracheal fiberoptic intubation and self-positioning followed by anesthesia induction in prone-positioned patients under general anesthesia. Sixty-two patients (ASA physical status I–II) scheduled for awake nasotracheal fiberoptic intubation and prone self-positioning before surgery under general anesthesia were selected. Patient preparation began with detailed preoperative counseling regarding the procedure. Premedication with sedative and antisialagogue was followed by airway anesthesia with topical lidocaine; then, awake nasotracheal fiberoptic intubation was carried out. The patients then positioned themselves comfortably before induction of general anesthesia. The changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), incidence of coughing or gagging, and rate pressure product (RPP) were assessed. Statistical analysis was performed with repeated-measures one-way analysis of variance. Fifty-eight of the 62 patients completed prone self-positioning smoothly. Compared with values before intubation, SBP, DBP, HR, and RPP were slightly increased after intubation, although the difference was not statistically significant (P > 0.05). One patient had moderate coughing and 1 patient had gagging during prone self-positioning, which were tolerable. These findings indicated that awake nasotracheal fiberoptic intubation and self-positioning followed by induction of anesthesia is safe and feasible alternative to routine prone positioning after induction of general anesthesia. PMID:27512858

  17. Adherence to Insulin Therapy.

    PubMed

    Sarbacker, G Blair; Urteaga, Elizabeth M

    2016-08-01

    IN BRIEF Six million people with diabetes use insulin either alone or in combination with an oral medication. Many barriers exist that lead to poor adherence with insulin. However, there is an underwhelming amount of data on interventions to address these barriers and improve insulin adherence. Until pharmacological advancements create easier, more acceptable insulin regimens, it is imperative to involve patients in shared decision-making. PMID:27574371

  18. Le sumatriptan intranasal pour la migraine chez les enfants

    PubMed Central

    Goldman, Ran D.; Meckler, Garth D.

    2015-01-01

    Résumé Question Je vois de plus en plus d’enfants et d’adolescents qui souffrent de céphalées pouvant se classer dans la catégorie des migraines. J’ai fait des lectures sur le sumatriptan par voie intranasale comme thérapie abortive. Est-ce un traitement efficace? Réponse La migraine aiguë chez les enfants et les adolescents est fréquente et difficile à traiter. Le sumatriptan intranasal est une option sûre et généralement efficace pour les enfants et les adolescents. La dose actuellement recommandée est de 20 mg pour les enfants qui pèsent plus de 40 kg et de 10 mg pour ceux dont le poids se situe entre 20 et 39 kg. Il faudrait faire des études de plus grande envergure pour contrecarrer les limitations des échantillons de petite taille et mieux comprendre la faible concentration plasmique et les effets placebo observés dans les études jusqu’à présent.

  19. Systemic and behavioral effects of intranasal administration of silver nanoparticles.

    PubMed

    Davenport, Laurie L; Hsieh, Heidi; Eppert, Bryan L; Carreira, Vinicius S; Krishan, Mansi; Ingle, Taylor; Howard, Paul C; Williams, Michael T; Vorhees, Charles V; Genter, Mary Beth

    2015-01-01

    Use of silver nanoparticles (AgNPs) for their antimicrobial properties is widespread. Much of the previous work on the toxicity of AgNPs has been conducted in vitro or following oral or intravenous administration in vivo. Intranasal (IN) instillation of AgNPs mimics inhalation exposure and allows further exploration of the toxicity of these particles via respiratory tract exposure. The present study involved 1) single-dose exposures to assess tissue distribution and toxicity and 2) repeated exposures to assess behavioral effects of IN AgNP exposure (nominally uncoated 25 nm AgNP). AgNP deposition was localized in the liver, gut-associated lymphoid tissue, and brain. Decrease cellularity in spleen follicles was observed in treated mice, along with changes in cell number and populations in the spleen. The splenic GSH:GSSG ratio was also reduced following AgNP exposure. Expression of the oxidative stress-responsive gene Hmox1 was elevated in the hippocampus, but not cortex of treated mice, as was the level of HMOX1 protein. Mice receiving 7 days of IN exposure to 50 mg/kg AgNPs exhibited similar learning- and memory-related behaviors to control mice, except that treated mice spent significantly less time in the target quadrant of the Morris Water Maze during the acquisition phase probe trial. These findings indicate systemic distribution and toxicity following IN administration of AgNPs. PMID:26340819

  20. Stimulus Selection for Intranasal Sensory Isolation: Eugenol Is an Irritant

    PubMed Central

    Wise, Paul M.; Lundström, Johan N.

    2012-01-01

    Both the olfactory and the trigeminal systems are able to respond to intranasal presentations of chemical vapor. Accordingly, when the nose detects a volatile chemical, it is often unclear whether we smell it, feel it, or both. The distinction may often be unimportant in our everyday perception of fragrances or aromas, but it can matter in experiments that purport to isolate olfactory processes or study the interaction between olfaction and chemesthesis. Researchers turn to a small pool of compounds that are believed to be “pure olfactory” stimuli with little or no trigeminal impact. The current report reexamines one such commonly used compound, namely eugenol, a flavor and fragrance ingredient that has anesthetic properties under some conditions. Using a standard method involving many trials during an experimental session (Experiment 1), subjects were unable to reliably lateralize eugenol, consistent with claims that this compound is detected primarily through olfaction. However, with more limited exposure (Experiments 2 and 3), subjects were able to lateralize eugenol. We speculate that anesthetic properties of eugenol could blunt its trigeminal impact in some paradigms. Regardless, the current experiments suggest that eugenol can in fact stimulate the trigeminal nerve but in a complex concentration–dependent manner. Implications and strategies for selection of model odorants are discussed. PMID:22293937

  1. Pupillary responses to intranasal trigeminal and olfactory stimulation.

    PubMed

    Schneider, Christine B; Ziemssen, Tjalf; Schuster, Benno; Seo, Han-Seok; Haehner, Antje; Hummel, Thomas

    2009-07-01

    The aim of the present study was to investigate whether pupillary responses to odorous stimuli reflect their intensity or hedonic tone. A total of 21 healthy subjects participated in the study. Using a computer-controlled olfactometer, subjects received intranasal stimuli including odors of rose (PEA; 2 concentrations), lemon and rotten eggs, plus the trigeminal irritant CO2 (also at two concentrations). Changes in the pupil diameter were obtained ipsilaterally to the side of stimulus presentation. Both trigeminal and olfactory stimulation produced an increase in pupillary diameter. Latencies for pupillary reaction were fastest for the higher concentration of CO2 and slowest after the presentation of PEA at the low concentration. Response amplitudes were largest in response to stimulation with CO2 at the high concentration, while they were smallest in response to odorous stimulation with PEA. Response latencies decreased with increasing stimulus intensity. No such correlation was found for hedonic ratings and pupillary reactions. Thus, the change in the pupillary diameter indicates differences between stimulus modalities and stimulus strength, but not pleasantness or unpleasantness of the odors. PMID:19484181

  2. Intranasal epidermal growth factor treatment rescues neonatal brain injury

    NASA Astrophysics Data System (ADS)

    Scafidi, Joseph; Hammond, Timothy R.; Scafidi, Susanna; Ritter, Jonathan; Jablonska, Beata; Roncal, Maria; Szigeti-Buck, Klara; Coman, Daniel; Huang, Yuegao; McCarter, Robert J.; Hyder, Fahmeed; Horvath, Tamas L.; Gallo, Vittorio

    2014-02-01

    There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.

  3. Intranasal epidermal growth factor treatment rescues neonatal brain injury

    PubMed Central

    Scafidi, Joseph; Hammond, Timothy R.; Scafidi, Susanna; Ritter, Jonathan; Jablonska, Beata; Roncal, Maria; Szigeti-Buck, Klara; Coman, Daniel; Huang, Yuegao; McCarter, Robert J.; Hyder, Fahmeed; Horvath, Tamas L.; Gallo, Vittorio

    2014-01-01

    There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (<32 weeks gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments1,2. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI3. In a previous study, we demonstrated that epidermal growth factor receptor (EGFR) plays an important role in oligodendrocyte development4. Here, we examine whether enhanced epidermal growth factor receptor (EGFR) signaling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioral recovery in the developing brain. Using an established model of very preterm brain injury, we demonstrate that selective overexpression of human (h)EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells (OPCs) and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioral deficits on white matter-specific paradigms. Inhibition of EGFR signaling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in OPCs at a specific time after injury is clinically feasible and applicable for the treatment of premature children with white matter injury. PMID:24390343

  4. Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Tam, V. H.; Chow, D. S. L.; Putcha, L.

    2015-01-01

    An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS). The bioavailability and pharmacokinetics (PK) were evaluated under IND (Investigational New Drug) guidelines. The aim of the project was to develop a PK model that can predict the relationships among plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial protocol with INSCOP. Twelve healthy human subjects were administered at three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min to 24 h after dosing and scopolamine concentrations were measured by using a validated LC-MS-MS assay. PK compartmental models, using actual dosing and sampling time, were established using Phoenix (version 1.2). Model selection was based on a likelihood ratio test on the difference of criteria (-2LL (i.e. log-likelihood ratio test)) and comparison of the quality of fit plots. The results: Predictable correlations among scopolamine concentrations in compartments of plasma, saliva and urine were established, and for the first time the model satisfactorily predicted the population and individual PK of INSCOP in plasma, saliva and urine. The model can be utilized to predict the INSCOP plasma concentration by saliva and urine data, and it will be useful for monitoring the PK of scopolamine in space and other remote environments using non-invasive sampling of saliva and/or urine.

  5. Systemic and Behavioral Effects of Intranasal Administration of Silver Nanoparticles

    PubMed Central

    Davenport, Laurie L.; Hsieh, Heidi; Eppert, Bryan L.; Carreira, Vinicius S.; Krishan, Mansi; Ingle, Taylor; Howard, Paul C.; Williams, Michael T.; Vorhees, Charles V.; Genter, Mary Beth

    2015-01-01

    Use of silver nanoparticles (AgNPs) for their antimicrobial properties is widespread. Much of the previous work on the toxicity of AgNPs has been conducted in vitro or following oral or intravenous administration in vivo. Intranasal (IN) instillation of AgNPs mimics inhalation exposure and allows further exploration of the toxicity of these particles via respiratory tract exposure. The present study involved 1) single-dose exposures to assess tissue distribution and toxicity and 2) repeated exposures to assess behavioral effects of IN AgNP exposure (nominally uncoated 25 nm AgNP). AgNP deposition was localized in the liver, gut-associated lymphoid tissue, and brain. Decrease cellularity in spleen follicles was observed in treated mice, along with changes in cell number and populations in the spleen. The splenic GSH:GSSG ratio was also reduced following AgNP exposure. Expression of the oxidative stress-responsive gene Hmox1 was elevated in the hippocampus, but not cortex of treated mice, as was the level of HMOX1 protein. Mice receiving 7 days of IN exposure to 50 mg/kg AgNPs exhibited similar learning- and memory-related behaviors to control mice, except that treated mice spent significantly less time in the target quadrant of the Morris Water Maze during the acquisition phase probe trial. These findings indicate systemic distribution and toxicity following IN administration of AgNPs. PMID:26340819

  6. Intranasal Midazolam Sedation in a Pediatric Emergency Dental Clinic.

    PubMed

    Peerbhay, Fathima; Elsheikhomer, Ahmed Mahgoub

    2016-01-01

    The purpose of this study was to compare the effectiveness and recovery times of 0.3 and 0.5 mg/kg intranasal midazolam (INM) administered with a mucosal atomizer device (MAD) in a pediatric emergency dental hospital clinic. One hundred eighteen children aged from 4 to 6 years were randomly administered either 0.3 or 0.5 mg/kg INM via an MAD in a triple-blinded randomized controlled trial. Sedation was achieved to some degree in 100% of the sample. The pulse rate and oxygen saturation were within the normal range in 99% of the patients. A burning sensation was reported in 9% of children. The recovery time of the 0.5 mg/kg group was statistically longer than that of the 0.3 mg/kg group (16.5 vs 18.8 minutes) but the difference was not clinically significant. The findings of this study show that 0.3 or 0.5 mg/kg doses of INM resulted in safe and effective sedation. The 0.5 mg/kg dose was more effective than the 0.3 mg/kg dose in reducing anxiety. PMID:27585415

  7. Brain Uptake of Neurotherapeutics after Intranasal versus Intraperitoneal Delivery in Mice

    PubMed Central

    Chauhan, Mihir B.; Chauhan, Neelima B.

    2015-01-01

    There is a growing global prevalence of neurodegenerative diseases such as Alzheimer’s disease and dementia. Current treatment for neurodegenerative diseases is limited due to the blood brain barrier’s ability to restrict the entry of therapeutics to the brain. In that context, direct delivery of drugs from nose to brain has gained emerging interest as an important alternative to oral and parenteral routes of administration. Although there are considerable reports showing promising results after intranasal drug delivery in various disease-models and investigatory human clinical trials, there are very few studies showing a detailed pharmacokinetics with regard to the uptake and retention of intranasally delivered material(s) within specific brain regions, which are critical determining factors for dosing conditions and optimal treatment regimen. This investigation compared a time-dependent brain uptake and resident time of various radiolabeled candidate neurotherapeutics after a single bolus intranasal or intraperitoneal administration in mice. Results indicate that the brain uptake of intranasally delivered therapeutic(s) is > 5 times greater than that after intraperitoneal delivery. The peak uptake and resident time of all intranasally delivered test therapeutics for all brain regions is observed to be between 30min-12h, depending upon the distance of brain region from the site of administration, followed by gradual fading of radioactive counts by 24h post intranasal administration. Current study confirms the usefulness of intranasal administration as a non- invasive and efficient means of delivering therapeutics to the brain to treat neurodegenerative diseases including Alzheimer’s disease. PMID:26366437

  8. Delivery of ziconotide to cerebrospinal fluid via intranasal pathway for the treatment of chronic pain.

    PubMed

    Manda, Prashanth; Kushwaha, Avadhesh Singh; Kundu, Santanu; Shivakumar, H N; Jo, Seong Bong; Murthy, S Narasimha

    2016-02-28

    The purpose of the current study was to investigate the plausibility of delivery of ziconotide to the cerebrospinal fluid (CSF) via intranasal administration. Ziconotide was administered either in the form of solution or Kolliphor P 407 gels (KP 407) intranasally in Sprague-Dawley rats. The effect of incorporation of chitosan in the formulation was also investigated. Time course of drug in the CSF was investigated by collecting CSF from cisterna magna. Pharmacokinetics of ziconotide in CSF following intrathecal and intravenous (i.v.) administration of ziconotide was investigated. Upon intrathecal administration the elimination rate constant of ziconotide in CSF was found to be 1.01±0.34h(-1). The Cmax and Tmax of ziconotide in CSF following intravenous administration were found to be 37.78±6.8ng/mL and ~2h respectively. The time required to attain maximum concentration (Tmax) in CSF was less upon intranasal administration (15min) compared to i.v. administration (120min). Presence of chitosan enhanced the overall bioavailability of ziconotide from intranasal solution and gel formulations. The elimination rate constant of ziconotide in CSF following intranasal and intravenous administration of ziconotide solution was found to be 0.54±0.08h(-1) and 0.42±0.10h(-1) respectively. Whereas, intranasal administration of ziconotide in the form of in situ forming gel lowered the elimination rate significantly. These results suggest that intranasal administration could be a potential noninvasive and patient compliant method of delivering ziconotide to CSF to treat chronic pain. PMID:26732557

  9. Insulin therapy in pregnancy.

    PubMed

    Kalra, Sanjay; Jawad, Fatema

    2016-09-01

    Insulin is the mainstay of pharmacotherapy in pregnancy complicated by diabetes. This review covers the various insulin regimes and preparations, explaining how to use them, and decide appropriate doses in pregnancy. It approaches insulin treatment from a patient - centred, as well as physician and obstetrician friendly viewpoint, providing pragmatic guidance for management of diabetes in pregnancy. PMID:27582152

  10. Bursting Activity of Substantia Nigra pars Reticulata Neurons in Mouse Parkinsonism in Awake and Anesthetized States

    PubMed Central

    Lobb, CJ; Jaeger, D

    2015-01-01

    Electrophysiological changes in basal ganglia neurons are hypothesized to underlie motor dysfunction in Parkinson’s disease (PD). Previous results in head-restrained MPTP-treated non-human primates have suggested that increased bursting within the basal ganglia and related thalamic and cortical areas may be a hallmark of pathophysiological activity. In this study, we investigated whether there is increased bursting in substantia nigra pars reticulata (SNpr) output neurons in anesthetized and awake, head-restrained unilaterally lesioned 6-OHDA mice when compared to control mice. Confirming previous studies, we show that there are significant changes in the firing rate and pattern in SNpr neuron activity under urethane anesthesia. The regular firing pattern of control urethane-anesthetized SNpr neurons was not present in the 6-OHDA-lesioned group, as the latter neurons instead became phase locked with cortical slow wave activity (SWA). Next, we examined whether such robust electrophysiological changes between groups carried over to the awake state. SNpr neurons from both groups fired at much higher frequencies in the awake state than in the anesthetized state and surprisingly showed only modest changes between awake control and 6-OHDA groups. While there were no differences in firing rate between groups in the awake state, an increase in the coefficient of variation (CV) was observed in the 6-OHDA group. Contrary to the bursting hypothesis, this increased CV was not due to changes in bursting but was instead due to a mild increase in pausing. Together, these results suggest that differences in SNpr activity between control and 6-OHDA lesioned mice may be strongly influenced by changes in network activity during different arousal and behavioral states. PMID:25576395

  11. Anesthetic agents modulate ECoG potentiation after spreading depression, and insulin-induced hypoglycemia does not modify this effect.

    PubMed

    de Souza, Thays Kallyne Marinho; E Silva-Gondim, Mariana Barros; Rodrigues, Marcelo Cairrão Araújo; Guedes, Rubem Carlos Araújo

    2015-04-10

    Cortical spreading depression (CSD) is characterized by reversible reduction of spontaneous and evoked electrical activity of the cerebral cortex. Experimental evidence suggests that CSD may modulate neural excitability and synaptic activity, with possible implications for long-term potentiation. Systemic factors like anesthetics and insulin-induced hypoglycemia can influence CSD propagation. In this study, we examined whether the post-CSD ECoG potentiation can be modulated by anesthetics and insulin-induced hypoglycemia. We found that awake adult rats displayed increased ECoG potentiation after CSD, as compared with rats under urethane+chloralose anesthesia or tribromoethanol anesthesia. In anesthetized rats, insulin-induced hypoglycemia did not modulate ECoG potentiation. Comparison of two cortical recording regions in awake rats revealed a similarly significant (p<0.05) potentiation effect in both regions, whereas in the anesthetized groups the potentiation was significant only in the recording region nearer to the stimulating point. Our data suggest that urethane+chloralose and tribromoethanol anesthesia modulate the post-CSD potentiation of spontaneous electrical activity in the adult rat cortex, and insulin-induced hypoglycemia does not modify this effect. Data may help to gain a better understanding of excitability-dependent mechanisms underlying CSD-related neurological diseases. PMID:25681772

  12. Insulin Degludec (rDNA Origin) Injection

    MedlinePlus

    ... man-made version of human insulin. Insulin degludec works by replacing the insulin that is normally produced ... insulin label to make sure you received the right type of insulin from the pharmacy.Insulin degludec ...

  13. Induction of systemic immune responses to measles virus synthetic peptides administered intranasally.

    PubMed

    Hathaway, L J; Partidos, C D; Vohra, P; Steward, M W

    1995-11-01

    A systemic antibody response was induced when a chimeric peptide containing two copies of a promiscuous T-cell epitope and one copy of a B-cell epitope (TTB) from the fusion protein of measles virus (MV) was administered to mice intranasally without adjuvant. A higher antibody titre was produced when the peptide was administered intranasally with cholera toxin B subunit (CTB) as an adjuvant and these antibodies crossreacted with the MV. Furthermore, splenocytes from intranasally immunized mice proliferated in vitro in the presence of the TTB peptide. The immune response following intranasal immunization with the peptide was influenced by the MHC haplotype of the strain of mice used. Thus CBA and BALB/c mice were high responders whereas C57BL/6 mice were low responders. Although peptide administered intranasally with CTB to CBA mice induced an immune response, no significant protection was observed against intra-cranial challenge with canine distemper virus which is antigenically related to MV. PMID:8578832

  14. Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines

    NASA Astrophysics Data System (ADS)

    Nochi, Tomonori; Yuki, Yoshikazu; Takahashi, Haruko; Sawada, Shin-Ichi; Mejima, Mio; Kohda, Tomoko; Harada, Norihiro; Kong, Il Gyu; Sato, Ayuko; Kataoka, Nobuhiro; Tokuhara, Daisuke; Kurokawa, Shiho; Takahashi, Yuko; Tsukada, Hideo; Kozaki, Shunji; Akiyoshi, Kazunari; Kiyono, Hiroshi

    2010-07-01

    Nanotechnology is an innovative method of freely controlling nanometre-sized materials. Recent outbreaks of mucosal infectious diseases have increased the demands for development of mucosal vaccines because they induce both systemic and mucosal antigen-specific immune responses. Here we developed an intranasal vaccine-delivery system with a nanometre-sized hydrogel (`nanogel') consisting of a cationic type of cholesteryl-group-bearing pullulan (cCHP). A non-toxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP-BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells after its release from the cCHP nanogel. Vigorous botulinum-neurotoxin-A-neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. Importantly, intranasally administered cCHP-BoHc/A did not accumulate in the olfactory bulbs or brain. Moreover, intranasally immunized tetanus toxoid with cCHP nanogel induced strong tetanus-toxoid-specific systemic and mucosal immune responses. These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination.

  15. Intranasal mite allergen induces allergic asthma-like responses in NC/Nga mice.

    PubMed

    Shibamori, Masafumi; Ogino, Keiki; Kambayashi, Yasuhiro; Ishiyama, Hironobu

    2006-01-25

    Airway responses induced by intranasal administration of mite allergen without adjuvant were studied in NC/Nga mice. A crude extract of Dermatophagoides farinae (Df) was administered for 5 consecutive days and a single intranasal challenge booster dose was given 1 week after the last sensitization. 24 h after the single challenge, the airway hyperresponsiveness (AHR) was measured and the bronchoalveolar lavage fluid (BALF) was analyzed for numbers of eosinophils and neutrophils, and both cytokine and chemokine levels. There were marked increases in number of eosinophils in the BALF, AHR, Th2 cytokines (IL-5 and IL-13), and chemokine (eotaxin-1 and eotaxin-2) levels in the BALF following Df exposure. C57BL/6N, A/J, BALB/c, and CBA/JN mouse strains were also exposed to Df crude extract, but all of the measured responses were strongest in NC/Nga mice. Furthermore, Df-exposed NC/Nga mice showed the goblet cell hyperplasia, pulmonary eosinophilic inflammation, and increases in both total serum IgE and Df-specific IgG1. After intranasal exposure of NC/Nga mice to crude extract of Dermatophagoides pteronyssinus, the BALF eosinophilia and AHR were similar to responses induced by Df. None of the study parameters were increased in response to intranasal exposure to ovalbumin. These data demonstrated that NC/Nga mice developed allergic asthma-like responses after intranasal exposure to mite allergens. PMID:16229861

  16. Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines.

    PubMed

    Nochi, Tomonori; Yuki, Yoshikazu; Takahashi, Haruko; Sawada, Shin-ichi; Mejima, Mio; Kohda, Tomoko; Harada, Norihiro; Kong, Il Gyu; Sato, Ayuko; Kataoka, Nobuhiro; Tokuhara, Daisuke; Kurokawa, Shiho; Takahashi, Yuko; Tsukada, Hideo; Kozaki, Shunji; Akiyoshi, Kazunari; Kiyono, Hiroshi

    2010-07-01

    Nanotechnology is an innovative method of freely controlling nanometre-sized materials. Recent outbreaks of mucosal infectious diseases have increased the demands for development of mucosal vaccines because they induce both systemic and mucosal antigen-specific immune responses. Here we developed an intranasal vaccine-delivery system with a nanometre-sized hydrogel ('nanogel') consisting of a cationic type of cholesteryl-group-bearing pullulan (cCHP). A non-toxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP-BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells after its release from the cCHP nanogel. Vigorous botulinum-neurotoxin-A-neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. Importantly, intranasally administered cCHP-BoHc/A did not accumulate in the olfactory bulbs or brain. Moreover, intranasally immunized tetanus toxoid with cCHP nanogel induced strong tetanus-toxoid-specific systemic and mucosal immune responses. These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination. PMID:20562880

  17. Preparation of lorazepam-loaded microemulsions for intranasal delivery and its pharmacokinetics.

    PubMed

    Yao, J; Hou, L; Zhou, J P; Zhang, Z Q; Sun, L

    2009-10-01

    The purpose of this study was to develop a microemulsion system for intranasal delivery of lorazepam. The phase behavior and properties of microemulsions were characterized in a pseudo-ternary system composed of Cremophor EL 35/Transcutol P/Lauroglycol FCC or Labrafil M 1944CS/water, and intranasal absorption of lorazepam from microemulsions was investigated in rabbit. The microemulsions, comprising of FCC, Cremophor EL 35/Transcutol P (1.5:1) and water, were optimal for intranasal delivery of lorazepam. These systems had a higher solubilization capacity with the particle size of <150 nm, and were stable at ambient conditions for at least six months. In vivo absorption studies showed that intranasal absorption of lorazepam from microemulsions at 0.38 mg/kg had the larger AUC(0-t), the longer half-life and the prolonged circulation time with the mean bioavailability of 80.84% for ME2 and 63.48% for ME8 as compared to the intramuscular injection at 0.16 mg/kg. These results indicate that microemulsions may bea promising approach for the intranasal delivery of lorazepam. PMID:19947165

  18. Evaluation of intranasal Midazolam spray as a sedative in pediatric patients for radiological imaging procedures

    PubMed Central

    Chokshi, Anisha A.; Patel, Vipul R.; Chauhan, Parthiv R.; Patel, Deep J.; Chadha, Indu A.; Ramani, Monal N.

    2013-01-01

    Context: Preoperative anxiety and uncooperativeness experienced by pediatric patients are commonly associated with postoperative behavioral problems. Aims: We aimed to evaluate the efficacy and safety of intranasal Midazolam as a sedative in a pediatric age group for radiological imaging procedures and to note onset of sedation, level of sedation, condition of patient during separation from parents and effect on the cardio-respiratory system. Settings and Design: Randomized double-blinded study. Subjects and Methods: Fifty patients of the pediatric age group of American Society of Anesthesiologist grade 2 and 3 who came for any radiological imaging procedures were studied. Patients were randomly allocated to receive, intranasally, either Midazolam 0.5 mg/kg (group A N = 25) or normal saline (group B N = 25) in both nostrils (0.25 mg/kg in each) 15 min before the procedure. Time for onset of sedation and satisfactory sedation, sedation score, separation score, hemodynamic changes and side-effects were recorded. Statistical Analysis Used: Student's t-test. Results: Intranasal Midazolam group had a significantly shorter time for onset of sedation and satisfactory sedation. Mean sedation score and mean separation score at 10 min and 15 min intervals were significant in intranasal Midazolam as compared with normal saline (P < 0.001). Conclusions: Intranasal Midazolam 0.5 mg/kg is safe and effective and provides adequate sedation for easy separation from the parents and reduced requirement of intravenous supplementation during radiological imaging procedures without any untoward side-effects. PMID:25885831

  19. Intranasal Rapamycin Rescues Mice from Staphylococcal Enterotoxin B-Induced Shock

    PubMed Central

    Krakauer, Teresa; Buckley, Marilyn

    2012-01-01

    Staphylococcal enterotoxin B (SEB) and related exotoxins produced by Staphylococcus aureus are potent activators of the immune system and cause toxic shock in humans. Currently there is no effective treatment except for the use of intravenous immunoglobulins administered shortly after SEB exposure. Intranasal SEB induces long-lasting lung injury which requires prolonged drug treatment. We investigated the effects of rapamycin, an immunosuppressive drug used to prevent graft rejection, by intranasal administration in a lethal mouse model of SEB-induced shock. The results show that intranasal rapamycin alone delivered as late as 17 h after SEB protected 100% of mice from lethal shock. Additionally, rapamycin diminished the weight loss and temperature fluctuations elicited by SEB. Intranasal rapamycin attenuated lung MCP-1, IL-2, IL-6, and IFNγ by 70%, 30%, 64%, and 68% respectively. Furthermore, short courses (three doses) of rapamycin were sufficient to block SEB-induced shock. Intranasal rapamycin represents a novel use of an immunosuppressant targeting directly to site of toxin exposure, reducing dosages needed and allowing a wider therapeutic window. PMID:23105977

  20. Blockade of STAT3 in T Cells Inhibits Germinal Center Reactions against Intranasal Allergens

    PubMed Central

    Choi, Garam; Chung, Yeonseok

    2016-01-01

    Understanding the developmental mechanisms of humoral immunity against intranasal antigens is essential for the development of therapeutic approaches against air-borne pathogens as well as allergen-induced pulmonary inflammation. Follicular helper T (Tfh) cells expressing CXCR5 are required for humoral immunity by providing IL-21 and ICOS costimulation to activated B cells. However, the regulation of Tfh cell responses against intranasal antigens remains unclear. Here, we found that the generation of Tfh cells and germinal center B cells in the bronchial lymph node against intranasal proteinase antigens was independent of TGF-β. In contrast, administration of STAT3 inhibitor STA-21 suppressed the generation of Tfh cells and germinal center B cells. Compared with wild-type OT-II T cells, STAT3-deficient OT-II T cells transferred into recipients lacking T cells not only showed significantly reduced frequency Tfh cells, but also induced diminished IgG as well as IgE specific for the intranasal antigens. Co-transfer study of wild-type OT-II and STAT3-deficient OT-II T cells revealed that the latter failed to differentiate into Tfh cells. These findings demonstrate that T cell-intrinsic STAT3 is required for the generation of Tfh cells to intranasal antigens and that targeting STAT3 might be an effective approach to ameliorate antibody-mediated pathology in the lung. PMID:27133258

  1. Chronic Intranasal Oxytocin Causes Long-term Impairments in Partner Preference Formation in Male Prairie Voles

    PubMed Central

    Bales, Karen L.; Perkeybile, Allison M.; Conley, Olivia G.; Lee, Meredith H.; Guoynes, Caleigh D.; Downing, Griffin M.; Yun, Catherine R.; Solomon, Marjorie; Jacob, Suma; Mendoza, Sally P.

    2012-01-01

    Background Oxytocin (OT) is a hormone shown to be involved in social bonding in animal models. Intranasal OT is currently in clinical trials for use in disorders such as autism and schizophrenia. We examined long-term effects of intranasal OT given developmentally in the prairie vole (Microtus ochrogaster), a socially monogamous rodent, often used as an animal model to screen drugs that have therapeutic potential for social disorders. Methods We treated voles with one of three dosages of intranasal OT, or saline, from day 21 (weaning) through day 42 (sexual maturity). We examined both social behavior immediately following administration, as well as long-term changes in social and anxiety behavior after treatment ceased. Group sizes varied from 8 to 15 voles (n = 89 voles total). Results Treatment with OT resulted in acute increases in social behavior in males with familiar partners, as seen in humans. However, long-term developmental treatment with low doses of intranasal OT resulted in a deficit in partner preference behavior (a reduction of contact with a familiar opposite-sex partner, used to index pair-bond formation) by males. Conclusions Long-term developmental treatment with OT may show results different to those predicted by short-term studies, as well as significant sex differences and dosage effects. Further animal study is crucial to determining safe and effective strategies for use of chronic intranasal OT, especially during development. PMID:23079235

  2. Intranasal hydroxypropyl-β-cyclodextrin-adjuvanted influenza vaccine protects against sub-heterologous virus infection.

    PubMed

    Kusakabe, Takato; Ozasa, Koji; Kobari, Shingo; Momota, Masatoshi; Kishishita, Natsuko; Kobiyama, Kouji; Kuroda, Etsushi; Ishii, Ken J

    2016-06-01

    Intranasal vaccination with inactivated influenza viral antigens is an attractive and valid alternative to currently available influenza (flu) vaccines; many of which seem to need efficient and safe adjuvant, however. In this study, we examined whether hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used pharmaceutical excipient to improve solubility and drug delivery, can act as a mucosal adjuvant for intranasal flu vaccines. We found that intranasal immunization of mice with hemagglutinin split- as well as inactivated whole-virion influenza vaccine with HP-β-CD resulted in secretion of antigen-specific IgA and IgGs in the airway mucosa and the serum as well. As a result, both HP-β-CD adjuvanted-flu intranasal vaccine protected mice against lethal challenge with influenza virus, equivalent to those induced by experimental cholera toxin-adjuvanted ones. Of note, intranasal use of HP-β-CD as an adjuvant induced significantly lower antigen-specific IgE responses than that induced by aluminum salt adjuvant. These results suggest that HP-β-CD may be a potent mucosal adjuvant for seasonal and pandemic influenza vaccine. PMID:27160037

  3. Intranasal Delivery of Umbilical Cord-Derived Mesenchymal Stem Cells Preserves Myelination in Perinatal Brain Damage.

    PubMed

    Oppliger, Byron; Joerger-Messerli, Marianne; Mueller, Martin; Reinhart, Ursula; Schneider, Philipp; Surbek, Daniel V; Schoeberlein, Andreina

    2016-08-15

    Preterm white matter injury (WMI) is an important cause for long-term disability. Stem cell transplantation has been proposed as a novel therapeutic approach. However, intracerebral transplantation is not feasible for clinical purpose in newborns. Intranasal delivery of cells to the brain might be a promising, noninvasive therapeutic approach to restore the damaged brain. Therefore, our goal is to study the remyelinating potential of human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) after intranasal delivery. Wistar rat pups, previously brain-damaged by a combined hypoxic-ischemic and inflammatory insult, received hWJ-MSC (150,000 cells in 3 μL) that were intranasally delivered twice to each nostril (600,000 cells total). WMI was assessed by immunohistochemistry and western blot for myelination, astrogliosis, and microgliosis. The expression of preoligodendrocyte markers, and neurotrophic factors, was analyzed by real-time polymerase chain reaction. Animals treated with intranasally delivered hWJ-MSC showed increased myelination and decreased gliosis compared to untreated animals. hWJ-MSC may, therefore, modulate the activation of microglia and astrocytes, resulting in a change of the brain microenvironment, which facilitates the maturation of oligodendrocyte lineage cells. This is the first study to show that intranasal delivery of hWJ-MSC in rats prevented hypomyelination and microgliosis in a model of WMI in the premature rat brain. Further studies should address the dose and frequency of administration. PMID:27392671

  4. Intranasal T-LysYal® as adjunctive therapy for patients after functional endoscopic sinus surgery.

    PubMed

    Gelardi, M; Taliente, S; Fiorella, M L; Quaranta, N; De Candia, N; Russo, C; Mola, P; Ciofalo, A; Zambetti, G; Cantone, E; Arnone, F; Macchi, A; Rosso, P; Ciprandi, G

    2016-01-01

    Functional Endoscopic Sinus Surgery (FESS) is a common day surgery technique for upper airway disorders. Hyaluronic acid (HA) is a fundamental component of the human connective tissue. HA may exert reparative, anti-inflammatory and immune-modulating activities. Recently, a new intranasal HA formulation has been proposed: a supramolecular system containing lysine hyaluronate, thymine and sodium chloride (T-LysYal®). This randomized study investigated whether intranasal T-LysYal® (RinoLysYal®, Farmigea, Italy) was able to reduce symptom severity, endoscopic features, and nasal cytology in 83 patients (49 males and 34 females mean age 45.4±6.2 years) treated with FESS. All patients were treated with isotonic saline solution for 4 weeks, and a sub-group (active group) was also treated with intranasal T-LysYal®. Patients were visited at baseline, after treatment, and after 4-week follow-up. Intranasal T-LysYal® treatment significantly reduced the quote of patients with symptoms, endoscopic features, and inflammatory cells in comparison to isotonic solution. In conclusion, the present study demonstrates that intranasal T-LysYal® is able to significantly improve patients after FESS and its effect is long lasting. PMID:27049103

  5. Intranasal immunization with protective antigen of Bacillus anthracis induces a long-term immunological memory response.

    PubMed

    Woo, Sun-Je; Kang, Seok-Seong; Park, Sung-Moo; Yang, Jae Seung; Song, Man Ki; Yun, Cheol-Heui; Han, Seung Hyun

    2015-10-01

    Although intranasal vaccination has been shown to be effective for the protection against inhalational anthrax, establishment of long-term immunity has yet to be achieved. Here, we investigated whether intranasal immunization with recombinant protective antigen (rPA) of Bacillus anthracis induces immunological memory responses in the mucosal and systemic compartments. Intranasal immunization with rPA plus cholera toxin (CT) sustained PA-specific antibody responses for 6 months in lung, nasal washes, and vaginal washes as well as serum. A significant induction of PA-specific memory B cells was observed in spleen, cervical lymph nodes (CLNs) and lung after booster immunization. Furthermore, intranasal immunization with rPA plus CT remarkably generated effector memory CD4(+) T cells in the lung. PA-specific CD4(+) T cells preferentially increased the expression of Th1- and Th17-type cytokines in lung, but not in spleen or CLNs. Collectively, the intranasal immunization with rPA plus CT promoted immunologic memory responses in the mucosal and systemic compartments, providing long-term immunity. PMID:26278659

  6. Oral Insulin Reloaded

    PubMed Central

    Heinemann, Lutz; Plum-Mörschel, Leona

    2014-01-01

    Optimal coverage of insulin needs is the paramount aim of insulin replacement therapy in patients with diabetes mellitus. To apply insulin without breaking the skin barrier by a needle and/or to allow a more physiological provision of insulin are the main reasons triggering the continuous search for alternative routes of insulin administration. Despite numerous attempts over the past 9 decades to develop an insulin pill, no insulin for oral dosing is commercially available. By way of a structured approach, we aim to provide a systematic update on the most recent developments toward an orally available insulin formulation with a clear focus on data from clinical-experimental and clinical studies. Thirteen companies that claim to be working on oral insulin formulations were identified. However, only 6 of these companies published new clinical trial results within the past 5 years. Interestingly, these clinical data reports make up a mere 4% of the considerably high total number of publications on the development of oral insulin formulations within this time period. While this picture clearly reflects the rising research interest in orally bioavailable insulin formulations, it also highlights the fact that the lion’s share of research efforts is still allocated to the preclinical stages. PMID:24876606

  7. Promnestic effects of intranasally applied pregnenolone in rats.

    PubMed

    Abdel-Hafiz, Laila; Chao, Owen Y; Huston, Joseph P; Nikolaus, Susanne; Spieler, Richard E; de Souza Silva, Maria A; Mattern, Claudia

    2016-09-01

    The neurosteroid pregnenolone (PREG) has been shown to have memory-enhancing and anti-depressant action. The present study addresses the question of whether intranasally applied pregnenolone (IN-PREG) also has promnestic properties in the rat. We examined the effects of IN-PREG at doses of 0.187 and 0.373mg/kg on memory for objects and their location on learning and retention of escape in a water maze, and on behavior on the elevated plus maze. The main findings were: (a) Pre-trial, but not post-trial, administration of IN-PREG facilitated long-term memory in a novel object-preference test and a novel object-location preference test when tested 48h after dosing. (b) Over the duration of 5days of extinction trials, after learning to escape onto a hidden platform in a water maze, the animals treated with IN-PREG spent more time in searching for the absent platform, indicating either, or both, superior memory for the former position of the escape platform, or a higher resistance to extinction. (c) Administration of the anticholinergic, scopolamine, disrupted learning to escape from the water maze in the vehicle-treated group. The IN-PREG treated groups exhibited superior escape learning in comparison with vehicle controls, indicating that the treatment countered the scopolamine effect. IN-PREG treatment had no influence on behaviors on the elevated plus maze. Our results demonstrate that IN-PREG is behaviorally active with cognitive enhancing properties comparable to those known from studies employing systemic PREG administration. PMID:27423520

  8. Intranasal Oxytocin Normalizes Amygdala Functional Connectivity in Posttraumatic Stress Disorder.

    PubMed

    Koch, Saskia B J; van Zuiden, Mirjam; Nawijn, Laura; Frijling, Jessie L; Veltman, Dick J; Olff, Miranda

    2016-07-01

    The neuropeptide oxytocin (OT) has been suggested as a promising pharmacological agent for medication-enhanced psychotherapy in posttraumatic stress disorder (PTSD) because of its anxiolytic and prosocial properties. We therefore investigated the behavioral and neurobiological effects of a single intranasal OT administration (40 IU) in PTSD patients. We conducted a randomized, placebo-controlled, cross-over resting-state fMRI study in male and female police officers with (n=37, 21 males) and without PTSD (n=40, 20 males). We investigated OT administration effects on subjective anxiety and functional connectivity of basolateral (BLA) and centromedial (CeM) amygdala subregions with prefrontal and salience processing areas. In PTSD patients, OT administration resulted in decreased subjective anxiety and nervousness. Under placebo, male PTSD patients showed diminished right CeM to left ventromedial prefrontal cortex (vmPFC) connectivity compared with male trauma-exposed controls, which was reinstated after OT administration. Additionally, female PTSD patients showed enhanced right BLA to bilateral dorsal anterior cingulate cortex (dACC) connectivity compared with female trauma-exposed controls, which was dampened after OT administration. Although caution is warranted, our findings tentatively suggest that OT has the potential to diminish anxiety and fear expression of the amygdala in PTSD, either via increased control of the vmPFC over the CeM (males) or via decreased salience processing of the dACC and BLA (females). Our findings add to accumulating evidence that OT administration could potentially enhance treatment response in PTSD. PMID:26741286

  9. Intranasal inhalation of oxytocin improves face processing in developmental prosopagnosia.

    PubMed

    Bate, Sarah; Cook, Sarah J; Duchaine, Bradley; Tree, Jeremy J; Burns, Edwin J; Hodgson, Timothy L

    2014-01-01

    Developmental prosopagnosia (DP) is characterised by a severe lifelong impairment in face recognition. In recent years it has become clear that DP affects a substantial number of people, yet little work has attempted to improve face processing in these individuals. Intriguingly, recent evidence suggests that intranasal inhalation of the hormone oxytocin can improve face processing in unimpaired participants, and we investigated whether similar findings might be noted in DP. Ten adults with DP and 10 matched controls were tested using a randomized placebo-controlled double-blind within-subject experimental design (AB-BA). Each participant took part in two testing sessions separated by a 14-25 day interval. In each session, participants inhaled 24 IU of oxytocin or placebo spray, followed by a 45 min resting period to allow central oxytocin levels to plateau. Participants then completed two face processing tests: one assessing memory for a set of newly encoded faces, and one measuring the ability to match simultaneously presented faces according to identity. Participants completed the Multidimensional Mood Questionnaire (MMQ) at three points in each testing session to assess the possible mood-altering effects of oxytocin and to control for attention and wakefulness. Statistical comparisons revealed an improvement for DP but not control participants on both tests in the oxytocin condition, and analysis of scores on the MMQ indicated that the effect cannot be attributed to changes in mood, attention or wakefulness. This investigation provides the first evidence that oxytocin can improve face processing in DP, and the potential neural underpinnings of the findings are discussed alongside their implications for the treatment of face processing disorders. PMID:24074457

  10. Intranasal midazolam administration enhances amnesic effect in rats.

    PubMed

    Kadono, Takao; Kawano, Takashi; Yamanaka, Daiki; Tateiwa, Hiroki; Urakawa, Manami; Locatelli, Fabricio M; Yokoyama, Masataka

    2016-06-01

    Intranasal (i.n.) administration of midazolam has been shown to be effective and safe for its sedative, anxiolytic, and anticonvulsant effects. However, there has been no investigation on the influence of i.n. administration on midazolam-induced anterograde amnesia. In addition, although the potential of direct drug delivery from the nose to the central nervous system (CNS) has recently become a topic of great interest, it remains unclear whether this pathway is also involved after i.n. midazolam. In this study, we examined the efficacy and the underlying mechanism of i.n. administration compared with intramuscular (i.m.) administration on midazolam-induced amnesia in rats. Equivalent doses of 0.6 mg/kg midazolam were administered via either the i.m or the i.n. route. Anterograde amnesia was assessed by a contextual/cued fear conditioning test. Each animal was conditioned 20 min after drug administration and then tested for a freezing response 24 h later. Midazolam administration by either route produced a similar level of light sedation (minimum spontaneous activity). However, i.n. administration of midazolam induced significantly less freezing behavior compared with i.m. midazolam. Furthermore, in rats with disrupted electrical input from the olfactory epithelium after an olfactotoxicant 3-methylindole administration, the i.n.-mediated enhanced amnesic effect of midazolam was not observed. Our findings indicate that i.n midazolam could probably generate olfactory signals to the brain via benzodiazepine receptors and, compared with i.m. administration, can produce a more significant amnesic effect without alteration in sedative levels. Further clinical studies are warranted. PMID:26943484

  11. Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Chow, D. S. L.; Tam, V.; Putcha, L.

    2014-01-01

    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials for an Investigative New Drug (IND). The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial with INSCOP. METHODS: Twelve healthy human subjects were administered three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min to 24 h after dosing and scopolamine concentrations measured by using a validated LC-MS-MS assay. Pharmacokinetic Compartmental models, using actual dosing and sampling times, were built using Phoenix (version 1.2). Model discrimination was performed, by minimizing the Akaike Information Criteria (AIC), maximizing the coefficient of determination (r²) and by comparison of the quality of fit plots. RESULTS: The best structural model to describe scopolamine disposition after INSCOP administration (minimal AIC =907.2) consisted of one compartment for plasma, saliva and urine respectively that were inter-connected with different rate constants. The estimated values of PK parameters were compiled in Table 1. The model fitting exercises revealed a nonlinear PK for scopolamine between plasma and saliva compartments for K21, Vmax and Km. CONCLUSION: PK model for INSCOP was developed and for the first time it satisfactorily predicted the PK of scopolamine in plasma, saliva and urine after INSCOP administration. Using non-linear PK yielded the best structural model to describe scopolamine disposition between plasma and saliva compartments, and inclusion of non-linear PK resulted in a significant improved model fitting. The model can be utilized to predict scopolamine plasma concentration using saliva and/or urine data that

  12. Anatomical and Histological Factors Affecting Intranasal Drug and Vaccine Delivery

    PubMed Central

    Gizurarson, Sveinbjörn

    2012-01-01

    The aim of this review is to provide an understanding of the anatomical and histological structure of the nasal cavity, which is important for nasal drug and vaccine delivery as well as the development of new devices. The surface area of the nasal cavity is about 160 cm2, or 96 m2 if the microvilli are included. The olfactory region, however, is only about 5 cm2 (0.3 m2 including the microvilli). There are 6 arterial branches that serve the nasal cavity, making this region a very attractive route for drug administration. The blood flow into the nasal region is slightly more than reabsorbed back into the nasal veins, but the excess will drain into the lymph vessels, making this region a very attractive route for vaccine delivery. Many of the side effects seen following intranasal administration are caused by some of the 6 nerves that serve the nasal cavity. The 5th cranial nerve (trigeminus nerve) is responsible for sensing pain and irritation following nasal administration but the 7th cranial nerve (facial nerve) will respond to such irritation by stimulating glands and cause facial expressions in the subject. The first cranial nerve (olfactory nerve), however, is the target when direct absorption into the brain is the goal, since this is the only site in our body where the central nervous system is directly expressed on the mucosal surface. The nasal mucosa contains 7 cell types and 4 types of glands. Four types of cells and 2 types of glands are located in the respiratory region but 6 cell types and 2 types of glands are found in the olfactory region. PMID:22788696

  13. Anatomical and histological factors affecting intranasal drug and vaccine delivery.

    PubMed

    Gizurarson, Sveinbjörn

    2012-11-01

    The aim of this review is to provide an understanding of the anatomical and histological structure of the nasal cavity, which is important for nasal drug and vaccine delivery as well as the development of new devices. The surface area of the nasal cavity is about 160 cm2, or 96 m2 if the microvilli are included. The olfactory region, however, is only about 5 cm2 (0.3 m2 including the microvilli). There are 6 arterial branches that serve the nasal cavity, making this region a very attractive route for drug administration. The blood flow into the nasal region is slightly more than reabsorbed back into the nasal veins, but the excess will drain into the lymph vessels, making this region a very attractive route for vaccine delivery. Many of the side effects seen following intranasal administration are caused by some of the 6 nerves that serve the nasal cavity. The 5th cranial nerve (trigeminus nerve) is responsible for sensing pain and irritation following nasal administration but the 7th cranial nerve (facial nerve) will respond to such irritation by stimulating glands and cause facial expressions in the subject. The first cranial nerve (olfactory nerve), however, is the target when direct absorption into the brain is the goal, since this is the only site in our body where the central nervous system is directly expressed on the mucosal surface. The nasal mucosa contains 7 cell types and 4 types of glands. Four types of cells and 2 types of glands are located in the respiratory region but 6 cell types and 2 types of glands are found in the olfactory region. PMID:22788696

  14. Pharmacokinetics of Scopolamine Intranasal Gel Formulation (INSCOP) During Antiorthostatic Bedrest

    NASA Technical Reports Server (NTRS)

    Putcha, L.; Du, B.; Daniels, V.

    2010-01-01

    Space Motion Sickness (SMS) is experienced during early flight days of space missions and on reduced gravity simulation flights which require treatment with medications. Oral administration of scopolamine tablets is still a common practice to prevent SMS symptoms. Bioavailability of medications taken by mouth for SMS is often low and variable. Intranasal (IN) administration of medications has been reported to achieve higher and more reliable bioavailability than from an equivalent oral dose. In this FDA reviewed phase II clinical trial, we evaluated pharmacokinetics of an investigative new drug formulation, INSCOP during ambulatory (AMB) and antiorthostatic bedrest (HBR), a ground-based microgravity analog. Twelve subjects including 6 males and 6 females received 0.2 and 0.4 mg doses of INSCOP on separate days during AMB and ABR in a randomized, double blind cross over experimental design. Blood samples were collected at regular time intervals for 24 h post dose and analyzed for free scopolamine concentrations by an LC-MS-MS method. Pharmacokinetic parameters were calculated using concentration versus time data and compared between AMB and ABR conditions. Results indicated that maximum concentration and relative bioavailability increased marginally during ABR compared to AMB; differences in PK parameters between AMB and ABR were greater with 0.2 mg than with 0.4 mg dose. Gender specific differences in PK parameters was observed both during AMB and ABR with differences higher in females between the two conditions than in males. A significant observation is that while gender differences in PK appear to exist, the differences in primary PK parameters between AMB and ABR after IN administration, unlike oral administration, are minimal and may not be clinically significant for both genders.

  15. In vivo extracellular recording of striatal neurons in the awake rat following unilateral 6-hydroxydopamine lesions.

    PubMed

    Chen, M T; Morales, M; Woodward, D J; Hoffer, B J; Janak, P H

    2001-09-01

    The purpose of this study was to further understand the functional effects of dopaminergic input to the dorsal striatum and to compare the effects of dopaminergic lesions in awake and anesthetized animals. We examined the effects of unilateral 6-hydroxydopamine (6-OHDA) lesions of the ascending dopaminergic bundle on the firing properties of dorsal striatal neurons in the awake freely moving rat using chronically implanted microwire electrode arrays. We recorded extracellular activity of striatal neurons under baseline conditions and following the systemic injection of apomorphine in awake and anesthetized subjects. Firing rates were higher in the hemisphere ipsilateral to the 6-OHDA lesion compared to rates of neurons from the contralateral unlesioned hemisphere. Striatal firing rates from sham and no-surgery control rats were, in general, higher than those from the contralateral unlesioned striatum of experimental subjects. Apomorphine (0.05 mg/kg, sc) normalized the differences in firing rates in lesioned animals by increasing firing of neurons within the contralateral unlesioned side, while simultaneously decreasing firing of neurons within the ipsilateral lesioned side. Mean firing rates were substantially higher in awake animals than in subjects anesthetized with chloral hydrate, perhaps reflecting anesthesia-induced decreases in excitatory input to striatal neurons. Chloral hydrate anesthesia decreased firing rates of neurons in the lesioned, unlesioned, and control striata to a similar degree, although absolute firing rates of neurons from the 6-OHDA-lesioned striata remained elevated over all other groups. Unilateral 6-OHDA lesions also altered the pattern of spike output in the awake animal as indicated by an increase in the number of bursts per minute following dopaminergic deafferentation. This and other burst parameters were altered by apomorphine. Our findings show that effects of dopaminergic deafferentation can be measured in the awake behaving

  16. Intranasal and oral vaccination with protein-based antigens: advantages, challenges and formulation strategies.

    PubMed

    Wang, Shujing; Liu, Huiqin; Zhang, Xinyi; Qian, Feng

    2015-07-01

    Most pathogens initiate their infections at the human mucosal surface. Therefore, mucosal vaccination, especially through oral or intranasal administration routes, is highly desired for infectious diseases. Meanwhile, protein-based antigens provide a safer alternative to the whole pathogen or DNA based ones in vaccine development. However, the unique biopharmaceutical hurdles that intranasally or orally delivered protein vaccines need to overcome before they reach the sites of targeting, the relatively low immunogenicity, as well as the low stability of the protein antigens, require thoughtful and fine-tuned mucosal vaccine formulations, including the selection of immunostimulants, the identification of the suitable vaccine delivery system, and the determination of the exact composition and manufacturing conditions. This review aims to provide an up-to-date survey of the protein antigen-based vaccine formulation development, including the usage of immunostimulants and the optimization of vaccine delivery systems for intranasal and oral administrations. PMID:25944045

  17. Combination of Continuous Dexmedetomidine Infusion with Titrated Ultra-Low-Dose Propofol-Fentanyl for an Awake Craniotomy.

    PubMed

    Das, Samaresh; Al-Mashani, Ali; Suri, Neelam; Salhotra, Neeraj; Chatterjee, Nilay

    2016-08-01

    An awake craniotomy is a continuously evolving technique used for the resection of brain tumours from the eloquent cortex. We report a 29-year-old male patient who presented to the Khoula Hospital, Muscat, Oman, in 2016 with a two month history of headaches and convulsions due to a space-occupying brain lesion in close proximity with the left motor cortex. An awake craniotomy was conducted using a scalp block, continuous dexmedetomidine infusion and a titrated ultra-low-dose of propofolfentanyl. The patient remained comfortable throughout the procedure and the intraoperative neuropsychological tests, brain mapping and tumour resection were successful. This case report suggests that dexmedetomidine in combination with titrated ultra-low-dose propofolfentanyl are effective options during an awake craniotomy, ensuring optimum sedation, minimal disinhibition and a rapid recovery. To the best of the authors' knowledge, this is the first awake craniotomy conducted successfully in Oman. PMID:27606116

  18. Combination of Continuous Dexmedetomidine Infusion with Titrated Ultra-Low-Dose Propofol-Fentanyl for an Awake Craniotomy

    PubMed Central

    Das, Samaresh; Al-Mashani, Ali; Suri, Neelam; Salhotra, Neeraj; Chatterjee, Nilay

    2016-01-01

    An awake craniotomy is a continuously evolving technique used for the resection of brain tumours from the eloquent cortex. We report a 29-year-old male patient who presented to the Khoula Hospital, Muscat, Oman, in 2016 with a two month history of headaches and convulsions due to a space-occupying brain lesion in close proximity with the left motor cortex. An awake craniotomy was conducted using a scalp block, continuous dexmedetomidine infusion and a titrated ultra-low-dose of propofolfentanyl. The patient remained comfortable throughout the procedure and the intraoperative neuropsychological tests, brain mapping and tumour resection were successful. This case report suggests that dexmedetomidine in combination with titrated ultra-low-dose propofolfentanyl are effective options during an awake craniotomy, ensuring optimum sedation, minimal disinhibition and a rapid recovery. To the best of the authors’ knowledge, this is the first awake craniotomy conducted successfully in Oman. PMID:27606116

  19. Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury.

    PubMed

    Donega, Vanessa; Nijboer, Cora H; van Tilborg, Geralda; Dijkhuizen, Rick M; Kavelaars, Annemieke; Heijnen, Cobi J

    2014-11-01

    Previous work from our group has shown that intranasal MSC-treatment decreases lesion volume and improves motor and cognitive behavior after hypoxic-ischemic (HI) brain damage in neonatal mice. Our aim was to determine the kinetics of MSC migration after intranasal administration, and the early effects of MSCs on neurogenic processes and gliosis at the lesion site. HI brain injury was induced in 9-day-old mice and MSCs were administered intranasally at 10days post-HI. The kinetics of MSC migration were investigated by immunofluorescence and MRI analysis. BDNF and NGF gene expression was determined by qPCR analysis following MSC co-culture with HI brain extract. Nestin, Doublecortin, NeuN, GFAP, Iba-1 and M1/M2 phenotypic expression was assessed over time. MRI and immunohistochemistry analyses showed that MSCs reach the lesion site already within 2h after intranasal administration. At 12h after administration the number of MSCs at the lesion site peaks and decreases significantly at 72h. The number of DCX(+) cells increased 1 to 3days after MSC administration in the SVZ. At the lesion, GFAP(+)/nestin(+) and DCX(+) expression increased 3 to 5days after MSC-treatment. The number of NeuN(+) cells increased within 5days, leading to a dramatic regeneration of the somatosensory cortex and hippocampus at 18days after intranasal MSC administration. Interestingly, MSCs expressed significantly more BDNF gene when exposed to HI brain extract in vitro. Furthermore, MSC-treatment resulted in the resolution of the glial scar surrounding the lesion, represented by a decrease in reactive astrocytes and microglia and polarization of microglia towards the M2 phenotype. In view of the current lack of therapeutic strategies, we propose that intranasal MSC administration is a powerful therapeutic option through its functional repair of the lesion represented by regeneration of the cortical and hippocampal structure and decrease of gliosis. PMID:24945601

  20. Intranasal delivery of progesterone after transient ischemic stroke decreases mortality and provides neuroprotection.

    PubMed

    Fréchou, Magalie; Zhang, Shaodong; Liere, Philippe; Delespierre, Brigitte; Soyed, Nouha; Pianos, Antoine; Schumacher, Michael; Mattern, Claudia; Guennoun, Rachida

    2015-10-01

    Progesterone is a potential neuroprotective agent for cerebral stroke. One of the STAIR's recommendations is to test different routes of delivery of therapeutic agents. Here, we investigated the neuroprotective efficacy of intranasal delivery of progesterone in oleogel. Male mice were subjected to transient middle cerebral occlusion (MCAO) for 1 h. Mice received intranasal or intraperitoneal administrations of progesterone (8 mg/kg) at 1, 6, and 24 h post-MCAO. Plasma and brain levels of steroids were measured by gas chromatography-mass spectrometry 2 and 24 h after the last administration of progesterone. Behavioral and histopathological analyzes were performed at 48 h post-MCAO. For blood-brain barrier (BBB) permeability analysis, mice received one intranasal administration of progesterone or placebo at reperfusion and Evans Blue and sodium fluorescein extravasations were assessed at 4 h post-MCAO. Two hours after its nasal administration, progesterone reached elevated levels in brain and plasma and was bioconverted to its 5α-reduced metabolites and to 20α-dihydroprogesterone. However, brain levels of progesterone and its metabolites were about half those measured after intraperitoneal injections, whereas levels of 11-deoxycorticosterone and corticosterone were 5-times lower. In contrast, after 24 h, higher levels of progesterone were measured in brain and plasma after intranasal than after intraperitoneal delivery. Intranasal progesterone decreased the mortality rate, improved motor functions, reduced infarct, attenuated neuronal loss, and decreased the early BBB disruption. This study demonstrates a good bioavailability, a prolonged absorption and a good neuroprotective efficacy of intranasal delivery of progesterone, thus potentially offering an efficient, safe, non-stressful and very easy mode of administration in stroke patients. PMID:26079443

  1. Protection of cattle against rinderpest by intranasal immunisation with a dry powder tissue culture vaccine.

    PubMed

    Anderson, J; Fishbourne, E; Corteyn, A; Donaldson, A I

    2000-11-22

    Dry powder tissue culture rinderpest vaccine containing 10(2.5) TCID(50) of virus per dose administered intranasally to cattle induced high titre circulating antibody responses and protection against challenge with a virulent strain of rinderpest virus. A reduction in the dose of virus to 10(1.1) TCID(50) resulted in a failure to elicit detectable antibody responses and a lack of protection. Intranasal powder vaccine offers several advantages over conventional needle-administered aqueous rinderpest vaccine, including greater stability in the absence of a cold chain, reduced risk of 'needle transfer' of other microbial agents present in the vaccinated herd and lower cost. PMID:11115707

  2. Retrospective evaluation of airway management with blind awake intubation in temporomandibular joint ankylosis patients: A review of 48 cases

    PubMed Central

    Sankar, Duraiswamy; Krishnan, Radhika; Veerabahu, Muthusubramanian; Vikraman, Bhaskara Pandian; Nathan, J. A.

    2016-01-01

    Aim: The aim was to determine the morbidity or mortality associated with the blind awake intubation technique in temporomandibular ankylosis patients. Settings and Design: A total of 48 cases with radiographically and clinically confirmed cases of temporomandibular joint (TMJ) ankylosis were included in the study for evaluation of anesthetic management and its complications. Materials and Methods: Airway assessment was done with standard proforma including Look externally, evaluate 3-3-2 rule, Mallampati classification, Obstruction, Neck mobility (LEMON) score assessment in all TMJ ankylosis patients. The intubation was carried out with the standard departmental anesthetic protocol in all the patients. The preoperative difficulty assessment and postoperative outcome were recorded. Results: Blind awake intubation was done in 92% of cases, 6% of cases were intubated by fiberoptic awake intubation, and 2% patient required surgical airway. Ninety-eight percent of the patients were cooperative during the awake intubation. The frequent complications encountered during the blind awake intubation were epistaxis and sore throat. Conclusion: In an anesthetic setup, where fiberoptic intubation is not available, blind awake intubation could be considered in the anesthetic management algorithm. PMID:27563608

  3. Behavioral Effects of Acclimatization To Restraint Protocol Used for Awake Animal Imaging

    PubMed Central

    Reed, Michael D.; Pira, Ashley S.; Febo, Marcelo

    2013-01-01

    Functional MRI of awake rats involves acclimatization to restraint to minimize motion. We designed a study to examine the effects of an acclimatization protocol (5 days of restraint, 60 minutes per day) on the emission of 22-kHz ultrasonic vocalizations and performance on a forced swim test (FST). Our results show that USV calls are reduced significantly by day 3, 4 and 5 of acclimatization. Although rats show less climbing activity (and more immobility) in FST on day 5 compared to the 1st day of restraint acclimatization, the difference is gone once animals are given a 2 week hiatus. Overall, we show that animals adapt to the restraint over the five day period, however, restraint may introduce confounding behavioral outcomes that may hinder the interpretation of results derived from awake rat imaging. The present data warrant further testing of the effects of MRI restraint on behavior. PMID:23562621

  4. Behavioral effects of acclimatization to restraint protocol used for awake animal imaging.

    PubMed

    Reed, Michael D; Pira, Ashley S; Febo, Marcelo

    2013-07-15

    Functional MRI in awake rats involves acclimatization to restraint to minimize motion. We designed a study to examine the effects of an acclimatization protocol (5 days of restraint, 60 min per day) on the emission of 22-kHz ultrasonic vocalizations and performance in a forced swim test (FST). Our results showed that USV calls are reduced significantly by days 3, 4 and 5 of acclimatization. Although the rats showed less climbing activity (and more immobility) in FST on day 5 compared to the 1st day of restraint acclimatization, the difference was not detected once the animals were given a 2-week hiatus. Overall, we showed that animals adapt to the restraint over a five-day period; however, restraint may introduce confounding behavioral outcomes that may hinder the interpretation of results derived from awake rat imaging. The present data warrants further testing of the effects of MRI restraint on behavior. PMID:23562621

  5. 5-aminolevulinic acid guidance during awake craniotomy to maximise extent of safe resection of glioblastoma multiforme.

    PubMed

    Corns, Robert; Mukherjee, Soumya; Johansen, Anja; Sivakumar, Gnanamurthy

    2015-01-01

    Overall survival for patients with glioblastoma multiforme (GBM) has been consistently shown to improve when the surgeon achieves a gross total resection of the tumour. It has also been demonstrated that surgical adjuncts such as 5-aminolevulinic acid (5-ALA) fluorescence--which delineates malignant tumour tissue--normal brain tissue margin seen using violet-blue excitation under an operating microscope--helps achieve this. We describe the case of a patient with recurrent left frontal GBM encroaching on Broca's area (eloquent brain). Gross total resection of the tumour was achieved by combining two techniques, awake resection to prevent damage to eloquent brain and 5-ALA fluorescence guidance to maximise the extent of tumour resection.This technique led to gross total resection of all T1-enhancing tumour with the avoidance of neurological deficit. The authors recommend this technique in patients when awake surgery can be tolerated and gross total resection is the aim of surgery. PMID:26177997

  6. Evolving Models of Pavlovian Conditioning: Cerebellar Cortical Dynamics in Awake Behaving Mice

    PubMed Central

    ten Brinke, Michiel M.; Boele, Henk-Jan; Spanke, Jochen K.; Potters, Jan-Willem; Kornysheva, Katja; Wulff, Peer; IJpelaar, Anna C.H.G.; Koekkoek, Sebastiaan K.E.; De Zeeuw, Chris I.

    2015-01-01

    Summary Three decades of electrophysiological research on cerebellar cortical activity underlying Pavlovian conditioning have expanded our understanding of motor learning in the brain. Purkinje cell simple spike suppression is considered to be crucial in the expression of conditional blink responses (CRs). However, trial-by-trial quantification of this link in awake behaving animals is lacking, and current hypotheses regarding the underlying plasticity mechanisms have diverged from the classical parallel fiber one to the Purkinje cell synapse LTD hypothesis. Here, we establish that acquired simple spike suppression, acquired conditioned stimulus (CS)-related complex spike responses, and molecular layer interneuron (MLI) activity predict the expression of CRs on a trial-by-trial basis using awake behaving mice. Additionally, we show that two independent transgenic mouse mutants with impaired MLI function exhibit motor learning deficits. Our findings suggest multiple cerebellar cortical plasticity mechanisms underlying simple spike suppression, and they implicate the broader involvement of the olivocerebellar module within the interstimulus interval. PMID:26655909

  7. Benefits of awake uniportal pulmonary resection in a patient with a previous contralateral lobectomy.

    PubMed

    Galvez, Carlos; Navarro-Martinez, Jose; Bolufer, Sergio; Lirio, Francisco; Mafe, Juan Jose; Rivera, Maria Jesus; Roca, Joaquin; Baschwitz, Benno

    2014-09-01

    Surgical resection of a contralateral recurrence of non-small cell lung cancer (NSCLC) is indicated in patients without evidence of disseminated disease and considered functionally operable. General anesthesia and double-lumen intubation involves one lobe ventilation in a patient treated with a previous lobectomy, thus increasing the risks of ventilator-induced injuries and the morbidity. Awake procedures facilitate the surgery decreasing the anesthetic and surgical times, keeping the diaphragm motion and diminishing the ventilator-induced injuries into the remaining contralateral lobe. We present a 43-year-old woman with a previous left-lower lobectomy for a 3.1-cm mucinous adenocarcinoma 15 months before without nodal involvement, who presents a right-lower lobe 8-mm cavitated nodule, with evident radiological growth and fine-needle aspiration concordant with mucinous adenocarcinoma. We suggest an awake procedure with locoregional epidural anesthesia. PMID:25405168

  8. Episodic-like memory trace in awake replay of hippocampal place cell activity sequences.

    PubMed

    Takahashi, Susumu

    2015-01-01

    Episodic memory retrieval of events at a specific place and time is effective for future planning. Sequential reactivation of the hippocampal place cells along familiar paths while the animal pauses is well suited to such a memory retrieval process. It is, however, unknown whether this awake replay represents events occurring along the path. Using a subtask switching protocol in which the animal experienced three subtasks as 'what' information in a maze, I here show that the replay represents a trial type, consisting of path and subtask, in terms of neuronal firing timings and rates. The actual trial type to be rewarded could only be reliably predicted from replays that occurred at the decision point. This trial-type representation implies that not only 'where and when' but also 'what' information is contained in the replay. This result supports the view that awake replay is an episodic-like memory retrieval process. PMID:26481131

  9. [Single-port video-assisted thoracic surgery in an awake patient].

    PubMed

    Alonso-García, F J; Navarro-Martínez, J; Gálvez, C; Rivera-Cogollos, M J; Sgattoni, C; Tarí-Bas, I M

    2016-03-01

    Video-assisted thoracic surgery is traditionally carried out with general anaesthesia and endotracheal intubation with double lumen tube. However, in the last few years procedures, such as lobectomies, are being performed with loco-regional anaesthesia, with and without sedation, maintaining the patient awake and with spontaneous breathing, in order to avoid the inherent risks of general anaesthesia, double lumen tube intubation and mechanical ventilation. This surgical approach has also shown to be effective in that it allows a good level of analgesia, maintaining a correct oxygenation and providing a better post-operative recovery. Two case reports are presented in which video-assisted thoracic surgery was used, a lung biopsy and a lung resection, both with epidural anaesthesia and maintaining the patient awake and with spontaneous ventilation, as part of a preliminary evaluation of the anaesthetic technique in this type of surgery. PMID:26298720

  10. Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents.

    PubMed

    Perry, Rachel J; Cardone, Rebecca L; Petersen, Max C; Zhang, Dongyan; Fouqueray, Pascale; Hallakou-Bozec, Sophie; Bolze, Sébastien; Shulman, Gerald I; Petersen, Kitt Falk; Kibbey, Richard G

    2016-08-01

    Imeglimin is a promising new oral antihyperglycemic agent that has been studied in clinical trials as a possible monotherapy or add-on therapy to lower fasting plasma glucose and improve hemoglobin A1c (1-3, 9). Imeglimin was shown to improve both fasting and postprandial glycemia and to increase insulin secretion in response to glucose during a hyperglycemic clamp after 1-wk of treatment in type 2 diabetic patients. However, whether the β-cell stimulatory effect of imeglimin is solely or partially responsible for its effects on glycemia remains to be fully confirmed. Here, we show that imeglimin directly activates β-cell insulin secretion in awake rodents without affecting hepatic insulin sensitivity, body composition, or energy expenditure. These data identify a primary amplification rather than trigger the β-cell mechanism that explains the acute, antidiabetic activity of imeglimin. PMID:27406738

  11. Flexibility in insulin prescription

    PubMed Central

    Kalra, Sanjay; Gupta, Yashdeep; Unnikrishnan, Ambika Gopalakrishnan

    2016-01-01

    This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage. PMID:27186563

  12. Flexibility in insulin prescription.

    PubMed

    Kalra, Sanjay; Gupta, Yashdeep; Unnikrishnan, Ambika Gopalakrishnan

    2016-01-01

    This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage. PMID:27186563

  13. Laryngeal Radiation Fibrosis: A Case of Failed Awake Flexible Fibreoptic Intubation

    PubMed Central

    Huitink, Johannes M.; Zijp, Lambert

    2011-01-01

    Awake fibreoptic intubation is accepted as the gold standard for intubation of patients with an anticipated difficult airway. Radiation fibrosis may cause difficulties during the intubation procedure. We present an unusual severe case of radiation induced changes to the larynx, with limited clinical symptoms, that caused failure of the fibreoptic intubation technique. A review of the known literature on radiation fibrosis and airway management is presented. PMID:22606397

  14. Mapping Sensorimotor Cortex Using Slow Cortical Potential Resting-State Networks While Awake and Under Anesthesia

    PubMed Central

    Breshears, Jonathan D.; Gaona, Charles M.; Roland, Jarod L.; Sharma, Mohit; Bundy, David T.; Shimony, Joshua S.; Rashid, Samiya; Eisenman, Lawrence N.; Hogan, R. Edward; Snyder, Abraham Z.; Leuthardt, Eric C.

    2015-01-01

    Background The emerging insight into resting-state cortical networks has been important in understanding the fundamental architecture of brain organization. These networks, which were originally identified with functional MRI, are also seen in the correlation topography of the infraslow rhythms of local field potentials. Because of the fundamental nature of these networks and their independence from task-related activations, we posit that in addition to their neuroscientific relevance, these slow cortical potential (SCP) networks could also play an important role in clinical brain mapping. Objective We hypothesized that these networks would be useful in identifying eloquent cortex, such as sensorimotor cortex, in patients both awake and under anesthesia. Methods This study included eight subjects undergoing surgical treatment for intractable epilepsy. SCPs were recorded from the cortical surface while awake and under propofol anesthesia. To test brain-mapping utility, slow cortical potential networks were identified using data-driven (seed-independent) and anatomy-driven (seed-based) approaches. Using electrocortical stimulation as the gold standard for comparison, the sensitivity and specificity of these networks for identifying sensorimotor cortex was calculated. Results Networks identified with a data-driven approach in patients under anesthesia and awake were 90% and 93% sensitive, and 58% and 55% specific for sensorimotor cortex, respectively. Networks identified with systematic seed selection in patients under anesthesia and awake were 78% and 83% sensitive, and 67% and 60% specific, respectively. Conclusion Resting-state networks may be useful for tailoring stimulation mapping and could provide a means of identifying eloquent regions in patients while under anesthesia. PMID:22517255

  15. The kinematic architecture of the Active Headframe: A new head support for awake brain surgery.

    PubMed

    Malosio, Matteo; Negri, Simone Pio; Pedrocchi, Nicola; Vicentini, Federico; Cardinale, Francesco; Tosatti, Lorenzo Molinari

    2012-01-01

    This paper presents the novel hybrid kinematic structure of the Active Headframe, a robotic head support to be employed in brain surgery operations for an active and dynamic control of the patient's head position and orientation, particularly addressing awake surgery requirements. The topology has been conceived in order to satisfy all the installation, functional and dynamic requirements. A kinetostatic optimization has been performed to obtain the actual geometric dimensions of the prototype currently being developed. PMID:23366166

  16. Development of a simultaneous optical/PET imaging system for awake mice

    NASA Astrophysics Data System (ADS)

    Takuwa, Hiroyuki; Ikoma, Yoko; Yoshida, Eiji; Tashima, Hideaki; Wakizaka, Hidekatsu; Shinaji, Tetsuya; Yamaya, Taiga

    2016-09-01

    Simultaneous measurements of multiple physiological parameters are essential for the study of brain disease mechanisms and the development of suitable therapies to treat them. In this study, we developed a measurement system for simultaneous optical imaging and PET for awake mice. The key elements of this system are the OpenPET, optical imaging and fixation apparatus for an awake mouse. The OpenPET is our original open-type PET geometry, which can be used in combination with another device because of the easily accessible open space of the former. A small prototype of the axial shift single-ring OpenPET was used. The objective lens for optical imaging with a mounted charge-coupled device camera was placed inside the open space of the AS-SROP. Our original fixation apparatus to hold an awake mouse was also applied. As a first application of this system, simultaneous measurements of cerebral blood flow (CBF) by laser speckle imaging (LSI) and [11C]raclopride-PET were performed under control and 5% CO2 inhalation (hypercapnia) conditions. Our system successfully obtained the CBF and [11C]raclopride radioactivity concentration simultaneously. Accumulation of [11C]raclopride was observed in the striatum where the density of dopamine D2 receptors is high. LSI measurements could be stably performed for more than 60 minutes. Increased CBF induced by hypercapnia was observed while CBF under the control condition was stable. We concluded that our imaging system should be useful for investigating the mechanisms of brain diseases in awake animal models.

  17. Off-pump awake coronary artery bypass grafting under high thoracic epidural anesthesia

    PubMed Central

    Paliwal, Bharat; Kamal, Manoj; Chauhan, Dilip Singh; Purohit, Anamika

    2016-01-01

    Conventionally general anesthesia has been the preferred anesthetic technique for coronary artery bypass grafting (CABG). Ever since the first awake CABG the concept though appearing promising is still being continually evaluated. From the Indian perspective, the practice has been largely limited to certain institutions and seems to be not widely practiced across India. This case reports our experience with this technique from the western part of the country. PMID:27275061

  18. Effects of specific carotid body and brain hypoxia on respiratory muscle control in the awake goat.

    PubMed Central

    Smith, C A; Engwall, M J; Dempsey, J A; Bisgard, G E

    1993-01-01

    1. We assessed the effects of specific brain hypoxia on the control of inspiratory and expiratory muscle electromyographic (EMG) activities in response to specific carotid body hypoxia in seven awake goats. We used an isolated carotid body perfusion technique that permitted specific, physiological, steady-state stimulation of the carotid bodies or maintenance of normoxia and normocapnia at the carotid bodies while varying the level of systemic, and therefore, brain oxygenation. 2. Isolated brain normocapnic hypoxia of up to 1.5 h duration increased inspired minute ventilation (VI) by means of increases in both tidal volume (VT) and respiratory frequency (fR). Electromyographic activities of both inspiratory and expiratory muscles were augmented as well. These responses were similar to those produced by low levels of whole-body normoxic hypercapnia. We conclude that moderate levels of brain hypoxia (Pa,O2 approximately 40 mmHg) in awake goats caused a net stimulation of ventilatory motor output. 3. Hypoxic stimulation of the carotid bodies alone caused comparable increases in VT and fR, and EMG augmentation of both inspiratory and expiratory muscles whether the brain was hypoxic or normoxic. These responses were quite similar to those obtained over a wide range of whole-body normoxic hypercapnia. We conclude that the integration of carotid body afferent information is not affected by moderate brain hypoxia in awake goats. 4. We found no evidence for an asymmetrical recruitment pattern of inspiratory vs. expiratory muscles in response to carotid body hypoxia or in response to brain hypoxia alone. 5. Our data support the concept that moderate brain hypoxia results in a net stimulation of respiratory motor output. These findings question the significance of 'central hypoxic depression' to the regulation of breathing under physiological levels of hypoxaemia in the awake animal. PMID:8487210

  19. Mapping brain networks in awake mice using combined optical neural control and fMRI.

    PubMed

    Desai, M; Kahn, I; Knoblich, U; Bernstein, J; Atallah, H; Yang, A; Kopell, N; Buckner, R L; Graybiel, A M; Moore, C I; Boyden, E S

    2011-03-01

    Behaviors and brain disorders involve neural circuits that are widely distributed in the brain. The ability to map the functional connectivity of distributed circuits, and to assess how this connectivity evolves over time, will be facilitated by methods for characterizing the network impact of activating a specific subcircuit, cell type, or projection pathway. We describe here an approach using high-resolution blood oxygenation level-dependent (BOLD) functional MRI (fMRI) of the awake mouse brain-to measure the distributed BOLD response evoked by optical activation of a local, defined cell class expressing the light-gated ion channel channelrhodopsin-2 (ChR2). The utility of this opto-fMRI approach was explored by identifying known cortical and subcortical targets of pyramidal cells of the primary somatosensory cortex (SI) and by analyzing how the set of regions recruited by optogenetically driven SI activity differs between the awake and anesthetized states. Results showed positive BOLD responses in a distributed network that included secondary somatosensory cortex (SII), primary motor cortex (MI), caudoputamen (CP), and contralateral SI (c-SI). Measures in awake compared with anesthetized mice (0.7% isoflurane) showed significantly increased BOLD response in the local region (SI) and indirectly stimulated regions (SII, MI, CP, and c-SI), as well as increased BOLD signal temporal correlations between pairs of regions. These collective results suggest opto-fMRI can provide a controlled means for characterizing the distributed network downstream of a defined cell class in the awake brain. Opto-fMRI may find use in examining causal links between defined circuit elements in diverse behaviors and pathologies. PMID:21160013

  20. Development of a simultaneous optical/PET imaging system for awake mice.

    PubMed

    Takuwa, Hiroyuki; Ikoma, Yoko; Yoshida, Eiji; Tashima, Hideaki; Wakizaka, Hidekatsu; Shinaji, Tetsuya; Yamaya, Taiga

    2016-09-01

    Simultaneous measurements of multiple physiological parameters are essential for the study of brain disease mechanisms and the development of suitable therapies to treat them. In this study, we developed a measurement system for simultaneous optical imaging and PET for awake mice. The key elements of this system are the OpenPET, optical imaging and fixation apparatus for an awake mouse. The OpenPET is our original open-type PET geometry, which can be used in combination with another device because of the easily accessible open space of the former. A small prototype of the axial shift single-ring OpenPET was used. The objective lens for optical imaging with a mounted charge-coupled device camera was placed inside the open space of the AS-SROP. Our original fixation apparatus to hold an awake mouse was also applied. As a first application of this system, simultaneous measurements of cerebral blood flow (CBF) by laser speckle imaging (LSI) and [(11)C]raclopride-PET were performed under control and 5% CO2 inhalation (hypercapnia) conditions. Our system successfully obtained the CBF and [(11)C]raclopride radioactivity concentration simultaneously. Accumulation of [(11)C]raclopride was observed in the striatum where the density of dopamine D2 receptors is high. LSI measurements could be stably performed for more than 60 minutes. Increased CBF induced by hypercapnia was observed while CBF under the control condition was stable. We concluded that our imaging system should be useful for investigating the mechanisms of brain diseases in awake animal models. PMID:27514436

  1. Impact of Gender on Pharmocokinetics of Intranasal Scopolamine

    NASA Technical Reports Server (NTRS)

    Putcha, L.; Lei, Wu.; S-L Chow, Diana

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS), which is commonly experienced by astronauts during space missions. The bioavailability and pharmacokinetics (PK) were evaluated under IND guidelines. Since information is lacking on the effect of gender on the PK of Scopolamine, we examined gender differences in PK parameters of INSCOP at three dose levels of 0.1, 0.2 and 0.4 mg. Methods: Plasma scopolamine concentrations as a function of time data were collected from twelve normal healthy human subjects (6 male/6 female) who participated in a fully randomized double blind crossover study. The PK parameters were derived using WinNonlin. Covariate analysis of PK profiles was performed using NONMEN and statistically compared using a likelihood ratio test on the difference of objective function value (OFV). Statistical significance for covariate analysis was set at P<0.05(?OFV=3.84). Results: No significant difference in PK parameters between male and female subjects was observed with 0.1 and 0.2 mg doses. However, CL and Vd were significantly different between male and female subjects at the 0.4 mg dose. Results from population covariate modeling analysis indicate that a onecompartment PK model with first-order elimination rate offers best fit for describing INSCOP concentration-time profiles. The inclusion of sex as a covariate enhanced the model fitting (?OFV=-4.1) owing to the genderdependent CL and Vd differences after the 0.4 mg dose. Conclusion: Statistical modeling of scopolamine concentration-time data suggests gender-dependent pharmacokinetics of scopolamine at the high dose level of 0.4 mg. Clearance of the parent compound was significantly faster and the volume of distribution was significantly higher in males than in females, As a result, including gender as a covariate to the pharmacokinetic model of scopolamine offers the best fit for PK modeling of the drug at dose

  2. Insulin structure and function.

    PubMed

    Mayer, John P; Zhang, Faming; DiMarchi, Richard D

    2007-01-01

    Throughout much of the last century insulin served a central role in the advancement of peptide chemistry, pharmacology, cell signaling and structural biology. These discoveries have provided a steadily improved quantity and quality of life for those afflicted with diabetes. The collective work serves as a foundation for the development of insulin analogs and mimetics capable of providing more tailored therapy. Advancements in patient care have been paced by breakthroughs in core technologies, such as semisynthesis, high performance chromatography, rDNA-biosynthesis and formulation sciences. How the structural and conformational dynamics of this endocrine hormone elicit its biological response remains a vigorous area of study. Numerous insulin analogs have served to coordinate structural biology and biochemical signaling to provide a first level understanding of insulin action. The introduction of broad chemical diversity to the study of insulin has been limited by the inefficiency in total chemical synthesis, and the inherent limitations in rDNA-biosynthesis and semisynthetic approaches. The goals of continued investigation remain the delivery of insulin therapy where glycemic control is more precise and hypoglycemic liability is minimized. Additional objectives for medicinal chemists are the identification of superagonists and insulins more suitable for non-injectable delivery. The historical advancements in the synthesis of insulin analogs by multiple methods is reviewed with the specific structural elements of critical importance being highlighted. The functional refinement of this hormone as directed to improved patient care with insulin analogs of more precise pharmacology is reported. PMID:17410596

  3. [Difficult Ventilation Requiring Emergency Endotracheal Intubation during Awake Craniotomy Managed by Laryngeal Mask Airway].

    PubMed

    Matsuda, Asako; Mizota, Toshiyuki; Tanaka, Tomoharu; Segawa, Hajime; Fukuda, Kazuhiko

    2016-04-01

    We report a case of difficult ventilation requiring emergency endotracheal intubation during awake craniotomy managed by laryngeal mask airway (LMA). A 45-year-old woman was scheduled to receive awake craniotomy for brain tumor in the frontal lobe. After anesthetic induction, airway was secured using ProSeal LMA and patient was mechanically ventilated in pressure-control mode. Patient's head was fixed with head-pins at anteflex position, and the operation started. About one hour after the start of the operation, tidal volume suddenly decreased. We immediately started manual ventilation, but the airway resistance was extremely high and we could not adequately ventilate the patient. We administered muscle relaxant for suspected laryngospasm, but ventilatory status did not improve; so we decided to conduct emergency endotracheal intubation. We tried to intubate using Airwayscope or LMA-Fastrach, but they were not effective in our case. Finally trachea was intubated using transnasal fiberoptic bronchoscopy. We discuss airway management during awake craniotomy, focusing on emergency endotracheal intubation during surgery. PMID:27188111

  4. Imaging Circulating Tumor Cells in Freely Moving Awake Small Animals Using a Miniaturized Intravital Microscope

    PubMed Central

    Sasportas, Laura Sarah; Gambhir, Sanjiv Sam

    2014-01-01

    Metastasis, the cause for 90% of cancer mortality, is a complex and poorly understood process involving the invasion of circulating tumor cells (CTCs) into blood vessels. These cells have potential prognostic value as biomarkers for early metastatic risk. But their rarity and the lack of specificity and sensitivity in measuring them render their interrogation by current techniques very challenging. How and when these cells are circulating in the blood, on their way to potentially give rise to metastasis, is a question that remains largely unanswered. In order to provide an insight into this "black box" using non-invasive imaging, we developed a novel miniature intravital microscopy (mIVM) strategy capable of real-time long-term monitoring of CTCs in awake small animals. We established an experimental 4T1-GL mouse model of metastatic breast cancer, in which tumor cells express both fluorescent and bioluminescent reporter genes to enable both single cell and whole body tumor imaging. Using mIVM, we monitored blood vessels of different diameters in awake mice in an experimental model of metastasis. Using an in-house software algorithm we developed, we demonstrated in vivo CTC enumeration and computation of CTC trajectory and speed. These data represent the first reported use we know of for a miniature mountable intravital microscopy setup for in vivo imaging of CTCs in awake animals. PMID:24497977

  5. Glutamatergic function in the resting awake human brain is supported by uniformly high oxidative energy

    PubMed Central

    Hyder, Fahmeed; Fulbright, Robert K; Shulman, Robert G; Rothman, Douglas L

    2013-01-01

    Rodent 13C magnetic resonance spectroscopy studies show that glutamatergic signaling requires high oxidative energy in the awake resting state and allowed calibration of functional magnetic resonance imaging (fMRI) signal in terms of energy relative to the resting energy. Here, we derived energy used for glutamatergic signaling in the awake resting human. We analyzed human data of electroencephalography (EEG), positron emission tomography (PET) maps of oxygen (CMRO2) and glucose (CMRglc) utilization, and calibrated fMRI from a variety of experimental conditions. CMRglc and EEG in the visual cortex were tightly coupled over several conditions, showing that the oxidative demand for signaling was four times greater than the demand for nonsignaling events in the awake state. Variations of CMRO2 and CMRglc from gray-matter regions and networks were within ±10% of means, suggesting that most areas required similar energy for ubiquitously high resting activity. Human calibrated fMRI results suggest that changes of fMRI signal in cognitive studies contribute at most ±10% CMRO2 changes from rest. The PET data of sleep, vegetative state, and anesthesia show metabolic reductions from rest, uniformly >20% across, indicating no region is selectively reduced when consciousness is lost. Future clinical investigations will benefit from using quantitative metabolic measures. PMID:23299240

  6. Spectrotemporal Response Properties of Core Auditory Cortex Neurons in Awake Monkey

    PubMed Central

    Massoudi, Roohollah; Van Wanrooij, Marc M.; Versnel, Huib; Van Opstal, A. John

    2015-01-01

    So far, most studies of core auditory cortex (AC) have characterized the spectral and temporal tuning properties of cells in non-awake, anesthetized preparations. As experiments in awake animals are scarce, we here used dynamic spectral-temporal broadband ripples to study the properties of the spectrotemporal receptive fields (STRFs) of AC cells in awake monkeys. We show that AC neurons were typically most sensitive to low ripple densities (spectral) and low velocities (temporal), and that most cells were not selective for a particular spectrotemporal sweep direction. A substantial proportion of neurons preferred amplitude-modulated sounds (at zero ripple density) to dynamic ripples (at non-zero densities). The vast majority (>93%) of modulation transfer functions were separable with respect to spectral and temporal modulations, indicating that time and spectrum are independently processed in AC neurons. We also analyzed the linear predictability of AC responses to natural vocalizations on the basis of the STRF. We discuss our findings in the light of results obtained from the monkey midbrain inferior colliculus by comparing the spectrotemporal tuning properties and linear predictability of these two important auditory stages. PMID:25680187

  7. Controlled Iontophoresis Coupled with Fast-Scan Cyclic Voltammetry/Electrophysiology in Awake, Freely Moving Animals

    PubMed Central

    2013-01-01

    Simultaneous electrochemical and electrophysiological data were recorded to evaluate the effects of controlled local application of dopaminergic agonists and antagonists in awake rats. Measurements were made with a probe consisting of a carbon-fiber microelectrode fused to three iontophoretic barrels used to introduce the drugs of interest. The probe and the manipulator used to position it in the brain of behaving animals were optimized to improve their performance. The effect of the dopamine autoreceptor on electrically stimulated release was demonstrated. Dopamine inhibited the release of endogenous dopamine whereas raclopride, a D2 antagonist, enhanced it, with similar responses in anesthetized and awake animals. We also examined changes in the firing rate of nucleus accumbens (NAc) neurons in awake animals during and after brief (15 s) iontophoretic ejections of SCH 23390 (D1 receptor antagonist) or raclopride. Changes in response to these antagonists were seen both immediately and on a prolonged time scale. Application of raclopride increased the firing rate in 40% of medium spiny neurons (MSNs), of which half responded immediately. Decreases in firing rate were observed in 46% of MSNs after SCH 23390 application. Only 11% of MSNs responded to both antagonists and one MSN (3%) showed no response to either drug. The same prolonged response in firing rate was seen for electrically stimulated and locally applied dopamine in 75% of MSNs. These results are in agreement with previously reported distributions for dopamine receptor subtypes on MSNs and probe the effects of dopamine on these cell populations. PMID:23480099

  8. Alternative Devices for Taking Insulin

    MedlinePlus

    ... pumps contain enough insulin for several days. An infusion set carries insulin from the pump to the ... tube or needle inserted under the skin. Disposable infusion sets are used with insulin pumps to deliver ...

  9. Anti-insulin antibody test

    MedlinePlus

    Insulin antibodies - serum; Insulin Ab test ... Normally, there are no antibodies against insulin in your blood. Normal value ranges may vary slightly among different laboratories. Some labs use different measurements or ...

  10. Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus

    PubMed Central

    Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

    2015-01-01

    Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal–bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID:26568812

  11. Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus.

    PubMed

    Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

    2015-11-01

    Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal-bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID:26568812

  12. Anaesthesia Management for Awake Craniotomy: Systematic Review and Meta-Analysis

    PubMed Central

    Rossaint, Rolf; Veldeman, Michael

    2016-01-01

    Background Awake craniotomy (AC) renders an expanded role in functional neurosurgery. Yet, evidence for optimal anaesthesia management remains limited. We aimed to summarise the latest clinical evidence of AC anaesthesia management and explore the relationship of AC failures on the used anaesthesia techniques. Methods Two authors performed independently a systematic search of English articles in PubMed and EMBASE database 1/2007-12/2015. Search included randomised controlled trials (RCTs), observational trials, and case reports (n>4 cases), which reported anaesthetic approach for AC and at least one of our pre-specified outcomes: intraoperative seizures, hypoxia, arterial hypertension, nausea and vomiting, neurological dysfunction, conversion into general anaesthesia and failure of AC. Random effects meta-analysis was used to estimate event rates for four outcomes. Relationship with anaesthesia technique was explored using logistic meta-regression, calculating the odds ratios (OR) and 95% confidence intervals [95%CI]. Results We have included forty-seven studies. Eighteen reported asleep-awake-asleep technique (SAS), twenty-seven monitored anaesthesia care (MAC), one reported both and one used the awake-awake-awake technique (AAA). Proportions of AC failures, intraoperative seizures, new neurological dysfunction and conversion into general anaesthesia (GA) were 2% [95%CI:1–3], 8% [95%CI:6–11], 17% [95%CI:12–23] and 2% [95%CI:2–3], respectively. Meta-regression of SAS and MAC technique did not reveal any relevant differences between outcomes explained by the technique, except for conversion into GA. Estimated OR comparing SAS to MAC for AC failures was 0.98 [95%CI:0.36–2.69], 1.01 [95%CI:0.52–1.88] for seizures, 1.66 [95%CI:1.35–3.70] for new neurological dysfunction and 2.17 [95%CI:1.22–3.85] for conversion into GA. The latter result has to be interpreted cautiously. It is based on one retrospective high-risk of bias study and significance was

  13. Intranasal immunization of mice with a bovine respiratory syncytial virus vaccine induces superior immunity and protection compared to those by subcutaneous delivery or combinations of intranasal and subcutaneous prime-boost strategies.

    PubMed

    Mapletoft, John W; Latimer, Laura; Babiuk, Lorne A; van Drunen Littel-van den Hurk, Sylvia

    2010-01-01

    Bovine respiratory syncytial virus (BRSV) infects cells of the respiratory mucosa, so it is desirable to develop a vaccination strategy that induces mucosal immunity. To achieve this, various delivery routes were compared for formalin-inactivated (FI) BRSV formulated with CpG oligodeoxynucleotide (ODN) and polyphosphazene (PP). Intranasal delivery of the FI-BRSV formulation was superior to subcutaneous delivery in terms of antibody, cell-mediated, and mucosal immune responses, as well as reduction in virus replication after BRSV challenge. Although intranasal delivery of FI-BRSV also induced higher serum and lung antibody titers and gamma interferon (IFN-gamma) production in the lungs than intranasal-subcutaneous and/or subcutaneous-intranasal prime-boost strategies, no significant differences were observed in cell-mediated immune responses or virus replication in the lungs of challenged mice. Interleukin 5 (IL-5), eotaxin, and eosinophilia were enhanced after BRSV challenge in the lungs of subcutaneously immunized mice compared to unvaccinated mice, but not in the lungs of mice immunized intranasally or through combinations of the intranasal and subcutaneous routes. These results suggest that two intranasal immunizations with FI-BRSV formulated with CpG ODN and PP are effective and safe as an approach to induce systemic and mucosal responses, as well to reduce virus replication after BRSV challenge. Furthermore, intranasal-subcutaneous and subcutaneous-intranasal prime-boost strategies were also safe and almost as efficacious. In addition to the implications for the development of a protective BRSV vaccine for cattle, formulation with CpG ODN and PP could also prove important in the development of a mucosal vaccine that induces protective immunity against human RSV. PMID:19864487

  14. Intranasal Dexmedetomidine on Stress Hormones, Inflammatory Markers, and Postoperative Analgesia after Functional Endoscopic Sinus Surgery

    PubMed Central

    Tang, Chaoliang; Huang, Xiang; Kang, Fang; Chai, Xiaoqing; Wang, Song; Yin, Guobing; Wang, Hongtao; Li, Juan

    2015-01-01

    Background. A strong ongoing intraoperative stress response can cause serious adverse reactions and affect the postoperative outcome. This study evaluated the effect of intranasally administered dexmedetomidine (DEX) in combination with local anesthesia (LA) on the relief of stress and the inflammatory response during functional endoscopic sinus surgery (FESS). Methods. Sixty patients undergoing FESS were randomly allocated to receive either intranasal DEX (DEX group) or intranasal saline (Placebo group) 1 h before surgery. Stress hormones, inflammatory markers, postoperative pain relief, hemodynamic variables, blood loss, surgical field quality, body movements, and satisfaction were assessed. Results. Plasma epinephrine, norepinephrine, and blood glucose levels were significantly lower in DEX group as were the plasma IL-6 and TNF-α levels (P < 0.05). The weighted areas under the curve (AUCw) of the VAS scores were also significantly lower in DEX group at 2–12 h after surgery (P < 0.001). Furthermore, hemodynamic variables, blood loss, body movements, discomfort with hemostatic stuffing, surgical field quality, and satisfaction scores of patients and surgeons were significantly better (P < 0.05) in DEX group. Conclusions. Patients receiving intranasal DEX with LA for FESS exhibited less perioperative stress and inflammatory response as well as better postoperative comfort with hemostatic stuffing and analgesia. PMID:26199465

  15. Brain microdialysate, CSF and plasma pharmacokinetics of ligustrazine hydrochloride in rats after intranasal and intravenous administration.

    PubMed

    Wang, Qiao; Tang, Zhan; Zhang, Wanggang

    2013-10-01

    The aim of this work was to investigate the pharmacokinetics of ligustrazine hydrochloride (LZH) in plasma, cerebrospinal fluid (CSF) and cerebral cortex after intranasal (10 mg/kg) or intravenous administration (10 mg/kg) in male Sprague-Dawley rats. Plasma, CSF and cerebral cortex microdialysates were collected at timed intervals for the measurement of LZH by a quick and sensitive HPLC-UV method. LZH entered the brain quickly following both routes of administration. No significant difference was observed between the AUCCSF or cortex /AUCplasma ratio of LZH after intranasal administration (38.4%, 17.4%) and that after intravenous injection (45.9%, 19.9%). The drug targeting index (DTI) was 0.85 and 0.91 in the CSF and cortex, respectively. In conclusion, LZH is rapidly absorbed into the systemic circulation following intranasal administration. There is no direct pathway for LZH transport from the nasal cavity to the brain. The rapidity and magnitude of LZH penetration into the brain indicate that intranasal administration of this agent is a promising alternative to intravenous administration. PMID:23868712

  16. Abuse Potential of Intranasal Buprenorphine versus Buprenorphine/Naloxone in Buprenorphine-Maintained Heroin Users

    PubMed Central

    Jones, Jermaine D.; Sullivan, Maria A.; Vosburg, Suzanne K.; Manubay, Jeanne M.; Mogali, Shanthi; Metz, Verena; Comer, Sandra D.

    2014-01-01

    In spite of the clinical utility of buprenorphine, parenteral abuse of this medication has been reported in several laboratory investigations and in the real world. Studies have demonstrated lower abuse liability of the buprenorphine/naloxone combination relative to buprenorphine alone. However, clinical research has not yet examined the utility of the combined formulation to deter intranasal use in a buprenorphine-maintained population. Heroin-using volunteers (n = 12) lived in the hospital for 8–9 weeks and were maintained on each of three sublingual buprenorphine doses (2, 8, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intranasal doses of buprenorphine (8, 16 mg), buprenorphine/naloxone (8/2, 8/8, 8/16, 16/4 mg) and controls (placebo, heroin 100 mg, naloxone 4 mg) were assessed. Intranasal buprenorphine alone typically produced increases in positive subjective effects and the 8 mg dose was self-administered above the level of placebo. The addition of naloxone dose-dependently reduced positive subjective effects and increased aversive effects. No buprenorphine/naloxone combination dose was self-administered significantly more than placebo. These data suggest that within a buprenorphine-dependent population, intranasal buprenorphine/naloxone has reduced abuse potential in comparison to buprenorphine alone. These data strongly argue in favor of buprenorphine/naloxone rather than buprenorphine alone as the more reasonable option for managing the risk of buprenorphine misuse. PMID:25060839

  17. Intranasal temperature and humidity profile in patients with nasal septal perforation before and after surgical closure.

    PubMed

    Lindemann, J; Leiacker, R; Stehmer, V; Rettinger, G; Keck, T

    2001-10-01

    Common complaints of patients with a nasal septal perforation are crusting, dryness and bleeding. As shown previously, intranasal humidity values are significantly lower in patients with a septal perforation compared with healthy volunteers. The aim of this study was to determine the influence of surgical closure of septal perforations on intranasal temperature and humidity, and to evaluate changes in clinical symptoms after surgery. Ten patients with septal perforations were included in the study. Intranasal temperature and humidity were measured at the nasal valve and anterior turbinate areas before and after surgical closure. Clinical symptoms were assessed using a nasal symptom score. The end-inspiratory humidity values were significantly (P < or = 0.05) higher postoperatively than preoperatively. The increase in temperature at the anterior turbinate area was significantly higher postoperatively. The temperature values at the nasal valve area were not significantly different. Recurrent epistaxis and nasal dryness were reduced after surgery. Nasal septal perforations disturb the intranasal temperature and humidity profile. After surgical closure, heating and humidification is improved. This may be responsible for the reduction of frequent complaints such as bleeding and dryness. PMID:11678954

  18. Development of an intranasal vaccine to prevent urinary tract infection by Proteus mirabilis.

    PubMed

    Li, Xin; Lockatell, C Virginia; Johnson, David E; Lane, M Chelsea; Warren, John W; Mobley, Harry L T

    2004-01-01

    Proteus mirabilis commonly infects the complicated urinary tract and is associated with urolithiasis. Stone formation is caused by bacterial urease, which hydrolyzes urea to ammonia, causing local pH to rise, and leads to the subsequent precipitation of magnesium ammonium phosphate (struvite) and calcium phosphate (apatite) crystals. To prevent these infections, we vaccinated CBA mice with formalin-killed bacteria or purified mannose-resistant, Proteus-like (MR/P) fimbriae, a surface antigen expressed by P. mirabilis during experimental urinary tract infection, via four routes of immunization: subcutaneous, intranasal, transurethral, and oral. We assessed the efficacy of vaccination using the CBA mouse model of ascending urinary tract infection. Subcutaneous or intranasal immunization with formalin-killed bacteria and intranasal or transurethral immunization with purified MR/P fimbriae significantly protected CBA mice from ascending urinary tract infection by P. mirabilis (P < 0.05). To investigate the potential of MrpH, the MR/P fimbrial tip adhesin, as a vaccine, the mature MrpH peptide (residues 23 to 275, excluding the signal peptide), and the N-terminal receptor-binding domain of MrpH (residues 23 to 157) were overexpressed as C-terminal fusions to maltose-binding protein (MBP) and purified on amylose resins. Intranasal immunization of CBA mice with MBP-MrpH (residues 23 to 157) conferred effective protection against urinary tract infection by P. mirabilis (P < 0.002). PMID:14688082

  19. Direct nose-to-brain delivery of lamotrigine following intranasal administration to mice.

    PubMed

    Serralheiro, Ana; Alves, Gilberto; Fortuna, Ana; Falcão, Amílcar

    2015-07-25

    Pharmacoresistance is considered one of the major causes underlying the failure of the anticonvulsant therapy, demanding the development of alternative and more effective therapeutic approaches. Due to the particular anatomical features of the nasal cavity, intranasal administration has been explored as a means of preferential drug delivery to the brain. The purpose of the present study was to assess the pharmacokinetics of lamotrigine administered by the intranasal route to mice, and to investigate whether a direct transport of the drug from nose to brain could be involved. The high bioavailability achieved for intranasally administered lamotrigine (116.5%) underscored the fact that a substantial fraction of the drug has been absorbed to the systemic circulation. Nonetheless, the heterogeneous biodistribution of lamotrigine in different brain regions, with higher concentration levels attained in the olfactory bulb comparatively to the frontal cortex and the remaining portion of the brain, strongly suggest that lamotrigine was directly transferred to the brain via the olfactory neuronal pathway, circumventing the blood-brain barrier. Therefore, it seems that intranasal route can be assumed as a suitable and valuable drug delivery strategy for the chronic treatment of epilepsy, also providing a promising alternative approach for a prospective management of pharmacoresistance. PMID:25979854

  20. Preclinical evaluation of dual action intranasal formulation intended for postoperative/cancer associated therapies.

    PubMed

    El-Setouhy, Doaa Ahmed; Ahmed, Sami; Badawi, Alia Abd El-Latif; El-Nabarawi, Mohamed Ahmed; Sallam, Nada

    2015-08-30

    Granisetron hydrochloride is a potent antiemetic yet experiencing first pass metabolism. Ketorolac tromethamine is a potent analgesic NSAID that is known to cause gastrointestinal complications. The purpose of this study is to prepare combined in situ nasal copolymer thermal gel combining both drugs for the management of postoperative and cancer associated nausea, vomiting and pain while avoiding the problems associated with their therapy. In situ gelling nasal formulations with/without different mucoadhesive polymers were prepared and evaluated. Viscosity of different formulations was measured and correlated to in-vitro drug release. Selected formulae were evaluated for in-vivo mucociliary transit time. Based on in-vitro release pattern and mucociliary transit time, the selected formula F4 was evaluated for chemical and thermal anti-nociception activity in rats following intranasal or intraperitoneal administration. Only the intra-nasal administration of the selected formulation F4 showed significant analgesia against chemical nociception during both the early and late phases. Also, intranasal administration of the selected formulation F4 showed significant analgesia against thermal nociception. F4 intranasal formulation may offer higher therapeutic value than oral administration as it may not only avoid granisetron first pass metabolism but may also minimize ketorolac gastrointestinal adverse effects as well. PMID:25917526

  1. Abuse potential of intranasal buprenorphine versus buprenorphine/naloxone in buprenorphine-maintained heroin users.

    PubMed

    Jones, Jermaine D; Sullivan, Maria A; Vosburg, Suzanne K; Manubay, Jeanne M; Mogali, Shanthi; Metz, Verena; Comer, Sandra D

    2015-07-01

    In spite of the clinical utility of buprenorphine, parenteral abuse of this medication has been reported in several laboratory investigations and in the real world. Studies have demonstrated lower abuse liability of the buprenorphine/naloxone combination relative to buprenorphine alone. However, clinical research has not yet examined the utility of the combined formulation to deter intranasal use in a buprenorphine-maintained population. Heroin-using volunteers (n = 12) lived in the hospital for 8-9 weeks and were maintained on each of three sublingual buprenorphine doses (2, 8, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intranasal doses of buprenorphine (8, 16 mg), buprenorphine/naloxone (8/2, 8/8, 8/16, 16/4 mg) and controls (placebo, heroin 100 mg, naloxone 4 mg) were assessed. Intranasal buprenorphine alone typically produced increases in positive subjective effects and the 8 mg dose was self-administered above the level of placebo. The addition of naloxone dose dependently reduced positive subjective effects and increased aversive effects. No buprenorphine/naloxone combination dose was self-administered significantly more than placebo. These data suggest that within a buprenorphine-dependent population, intranasal buprenorphine/naloxone has reduced abuse potential in comparison to buprenorphine alone. These data strongly argue in favor of buprenorphine/naloxone rather than buprenorphine alone as the more reasonable option for managing the risk of buprenorphine misuse. PMID:25060839

  2. Intranasal delivery to the central nervous system: mechanisms and experimental considerations.

    PubMed

    Dhuria, Shyeilla V; Hanson, Leah R; Frey, William H

    2010-04-01

    The blood-brain barrier (BBB) limits the distribution of systemically administered therapeutics to the central nervous system (CNS), posing a significant challenge to drug development efforts to treat neurological and psychiatric diseases and disorders. Intranasal delivery is a noninvasive and convenient method that rapidly targets therapeutics to the CNS, bypassing the BBB and minimizing systemic exposure. This review focuses on the current understanding of the mechanisms underlying intranasal delivery to the CNS, with a discussion of pathways from the nasal cavity to the CNS involving the olfactory and trigeminal nerves, the vasculature, the cerebrospinal fluid, and the lymphatic system. In addition to the properties of the therapeutic, deposition of the drug formulation within the nasal passages and composition of the formulation can influence the pathway a therapeutic follows into the CNS after intranasal administration. Experimental factors, such as head position, volume, and method of administration, and formulation parameters, such as pH, osmolarity, or inclusion of permeation enhancers or mucoadhesives, can influence formulation deposition within the nasal passages and pathways followed into the CNS. Significant research will be required to develop and improve current intranasal treatments and careful consideration should be given to the factors discussed in this review. PMID:19877171

  3. Protein Crystal Bovine Insulin

    NASA Technical Reports Server (NTRS)

    1991-01-01

    The comparison of protein crystal, Bovine Insulin space-grown (left) and earth-grown (right). Facilitates the incorporation of glucose into cells. In diabetics, there is either a decrease in or complete lack of insulin, thereby leading to several harmful complications. Principal Investigator is Larry DeLucas.

  4. Devices for insulin administration.

    PubMed

    Selam, J L; Charles, M A

    1990-09-01

    There is a significant need for revised, safe, and more effective insulin-delivery methods than subcutaneous injections in the treatment of both type I (insulin-dependent) and type II (non-insulin-dependent) diabetes. The aim of this review is to describe the rationale and methods for better use of injection and infusion devices for intensive insulin therapy and to describe results of animal and human research that will lead to an implantable artificial pancreas. Injection devices, e.g., jet injectors, insulin pens, and access ports, cannot be considered as a major breakthrough in the quest for improved control, although they may improve the patient's comfort. External pumps have benefits over multiple injections and conventional insulin therapy only in specific subgroups of patients, e.g., those with recurrent severe hypoglycemia, but only when used by experienced personnel. The external artificial pancreas (Biostator) is also to be used by experienced personnel for limited clinical and research applications, e.g., surgery of the diabetic patient. The development of an implantable version of the artificial pancreas is linked to progress in the field of reliable long-duration glucose sensors. Finally, programmable implantable insulin pumps, used as an open-loop delivery system, are the most promising alternative to intensive subcutaneous insulin strategies in the short term, although clear evidence of improved safety and efficacy remains to be documented. PMID:2226111

  5. Insulin use: preventable errors.

    PubMed

    2014-01-01

    Insulin is vital for patients with type 1 diabetes and useful for certain patients with type 2 diabetes. The serious consequences of insulin-related medication errors are overdose, resulting in severe hypoglycaemia, causing seizures, coma and even death; or underdose, resulting in hyperglycaemia and sometimes ketoacidosis. Errors associated with the preparation and administration of insulin are often reported, both outside and inside the hospital setting. These errors are preventable. By analysing reports from organisations devoted to medication error prevention and from poison control centres, as well as a few studies and detailed case reports of medication errors, various types of error associated with insulin use have been identified, especially in the hospital setting. Generally, patients know more about the practicalities of their insulin treatment than healthcare professionals with intermittent involvement. Medication errors involving insulin can occur at each step of the medication-use process: prescribing, data entry, preparation, dispensing and administration. When prescribing insulin, wrong-dose errors have been caused by the use of abbreviations, especially "U" instead of the word "units" (often resulting in a 10-fold overdose because the "U" is read as a zero), or by failing to write the drug's name correctly or in full. In electronic prescribing, the sheer number of insulin products is a source of confusion and, ultimately, wrong-dose errors, and often overdose. Prescribing, dispensing or administration software is rarely compatible with insulin prescriptions in which the dose is adjusted on the basis of the patient's subsequent capillary blood glucose readings, and can therefore generate errors. When preparing and dispensing insulin, a tuberculin syringe is sometimes used instead of an insulin syringe, leading to overdose. Other errors arise from confusion created by similar packaging, between different insulin products or between insulin and other

  6. The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers

    PubMed Central

    Middleton, L.S.; Nuzzo, P.A.; Lofwall, M.R.; Moody, D.E.; Walsh, S.L.

    2011-01-01

    Aims Sublingual buprenorphine and buprenorphine/naloxone are efficacious opioid dependence pharmacotherapies, but there are reports of their diversion and misuse by the intranasal route. The study objectives were to characterize and compare their intranasal pharmacodynamic and pharmacokinetic profiles. Design A randomized, double-blind, placebo-controlled, crossover study. Setting An in-patient research unit at the University of Kentucky. Participants Healthy adults (n=10) abusing, but not physically dependent on, intranasal opioids. Measurements Six sessions (72 hours apart) tested five intranasal doses [0/0, crushed buprenorphine (2, 8 mg), crushed buprenorphine/naloxone (2/0.5, 8/2 mg)] and one intravenous dose (0.8 mg buprenorphine/0.2 mg naloxone for bioavailability assessment). Plasma samples, physiological, subject- and observer-rated measures were collected before and for up to 72 hours after drug administration. Findings Both formulations produced time- and dose-dependent increases on subjective and physiological mu-opioid agonist effects (e.g. ‘liking’, miosis). Subjects reported higher subjective ratings and street values for 8 mg compared to 8/2 mg, but these differences were not statistically significant. No significant formulation differences in peak plasma buprenorphine concentration or time-course were observed. Buprenorphine bioavailability was 38–44% and Tmax was 35–40 minutes after all intranasal doses. Naloxone bioavailability was 24% and 30% following 2/0.5 and 8/2 mg, respectively. Conclusions It is difficult to determine if observed differences in abuse potential between intranasal buprenorphine and buprenorphine/naloxone are clinically relevant at the doses tested. Greater bioavailability and faster onset of pharmacodynamic effects compared to sublingual administration suggests a motivation for intranasal misuse in non-dependent opioid abusers. However, significant naloxone absorption from intranasal buprenorphine

  7. Effects of intranasal and peripheral oxytocin or gastrin-releasing peptide administration on social interaction and corticosterone levels in rats.

    PubMed

    Kent, Pamela; Awadia, Alisha; Zhao, Leah; Ensan, Donna; Silva, Dinuka; Cayer, Christian; James, Jonathan S; Anisman, Hymie; Merali, Zul

    2016-02-01

    The intranasal route of drug administration has gained increased popularity as it is thought to allow large molecules, such as peptide hormones, more direct access to the brain, while limiting systemic exposure. Several studies have investigated the effects of intranasal oxytocin administration in humans as this peptide is associated with prosocial behavior. There are, however, few preclinical studies investigating the effects of intranasal oxytocin administration in rodents. Oxytocin modulates hypothalamic-pituitary-adrenal (HPA) axis functioning and it has been suggested that oxytocin's ability to increase sociability may occur through a reduction in stress reactivity. Another peptide that appears to influence both social behavior and HPA axis activity is gastrin-releasing peptide (GRP), but it is not known if these GRP-induced effects are related. With this in mind, in the present study, we assessed the effects of intranasal and intraperitoneal oxytocin and GRP administration on social interaction and release of corticosterone in rats. Intranasal and intraperitoneal administration of 20, but not 5 μg, of oxytocin significantly increased social interaction, whereas intranasal and peripheral administration of GRP (20 but not 5 μg) significantly decreased levels of social interaction. In addition, while intranasal oxytocin (20 μg) had no effect on blood corticosterone levels, a marked increase in blood corticosterone levels was observed following intraperitoneal oxytocin administration. With GRP, intranasal (20 μg) but not peripheral administration increased corticosterone levels. These findings provide further evidence that intranasal peptide delivery can induce behavioral alterations in rodents which is consistent with findings from human studies. In addition, the peptide-induced changes in social interaction were not linked to fluctuations in corticosterone levels. PMID:26658172

  8. Insulin Resistance of Puberty.

    PubMed

    Kelsey, Megan M; Zeitler, Philip S

    2016-07-01

    Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity. PMID:27179965

  9. Evaluation of brain targeting efficiency of intranasal microemulsion containing olanzapine: pharmacodynamic and pharmacokinetic consideration.

    PubMed

    Patel, Rashmin B; Patel, Mrunali R; Bhatt, Kashyap K; Patel, Bharat G; Gaikwad, Rajiv V

    2016-01-01

    The objective of this study was to develop and evaluate olanzapine (OZP) -loaded microemulsions (OZPME) for intranasal delivery in the treatment of schizophrenia. The OZPME was formulated by the spontaneous microemulsification method and characterized for physicochemical parameters. Pharmacodynamic assessments (apomorphine - induced compulsive behavior and spontaneous locomotor activity) were performed using mice. All formulations were radiolabeled with technetium-99 ((99m)Tc), and biodistribution of drug in the brain was investigated using Swiss albino rats. Brain scintigraphy imaging in rabbits was performed to determine the uptake of the OZP into the brain. OZPME were found clear and stable with average globule size of 23.87 ± 1.07 nm. In pharmacodynamic assessments, significant (p < 0.05) difference in parameters estimated were found between the treated and control groups. (99m)Tc-labeled OZP solution (OZPS)/OZPME/OZP mucoadhesive microemulsion (OZPMME) were found to be stable and suitable for in vivo studies. Brain/blood ratio at all sampling points up to 8 h following intranasal administration of OZPMME compared to intravenous OZPME was found to be five to six times higher signifying larger extent of distribution of the OZP in brain. Drug targeting efficiency and direct drug transport were found to be highest for intranasal OZPMME, compared to intravenous OZPME. Furthermore, rabbit brain scintigraphy also demonstrated higher intranasal uptake of the OZP into the brain. This investigation demonstrates a prompt and larger extent of transport of OZP into the brain through intranasal OZPMME, which may prove beneficial for treatment of schizophrenia. PMID:24845478

  10. Protection of mice from rabies by intranasal immunization with inactivated rabies virus.

    PubMed

    Yoneda, Atsushi; Tuchiya, Kotaro; Takashima, Yasuhiro; Arakawa, Takeshi; Tsuji, Naotoshi; Hayashi, Yoshihiro; Matsumoto, Yasunobu

    2008-01-01

    The mucosal immunization method is a needle-free alternative way of vaccination. This study evaluated the efficacy of mucosal immunization for rabies. Mice were intranasally administered five times with inactivated and concentrated rabies virus antigen (CRV) supplemented with or without cholera toxin (CT). The anti-rabies virus antibody titer of mice intranasally immunized with CRV plus CT (CRV/CT) was comparable to that of mice intraperitoneally immunized twice with the same amount of CRV. Virus neutralizing (VNA) titers of mice immunized intranasally with CRV/CT were slightly lower than those of intraperitoneally immunized mice. Both anti-rabies virus ELISA antibody and VNA titers of mice immunized with CRV without CT were significantly lower than those of mice immunized with CRV/CT. In mice intranasally immunized with CRV/CT, and intraperitoneally immunized mice, high levels of IgG(2a) antibody were detected, suggesting the activation of Th1-driven cellular immunity by the two ways of immunization. All immunized mice were challenged intracerebrally with a lethal dose of virulent rabies virus CVS strain. The survival rates of mice immunized with CRV/CT and CRV without CT were 67% and 17%, respectively, while the rate of intraperitoneally immunized mice was 100%. Antigen-specific whole IgG and IgG(2a), and VNA titers of survived mice were significantly higher than those of dead mice at the challenge day. These data suggest the possibility of intranasal immunization with inactivated antigen as a rabies vaccination strategy and the importance of a mucosal adjuvant such as CT. PMID:18256513

  11. Intranasal steroids: managing allergic rhinitis and tailoring treatment to patient preference.

    PubMed

    Meltzer, Eli O

    2005-01-01

    Allergic rhinitis (AR) can have a significant impact on patient quality of life (QoL), affecting learning ability and work productivity. Both the consequences of the impairment and the costs of treatment are associated with a large economic burden. The management of AR includes allergen avoidance, pharmacotherapy, and immunotherapy. Current pharmacotherapy options are oral and intranasal antihistamines, intranasal corticosteroids (INS), intranasal chromones, oral and intranasal decongestants, oral and intranasal anticholinergic agents, and antileukotrienes. A number of guidelines recommend INS as first-line treatment for persistent and moderate-to-severe AR. Although both patient and physician concern over the long-term safety of oral systemic steroids has previously prevented widespread use of INS, it is important to note that they have a superior risk/benefit ratio compared with other monotherapies. Indeed, the limited systemic bioavailability of INS agents, when used at recommended doses, has resulted in very low rates of systemic adverse effects, as shown by a lack of either hypothalamic-pituitary-adrenal axis or growth suppression. Large, controlled clinical studies have shown comparable efficacy and safety among the newer INS; therefore, clinicians may need to consider other factors, such as good patient compliance, when selecting an appropriate INS agent for a patient. In addition, patients often prefer one agent over another, and compliance may be improved by selecting the preferred agent. The development of two new questionnaires, the Clinical Practice Patient Preference Questionnaire and the Clinical Trial Patient Preference Questionnaire, may prove useful in selecting the optimal treatment regimen for patients. PMID:16541967

  12. Intranasal vaccination with adjuvant-free S. aureus antigens effectively protects mice against experimental sepsis.

    PubMed

    Stegmiller, Nataly Pescinalli; Barcelos, Estevão Carlos; Leal, Janine Miranda; Covre, Luciana Polaco; Donatele, Dirlei Molinari; de Matos Guedes, Herbet Leonel; Cunegundes, Marco Cesar; Rodrigues, Rodrigo Ribeiro; Gomes, Daniel Cláudio Oliviera

    2016-06-24

    Staphylococcus aureus (S. aureus) is a Gram-positive coccal bacterium comprising part of the human skin, nares and gastrointestinal tract normal microbiota. It is also an important cause of nosocomial/community-acquired infections in humans and animals, which can cause a diverse array of infections, including sepsis, which is a progressive systemic inflammation response syndrome that is frequently fatal. The emergence of drug-resistant strains and the high toxicity of the treatments used for these infections point out the need to develop an effective, inexpensive and safe vaccine that can be used prophylactically. In this work, we used an experimental sepsis model to evaluate the effectiveness of whole antigens from S. aureus (SaAg) given by the intranasal route to induce protective immunity against S. aureus infection in mice. BALB/c mice were vaccinated via intranasal or intramuscular route with two doses of SaAg, followed by biocompatibility and immunogenicity evaluations. Vaccinated animals did not show any adverse effects associated with the vaccine, as determined by transaminase and creatinine measurements. Intranasal, but not intramuscular vaccination with SaAg led to a significant reduction in IL-10 production and was associated with increased level of IFN-γ and NO. SaAg intranasal vaccination was able to prime cellular and humoral immune responses and inducing a higher proliferation index and increased production of specific IgG1/IgG2, which contributed to decrease the bacterial load in both liver and the spleen and improve survival during sepsis. These findings present the first evidence of the effectiveness of whole Ag intranasal-based vaccine administration, which expands the vaccination possibilities against S. aureus infection. PMID:27091687

  13. Intranasal Corticosteroids in Management of Acute Sinusitis: A Systematic Review and Meta-Analysis

    PubMed Central

    Hayward, Gail; Heneghan, Carl; Perera, Rafael; Thompson, Matthew

    2012-01-01

    PURPOSE Acute sinusitis is a common condition in ambulatory care, where it is frequently treated with antibiotics, despite little evidence of their benefit. Intranasal corticosteroids might relieve symptoms; however, evidence for this benefit is currently unclear. We performed a systematic review and meta-analysis of the effects of intranasal corticosteroids on the symptoms of acute sinusitis. METHODS We searched MEDLINE, EMBASE, the Cochrane Central register of Controlled Trials (CENTRAL), and Centre for Reviews and Dissemination databases until February 2011 for studies comparing intranasal corticosteroids with placebo in children or adults having clinical symptoms and signs of acute sinusitis or rhinosinusitis in ambulatory settings. We excluded chronic/allergic sinusitis. Two authors independently extracted data and assessed the studies’ methodologic quality. RESULTS We included 6 studies having a total of 2,495 patients. In 5 studies, antibiotics were prescribed in addition to corticosteroids or placebo. Intranasal corticosteroids resulted in a significant, small increase in resolution of or improvement in symptoms at days 14 to 21 (risk difference [RD] = 0.08; 95% CI, 0.03–0.13). Analysis of individual symptom scores revealed most consistently significant benefits for facial pain and congestion. Subgroup analysis by time of reported outcomes showed a significant beneficial effect at 21 days (RD = 0.11; 95% CI, 0.06–0.17), but not at 14 to 15 days (RD = 0.05; 95% CI, −0.01 to 0.11). Meta-regression analysis of trials using different doses of mometasone furoate showed a significant dose-response relationship (P=.02). CONCLUSIONS Intranasal corticosteroids offer a small therapeutic benefit in acute sinusitis, which may be greater with high doses and with courses of 21 days’ duration. Further trials are needed in antibiotic-naïve patients. PMID:22585889

  14. OUTCOME OF DOGS WITH INTRANASAL LYMPHOMA TREATED WITH VARIOUS RADIATION AND CHEMOTHERAPY PROTOCOLS: 24 CASES.

    PubMed

    George, Rebecca; Smith, Annette; Schleis, Stephanie; Brawner, William; Almond, Gregory; Kent, Michael; Wypij, Jackie; Borrego, Juan; Moore, Antony; Keyerleber, Michele; Kraiza, Sarah

    2016-05-01

    Tumors of the nasal cavity comprise approximately 1% of all neoplasms in dogs. Canine intranasal lymphoma is rare and reports evaluating the outcome of treatment are lacking. The goal of this observational, descriptive, multi-institutional study was to evaluate the overall median survival times (MSTs) in a group of dogs with intranasal lymphoma that were treated with irradiation and/or chemotherapy. Dogs meeting these inclusion criteria were retrospectively recruited from medical archives at multiple institutions. Eighteen cases of intermediate to high grade intranasal lymphoma and six cases of low-grade intranasal lymphoma were identified. The date of diagnosis, method of diagnosis, treatment received (radiation and/or chemotherapy protocols), and date of death were recorded. Kaplan-Meier survival analysis was performed on the intermediate to high grade group to calculate overall MST. Log-rank tests were performed to compare effects of treatment with radiation therapy ± chemotherapy and chemotherapy alone. Kaplan-Meier survival analysis was performed separately on the low-grade group. The overall MST was 375 days for the intermediate to high grade group. Cases treated with radiation ± chemotherapy had an MST of 455 days (n = 12) and those treated with chemotherapy alone (n = 6) had an MST of 157 days in the intermediate to high grade group. The MST was 823 days for the low-grade group. Results support the use of radiation therapy for treatment of canine intranasal lymphoma, however a randomized, controlled, clinical trial would be needed for more definitive recommendations. The role of adjunctive chemotherapy also may require further investigation. PMID:26763938

  15. Effect of intranasal rosiglitazone on airway inflammation and remodeling in a murine model of chronic asthma

    PubMed Central

    Lee, Hwa Young; Rhee, Chin Kook; Kang, Ji Young; Park, Chan Kwon; Lee, Sook Young; Kwon, Soon Suk; Kim, Young Kyoon; Yoon, Hyoung Kyu

    2016-01-01

    Background/Aims: Asthma is characterized by airway hyperresponsiveness, inflammation, and remodeling. Peroxisome proliferator-activated receptors have been reported to regulate inflammatory responses in many cells. In this study, we examined the effects of intranasal rosiglitazone on airway remodeling in a chronic asthma model. Methods: We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated intranasally with rosiglitazone with or without an antagonist during OVA challenge. We determined airway inflammation and the degree of airway remodeling by smooth muscle actin area and collagen deposition. Results: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, compared with control mice. Additionally, the mice developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of rosiglitazone intranasally inhibited the eosinophilic inflammation significantly, and, importantly, airway smooth muscle remodeling in mice chronically exposed to OVA. Expression of Toll-like receptor (TLR)-4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was increased in the OVA group and decreased in the rosiglitazone group. Co-treatment with GW9660 (a rosiglitazone antagonist) and rosiglitazone increased the expression of TLR-4 and NF-κB. Conclusions: These results suggest that intranasal administration of rosiglitazone can prevent not only air way inf lammation but also air way remodeling associated with chronic allergen challenge. This beneficial effect is mediated by inhibition of TLR-4 and NF-κB pathways. PMID:26767862

  16. Long-term exposure to intranasal oxytocin in a mouse autism model.

    PubMed

    Bales, K L; Solomon, M; Jacob, S; Crawley, J N; Silverman, J L; Larke, R H; Sahagun, E; Puhger, K R; Pride, M C; Mendoza, S P

    2014-01-01

    Oxytocin (OT) is a neuropeptide involved in mammalian social behavior. It is currently in clinical trials for the treatment of autism spectrum disorder (ASD). Previous studies in healthy rodents (prairie voles and C57BL/6J mice) have shown that there may be detrimental effects of long-term intranasal administration, raising the questions about safety and efficacy. To investigate the effects of OT on the aspects of ASD phenotype, we conducted the first study of chronic intranasal OT in a well-validated mouse model of autism, the BTBR T+ Itpr3tf/J inbred strain (BTBR), which displays low sociability and high repetitive behaviors. BTBR and C57BL/6J (B6) mice (N=94) were administered 0.8  IU/kg of OT intranasally, daily for 30 days, starting on day 21. We ran a well-characterized set of behavioral tasks relevant to diagnostic and associated symptoms of autism, including juvenile reciprocal social interactions, three-chambered social approach, open-field exploratory activity, repetitive self-grooming and fear-conditioned learning and memory, some during and some post treatment. Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test. Male saline-treated BTBR mice showed increased interest in a novel mouse, both in chamber time and sniffing time, whereas OT-treated male BTBR mice showed a preference for the novel mouse in sniffing time only. No deleterious effects of OT were detected in either B6 or BTBR mice, except possibly for the lack of a preference for the novel mouse's chamber in OT-treated male BTBR mice. These results highlight the complexity inherent in understanding the effects of OT on behavior. Future investigations of chronic intranasal OT should include a wider dose range and early developmental time points in both healthy rodents and ASD models to affirm the efficacy and safety of OT. PMID:25386957

  17. Is it dietary insulin?

    PubMed

    Vaarala, Outi

    2006-10-01

    In humans the primary trigger of insulin-specific immunity is a modified self-antigen, that is, dietary bovine insulin, which breaks neonatal tolerance to self-insulin. The immune response induced by bovine insulin spreads to react with human insulin. This primary immune response induced in the gut immune system is regulated by the mechanisms of oral tolerance. Genetic factors and environmental factors, such as the gut microflora, breast milk-derived factors, and enteral infections, control the development of oral tolerance. The age of host modifies the immune response to oral antigens because the permeability of the gut decreases with age and mucosal immune response, such as IgA response, develops with age. The factors that control the function of the gut immune system may either be protective from autoimmunity by supporting tolerance, or they may induce autoimmunity by abating tolerance to dietary insulin. There is accumulating evidence that the intestinal immune system is aberrant in children with type 1 diabetes (T1D). Intestinal immune activation and increased gut permeability are associated with T1D. These aberrancies may be responsible for the impaired control of tolerance to dietary insulin. Later in life, factors that activate insulin-specific immune cells derived from the gut may switch the response toward cytotoxic immunity. Viruses, which infect beta cells, may release autoantigens and potentiate their presentation by an infection-associated "danger signal." This kind of secondary immunization may cause functional changes in the dietary insulin primed immune cells, and lead to the infiltration of insulin-reactive T cells to the pancreatic islets. PMID:17130578

  18. Drosophila insulin degrading enzyme and rat skeletal muscle insulin protease cleave insulin at similar sites

    SciTech Connect

    Duckworth, W.C.; Garcia, J.V.; Liepnieks, J.J.; Hamel, F.G.; Hermodson, M.A.; Frank, B.H.; Rosner, M.R. )

    1989-03-21

    Insulin degradation is an integral part of the cellular action of insulin. Recent evidence suggests that the enzyme insulin protease is involved in the degradation of insulin in mammalian tissues. Drosophila, which has insulin-like hormones and insulin receptor homologues, also expresses an insulin degrading enzyme with properties that are very similar to those of mammalian insulin protease. In the present study, the insulin cleavage products generated by the Drosophila insulin degrading enzyme were identified and compared with the products generated by the mammalian insulin protease. Both purified enzymes were incubated with porcine insulin specifically labeled with {sup 125}I on either the A19 or B26 position, and the degradation products were analyzed by HPLC before and after sulfitolysis. Isolation and sequencing of the cleavage products indicated that both enzymes cleave the A chain of intact insulin at identical sites between residues A13 and A14 and A14 and A15. These results demonstrate that all the insulin cleavage sites generated by the Drosopohila insulin degrading enzyme are shared in common with the mammalian insulin protease. These data support the hypothesis that there is evolutionary conservation of the insulin degrading enzyme and further suggest that this enzyme plays an important role in cellular function.

  19. Tagging insulin in microgravity

    NASA Technical Reports Server (NTRS)

    Dobeck, Michael; Nelson, Ronald S.

    1992-01-01

    Knowing the exact subcellular sites of action of insulin in the body has the potential to give basic science investigators a basis from which a cause and cure for this disease can be approached. The goal of this project is to create a test reagent that can be used to visualize these subcellular sites. The unique microgravity environment of the Shuttle will allow the creation of a reagent that has the possibility of elucidating the subcellular sites of action of insulin. Several techniques have been used in an attempt to isolate the sites of action of items such as insulin. One of these is autoradiography in which the test item is obtained from animals fed radioactive materials. What is clearly needed is to visualize individual insulin molecules at their sites of action. The insulin tagging process to be used on G-399 involves the conjugation of insulin molecules with ferritin molecules to create a reagent that will be used back on Earth in an attempt to elucidate the sites of action of insulin.

  20. Technosphere inhaled insulin (Afrezza).

    PubMed

    Rendell, M

    2014-12-01

    Technosphere® insulin uses a unique carrier -fumaryl diketopiperazine (FDKP)- which adsorbs insulin to form microparticles to permit delivery to the alveoli by inhalation. Toxicity studies have been entirely negative. The pulmonary absorption of insulin is very rapid, and the disappearance time is shorter than for subcutaneously delivered rapid-acting insulins. As a result, after inhalation, there is a rapid drop in glucose levels which subsequently return to normal in a shorter time than after subcutaneous insulin administration. Consequently, there is a lower incidence of hypoglycemic reactions. Pulmonary function studies have shown a small, reversible decrease in FEV1, and pulmonary imaging studies have shown no adverse effect. The inhalation of Technosphere insulin can produce a cough in up to 27% of patients. The cough has resulted in discontinuance in as many as 9% of users. Technosphere insulin has been approved for use in type 1 and type 2 diabetes. Long-term studies of pulmonary safety and surveillance for malignancy will be performed in the future. Studies to assess the optimal time dosing regimen are needed. PMID:25588086

  1. [Alleged suicide by insulin].

    PubMed

    Birngruber, Christoph G; Krüll, Ralf; Dettmeyer, Reinhard; Verhoff, Marcel A

    2015-01-01

    A 26-year-old man, who was on probation, was found dead in his home by his mother. Insulin vials and 2 insulin pens, which the man's stepfather (an insulin-dependent diabetic) had been missing for over a week, were found next to the deceased. The circumstances suggested suicide by an injected insulin overdose. At the time of the autopsy, the corpse showed already marked signs of autolysis. Clinical chemical tests confirmed the injection of insulin, but indicated hyperglycemia at the time of death. Toxicological analyses revealed that the man had consumed amphetamine, cannabinoids, and tramadol in the recent past. Histological examination finally revealed extensive bronchopneumonia as the cause of death. The most plausible explanation for the results of the autopsy and the additional examinations was an injection of insulin as a failed attempt of self-treatment. It is conceivable that the man had discovered by a rapid test that he was a diabetic, but had decided not to go to a doctor to avoid disclosure of parole violation due to continued drug abuse. He may have misinterpreted the symptoms caused by his worsening bronchitis and the developing bronchopneumonia as symptoms of a diabetic metabolic status and may have felt compelled to treat himself with insulin. PMID:26419091

  2. Insulin and the law.

    PubMed

    Marks, Vincent

    2015-11-01

    Hypoglycaemia, if it can be proved, may be used as a defence against almost any criminal charge provided it can be established that the perpetrator was in a state of neuroglycopenic (hypoglycaemic) automatism at the time of the offence. Hypoglycaemia produced by exogenous insulin can also be used as a suicidal or homicidal weapon. This paper discusses some of the pitfalls confronting the investigator of suspected insulin misuse including problems arising from the increasing prevalence of insulin analogues and the unreliability of immunoassays for their detection and measurement in the forensic context. PMID:26092979

  3. Insulin glulisine: insulin receptor signaling characteristics in vivo.

    PubMed

    Hennige, Anita M; Lehmann, Rainer; Weigert, Cora; Moeschel, Klaus; Schäuble, Myriam; Metzinger, Elisabeth; Lammers, Reiner; Häring, Hans-Ulrich

    2005-02-01

    In recent years, recombinant DNA technology has been used to design insulin molecules that overcome the limitations of regular insulin in mealtime supplementation. However, safety issues have been raised with these alternatives, as the alteration of the three-dimensional structure may alter the interaction with the insulin and/or IGF-I receptors and therefore lead to the activation of alternate metabolic as well as mitogenic signaling pathways. It is therefore essential to carefully study acute and long-term effects in a preclinical state, as insulin therapy is meant to be a lifelong treatment. In this study, we determined in vivo the insulin receptor signaling characteristics activated by insulin glulisine (Lys(B3), Glu(B29)) at the level of insulin receptor phosphorylation, insulin receptor substrate phosphorylation, and downstream signaling elements such as phosphatidylinositol (PI) 3-kinase, AKT, and mitogen-activated protein kinase. C57BL/6 mice were injected with insulin glulisine or regular insulin and Western blot analysis was performed for liver and muscle tissue. The extent and time course of insulin receptor phosphorylation and activation of downstream signaling elements after insulin glulisine treatment was similar to that of human regular insulin in vivo. Moreover, insulin signaling in hypothalamic tissue determined by PI 3-kinase activity was comparable. Therefore, insulin glulisine may be a useful tool for diabetes treatment. PMID:15677493

  4. MATLAB-based automated patch-clamp system for awake behaving mice

    PubMed Central

    Siegel, Jennifer J.; Taylor, William; Chitwood, Raymond A.; Johnston, Daniel

    2015-01-01

    Automation has been an important part of biomedical research for decades, and the use of automated and robotic systems is now standard for such tasks as DNA sequencing, microfluidics, and high-throughput screening. Recently, Kodandaramaiah and colleagues (Nat Methods 9: 585–587, 2012) demonstrated, using anesthetized animals, the feasibility of automating blind patch-clamp recordings in vivo. Blind patch is a good target for automation because it is a complex yet highly stereotyped process that revolves around analysis of a single signal (electrode impedance) and movement along a single axis. Here, we introduce an automated system for blind patch-clamp recordings from awake, head-fixed mice running on a wheel. In its design, we were guided by 3 requirements: easy-to-use and easy-to-modify software; seamless integration of behavioral equipment; and efficient use of time. The resulting system employs equipment that is standard for patch recording rigs, moderately priced, or simple to make. It is written entirely in MATLAB, a programming environment that has an enormous user base in the neuroscience community and many available resources for analysis and instrument control. Using this system, we obtained 19 whole cell patch recordings from neurons in the prefrontal cortex of awake mice, aged 8–9 wk. Successful recordings had series resistances that averaged 52 ± 4 MΩ and required 5.7 ± 0.6 attempts to obtain. These numbers are comparable with those of experienced electrophysiologists working manually, and this system, written in a simple and familiar language, will be useful to many cellular electrophysiologists who wish to study awake behaving mice. PMID:26084901

  5. Extracellular Recording of Neuronal Activity Combined with Microiontophoretic Application of Neuroactive Substances in Awake Mice.

    PubMed

    Ayala, Yaneri A; Pérez-González, David; Duque, Daniel; Palmer, Alan R; Malmierca, Manuel S

    2016-01-01

    Differences in the activity of neurotransmitters and neuromodulators, and consequently different neural responses, can be found between anesthetized and awake animals. Therefore, methods allowing the manipulation of synaptic systems in awake animals are required in order to determine the contribution of synaptic inputs to neuronal processing unaffected by anesthetics. Here, we present methodology for the construction of electrodes to simultaneously record extracellular neural activity and release multiple neuroactive substances at the vicinity of the recording sites in awake mice. By combining these procedures, we performed microiontophoretic injections of gabazine to selectively block GABAA receptors in neurons of the inferior colliculus of head-restrained mice. Gabazine successfully modified neural response properties such as the frequency response area and stimulus-specific adaptation. Thus, we demonstrate that our methods are suitable for recording single-unit activity and for dissecting the role of specific neurotransmitter receptors in auditory processing. The main limitation of the described procedure is the relatively short recording time (~3 hr), which is determined by the level of habituation of the animal to the recording sessions. On the other hand, multiple recording sessions can be performed in the same animal. The advantage of this technique over other experimental procedures used to manipulate the level of neurotransmission or neuromodulation (such as systemic injections or the use of optogenetic models), is that the drug effect is confined to the local synaptic inputs to the target neuron. In addition, the custom-manufacture of electrodes allows adjustment of specific parameters according to the neural structure and type of neuron of interest (such as the tip resistance for improving the signal-to-noise ratio of the recordings). PMID:27286308

  6. The VetMousetrap: a device for computed tomographic imaging of the thorax of awake cats.

    PubMed

    Oliveira, Cintia R; Ranallo, Frank N; Pijanowski, Gerald J; Mitchell, Mark A; O'Brien, Mauria A; McMichael, Maureen; Hartman, Susan K; Matheson, Jodi S; O'Brien, Robert T

    2011-01-01

    The VetMousetrap, a novel device that allows computed tomography (CT) of awake cats and provides a clinically supportive environment, is described. Ten normal cats were used to test the device for ambient internal oxygen, carbon dioxide levels, and temperature. Twenty-two awake normal cats were imaged using a 16-multislice helical CT unit to evaluate dose-equivalent protocols. Two different X-ray tube potentials (kV), 80 and 120, and two different helical pitches, 0.562 and 1.75, were evaluated. The signal intensity of the pulmonary parenchyma (SIlung), signal intensity of background (SIbackgr), contrast, noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were calculated. Three evaluators ranked the images for sharpness of liver margins, motion, helical, and windmill artifacts. CT was successfully completed in 20 of 22 cats. No artifacts directly related to the device were detected. Overall, 75 of 80 (94%) examinations were judged to have absent or minimal motion artifact. A statistically significant difference was found for SNR (P = 0.001) and CNR (P = 0.001) between all protocols. The higher pitch protocols had significantly lower noise and higher SNR and CNR, lower motion artifact but greater helical artifacts. A protocol using 80 kV, 130 mA, 0.5s, and 0.562 pitch with 1.25mm slice thickness, and 0.625 mm slice reconstruction interval is recommended. The VetMousetrap appears to provide the opportunity for diagnostic CT imaging of the thorax of awake cats. PMID:21322386

  7. In Vivo Tumour Mapping Using Electrocorticography Alterations During Awake Brain Surgery: A Pilot Study.

    PubMed

    Boussen, Salah; Velly, Lionel; Benar, Christian; Metellus, Philippe; Bruder, Nicolas; Trébuchon, Agnès

    2016-09-01

    During awake brain surgery for tumour resection, in situ EEG recording (ECoG) is used to identify eloquent areas surrounding the tumour. We used the ECoG setup to record the electrical activity of cortical and subcortical tumours and then performed frequency and connectivity analyses in order to identify ECoG impairments and map tumours. We selected 16 patients with cortical (8) and subcortical (8) tumours undergoing awake brain surgery. For each patient, we computed the spectral content of tumoural and healthy areas in each frequency band. We computed connectivity of each electrode using connectivity markers (linear and non-linear correlations, phase-locking and coherence). We performed comparisons between healthy and tumour electrodes. The ECoG alterations were used to implement automated classification of the electrodes using clustering or neural network algorithms. ECoG alterations were used to image cortical tumours.Cortical tumours were found to profoundly alter all frequency contents (normalized and absolute power), with an increase in the δ activity and a decreases for the other bands (P < 0.05). Cortical tumour electrodes showed high level of connectivity compared to surrounding electrodes (all markers, P < 0.05). For subcortical tumours, a relative decrease in the γ1 band and in the alpha band in absolute amplitude (P < 0.05) were the only abnormalities. The neural network algorithm classification had a good performance: 93.6 % of the electrodes were classified adequately on a test subject. We found significant spectral and connectivity ECoG changes for cortical tumours, which allowed tumour recognition. Artificial neural algorithm pattern recognition seems promising for electrode classification in awake tumour surgery. PMID:27324381

  8. Functional recordings from awake, behaving rodents through a microchannel based regenerative neural interface

    NASA Astrophysics Data System (ADS)

    Gore, Russell K.; Choi, Yoonsu; Bellamkonda, Ravi; English, Arthur

    2015-02-01

    Objective. Neural interface technologies could provide controlling connections between the nervous system and external technologies, such as limb prosthetics. The recording of efferent, motor potentials is a critical requirement for a peripheral neural interface, as these signals represent the user-generated neural output intended to drive external devices. Our objective was to evaluate structural and functional neural regeneration through a microchannel neural interface and to characterize potentials recorded from electrodes placed within the microchannels in awake and behaving animals. Approach. Female rats were implanted with muscle EMG electrodes and, following unilateral sciatic nerve transection, the cut nerve was repaired either across a microchannel neural interface or with end-to-end surgical repair. During a 13 week recovery period, direct muscle responses to nerve stimulation proximal to the transection were monitored weekly. In two rats repaired with the neural interface, four wire electrodes were embedded in the microchannels and recordings were obtained within microchannels during proximal stimulation experiments and treadmill locomotion. Main results. In these proof-of-principle experiments, we found that axons from cut nerves were capable of functional reinnervation of distal muscle targets, whether regenerating through a microchannel device or after direct end-to-end repair. Discrete stimulation-evoked and volitional potentials were recorded within interface microchannels in a small group of awake and behaving animals and their firing patterns correlated directly with intramuscular recordings during locomotion. Of 38 potentials extracted, 19 were identified as motor axons reinnervating tibialis anterior or soleus muscles using spike triggered averaging. Significance. These results are evidence for motor axon regeneration through microchannels and are the first report of in vivo recordings from regenerated motor axons within microchannels in a small

  9. MATLAB-based automated patch-clamp system for awake behaving mice.

    PubMed

    Desai, Niraj S; Siegel, Jennifer J; Taylor, William; Chitwood, Raymond A; Johnston, Daniel

    2015-08-01

    Automation has been an important part of biomedical research for decades, and the use of automated and robotic systems is now standard for such tasks as DNA sequencing, microfluidics, and high-throughput screening. Recently, Kodandaramaiah and colleagues (Nat Methods 9: 585-587, 2012) demonstrated, using anesthetized animals, the feasibility of automating blind patch-clamp recordings in vivo. Blind patch is a good target for automation because it is a complex yet highly stereotyped process that revolves around analysis of a single signal (electrode impedance) and movement along a single axis. Here, we introduce an automated system for blind patch-clamp recordings from awake, head-fixed mice running on a wheel. In its design, we were guided by 3 requirements: easy-to-use and easy-to-modify software; seamless integration of behavioral equipment; and efficient use of time. The resulting system employs equipment that is standard for patch recording rigs, moderately priced, or simple to make. It is written entirely in MATLAB, a programming environment that has an enormous user base in the neuroscience community and many available resources for analysis and instrument control. Using this system, we obtained 19 whole cell patch recordings from neurons in the prefrontal cortex of awake mice, aged 8-9 wk. Successful recordings had series resistances that averaged 52 ± 4 MΩ and required 5.7 ± 0.6 attempts to obtain. These numbers are comparable with those of experienced electrophysiologists working manually, and this system, written in a simple and familiar language, will be useful to many cellular electrophysiologists who wish to study awake behaving mice. PMID:26084901

  10. Suicide and sleep: Is it a bad thing to be awake when reason sleeps?

    PubMed

    Perlis, Michael L; Grandner, Michael A; Chakravorty, Subhajit; Bernert, Rebecca A; Brown, Gregory K; Thase, Michael E

    2016-10-01

    Suicide is the second leading cause of death, worldwide, for those between the ages of 24 and 44 y old. In 2013, more than 41,000 suicides occurred in the United States. These statistics underscore the need to 1) understand why people die by suicide and 2) identify risk factors that are potentially modifiable. While it has been posited that sleep disturbance may represent one such factor, systematic research in this arena did not begin until the 2000s. Since that time, sleep disturbance has been reliably identified as a risk factor for suicidal ideation, suicide attempts, and suicide. While insomnia, nightmares, and other sleep disorders have each been found to contribute to the risk for suicidal ideation and behavior, it is also possible that these factors share some common variance. One possibility is that sleep disturbance results in being awake at night, and being awake at night also confers risk. The hypothesis proffered here is that being awake when one is not biologically prepared to be so results in "hypofrontality" and diminished executive function, and that this represents a common pathway to suicidal ideation and behavior. Such a proposition is highly testable under a variety of possible protocols. The current review summarizes the extant literature on suicide rates by time-of-day, and discusses circadian, psychosocial, and neurocognitive explanations of risk. Such a focus promises to enhance our understanding of how sleep disturbance may confer risk, allows for the identification of future lines of research, and further justifies the need for interventions that promote good sleep continuity among at-risk individuals. PMID:26706755

  11. Functional recordings from awake, behaving rodents through a microchannel based regenerative neural interface

    PubMed Central

    Gore, Russell K.; Choi, Yoonsu; Bellamkonda, Ravi; English, Arthur

    2015-01-01

    Objective Neural interface technologies could provide controlling connections between the nervous system and external technologies, such as limb prosthetics. The recording of efferent, motor potentials is a critical requirement for a peripheral neural interface, as these signals represent the user-generated neural output intended to drive external devices. Our objective was to evaluate structural and functional neural regeneration through a microchannel neural interface and to characterize potentials recorded from electrodes placed within the microchannels in awake and behaving animals. Approach Female rats were implanted with muscle EMG electrodes and, following unilateral sciatic nerve transection, the cut nerve was repaired either across a microchannel neural interface or with end-to-end surgical repair. During a 13-week recovery period, direct muscle responses to nerve stimulation proximal to the transection were monitored weekly. In two rats repaired with the neural interface, four wire electrodes were embedded in the microchannels and recordings were obtained within microchannels during proximal stimulation experiments and treadmill locomotion. Main results In these proof-of-principle experiments, we found that axons from cut nerves were capable of functional reinnervation of distal muscle targets, whether regenerating through a microchannel device or after direct end-to-end repair. Discrete stimulation-evoked and volitional potentials were recorded within interface microchannels in a small group of awake and behaving animals and their firing patterns correlated directly with intramuscular recordings during locomotion. Of 38 potentials extracted, 19 were identified as motor axons reinnervating tibialis anterior or soleus muscles using spike triggered averaging. Significance These results are evidence for motor axon regeneration through microchannels and are the first report of in vivo recordings from regenerated motor axons within microchannels in a small

  12. Electrical stimulation of the midbrain increases heart rate and arterial blood pressure in awake humans

    PubMed Central

    Thornton, Judith M; Aziz, Tipu; Schlugman, David; Paterson, David J

    2002-01-01

    Electrical stimulation of the hypothalamus, basal ganglia or pedunculopontine nucleus in decorticate animals results in locomotion and a cardiorespiratory response resembling that seen during exercise. This has led to the hypothesis that parallel activation of cardiorespiratory and locomotor systems from the midbrain could form part of the ‘central command’ mechanism of exercise. However, the degree to which subcortical structures play a role in cardiovascular activation in awake humans has not been established. We studied the effects on heart rate (HR) and mean arterial blood pressure (MAP) of electrically stimulating the thalamus and basal ganglia in awake humans undergoing neurosurgery for movement disorders (n = 13 Parkinson's disease, n = 1 myoclonic dystonia, n = 1 spasmodic torticollis). HR and MAP increased during high frequency (> 90 Hz) electrical stimulation of the thalamus (HR 5 ± 3 beats min−1, P = 0.002, MAP 4 ± 3 mmHg, P = 0.05, n = 9), subthalamic nucleus (HR 5 ± 3 beats min−1, P = 0.002, MAP 5 ± 3 mmHg, P = 0.006, n = 8) or substantia nigra (HR 6 ± 3 beats min−1, P = 0.001, MAP 5 ± 2 mmHg, P = 0.005, n = 8). This was accompanied by the facilitation of movement, but without the movement itself. Stimulation of the internal globus pallidus did not increase cardiovascular variables but did facilitate movement. Low frequency (< 20 Hz) stimulation of any site did not affect cardiovascular variables or movement. Electrical stimulation of the midbrain in awake humans can cause a modest increase in cardiovascular variables that is not dependent on movement feedback from exercising muscles. The relationship between this type of response and that occurring during actual exercise is unclear, but it indicates that subcortical command could be involved in ‘parallel activation’ of the locomotor and cardiovascular systems and thus contribute to the neurocircuitry of ‘central command’. PMID:11882692

  13. High-field localized 1H NMR spectroscopy in the anesthetized and in the awake monkey.

    PubMed

    Pfeuffer, Josef; Juchem, Christoph; Merkle, Hellmut; Nauerth, Arno; Logothetis, Nikos K

    2004-12-01

    Localized cerebral in vivo 1H NMR spectroscopy (MRS) was performed in the anesthetized as well as the awake monkey using a novel vertical 7 T/60 cm MR system. The increased sensitivity and spectral dispersion gained at high field enabled the quantification of up to 16 metabolites in 0.1- to 1-ml volumes. Quantification was accomplished by using simulations of 18 metabolite spectra and a macromolecule (MM) background spectrum consisting of 12 components. Major cerebral metabolites (concentrations >3 mM) such as glutamate (Glu), N-acetylaspartate (NAA), creatine (Cr)/phosphocreatine (PCr) and myo-inositol (Ins) were identified with an error below 3%; most other metabolites were quantified with errors in the order of 10%. Metabolite ratios were 1.39:1 for total NAA, 1.38:1 for glutamate (Glu)/glutamine (Gln) and 0.09:1 for cholines (Cho) relative to total Cr. Taurine (Tau) was detectable at concentrations lower than 1 mM, while lactate (Lac) remained below the detection limit. The spectral dispersion was sufficient to separate metabolites of similar spectral patterns, such as Gln and Glu, N-acetylaspartylglutamate (NAAG) and NAA, and PCr-Cr. MRS in the awake monkey required the development and refinement of acquisition and correction strategies to minimize magnetic susceptibility artifacts induced by respiration and movement of the mouth or body. Periods with major motion artifacts were rejected, while a frequency/phase correction was performed on the remaining single spectra before averaging. In resting periods, both spectral amplitude and line width, that is, the voxel shim, were unaffected permitting reliable measurements. The corrected spectra obtained from the awake monkey afforded the reliable detection of 6-10 cerebral metabolites of 1-ml volumes. PMID:15707786

  14. BOLD fMRI in awake prairie voles: A platform for translational social and affective neuroscience.

    PubMed

    Yee, J R; Kenkel, W M; Kulkarni, P; Moore, K; Perkeybile, A M; Toddes, S; Amacker, J A; Carter, C S; Ferris, C F

    2016-09-01

    The advancement of neuroscience depends on continued improvement in methods and models. Here, we present novel techniques for the use of awake functional magnetic resonance imaging (fMRI) in the prairie vole (Microtus ochrogaster) - an important step forward in minimally-invasive measurement of neural activity in a non-traditional animal model. Imaging neural responses in prairie voles, a species studied for its propensity to form strong and selective social bonds, is expected to greatly advance our mechanistic understanding of complex social and affective processes. The use of ultra-high-field fMRI allows for recording changes in region-specific activity throughout the entire brain simultaneously and with high temporal and spatial resolutions. By imaging neural responses in awake animals, with minimal invasiveness, we are able to avoid the confound of anesthesia, broaden the scope of possible stimuli, and potentially make use of repeated scans from the same animals. These methods are made possible by the development of an annotated and segmented 3D vole brain atlas and software for image analysis. The use of these methods in the prairie vole provides an opportunity to broaden neuroscientific investigation of behavior via a comparative approach, which highlights the ethological relevance of pro-social behaviors shared between voles and humans, such as communal breeding, selective social bonds, social buffering of stress, and caregiving behaviors. Results using these methods show that fMRI in the prairie vole is capable of yielding robust blood oxygen level dependent (BOLD) signal changes in response to hypercapnic challenge (inhaled 5% CO2), region-specific physical challenge (unilateral whisker stimulation), and presentation of a set of novel odors. Complementary analyses of repeated restraint sessions in the imaging hardware suggest that voles do not require acclimation to this procedure. Taken together, awake vole fMRI represents a new arena of neurobiological

  15. Cost analysis of awake versus asleep deep brain stimulation: a single academic health center experience.

    PubMed

    Jacob, R Lorie; Geddes, Jonah; McCartney, Shirley; Burchiel, Kim J

    2016-05-01

    OBJECT The objective of this study was to compare the cost of deep brain stimulation (DBS) performed awake versus asleep at a single US academic health center and to compare costs across the University HealthSystem Consortium (UHC) Clinical Database. METHODS Inpatient and outpatient demographic and hospital financial data for patients receiving a neurostimulator lead implant (from the first quarter of 2009 to the second quarter of 2014) were collected and analyzed. Inpatient charges included those associated with International Classification of Diseases, Ninth Revision (ICD-9) procedure code 0293 (implantation or replacement of intracranial neurostimulator lead). Outpatient charges included all preoperative charges ≤ 30 days prior to implant and all postoperative charges ≤ 30 days after implant. The cost of care based on reported charges and a cost-to-charge ratio was estimated. The UHC database was queried (January 2011 to March 2014) with the same ICD-9 code. Procedure cost data across like hospitals (27 UHC hospitals) conducting similar DBS procedures were compared. RESULTS Two hundred eleven DBS procedures (53 awake and 158 asleep) were performed at a single US academic health center during the study period. The average patient age ( ± SD) was 65 ± 9 years old and 39% of patients were female. The most common primary diagnosis was Parkinson's disease (61.1%) followed by essential and other forms of tremor (36%). Overall average DBS procedure cost was $39,152 ± $5340. Asleep DBS cost $38,850 ± $4830, which was not significantly different than the awake DBS cost of $40,052 ± $6604. The standard deviation for asleep DBS was significantly lower (p ≤ 0.05). In 2013, the median cost for a neurostimulator implant lead was $34,052 at UHC-affiliated hospitals that performed at least 5 procedures a year. At Oregon Health & Science University, the median cost was $17,150 and the observed single academic health center cost for a neurostimulator lead implant was

  16. Laser pulse propagation in a meter scale rubidium vapor/plasma cell in AWAKE experiment

    NASA Astrophysics Data System (ADS)

    Joulaei, A.; Moody, J.; Berti, N.; Kasparian, J.; Mirzanejhad, S.; Muggli, P.

    2016-09-01

    We present the results of numerical studies of laser pulse propagating in a 3.5 cm Rb vapor cell in the linear dispersion regime by using a 1D model and a 2D code that has been modified for our special case. The 2D simulation finally aimed at finding laser beam parameters suitable to make the Rb vapor fully ionized to obtain a uniform, 10 m-long, at least 1 mm in radius plasma in the next step for the AWAKE experiment.

  17. Resting state functional connectivity magnetic resonance imaging integrated with intraoperative neuronavigation for functional mapping after aborted awake craniotomy

    PubMed Central

    Batra, Prag; Bandt, S. Kathleen; Leuthardt, Eric C.

    2016-01-01

    Background: Awake craniotomy is currently the gold standard for aggressive tumor resections in eloquent cortex. However, a significant subset of patients is unable to tolerate this procedure, particularly the very young or old or those with psychiatric comorbidities, cardiopulmonary comorbidities, or obesity, among other conditions. In these cases, typical alternative procedures include biopsy alone or subtotal resection, both of which are associated with diminished surgical outcomes. Case Description: Here, we report the successful use of a preoperatively obtained resting state functional connectivity magnetic resonance imaging (MRI) integrated with intraoperative neuronavigation software in order to perform functional cortical mapping in the setting of an aborted awake craniotomy due to loss of airway. Conclusion: Resting state functional connectivity MRI integrated with intraoperative neuronavigation software can provide an alternative option for functional cortical mapping in the setting of an aborted awake craniotomy. PMID:26958419

  18. Exacerbation of Influenza Virus Infections in Mice by Intranasal Treatments and Implications for Evaluation of Antiviral Drugs

    PubMed Central

    von Itzstein, Mark; Bhatt, Beenu; Tarbet, E. Bart

    2012-01-01

    Compounds lacking oral activity may be delivered intranasally to treat influenza virus infections in mice. However, intranasal treatments greatly enhance the virulence of such virus infections. This can be partially compensated for by giving reduced virus challenge doses. These can be 100- to 1,000-fold lower than infections without such treatment and still cause equivalent mortality. We found that intranasal liquid treatments facilitate virus production (probably through enhanced virus spread) and that lung pneumonia was delayed by only 2 days relative to a 1,000-fold higher virus challenge dose not accompanied by intranasal treatments. In one study, zanamivir was 90 to 100% effective at 10 mg/kg/day by oral, intraperitoneal, and intramuscular routes against influenza A/California/04/2009 (H1N1) virus in mice. However, the same compound administered intranasally at 20 mg/kg/day for 5 days gave no protection from death although the time to death was significantly delayed. A related compound, Neu5Ac2en (N-acetyl-2,3-dehydro-2-deoxyneuraminic acid), was ineffective at 100 mg/kg/day. Intranasal zanamivir and Neu5Ac2en were 70 to 100% protective against influenza A/NWS/33 (H1N1) virus infections at 0.1 to 10 and 30 to 100 mg/kg/day, respectively. Somewhat more difficult to treat was A/Victoria/3/75 virus that required 10 mg/kg/day of zanamivir to achieve full protection. These results illustrate that treatment of influenza virus infections by the intranasal route requires consideration of both virus challenge dose and virus strain in order to avoid compromising the effectiveness of a potentially useful antiviral agent. In addition, the intranasal treatments were shown to facilitate virus replication and promote lung pathology. PMID:23027194

  19. All about Insulin Resistance

    MedlinePlus

    ... news is that cutting calories, being active, and losing weight can reverse insulin resistance and lower your ... you’ll lose weight. Studies have shown that losing even 7% of your weight, may help. For ...

  20. Insulin Delivery System

    NASA Technical Reports Server (NTRS)

    1988-01-01

    When Programmable Implantable Medication System (PIMS) is implanted in human body, it delivers precise programmed amounts of insulin over long periods of time. Mini-Med Technologies has been refining the Technologies since initial development at APL. The size of a hockey puck, and encased in titanium shell, PIMS holds about 2 1/2 teaspoons of insulin at a programmed basal rate. If a change in measured blood sugar level dictates a different dose, the patient can vary the amount of insulin delivered by holding a small radio transceiver over the implanted system and dialing in a specific program held in the PIMS computer memory. Insulin refills are accomplished approximately 4 times a year by hypodermic needle.

  1. Insulin Resistance and Prediabetes

    MedlinePlus

    ... sleep apnea; and cigarette smoking. [ Top ] Does sleep matter? Yes. Studies show that untreated sleep problems, especially ... a severe form of insulin resistance may have dark patches of skin, usually on the back of ...

  2. Insulin Lispro Injection

    MedlinePlus

    ... a solution (liquid) and a suspension (liquid with particles that will settle on standing) to inject subcutaneously ( ... if it is colored, cloudy, or contains solid particles. If you are using insulin lispro suspension, the ...

  3. Insulin Human Inhalation

    MedlinePlus

    ... inhalation comes as a powder to inhale by mouth using a special inhaler. It is usually used ... to your doctor.Before you use your insulin oral inhaler the first time, read the written instructions ...

  4. Respiratory and hemodynamic outcomes following exchange extubation with laryngeal mask airway as compared to traditional awake extubation

    PubMed Central

    Suppiah, Ramanathan Kannan; Rajan, Sunil; Paul, Jerry; Kumar, Lakshmi

    2016-01-01

    Background: Traditional awake extubation leads to respiratory complications and hemodynamic response which are detrimental in neurosurgery, ENT surgery and patients with comorbidities. Aims: The primary objective was to compare the respiratory complications and hemodynamic stress response between traditional awake extubation of a endotracheal tube (ETT) and that following exchange extubation of ETT by using a laryngeal mask airway (LMA). Settings and Design: This prospective randomized study was conducted in a Tertiary Care Centre in 60 American Society of Anesthesiologists I and II patients coming for general surgery. Materials and Methods: Patients were randomized by permuted blocks into traditional awake extubation group and exchange extubation group. At the end of surgery in traditional group, awake extubation of ETT was done. In exchange group, 0.3 mg/kg propofol was administered, and the ETT was exchanged for a LMA. Awake extubation of LMA was then performed. Respiratory complications such as bucking, coughing, desaturation and the need for airway maneuvers and hemodynamic response were noted in both groups. Analysis Tools: Chi-square test, independent sample t- and paired t-tests were used as applicable. Results: Incidence of respiratory complication was 93.3% in traditional extubation while it was only 36.7% in exchange extubation group (P < 0.001). Hemodynamic response measured immediately at extubation in terms of heart rate, systolic blood pressure (BP), diastolic BP, mean arterial pressure, and rate pressure product were all significantly lesser in exchange group when compared to traditional extubation. Conclusion: Exchange extubation with LMA decreases respiratory complications and hemodynamic stress response when compared to traditional awake extubation. PMID:27212749

  5. Moving toward the ideal insulin for insulin pumps.

    PubMed

    Cengiz, Eda; Bode, Bruce; Van Name, Michelle; Tamborlane, William V

    2016-01-01

    Advances in insulin formulations have been important for diabetes management and achieving optimal glycemic control. Rapid-acting insulin analogs provide a faster time-action profile than regular insulin and are approved for use in pumps. However, the need remains for therapy to deliver a more physiologic insulin profile. New insulin formulations and delivery methods are in development, with the aim of accelerating insulin absorption to accomplish ultra-fast-acting insulin time-action profiles. Furthermore, the integration of continuous glucose monitoring with insulin pump therapy enables on-going adjustment of insulin delivery to optimize glycemic control throughout the day and night. These technological and pharmacological advances are likely to facilitate the development of closed-loop pump systems (i.e., artificial pancreas), and improve glycemic control and quality of life for patients with diabetes. PMID:26560137

  6. Insulin allergy treated with human insulin (recombinant DNA).

    PubMed

    De Leeuw, I; Delvigne, C; Bekaert, J

    1982-01-01

    Two insulin-dependent diabetic subjects treated with pork and beef insulin during a period of 6 mo developed severe local reactions. Both patients had an important allergic history (asthma, urticaria, drug reactions, rhinitis). Skin-testing revealed type I allergy to beef and pork insulin. Specific IgE-insulin binding was demonstrated with both insulins. After negative skin testing with NPH Lilly human insulin (recombinant DNA), treatment was started with this compound and remained successful during a period of 6-9 mo. In one patient a local reaction occurred when regular human insulin (recombinant DNA) was added to NPH in order to obtain better control. Skin testing with regular human insulin was positive, but not with NPH human insulin alone. The mechanism of this phenomenon remains unsolved. PMID:6765530

  7. Salivary Oxytocin Concentrations in Males following Intranasal Administration of Oxytocin: A Double-Blind, Cross-Over Study

    PubMed Central

    Daughters, Katie; Manstead, Antony S. R.; Hubble, Kelly; Rees, Aled; Thapar, Anita; van Goozen, Stephanie H. M.

    2015-01-01

    The use of intranasal oxytocin (OT) in research has become increasingly important over the past decade. Although researchers have acknowledged a need for further investigation of the physiological effects of intranasal administration, few studies have actually done so. In the present double-blind cross-over study we investigated the longevity of a single 24 IU dose of intranasal OT measured in saliva in 40 healthy adult males. Salivary OT concentrations were significantly higher in the OT condition, compared to placebo. This significant difference lasted until the end of testing, approximately 108 minutes after administration, and peaked at 30 minutes. Results showed significant individual differences in response to intranasal OT administration. To our knowledge this is the largest and first all-male within-subjects design study to demonstrate the impact of intranasal OT on salivary OT concentrations. The results are consistent with previous research in suggesting that salivary OT is a valid matrix for OT measurement. The results also suggest that the post-administration ‘wait-time’ prior to starting experimental tasks could be reduced to 30 minutes, from the 45 minutes typically used, thereby enabling testing during peak OT concentrations. Further research is needed to ascertain whether OT concentrations after intranasal administration follow similar patterns in females, and different age groups. PMID:26669935

  8. Salivary Oxytocin Concentrations in Males following Intranasal Administration of Oxytocin: A Double-Blind, Cross-Over Study.

    PubMed

    Daughters, Katie; Manstead, Antony S R; Hubble, Kelly; Rees, Aled; Thapar, Anita; van Goozen, Stephanie H M

    2015-01-01

    The use of intranasal oxytocin (OT) in research has become increasingly important over the past decade. Although researchers have acknowledged a need for further investigation of the physiological effects of intranasal administration, few studies have actually done so. In the present double-blind cross-over study we investigated the longevity of a single 24 IU dose of intranasal OT measured in saliva in 40 healthy adult males. Salivary OT concentrations were significantly higher in the OT condition, compared to placebo. This significant difference lasted until the end of testing, approximately 108 minutes after administration, and peaked at 30 minutes. Results showed significant individual differences in response to intranasal OT administration. To our knowledge this is the largest and first all-male within-subjects design study to demonstrate the impact of intranasal OT on salivary OT concentrations. The results are consistent with previous research in suggesting that salivary OT is a valid matrix for OT measurement. The results also suggest that the post-administration 'wait-time' prior to starting experimental tasks could be reduced to 30 minutes, from the 45 minutes typically used, thereby enabling testing during peak OT concentrations. Further research is needed to ascertain whether OT concentrations after intranasal administration follow similar patterns in females, and different age groups. PMID:26669935

  9. Brain Transit and Ameliorative Effects of Intranasally Delivered Anti-Amyloid-β Oligomer Antibody in 5XFAD Mice

    PubMed Central

    Xiao, Chun; Davis, Francesca J.; Chauhan, Balwantsinh C.; Viola, Kirsten L.; Lacor, Pascale N.; Velasco, Pauline T.; Klein, William L.; Chauhan, Neelima B.

    2013-01-01

    Alzheimer’s disease (AD) is a global health crisis with limited treatment options. Despite major advances in neurotherapeutics, poor brain penetration due to the blood-brain barrier continues to pose a big challenge in overcoming the access of therapeutics to the central nervous system. In that regard, the non-invasive intranasal route of brain targeting is gaining considerable attention. The nasal mucosa offers a large surface area, rapid absorption, and avoidance of first-pass metabolism increasing drug bioavailability with less systemic side effects. Intranasal delivery is known to utilize olfactory, rostral migratory stream, and trigeminal routes to reach the brain. This investigation confirmed that intranasal delivery of oligomeric amyloid-β antibody (NU4) utilized all three routes to enter the brain with a resident time of 96 hours post single bolus intranasal administration, and showed evidence of perikaryal and parenchymal uptake of NU4 in 5XFAD mouse brain, confirming the intranasal route as a non-invasive and efficient way of delivering therapeutics to the brain. In addition, this study demonstrated that intranasal delivery of NU4 antibody lowered cerebral amyloid-β and improved spatial learning in 5XFAD mice. PMID:23542865

  10. Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.

    PubMed

    Sun, Bao-liang; He, Mei-qing; Han, Xiang-yu; Sun, Jing-yi; Yang, Ming-feng; Yuan, Hui; Fan, Cun-dong; Zhang, Shuai; Mao, Lei-lei; Li, Da-wei; Zhang, Zong-yong; Zheng, Cheng-bi; Yang, Xiao-yi; Li, Yang V; Stetler, R Anne; Chen, Jun; Zhang, Feng

    2016-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic. PMID:25432887

  11. Characterization and treatment of postsurgical dental implant pain employing intranasal ketorolac.

    PubMed

    Bockow, Rebecca; Korostoff, Jonathan; Pinto, Andres; Hutcheson, Matthew; Secreto, Stacey A; Bodner, Laura; Hersh, Elliot V

    2013-09-01

    The intensity and duration of pain following surgical placement of dental implants has not been well studied. Thus, the aim of this open-label study was to characterize the nature of postsurgical pain following the placement of one to three implants. The secondary goal was to explore the analgesic efficacy and tolerability of intranasal ketorolac in this patient population. Following implant surgery, postoperative pain was rated moderate or severe in 25/28 patients (89 percent), requiring prn analgesic dosing for up to 3 days in 14/25 individuals (56 percent). Intranasal ketorolac displayed an analgesic onset within 20 minutes, a duration of at least 6 hours, and was well tolerated by the cohort with brief stinging of the nasal mucosa reported by 9/25 individuals (36 percent). PMID:24564610

  12. Surgical and Localized Radiation Therapy for an Intranasal Adenocarcinoma in a Rabbit

    PubMed Central

    NAKATA, Makoto; MIWA, Yasutsugu; TSUBOI, Masaya; UCHIDA, Kazuyuki

    2014-01-01

    An 8-year-old spayed female Netherland Dwarf rabbit presented with a two-month history of dyspnea and snoring. A computed tomography (CT) scan of the head revealed mass lesions in the right nasal cavity. Surgical exenteration of the lesions was performed, and the histopathological diagnosis was an intranasal adenocarcinoma. On the basis of this diagnosis, radiotherapy was planned and consisted of eight fractions of 6 Gy administered once a week. After the completion of radiation therapy, the soft tissue density in the right nasal cavity, as detected by CT, significantly decreased. The prognosis has remained good for over 3 years after treatment. This paper is the first to describe the clinical and pathological features of an intranasal tumor in a rabbit. PMID:25649953

  13. Chitosan and cyclodextrin in intranasal microemulsion for improved brain buspirone hydrochloride pharmacokinetics in rats.

    PubMed

    Bshara, Hamza; Osman, Rihab; Mansour, Samar; El-Shamy, Abd El-Hameed A

    2014-01-01

    The aim of this study was to develop buspirone hydrochloride microemulsion formulations for intranasal administration to improve the drug bioavailability and provide high drug brain levels. For the purpose, chitosan aspartate, and hydroxypropyl-β-cyclodextrin were incorporated in the microemulsions. The prepared formulations were characterized. Biological investigations including pharmacokinetic studies, brain drug targeting efficiency determinations and histopathological examinations were performed on rats. The results showed that safe and stable mucoadhesive microemulsion suitable for nasal administration were successfully prepared. Ex vivo drug permeation revealed high drug permeation from microemulsions. Absolute bioavailability after intranasal administration of buspirone mucoadhesive microemulsion increased significantly and plasma concentration peaked at 15 min. The AUC0-360(brain) was 3 times that obtained after intravenous administration. A high brain targeting efficiency (86.6%) and a direct nose to brain transport (88%) confirmed the direct nose to brain transport of buspirone following nasal administration of the microemulsions. PMID:24274510

  14. Brain Targeting of a Water Insoluble Antipsychotic Drug Haloperidol via the Intranasal Route Using PAMAM Dendrimer.

    PubMed

    Katare, Yogesh K; Daya, Ritesh P; Sookram Gray, Christal; Luckham, Roger E; Bhandari, Jayant; Chauhan, Abhay S; Mishra, Ram K

    2015-09-01

    Delivery of therapeutics to the brain is challenging because many organic molecules have inadequate aqueous solubility and limited bioavailability. We investigated the efficiency of a dendrimer-based formulation of a poorly aqueous soluble drug, haloperidol, in targeting the brain via intranasal and intraperitoneal administration. Aqueous solubility of haloperidol was increased by more than 100-fold in the developed formulation. Formulation was assessed via different routes of administration for behavioral (cataleptic and locomotor) responses, and for haloperidol distribution in plasma and brain tissues. Dendrimer-based formulation showed significantly higher distribution of haloperidol in the brain and plasma compared to a control formulation of haloperidol administered via intraperitoneal injection. Additionally, 6.7 times lower doses of the dendrimer-haloperidol formulation administered via the intranasal route produced behavioral responses that were comparable to those induced by haloperidol formulations administered via intraperitoneal injection. This study demonstrates the potential of dendrimer in improving the delivery of water insoluble drugs to brain. PMID:26226403

  15. A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder

    PubMed Central

    Lapidus, Kyle A.B.; Levitch, Cara F.; Perez, Andrew M.; Brallier, Jess W.; Parides, Michael K.; Soleimani, Laili; Feder, Adriana; Iosifescu, Dan V.; Charney, Dennis S.; Murrough, James W.

    2014-01-01

    Background The N-methyl-d-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. Methods Twenty patients with major depression were randomized and 18 completed two treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution in a randomized, double-blind, crossover study. The primary efficacy outcome measure was change in depression severity 24 hours following ketamine or placebo, measured using the Montgomery-Asberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. Results Patients showed significant improvement in depressive symptoms at 24 hours following ketamine compared to placebo [t=4.39, p<0.001; estimated mean MADRS score difference of 7.6 ± 3.7 (95% CI: 3.9 – 11.3)]. Eight of 18 patients (44%) met response criteria 24 hours following ketamine administration, compared to 1 of 18 (6%) following placebo (p=0.033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. Conclusions This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression. Trial Registration clinicaltrials.gov identifier NCT01304147 PMID:24821196

  16. The reinforcing and subjective effects of intravenous and intranasal buprenorphine in heroin users.

    PubMed

    Jones, Jermaine D; Madera, Gabriela; Comer, Sandra D

    2014-07-01

    Abuse of buprenorphine (BUP) by the intravenous (IV) route has been documented in several studies, and reports of intranasal (IN) abuse are increasing. However, no studies have directly compared the effects of BUP when it is administered intranasally and intravenously. The present secondary analysis used data from two separate studies to compare the reinforcing and subjective effects of IV and IN buprenorphine. One study evaluated IV buprenorphine (N=13) and the other evaluated IN buprenorphine (N=12). Participants were maintained on 2 mg sublingual (SL) BUP and tested with each intranasal or intravenous buprenorphine test dose (0 mg, 2 mg, 4 mg, 8 mg, and 16 mg). During morning laboratory sessions, participants received money (US $20) and sample doses of IN or IV BUP, and then completed subjective effects questionnaires. Later that day, they completed a self-administration task to receive 10% portions of the drug and/or money they previously sampled. In general, positive subjective ratings for both IV and IN BUP were significantly greater than placebo, with IV BUP having a greater effect than IN BUP. All active BUP doses (IV and IN) maintained significantly higher progressive ratio breakpoint values than placebo, but breakpoint values for IV BUP were greater than for IN BUP. Buprenorphine is an effective maintenance treatment for opioid dependence, valued for its ability to reduce the positive subjective effects of other opioids. Nevertheless, the present data demonstrate that in participants maintained on a low dose of SL BUP, the medication itself has abuse liability when used intravenously or intranasally. PMID:24793093

  17. Prehospital intranasal evaporative cooling for out-of-hospital cardiac arrest: a pilot, feasibility study.

    PubMed

    Lyon, Richard M; Van Antwerp, Jerry; Henderson, Charles; Weaver, Anne; Davies, Gareth; Lockey, David

    2014-10-01

    Intranasal evaporative cooling presents a novel means of initiating therapeutic hypothermia after an out-of-hospital cardiac arrest (OHCA). Few studies have evaluated the use of intranasal therapeutic hypothermia using the Rhinochill device in the prehospital setting. We sought to evaluate the use of Rhinochill in the Physician Response Unit of London's Air Ambulance, aiming to describe the feasibility of employing it during prehospital resuscitation for OHCA. We prospectively evaluated the Rhinochill device over a 7-month period. Inclusion criteria for deployment included: age above 18 years, Physician Response Unit on-scene within maximum of 10 min after return-of-spontaneous circulation (ROSC), witnessed OHCA or unwitnessed downtime of less than 10 min, pregnancy not suspected, normal nasal anatomy, and likely ICU candidate if ROSC were to be achieved. Thirteen patients were included in the evaluation. The average time from the 999 call to initiation of cooling was 39.5 min (range 22-61 min). The average prehospital temperature change in patients who achieved ROSC was -1.9°C. Patients were cooled for an average of 38 min prehospital. In all cases, the doctor and paramedic involved with the resuscitation reported that the Rhinochill was easy to set up and use during resuscitation and that it did not interfere with standard resuscitation practice. Intranasal evaporative cooling using the Rhinochill system is feasible in an urban, prehospital, doctor/paramedic response unit. Cooling with Rhinochill was not found to interfere with prehospital resuscitation and resulted in significant core body temperature reduction. Further research on the potential benefit of intra-arrest and early initiation of intranasal evaporative cooling is warranted. PMID:24300245

  18. Mouse Model of Cat Allergic Rhinitis and Intranasal Liposome-Adjuvanted Refined Fel d 1 Vaccine

    PubMed Central

    Tasaniyananda, Natt; Chaisri, Urai; Tungtrongchitr, Anchalee; Chaicumpa, Wanpen; Sookrung, Nitat

    2016-01-01

    Cats (Felis domesticus) are rich source of airborne allergens that prevailed in the environment and sensitized a number of people to allergy. In this study, a mouse model of allergic rhinitis caused by the cat allergens was developed for the first time and the model was used for testing therapeutic efficacy of a novel intranasal liposome-entrapped vaccines made of native Fel d 1 (major cat allergen) in comparison with the vaccine made of crude cat hair extract (cCE). BALB/c mice were sensitized with cCE mixed with alum intraperitoneally and intranasally. The allergic mice were treated with eight doses of either liposome (L)-entrapped native Fel d 1 (L-nFD1), L-cCE), or placebo on every alternate day. Vaccine efficacy evaluation was performed one day after provoking the treated mice with aerosolic cCE. All allergenized mice developed histological features of allergic rhinitis with rises of serum specific-IgE and Th2 cytokine gene expression. Serum IgE and intranasal mucus production of allergic mice reduced significantly after vaccination in comparison with the placebo mice. The vaccines also caused a shift of the Th2 response (reduction of Th2 cytokine expressions) towards the non-pathogenic responses: Th1 (down-regulation of the Th1 suppressive cytokine gene, IL-35) and Treg (up-regulation of IL-10 and TGF-β). In conclusions, a mouse model of allergic rhinitis to cat allergens was successfully developed. The intranasal, liposome-adjuvanted vaccines, especially the refined single allergen formulation, assuaged the allergic manifestations in the modeled mice. The prototype vaccine is worthwhile testing further for clinical use in the pet allergic patients. PMID:26954254

  19. Physiological and subjective effects of acute intranasal methamphetamine during extended-release alprazolam maintenance

    PubMed Central

    Lile, Joshua A.; Stoops, William W.; Glaser, Paul E.A.; Hays, Lon R.; Rush, Craig R.

    2015-01-01

    Background Medications development for methamphetamine dependence is ongoing, but no widely accepted, effective pharmacotherapy has been identified. Previous studies have demonstrated neurobiological perturbations to central GABAA activity following chronic stimulant use, and that positive modulation of GABAA receptors attenuates the neurochemical and behavioral response to stimulant drugs such as methamphetamine. Therefore, GABAA modulators could be useful as pharmacotherapies for stimulant-use disorders. Methods This study tested the hypothesis that intranasal methamphetamine would be safe and well tolerated during maintenance on extended-release alprazolam (XR), and that the effects of methamphetamine would be attenuated. Eight non-treatment-seeking, stimulant-dependent individuals completed an inpatient experiment in which ascending doses of intranasal methamphetamine (0, 5, 10, 20 and 30 mg) were administered after four days of alprazolam XR maintenance (0 and 1 mg/day). Results Intranasal methamphetamine produced prototypical effects (e.g., increased positive subjective ratings and elevated cardiovascular signs). The combination of intranasal methamphetamine and alprazolam XR was safe and well tolerated. Alprazolam XR produced small, but orderly, reductions in some of the subjective effects of methamphetamine, and performance impairment. Conclusions The present results demonstrate that methamphetamine use during alprazolam XR treatment would not pose a significant safety risk. Given the potential of GABAA positive modulators to manage certain aspects of stimulant abuse and dependence (i.e., drug-induced seizures, anxiety and stress), but the relatively small impact on the acute abuse-related effects of methamphetamine observed here, additional research with GABAA positive modulators is warranted, but should consider their use as an adjunct component of combination behavioral and/or drug treatment. PMID:21737214

  20. Mouse Model of Cat Allergic Rhinitis and Intranasal Liposome-Adjuvanted Refined Fel d 1 Vaccine.

    PubMed

    Tasaniyananda, Natt; Chaisri, Urai; Tungtrongchitr, Anchalee; Chaicumpa, Wanpen; Sookrung, Nitat

    2016-01-01

    Cats (Felis domesticus) are rich source of airborne allergens that prevailed in the environment and sensitized a number of people to allergy. In this study, a mouse model of allergic rhinitis caused by the cat allergens was developed for the first time and the model was used for testing therapeutic efficacy of a novel intranasal liposome-entrapped vaccines made of native Fel d 1 (major cat allergen) in comparison with the vaccine made of crude cat hair extract (cCE). BALB/c mice were sensitized with cCE mixed with alum intraperitoneally and intranasally. The allergic mice were treated with eight doses of either liposome (L)-entrapped native Fel d 1 (L-nFD1), L-cCE), or placebo on every alternate day. Vaccine efficacy evaluation was performed one day after provoking the treated mice with aerosolic cCE. All allergenized mice developed histological features of allergic rhinitis with rises of serum specific-IgE and Th2 cytokine gene expression. Serum IgE and intranasal mucus production of allergic mice reduced significantly after vaccination in comparison with the placebo mice. The vaccines also caused a shift of the Th2 response (reduction of Th2 cytokine expressions) towards the non-pathogenic responses: Th1 (down-regulation of the Th1 suppressive cytokine gene, IL-35) and Treg (up-regulation of IL-10 and TGF-β). In conclusions, a mouse model of allergic rhinitis to cat allergens was successfully developed. The intranasal, liposome-adjuvanted vaccines, especially the refined single allergen formulation, assuaged the allergic manifestations in the modeled mice. The prototype vaccine is worthwhile testing further for clinical use in the pet allergic patients. PMID:26954254

  1. Chemoprevention of lung tumorigenesis by intranasally administered diindolylmethane in A/J mice

    PubMed Central

    Kassie, Fekadu

    2013-01-01

    The main reasons for the failure of most chemopreventive agents during clinical trials are poor in vivo bioavailability and dose-limiting side effects. One potential approach to surmount these problems in lung cancer chemoprevention trials could be direct delivery of agents into the pulmonary tissue. In this study, we assessed the efficacy of intranasally delivered bio-response diindolylmethane (BRD) against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in mice. Mice treated with NNK (two doses of 50mg/kg at an interval of a week, intraperitoneal) developed 16.3±2.9 lung tumors per mouse. Post-carcinogen administration of BRD, via intranasal instillation, for 24 weeks, twice a week, at a dose of 2mg per mouse (0.6mg pure diindolylmethane per mouse) reduced the lung tumor multiplicity to 4.6±2.2 tumors per mouse (72% reduction). Likewise, large tumors (>1mm) were almost completely abolished and multiplicities of tumors with a size of 0.5–1mm were reduced by 74%. Tumor volume was also reduced by 82%. Further studies using an in vitro model of lung tumorigenesis showed that BRD exhibited pronounced antiproliferative and apoptotic effects in premalignant and malignant bronchial cells but only minimal effects in parental immortalized cells through, at least in part, suppression of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. These results showed the potent lung tumor inhibitory activities of low doses of BRD given via intranasal instillation and, therefore, intranasal delivery of BRD holds a great promise for lung cancer chemoprevention in subjects at high risk to develop lung cancer. PMID:23239747

  2. Awareness and Attitudes Toward Intranasal Naloxone Rescue for Opioid Overdose Prevention.

    PubMed

    Kirane, Harshal; Ketteringham, Michael; Bereket, Sewit; Dima, Richie; Basta, Ann; Mendoza, Sonia; Hansen, Helena

    2016-10-01

    Opioid overdose prevention is a pressing public health concern and intranasal naloxone rescue kits are a useful tool in preventing fatal overdose. We evaluated the attitudes, knowledge, and experiences of patients and providers related to overdose and naloxone rescue. Over a six month period, patients and providers within a large community hospital in Staten Island were recruited to complete tailored questionnaires for their respective groupings. 100 patients and 101 providers completed questionnaires between August, 2014 and January, 2015. Patient participants were primarily Caucasian males with a mean age of 37.7 years, of which 65% accurately identified naloxone for opioid overdose, but only 21% knew more specific clinical features. 68% of patients had previously witnessed a drug overdose. Notably, 58% of patients anticipated their behavior would change if provided access to an intranasal naloxone rescue kit, of which 83% predicted an increase in opioid use. Prior overdose was significantly correlated with anticipating no change in subsequent opioid use pattern (p=0.02). 99% of patients reported that their rapport with their health-care provider would be enhanced if offered an intranasal naloxone rescue kit. As for providers, 24% had completed naloxone rescue kit training, and 96% were able to properly identify its clinical application. 50% of providers felt naloxone access would decrease the likelihood of an overdose occurring, and 58% felt it would not contribute to high-risk behavior. Among providers, completion of naloxone training was correlated with increased awareness of where to access kits for patients (p<0.001). This study suggests that patients and providers have distinct beliefs and attitudes toward overdose prevention. Patient-Provider discussion of overdose prevention enhances patients' rapport with providers. However, access to an intranasal naloxone rescue kit may make some patients more vulnerable to high-risk behavior. Future research efforts

  3. Intranasal oxytocin administration is associated with enhanced endogenous pain inhibition and reduced negative mood states

    PubMed Central

    Goodin, Burel R.; Anderson, Austen J. B.; Freeman, Emily L.; Bulls, Hailey W.; Robbins, Meredith T.; Ness, Timothy J.

    2014-01-01

    Objectives This study examined whether the administration of intranasal oxytocin was associated with pain sensitivity, endogenous pain inhibitory capacity, and negative mood states. Methods A total of 30 pain-free, young adults each completed three laboratory sessions on consecutive days. The first session (baseline) assessed ischemic pain sensitivity, endogenous pain inhibition via conditioned pain modulation (CPM), and negative mood using the Profile of Mood States (POMS). CPM was tested on the dominant forearm and ipsilateral masseter muscle using algometry (test stimulus) and the cold pressor task (conditioning stimulus; non-dominant hand). For the second and third sessions, participants initially completed the State-Trait Anxiety Inventory (STAI) and then self-administered a single (40IU/1mL) dose of intranasal oxytocin or placebo in a randomized counter-balanced order. Thirty minutes post-administration, participants again completed the STAI and repeated assessments of ischemic pain sensitivity and CPM followed by the POMS. Results Findings demonstrated that ischemic pain sensitivity did not significantly differ across the three study sessions. CPM at the masseter, but not the forearm, was significantly greater following administration of oxytocin compared to placebo. Negative mood was also significantly lower following administration of oxytocin compared to placebo. Similarly, anxiety significantly decreased following administration of oxytocin but not placebo. Discussion This study incorporated a placebo-controlled, double-blind, within-subjects crossover design with randomized administration of intranasal oxytocin and placebo. The data suggest that the administration of intranasal oxytocin may augment endogenous pain inhibitory capacity and reduce negative mood states including anxiety. PMID:25370147

  4. Treatment of renal colic by desmopressin intranasal spray and diclofenac sodium.

    PubMed

    el-Sherif, A E; Salem, M; Yahia, H; al-Sharkawy, W A; al-Sayrafi, M

    1995-05-01

    The vasopressin analogue, 1-desamino-8-arginine vasopressin (desmopressin), is a potent antidiuretic without the pressor effects of vasopressin. A total of 18 patients with acute renal colic due to stone disease received 40 microgramsf1p4mopressin intranasal spray with encouraging results. There was a significant decrease in the colic pain intensity from an initial mean visual analogue score of 67 +/- 17 mm. to 39 +/- 36 mm. within 30 minutes (p < 0.001). Eight patients (44.4%) had complete pain relief within 30 minutes of administering intranasal desmopressin spray. Nine of 10 patients who required intramuscular diclofenac sodium achieved complete pain relief within another 30 minutes. In other words, when intranasal desmopressin spray was administered before diclofenac sodium, 94.4% of the patients achieved complete pain relief and were discharged home. The mechanism of analgesic action of desmopressin in renal colic is uncertain. At the peripheral level, desmopressin may alleviate the acute renal colic through its potent antidiuretic effect or by relaxing the renal pelvic and ureteral smooth muscles. The central analgesic effect of desmopressin by stimulating the release of the hypothalamic beta-endorphin is proposed. We conclude that intranasal desmopressin spray can be used successfully in the treatment of renal colic. It may also replace prostaglandin synthetase inhibitors in treating renal colic with the advantage of avoiding the potential side effects. Further studies are needed to investigate whether the combination of desmopressin with analgesics or spasmolytic drugs offers competitive results compared with those achieved by prostaglandin synthetase inhibitors in the treatment of renal colic. PMID:7714949

  5. Chitosan coated nanostructured lipid carriers for brain delivery of proteins by intranasal administration.

    PubMed

    Gartziandia, Oihane; Herran, Enara; Pedraz, Jose Luis; Carro, Eva; Igartua, Manoli; Hernandez, Rosa Maria

    2015-10-01

    The remarkable increase in the prevalence of neurodegenerative diseases has become a serious public health problem. Considering the lack of effective treatments to address these diseases and the difficulties in accessing the brain due to the blood-brain barrier (BBB), to attain a successful strategy to improve drug delivery to the brain, the administration route becomes a point of interest. The intranasal route provides a non-invasive method to bypass the BBB. Moreover, the development of new technologies for the protection and delivery of peptides is an interesting approach to consider. Thus, in this work, a suitable chitosan coated nanostructured lipid carrier (CS-NLC) formulation with the capacity to reach the brain after being intranasally administered was successfully developed and optimized. The optimal formulation displayed a particle size of 114 nm with a positive surface charge of +28 mV. The in vitro assays demonstrated the biocompatibility of the nanocarrier and its cellular uptake by 16HBE14o- cells. Furthermore, no haemagglutination or haemolysis processes were observed when the particles were incubated with erythrocytes, and no toxicity signals appeared in the nasal mucosa of mice after the administration of CS-NLCs. Finally, the biodistribution study of CS-NLC-DiR demonstrated an efficient brain delivery of the particles after intranasal administration. In conclusion, CS-NLC can be considered to be a safe and effective nanocarrier for nose-to-brain drug delivery; however, to obtain a higher concentration of the drug in the brain following intranasal administration, further modifications are warranted in the CS-NLC formulation. PMID:26209963

  6. Insulin pump therapy in pregnancy.

    PubMed

    Kesavadev, Jothydev

    2016-09-01

    Control of blood glucose during pregnancy is difficult because of wide variations, ongoing hormonal changes and mood swings. The need for multiple injections, pain at the injection site, regular monitoring and skillful handling of the syringes/pen further makes insulin therapy inconvenient. Insulin pump is gaining popularity in pregnancy because it mimics the insulin delivery of a healthy human pancreas. Multiple guidelines have also recommended the use of insulin pump in pregnancy to maintain the glycaemic control. The pump can release small doses of insulin continuously (basal), or a bolus dose close to mealtime to control the spike in blood glucose after a meal and the newer devices can shut down insulin delivery before the occurrence of hypoglycaemia. Pump insulin of choice is rapid acting analogue insulin. This review underscores the role of insulin pump in pregnancy, their usage, advantages and disadvantages in the light of existing literature and clinic experience. PMID:27582150

  7. The discriminatory value of cardiorespiratory interactions in distinguishing awake from anaesthetised states: a randomised observational study.

    PubMed

    Kenwright, D A; Bernjak, A; Draegni, T; Dzeroski, S; Entwistle, M; Horvat, M; Kvandal, P; Landsverk, S A; McClintock, P V E; Musizza, B; Petrovčič, J; Raeder, J; Sheppard, L W; Smith, A F; Stankovski, T; Stefanovska, A

    2015-12-01

    Depth of anaesthesia monitors usually analyse cerebral function with or without other physiological signals; non-invasive monitoring of the measured cardiorespiratory signals alone would offer a simple, practical alternative. We aimed to investigate whether such signals, analysed with novel, non-linear dynamic methods, would distinguish between the awake and anaesthetised states. We recorded ECG, respiration, skin temperature, pulse and skin conductivity before and during general anaesthesia in 27 subjects in good cardiovascular health, randomly allocated to receive propofol or sevoflurane. Mean values, variability and dynamic interactions were determined. Respiratory rate (p = 0.0002), skin conductivity (p = 0.03) and skin temperature (p = 0.00006) changed with sevoflurane, and skin temperature (p = 0.0005) with propofol. Pulse transit time increased by 17% with sevoflurane (p = 0.02) and 11% with propofol (p = 0.007). Sevoflurane reduced the wavelet energy of heart (p = 0.0004) and respiratory (p = 0.02) rate variability at all frequencies, whereas propofol decreased only the heart rate variability below 0.021 Hz (p < 0.05). The phase coherence was reduced by both agents at frequencies below 0.145 Hz (p < 0.05), whereas the cardiorespiratory synchronisation time was increased (p < 0.05). A classification analysis based on an optimal set of discriminatory parameters distinguished with 95% success between the awake and anaesthetised states. We suggest that these results can contribute to the design of new monitors of anaesthetic depth based on cardiovascular signals alone. PMID:26350998

  8. Distinct spatiotemporal activity in principal neurons of the mouse olfactory bulb in anesthetized and awake states

    PubMed Central

    Blauvelt, David G.; Sato, Tomokazu F.; Wienisch, Martin; Murthy, Venkatesh N.

    2013-01-01

    The acquisition of olfactory information and its early processing in mammals are modulated by brain states through sniffing behavior and neural feedback. We imaged the spatiotemporal pattern of odor-evoked activity in a population of output neurons (mitral/tufted cells, MTCs) in the olfactory bulb (OB) of head-restrained mice expressing a genetically-encoded calcium indicator. The temporal dynamics of MTC population activity were relatively simple in anesthetized animals, but were highly variable in awake animals. However, the apparently irregular activity in awake animals could be predicted well using sniff timing measured externally, or inferred through fluctuations in the global responses of MTC population even without explicit knowledge of sniff times. The overall spatial pattern of activity was conserved across states, but odor responses had a diffuse spatial component in anesthetized mice that was less prominent during wakefulness. Multi-photon microscopy indicated that MTC lateral dendrites were the likely source of spatially disperse responses in the anesthetized animal. Our data demonstrate that the temporal and spatial dynamics of MTCs can be significantly modulated by behavioral state, and that the ensemble activity of MTCs can provide information about sniff timing to downstream circuits to help decode odor responses. PMID:23543674

  9. Technical and Conceptual Considerations for Performing and Interpreting Functional MRI Studies in Awake Rats

    PubMed Central

    Febo, Marcelo

    2011-01-01

    Functional neuroimaging studies in rodents have the potential to provide insight into neurodevelopmental and psychiatric conditions. The strength of the technique lies in its non-invasive nature that can permit longitudinal functional studies in the same animal over its adult life. The relatively good spatial and temporal resolution and the ever-growing database on the biological and biophysical basis of the blood oxygen level dependent (BOLD) signal make it a unique technique in preclinical neuroscience research. Our laboratory has used imaging to investigate brain activation in awake rats following cocaine administration and during the presentation of lactation-associated sensory stimuli. Factors that deserve attention when planning functional magnetic resonance imaging studies in rats include technical issues, animal physiology and interpretability of the resulting data. The present review discusses the pros and cons of animal imaging with a particular focus on the technical aspects of studies with awake rats. Overall, the benefits of the technique outweigh its limitations and the rapidly evolving methods will open the way for more laboratories to employ the technique in neuroscience research. PMID:21808625

  10. A novel tablet computer platform for advanced language mapping during awake craniotomy procedures.

    PubMed

    Morrison, Melanie A; Tam, Fred; Garavaglia, Marco M; Golestanirad, Laleh; Hare, Gregory M T; Cusimano, Michael D; Schweizer, Tom A; Das, Sunit; Graham, Simon J

    2016-04-01

    A computerized platform has been developed to enhance behavioral testing during intraoperative language mapping in awake craniotomy procedures. The system is uniquely compatible with the environmental demands of both the operating room and preoperative functional MRI (fMRI), thus providing standardized testing toward improving spatial agreement between the 2 brain mapping techniques. Details of the platform architecture, its advantages over traditional testing methods, and its use for language mapping are described. Four illustrative cases demonstrate the efficacy of using the testing platform to administer sophisticated language paradigms, and the spatial agreement between intraoperative mapping and preoperative fMRI results. The testing platform substantially improved the ability of the surgeon to detect and characterize language deficits. Use of a written word generation task to assess language production helped confirm areas of speech apraxia and speech arrest that were inadequately characterized or missed with the use of traditional paradigms, respectively. Preoperative fMRI of the analogous writing task was also assistive, displaying excellent spatial agreement with intraoperative mapping in all 4 cases. Sole use of traditional testing paradigms can be limiting during awake craniotomy procedures. Comprehensive assessment of language function will require additional use of more sophisticated and ecologically valid testing paradigms. The platform presented here provides a means to do so. PMID:26473779

  11. Indirect self-modulation instability measurement concept for the AWAKE proton beam

    NASA Astrophysics Data System (ADS)

    Turner, M.; Petrenko, A.; Biskup, B.; Burger, S.; Gschwendtner, E.; Lotov, K. V.; Mazzoni, S.; Vincke, H.

    2016-09-01

    AWAKE, the Advanced Proton-Driven Plasma Wakefield Acceleration Experiment, is a proof-of-principle R&D experiment at CERN using a 400 GeV / c proton beam from the CERN SPS (longitudinal beam size σz = 12 cm) which will be sent into a 10 m long plasma section with a nominal density of ≈ 7 ×1014 atoms /cm3 (plasma wavelength λp = 1.2 mm). In this paper we show that by measuring the time integrated transverse profile of the proton bunch at two locations downstream of the AWAKE plasma, information about the occurrence of the self-modulation instability (SMI) can be inferred. In particular we show that measuring defocused protons with an angle of 1 mrad corresponds to having electric fields in the order of GV/m and fully developed self-modulation of the proton bunch. Additionally, by measuring the defocused beam edge of the self-modulated bunch, information about the growth rate of the instability can be extracted. If hosing instability occurs, it could be detected by measuring a non-uniform defocused beam shape with changing radius. Using a 1 mm thick Chromox scintillation screen for imaging of the self-modulated proton bunch, an edge resolution of 0.6 mm and hence an SMI saturation point resolution of 1.2 m can be achieved.

  12. Brain imaging in awake infants by near-infrared optical topography

    NASA Astrophysics Data System (ADS)

    Taga, Gentaro; Asakawa, Kayo; Maki, Atsushi; Konishi, Yukuo; Koizumi, Hideaki

    2003-09-01

    Studies of young infants are critical to understand perceptual, motor, and cognitive processing in humans. However, brain mechanisms involved are poorly understood, because the use of brain-imaging methods such as functional magnetic resonance imaging in awake infants is difficult. In the present study we show functional brain imaging of awake infants viewing visual stimuli by means of multichannel near-infrared spectroscopy, a technique that permits a measurement of cerebral hemoglobin oxygenation in response to brain activation through the intact skull without subject constraint. We found that event-related increases in oxyhemoglobin were evident in localized areas of the occipital cortex of infants aged 2-4 months in response to a brief presentation of a checkerboard pattern reversal while they maintained fixation to attention-grabbing stimuli. The dynamic change in cerebral blood oxygenation was qualitatively similar to that observed in the adult brain. This result introduces near-infrared optical topography as a method for investigating the functional development of the brain in early infancy.

  13. Association of Awake Bruxism with Khat, Coffee, Tobacco, and Stress among Jazan University Students

    PubMed Central

    Quadri, Mir Faeq Ali; Mahnashi, Ali; Al Almutahhir, Ayman; Tubayqi, Hamzah; Hakami, Abdullah; Arishi, Mohamed; Alamir, Abdulwahab

    2015-01-01

    Objective. The objective is to assess the prevalence of bruxism among the university students and to check its association with their khat chewing habit. Materials and Methods. A cross-sectional descriptive study is designed using cluster random sampling. Pretested questionnaire was administered by a trained interviewer to assess awake bruxism and the use of variables like khat, coffee, tobacco, and stress. Chi-square test at 5% significance was used for assessing the association. Logistic regression was also performed after adjusting for covariates. Results. A high response rate (95%) was obtained as the distribution and collection of questionnaire was within an hour interval. 85% (63%, males; 22%, females) experienced an episode of bruxism at least one time in the past six months. Regression analysis revealed an association of stress (P = 0.00; OR = 5.902, 95% CI 2.614–13.325) and khat use (P = 0.05; OR = 1.629, 95% CI 0.360–7.368) with bruxism. Interestingly, it is observed that the one who chew khat experienced 3.56 times (95% CI; 2.62–11.22) less pain when compared to the nonusers. Conclusion. This study is the first of its kind to assess the association of bruxism with khat chewing. High amount of stress and khat use can be considered as important risk indicators for awake bruxism. PMID:26491448

  14. Status of the proton and electron transfer lines for the AWAKE Experiment at CERN

    NASA Astrophysics Data System (ADS)

    Schmidt, J. S.; Bauche, J.; Biskup, B.; Bracco, C.; Doebert, S.; Goddard, B.; Gschwendtner, E.; Jensen, L. K.; Jones, O. R.; Mazzoni, S.; Meddahi, M.; Pepitone, K.; Petrenko, A.; Velotti, F. M.; Vorozhtsov, A.

    2016-09-01

    The AWAKE project at CERN is planned to study proton driven plasma wakefield acceleration with an externally injected electron beam. Therefore two transfer lines are being designed in order to provide the proton beam from the SPS and the electron beam from an RF gun to the plasma cell. The commissioning of the proton line will take place in 2016 for the first phase of the experiment, which is focused on the self-modulation of a 12 cm long proton bunch in the plasma. The electron line will be added for the second phase of AWAKE in 2017, when the wakefield will be probed with an electron beam of 10-20 MeV/c. The challenge for these transfer lines lies in the parallel operation of the proton, electron and laser beam used to ionize the plasma and seed the self-modulation. These beams, of different characteristics, need to be synchronized and positioned for optimized injection conditions into the wakefield. This task requires great flexibility in the transfer line optics. The status of these designs will be presented in this paper.

  15. Layer-Specific Refinement of Visual Cortex Function after Eye Opening in the Awake Mouse

    PubMed Central

    Hoy, Jennifer L.

    2015-01-01

    The laminar structure and conserved cellular organization of mouse visual cortex provide a useful model to determine the mechanisms underlying the development of visual system function. However, the normal development of many receptive field properties has not yet been thoroughly quantified, particularly with respect to layer identity and in the absence of anesthesia. Here, we use multisite electrophysiological recording in the awake mouse across an extended period of development, starting at eye opening, to measure receptive field properties and behavioral-state modulation of responsiveness. We find selective responses for orientation, direction, and spatial frequency at eye opening, which are similar across cortical layers. After this initial similarity, we observe layer-specific maturation of orientation selectivity, direction selectivity, and linearity over the following week. Developmental increases in selectivity are most robust and similar between layers 2–4, whereas layers 5 and 6 undergo distinct refinement patterns. Finally, we studied layer-specific behavioral-state modulation of cortical activity and observed a striking reorganization in the effects of running on response gain. During week 1 after eye opening, running increases responsiveness in layers 4 and 5, whereas in adulthood, the effects of running are most pronounced in layer 2/3. Together, these data demonstrate that response selectivity is present in all layers of the primary visual cortex (V1) at eye opening in the awake mouse and identify the features of basic V1 function that are further shaped over this early developmental period in a layer-specific manner. PMID:25716837

  16. Disrupting neural activity related to awake-state sharp wave-ripple complexes prevents hippocampal learning.

    PubMed

    Nokia, Miriam S; Mikkonen, Jarno E; Penttonen, Markku; Wikgren, Jan

    2012-01-01

    Oscillations in hippocampal local-field potentials (LFPs) reflect the crucial involvement of the hippocampus in memory trace formation: theta (4-8 Hz) oscillations and ripples (~200 Hz) occurring during sharp waves are thought to mediate encoding and consolidation, respectively. During sharp wave-ripple complexes (SPW-Rs), hippocampal cell firing closely follows the pattern that took place during the initial experience, most likely reflecting replay of that event. Disrupting hippocampal ripples using electrical stimulation either during training in awake animals or during sleep after training retards spatial learning. Here, adult rabbits were trained in trace eyeblink conditioning, a hippocampus-dependent associative learning task. A bright light was presented to the animals during the inter-trial interval (ITI), when awake, either during SPW-Rs or irrespective of their neural state. Learning was particularly poor when the light was presented following SPW-Rs. While the light did not disrupt the ripple itself, it elicited a theta-band oscillation, a state that does not usually coincide with SPW-Rs. Thus, it seems that consolidation depends on neuronal activity within and beyond the hippocampus taking place immediately after, but by no means limited to, hippocampal SPW-Rs. PMID:23316148

  17. DIEP Flap for Breast Reconstruction Using Epidural Anesthesia with the Patient Awake

    PubMed Central

    Camacho, Marco; de la Garza, Jonatan

    2016-01-01

    Background: Many articles have been published about breast reconstruction using the deep inferior epigastric perforator (DIEP) flap; however, few articles have been published in plastic/reconstructive surgery journals describing the difference between anesthetic techniques and recovery in microsurgical patients. Methods: We analyzed 16 patients who underwent DIEP flap for breast reconstruction. Patients were divided into 2 groups: group 1: general anesthesia (n = 9); group 2: epidural block with the patient awake (n = 7). In group 2, the peridural block was done at 2 levels: thoracic (T2–T3) and lumbar (L2–L3). Results: The success rate was 100% with no partial or total loss of the flap. There was no difference between groups in regard to postoperative pain in the first 5 days (Visual Analog Scale). Analgesia used in group 1 was buprenorphine and ketorolac, and in group 2, only ketorolac without opioid derivatives. Immediate postoperative recovery was better in the peridural group than in the group administered general anesthesia (P = 0.0001). Conclusions: DIEP flap with peridural block and the patient awake during surgery is a feasible technique with better recovery in the immediate postoperative period, achieving good analgesia level with minimal intravenous medication.

  18. Right Cortical and Axonal Structures Eliciting Ocular Deviation During Electrical Stimulation Mapping in Awake Patients.

    PubMed

    Montemurro, Nicola; Herbet, Guillaume; Duffau, Hugues

    2016-07-01

    To investigate the neural network underpinning eye movements, a cortical and subcortical intraoperative mapping using direct electrical stimulation (DES) was achieved in six awake patients during surgery for a right frontal low-grade glioma. We assessed the relationship between the occurrence of ocular deviation during both cortical and axonal DES and the anatomic location for each response. The corresponding stimulation sites were reported on a standard brain template for visual analysis and between-subjects comparisons. Our results showed that DES of the cortical frontal eye field (FEF) elicited horizontal (anterior FEF) or upward (posterior FEF) eye movements in 3 patients, supporting the fact that FEF comprises several distinct functional subregions. In addition, subcortical stimulation of the white matter tracts underneath the FEF evoked conjugate contraversive ocular deviation in 3 other patients. Interestingly, this region seems to be a crossroad between the fronto-striatal tract, the frontal aslant tract, the inferior fronto-occipital fascicle and the superior longitudinal fascicle. No deficits in eye movements were observed following surgery. To our knowledge, this is the first study reporting ocular deviation during axonal electrostimulation mapping of the white matter fibers in awake patients. Therefore, our original data issued from DES give new insights into the cortical and subcortical structures involved in the control of eye movements and their strong relationships with other functional pathways. PMID:27067598

  19. No short-term effects of digital mobile radio telephone on the awake human electroencephalogram

    SciTech Connect

    Roeschke, J.; Mann, K.

    1997-05-01

    A recent study reported the results of an exploratory study of alterations of the quantitative sleep profile due to the effects of a digital mobile radio telephone. Rapid eye movement (REM) was suppressed, and the spectral power density in the 8--13 Hz frequency range during REM sleep was altered. The aim of the present study was to illuminate the influence of digital mobile radio telephone on the awake electroencephalogram (EEG) of healthy subjects. For this purpose, the authors investigated 34 male subjects in a single-blind cross-over design experiment by measuring spontaneous EEGs under closed-eyes condition from scalp positions C{sub 3} and C{sub 4} and comparing the effects of an active and an inactive digital mobile radio telephone (GSM) system. During exposure of nearly 3.5 min to the 900 MHz electromagnetic field pulsed at a frequency of 217 Hz and with a pulse width of 580 {micro}s, the authors could not detect any difference in the awake EEGs in terms of spectral power density measures.

  20. Lower "awake and fed thermogenesis" predicts future weight gain in subjects with abdominal adiposity.

    PubMed

    Piaggi, Paolo; Krakoff, Jonathan; Bogardus, Clifton; Thearle, Marie S

    2013-12-01

    Awake and fed thermogenesis (AFT) is the energy expenditure (EE) of the nonactive fed condition above the minimum metabolic requirement during sleep and is composed of the thermic effect of food and the cost of being awake. AFT was estimated from whole-room 24-h EE measures in 509 healthy subjects (368 Native Americans and 141 whites) while subjects consumed a eucaloric diet. Follow-up data were available for 290 Native Americans (median follow-up time: 6.6 years). AFT accounted for ~10% of 24-h EE and explained a significant portion of deviations from expected energy requirements. Energy intake was the major determinant of AFT. AFT, normalized as a percentage of intake, was inversely related to age and fasting glucose concentration and showed a nonlinear relationship with waist circumference and BMI. Spline analysis demonstrated that AFT becomes inversely related to BMI at an inflection point of 29 kg/m(2). The residual variance of AFT, after accounting for covariates, predicted future weight change only in subjects with a BMI >29 kg/m(2). AFT may influence daily energy balance, is reduced in obese individuals, and predicts future weight gain in these subjects. Once central adiposity develops, a blunting of AFT may occur that then contributes to further weight gain. PMID:23974925

  1. [Perioperative management of an obese patient complicated with sleep apnea syndrome (SAS) undergoing awake craniotomy].

    PubMed

    Komayama, Noriaki; Kamata, Kotoe; Maruyama, Takashi; Nitta, Masayuki; Muragaki, Yoshihiro; Ozaki, Makoto

    2014-10-01

    Both obesity (BMI over 30) and SAS are risks for Supper airway maintenance. We report an obese patient (BMI 33.5) with SAS who underwent awake craniotomy. Weight reduction was instructed 1 month before the operation, and the patient lost enough weight to use intraoperative MRI. Under general anesthesia, surgical pads containing 2% lidocaine with adrenaline were inserted into the nasal cavities. The patient's airway S was secured by i-gel® until dura was opened. A nasal airway was then inserted to confirm the upper airway patency and anesthetics were terminated The patient regained consciousness and started respiration. The i-gel® was removed. The nasal airway was changed to an RAE tracheal tube ; the tube was fixed above the vocal cords under bronchofiberscopic observation. Continuous positive airway pressure (CPAP) via RAE tube was started. Neither coughing nor epistaxis was observed.The RAE tube prevented glossoptosis and did not disturb speech mapping. Emergent endotracheal intubation was easily managed because the tube was close to the glottis. The RAE tube was removed and nasal CP AP was applied overnight Carefully prepared CP AP support via nasal RAE tube was practical in keeping upper airway patency for an obese patient complicated with SAS undergoing awake craniotomy. PMID:25693340

  2. Membrane Potential Dynamics of Spontaneous and Visually Evoked Gamma Activity in V1 of Awake Mice

    PubMed Central

    Perrenoud, Quentin; Pennartz, Cyriel M. A.; Gentet, Luc J.

    2016-01-01

    Cortical gamma activity (30–80 Hz) is believed to play important functions in neural computation and arises from the interplay of parvalbumin-expressing interneurons (PV) and pyramidal cells (PYRs). However, the subthreshold dynamics underlying its emergence in the cortex of awake animals remain unclear. Here, we characterized the intracellular dynamics of PVs and PYRs during spontaneous and visually evoked gamma activity in layers 2/3 of V1 of awake mice using targeted patch-clamp recordings and synchronous local field potentials (LFPs). Strong gamma activity patterned in short bouts (one to three cycles), occurred when PVs and PYRs were depolarizing and entrained their membrane potential dynamics regardless of the presence of visual stimulation. PV firing phase locked unconditionally to gamma activity. However, PYRs only phase locked to visually evoked gamma bouts. Taken together, our results indicate that gamma activity corresponds to short pulses of correlated background synaptic activity synchronizing the output of cortical neurons depending on external sensory drive. PMID:26890123

  3. Bidirectional synaptic plasticity in the dentate gyrus of the awake freely behaving mouse

    PubMed Central

    Koranda, Jessica L.; Masino, Susan A.; Blaise, J. Harry

    2008-01-01

    There is significant interest in in vivo synaptic plasticity in mice due to the many relevant genetic mutants now available. Nevertheless, use of in vivo models remains limited. To date long-term potentiation (LTP) has been studied infrequently, and long-term depression (LTD) has not been characterized in the mouse in vivo. Herein we describe protocols and improved methodologies we developed to record hippocampal synaptic plasticity reliably from the dentate gyrus of the awake freely behaving mouse. Seven days prior to recording, we implanted microelectrodes encapsulated within a lightweight, low-profile headstage assembly. On the day of recording, we induced either LTP or LTD in the awake freely behaving animal and monitored subsequent changes in population spike amplitude for at least 24 hrs. Using this protocol we attained 80% success in inducing and maintaining either LTP or LTD. Recording from a chronic implant using this improved methodology is best suited to reveal naturally occurring brain activity, and avoids both acute effects of local electrode insertion and drifts in neuronal excitability associated with anesthesia. Ultimately a reliable freely behaving mouse model of bidirectional synaptic plasticity is invaluable for full characterization of genetic models of disease states and manipulations of the mechanisms implicated in learning and memory. PMID:17875326

  4. Mismatch Responses in the Awake Rat: Evidence from Epidural Recordings of Auditory Cortical Fields

    PubMed Central

    Jung, Fabienne; Stephan, Klaas Enno; Backes, Heiko; Moran, Rosalyn; Gramer, Markus; Kumagai, Tetsuya; Graf, Rudolf

    2013-01-01

    Detecting sudden environmental changes is crucial for the survival of humans and animals. In the human auditory system the mismatch negativity (MMN), a component of auditory evoked potentials (AEPs), reflects the violation of predictable stimulus regularities, established by the previous auditory sequence. Given the considerable potentiality of the MMN for clinical applications, establishing valid animal models that allow for detailed investigation of its neurophysiological mechanisms is important. Rodent studies, so far almost exclusively under anesthesia, have not provided decisive evidence whether an MMN analogue exists in rats. This may be due to several factors, including the effect of anesthesia. We therefore used epidural recordings in awake black hooded rats, from two auditory cortical areas in both hemispheres, and with bandpass filtered noise stimuli that were optimized in frequency and duration for eliciting MMN in rats. Using a classical oddball paradigm with frequency deviants, we detected mismatch responses at all four electrodes in primary and secondary auditory cortex, with morphological and functional properties similar to those known in humans, i.e., large amplitude biphasic differences that increased in amplitude with decreasing deviant probability. These mismatch responses significantly diminished in a control condition that removed the predictive context while controlling for presentation rate of the deviants. While our present study does not allow for disambiguating precisely the relative contribution of adaptation and prediction error processing to the observed mismatch responses, it demonstrates that MMN-like potentials can be obtained in awake and unrestrained rats. PMID:23646197

  5. Episodic-like memory trace in awake replay of hippocampal place cell activity sequences

    PubMed Central

    Takahashi, Susumu

    2015-01-01

    Episodic memory retrieval of events at a specific place and time is effective for future planning. Sequential reactivation of the hippocampal place cells along familiar paths while the animal pauses is well suited to such a memory retrieval process. It is, however, unknown whether this awake replay represents events occurring along the path. Using a subtask switching protocol in which the animal experienced three subtasks as ‘what’ information in a maze, I here show that the replay represents a trial type, consisting of path and subtask, in terms of neuronal firing timings and rates. The actual trial type to be rewarded could only be reliably predicted from replays that occurred at the decision point. This trial-type representation implies that not only ‘where and when’ but also ‘what’ information is contained in the replay. This result supports the view that awake replay is an episodic-like memory retrieval process. DOI: http://dx.doi.org/10.7554/eLife.08105.001 PMID:26481131

  6. Role of mucoadhesive polymers in enhancing delivery of nimodipine microemulsion to brain via intranasal route

    PubMed Central

    Pathak, Rudree; Prasad Dash, Ranjeet; Misra, Manju; Nivsarkar, Manish

    2014-01-01

    Intranasal drug administration is receiving increased attention as a delivery method for bypassing the blood–brain barrier and rapidly targeting therapeutics to the CNS. However, rapid mucociliary clearance in the nasal cavity is a major hurdle. The purpose of this study was to evaluate the effect of mucoadhesive polymers in enhancing the delivery of nimodipine microemulsion to the brain via the intranasal route. The optimized mucoadhesive microemulsion was characterized, and the in vitro drug release and in vivo nasal absorption of drug from the new formulation were evaluated in rats. The optimized formulation consisted of Capmul MCM as oil, Labrasol as surfactant, and Transcutol P as co-surfactant, with a particle size of 250 nm and zeta potential value of −15 mV. In vitro and ex vivo permeation studies showed an initial burst of drug release at 30 min and sustained release up to 6 h, attributable to the presence of free drug entrapped in the mucoadhesive layer. In vivo pharmacokinetic studies in rats showed that the use of the mucoadhesive microemulsion enhanced brain and plasma concentrations of nimodipine. These results suggest that incorporation of a mucoadhesive agent in a microemulsion intranasal delivery system can increase the retention time of the formulation and enhance brain delivery of drugs. PMID:26579378

  7. Attenuation of histamine-induced airway effects by intranasal application of levocetirizine in mice.

    PubMed

    Kitayama-Sugiyama, Chie; Mochizuki, Naoko; Murata, Hitomi; Katsura, Masashi; Kamei, Chiaki

    2013-10-01

    The present study was performed to investigate the histamine-induced airway effect of levocetirizine, an active enantiomer of cetirizine, by intranasal application using ddY mice. Nasal rubbing and sneezing after histamine application into the nasal cavity were used as an index of histamine-induced airway effect in mice. Intranasal application of levocetirizine inhibited both nasal rubbing and sneezing concentration-dependently, and the ED50 values were 0.62 (0.51-0.77) and 0.70 (0.51-1.02) %/site for nasal rubbing and sneezing, respectively. ED50 values of cetirizine were 1.24 (1.02-1.59) and 1.35 (1.02-2.08) %/site for nasal rubbing and sneezing, respectively. Levocetirizine also inhibited nasal rubbing and sneezing when administered orally. These results clearly indicate that levocetirizine was about two times more potent than cetirizine by intranasal application, similar to the findings of the former's affinity for human histamine H1 receptors. In addition, the present findings raise the expectation of the development of levocetirizine nasal drops. PMID:23855419

  8. Preparation, characterization, and in vivo evaluation of intranasally administered liposomal formulation of donepezil.

    PubMed

    Al Asmari, Abdulrahman K; Ullah, Zabih; Tariq, Mohammad; Fatani, Amal

    2016-01-01

    The adequate amount of drug delivery to the brain in neurological patients is a major problem faced by the physicians. Recent studies suggested that intranasal administration of liposomal formulation may improve the drug delivery to the brain. In the present study, an attempt was made to study the brain bioavailability of commonly used anti-Alzheimer drug donepezil (DNP) liposomal formulation by intranasal route in rats. We adopted the thin layer hydration technique for the preparation of liposomes by using cholesterol, polyethylene glycol, and 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC). The prepared liposomes were characterized by determining particle size, shape, surface morphology, zeta potential, encapsulation efficiency, and in vitro release of DNP. The pharmacokinetic parameters of liposomal DNP in plasma and brain of rats were determined following oral and nasal administration. The results of this study showed that the DNP liposomal formulation was stable with a consistent size (102 ± 3.3 nm) and shape. The prepared liposomes showed high encapsulation efficiency (84.91% ±3 .31%) and sustained-release behavior. The bioavailability of DNP in plasma and brain increased significantly (P<0.05) after administration of liposomal formulation by the intranasal route. Histopathological examination showed that the formulation was safe and free from toxicity. It can be concluded that the nasal administration of liposomal preparation may provide an efficient and reliable mode of drug delivery to the central nervous system. PMID:26834457

  9. Intranasal Flu Vaccine Protective against Seasonal and H5N1 Avian Influenza Infections

    PubMed Central

    Alsharifi, Mohammed; Lobigs, Mario; Koskinen, Aulikki; Regner, Matthias; Trinidad, Lee; Boyle, David B.; Müllbacher, Arno

    2009-01-01

    Background Influenza A (flu) virus causes significant morbidity and mortality worldwide, and current vaccines require annual updating to protect against the rapidly arising antigenic variations due to antigenic shift and drift. In fact, current subunit or split flu vaccines rely exclusively on antibody responses for protection and do not induce cytotoxic T (Tc) cell responses, which are broadly cross-reactive between virus strains. We have previously reported that γ-ray inactivated flu virus can induce cross-reactive Tc cell responses. Methodology/Principal Finding Here, we report that intranasal administration of purified γ-ray inactivated human influenza A virus preparations (γ-Flu) effectively induces heterotypic and cross-protective immunity. A single intranasal administration of γ-A/PR8[H1N1] protects mice against lethal H5N1 and other heterotypic infections. Conclusions/Significance Intranasal γ-Flu represents a unique approach for a cross-protective vaccine against both seasonal as well as possible future pandemic influenza A virus infections. PMID:19401775

  10. Intranasal microemulsion for targeted nose to brain delivery in neurocysticercosis: Role of docosahexaenoic acid.

    PubMed

    Shinde, Rajshree L; Bharkad, Gopal P; Devarajan, Padma V

    2015-10-01

    Intranasal Microemulsions (MEs) for nose to brain delivery of a novel combination of Albendazole sulfoxide (ABZ-SO) and Curcumin (CUR) for Neurocysticercosis (NCC), a brain infection are reported. MEs prepared by simple solution exhibited a globule size <20nm, negative zeta potential and good stability. The docosahexaenoic acid (DHA) ME revealed high and rapid ex vivo permeation of drugs through sheep nasal mucosa. Intranasal DHA ME resulted in high brain concentrations and 10.76 (ABZ-SO) and 3.24 (CUR) fold enhancement in brain area-under-the-curve (AUC) compared to intravenous DHA MEs at the same dose. Direct nose to brain transport (DTP) of >95% was seen for both drugs. High drug targeting efficiency (DTE) to the brain compared to Capmul ME and drug solution (P<0.05) suggested the role of DHA in aiding nose to brain delivery. Histopathology study confirmed no significant changes. High efficacy of ABZ-SO: CUR (100:10ng/mL) DHA ME in vitro on Taenia solium cysts was confirmed by complete ALP inhibition and disintegration of cysts at 96h. Considering that the brain concentration at 24h was 1400±160.1ng/g (ABZ-SO) and 120±35.2ng/g (CUR), the in vitro efficacy seen at a 10 fold lower concentration of the drugs strongly supports the assumption of clinical efficacy. The intranasal DHA ME is a promising delivery system for targeted nose to brain delivery. PMID:26318978

  11. Intranasal delivery of systemic-acting drugs: small-molecules and biomacromolecules.

    PubMed

    Fortuna, Ana; Alves, Gilberto; Serralheiro, Ana; Sousa, Joana; Falcão, Amílcar

    2014-09-01

    As a non-invasive route, intranasal administration offers patient comfort and compliance which are hurdled in parenteral drug therapy. In addition, the current recognition that the high permeability and vascularization of nasal mucosa coupled to the avoidance of the first-pass elimination and/or gastrointestinal decomposition ensure higher systemic drug absorption than oral route has contributed to the growing interest for intranasal delivery of drugs that require considerable systemic exposure to exert their therapeutic actions (systemic-acting drugs). Nevertheless, several features may hamper drug absorption through the nasal mucosa, particularly the drug molecular weight and intrinsic permeability, and, therefore, several strategies have been employed to improve it, propelling a constant challenge during nasal drug (formulation) development. This review will firstly provide an anatomical, histological and mechanistic overview of drug systemic absorption after nasal administration and the relevant aspects of the therapeutic interest and limitations of the intranasal systemic delivery. The current studies regarding the nasal application of systemic-acting small drugs (analgesic drugs, cardiovascular drugs and antiviral drugs) and biomacromolecular drugs (peptide/protein drugs and vaccines) will also be outlined, addressing drug pharmacokinetics and pharmacodynamic improvements. PMID:24681294

  12. Optimization of artemether-loaded NLC for intranasal delivery using central composite design.

    PubMed

    Jain, Kunal; Sood, Sumeet; Gowthamarajan, Kuppusamy

    2015-01-01

    The objective of the study was to optimize artemether-loaded nanostructured lipid carriers (ARM-NLC) for intranasal delivery using central composite design. ARM-NLC was prepared by microemulsion method with optimized formulation having particle size of 123.4 nm and zeta potential of -34.4 mV. Differential scanning calorimetry and powder X-ray diffraction studies confirmed that drug existed in amorphous form in NLC formulation. In vitro cytotoxicity assay using SVG p12 cell line and nasal histopathological studies on sheep nasal mucosa indicated the developed formulations were non-toxic and safe for intranasal administration. In vitro release studies revealed that NLC showed sustained release up to 96 h. Ex vivo diffusion studies using sheep nasal mucosa revealed that ARM-NLC had significantly lower flux compared to drug solution (ARM-SOL). Pharmacokinetic and brain uptake studies in Wistar rats showed significantly higher drug concentration in brain in animals treated intranasally (i.n.) with ARM-NLC. Brain to blood ratios for ARM-NLC (i.n.), ARM-SOL (i.n.) and ARM-SOL (i.v.) were 2.619, 1.642 and 0.260, respectively, at 0.5 h indicating direct nose to brain transport of ARM. ARM-NLC showed highest drug targeting efficiency and drug transport percentage of 278.16 and 64.02, respectively, which indicates NLC had better brain targeting efficiency compared to drug solution. PMID:24512368

  13. Effects of recombinant IL-17F intranasal inoculation against Streptococcus pneumoniae infection in a murine model.

    PubMed

    Chen, Ling; Guo, Sheng; Wu, Liangxia; Hao, Chunli; Xu, Wanting; Zhang, Jianhua

    2015-01-01

    Interleukin-17F (IL-17F) is an important member of IL-17 cytokine family, which plays important roles in host defense against microbial infections. Streptococcus pneumoniae is a common pathogen associated with several invasive and noninvasive pneumococcal diseases, and mucosal immune response plays crucial roles in defenses against pneumococcal infection. Thus, intranasal inoculation may be an alternative approach against pneumococci. In this study, BALB/c mice were intranasally inoculated with recombinant IL-17F (rIL-17F) prior to S. pneumoniae (American Type Culture Collection 6303, serotype 3) infection. As compared with the control group, numbers of total leukocyte, neutrophil, and macrophage in lungs were significantly increased in mice inoculated with rIL-17F. The levels of macrophage inflammatory protein 1α (MIP-1α), MIP-2β, and interferon γ were significantly increased in bronchoalveolar lavage fluid and culture supernatant of splenocytes from mice inoculated with rIL-17F. rIL-17F inoculation also significantly elevated β-defensin-2 expression in lung tissues. Furthermore, compared with S. pneumoniae infection group, rIL-17F inoculation prior to infection significantly reduced S. pneumoniae colonization in lungs. These findings demonstrated that rIL-17F intranasal inoculation strengthened host defense against pneumococci, which may be developed to prevent pneumococcal infection. PMID:25196250

  14. Toll-like receptors 2 and 4 impair insulin-mediated brain activity by interleukin-6 and osteopontin and alter sleep architecture.

    PubMed

    Sartorius, Tina; Lutz, Stefan Z; Hoene, Miriam; Waak, Jens; Peter, Andreas; Weigert, Cora; Rammensee, Hans-Georg; Kahle, Philipp J; Häring, Hans-Ulrich; Hennige, Anita M

    2012-05-01

    Impaired insulin action in the brain represents an early step in the progression toward type 2 diabetes, and elevated levels of saturated free fatty acids are known to impair insulin action in prediabetic subjects. One potential mediator that links fatty acids to inflammation and insulin resistance is the Toll-like receptor (TLR) family. Therefore, C3H/HeJ/TLR2-KO (TLR2/4-deficient) mice were fed a high-fat diet (HFD), and insulin action in the brain as well as cortical and locomotor activity was analyzed by using telemetric implants. TLR2/4-deficient mice were protected from HFD-induced glucose intolerance and insulin resistance in the brain and displayed an improvement in cortical and locomotor activity that was not observed in C3H/HeJ mice. Sleep recordings revealed a 42% increase in rapid eye movement sleep in the deficient mice during daytime, and these mice spent 41% more time awake during the night period. Treatment of control mice with a neutralizing IL-6 antibody improved insulin action in the brain as well as cortical activity and diminished osteopontin protein to levels of the TLR2/4-deficient mice. Together, our data suggest that the lack of functional TLR2/4 protects mice from a fat-mediated impairment in insulin action, brain activity, locomotion, and sleep architecture by an IL-6/osteopontin-dependent mechanism. PMID:22278939

  15. Influence of anti-insulin antibodies on insulin immunoassays in the autoimmune insulin syndrome.

    PubMed

    Casesnoves, A; Mauri, M; Dominguez, J R; Alfayate, R; Picó, A M

    1998-11-01

    The autoimmune insulin syndrome (AIS) is a rare, benign syndrome characterized by hyperinsulinaemia and hypoglycaemia associated with the presence of autoantibodies to insulin in patients who have not been treated with insulin. We report here the case of a 52-year-old patient with recurrent attacks of severe postprandial hypoglycaemia and we also present the effect of anti-insulin antibodies on insulin immunoassays. The patient was submitted to the following diagnostic tests: 5-h oral glucose tolerance test (OGTT), a prolonged 72-h fast and an insulin tolerance test (ITT). Serum glucose, total and free insulin, C-peptide, proinsulin, insulin antibodies and other autoantibodies were measured. Insulin concentrations were measured by two methods: a double antibody radioimmunoassay (RIA) and an immunoradiometric assay (IRMA). Insulin concentration measured by RIA was extremely high in the OGTT and 72-h fast. In contrast, insulin concentrations measured by IRMA were between 120 and 888 pmol/L in the OGTT and between 37 and 133 pmol/L during the 72-h fast. Fasting free-insulin concentrations measured by RIA were between 2224 and 2669 pmol/L, whereas free-insulin concentrations measured by IRMA ranged between 93 and 237 pmol/L. Total insulin concentrations measured by RIA and IRMA were 57,615 and 94,021 pmol/L, respectively. The C-peptide concentrations were moderately high in the three tests. Serum insulin antibody concentrations were extremely high (62-71%), compared with less than 3% in normal serum samples. In conclusion, the high insulin concentrations measured by RIA were caused by insulin autoantibodies. However, insulin concentrations measured by IRMA were not influenced by them. We conclude that IRMA is the more accurate method for measuring insulin concentrations in such cases. PMID:9838991

  16. Patterns of activity evoked in cerebellar interpositus nuclear neurones by natural somatosensory stimuli in awake cats

    PubMed Central

    Cody, Frederick W. J.; Moore, R. Brantingham; Richardson, Helen C.

    1981-01-01

    1. Stable extracellular unitary recordings were made from 138 cerebellar interpositus nuclear neurones (IPNs) in awake cats. Mean background discharge, in animals in a state of relaxed wakefulness and in the absence of overt movement, was 41·0±2·6 impulses/sec (mean±s.e.m). 2. Animals were trained to accept a variety of sensory testing procedures without producing detectable motor reactions. Mechanical taps (1 mm amplitude; 20 msec overall duration) applied to the main pads or dorsal surfaces of the forepaws and/or hind paws modified discharge in forty-eight of 110 IPNs tested. Response patterns to taps generally comprised one or more of three basic components, namely: short-latency excitation, e1, at onset latencies of 13·0±0·9 msec (mean±s.e.m.) for ipsilateral forepaw (iF) and 17·0±0·7 msec for ipsilateral hind paw (iH); a period of reduced discharge, at latencies 25·6±2·6 msec for iF and 32·3±2·1 msec for iH; a delayed acceleration of discharge, e2, at latencies 47·4±4·6 msec for iF and 46·4±4·1 msec for iH. The component e1 was the most common (present in 80% of responses) and e2 the least common (present in 18% of responses). 3. The majority (> 70%) of responses of IPNs to tap stimulation of the paws comprised net excitation. 4. Convergence of tap-evoked sensory input from iF and iH on to individual IPNs was evident in eight of the thirty-five units tested with stimulation of both afferent sites. 5. Approximately one third of IPNs so tested were sensitive to passive manipulation of limb joints in the quiet, awake cat. Sixteen of the forty-three IPNs so tested responded to displacement of the ipsilateral wrist and/or elbow joints and three of ten IPNs so tested responded to movement of contralateral forepaw joints. Corresponding proportions of IPNs responding to passive ankle and/or knee joint displacements were sixteen of thirty-six units tested and three of three units tested for ipsilateral and contralateral hind paws respectively

  17. Depression and Insulin Resistance

    PubMed Central

    Pearson, Sue; Schmidt, Mike; Patton, George; Dwyer, Terry; Blizzard, Leigh; Otahal, Petr; Venn, Alison

    2010-01-01

    OBJECTIVE To examine the association between depressive disorder and insulin resistance in a sample of young adults using the Composite International Diagnostic Interview to ascertain depression status. RESEARCH DESIGN AND METHODS Cross-sectional data were collected from 1,732 participants aged between 26 and 36 years. Insulin resistance was derived from blood chemistry measures of fasting insulin and glucose using the homeostasis model assessment method. Those identified with mild, moderate, or severe depression were classified as having depressive disorder. RESULTS The 12-month prevalence of depressive disorder was 5.4% among men and 11.7% among women. In unadjusted models mean insulin resistance was 17.2% (95% CI 0.7–36.0%, P = 0.04) higher in men and 11.4% (1.5–22.0%, P = 0.02) higher in women with depressive disorder. After adjustment for behavioral and dietary factors, the increased level of insulin resistance associated with depressive disorder was 13.2% (−3.1 to 32.3%, P = 0.12) in men and 6.1% (−4.1 to 17.4%, P = 0.25) in women. Waist circumference was identified as a mediator in the relationship between depression and insulin resistance, reducing the β coefficient in the fully adjusted models in men by 38% and in women by 42%. CONCLUSIONS A positive association was found between depressive disorder and insulin resistance in this population-based sample of young adult men and women. The association seemed to be mediated partially by waist circumference. PMID:20185745

  18. Molecular Mechanisms of Insulin Secretion and Insulin Action.

    ERIC Educational Resources Information Center

    Flatt, Peter R.; Bailey, Clifford J.

    1991-01-01

    Information and current ideas on the factors regulating insulin secretion, the mechanisms underlying the secretion and biological actions of insulin, and the main characteristics of diabetes mellitus are presented. (Author)

  19. New Insulins and New Aspects in Insulin Delivery.

    PubMed

    Woo, Vincent C

    2015-08-01

    The major abnormality in both type 1 and type 2 diabetes is insulin deficiency. The methods of replacing insulin have improved throughout the decades, but hypoglycemia is still the limiting factor for many individuals with diabetes, and it prevents them from achieving ideal glycemic targets. New insulin and newer delivery systems are being developed that can improve some of the limitations of current insulins or make the delivery of insulins more acceptable for some patients. Extending the duration of action of basal insulins and shortening the peak of fast-acting insulins may have advantages for individuals with diabetes. Different delivery systems may make insulin more acceptable to patients and may have other advantages, which may aid in attaining better glycemic control. PMID:26233724

  20. Insulin Aspart (rDNA Origin) Injection

    MedlinePlus

    ... unless it is used in an external insulin pump. In patients with type 2 diabetes, insulin aspart ... also can be used with an external insulin pump. Before using insulin aspart in a pump system, ...

  1. Insulin Detemir (rDNA Origin) Injection

    MedlinePlus

    ... man-made version of human insulin. Insulin detemir works by replacing the insulin that is normally produced ... using an insulin pen, always remove the needle right after you inject your dose. Dispose of needles ...

  2. Development of insulin delivery systems.

    PubMed

    Siddiqui, N I; Siddiqui, Ni; Rahman, S; Nessa, A

    2008-01-01

    Delivery system of insulin is vital for its acceptance and adherence to therapy for achieving the glycemic targets. Enormous developments have occurred in the delivery system of insulin during the last twenty years and each improvement was aimed at two common goals: patients convenience and better glycemic control. Till to date, the various insulin delivery systems are: syringes/vials, injection aids, jet injectors, transmucosal delivery, transdermal delivery, external insulin infusion pump, implantable insulin pumps, insulin pens and insulin inhalers. Syringe/vial is the oldest and conventional method, still widely used and relatively cheaper. Modern plastic syringes are disposable, light weight with microfine needle for patients convenience and comfort. Oral route could be the most acceptable and viable, if the barriers can be overcome and under extensive trial. Insulin pen device is an important milestone in the delivery system of insulin as it is convenient, discrete, painless, attractive, portable with flexible life style and improved quality of life. More than 80% of European diabetic patients are using insulin pen. Future digital pen will have better memory option, blood glucose monitoring system, insulin dose calculator etc. Insulin infusion pump is a good option for the children, busy patients with flexible lifestyle and those who want to avoid multiple daily injections. Pulmonary route of insulin delivery is a promising, effective, non-invasive and acceptable alternative method. Exubera, the world first insulin inhaler was approved by FDA in 28 January 2006. But due to certain limitations, it has been withdrawn from the market in October 2007. The main concern of inhaled insulin are: long term pulmonary safety issues, cost effectiveness and user friendly device. In future, more acceptable and cost effective insulin inhaler will be introduced. Newer avenues are under extensive trial for better future insulin delivery systems. PMID:18285745

  3. Awake Craniotomy

    MedlinePlus Videos and Cool Tools

    ... development and features the area’s only neuro intensive care unit. In today’s broadcast you will be part ... brain tumor centers are offering this type of care, and I feel like we’re fortunate here ...

  4. Organ distribution of transgene expression following intranasal mucosal delivery of recombinant replication-defective adenovirus gene transfer vector

    PubMed Central

    Damjanovic, Daniela; Zhang, Xizhong; Mu, Jingyu; Fe Medina, Maria; Xing, Zhou

    2008-01-01

    It is believed that respiratory mucosal immunization triggers more effective immune protection than parenteral immunization against respiratory infection caused by viruses and intracellular bacteria. Such understanding has led to the successful implementation of intranasal immunization in humans with a live cold-adapted flu virus vaccine. Furthermore there has been an interest in developing effective mucosal-deliverable genetic vaccines against other infectious diseases. However, there is a concern that intranasally delivered recombinant viral-based vaccines may disseminate to the CNS via the olfactory tissue. Initial experimental evidence suggests that intranasally delivered recombinant adenoviral gene transfer vector may transport to the olfactory bulb. However, there is a lack of quantitative studies to compare the relative amounts of transgene products in the respiratory tract, lung, olfactory bulb and brain after intranasal mucosal delivery of viral gene transfer vector. To address this issue, we have used fluorescence macroscopic imaging, luciferase quantification and PCR approaches to compare the relative distribution of transgene products or adenoviral gene sequences in the respiratory tract, lung, draining lymph nodes, olfactory bulb, brain and spleen. Intranasal mucosal delivery of replication-defective recombinant adenoviral vector results in gene transfer predominantly in the respiratory system including the lung while it does lead to a moderate level of gene transfer in the olfactory bulb. However, intranasal inoculation of adenoviral vector leads to little or no viral dissemination to the major region of the CNS, the brain. These experimental findings support the efficaciousness of intranasal adenoviral-mediated gene transfer for the purpose of mucosal immunization and suggest that it may not be of significant safety concern. PMID:18261231

  5. REAL-TIME MEASUREMENT OF AIRWAY RESPONSES TO SULOFUR DIOXIDE (SO2) IN AN INTACT, AWAKE GUINEA PIG MODEL

    EPA Science Inventory

    Real-time measurment of airway responses to Sulfur Dioxide (SO2) in an intact, awake guinea pig model. J Stanek1,2, Q Krantz2, J Nolan2, D Winsett2, W Watkinson2, and D Costa2. 1College of Veterinary Medicine, NCSU, Raleigh, NC, USA; 2Pulmonary Toxicology Branch, ETD, NHEERL, US...

  6. COMPARISON OF CARDIOPULMONARY FUNCTION IN AWAKE FISCHER-344 AND SPRAGUE-DAWLEY RATS EXPOSED TO CARBON DIOXIDE: A COMPUTERIZED TECHNIQUE

    EPA Science Inventory

    A system has been developed to measure simultaneously the effects of inhaled toxicants on cardiopulmonary function in four awake rats before, during and after exposure. ne day prior to testing, Fischer-344 and Sprague-Dawley rats were implanted with an intrapleural or carotid cat...

  7. Awake nasotracheal fiberoptic intubation and self-positioning followed by anesthesia induction in prone patients: A pilot observational study.

    PubMed

    Heng, Lei; Wang, Ming-Yu; Sun, Hou-Liang; Zhu, Shan-Shan

    2016-08-01

    Anesthesia followed by placement in the prone position takes time and may result in complications. This study aimed to evaluate the feasibility of awake nasotracheal fiberoptic intubation and self-positioning followed by anesthesia induction in prone-positioned patients under general anesthesia.Sixty-two patients (ASA physical status I-II) scheduled for awake nasotracheal fiberoptic intubation and prone self-positioning before surgery under general anesthesia were selected. Patient preparation began with detailed preoperative counseling regarding the procedure. Premedication with sedative and antisialagogue was followed by airway anesthesia with topical lidocaine; then, awake nasotracheal fiberoptic intubation was carried out. The patients then positioned themselves comfortably before induction of general anesthesia. The changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), incidence of coughing or gagging, and rate pressure product (RPP) were assessed. Statistical analysis was performed with repeated-measures one-way analysis of variance.Fifty-eight of the 62 patients completed prone self-positioning smoothly. Compared with values before intubation, SBP, DBP, HR, and RPP were slightly increased after intubation, although the difference was not statistically significant (P > 0.05). One patient had moderate coughing and 1 patient had gagging during prone self-positioning, which were tolerable.These findings indicated that awake nasotracheal fiberoptic intubation and self-positioning followed by induction of anesthesia is safe and feasible alternative to routine prone positioning after induction of general anesthesia. PMID:27512858

  8. Ovarian tumors secreting insulin.

    PubMed

    Battocchio, Marialberta; Zatelli, Maria Chiara; Chiarelli, Silvia; Trento, Mariangela; Ambrosio, Maria Rosaria; Pasquali, Claudio; De Carlo, Eugenio; Dassie, Francesca; Mioni, Roberto; Rebellato, Andrea; Fallo, Francesco; Degli Uberti, Ettore; Martini, Chiara; Vettor, Roberto; Maffei, Pietro

    2015-08-01

    Combined ovarian germ cell and neuroendocrine tumors are rare. Only few cases of hyperinsulinism due to ovarian ectopic secretion have been hypothesized in the literature. An ovarian tumor was diagnosed in a 76-year-old woman, referred to our department for recurrent hypoglycemia with hyperinsulinism. In vivo tests, in particular fasting test, rapid calcium infusion test, and Octreotide test were performed. Ectopic hyperinsulinemic hypoglycemia was demonstrated in vivo and hypoglycemia disappeared after hysteroadnexectomy. Histological exam revealed an ovarian germ cell tumor with neuroendocrine and Yolk sac differentiation, while immunostaining showed insulin positivity in neuroendocrine cells. A cell culture was obtained by tumoral cells, testing Everolimus, and Pasireotide. Insulin was detected in cell culture medium and Everolimus and Pasireotide demonstrated their potentiality in reducing insulin secretion, more than controlling cell viability. Nine cases of hyperinsulinism due to ovarian ectopic secretion reported in literature have been reviewed. These data confirm the ovarian tissue potentiality to induce hyperinsulinemic hypoglycemic syndrome after neoplastic transformation. PMID:25896552

  9. Acetoacetylation of insulin

    PubMed Central

    Lindsay, D. G.; Shall, S.

    1969-01-01

    Insulin was treated with diketen at pH6·9. The reaction mixture was resolved into four components by DEAE-Sephadex chromatography. The first component was unchanged insulin. The second and third components were shown by end-group analysis to be substituted on phenylalanine B-1 and glycine A-1 respectively. The fourth component was disubstituted on both phenylalanine B-1 and glycine A-1. The ∈-amino group of lysine B-29 was not involved in the reaction at low reagent concentrations. The purity of these derivatives was checked by their electrophoretic behaviour and by measurement of the rate of their reaction with trinitrobenzenesulphonic acid. The hormonal activity of the derivatives was determined. The effect of the modifications on the hormonal activity and the tertiary structure of insulin is discussed. ImagesFig. 10. PMID:5353531

  10. Insulin and carbohydrate dysregulation.

    PubMed

    Gelato, Marie C

    2003-04-01

    Patients with human immunodeficiency virus receiving highly active antiretroviral therapy (HAART) may experience abnormal body composition changes as well as metabolic abnormalities, including dyslipidemia, increases in triglycerides, low high-density lipoprotein cholesterol levels, and abnormal carbohydrate metabolism, ranging from insulin resistance with and without glucose intolerance to frank diabetes. Whether the body composition changes (i.e., increased visceral adiposity and fat wasting in the peripheral tissues) are linked to abnormalities in carbohydrate metabolism is unclear. The use of HAART with and without therapy with protease inhibitors (PIs) is related to carbohydrate abnormalities and changes in body composition. Regimens that include PIs appear to have a higher incidence of insulin resistance (up to 90%) and diabetes mellitus (up to 40%). The etiology of these abnormalities is not well understood; what is known about insulin and carbohydrate dysregulation with HAART is discussed. PMID:12652377

  11. Insulin C-peptide test

    MedlinePlus

    C-peptide ... the test depends on the reason for the C-peptide measurement. Ask your health care provider if ... C-peptide is measured to tell the difference between insulin produced by the body and insulin injected ...

  12. Alternative Devices for Taking Insulin

    MedlinePlus

    ... continuous glucose monitoring (CGM) system an insulin delivery system a computer program that adjusts insulin delivery based on changes in glucose levels CGM systems approved by the U.S. Food and Drug Administration ( ...

  13. Functional magnetic resonance imaging of awake monkeys: some approaches for improving imaging quality

    PubMed Central

    Chen, Gang; Wang, Feng; Dillenburger, Barbara C.; Friedman, Robert M.; Chen, Li M.; Gore, John C.; Avison, Malcolm J.; Roe, Anna W.

    2011-01-01

    Functional magnetic resonance imaging (fMRI), at high magnetic field strength can suffer from serious degradation of image quality because of motion and physiological noise, as well as spatial distortions and signal losses due to susceptibility effects. Overcoming such limitations is essential for sensitive detection and reliable interpretation of fMRI data. These issues are particularly problematic in studies of awake animals. As part of our initial efforts to study functional brain activations in awake, behaving monkeys using fMRI at 4.7T, we have developed acquisition and analysis procedures to improve image quality with encouraging results. We evaluated the influence of two main variables on image quality. First, we show how important the level of behavioral training is for obtaining good data stability and high temporal signal-to-noise ratios. In initial sessions, our typical scan session lasted 1.5 hours, partitioned into short (<10 minutes) runs. During reward periods and breaks between runs, the monkey exhibited movements resulting in considerable image misregistrations. After a few months of extensive behavioral training, we were able to increase the length of individual runs and the total length of each session. The monkey learned to wait until the end of a block for fluid reward, resulting in longer periods of continuous acquisition. Each additional 60 training sessions extended the duration of each session by 60 minutes, culminating, after about 140 training sessions, in sessions that last about four hours. As a result, the average translational movement decreased from over 500 μm to less than 80 μm, a displacement close to that observed in anesthetized monkeys scanned in a 7 T horizontal scanner. Another major source of distortion at high fields arises from susceptibility variations. To reduce such artifacts, we used segmented gradient-echo echo-planar imaging (EPI) sequences. Increasing the number of segments significantly decreased susceptibility

  14. Cardiorespiratory effects of a 5HT2 antagonist (R51703) in awake and anesthetized dogs.

    PubMed Central

    Doherty, T J; McDonell, W N; Dyson, D H; Black, W D

    1996-01-01

    To investigate cardiorespiratory effects of an experimental 5-hydroxytryptamine receptor antagonist (R51703) with sedative properties, intramuscular doses of the drug were studied in 6 awake dogs of mixed breed, and in 6 anesthetized beagles. Two doses (0.2 and 0.4 mg/kg) of R51703 and a saline control were studied in the awake dogs using a randomized crossover trial. Subsequently, the higher dose of R51703 was included as a component of halothane anesthesia to determine whether the halothane sparing effect of R51703 produced a beneficial alteration of hemodynamic function. Data were obtained at equipotent halothane/R51703 (H/R) and halothane/saline (H/S) doses equivalent to 1.0, 1.5 and 2.0 MAC. In awake dogs, heart rates tended to be lower in dogs sedated with R51703, significantly so at 30 min for both doses, and at 90 and 120 min for the 0.2 and 0.4 mg/kg doses, respectively (P < 0.05). The cardiac index (CI) was lower at 60 min with both doses compared to the saline control group. Both doses of R51703 reduced mean blood pressure at 30, 90 and 120 min, and diastolic pressure at 30 and 90 min after administration; however, systolic blood pressure (SBP) was not altered. Overall, the cardiovascular alterations were minimal in conscious dogs and there was no evidence of respiratory depression. In the anesthetized dogs, at equipotent MAC, CI tended to be lower with H/R than with H/S, though the difference was not significant. Heart rate and stroke volume index also tended to be lower in the dogs treated with R51703, while systemic vascular resistance tended to be higher: these changes were not significant. Mean and SBP were higher at each MAC multiple in the H/R group. It was concluded that the halothane sparing effect of R51703 did not substantially improve hemodynamic function compared to the use of halothane alone at equipotent doses. PMID:8809379

  15. Insulin formulations--a review.

    PubMed

    Gualandi-Signorini, A M; Giorgi, G

    2001-01-01

    Although the improvement on insulin therapy since it was first conceived, it is still far from mimicking physiological secretion of pancreatic b-cells and research to find new insulin formulations and new routes of administration continues. Human biosynthetic insulin (rapid-acting, intermediate-acting and long-acting), produced by recombinant DNA technique, is currently available. The pharmacokinetic profile of rapid-acting insulin (regular) does not adequately reproduce the physiological post-prandial insulin response. This has led to the development of molecular analogues with slight modifications that prevent the spontaneous polymerisation underlying delayed absorption. Fast-acting analogues such as Lyspro and Aspart can be injected immediately before the meal, inducing a very fast and substantial peak of insulin, similar to that produced by b-cells, but have the disadvantage of short duration of action. For this reason, and because of the difficulty of obtaining sufficient basal insulin concentrations to control preprandial blood glucose levels with current long-acting insulins, analogues known as Glargine and Detemir have been synthesized. They have virtually no plasma peak and acts for about 24 h. These characteristics make it ideal to cover basal insulin requirement. With insulin analogues, it also seems possible to overcome the problem of intra- and inter-individual variability in absorption after subcutaneous injection. This variability is directly proportional to the duration of insulin action. Research into new routes of administration has led to production of inhaled insulin powder, soon to become commercially available. Insulin is absorbed through the lung alveoli. Trials to evaluate efficacy and toleration have shown that inhaled insulin has a similar kinetic profile to the fast-acting injected analogue and can therefore be used for mealtime requirement, combined with a single daily injection of long-acting insulin. Oral insulin is currently being

  16. Classifying multiple types of hand motions using electrocorticography during intraoperative awake craniotomy and seizure monitoring processes-case studies.

    PubMed

    Xie, Tao; Zhang, Dingguo; Wu, Zehan; Chen, Liang; Zhu, Xiangyang

    2015-01-01

    In this work, some case studies were conducted to classify several kinds of hand motions from electrocorticography (ECoG) signals during intraoperative awake craniotomy & extraoperative seizure monitoring processes. Four subjects (P1, P2 with intractable epilepsy during seizure monitoring and P3, P4 with brain tumor during awake craniotomy) participated in the experiments. Subjects performed three types of hand motions (Grasp, Thumb-finger motion and Index-finger motion) contralateral to the motor cortex covered with ECoG electrodes. Two methods were used for signal processing. Method I: autoregressive (AR) model with burg method was applied to extract features, and additional waveform length (WL) feature has been considered, finally the linear discriminative analysis (LDA) was used as the classifier. Method II: stationary subspace analysis (SSA) was applied for data preprocessing, and the common spatial pattern (CSP) was used for feature extraction before LDA decoding process. Applying method I, the three-class accuracy of P1~P4 were 90.17, 96.00, 91.77, and 92.95% respectively. For method II, the three-class accuracy of P1~P4 were 72.00, 93.17, 95.22, and 90.36% respectively. This study verified the possibility of decoding multiple hand motion types during an awake craniotomy, which is the first step toward dexterous neuroprosthetic control during surgical implantation, in order to verify the optimal placement of electrodes. The accuracy during awake craniotomy was comparable to results during seizure monitoring. This study also indicated that ECoG was a promising approach for precise identification of eloquent cortex during awake craniotomy, and might form a promising BCI system that could benefit both patients and neurosurgeons. PMID:26483627

  17. Peri-infarct depolarizations during focal ischemia in the awake Spontaneously Hypertensive Rat. Minimizing anesthesia confounds in experimental stroke.

    PubMed

    Kudo, K; Zhao, L; Nowak, T S

    2016-06-14

    Anesthesia profoundly impacts peri-infarct depolarizations (PIDs), but only one prior report has described their monitoring during experimental stroke in awake animals. Since temporal patterns of PID occurrence are model specific, the current study examined PID incidence during focal ischemia in the awake Spontaneously Hypertensive Rat (SHR), and documented the impact of both prior and concurrent isoflurane anesthesia. For awake recordings, electrodes were implanted under isoflurane anesthesia 1day to 5weeks prior to occlusion surgery. Rats were then subjected to permanent or transient (2h) tandem occlusion of the middle cerebral and ipsilateral common carotid arteries, followed by PID monitoring for up to 3days. Comparison perfusion imaging studies evaluated PID-associated hyperemic transients during permanent ischemia under anesthesia at varied intervals following prior isoflurane exposure. Prior anesthesia attenuated PID number at intervals up to 1week, establishing 2weeks as a practical recovery duration following surgical preparation to avoid isoflurane preconditioning effects. PIDs in awake SHR were limited to the first 4h after permanent occlusions. Maintaining anesthesia during this interval reduced PID number, and prolonged their occurrence through several hours following anesthesia termination. Although PID number otherwise correlated with infarct size, PID suppression by anesthesia was not protective in the absence of reperfusion. PIDs persisted up to 36h after transient occlusions. These results differ markedly from the one previous report of such monitoring in awake Sprague-Dawley rats, which found an extended biphasic PID time course during 24h after both permanent and transient filament occlusions. PID occurrence closely reflects the time course of infarct progression in the respective models, and may be more useful than absolute PID number as an index of ongoing pathology. PMID:27026594

  18. Oral Insulin and Buccal Insulin: A Critical Reappraisal

    PubMed Central

    Heinemann, Lutz; Jacques, Yves

    2009-01-01

    Despite the availability of modern insulin injection devices with needles that are so sharp and thin that practically no injection pain takes place, it is still the dream of patients with diabetes to, for example, swallow a tablet with insulin. This is not associated with any pain and would allow more discretion. Therefore, availability of oral insulin would not only ease insulin therapy, it would certainly increase compliance. However, despite numerous attempts to develop such a “tablet” in the past 85 years, still no oral insulin is commercially available. Buccal insulin is currently in the last stages of clinical development by one company and might become available in the United States and Europe in the coming years (it is already on the market in some other countries). The aim of this review is to critically describe the different approaches that are currently under development. Optimal coverage of prandial insulin requirements is the aim with both routes of insulin administration (at least with most approaches). The speed of onset of metabolic effect seen with some oral insulin approaches is rapid, but absorption appears to be lower when the tablet is taken immediately prior to a meal. With all approaches, considerable amounts of insulin have to be applied in order to induce therapeutically relevant increases in the metabolic effect because of the low relative biopotency of buccal insulin. Unfortunately, the number of publications about clinical–experimental and clinical studies is surprisingly low. In addition, there is no study published in which the variability of the metabolic effect induced (with and without a meal) was studied adequately. In summary, after the failure of inhaled insulin, oral insulin and buccal insulin are hot candidates to come to the market as the next alternative routes of insulin administration. PMID:20144297

  19. Cinnamon, glucose and insulin sensitivity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Compounds found in cinnamon not only improve the function of insulin but also function as antioxidants and may be anti-inflammatory. This is very important since insulin function, antioxidant status, and inflammatory response are closely linked; with decreased insulin sensitivity there is also decr...

  20. Insulin Resistance in Alzheimer's Disease

    PubMed Central

    Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

    2014-01-01

    Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

  1. Enhancement in bioavailability of ketorolac tromethamine via intranasal in situ hydrogel based on poloxamer 407 and carrageenan.

    PubMed

    Li, Chenxi; Li, Chunyan; Liu, Zheshuo; Li, Qiuhong; Yan, Xueying; Liu, Yu; Lu, Weiyue

    2014-10-20

    The objective of this study was to construct a new in situ gel system based on the combination of poloxamer 407 and carrageenan (carrageenan-poloxamer 407 hydrogel, CPH) for intranasal delivery of ketorolac tromethamine. CPH showed potassium ion concentration - dependent erosion characteristics which ensured slow erosion in aqueous environment containing potassium ion at the physiological level. Loading with ketorolac tromethamine influenced erosion, drug release and thermosensitive properties of CPH. CPH containing 15% ketorolac tromethamine showed suitable gelation temperature (near 35°C) and in vitro sustained release profiles. Pharmacokinetic study of intranasal CPH containing 15% ketorolac tromethamine in rats demonstrated enhanced absolute bioavailability (68.8 ± 23.3%) and prolonged mean residence time (8.8 ± 3.5h) in comparison with the intranasal solution group (24.8 ± 13.8%, 3.9 ± 0.6h). Nasal ciliotoxicity evaluation on an in situ toad palate model preliminarily showed the safety of CPH for intranasal use. All results suggested the potential of CPH as a new sustained - release platform for the intranasal delivery of ketorolac tromethamine. PMID:25138250

  2. Ancillary therapy of intranasal T-LysYal® for patients with allergic, non-allergic, and mixed rhinitis.

    PubMed

    Gelardi, M; Taliente, S; Fiorella, M L; Quaranta, N; Ciancio, G; Russo, C; Mola, P; Ciofalo, A; Zambetti, G; Caruso Armone, A; Cantone, E; Ciprandi, G

    2016-01-01

    Allergic rhinitis (AR) is caused by an IgE-mediated inflammatory reaction. Non-allergic rhinitis (NAR) is characterized by a non-IgE-mediated pathogenesis. Frequently, patients have the two disorders associated: such as mixed rhinitis (MR). Hyaluronic acid (HA) is a fundamental component of the human connective tissue. HA may exert anti-inflammatory and immune-modulating activities. Recently, an intranasal HA formulation was proposed: a supramolecular system containing lysine hyaluronate, thymine and sodium chloride (T-LysYal®). This randomized study investigated whether intranasal T-LysYal® (rinoLysYal®, Farmigea, Italy) was able to reduce symptom severity, endoscopic features, and nasal cytology in 89 patients (48 males and 41 females, mean age 36.3±7.1 years) with AR, NAR, and MR. Patients were treated with intranasal T-LysYal® or isotonic saline solution as adjunctive therapy to nasal corticosteroid and oral antihistamine for 4 weeks. Patients were visited at baseline, after treatment and after 4-week follow-up. Intranasal T-LysYal® treatment significantly reduced the quote of patients with symptoms, endoscopic features, and inflammatory cells. In conclusion, the present study demonstrates that intranasal T-LysYal® is able, as ancillary therapy, to significantly improve patients with AR, NAR, and MR, and its effect is long lasting. PMID:27049100

  3. Intranasal inoculation of white-tailed deer (Odocoileus virginianus) with lyophilized chronic wasting disease prion particulate complexed to montmorillonite clay.

    PubMed

    Nichols, Tracy A; Spraker, Terry R; Rigg, Tara D; Meyerett-Reid, Crystal; Hoover, Clare; Michel, Brady; Bian, Jifeng; Hoover, Edward; Gidlewski, Thomas; Balachandran, Aru; O'Rourke, Katherine; Telling, Glenn C; Bowen, Richard; Zabel, Mark D; VerCauteren, Kurt C

    2013-01-01

    Chronic wasting disease (CWD), the only known prion disease endemic in wildlife, is a persistent problem in both wild and captive North American cervid populations. This disease continues to spread and cases are found in new areas each year. Indirect transmission can occur via the environment and is thought to occur by the oral and/or intranasal route. Oral transmission has been experimentally demonstrated and although intranasal transmission has been postulated, it has not been tested in a natural host until recently. Prions have been shown to adsorb strongly to clay particles and upon oral inoculation the prion/clay combination exhibits increased infectivity in rodent models. Deer and elk undoubtedly and chronically inhale dust particles routinely while living in the landscape while foraging and rutting. We therefore hypothesized that dust represents a viable vehicle for intranasal CWD prion exposure. To test this hypothesis, CWD-positive brain homogenate was mixed with montmorillonite clay (Mte), lyophilized, pulverized and inoculated intranasally into white-tailed deer once a week for 6 weeks. Deer were euthanized at 95, 105, 120 and 175 days post final inoculation and tissues examined for CWD-associated prion proteins by immunohistochemistry. Our results demonstrate that CWD can be efficiently transmitted utilizing Mte particles as a prion carrier and intranasal exposure. PMID:23671598

  4. Intranasal Inoculation of White-Tailed Deer (Odocoileus virginianus) with Lyophilized Chronic Wasting Disease Prion Particulate Complexed to Montmorillonite Clay

    PubMed Central

    Nichols, Tracy A.; Spraker, Terry R.; Rigg, Tara D.; Meyerett-Reid, Crystal; Hoover, Clare; Michel, Brady; Bian, Jifeng; Hoover, Edward; Gidlewski, Thomas; Balachandran, Aru; O'Rourke, Katherine; Telling, Glenn C.; Bowen, Richard

    2013-01-01

    Chronic wasting disease (CWD), the only known prion disease endemic in wildlife, is a persistent problem in both wild and captive North American cervid populations. This disease continues to spread and cases are found in new areas each year. Indirect transmission can occur via the environment and is thought to occur by the oral and/or intranasal route. Oral transmission has been experimentally demonstrated and although intranasal transmission has been postulated, it has not been tested in a natural host until recently. Prions have been shown to adsorb strongly to clay particles and upon oral inoculation the prion/clay combination exhibits increased infectivity in rodent models. Deer and elk undoubtedly and chronically inhale dust particles routinely while living in the landscape while foraging and rutting. We therefore hypothesized that dust represents a viable vehicle for intranasal CWD prion exposure. To test this hypothesis, CWD-positive brain homogenate was mixed with montmorillonite clay (Mte), lyophilized, pulverized and inoculated intranasally into white-tailed deer once a week for 6 weeks. Deer were euthanized at 95, 105, 120 and 175 days post final inoculation and tissues examined for CWD-associated prion proteins by immunohistochemistry. Our results demonstrate that CWD can be efficiently transmitted utilizing Mte particles as a prion carrier and intranasal exposure. PMID:23671598

  5. Long-term optical imaging of intrinsic signals in anesthetized and awake monkeys

    NASA Astrophysics Data System (ADS)

    Roe, Anna W.

    2007-04-01

    Some exciting new efforts to use intrinsic signal optical imaging methods for long-term studies in anesthetized and awake monkeys are reviewed. The development of such methodologies opens the door for studying behavioral states such as attention, motivation, memory, emotion, and other higher-order cognitive functions. Long-term imaging is also ideal for studying changes in the brain that accompany development, plasticity, and learning. Although intrinsic imaging lacks the temporal resolution offered by dyes, it is a high spatial resolution imaging method that does not require application of any external agents to the brain. The bulk of procedures described here have been developed in the monkey but can be applied to the study of surface structures in any in vivo preparation.

  6. Irregular spiking of pyramidal neurons organizes as scale-invariant neuronal avalanches in the awake state.

    PubMed

    Bellay, Timothy; Klaus, Andreas; Seshadri, Saurav; Plenz, Dietmar

    2015-01-01

    Spontaneous fluctuations in neuronal activity emerge at many spatial and temporal scales in cortex. Population measures found these fluctuations to organize as scale-invariant neuronal avalanches, suggesting cortical dynamics to be critical. Macroscopic dynamics, though, depend on physiological states and are ambiguous as to their cellular composition, spatiotemporal origin, and contributions from synaptic input or action potential (AP) output. Here, we study spontaneous firing in pyramidal neurons (PNs) from rat superficial cortical layers in vivo and in vitro using 2-photon imaging. As the animal transitions from the anesthetized to awake state, spontaneous single neuron firing increases in irregularity and assembles into scale-invariant avalanches at the group level. In vitro spike avalanches emerged naturally yet required balanced excitation and inhibition. This demonstrates that neuronal avalanches are linked to the global physiological state of wakefulness and that cortical resting activity organizes as avalanches from firing of local PN groups to global population activity. PMID:26151674

  7. The Dutch Linguistic Intraoperative Protocol: a valid linguistic approach to awake brain surgery.

    PubMed

    De Witte, E; Satoer, D; Robert, E; Colle, H; Verheyen, S; Visch-Brink, E; Mariën, P

    2015-01-01

    Intraoperative direct electrical stimulation (DES) is increasingly used in patients operated on for tumours in eloquent areas. Although a positive impact of DES on postoperative linguistic outcome is generally advocated, information about the neurolinguistic methods applied in awake surgery is scarce. We developed for the first time a standardised Dutch linguistic test battery (measuring phonology, semantics, syntax) to reliably identify the critical language zones in detail. A normative study was carried out in a control group of 250 native Dutch-speaking healthy adults. In addition, the clinical application of the Dutch Linguistic Intraoperative Protocol (DuLIP) was demonstrated by means of anatomo-functional models and five case studies. A set of DuLIP tests was selected for each patient depending on the tumour location and degree of linguistic impairment. DuLIP is a valid test battery for pre-, intraoperative and postoperative language testing and facilitates intraoperative mapping of eloquent language regions that are variably located. PMID:25526520

  8. Epidural anaesthesia through caudal catheters for inguinal herniotomies in awake ex-premature babies.

    PubMed

    Peutrell, J M; Hughes, D G

    1993-02-01

    Ex-premature babies are at risk of apnoea after surgery. Regional anaesthesia has been used as an alternative to general anaesthesia for some surgical procedures in the belief that it may be safer. However, single dose caudal epidural and subarachnoid anaesthetics have a duration of action which may be insufficient for some operations. The level and duration of anaesthesia can be extended if local anaesthetic is given through an epidural catheter. In addition, the dose needed to provide adequate anaesthesia may be lower because the local anaesthetic is given at an appropriate segmental level. We report our experience of caudal epidural anaesthesia in nine, awake ex-premature babies who were having inguinal herniotomies. The anaesthesia was excellent in six babies. Two babies cried briefly with peritoneal or spermatic cord traction. One other baby needed supplementation with nitrous oxide in oxygen in order to complete the surgery. The majority of babies slept throughout surgery. There were no reported postoperative complications. PMID:8460759

  9. Pleural liquid clearance rate measured in awake sheep by the volume of dilution method

    SciTech Connect

    Broaddus, V.C.; Wiener-Kronish, J.P.; Berthiaume, Y.; Staub, N.C.

    1986-03-01

    The authors reported 24h clearance of mock pleural effusions measured terminally in sheep. To measure effusion volume at different times in the same sheep, they injected /sup 111/In-transferrin and measured its dilution. In 5 sheep with effusions of known sizes, the method was accurate to +/-10%. In 5 awake sheep, the authors injected 10 ml/kg of a 1% protein solution via a non-penetrating rib capsule. At 6h, the authors measured the volume by the dilution method and at 24h by direct recovery. The clearance rate in each animal was constant at 2.9-6.0%/h (average 4.8 +/- 1.3%/h). This new method gives a reliable two point clearance rate and requires fewer animals.

  10. Inspiratory flow dynamics during phrenic nerve stimulation in awake normals during nasal breathing.

    PubMed

    Sériès, F; Demoule, A; Marc, I; Sanfaçon, C; Derenne, J P; Similowski, T

    1999-08-01

    The loss of upper airway (UA) dilators preactivation before inspiratory muscle contraction is an important determinant of the pathophysiology of obstructive sleep apnea. We hypothetized that phrenic nerve stimulation could provide a practical way to explore the effects of the dissociation between UA dilators and inspiratory muscles, and possibly to determine UA critical closing pressure during wakefulness. The pattern of inspiratory airflow was therefore studied in normal awake subjects during diaphragm twitches induced by either electrical phrenic stimulation (ES) or cervical magnetic stimulation (CMS) (n = 9) and with and without a nasal stent during ES (n = 7). End-expiratory stimulations applied during exclusive nasal breathing induced 200 to 300 ms twitch inspiratory flow. The average maximal twitch flow of flow-limited twitches was higher during CMS than ES (1.18 +/- 0.29 L. PMID:10430737

  11. Replicability and Heterogeneity of Awake Unrestrained Canine fMRI Responses

    PubMed Central

    Berns, Gregory S.; Brooks, Andrew; Spivak, Mark

    2013-01-01

    Previously, we demonstrated the possibility of fMRI in two awake and unrestrained dogs. Here, we determined the replicability and heterogeneity of these results in an additional 11 dogs for a total of 13 subjects. Based on an anatomically placed region-of-interest, we compared the caudate response to a hand signal indicating the imminent availability of a food reward to a hand signal indicating no reward. 8 of 13 dogs had a positive differential caudate response to the signal indicating reward. The mean differential caudate response was 0.09%, which was similar to a comparable human study. These results show that canine fMRI is reliable and can be done with minimal stress to the dogs. PMID:24324719

  12. Neurons Differentiated from Transplanted Stem Cells Respond Functionally to Acoustic Stimuli in the Awake Monkey Brain.

    PubMed

    Wei, Jing-Kuan; Wang, Wen-Chao; Zhai, Rong-Wei; Zhang, Yu-Hua; Yang, Shang-Chuan; Rizak, Joshua; Li, Ling; Xu, Li-Qi; Liu, Li; Pan, Ming-Ke; Hu, Ying-Zhou; Ghanemi, Abdelaziz; Wu, Jing; Yang, Li-Chuan; Li, Hao; Lv, Long-Bao; Li, Jia-Li; Yao, Yong-Gang; Xu, Lin; Feng, Xiao-Li; Yin, Yong; Qin, Dong-Dong; Hu, Xin-Tian; Wang, Zheng-Bo

    2016-07-26

    Here, we examine whether neurons differentiated from transplanted stem cells can integrate into the host neural network and function in awake animals, a goal of transplanted stem cell therapy in the brain. We have developed a technique in which a small "hole" is created in the inferior colliculus (IC) of rhesus monkeys, then stem cells are transplanted in situ to allow for investigation of their integration into the auditory neural network. We found that some transplanted cells differentiated into mature neurons and formed synaptic input/output connections with the host neurons. In addition, c-Fos expression increased significantly in the cells after acoustic stimulation, and multichannel recordings indicated IC specific tuning activities in response to auditory stimulation. These results suggest that the transplanted cells have the potential to functionally integrate into the host neural network. PMID:27425612

  13. Spontaneous high-gamma band activity reflects functional organization of auditory cortex in the awake macaque.

    PubMed

    Fukushima, Makoto; Saunders, Richard C; Leopold, David A; Mishkin, Mortimer; Averbeck, Bruno B

    2012-06-01

    In the absence of sensory stimuli, spontaneous activity in the brain has been shown to exhibit organization at multiple spatiotemporal scales. In the macaque auditory cortex, responses to acoustic stimuli are tonotopically organized within multiple, adjacent frequency maps aligned in a caudorostral direction on the supratemporal plane (STP) of the lateral sulcus. Here, we used chronic microelectrocorticography to investigate the correspondence between sensory maps and spontaneous neural fluctuations in the auditory cortex. We first mapped tonotopic organization across 96 electrodes spanning approximately two centimeters along the primary and higher auditory cortex. In separate sessions, we then observed that spontaneous activity at the same sites exhibited spatial covariation that reflected the tonotopic map of the STP. This observation demonstrates a close relationship between functional organization and spontaneous neural activity in the sensory cortex of the awake monkey. PMID:22681693

  14. Spontaneous high-gamma band activity reflects functional organization of auditory cortex in the awake macaque

    PubMed Central

    Fukushima, Makoto; Saunders, Richard C.; Leopold, David A.; Mishkin, Mortimer; Averbeck, Bruno B.

    2012-01-01

    Summary In the absence of sensory stimuli, spontaneous activity in the brain has been shown to exhibit organization at multiple spatiotemporal scales. In the macaque auditory cortex, responses to acoustic stimuli are tonotopically organized within multiple, adjacent frequency maps aligned in a caudorostral direction on the supratemporal plane (STP) of the lateral sulcus. Here we used chronic micro-electrocorticography to investigate the correspondence between sensory maps and spontaneous neural fluctuations in the auditory cortex. We first mapped tonotopic organization across 96 electrodes spanning approximately two centimeters along the primary and higher auditory cortex. In separate sessions we then observed that spontaneous activity at the same sites exhibited spatial covariation that reflected the tonotopic map of the STP. This observation demonstrates a close relationship between functional organization and spontaneous neural activity in the sensory cortex of the awake monkey. PMID:22681693

  15. Millisecond Coupling of Local Field Potentials to Synaptic Currents in the Awake Visual Cortex

    PubMed Central

    Haider, Bilal; Schulz, David P.A.; Häusser, Michael; Carandini, Matteo

    2016-01-01

    Summary The cortical local field potential (LFP) is a common measure of population activity, but its relationship to synaptic activity in individual neurons is not fully established. This relationship has been typically studied during anesthesia and is obscured by shared slow fluctuations. Here, we used patch-clamp recordings in visual cortex of anesthetized and awake mice to measure intracellular activity; we then applied a simple method to reveal its coupling to the simultaneously recorded LFP. LFP predicted membrane potential as accurately as synaptic currents, indicating a major role for synaptic currents in the relationship between cortical LFP and intracellular activity. During anesthesia, cortical LFP predicted excitation far better than inhibition; during wakefulness, it predicted them equally well, and visual stimulation further enhanced predictions of inhibition. These findings reveal a central role for synaptic currents, and especially inhibition, in the relationship between the subthreshold activity of individual neurons and the cortical LFP during wakefulness. PMID:27021173

  16. Insulin resistance in the liver: Deficiency or excess of insulin?

    PubMed Central

    Bazotte, Roberto B; Silva, Lorena G; Schiavon, Fabiana PM

    2014-01-01

    In insulin-resistant states (obesity, pre-diabetes, and type 2 diabetes), hepatic production of glucose and lipid synthesis are heightened in concert, implying that insulin deficiency and insulin excess coexists in this setting. The fact that insulin may be inadequate or excessive at any one point in differing organs and tissues has many biologic ramifications. In this context the concept of metabolic compartmentalization in the liver is offered herein as one perspective of this paradox. In particular, we focus on the hypothesis that insulin resistance accentuates differences in periportal and perivenous hepatocytes, namely periportal glucose production and perivenous lipid synthesis. Subsequently, excessive production of glucose and accumulation of lipids could be expected in the livers of patients with obesity and insulin resistance. Overall, in this review, we provide our integrative perspective regarding how excessive production of glucose in periportal hepatocytes and accumulation of lipids in perivenous hepatocytes interact in insulin resistant states. PMID:25486190

  17. Complex spatiotemporal haemodynamic response following sensory stimulation in the awake rat.

    PubMed

    Martin, Chris; Zheng, Ying; Sibson, Nicola R; Mayhew, John E W; Berwick, Jason

    2013-02-01

    Detailed understanding of the haemodynamic changes that underlie non-invasive neuroimaging techniques such as blood oxygen level dependent functional magnetic resonance imaging is essential if we are to continue to extend the use of these methods for understanding brain function and dysfunction. The use of animal and in particular rodent research models has been central to these endeavours as they allow in-vivo experimental techniques that provide measurements of the haemodynamic response function at high temporal and spatial resolution. A limitation of most of this research is the use of anaesthetic agents which may disrupt or mask important features of neurovascular coupling or the haemodynamic response function. In this study we therefore measured spatiotemporal cortical haemodynamic responses to somatosensory stimulation in awake rats using optical imaging spectroscopy. Trained, restrained animals received non-noxious stimulation of the whisker pad via chronically implanted stimulating microwires whilst optical recordings were made from the contralateral somatosensory cortex through a thin cranial window. The responses we measure from un-anaesthetised animals are substantially different from those reported in previous studies which have used anaesthetised animals. These differences include biphasic response regions (initial increases in blood volume and oxygenation followed by subsequent decreases) as well as oscillations in the response time series of awake animals. These haemodynamic response features do not reflect concomitant changes in the underlying neuronal activity and therefore reflect neurovascular or cerebrovascular processes. These hitherto unreported hyperemic response dynamics may have important implications for the use of anaesthetised animal models for research into the haemodynamic response function. PMID:23063446

  18. Complex spatiotemporal haemodynamic response following sensory stimulation in the awake rat☆

    PubMed Central

    Martin, Chris; Zheng, Ying; Sibson, Nicola R.; Mayhew, John E.W.; Berwick, Jason

    2013-01-01

    Detailed understanding of the haemodynamic changes that underlie non-invasive neuroimaging techniques such as blood oxygen level dependent functional magnetic resonance imaging is essential if we are to continue to extend the use of these methods for understanding brain function and dysfunction. The use of animal and in particular rodent research models has been central to these endeavours as they allow in-vivo experimental techniques that provide measurements of the haemodynamic response function at high temporal and spatial resolution. A limitation of most of this research is the use of anaesthetic agents which may disrupt or mask important features of neurovascular coupling or the haemodynamic response function. In this study we therefore measured spatiotemporal cortical haemodynamic responses to somatosensory stimulation in awake rats using optical imaging spectroscopy. Trained, restrained animals received non-noxious stimulation of the whisker pad via chronically implanted stimulating microwires whilst optical recordings were made from the contralateral somatosensory cortex through a thin cranial window. The responses we measure from un-anaesthetised animals are substantially different from those reported in previous studies which have used anaesthetised animals. These differences include biphasic response regions (initial increases in blood volume and oxygenation followed by subsequent decreases) as well as oscillations in the response time series of awake animals. These haemodynamic response features do not reflect concomitant changes in the underlying neuronal activity and therefore reflect neurovascular or cerebrovascular processes. These hitherto unreported hyperemic response dynamics may have important implications for the use of anaesthetised animal models for research into the haemodynamic response function. PMID:23063446

  19. Epilepsy and hippocampal neurodegeneration induced by glutamate decarboxylase inhibitors in awake rats.

    PubMed

    Salazar, Patricia; Tapia, Ricardo

    2015-10-01

    Glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, requires pyridoxal phosphate (PLP) as a cofactor. Thiosemicarbazide (TSC) and γ-glutamyl-hydrazone (PLPGH) inhibit the free PLP-dependent isoform (GAD65) activity after systemic administration, leading to epilepsy in mice and in young, but not in adult rats. However, the competitive GAD inhibitor 3-mercaptopropionic acid (MPA) induces convulsions in both immature and adult rats. In the present study we tested comparatively the epileptogenic and neurotoxic effects of PLPGH, TSC and MPA, administered by microdialysis in the hippocampus of adult awake rats. Cortical EEG and motor behavior were analyzed during the next 2h, and aspartate, glutamate and GABA were measured by HPLC in the microdialysis-collected fractions. Twenty-four hours after drug administration rats were fixed for histological analysis of the hippocampus. PLPGH or TSC did not affect the motor behavior, EEG or cellular morphology, although the extracellular concentration of GABA was decreased. In contrast, MPA produced intense wet-dog shakes, EEG epileptiform discharges, a >75% reduction of extracellular GABA levels and remarkable neurodegeneration of the CA1 region, with >80% neuronal loss. The systemic administration of the NMDA glutamate receptor antagonist MK-801 30 min before MPA did not prevent the MPA-induced epilepsy but significantly protected against its neurotoxic effect, reducing neuronal loss to <30%. We conclude that in adult awake rats, drugs acting on PLP availability have only a weak effect on GABA neurotransmission, whereas direct GAD inhibition produced by MPA induces hyperexcitation leading to epilepsy and hippocampal neurodegeneration. Because this degeneration was prevented by the blockade of NMDA receptors, we conclude that it is due to glutamate-mediated excitotoxicity consequent to disinhibition of the hippocampal excitatory circuits. PMID:26354164

  20. Cardiovascular Alterations during the Interictal Period in Awake and Pithed Amygdala-Kindled Rats.

    PubMed

    Ruiz-Salinas, Inna; Rocha, Luisa; Marichal-Cancino, Bruno A; Villalón, Carlos M

    2016-08-01

    Epileptic seizures are often accompanied by increased sympathetic cardiovascular activity (even interictally), but it remains unknown whether this increased activity is of central and/or peripheral origin. Hence, this study investigated the cardiovascular alterations produced by amygdala kindling in awake and pithed Wistar rats. Blood pressure (BP) and heart rate (HR) were initially recorded by tail cuff plethysmography in awake control, sham-operated and amygdala-kindled rats before and 24 hr after the kindling process. The after-discharge threshold (ADT) was measured under different conditions to correlate brain excitability with BP and HR in kindled rats. Twenty-four hours after the last kindling seizure, (i) HR, systolic and diastolic BP were increased and (ii) only higher HR values correlated with lower ADT values. Forty-eight hr after the last kindled seizure, all rats were pithed and prepared for analysing the tachycardic, vasopressor and vasodepressor responses by (i) stimulation of the sympathetic or sensory vasodepressor CGRPergic out-flows (stimulus-response curves, S-R curves) and (ii) intravenous injections of noradrenaline or α-CGRP (dose-response curves, D-R curves). Interestingly, (i) the tachycardic S-R and D-R curves were attenuated, whilst the CGRPergic S-R and D-R curves were potentiated in kindled rats, and (ii) the vasopressor noradrenergic S-R and D-R curves were not significantly different in all groups. Therefore, the kindling process may be associated with overstimulation in the central sympathetic and sensory out-flows interictally, producing (i) peripheral attenuation of cardiac sympathetic out-flow and β-adrenoceptor activity and (ii) peripheral potentiation of vasodepressor sensory CGRPergic out-flow and CGRP receptor activity. PMID:26797796

  1. Long-term facilitation of ventilation following repeated hypoxic episodes in awake goats.

    PubMed Central

    Turner, D L; Mitchell, G S

    1997-01-01

    1. This study tested two hypotheses: (1) that episodic hypoxia elicits long-term facilitation (LTF) in respiratory neurons that is manifest as an increase in ventilation in awake goats; and (2) that LTF causes complex changes in respiratory pattern which are responsible for the increase in ventilation. 2. Each goat participated in two protocols. In the first, inspired gas mixtures were alternated between isocapnic normoxia and hypoxia (arterial partial pressure of oxygen, Pa,O2 = 47 mmHg) for ten cycles. Each hypoxic episode lasted 3 min and normoxic intervals were 5 min. Ventilatory variables were measured during the last minute of each episode and periodically for up to 1 h following the last hypoxic episode. The second, sham protocol was undertaken at least 2 weeks later and was identical to the first, except that isocapnic hypoxia was replaced with normoxia. 3. Inspired ventilation (VI) increased during the first isocapnic hypoxic episode and reached progressively higher levels in subsequent hypoxic episodes. VI also increased progressively among normoxic intervals, such that by the tenth normoxic interval, it had increased 68% relative to the comparable sham value (P < 0.05). Respiratory frequency (FR), tidal volume and mean inspiratory flow all contributed to the augmented VI during both isocapnic normoxia and hypoxia. The increase in VI lasted up to 40 min after the final hypoxic episode, with an increased FR making the greatest contribution. The persistent increase in VI strongly suggests that episodic hypoxia elicits LTF in respiratory neurons in the awake goat. Complex changes in respiratory pattern underpin the ventilatory manifestation of LTF. PMID:9080380

  2. Continuous thoracic epidural anesthesia induces segmental sympathetic block in the awake rat.

    PubMed

    Freise, Hendrik; Anthonsen, Sören; Fischer, Lars G; Van Aken, Hugo K; Sielenkämper, Andreas W

    2005-01-01

    Thoracic epidural anesthesia (TEA) is used increasingly in critical care, especially for cardiac and intestinal sympathetic block. In this study we evaluated cardiorespiratory function and sympathetic activity in a new model of continuous TEA in awake rats. Thirteen rats received epidural saline control (CON) or bupivacaine 0.5% epidural infusion (EPI) at 15 microl/h for 2 h on day 1 and day 3. Mean arterial blood pressure, heart rate, respiration rate, arterial PCO2, and motor score were recorded at baseline and after 30, 60, 90, and 120 min. Skin temperature was measured at front paws, high-thoracic, mid-thoracic, and low-thoracic, hind paws, and the proximal and distal tail. Changes in sympathetic activity were assessed by skin temperature changes from baseline (DeltaT). In the EPI group, hemodynamics and respiration remained unchanged and only mild motor deficits occurred. DeltaT in thoracic segments was higher in the EPI than in the CON group (P <0.001 at all times at high-thoracic, mid-thoracic, and low-thoracic segments). Skin temperature decreased in the distal tail in the EPI group, e.g., after 90 min DeltaT=-0.86 +/- 0.25 degrees C (EPI) versus 0.4 +/- 0.12 degrees C (CON) (P <0.05 at 60, 90, and 120 min). DeltaT on day 3 was comparable to day 1. TEA induced stable segmental sympathetic block without cardiorespiratory and motor side effects in awake rats. This new technique may be applied in prolonged models of critical illness. PMID:15616087

  3. [Insulin therapy of diabetes].

    PubMed

    Lechleitner, Monika; Roden, Michael; Weitgasser, Raimund; Ludvik, Bernhard; Fasching, Peter; Hoppichler, Friedrich; Kautzky-Willer, Alexandra; Schernthaner, Guntram; Prager, Rudolf; Wascher, Thomas C

    2016-04-01

    Hyperglycemia contributes to morbidity and mortality in patients with diabetes. Thus, reaching treatment targets with regard to control of glycemia is a central goal in the therapy of diabetic patients. The present article represents the recommendations of the Austrian Diabetes Association for the practical use of insulin according to current scientific evidence and clinical studies. PMID:27052221

  4. Insulin Resistance and Prediabetes

    MedlinePlus

    ... to be used in most health care providers' offices. The clamp is a research tool used by scientists to learn more about glucose metabolism. Research has shown that if blood tests indicate prediabetes, insulin ... care provider's office or commercial facility and sending the sample to ...

  5. New Insulin Delivery Recommendations.

    PubMed

    Frid, Anders H; Kreugel, Gillian; Grassi, Giorgio; Halimi, Serge; Hicks, Debbie; Hirsch, Laurence J; Smith, Mike J; Wellhoener, Regine; Bode, Bruce W; Hirsch, Irl B; Kalra, Sanjay; Ji, Linong; Strauss, Kenneth W

    2016-09-01

    Many primary care professionals manage injection or infusion therapies in patients with diabetes. Few published guidelines have been available to help such professionals and their patients manage these therapies. Herein, we present new, practical, and comprehensive recommendations for diabetes injections and infusions. These recommendations were informed by a large international survey of current practice and were written and vetted by 183 diabetes experts from 54 countries at the Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop held in Rome, Italy, in 2015. Recommendations are organized around the themes of anatomy, physiology, pathology, psychology, and technology. Key among the recommendations are that the shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and, therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them; effective long-term therapy with insulin is critically dependent on addressing psychological hurdles upstream, even before insulin has been started; inappropriate disposal of used sharps poses a risk of infection with blood-borne pathogens; and mitigation is possible with proper training, effective disposal strategies, and the use of safety devices. Adherence to these new recommendations should lead to more effective therapies, improved outcomes, and lower costs for patients with diabetes. PMID:27594187

  6. Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat Alzheimer's disease.

    PubMed

    Zhang, Chi; Chen, Jie; Feng, Chengcheng; Shao, Xiayan; Liu, Qingfeng; Zhang, Qizhi; Pang, Zhiqing; Jiang, Xinguo

    2014-01-30

    Disabilities caused by neurodegeneration have become one of the main causes of mortality in elderly population, with drug distribution to the brain remaining one of the most difficult challenges in the treatment of the central nervous system (CNS) diseases due to the existence of blood-brain barrier. Lectins modified polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticles could enhance the drug delivery to the brain following intranasal administration. In this study, basic fibroblast growth factor (bFGF) was entrapped in nanoparticles conjugated with Solanum tuberosum lectin (STL), which selectively binds to N-acetylglucosamine on the nasal epithelial membrane for its brain delivery. The resulting nanoparticles had uniform particle size and negative zeta potential. The brain distribution of the formulations following intranasal administration was assessed using radioisotopic tracing method. The areas under the concentration-time curve of (125)I-bFGF in the olfactory bulb, cerebrum, and cerebellum of rats following nasal application of STL modified nanoparticles (STL-bFGF-NP) were 1.79-5.17 folds of that of rats with intravenous administration, and 0.61-2.21 and 0.19-1.07 folds higher compared with intranasal solution and unmodified nanoparticles, respectively. Neuroprotective effect was evaluated using Mirror water maze task in rats with intracerebroventricular injection of β-amyloid25-35 and ibotenic acid. The spatial learning and memory of Alzheimer's disease (AD) rats in STL-bFGF-NP group were significantly improved compared with AD model group, and were also better than other preparations. The results were consistent with the value of choline acetyltransferase activity of rat hippocampus as well as the histological observations of rat hippocampal region. The histopathology assays also confirmed the in vivo safety of STL-bFGF-NP. These results clearly indicated that STL-NP was a promising drug delivery system for peptide and protein drugs such as

  7. Intrinsic intranasal chemosensory brain networks shown by resting-state functional MRI.

    PubMed

    Tobia, Michael J; Yang, Qing X; Karunanayaka, Prasanna

    2016-05-01

    The human brain is organized into functional networks for sensory-motor and cognitive processing. Intrinsic networks are detectable in the absence of stimulation or task demands, whereas extrinsic networks are detectable when stimulated by sensory or cognitive demands. Intranasal chemosensory processing relies on two dissociable networks for processing incoming trigeminal and olfactory stimulation, but it is not known whether these networks are intrinsically organized. The aim of this study was to identify whether brain networks for intranasal chemosensory processing are detectable in functional connectivity resting-state functional MRI (fMRI). Sixteen healthy adults participated in a 5-min resting-state fMRI study. Functional connectivity seeds were defined from coordinates that anchor olfactory (i.e. bilateral piriform and orbitofrontal cortex) and trigeminal (bilateral anterior insula and cingulate cortex) networks in published task activation studies, and the resulting networks were thresholded at P less than 0.001. The olfactory network showed extended functional connectivity to the thalamus, medial prefrontal cortex, caudate, nucleus accumbens, parahippocampal gyrus, and hippocampus. The trigeminal network showed extended functional connectivity to the precuneus, thalamus, caudate, brainstem, and cerebellum. Both networks overlapped in the thalamus, caudate, medial prefrontal cortex, and insula. These results show that brain networks for intranasal chemosensory processing are intrinsically organized, not just extrinsically instantiated in response to task demands, and resemble networks for processing olfactory and trigeminal stimulation. As such, it may be possible to study the functional organization and dynamics of the olfactory network in resting-state fMRI as well as its implications for aging and disease. PMID:27031873

  8. Intranasal oxytocin administration in relationship to social behaviour in domestic pigs.

    PubMed

    Camerlink, Irene; Reimert, Inonge; Bolhuis, J Elizabeth

    2016-09-01

    Intranasal administration of oxytocin has been shown to alter positive and negative social behaviour. Positive social behaviour in pigs (Sus scrofa) may be expressed through gentle social nosing, and greater insight in the specific expression hereof might contribute to the current search for positive indicators of animal welfare. We investigated whether oxytocin alters social nosing and whether this is specific to nose-body or nose-nose contact. Sixty-four focal female pigs of 13weeks of age (out of 16 groups) were given oxytocin (24IU dose) and saline (placebo) intranasally once on two consecutive days. The frequency of nose-to-nose contact and nose-to-body contact was recorded upon pigs' return in the home pen after being for 10min located in a separate area near pen mates undergoing a positive or negative event or not. The effect of intranasal oxytocin depended on the social context in which pigs were studied. Control pigs, which were not exposed to positively or negatively aroused pen mates, gave and received less nose-nose contact after oxytocin administration than after saline administration. Pigs exposed to positively aroused pen mates also tended to give less nose contact when given oxytocin compared to saline, whereas pigs exposed to negatively aroused pen mates and administered oxytocin tended to receive more nose contact. Nose-body contact was lowest in groups of negative social context, suggesting an effect of emotional state on social nosing. In contrast to nose-nose contact, nose-body contact was unaffected by oxytocin treatment. The relationship between social nosing and oxytocin merits further research. PMID:27143253

  9. Effect of intranasal manganese administration on neurotransmission and spatial learning in rats

    SciTech Connect

    Blecharz-Klin, Kamilla; Piechal, Agnieszka; Joniec-Maciejak, Ilona; Pyrzanowska, Justyna; Widy-Tyszkiewicz, Ewa

    2012-11-15

    The effect of intranasal manganese chloride (MnCl{sub 2}·4H{sub 2}O) exposure on spatial learning, memory and motor activity was estimated in Morris water maze task in adult rats. Three-month-old male Wistar rats received for 2 weeks MnCl{sub 2}·4H{sub 2}O at two doses the following: 0.2 mg/kg b.w. (Mn0.2) or 0.8 mg/kg b.w. (Mn0.8) per day. Control (Con) and manganese-exposed groups were observed for behavioral performance and learning in water maze. ANOVA for repeated measurements did not show any significant differences in acquisition in the water maze between the groups. However, the results of the probe trial on day 5, exhibited spatial memory deficits following manganese treatment. After completion of the behavioral experiment, the regional brain concentrations of neurotransmitters and their metabolites were determined via HPLC in selected brain regions, i.e. prefrontal cortex, hippocampus and striatum. ANOVA demonstrated significant differences in the content of monoamines and metabolites between the treatment groups compared to the controls. Negative correlations between platform crossings on the previous platform position in Southeast (SE) quadrant during the probe trial and neurotransmitter turnover suggest that impairment of spatial memory and cognitive performance after manganese (Mn) treatment is associated with modulation of the serotonergic, noradrenergic and dopaminergic neurotransmission in the brain. These findings show that intranasally applied Mn can impair spatial memory with significant changes in the tissue level and metabolism of monoamines in several brain regions. -- Highlights: ► Intranasal exposure to manganese in rats impairs spatial memory in the water maze. ► Regional changes in levels of neurotransmitters in the brain have been identified. ► Cognitive disorder correlates with modulation of 5-HT, NA and DA neurotransmission.

  10. Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice

    PubMed Central

    Chen, Dongdong; Lee, Jinhwan; Gu, Xiaohuan; Wei, Ling

    2015-01-01

    Apelin is a peptide originally isolated from bovine stomach tissue extracts and identified as an endogenous ligand of the APJ receptor; recent work showed that apelin ameliorates the ischemic injury in the heart and the brain. Being an analogue to the angiotensin II receptor, the apelin/APJ signaling may mediate angiogenesis process. We explored the noninvasive intranasal brain delivery method and investigated therapeutic effects of apelin-13 in a focal ischemic stroke model of mice. Intranasal administration of apelin-13 (4 mg/kg) was given 30 min after the onset of stroke and repeated once daily. Three days after stroke, mice received apelin-13 had significantly reduced infarct volume and less neuronal death in the penumbra. Western blot analyses showed upregulated levels of apelin, apelin receptor APLNR, and Bcl-2 and decreased caspase-3 activation in the apelin-13-treated brain. The proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1β, and chemokine monocyte chemoattractant protein-1 mRNA increased in the ischemic brain, which were significantly attenuated by apelin-13. Apelin-13 remarkably reduced microglia recruitment and activation in the penumbra according to morphological features of Iba-1-positive cells 3 days after ischemia. Apelin-13 significantly increased the expression of angiogenic factor vascular endothelial growth factor and matrix metalloproteinase-9 14 days after stroke. Angiogenesis illustrated by collagen IV + /5-bromo-2′-deoxyuridin + colabeled cells was significantly increased by the apelin-13 treatment 21 days after stroke. Finally, apelin-13 promoted the local cerebral blood flow restoration and long-term functional recovery. This study demonstrates a noninvasive intranasal delivery of apelin-13 after stroke, suggesting that the reduced inflammatory activities, decreased cell death, and increased angiogenesis contribute to the therapeutic benefits of apelin-13. PMID:26391329

  11. Comparison of preanesthetic sedation in pediatric patients with oral and intranasal midazolam

    PubMed Central

    Deshmukh, Purvashree Vijay; Kulkarni, Sadhana Sudhir; Parchandekar, Mukund Kachru; Sikchi, Sneha Purshottam

    2016-01-01

    Background and Aims: Preoperative anxiety in children leading to postoperative negative changes and long-term behavioral problems needs better preanesthetic sedation. Across the world, midazolam is the most commonly used premedicant in pediatric patients. The fact that no single route has achieved universal acceptance for its administration suggests that each route has its own merits and demerits. This study compares oral midazolam syrup and intranasal midazolam spray as painless and needleless systems of drug administration for preanesthetic sedation in children. Material and Methods: With randomization, Group O (30 children): Received oral midazolam syrup 0.5 mg/kg and Group IN (30 children): Received intranasal midazolam spray 0.2 mg/kg. Every child was observed for acceptance of drug, response to drug administration, sedation scale, separation score, acceptance to mask, recovery score and side effects of drug. Data were analyzed using Student's t-test, standard error of the difference between two means and Chi-square test. Results: In Group O and IN, 15/30 children (50%) and 7/30 children (23%) accepted drug easily (P < 0.05); 4/22 children (18%) in Group O and 11/20 children (55%) in Group IN cried after drug administration (P < 0.05). In both the groups, sedation at 20 min after premedication (Group O [80%] 24/30 vs. Group IN [77%] 23/30), parental separation and acceptance to mask were comparable (P > 0.05); 12/30 children (40%) in Group IN showed transient nasal irritation. Conclusion: Oral midazolam and intranasal midazolam spray produce similar anxiolysis and sedation, but acceptance of drug and response to drug administration is better with oral route. PMID:27625485

  12. Differential effects of intranasal oxytocin on sexual experiences and partner interactions in couples.

    PubMed

    Behnia, Behnoush; Heinrichs, Markus; Bergmann, Wiebke; Jung, Stefanie; Germann, Janine; Schedlowski, Manfred; Hartmann, Uwe; Kruger, Tillmann H C

    2014-03-01

    Knowledge about the effects of the neuropeptide oxytocin (OXT) on human sexual behaviors and partner interactions remains limited. Based on our previous studies, we hypothesize that OXT should be able to positively influence parameters of sexual function and couple interactions. Employing a naturalistic setting involving 29 healthy heterosexual couples (n=58 participants), we analyzed the acute effects of intranasally administered OXT (24IU) on sexual drive, arousal, orgasm and refractory aspects of sexual behavior together with partner interactions. Data were assessed by psychometric instruments (Acute Sexual Experiences Scale, Arizona Sexual Experience Scale) as well as biomarkers, such as cortisol, α-amylase and heart rate. Intranasal OXT administration did not alter "classical" parameters of sexual function, such as sexual drive, arousal or penile erection and lubrication. However, analysis of variance and a hierarchical linear model (HLM) revealed specific effects related to the orgasmic/post-orgasmic interval as well as parameters of partner interactions. According to HLM analysis, OXT increased the intensity of orgasm, contentment after sexual intercourse and the effect of study participation. According to ANOVA analysis, these effects were more pronounced in men. Men additionally indicated higher levels of sexual satiety after sexual intercourse with OXT administration. Women felt more relaxed and subgroups indicated better abilities to share sexual desires or to empathize with their partners. The effect sizes were small to moderate. Biomarkers indicated moderate psychophysiological activation but were not affected by OXT, gender or method of contraception. Using a naturalistic setting, intranasal OXT administration in couples exerted differential effects on parameters of sexual function and partner interactions. These results warrant further investigations, including subjects with sexual and relationship problems. PMID:24503174

  13. Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis After Ischemic Stroke in Mice.

    PubMed

    Chen, Dongdong; Lee, Jinhwan; Gu, Xiaohuan; Wei, Ling; Yu, Shan Ping

    2015-01-01

    Apelin is a peptide originally isolated from bovine stomach tissue extracts and identified as an endogenous ligand of the APJ receptor; recent work showed that apelin ameliorates the ischemic injury in the heart and the brain. Being an analogue to the angiotensin II receptor, the apelin/APJ signaling may mediate angiogenesis process. We explored the noninvasive intranasal brain delivery method and investigated therapeutic effects of apelin-13 in a focal ischemic stroke model of mice. Intranasal administration of apelin-13 (4 mg/kg) was given 30 min after the onset of stroke and repeated once daily. Three days after stroke, mice received apelin-13 had significantly reduced infarct volume and less neuronal death in the penumbra. Western blot analyses showed upregulated levels of apelin, apelin receptor APLNR, and Bcl-2 and decreased caspase-3 activation in the apelin-13-treated brain. The proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1β, and chemokine monocyte chemoattractant protein-1 mRNA increased in the ischemic brain, which were significantly attenuated by apelin-13. Apelin-13 remarkably reduced microglia recruitment and activation in the penumbra according to morphological features of Iba-1-positive cells 3 days after ischemia. Apelin-13 significantly increased the expression of angiogenic factor vascular endothelial growth factor and matrix metalloproteinase-9 14 days after stroke. Angiogenesis illustrated by collagen IV + /5-bromo-2'-deoxyuridin + colabeled cells was significantly increased by the apelin-13 treatment 21 days after stroke. Finally, apelin-13 promoted the local cerebral blood flow restoration and long-term functional recovery. This study demonstrates a noninvasive intranasal delivery of apelin-13 after stroke, suggesting that the reduced inflammatory activities, decreased cell death, and increased angiogenesis contribute to the therapeutic benefits of apelin-13. PMID:26391329

  14. Intranasal Delivery of E-Selectin Reduces Atherosclerosis in ApoE−/− Mice

    PubMed Central

    Li, Xinhui; Johnson, Kory R.; Bryant, Mark; Elkahloun, Abdel G.; Amar, Marcelo; Remaley, Alan T.; De Silva, Ranil; Hallenbeck, John M.; Quandt, Jacqueline A.

    2011-01-01

    Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or “tolerogenic” responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE−/− mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE−/− mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke. PMID:21701687

  15. Intranasal immunogenicity and adjuvanticity of site-directed mutant derivatives of cholera toxin.

    PubMed

    Douce, G; Fontana, M; Pizza, M; Rappuoli, R; Dougan, G

    1997-07-01

    Genetically modified derivatives of cholera toxin (CT), harboring a single amino acid substitution in and around the NAD binding cleft of the A subunit, were isolated following site-directed mutagenesis of the ctxA gene. Two mutants of CT, designated CTS106 (with a proline-to-serine change at position 106) and CTK63 (with a serine-to-lysine change at position 63), were found to have substantially reduced ADP-ribosyltransferase activity and toxicity; CTK63 was completely nontoxic in all assays, whereas CTS106 was 10(4) times less toxic than wild-type CT. The mucosal adjuvanticity and immunogenicity of derivatives of CT were assessed by intranasal immunization of mice, with either ovalbumin or fragment C of tetanus toxin as a bystander antigen. Mice immunized with wild-type CT produced both local (immunoglobulin A in mucosal washes) and systemic immune responses to both CT and bystander antigens. CTS106 showed good local and systemic responses to bystander proteins and to itself. Interestingly, mice immunized with the nontoxic derivative of CT, CTK63, generated weak immune responses to the bystander antigens which were similar to those achieved when CT B subunit was used as an adjuvant. In parallel experiments, an equivalent nontoxic mutant of the Escherichia coli heat-labile enterotoxin, LTK63 (with a serine-to-lysine change at position 63), was tested (9). In contrast to CTK63, LTK63 was found to be more immunogenic and a better intranasal adjuvant than recombinant heat-labile enterotoxin B subunit or CTK63. This information, together with data on immunoglobulin subclass responses, suggests that although highly homologous, CT and heat-labile enterotoxin should not be considered biologically identical in terms of their ability to act as intranasal adjuvants. PMID:9199455

  16. Selective Insulin Resistance in Adipocytes*

    PubMed Central

    Tan, Shi-Xiong; Fisher-Wellman, Kelsey H.; Fazakerley, Daniel J.; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C.; Coster, Adelle C. F.; Stöckli, Jacqueline; James, David E.

    2015-01-01

    Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. PMID:25720492

  17. Adipocyte lipolysis and insulin resistance.

    PubMed

    Morigny, Pauline; Houssier, Marianne; Mouisel, Etienne; Langin, Dominique

    2016-06-01

    Obesity-induced insulin resistance is a major risk factor for the development of type 2 diabetes. Basal fat cell lipolysis (i.e., fat cell triacylglycerol breakdown into fatty acids and glycerol in the absence of stimulatory factors) is elevated during obesity and is closely associated with insulin resistance. Inhibition of adipocyte lipolysis may therefore be a promising therapeutic strategy for treating insulin resistance and preventing obesity-associated type 2 diabetes. In this review, we explore the relationship between adipose lipolysis and insulin sensitivity. After providing an overview of the components of fat cell lipolytic machinery, we describe the hypotheses that may support the causality between lipolysis and insulin resistance. Excessive circulating fatty acids may ectopically accumulate in insulin-sensitive tissues and impair insulin action. Increased basal lipolysis may also modify the secretory profile of adipose tissue, influencing whole body insulin sensitivity. Finally, excessive fatty acid release may also worsen adipose tissue inflammation, a well-known parameter contributing to insulin resistance. Partial genetic or pharmacologic inhibition of fat cell lipases in mice as well as short term clinical trials using antilipolytic drugs in humans support the benefit of fat cell lipolysis inhibition on systemic insulin sensitivity and glucose metabolism, which occurs without an increase of fat mass. Modulation of fatty acid fluxes and, putatively, of fat cell secretory pattern may explain the amelioration of insulin sensitivity whereas changes in adipose tissue immune response do not seem involved. PMID:26542285

  18. Transdermal Insulin Delivery Using Microdermabrasion

    PubMed Central

    Andrews, Samantha; Lee, Jeong Woo; Choi, Seong-O

    2011-01-01

    Purpose Transdermal insulin delivery is an attractive needle-free alternative to subcutaneous injection conventionally used to treat diabetes. However, skin’s barrier properties prevent insulin permeation at useful levels. Methods We investigated whether microdermabrasion can selectively remove skin’s surface layers to increase skin permeability as a method to administer insulin to diabetic rats. We further assessed the relative roles of stratum corneum and viable epidermis as barriers to insulin delivery. Results Pretreatment of skin with microdermabrasion to selectively remove stratum corneum did not have a significant effect on insulin delivery or reduction in blood glucose level (BGL). Removal of full epidermis by microdermabrasion significantly reduced BGL, similar to the positive control involving subcutaneous injection of 0.1U insulin. Significant pharmacokinetic differences between microdermabrasion and subcutaneous injection were faster time to peak insulin concentration after injection and larger peak insulin concentration and area-under-the-curve after microdermabrasion. Conclusions Microdermabrasion can increase skin permeability to insulin at levels sufficient to reduce BGL. Viable epidermis is a barrier to insulin delivery such that removal of full epidermis enables significantly more insulin delivery than removal of stratum corneum alone. PMID:21499837

  19. Evidence against extrapancreatic insulin synthesis.

    PubMed Central

    Eng, J; Yalow, R S

    1981-01-01

    Labeled and unlabeled insulin in acid/ethanol tissue extracts can be concentrated up to 100-fold by using a hydrophobic adsorption technique. After adsorption to and elution from an octadecylsilyl silica column, insulin is recovered in yields greater than 75%. By using this method of concentration, insulin in brain tissues of three of four fed rats and one rabbit was found to be less than 20% of plasma concentration. The kidney is the only extrapancreatic organ in which insulin is observed to be markedly above plasma levels. Porcine-insulin-like material was not detectable in guinea pig tissues (less than 0.02 ng/g). It is concluded that insulin is not synthesized in brain or other extrapancreatic tissues and that other mammalian insulins are not found in guinea pig tissues. PMID:6270683

  20. Insulin degludec for diabetes mellitus.

    PubMed

    2013-07-01

    Over the last few years there has been a steady increase in the number of prescriptions dispensed in primary care for intermediate and long-acting insulin analogues and a reduction in prescriptions for biphasic isophane insulin. For example, in England, the volume of intermediate and long-acting insulin analogues in general practice has risen from approximately 650,000 prescriptions per quarter in 2007 to over 850,000 per quarter in 2012.(1) ▾Insulin degludec (Tresiba, Novo Nordisk) is a new long acting basal insulin analogue for the management of diabetes mellitus in adults.(2) Two strengths of insulin degludec (100 units/mL and 200 units/mL) were launched in the UK in February 2013. Here we discuss evidence for the effectiveness and safety of insulin degludec. PMID:23842634

  1. [Current concept of insulin therapy intensification, and the role of human regular insulin and rapid-acting insulin analogs in insulin treatment].

    PubMed

    Hamaguchi, Tomoya; Sadahiro, Katsuhiko; Satoh, Tomomi

    2015-03-01

    The evolution of insulin therapy from animal insulin to recombinant human regular insulin has improved diabetes treatment. Generating of rapid-acting insulin analogs, mimicking physiologic insulin action enables us to provide better control of post-prandial glucose level and lower incidence of hypoglycemia compared with human regular insulin. These rapid-acting insulin analogs show lower susceptibility of insulin precipitation and catheter occlusions, and are suitable for insulin pump therapy of continuous subcutaneous insulin infusion. Insulin lispro and insulin aspart are also applicable for diabetic patients with pregnancy, requiring excellent glycemic control. In some studies, stepwise addition of prandial insulin, as well as full basal-bolus regimen can improve glycemic control with less hypoglycemia. Treatment intensification with rapid-acting insulin analogs may offer a proper method to reach glycemic goals. PMID:25812371

  2. Intraoperative acridine orange photodynamic therapy and cribriform electron-beam irradiation for canine intranasal tumors: A pilot study

    PubMed Central

    Maruo, Takuya; Nagata, Koichi; Fukuyama, Yasuhiro; Nemoto, Yuki; Kawarai, Shinpei; Fujita, Yukihiro; Nakayama, Tomohiro

    2015-01-01

    Untreated canine intranasal tumors carry a poor prognosis. We retrospectively evaluated the efficacy of marginal tumor resection in combination with intraoperative acridine orange (AO) photodynamic therapy (PDT) and 1 fraction of 5 Gy megavoltage irradiation for canine intranasal malignant tumors. When cribriform plate invasion or turbinate destruction around the cribriform plate was present, an additional fraction of 20 Gy was delivered with an electron beam during surgery. The study included 6 dogs, 2 of which were classified as stage I, 1 as stage II, and 3 as stage IV. The median local disease-free survival time and overall survival after the treatment were 8.5 and 13 months, respectively. Recurrence was noted in 2 of the 6 dogs after 4 and 7 months. Adverse events were mild (subcutaneous emphysema in 1 case, and rhinitis in 3 cases). Combination AO therapy may increase the tumor control time of dogs with marginally resectable intranasal malignant tumors. PMID:26663917

  3. Brain delivery of intranasal in situ gel of nanoparticulated polymeric carriers containing antidepressant drug: behavioral and biochemical assessment.

    PubMed

    Kaur, Prabhjot; Garg, Tarun; Vaidya, Bhuvaneshwar; Prakash, Atish; Rath, Goutam; Goyal, Amit K

    2015-04-01

    This study was aimed for brain delivery of Tramadol HCl (centrally acting synthetic opioid) following intranasal administration for treatment of depression. Chitosan nanoparticles (NPs) were prepared by ionic gelation method followed by the addition of developed NPs with in the Pluronic and HPMC-based mucoadhesive thermo-reversible gel. Developed formulation optimized based on the various parameters such as particle size, entrapment efficiency, in vitro release study. Depression induction was done by forced swim test and evaluated by various behavioral and biochemical parameters. Furthermore, results showed significantly increased in locomotors activity, body weight as compared to control group. It also showed alteration in biochemical parameters such glutathione level and catalase levels significantly increased other than lipid peroxidation and nitrite level was found to be decreased after intranasal administration of formulation. Thus, intranasal TRM HCl NP-loaded in situ gel was found to be a promising formulation for the treatment of depression. PMID:25539073

  4. No relevant modulation of TRPV1-mediated trigeminal pain by intranasal carbon dioxide in healthy humans

    PubMed Central

    2013-01-01

    Background Nasal insufflation of CO2 has been shown to exert antinociceptive respectively antihyperalgesic effects in animal pain models using topical capsaicin with activation of TRPV1-receptor positive nociceptive neurons. Clinical benefit from CO2 inhalation in patients with craniofacial pain caused by a putative activation of TRPV1 receptor positive trigeminal neurons has also been reported. These effects are probably mediated via an activation of TRPV1 receptor - positive neurons in the nasal mucosa with subsequent central inhibitory effects (such as conditioned pain modulation). In this study, we aimed to examine the effects of intranasal CO2 on a human model of craniofacial pain elicited by nasal application of capsaicin. Methods In a first experiment, 48 healthy volunteers without previous craniofacial pain received intranasal capsaicin to provoke trigeminal pain elicited by activation of TRVP1 positive nociceptive neurons. Then, CO2 or air was insufflated alternatingly into the nasal cavity at a flow rate of 1 l/min for 60 sec each. In the subsequent experiment, all participants were randomized into 2 groups of 24 each and received either continuous nasal insufflation of CO2 or placebo for 18:40 min after nociceptive stimulation with intranasal capsaicin. In both experiments, pain was rated on a numerical rating scale every 60 sec. Results Contrary to previous animal studies, the effects of CO2 on experimental trigeminal pain were only marginal. In the first experiment, CO2 reduced pain ratings only minimally by 5.3% compared to air if given alternatingly with significant results for the main factor GROUP (F1,47 = 4.438; p = 0.041) and the interaction term TIME*GROUP (F2.6,121.2 = 3.3; p = 0.029) in the repeated-measures ANOVA. However, these effects were abrogated after continuous insufflation of CO2 or placebo with no significant changes for the main factors or the interaction term. Conclusions Although mild modulatory effects of low

  5. Cationic liposome-hyaluronic acid hybrid nanoparticles for intranasal vaccination with subunit antigens

    PubMed Central

    Ochyl, Lukasz J.; Akerberg, Jonathan; Moon, James J.

    2015-01-01

    Here we report the development of a new cationic liposome-hyaluronic acid (HA) hybrid nanoparticle (NP) system and present our characterization of these NPs as an intranasal vaccine platform using a model antigen and F1-V, a candidate recombinant antigen for Yersinia pestis, the causative agent of plague. Incubation of cationic liposomes composed of DOTAP and DOPE with anionic HA biopolymer led to efficient ionic complexation and formation of homogenous liposome-polymer hybrid NPs, as evidenced by fluorescence resonance energy transfer, dynamic light scattering, and nanoparticle tracking analyses. Incorporation of cationic liposomes with thiolated HA allowed for facile surface decoration of NPs with thiol-PEG, resulting in the formation of DOTAP/HA core-PEG shell nanostructures. These NPs, termed DOTAP-HA NPs, exhibited improved colloidal stability and prolonged antigen release. In addition, cytotoxicity associated with DOTAP liposomes (LC50 ~0.2 mg/ml) was significantly reduced by at least 20-fold with DOTAP-HA NPs (LC50 > 4 mg/ml), as measured with bone marrow dendritic cells (BMDCs). Furthermore, NPs co-loaded with ovalbumin (OVA) and a molecular adjuvant, monophosphoryl lipid A (MPLA) promoted BMDC maturation and upregulation of co-stimulatory markers, including CD40, CD86, and MHC-II, and C57BL/6 mice vaccinated with NPs via intranasal route generated robust OVA-specific CD8+ T cell and antibody responses. Importantly, intranasal vaccination with NPs co-loaded with F1-V and MPLA induced potent humoral immune responses with 11-, 23-, and 15-fold increases in F1-V-specific total IgG, IgG1, and IgG2c titers in immune sera by day 77, respectively, and induced balanced Th1/Th2 humoral immune responses, compared with the lack of sero-conversion in mice immunized with the equivalent doses of soluble F1-V vaccine. Overall, these results suggest that liposome-polymer hybrid NPs may serve as a promising vaccine delivery platform for intranasal vaccination against Y

  6. Intranasal administration of neuropeptide Y in man: systemic absorption and functional effects.

    PubMed Central

    Lacroix, J. S.; Ricchetti, A. P.; Morel, D.; Mossimann, B.; Waeber, B.; Grouzmann, E.

    1996-01-01

    1. Exogenous neuropeptide Y (NPY, 10 nmol, 50 nmol and 100 nmol) and its vehicle (NaCl 0.9%) were administered in a double blind, randomized and controlled manner by intranasal spray in 7 healthy volunteers. Variations of plasma NPY concentration over time were measured during 120 min. Forty min after the administration of 50 nmol and 100 nmol of exogenous NPY, plasma NPY increased from 5.5 +/- 1.1 pM to 9.8 +/- 2.3 pM (P < 0.05) and from 9.06 +/- 5.1 pM to 20.8 +/- 6.16 pM (P < 0.001), respectively. There was no significant modification of the mean arterial blood pressure and no subjective discomfort was reported. 2. Nasal airway resistance (NAR) was measured by anterior rhinomanometry and was reduced by 25 +/- 3% and 32 +/- 5% after the spray of 50 nmol and 100 nmol, respectively, for about 90 min. 3. Double-blind, randomized, placebo-controlled and 3-way crossover design experiments were performed in 8 healthy volunteers to evaluate the influence of intranasal pretreatment with NPY (20 nmol) and the mixed alpha 1/alpha 2-adrenoceptor agonist oxymetazoline (20 nmol) on the functional effects of subsequent local irritation evoked by capsaicin (3.3 x 10(-4) mol). Subjective evaluation of NAR and local intensity of discomfort were evaluated by means of a visual analogue scale. Nasal secretions were collected and objective NAR was recorded by rhinomanometry. 4. Subjective NAR, nasal secretions and rhinomanometry recordings were not modified by intranasal application of saline, NPY or oxymetazoline. Subjective nasal obstruction, local discomfort, nasal secretions and NAR increase evoked by capsaicin were markedly reduced by NPY pretreatment (P < 0.05) when compared to saline or oxymetazoline. 5. It is concluded that intranasal application of exogenous NPY has very low systemic absorption but induced long lasting nasal vasoconstriction without cardiovascular effects. Pretreatment of the nasal mucosa with exogenous NPY reduces both secretagogue and vasodilator responses

  7. Validation of a Best-Fit Pharmacokinetic Model for Scopolamine Disposition after Intranasal Administration

    NASA Technical Reports Server (NTRS)

    Wu, L.; Chow, D. S-L.; Tam, V.; Putcha, L.

    2015-01-01

    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Motion Sickness. Bioavailability and pharmacokinetics (PK) were determined per Investigative New Drug (IND) evaluation guidance by the Food and Drug Administration. Earlier, we reported the development of a PK model that can predict the relationship between plasma, saliva and urinary scopolamine (SCOP) concentrations using data collected from an IND clinical trial with INSCOP. This data analysis project is designed to validate the reported best fit PK model for SCOP by comparing observed and model predicted SCOP concentration-time profiles after administration of INSCOP.

  8. Locus coeruleus response to single-prolonged stress and early intervention with intranasal neuropeptide Y.

    PubMed

    Sabban, Esther L; Laukova, Marcela; Alaluf, Lishay G; Olsson, Emelie; Serova, Lidia I

    2015-12-01

    Dysregulation of the central noradrenergic system is a core feature of post-traumatic stress disorder (PTSD). Here, we examined molecular changes in locus coeruleus (LC) triggered by single-prolonged stress (SPS) PTSD model at a time when behavioral symptoms are manifested, and the effect of early intervention with intranasal neuropeptide Y (NPY). Immediately following SPS stressors, male SD rats were administered intranasal NPY (SPS/NPY) or vehicle (SPS/V). Seven days later, TH protein, but not mRNA, was elevated in LC only of the SPS/V group. Although 90% of TH positive cells expressed GR, its levels were unaltered. Compared to unstressed controls, LC of SPS/V, but not SPS/NPY, expressed less Y2 receptor mRNA with more CRHR1 mRNA in subset of animals, and elevated corticotropin-releasing hormone (CRH) in central nucleus of amygdala. Following testing for anxiety on elevated plus maze (EPM), there were significantly increased TH, DBH and NPY mRNAs in LC of SPS-treated, but not previously unstressed animals. Their levels highly correlated with each other but not with behavioral features on EPM. Thus, SPS triggers long-term noradrenergic activation and higher sensitivity to mild stressors, perhaps mediated by the up-regulation influence of amygdalar CRH input and down-regulation of Y2R presynaptic inhibition in LC. Results also demonstrate the therapeutic potential of early intervention with intranasal NPY for traumatic stress-elicited noradrenergic impairments. Single-prolonged stress (SPS)-triggered long-term changes in the locus coeruleus/norepinephrine (LC/NE) system with increased tyrosine hydroxylase (TH) protein and CRH receptor 1(CRHR1) mRNA and lower neuropeptide Y receptor 2 (Y2R) mRNA levels as well as elevated corticotropin-releasing hormone (CRH) in the central nucleus of amygdala (CeA) that were prevented by early intervention with intranasal neuropeptide Y (NPY). SPS treatment led to increased sensitivity of LC to mild stress of elevated plus maze

  9. Cationic liposome-hyaluronic acid hybrid nanoparticles for intranasal vaccination with subunit antigens.

    PubMed

    Fan, Yuchen; Sahdev, Preety; Ochyl, Lukasz J; J Akerberg, Jonathan; Moon, James J

    2015-06-28

    Here we report the development of a new cationic liposome-hyaluronic acid (HA) hybrid nanoparticle (NP) system and present our characterization of these NPs as an intranasal vaccine platform using a model antigen and F1-V, a candidate recombinant antigen for Yersinia pestis, the causative agent of plague. Incubation of cationic liposomes composed of DOTAP and DOPE with anionic HA biopolymer led to efficient ionic complexation and formation of homogenous liposome-polymer hybrid NPs, as evidenced by fluorescence resonance energy transfer, dynamic light scattering, and nanoparticle tracking analyses. Incorporation of cationic liposomes with thiolated HA allowed for facile surface decoration of NPs with thiol-PEG, resulting in the formation of DOTAP/HA core-PEG shell nanostructures. These NPs, termed DOTAP-HA NPs, exhibited improved colloidal stability and prolonged antigen release. In addition, cytotoxicity associated with DOTAP liposomes (LC50~0.2mg/ml) was significantly reduced by at least 20-fold with DOTAP-HA NPs (LC50>4mg/ml), as measured with bone marrow derived dendritic cells (BMDCs). Furthermore, NPs co-loaded with ovalbumin (OVA) and a molecular adjuvant, monophosphoryl lipid A (MPLA) promoted BMDC maturation and upregulation of co-stimulatory markers, including CD40, CD86, and MHC-II, and C57BL/6 mice vaccinated with NPs via intranasal route generated robust OVA-specific CD8(+) T cell and antibody responses. Importantly, intranasal vaccination with NPs co-loaded with F1-V and MPLA induced potent humoral immune responses with 11-, 23-, and 15-fold increases in F1-V-specific total IgG, IgG1, and IgG2c titers in immune sera by day 77, respectively, and induced balanced Th1/Th2 humoral immune responses, whereas mice immunized with the equivalent doses of soluble F1-V vaccine failed to achieve sero-conversion. Overall, these results suggest that liposome-polymer hybrid NPs may serve as a promising vaccine delivery platform for intranasal vaccination against Y

  10. Brief Report: Oxytocin Enhances Paternal Sensitivity to a Child with Autism--A Double-Blind Within-Subject Experiment with Intranasally Administered Oxytocin

    ERIC Educational Resources Information Center

    Naber, Fabienne B. A.; Poslawsky, Irina E.; van Ijzendoorn, Marinus H.; van Engeland, Herman; Bakermans-Kranenburg, Marian J.

    2013-01-01

    Oxytocin seems associated with parenting style, and experimental work showed positive effects of intranasally administered oxytocin on parenting style of fathers. Here, the first double-blind, placebo-controlled, within-subject experiment with intranasal oxytocin administration to fathers of children with autism spectrum disorder (ASD) is…

  11. A role for the intranasal formulation of azelastine hydrochloride/fluticasone propionate in the treatment of allergic rhinitis.

    PubMed

    Ridolo, Erminia; Montagni, Marcello; Melli, Valerie; Bonzano, Laura; Incorvaia, Cristoforo; Canonica, Giorgio Walter

    2015-01-01

    Rhinitis is a very common disease and represents a health problem for both children and adults globally. Rhinitis can be allergic or occur without any IgE-mediated sensitization to aeroallergens. Common symptoms include nasal congestion, postnasal drainage, nasal itching, rhinorrhea and sneezing. The most effective drugs for the treatment of rhinitis are antihistamines and topical glucocorticoids. MP29-02 (Dymista(®)) is a novel intranasal formulation combining the second-generation antihistamine, azelastine hydrochloride, with fluticasone propionate in a single device that has recently been developed. Here, we review the efficacy and safety profile of this intranasal formulation in the treatment of allergic and nonallergic rhinitis. PMID:25913181

  12. Insulin receptor in Drosophila melanogaster

    SciTech Connect

    Petruzzelli, L.; Herrera, R.; Rosen, O.

    1986-05-01

    A specific, high affinity insulin receptor is present in both adult Drosophila and in Drosophila embryos. Wheat germ lectin-enriched extracts of detergent-solubilized membranes from embryos and adults bind insulin with a K/sub d/ of 15 nM. Binding is specific for insulin; micromolar concentrations of proinsulin, IGFI, and IGFII are required to displace bound /sup 125/I-insulin. Insulin-dependent protein tyrosine kinase activity appears during embryogenesis. It is evident between 6 and 12 hours of development, peaks between 12 and 18 hours and falls in the adult. During 0-6 hours of embryogenesis, and in the adult, a specific protein band (Mr = 135,000) is crosslinked to /sup 125/I-insulin. During 6-12 and 12-18 hours of embryogenesis stages in which insulin-dependent protein tyrosine kinase is high, an additional band (Mr = 100,000) becomes crosslinked to /sup 125/I-insulin. Isolation and DNA sequence analysis of genomic clones encoding the Drosophila insulin receptor will be presented as will the characterization of insulin receptor mRNA's during development.

  13. Variability of NPH Insulin Preparations

    PubMed Central

    Belmonte, M. M.; Colle, E.; deBelle, R.; Murthy, D. Y. N.

    1971-01-01

    In 1968-69 certain juvenile diabetics receiving NPH insulin began having pre-breakfast glucosuria and mid-morning hypoglycemic reactions. A mail survey of our clinic population and a study done at the Quebec camp for diabetic children in 1969 revealed that certain lot numbers were associated with poor control and that a change to new lot numbers or alternate insulin preparations resulted in better control. “Suspect” insulin preparations and non-suspect insulins were given to newly diagnosed diabetics, and plasma insulin and glucose levels were measured over a 24-hour period. The data confirmed that the “suspect” insulins were causing early hypoglycemia and failing to control hyperglycemia during the latter hours of the 24-hour period. The lower glucose levels were associated with higher plasma insulin levels. The “suspect” insulins were further found to have elevated levels of free insulin in the supernatant fluid. The requirements for quality control of modified insulin preparations are reviewed and suggestions are offered for their improvement. PMID:5539004

  14. Pitfalls of Insulin Pump Clocks

    PubMed Central

    Reed, Amy J.

    2014-01-01

    The objective was to raise awareness about the importance of ensuring that insulin pumps internal clocks are set up correctly at all times. This is a very important safety issue because all commercially available insulin pumps are not GPS-enabled (though this is controversial), nor equipped with automatically adjusting internal clocks. Special attention is paid to how basal and bolus dose errors can be introduced by daylight savings time changes, travel across time zones, and am-pm clock errors. Correct setting of insulin pump internal clock is crucial for appropriate insulin delivery. A comprehensive literature review is provided, as are illustrative cases. Incorrect setting can potentially result in incorrect insulin delivery, with potential harmful consequences, if too much or too little insulin is delivered. Daylight saving time changes may not significantly affect basal insulin delivery, given the triviality of the time difference. However, bolus insulin doses can be dramatically affected. Such problems may occur when pump wearers have large variations in their insulin to carb ratio, especially if they forget to change their pump clock in the spring. More worrisome than daylight saving time change is the am-pm clock setting. If this setting is set up incorrectly, both basal rates and bolus doses will be affected. Appropriate insulin delivery through insulin pumps requires correct correlation between dose settings and internal clock time settings. Because insulin pumps are not GPS-enabled or automatically time-adjusting, extra caution should be practiced by patients to ensure correct time settings at all times. Clinicians and diabetes educators should verify the date/time of insulin pumps during patients’ visits, and should remind their patients to always verify these settings. PMID:25355713

  15. Ribavirin Protects Syrian Hamsters against Lethal Hantavirus Pulmonary Syndrome — After Intranasal Exposure to Andes Virus

    PubMed Central

    Ogg, Monica; Jonsson, Colleen B.; Camp, Jeremy V.; Hooper, Jay W.

    2013-01-01

    Andes virus, ANDV, harbored by wild rodents, causes the highly lethal hantavirus pulmonary syndrome (HPS) upon transmission to humans resulting in death in 30% to 50% of the cases. As there is no treatment for this disease, we systematically tested the efficacy of ribavirin in vitro and in an animal model. In vitro assays confirmed antiviral activity and determined that the most effective doses were 40 µg/mL and above. We tested three different concentrations of ribavirin for their capability to prevent HPS in the ANDV hamster model following an intranasal challenge. While the highest level of ribavirin (200 mg/kg) was toxic to the hamster, both the middle (100 mg/kg) and the lowest concentration (50 mg/kg) prevented HPS in hamsters without toxicity. Specifically, 8 of 8 hamsters survived intranasal challenge for both of those groups whereas 7 of 8 PBS control-treated animals developed lethal HPS. Further, we report that administration of ribavirin at 50 mg/kg/day starting on days 6, 8, 10, or 12 post-infection resulted in significant protection against HPS in all groups. Administration of ribavirin at 14 days post-infection also provided a significant level of protection against lethal HPS. These data provide in vivo evidence supporting the potential use of ribavirin as a post-exposure treatment to prevent HPS after exposure by the respiratory route. PMID:24217424

  16. Intranasal oxytocin attenuates attentional bias for eating and fat shape stimuli in patients with anorexia nervosa.

    PubMed

    Kim, Youl-Ri; Kim, Chan-Hyung; Cardi, Valentina; Eom, Jin-Sup; Seong, Yoori; Treasure, Janet

    2014-06-01

    We examined the impact of oxytocin on attentional processes for eating, shape, and weight stimuli in patients with anorexia nervosa (AN). A double-blind, placebo-controlled within-subject crossover design was used. Intranasal oxytocin or placebo followed by a visual probe detection task with food, weight, and shape images was administered to 64 female subjects: 31 patients with AN and 33 control students. The AN group showed significant reductions in the attentional biases toward eating-related stimuli (p=0.030, d=0.516) and toward negative shape stimuli (p=0.015, d=0.498) under the influence of intranasal oxytocin. The effect of oxytocin was correlated with autistic spectrum traits in the AN group. Oxytocin had no effect on the amount of juice consumed in either group. The results of this study suggest that oxytocin attenuates the attentional vigilance to eating and fat shape stimuli in patients with AN. Further studies using oxytocin as a form of intervention for patients with AN are needed. PMID:24703429

  17. A Unique Case of Intranasal Metastasis from Occult Poorly Differentiated Thyroid Carcinoma

    PubMed Central

    Kum, Rauf Oğuzhan; Aygenç, Erdinç; Somuk, Battal Tahsin; Börcek, Pelin; Özdem, Cafer

    2015-01-01

    Background: Poorly differentiated thyroid carcinomas (PDTCs) lie, both morphologically and behaviorally, between well-differentiated and undifferentiated carcinomas. Metastasis of poorly differentiated thyroid carcinoma to the intranasal cavity has not been reported previously in the literature. Case Report: A 48-year-old male patient presented with massive epistaxis and nasal obstruction. On nasal examination, a bleeding, vascular mass was seen filling the left nasal cavity. The histopathological report of the nasal mass was well-differentiated thyroid carcinoma metastasis. Whole body scintigraphy, ultrasonography and positron emission tomography were done to rule out other possible metastases in the body and determine the origin of the tumor, which was identified as the left lobe of the thyroid gland, and there were multiple metastases involving the lung, sacroiliac area, and left humerus. Histopathological examination of a thyroidectomy specimen revealed PDTC consisting of insular, follicular, and papillary components. Postoperatively, the patient received radioactive iodine ablation therapy (iodine-131) and a course of external beam radiation therapy to the sacroiliac area and other metastatic regions. No recurrences were observed in a follow-up period of 5 years after surgery. Conclusion: The metastasis of differentiated thyroid carcinoma as a component of PDTC to the intranasal cavity has not been reported before. It is interesting that the well-differentiated component of the tumor was metastasized in our patient. Due to the aggressiveness of PDTC and the poor survival rates in patients who undergo surgery alone, a multidisciplinary treatment approach is required. PMID:26185723

  18. Food consumption and activity levels increase in rats following intranasal Hypocretin-1.

    PubMed

    Dhuria, Shyeilla V; Fine, Jared M; Bingham, Deborah; Svitak, Aleta L; Burns, Rachel B; Baillargeon, Amanda M; Panter, Scott S; Kazi, Abdul N; Frey, William H; Hanson, Leah R

    2016-08-01

    Hypocretin-1 (HC, orexin-A) is a neuropeptide involved in regulating physiological functions of sleep, appetite and arousal, and it has been shown that intranasal (IN) administration can target HC to the brain. Recent clinical studies have shown that IN HC has functional effects in human clinical trials. In this study, we use rats to determine whether IN HC has an immediate effect on food consumption and locomotor activity, whether distribution in the brain after IN delivery is dose-dependent, and whether MAPK and PDK1 are affected after IN delivery. Food intake and wheel-running activity were quantified for 24h after IN delivery. Biodistribution was determined 30min after IN delivery of both a high and low dose of 125I-radiolabelled HC throughout the brain and other bodily tissues, while Western blots were used to quantify changes in cell signaling pathways (MAPK and PDK1) in the brain. Intranasal HC significantly increased food intake and wheel activity within 4h after delivery, but balanced out over the course of 24h. The distribution studies showed dose-dependent delivery in the CNS and peripheral tissues, while PDK1 was significantly increased in the brain 30min after IN delivery of HC. This study adds to the growing body of evidence that IN administration of HC is a promising strategy for treatment of HC related behaviors. PMID:27264485

  19. Intranasal Immunization of Mice to Avoid Interference of Maternal Antibody against H5N1 Infection

    PubMed Central

    Zhang, Fenghua; Peng, Bo; Chang, Haiyan; Zhang, Ran; Lu, Fangguo; Wang, Fuyan; Fang, Fang

    2016-01-01

    Maternally-derived antibodies (MDAs) can protect offspring against influenza virus infection but may also inhibit active immune responses. To overcome MDA- mediated inhibition, active immunization of offspring with an inactivated H5N1 whole-virion vaccine under the influence of MDAs was explored in mice. Female mice were vaccinated twice via the intraperitoneal (IP) or intranasal (IN) route with the vaccine prior to mating. One week after birth, the offspring were immunized twice via the IP or IN route with the same vaccine and then challenged with a lethal dose of a highly homologous virus strain. The results showed that, no matter which immunization route (IP or IN) was used for mothers, the presence of MDAs severely interfered with the active immune response of the offspring when the offspring were immunized via the IP route. Only via the IN immunization route did the offspring overcome the MDA interference. These results suggest that intranasal immunization could be a suitable inoculation route for offspring to overcome MDA interference in the defense against highly pathogenic H5N1 virus infection. This study may provide references for human and animal vaccination to overcome MDA-induced inhibition. PMID:27280297

  20. Intranasal immunisation with inactivated RSV and bacterial adjuvants induces mucosal protection and abrogates eosinophilia upon challenge.

    PubMed

    Etchart, Nathalie; Baaten, Bas; Andersen, Svein Rune; Hyland, Lisa; Wong, Simon Y C; Hou, Sam

    2006-05-01

    We have previously shown that following intranasal exposure to influenza virus, specific plasma cells are generated in the nasal-associated lymphoid tissue (NALT) and maintained for the life of the animal. However, we also showed that following infection with respiratory syncytial virus (RSV), specific plasma cells are generated in the NALT but wane quickly and are not maintained even after challenge, even though RSV-specific serum antibody responses remain robust. Only infection with influenza virus generated sterilising immunity, implying a role for these long-lived plasma cells in protection. We show here that the RSV-specific IgA NALT plasma cell population and lung antibody levels can be substantially boosted, both at acute and memory time points, by intranasal immunisation with inactivated RSV (iRSV) in combination with bacterial outer membrane vesicles (OMV) compared to live RSV alone. Finally, challenge with live RSV showed that immunisation with iRSV and OMV protect against both virus replication in the lung and the eosinophil infiltrate generated by either live RSV or iRSV alone. These data show that immunisation with iRSV and OMV maintains a NALT RSV-specific plasma cell population and generates an efficient protective immune response following RSV infection. PMID:16619288

  1. Pharmacokinetics of Intranasal Scopolamine Gel Formation During Antiorthostatic Bedrest - A Microgravity Analog

    NASA Technical Reports Server (NTRS)

    Lakshmi, Putcha; Singh, R. P.; Crady, V. A.; Derendorf, H.

    2011-01-01

    Space Motion sickness (SMS) is an age old problem for astronauts on both short and long duration space flights. Scopolamine (SCOP) is the most frequently used drug for the treatment of motion sickness (MS) which is currently available in transdermal patch and tablet dosage forms. These formulations of SCOP are ineffective for the treatment of SMS. Intranasal dosage forms are noninvasive with rapid absorption and enhanced bioavailability thus allowing precise and reduced dosing options in addition to offering rescue and treatment options. As such, an intranasal gel dosage formulation of scopolamine (INSCOP) was developed and Pharmacokinetics (PK) and bioavailability were determined under IND guidelines. The present clinical trial compares PK and bioavailability of INSCOP in 12 normal, healthy subjects (6 male/ 6 female) during ambulation (AMB) and antiorthostatic bedrest (ABR) used as a ground-based microgravity analog. Subjects received 0.2 and 0.4 mg doses of INSCOP during AMB and ABR in a four-way crossover design. Results indicated no difference between AMB and ABR in PK parameters after 0.2 mg dose. Clearance (Cls) decreased with a concomitant increase in maximum concentration and area under concentration versus time curve (AUC) during ABR after the 0.4 mg dose. This difference in AUC and Cls at the higher but not the lower dose during ABR may suggest that ABR may affect metabolism and/or clearance at higher doses of INSCOP. These results indicate that dosing adjustment may be required for treatment of SMS with INSCOP in space.

  2. Intranasal DNA Vaccine for Protection against Respiratory Infectious Diseases: The Delivery Perspectives

    PubMed Central

    Xu, Yingying; Yuen, Pak-Wai; Lam, Jenny Ka-Wing

    2014-01-01

    Intranasal delivery of DNA vaccines has become a popular research area recently. It offers some distinguished advantages over parenteral and other routes of vaccine administration. Nasal mucosa as site of vaccine administration can stimulate respiratory mucosal immunity by interacting with the nasopharyngeal-associated lymphoid tissues (NALT). Different kinds of DNA vaccines are investigated to provide protection against respiratory infectious diseases including tuberculosis, coronavirus, influenza and respiratory syncytial virus (RSV) etc. DNA vaccines have several attractive development potential, such as producing cross-protection towards different virus subtypes, enabling the possibility of mass manufacture in a relatively short time and a better safety profile. The biggest obstacle to DNA vaccines is low immunogenicity. One of the approaches to enhance the efficacy of DNA vaccine is to improve DNA delivery efficiency. This review provides insight on the development of intranasal DNA vaccine for respiratory infections, with special attention paid to the strategies to improve the delivery of DNA vaccines using non-viral delivery agents. PMID:25014738

  3. UEA I-bearing nanoparticles for brain delivery following intranasal administration.

    PubMed

    Gao, Xiaoling; Chen, Jun; Tao, Weixing; Zhu, Jianhua; Zhang, Qizhi; Chen, Hongzhuan; Jiang, Xinguo

    2007-08-01

    Surface engineering of nanoparticles with lectins opened a novel pathway to improve the brain uptake of agents loaded by biodegradable PEG-PLA nanoparticles following intranasal administration. Ulex europeus agglutinin I (UEA I), specifically binding to l-fucose, which is largely located in the olfactory epithelium, was selected as a promising targeting ligand and conjugated onto the PEG-PLA nanoparticles surface with an optimized protocol relying on maleimide-mediated covalent binding technique. The in vivo results in rats suggested that UEA I modification at the nanoparticles surface facilitated the absorption of a fluorescent marker--6-coumarin associated with the nanoparticles into the brain following intranasal administration with significant increase in the area under the concentration-time curve (about 1.7 times) in different brain tissues compared with that of coumarin incorporated in the unmodified ones. UEA I-conjugation also elevated the brain-targeting efficiency of nanoparticles. Inhibition experiment of specific sugar suggested that the interactions between the nasal mucosa and the lectinised nanoparticles were due to the immobilization of carbohydrate-binding pockets on the surface of the nanoparticles. Distribution profiles of UEA I-modified nanoparticles indicated their higher affinity to the olfactory mucosa than to the respiratory one. Therefore, the UEA I-modified nanoparticles might serve as potential carriers for brain drug delivery, especially for mental therapeutics with multiple biological effects. PMID:17499948

  4. Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome.

    PubMed

    Hall, Scott S; Lightbody, Amy A; McCarthy, Brigid E; Parker, Karen J; Reiss, Allan L

    2012-04-01

    Fragile X syndrome (FXS) is a rare inherited genetic disorder causing severe intellectual disability and autistic-like symptoms. Individuals with FXS, males in particular, often exhibit extreme eye gaze avoidance and hyperarousal when they encounter stressful social situations. We investigated whether oxytocin (OT), a hormone with prosocial and anxiolytic effects, could alleviate symptoms of social anxiety in this population. A randomized double-blind placebo-controlled single-dose trial was performed with intranasal administration of placebo, 24 IU OT and 48 IU OT. Measures of eye gaze frequency, heart rate, respiratory sinus arrhythmia (RSA), heart rate variability (HRV) and salivary cortisol were obtained during a structured social challenge conducted 50 min following OT administration. Ten low-functioning males with FXS (aged 13-28 years) traveled to Stanford for the initial visit: 8 completed the study. Eye gaze frequency improved significantly in response to the 24 IU OT dose and salivary cortisol levels decreased significantly in response to the 48 IU OT dose. There was no effect of OT on heart rate, RSA or HRV although individual plots of the heart rate data suggested that OT increased heart rate in some participants and decreased heart rate in others. These findings suggest that intranasal administration of OT may ameliorate some symptoms of social anxiety in patients with FXS. Further double-blind placebo-controlled studies of OT, conducted in combination with behavioral treatment programs, may be warranted. PMID:21862226

  5. Intranasal budesonide spray as an adjunct to oral antibiotic therapy for acute sinusitis in children.

    PubMed

    Yilmaz, G; Varan, B; Yilmaz, T; Gürakan, B

    2000-01-01

    We investigated the clinical value of intranasal budesonide in acute sinusitis in 52 children with acute maxillary sinusitis. We randomly divided them into two groups: group 1 received oral pseudoephedrine (2 x 30 mg) and cefaclor (40 mg/kg) for 10 days, and group 2 received intranasal budesonide (2 x 100 microg) and cefaclor (40 mg/kg) for 10 days. Symptoms of headache, cough, and nasal stuffiness and signs of nasal discharge were graded before and after treatment. The patients whose symptoms and signs completely normalized after treatment were considered to have recovered, and those with persisting symptoms and signs after treatment as having not recovered. The results of the two treatment groups were compared. The recovery rate of the children in group 2 were significantly higher than those in group 1 (P < 0.05). No adverse drug effects were determined during the study period. These findings suggest that topical steroids may be a useful adjunctive agent in the treatment of acute sinusitis of children without apparent side effects and can possibly hasten the resolution of symptoms. PMID:10923938

  6. Study of sodium hyaluronate-based intranasal formulations containing micro- or nanosized meloxicam particles.

    PubMed

    Bartos, Csilla; Ambrus, Rita; Sipos, Péter; Budai-Szűcs, Mária; Csányi, Erzsébet; Gáspár, Róbert; Márki, Árpád; Seres, Adrienn B; Sztojkov-Ivanov, Anita; Horváth, Tamás; Szabó-Révész, Piroska

    2015-08-01

    This article reports on the micro- and nanonization of meloxicam (MEL) with the aim of developing pre-dispersions as intermediates for the design of intranasal formulations. As a new approach, combined wet milling technology was developed in order to reduce the particle size of the MEL. Different milling times resulted in micro- or nanosized MEL in the pre-dispersions with polyvinyl alcohol as stabilizer agent, which were directly used for preparing intranasal liquid formulations with the addition of sodium hyaluronate as mucoadhesive agent. Reduction of the MEL particle size into the nano range led to increased saturation solubility and dissolution velocities, and increased adhesiveness to surfaces as compared with microsized MEL particles. A linear correlation was demonstrated between the specific surface area of MEL and the AUC. The in vitro and in vivo studies indicated that the longer residence time and the uniform distribution of nano MEL spray throughout an artificial membrane and the nasal mucosa resulted in better diffusion and a higher AUC. Nanosized MEL may be suggested for the development of an innovative dosage form with a different dose of the drug, as a possible administration route for pain management. PMID:26142244

  7. Effects of intranasal oxytocin administration on memory for infant cues: moderation by childhood emotional maltreatment.

    PubMed

    Bhandari, Ritu; van der Veen, Rixt; Parsons, Christine E; Young, Katherine S; Voorthuis, Alexandra; Bakermans-Kranenburg, Marian J; Stein, Alan; Kringelbach, Morten L; van IJzendoorn, Marinus H

    2014-01-01

    Oxytocin has been implicated in parent-infant attachment and social recognition. With respect to emotion recognition memory, both memory-enhancing and impairing effects have been observed, suggesting an influence of individual factors. We assessed the effects of oxytocin on memory for infant cues, and whether these effects are moderated by self-reported childhood emotional maltreatment. Nulliparous females (N = 102) participated in a randomized, double-blind, between-subjects study with intranasal oxytocin or placebo administration. Participants' memory was tested using the Baby Social Reward Task, where participants were asked to select the happier infant from a pair of two infants based on the information that they received about the infants' mood in the previous phase. Participants reporting more childhood emotional maltreatment were less accurate in this task after inhaling oxytocin. Our findings add to a growing body of literature showing that the effects of intranasal oxytocin on memory and social behavior are moderated by adverse early life experiences. PMID:24968101

  8. Intranasal Delivery of Recombinant NT4-NAP/AAV Exerts Potential Antidepressant Effect.

    PubMed

    Ma, Xian-Cang; Chu, Zheng; Zhang, Xiao-Ling; Jiang, Wen-Hui; Jia, Min; Dang, Yong-Hui; Gao, Cheng-Ge

    2016-06-01

    The present study was designed to construct a recombinant adeno-associated virus (rAAV) which can express NAP in the brain and examine whether this virus can produce antidepressant effects on C57 BL/6 mice that had been subjected to open field test and forced swimming test, via nose-to-brain pathway. When the recombinant plasmid pGEM-T Easy/NT4-NAP was digested by EcoRI, 297 bp fragments can be obtained and NT4-NAP sequence was consistent with the designed sequence confirmed by DNA sequencing. When the recombinant plasmid pSSCMV/NT4-NAP was digested by EcoRI, 297 bp fragments is visible. Immunohistochemical staining of fibroblasts revealed that expression of NAP was detected in NT4-NAP/AAV group. Intranasal delivery of NT4-NAP/AAV significantly reduced immobility time when the FST was performed after 1 day from the last administration. The effects observed in the FST could not be attributed to non-specific increases in activity since intranasal delivery of NT4-NAP/AAV did not alter the behavior of the mice during the open field test. The results indicated that a recombinant AAV vector which could express NAP in cells was successfully constructed and NAP may be a potential target for therapeutic action of antidepressant treatment. PMID:26846142

  9. Effects of positive and negative human contacts and intranasal oxytocin on cerebrospinal fluid oxytocin.

    PubMed

    Rault, Jean-Loup

    2016-07-01

    Despite the popularity of oxytocin (OT) research for its role in social behavior, the relationship between the social environment and endogenous central OT remains poorly understood. This study investigated the effects of positive and negative human contacts and intranasal OT administration on OT concentration in the cerebrospinal fluid (CSF). The pig was used as a model, with repeated CSF sampling through a spinal catheter using a within-subject design. Positive human contact led to sustained CSF OT elevation in pigs over 120min which outlasted the 15min interaction. Furthermore, the frequency of positive interactions was correlated with CSF OT increase. This provides a neurophysiological basis to positive human-animal relationships, with OT preserving bonds within but also between species through interactions. Conversely, CSF OT concentration did not vary during or after negative contact with an unfamiliar person, supporting CSF OT as a biomarker of positive valence in the human-animal relationship context. Intranasal OT administration resulted in peak CSF OT within 10min, with approximately 0.001% of the administered dose reaching the CSF. The sensitivity of the oxytocinergic system to variations in the social environment is a worthy area of investigation for its scientific and clinical implications. In particular, positive interactions result in outlasting central OT release. PMID:27032064

  10. Use of extracorporeal membrane oxygenation in an awake patient after a major trauma with an incidental finding of tuberculosis.

    PubMed

    Haneke, F; Schildhauer, T A; Strauch, J; Swol, J

    2016-05-01

    We report the use of extracorporeal membrane oxygenation (ECMO) in a trauma patient with an incidental finding of open tuberculosis (TB). Sedation was reduced during extracorporeal support and awake veno-venous ECMO was successfully performed. Subsequently, accidental cannula removal caused major blood loss which required the administration of cardiopulmonary resuscitation (CPR). Our case report demonstrates that the incidental finding of open TB is an important hint for differential diagnosis and that it should still be considered in high-income countries. In addition, awake ECMO appears to be a feasible therapeutic option in non-transplant patients, although the described case demonstrates that patient compliance and nursing care are important for therapeutic success to avoid complications, for example, inadvertent decannulation. PMID:26498750

  11. [Intensified insulin therapy and insulin micro-pumps during pregnancy].

    PubMed

    Galuppi, V

    1994-06-01

    Before conception and during pregnancy in diabetic patients, every possible effort should be made in order to obtain a good, if not perfect, metabolic control and to warrant maternal and fetal health. Multiple daily injections are required to achieve a very strict glucose regulation in pregnant patients with insulin-dependent diabetes mellitus. The most usual intensive insulin administration patterns require 3 premeal doses of short-acting insulin and 1 (at bedtime) or 2 (one in the morning and one at bedtime) injections of intermediate or slow-acting insulin. As an alternative choice, insulin pumps allow a continuous subcutaneous infusion with short-acting insulin according to a basal rate which cover the insulin need during the night and between meals. Premeal and presnack surges of insulin are administrated by the patient herself. Home glucose monitoring must be used to adjust insulin doses. Target glucose levels every diabetic pregnant woman should try to achieve are lower than in non-pregnant women: fasting glycaemia should be below 100 mg/dl, 1 hour post-prandial value below 140 mg/dl and 2 hour post-prandial level below 120 mg/dl. The stricter the control and treatment goals are, the more frequently hypoglycaemia may occur. Hypoglycaemia may be harmful especially for patients with severe diabetic complications and may affect the fetus. Therefore, every pregnant diabetic woman should receive individualized treatment and glycaemic goals according to her clinical features, her compliance and her social and cultural background. PMID:7968932

  12. Clinical Use and Evaluation of Insulin Pens.

    PubMed

    Ginsberg, Barry H

    2016-01-01

    Insulin pens are more accurate and easier to teach than other methods of insulin delivery. They also do not suffer from the risk of mismatch of insulin concentration and type of insulin syringe. The ISO standard used to test insulin pens, however, needs to be updated to reflect their clinical use. PMID:26323484

  13. Basal insulin treatment in type 2 diabetes.

    PubMed

    Hedrington, Maka S; Pulliam, Lindsay; Davis, Stephen N

    2011-06-01

    Insulin glargine is the first 24-h recombinant DNA insulin analog introduced to the market. Substitution of glycine for asparagine and addition of two arginine residues raise the isoelectric point of insulin glargine and result in microprecipitates, delaying absorption from subcutaneous tissue. This delayed absorption result in fairly flat 24-h insulin concentration profiles with no discernible peak. Large, multicenter, randomized, controlled trials in patients with type 2 diabetes show that although NPH insulin and insulin glargine are equally effective in lowering glycosylated hemoglobin (A1c) and fasting blood glucose, there is a clear advantage of insulin glargine over NPH insulin in reducing nocturnal and overall hypoglycemia. Lower risk of hypoglycemia with glargine was also consistently demonstrated by trials comparing insulin glargine and premixed analog insulins. These studies also showed greater reduction in A1c with twice-daily premixed insulins compared with glargine, when insulin glargine was administered without mealtime insulin coverage. Insulin glargine was also compared with another insulin analog, insulin detemir. Trials showed that both insulin analogs are equally effective in lowering A1c and have comparable r